nbx-2022-12-31-en

PROFILE

Nanobiotix is a late-stage biotechnology company pioneering disruptive, physics-based therapeutic approaches to

revolutionize treatment outcomes for millions of patients; supported by people committed to making a difference for

humanity. The Company is leveraging its proprietary nanoparticle platform, including its lead product candidate,

radiotherapy-activated NBTXR3 (RT-NBTXR3), to develop a pipeline of therapeutic options designed to enhance

local and systemic control of solid tumors with an initial focus on the treatment of head and neck cancers.

In tandem with the Company’s priority registrational program for NBTXR3 as a single agent activated by

radiotherapy for the treatment of head and neck cancer, led by ongoing pivotal Phase 3 study NANORAY-312,

Nanobiotix is also prioritizing the development of NBTXR3 in combination with immune checkpoint inhibitors (ICIs)

to: (i) overcome resistance to ICIs; (ii) provide better local and systemic disease control; and (iii) to meaningfully

improve survival outcomes.

Through these two Company-led programs, Nanobiotix aims to address the global unmet needs of elderly and frail

patients with locally advanced head and neck cancer who are ineligible for platinum-based chemotherapy--the

current standard of care--along with adult patients with recurrent or metastatic head and neck cancers that are

resistant to immune checkpoint inhibitors.

Parallel to Company-led development, Nanobiotix is working with world class collaborators to expand the evaluation

of NBTXR3 across solid tumor indications and treatment combinations. To date, positive safety and feasibility data

for NBTXR3 have been reported in head and neck cancer, liver cancer, rectal cancer, prostate cancer, and soft

tissue sarcoma. Additionally, clinical evaluations are currently ongoing in pancreatic, esophageal and lung cancers.

Moreover, NBTXR3 has been shown to be feasible and well tolerated as a single agent activated by radiotherapy, in

combination with concurrent chemoradiation, in combination with immune checkpoint inhibitors, and in combination

with cetuximab across multiple indications.

Consistent with the Company’s strategic priorities, Nanobiotix expects to build a comprehensive treatment franchise

across head and neck cancer indications where radiotherapy is a part of the treatment protocol. The Company

believes this model can be replicated across any solid tumor indication that can be injected with NBTXR3.

The Company is listed on the Euronext regulated market in Paris (under the ticker symbol “NANO”; Code ISIN:

FR0011341205, Bloomberg code: NANO:FP) and on the Nasdaq Global Select Market (under the ticker symbol

“NBTX”).

NOTES

Definitions

In the Universal Registration Document, and unless otherwise stated:

The terms “Company” or “Nanobiotix” refer to Nanobiotix, headquartered at 60, rue de Wattignies, 75012 Paris,

registered in the Paris Trade and Corporate Register under number 447 521 600;

The term “Group” refers to the group of companies formed by the Company and its subsidiaries;

The term “we” refers to the Company or the Group, as appropriate.

A glossary defining certain terms used in the Universal Registration Document can be found in Section 6.6 of the

Universal Registration Document.

The Universal Registration Document includes, among other things, the Company's financial statements prepared in

accordance with accounting standards applicable in France for the year ended December 31, 2022, as well as a set

of consolidated financial statements for the same year in accordance with IFRS accounting standards adopted by

the European Union.

In accordance with Article 19 of the Regulation (EU) 2017/1129, the following information is incorporated by

reference in the Universal Registration Document:

◦the consolidated financial statements and the related statutory auditors’ report, as well as the

management report for the year ended December 31, 2021, included in the 2021 universal registration

document filed with the AMF on April 8, 2022, under number D.22-0267, and

◦the consolidated financial statements and the related statutory auditors’ report, as well as the

management report for the year ended December 31, 2020, included in the 2020 universal registration

document approved by the AMF on April 7, 2021, under number D.21-0272.

The 2021 universal registration document and the 2020 universal registration document are available on the

Company’s website.

Disclaimer

Market and competition information

The Universal Registration Document includes, in particular in Section 1.3 “Description of activities”, information

relating to the Group’s markets and its competitive position. This information comes primarily from studies carried out

by external sources. Publicly available information, which the Company considers reliable, has not been verified by

an independent expert, and the Company cannot guarantee that a third party using different methods to collect,

analyze or calculate data on these markets would achieve the same results.

Forward-looking information

The Universal Registration Document contains information and statements on the Group’s prospects and

development strategy. These indications are sometimes identified by the use of the future, conditional tense or

forward-looking terms such as “at this time,” “consider,” “anticipate”, “think,” “aim,” “expect,” “intend,” “must,”

“ambition,” “estimate,” “believe,” “wish,” “may,” “can,” “could, ”is designated to,” “might,” “on track,” “plan,” “potential,”

“predict,” “objective,” “shall,” “should,” “scheduled,” and “will or, as the case may be, the negative form of those same

terms, or any other similar variation or terminology. This information is not historical data and should not be

construed as guarantees that the stated facts and data will occur. This information is based on data, assumptions

and estimates considered to be reasonable by the Company. It is subject to change or modification due to

uncertainties related in particular to the economic, financial, competitive or regulatory environment. This information

is mentioned in various chapters of the Universal Registration Document and contains data on the Group's

intentions, estimates and objectives concerning, in particular, the market in which it operates, its strategy, growth,

results, financial position, cash flow and forecasts. The forward-looking information mentioned in the Universal

Registration Document is given only as of the date of the Universal Registration Document. Except as required by

law, the Company assumes no obligation to update these forward-looking statements publicly, or to update the

reasons why actual results could differ materially from those anticipated in the forward-looking statements. The

Group operates in a competitive and ever-changing environment. It therefore cannot anticipate any risks,

uncertainties or other factors that could affect its business, their potential impact on its business or the extent to

which the materialization of a risk or combination of risks could have significantly different results from those

mentioned in any forward-looking information, it being recalled that none of this forward-looking information

constitutes a guarantee of actual results.

Risk factors

Investors are encouraged to carefully read the risk factors described in Section 1.5 “Risk Factors” in the Universal

Registration Document before making any investment decision. The realization of some or all of these risks could

have a significant adverse effect on the Group's business, financial situation, results or future prospects. In addition,

other risks, not yet identified or considered insignificant by the Company as of the date of the Universal Registration

Document, could also have a significant adverse effect.

Message from the Chairman of the Executive Board

To my fellow shareholders,

Thank you for continued support of Nanobiotix. While environmental factors like economic volatility, geopolitical

unrest, and intense competition come and go, what never changes is the need to find new, more effective, and less

toxic therapeutic options to meet the unmet needs of patients around the world. With that fact in mind and as

pioneers of physics-based nanotechnology platforms designed to significantly improve treatment outcomes, my team

and I are humbled that you see the opportunity presented by approaching treatment of major illnesses like cancer

through the universal lens of physics, rather than purely through biology and chemistry. From this approach we

believe that we can deliver first-in-class, best-in-class therapeutic innovation designed for the many rather than the

few. We believe that physics-based therapeutics can usher in an era of improved therapy through precision without

personalization--disrupting treatment outcomes without disrupting clinical practice or patients’ lives. And we believe

the first of those innovations from Nanobiotix will be our lead product candidate NBTXR3.

Proactive Strategic and Operational Discipline

We entered the year 2022 with sharp goals in focus. From a development strategy perspective, we continued to

develop toward a potentially industry-leading head and neck cancer treatment franchise powered by NBTXR3 that

could be scaled across indications.

Our primary aim was to progress our global registration pathway for NBTXR3 as a local control agent for elderly

patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) who are ineligible for standard-

of-care platinum-based chemotherapy by activating sites and enrolling patients in the major regions of the pivotal

Phase 3 NANORAY-312 study together with LianBio regarding our respective territory. In parallel with our primary,

Company-led development pathway in head and neck cancer, we also set out to strengthen the rationale for

NBTXR3 in combination with anti-PD-1 immune checkpoint inhibitors for patients with recurrent and/or metastatic (R/

M) HNSCC through Phase 1 dose escalation and dose expansion Study 1100.

To support the expansion of NBTXR3 across indications and modalities while Nanobiotix remains focused on its

priority pathways in head and neck cancer, the Company also continued its large scale clinical collaboration led by

The University of Texas MD Anderson Cancer Center (MD Anderson) with intent to build rationale for later stage

development of NBTXR3 in head and neck cancer, pancreatic cancer, esophageal cancer, and lung cancer.

In combination with our development focus, we also saw significant macroeconomic headwinds in 2022. I am proud

that we did not wait for the financial climate to force our hand, and behind the leadership of Chief Financial Officer,

Bart Van Rhijn, we took proactive steps with a view to pursuing the long term health of the Company. By prioritizing

registration pathways and reducing operating expenses, we were able to extend our operating runway without

jeopardizing core programs or resorting to the broad-based headcount reductions we saw across the industry.

Supported by People Committed to Making A Difference

While focused strategy and disciplined resource allocation are essential to our continued progress, nothing we do

would be possible without the amazing talent that supports Nanobiotix. Whether they be our internal colleagues, our

strategic collaborators, our clinical partners, or our scientific advisors--I am humbled by our shared singular focus on

making a difference for humanity and bringing novel innovation to patients.

In particular, 2022 saw us enhance our strategic development capability as we evolved our scientific advisory board

to include world renowned experts across radiotherapy, radiology, medical oncology, and surgery. As we continue to

advance our lead programs and expand our global development strategy, we believe that working closely with

multidisciplinary leaders in the field will help ensure that patients receive the maximum possible benefit from

NBTXR3.

Advancing a Potentially Industry-Leading Head and Neck Cancer Treatment Franchise

The fundamental hypothesis behind our potentially first-in-class radioenhancer is that by leveraging the universal

principles of physics at the sub-cellular level, radiotherapy-activated NBTXR3 could improve local control, prime

immune response for improved systemic control in combination with immune checkpoint inhibitors, as well as

combine with other major modalities such as chemotherapy and targeted therapy. We believe that because of its

universal MoA, and administration via targeted intratumoral injection, NBTXR3’s potential benefits could scale to any

solid tumor indication where radiotherapy is a part of the protocol and a tumor can be reached for injection.

Today, we are focused on head and neck cancer as the first indication but well prepared to replicate our model

across solid tumors.

Validating the Local Control Benefit of NBTXR3

Our local control program within our head and neck cancer pipeline focuses on the patients in most desperate need

of innovation--elderly patients who are ineligible for standard of care platinum-based chemotherapy. To this end, we

are evaluating radiotherapy-activated NBTXR3 alone or in combination with cetuximab for global registration in this

patient population. In 2022, we randomized our first patients in Europe and the United States, while LianBio

randomized our first patient in Asia. As of the end of the year, we had activated more than 80 sites globally.

Enhancing Systemic Control Through Immune Priming

The systemic control program within our head and neck cancer pipeline aims to address one of the most critical

challenges facing the oncology community today--response rates to immune checkpoint inhibitors. While several

different strategies are being tested across the oncology landscape, our contention is that an effective way to expand

the benefits of immune checkpoint inhibitors like anti-PD-1 to more patients will be to modulate the tumor

microenvironment through the immune priming effects of NBTXR3 that we have seen subsequent to the physical

tumor destruction caused by the radioenhancer’s physics-based MoA.

In the first quarter of 2022, the United States Food and Drug Administration (FDA) provided instructive feedback to

inform a registrational Phase 3 protocol for radiotherapy-activated NBTXR3 in combination with anti-PD-1 for

patients with recurrent and/or metastatic head and neck cancer. In response to this feedback and in preparation for a

registrational protocol submission, we re-designed the expansion phase of Study 1100--our Phase 1 immunotherapy

evaluating radiotherapy-activated NBTXR3 plus anti-PD-1 for patients with advanced cancers--to focus on patients

with the recurrent and/or metastatic cancer who are either resistant to anti-PD-1 or naive to anti-PD-1. In the fourth

quarter of 2022, we reported updated data from the complete dose escalation phase of Study 1100 at the 37th

Annual Meeting of the Society for Immunotherapy of Cancer (SITC). These data showed several signals of the

immune stimulation potential of NBTXR3, including objective reduction in all target lesions in two-thirds of evaluable

patients with cancer resistant to anti-PD-1.

Expanding Development Through Strategic Collaboration

One of the most important questions we face as a company seeking to revolutionize treatment for patients with

cancer around the world is, "How do we ensure that the potential benefits of NBTXR3 reach as many patients as

possible, as swiftly as possible, while also remaining disciplined and focused with our resources?" Our answer to this

question has been to lean on strategic collaborator-led NBTXR3 development in indications and combination

modalities outside of and in parallel to company-led development.

In 2022, MD Anderson took important steps forward across four clinical programs they are currently leading. We

published a case study on the experience of the first patient to ever receive intratumoral injection in a pancreatic

adenocarcinoma (pancreatic cancer) in the Red Journal in the first quarter of 2022, and were able to announce

determination of the recommended Phase 2 dose (RP2D) of radiotherapy-activated NBTXR3 in pancreatic cancer.

We also saw progress in MD Anderson’s head and neck cancer, non-small cell lung cancer, and esophageal cancer

studies as well.

On the Horizon

•With our overall ambition of revolutionizing treatment ever-present in our minds, Nanobiotix has re-

doubled our focus in 2023. Building on a successful 2022, our strategic priorities include:

◦Acceleration of site activation and patient recruitment for NANORAY-312 in collaboration with

LianBio

◦Final study reporting from Study 102, our Phase 1 dose escalation and dose expansion trial

evaluating NBTXR3 for elderly patients who are ineligible for cisplatin and intolerant to cetuximab

◦Advancement of our registrational program for NBTXR3 in combination with anti-PD-1 for the

treatment of recurrent/metastatic head and neck cancer

◦Strengthening of our development capabilities

◦First data from our strategic collaboration with MD Anderson

◦Achievement of sustainable financing for our company-led development programs

◦Continued investment in our people, capabilities, platforms, and our culture

While focused on these priorities, we also know that key to our long-term success are our agility and our

commitment to our goal. At the end of the day, this goal is singular: bring novel, physics-based innovation to

revolutionize treatment for patients around the world.

I am inspired by the tireless commitment of our colleagues and partners. I am grateful for the trust and support we

receive from the medical community and our shareholders. More than anything, I am energized by the opportunity to

help the patients we serve and thankful to all of the amazing people walking with us on this journey.

With gratitude,

Laurent Levy

Chief Executive Officer

Key events

Nanobiotix, founded in 2003, is a pioneering and leading nanomedicine company that has developed new

approaches to local cancer treatment. Nanobiotix aims to become a major player in healthcare, providing new and

innovative solutions for the benefit of patients, while creating sustainable value for its shareholders.

_2003

Nanobiotix was created in France from a spin-off of the State University of New York at Buffalo (USA).

_2007-2010

The Company developed the NanoXray research program, leading to the filing of several patent families and the

launch of preclinical trials.

_2011

Nanobiotix received approval from the Affsaps (ex-ANSM, Agence Nationale de Sécurité du Médicament et des

produits de Santé, France) to start the first Phase 1/2 clinical study in humans evaluating NBTXR3 for patients with

locally advanced soft tissue sarcoma.

_2012

In August, the Company entered into a licensing agreement for the development and commercialization of NBTXR3

in the Asia-Pacific region with the Taiwanese company PharmaEngine.

On October 29, 2012, Nanobiotix shares were listed on the regulated market of Euronext Paris.

_2013

Nanobiotix received approval by the ANSM to start a new Phase 1 clinical trial in head and neck cancer.

_2014

In September, the Company’s first US subsidiary was established in Cambridge, Massachusetts. At the same time,

the Company received authorization from the ANSM to start the Phase 2/3 clinical study evaluating NBTXR3 for

patients with locally advanced soft tissue sarcoma.

_2015

In July, the ANSM authorized the start of a Phase 1/2 clinical study evaluating NBTXR3 for patients with primary and

metastatic liver cancers.

In late December, the Company received approval from the U.S. Food and Drug Administration (FDA) regarding the

application for Investigational New Drug (IND) status to start the first clinical study in the United States (US)

evaluating NBTXR3 in prostate cancer.

_2016

Nanobiotix launched a new immuno-oncology research program with NBTXR3 and the first application for market

authorization (CE mark) for the product candidate.

_2017

The Company opened its own manufacturing site - at BioPark in Villejuif (France) - increasing its capacity to produce

NBTXR3 to meet the growing future demand related to clinical trials and patient needs.

Concurrently, the FDA provided approval of the IND application for the first immuno-oncology clinical study in the

U.S. evaluating NBTXR3 in combination with an anti-PD-1 antibody for patients with lung and head and neck

cancers.

This year also saw the creation of two new Nanobiotix subsidiaries: one in Germany and the other in Spain.

_2018

Nanobiotix reached agreement on a non-dilutive financial partnership with the European Investment Bank (EIB) in

July to boost the Company’s research, development, and innovation activities, in the form of a loan of up to €40

million until July 26, 2020. The contract consisted of an initial tranche of €16.0 million drawn in October 2018 and

was subject to the achievement of a set of agreed upon performance criteria.

The Company also disclosed positive results from its Phase 2/3 clinical study evaluating NBTXR3 in soft tissue

sarcoma, which demonstrated significant superiority and clinical benefits over the standard of care. This randomized

clinical study validated the mode of action of NBTXR3.

_2019

In January, the Company launched a new clinical collaboration with The University of Texas MD Anderson Cancer

Center (MD Anderson)—one of the world’s leading specialized hospitals for the treatment of cancer. The

collaboration was structured with the perspective to include approximately 312 patients across multiple Phase 1 and

2 clinical studies evaluating NBTXR3 for the treatment of different types of cancer.

A €14 million second tranche disbursement of loan financing from the EIB was received in March. Also in March,

following feedback from the FDA, the Company announced its clinical registration plan for NBTXR3 in head and

neck cancer in the U.S. In April, NBTXR3 received European market approval (CE mark), enabling the Company to

commercialize NBTXR3, under the brand name Hensify®, for the treatment of locally advanced soft tissue sarcoma

in 27 European Union countries. Concurrently, the Company raised €29.5 million through a private placement.

In May, Curadigm SAS, a wholly owned subsidiary of Nanobiotix, was launched. The technology aims to prime the

body to receive various therapeutics and could reshape the balance between efficacy and toxicity for patients. In

December, the Company was awarded the French Prix Galien Award for most innovative MedTech.

_2020

In January, the Company articulated the plan for its global Phase 3 registration study in head and neck cancer along

with an overall update on its broad applicability of its development program.

In February, the FDA granted fast track designation to NBTXR3 for treatment of the head and neck cancer

population in the planned global Phase 3 study.

In May, the first Phase 1 study in collaboration with MD Anderson evaluating NBTXR3 in pancreatic cancer received

a ‘Safe to Proceed’ notification from the FDA.

In July, the Company raised €20 million in a placement of new ordinary shares with US and European investors.

In November, the Company presented positive first clinical data from its Phase 1 immuno-oncology study showing a

possible conversion of anti-PD-1 non-responders to responders with NBTXR3.

In November, two new studies in collaboration with MD Anderson evaluating NBTXR3 in combination with anti-PD-1

for head and neck cancer received ‘Safe to Proceed’ notifications from the FDA.

In December, Nanobiotix shares were listed, through ADS’s, on the Nasdaq Global Select Market under the symbol

“NBTX”, providing gross proceeds of $113.3 million.

_2021

In January, Nanobiotix’ subsidiary Curadigm secured a new collaboration agreement with Sanofi focused on gene

therapy pipeline.

In May, the Company partnered with Lian Oncology Limited (LianBio) to develop and commercialize potential first-in-

class radioenhancer NBTXR3 across tumor types and therapeutic combinations in China and other Asian markets.

In June, MD Anderson initiated the fifth clinical study under the clinical collaboration agreement with Nanobiotix

evaluating NBTXR3 in lung cancer.

In October, Nanobiotix presented the first survival data from its priority head and neck cancer pathway among five

presentations at the 2021 Annual Meeting of the American Society for Radiation Oncology.

In November, Nanobiotix announced new preclinical data highlighting NBTXR3 immune priming and checkpoint

inhibitor combination.

_2022

In January, Nanobiotix enrolled the first patient in NANORAY-312, a global Phase 3 study of NBTXR3 in head and

neck cancer, completed enrollment of 44 patients for the expansion cohort of Study 102 in head and neck cancer,

and announced publication of new preclinical immunotherapy data showcasing the combination potential of NBTXR3

with anti-PD-1 and anti-CTLA-4.

In February, a new clinical case study highlighting first patient experience of NBTXR3 treatment for pancreatic

cancer was published in the International Journal of Nanobiotechnology.

In April, new preclinical immunotherapy data showed boosted anti-tumor immune activation via triple blockade of

PD-1, LAG-3, and TIGIT when combined with radiotherapy-activated NBTXR3.

In June new data featuring NBTXR3 plus chemoradiation in the preoperative setting showed support to broad

applicability for head and neck cancer and other solid tumor indications.

In September, LianBio enrolled the first patient the NANORAY-312 trial in Asia. Nanobiotix also announced the

recommended dose for planned registrational study evaluating NBTXR3 plus anti-PD-1 for patients with metastatic

Head and Neck cancer resistant to prior immunotherapy.

In October, Nanobiotix restructured its existing loan with the European Investment Bank.

In November, Nanobiotix reported updated Phase 1 anti-PD-1 combination data that may support the immune

stimulation potential of radioenhancer NBTXR3 and announced Recommended Phase 2 Dose for NBTXR3 in

pancreatic cancer. Nanobiotix also appointed renowned global experts to a comprehensive scientific advisory board

for its potential first-in-class radioenhancer NBTXR3.

In December, Nanobiotix enrolled the first US patient of the NANORAY-312 trial.

NBTXR3 / Hensify® key figures

◦First European market approval (CE mark) obtained, enabling the marketing of Hensify® (NBTXR3 brand

name in soft tissue sarcoma) for the treatment of locally advanced soft tissue sarcoma in 27 EU countries

◦More than 13 clinical trials in several types of cancer

◦RT-activated NBTXR3 being developed for use alone or in combination with other cancer therapies,

including chemotherapy and checkpoint inhibitors such as anti-PD-1 immunotherapy,

◦Proof of concept in a randomized Phase 2/3 in soft tissue sarcoma featured in The Lancet Oncology

◦450+ patents issued or in process of examination

◦Fast track designation granted by US FDA for investigation in head and neck cancer

◦90+ clinical sites activated worldwide

◦300+ patients treated in the studies

◦Countries where Nanobiotix runs or has run clinical trials, directly or through its partners: France, Belgium,

Italy, Spain, Poland, Norway, Hungary, Romania, Hong Kong, Taiwan, Philippines, Germany, United

States of America, South Africa, Australia, Georgia, Bulgaria, Czech Republic, Serbia, Croatia, Finland,

Israel, Greece, Portugal, Austria, Sweden, Japan, China, South Korea and India.

Key financial figures

102 employees (excluding trainees), as of December 31, 2022

Headquarters in Paris, 5 wholly owned subsidiaries based in France, Cambridge (USA), Madrid (Spain) and Munich

(Germany), including Curadigm, a spin-off based in Paris (France) and Boston (USA).

*To the Company’s knowledge

Stock market information

2022 share price & volume evolution on Euronext

2022 share price and volume Euronext.png

2022 share price & volume evolution on Nasdaq

Stock market data

Share code

Name: Nanobiotix

Places of listing: regulated market of Euronext Paris, compartment B (ISIN code: FR0011341205, Mnemonic code:

NANO) and Nasdaq Global Select Market (Mnemonic: NBTX)

Date of initial public offering on the regulated market of Euronext Paris: 29 October 2012

Date of initial public offering on the Nasdaq Global Select Market: 11 December 2020

NANO indices

CAC Health Care

CAC Mid & Small

CAC Small

CAC PME

EN TECH CROISSANCE

ENT PEA-PME 150

NEXT BIOTECH

NBTX indices

NASDAQ COMPOSITE

Additional information

Share eligible for SRD

Tickers

Reuters: NANO.PA

Bloomberg: NANO.FP

Nasdaq: NBTX

International analyst coverage

Nanobiotix has benefited from international analyst coverage since its initial public offering, mainly in France, the

United States, the Netherlands and the United Kingdom:


JEFFERIES (UK)	Lucy Codrington
KEMPEN (NL)	Suzanne van Voorthuizen
GILBERT DUPONT (FR)	Guillaume Cuvillier
H.C. WAINWRIGHT & Co. (US)	Ramakanth Swayampakula
DEGROOF PETERCAM (BE)	David Seynnaeve
UBS (US)	Colin Bristow
Evercore ISI (US)	Jonathan Miller / Mike DiFiore

NBTXR3 Development Pipeline


(1)	NANORAY-312, a global Phase 3 clinical trial with NBTXR3 for elderly patients with locally-advanced head and neck cancer who are ineligible for platinum-based chemotherapy. NBTXR3 for the treatment of locally advanced head and neck cancers received Fast Track designation from the FDA in February 2020.
(2)	LianBio has been granted development and commercialization rights for NBTXR3 in key countries in Asia.
(3)	NBTXR3 activated by radiotherapy
(4)	Phase 1/2 study conducted in Asia by former partner, PharmaEngine. In conjunction with the termination of the license and collaboration agreement, PharmaEngine implemented the early termination and wind-down of the Phase 1 of this clinical trial in accordance with good clinical practice guidelines. The trial was deemed completed when all enrolled patients reached “end-of-study” and PharmaEngine issued a final study report. See “1.3.7. of the Universal Registration Document” for additional details.
(5)	Phase 1/2 study conducted in Asia by former partner, PharmaEngine. In conjunction with the termination of the license and collaboration agreement, PharmaEngine implemented the early termination and wind-down of the Phase 2 of this clinical trial in accordance with good clinical practice guidelines. The trial was deemed completed when all enrolled patients reached “end-of-study” and PharmaEngine issued a final study report. See “1.3.7. of the Universal Registration Document” for additional details.

Following proof-of-concept and European market approval for NBTXR3 in locally advanced soft tissue sarcoma of

the extremities and trunk wall (Brand Name: Hensify®) in 2019, Nanobiotix is prioritizing development of NBTXR3 to

meet the global unmet needs of head and neck cancer patients. This includes evaluation of NBTXR3 activated by

radiotherapy, with or without cetuximab, for the treatment of locally-advanced head and neck cancer, as well as in

combination with anti-PD-1 immune checkpoint inhibitors (ICIs) for the treatment of recurrent and/or metastatic head

and neck cancers.

To implement this plan, Nanobiotix will focus on head and neck cancers while its strategic collaborator, The

University of Texas MD Anderson Cancer Center (MD Anderson), explores other potential indications and

combinations for NBTXR3.

Development in head and neck cancers moving forward

There are approximately 700,000 new head and neck cancer patients worldwide each year—300,000 of these

patients reside in the U.S. and the European Union (EU)1. 70-80% of all head and neck cancer patients will receive

radiation therapy, but significant unmet medical needs remain regarding either local control, systemic control, toxicity,

or some combination of the three2. This is especially challenging for patients ineligible for standard-of-care cisplatin.

In February 2020, the U.S. Food and Drug Administration reviewed the Company’s request for Fast Track

designation and concluded that investigation of RT-activated NBTXR3, with or without cetuximab, for the treatment

of patients with locally advanced head and neck squamous cell cancer (LA-HNSCC) who are not eligible for

platinum-based chemotherapy meets the criteria for a Fast Track development program.

In January 2022, Nanobiotix randomized the first patient in NANORAY-312 — an open-label, Phase 3 dual-arm,

investigator’s choice, randomized (1:1) global registration trial including approximately 500 elderly patients with LA-

HNSCC who are ineligible for platinum-based chemotherapy. Patients in the control arm will receive radiation

therapy with or without cetuximab (investigator’s choice), and patients in the treatment arm will receive RT-activated

1 Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality

worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians, 68(6), 394-424.

2 Delaney, G., Jacob, S., Featherstone, C., & Barton, M. (2005). The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence‐based

clinical guidelines. Cancer: Interdisciplinary International Journal of the American Cancer Society, 104(6), 1129-1137.

NBTXR3 with or without cetuximab (investigator’s choice). The primary endpoint of the study is progression-free

survival (PFS) and the key secondary endpoint is overall survival (OS). The study is designed to demonstrate

superiority if results show Hazard Ratios of at least 0.692 and 0.75 for PFS and OS, respectively, of RT-activated

NBTXR3 over control with a statistical power of 89% on PFS and on OS with a statistical power of 80%.

NANORAY-312 is designed to enroll approximately 500 patients to achieve 424 PFS and 389 OS events in

approximately 48 months. A planned futility analysis is expected in the first half of 2024 after approximately 25% of

planned PFS events, and a pre-specified interim efficacy analysis after approximately 67% of planned PFS events is

expected to occur in the second half of 2024. If results of the interim analysis are positive (≥ 6 months PFS

difference), the Company plans to submit an application for accelerated approval to the U.S. FDA

Confirming signals of efficacy with Phase 1 dose expansion (Study 102)

Nanobiotix has already reported promising early signs of efficacy for patients with head and neck cancer from Study

102 — a Phase 1 trial evaluating NBTXR3 activated by intensity-modulated radiation therapy (IMRT) in LA-HNSCC.

The patient population for Study 102 includes elderly, or frail patients who are ineligible for cisplatin and intolerant to

cetuximab. As a result of these findings, the Company launched an expansion cohort to strengthen preliminary

efficacy data. Recruitment for the expansion cohort reached its target of 44 evaluable patients in the first quarter of

2022.

Improving immuno-oncology outcomes with NBTXR3

In addition to the main program evaluating the use of NBTXR3 as a single agent, Nanobiotix is running an immuno-

oncology (I-O) combination program in the United States. For the past decade, there has been excitement around

the ability of I-O agents (immune checkpoint inhibitors or ICIs) to activate the immune system to attack tumor cells.

However, many tumors exhibit little or no response to these therapies and are considered “cold,” due to a lack of

immunogenicity. As a result, a small fraction of patients realize the benefits of ICIs3. The Nanobiotix I-O combination

program is comprised of Study 1100—a multi-cohort Phase 1 trial in the U.S.—, and a large-scale collaboration with

MD Anderson evaluating RT-activated NBTXR3 in combination with various ICIs (anti-PD-1, anti-PD-L1, anti-CTLA4,

and LAG-3) across several preclinical and clinical trials. The program aims to evaluate the potential for the immune

priming effects of RT-activated NBTXR3 in combination with immune checkpoint inhibitors to provide better local and

systemic control; convert checkpoint inhibitor non-responders into responders; and increase survival.

Study 1100 is an ongoing Phase 1 study evaluating safety and early signs of efficacy for NBTXR3 activated by

radiotherapy followed by an anti-PD-1 therapy. The study includes both a dose escalation and dose expansion

phase. The completed dose escalation phase included three cohorts: (i) patients with locoregional recurrent (LRR) or

recurrent and metastatic (R/M) HNSCC; (ii) patients with lung metastases from any primary cancer eligible for anti-

PD-1 therapy ; and, (iii) liver metastases from any primary cancer eligible for anti-PD-1 therapy. To further strengthen

the rationale for a registrational study in patients with R/M HNSCC, the Company enacted a protocol amendment to

adjust the cohorts in the ongoing dose expansion phase. These new cohorts include: (i) patients with R/M HNSCC

that are resistant to anti-PD-1; (ii) patients with R/M HNSCC that are naive to anti-PD-1; and, (iii) patients with lung,

liver, or soft tissue metastases from primary non-small cell lung cancer (NSCLC), malignant melanoma,

hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), urothelial cancer, cervical cancer, or triple-negative

breast cancer (TNBC).

Additional development in head and neck cancer with MD Anderson

Nanobiotix is engaged in an ongoing clinical collaboration with MD Anderson in the US. The collaboration agreement

includes several clinical trials across multiple indications, one (1) of which is ongoing in combination with IO for

patients with head and neck cancer in patient population. The Company previously explored the safety and feasibility

of RT-activated NBTXR3 in combination with cisplatin in a Phase 1/2 trial for patients with locally advanced cancer of

the oral cavity and oropharynx with former regional partner in Asia, PharmaEngine.

Development across other indications

Nanobiotix announced determination of the recommended Phase 2 dose (RP2D) of NBTXR3 in pancreatic cancer

from the complete dose escalation phase of MD Anderson Study 2019-1001. The expansion phase is ongoing at

RP2D level. Furthermore, the Company is evaluating RT-activated NBTXR3 for patients with NSCLC, naïve

esophageal cancer, and pancreatic cancer through the clinical collaboration with MD Anderson.

Study 103 - evaluating RT-activated NBTXR3 for the treatment of patients with HCC and liver metastasis - has

finished recruitment and final results were presented in the first quarter of 2021.

3 Spigel, David R., et al. (2015): 8009-8009. ; Ferris, Robert L., et al. New England Journal of Medicine 375.19 (2016): 1856-1867. ; Borghaei, Hossein, et al. New England

Journal of Medicine 373.17 (2015): 1627-1639. ; Garon, Edward B., et al. New England Journal of Medicine 372.21 (2015): 2018- 2028. ; Seiwert, Tanguy Y., et al. The lancet

oncology 17.7 (2016): 956-965. ; Antonia, Scott J., et al. New England Journal of Medicine 377.20 (2017): 1919-1929

Next steps in soft tissue sarcoma

In conjunction with the Company’s decision to reduce operating expenses and prioritize on-going and planned

registration programs in head & neck cancer in May 2022, the Company announced its intention to postpone the

initiation of a post-marketing clinical safety study intended to provide additional long-term safety data required to

maintain its CE mark for Hensify® (NBTXR3) in soft tissue sarcoma. As the Company has no current plans to market

or sell the product in the EU until after approval of NBTXR3 in a second indication, the CE mark for the STS

indication has no impact on expected cash inflow prior to approval in a second indication. The Company has

informed the GMED, the French notified body for the conformity assessment of medical devices, of its revised

development plans and its intention to seek revision of its post marketing surveillance plan to be inclusive of the

intended patient populations at the time of planned commercialization.

Anticipated Upcoming milestones

•Advance toward NBTXR3 global commercial registration through NANORAY-312, a Phase 3 trial

evaluating RT-activated NBTXR3, with or without cetuximab, for elderly patients with LA-HNSCC ineligible

for platinum-based chemotherapy following preliminary survival data from Phase 1 dose expansion study

(Study 102 Expansion) showing a potential clinical benefit for elderly patients with a poor prognosis.

Expected 2023 milestones include:

◦Final Study 102 results, including analysis of PFS and OS (H2 2023)

•Establish a registrational pathway for NBTXR3 followed by an anti-PD-1 following initial feedback from

Regulatory Agency received in March 2022 and data from the Company’s ongoing Phase 1 study (Study

1100) suggesting NBTXR3 may prime immune response, enhance response rates in anti-PD-1 naïve

patients, and help overcome resistance to prior anti-PD-1 therapy in non-responders.

Expected 2023 milestones include:

◦Update on potential future pivotal Phase 3 study for the treatment of patients with locoregional/

recurrent (LRR) or recurrent/metastatic (R/M) head and neck cancers that are resistant to prior

anti-PD-1 therapy (Q3 2023)

◦Present updated study 1100 data

•Expand evaluation of NBTXR3 safety and feasibility to additional solid tumor indications and therapeutic

combinations outside of Company-led pathways through collaborators.

Expected 2023 milestones include:

◦Present preliminary Phase 1 data from ongoing MD Anderson study in pancreatic cancer (H2

2023)

◦Determination of RP2D for NBTXR3 in non-small cell lung cancer (NSCLC) from ongoing Phase 1

MD Anderson study (H2 2023)

About NBTXR3

NBTXR3 is a novel, potentially first-in-class oncology product composed of functionalized hafnium oxide

nanoparticles that is administered via one-time intratumoral injection and activated by radiotherapy. The

product candidate’s physical mechanism of action (MoA) is designed to induce significant tumor cell

death in the injected tumor when activated by radiotherapy, subsequently triggering adaptive immune

response and long-term anti-cancer memory. Given the physical MoA, Nanobiotix believes that

NBTXR3 could be scalable across any solid tumor that can be treated with radiotherapy and across any

therapeutic combination, particularly immune checkpoint inhibitors.

Table of Contents


1. NANOBIOTIX AND ITS ACTIVITIES PRESENTATION ...................................		22
1.1. SELECTED FINANCIAL INFORMATION ........................................................................		22
1.1.1.	Indicators and key figures ...........................................................................................	22
1.1.2.	Highlights of the financial year ...................................................................................	24
1.1.3.	Recent events ...............................................................................................................	26
1.2. PRESENTATION AND EVOLUTION OF THE COMPANY ...........................................		26
1.2.1.	General presentation of the Company’s activities ..................................................	26
1.2.2.	Organizational chart ....................................................................................................	27
1.2.3.	Property, plant and equipment ...................................................................................	30
1.2.4.	Investments ...................................................................................................................	31
1.3. DESCRIPTION OF ACTIVITIES ........................................................................................		31
1.3.1.	Overview .......................................................................................................................	32
1.3.2.	Current cancer treatment options and limitations ...................................................	36
1.3.3.	NBTXR3: Addressing the challenges of radiotherapy and I-O .............................	36
1.3.4.	Our NBTXR3 technology ............................................................................................	37
1.3.5.	Overview of NBTXR3 ..................................................................................................	39
1.3.6.	Our Clinical Programs .................................................................................................	39
1.3.7.	PharmaEngine Trials ...................................................................................................	57
1.3.8.	Scientific Advisory Board .................................................................................................................	58
1.3.9.	The Curadigm Platform ...............................................................................................	59
1.3.10.	Manufacturing ...............................................................................................................	60
1.3.11.	Commercialization .......................................................................................................	60
1.3.12.	Competition ...................................................................................................................	60
1.3.13.	Research & Development and patents .....................................................................	60
1.3.14.	Our Collaboration Contracts .......................................................................................	69
1.3.15.	Our research agreements ...........................................................................................	75
1.3.16.	Trademarks, trademark applications and domain names .....................................	75
1.3.17.	Government regulation, product approval and certification ..................................	75
1.4. ANALYSIS AND COMMENTS ON THE GROUP’S FINANCIAL RESULTS .............		88
1.4.1.	Income statement analysis .........................................................................................	88
1.4.2.	Balance sheet analysis ...............................................................................................	91
1.4.3.	Outlook and subsequent events ................................................................................	94
1.4.4.	Cash flow, capital financing ........................................................................................	95
1.4.5.	Accounting and reporting on allocation of the profit ...............................................	97
1.4.6.	Information on dividends .............................................................................................	97
1.4.7.	Non-tax-deductible expenses ....................................................................................	98
1.4.8.	Results for the last five years of Nanobiotix SA ......................................................	98

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1.5. RISK FACTORS ....................................................................................................................		98
1.5.1.	Risks Related to Our Business ..................................................................................	103
1.5.2.	Risks Related to the Discovery, Development and Commercialization of Our Product Candidates .....................................................................................................	105
1.5.3.	Risks Related to Our Reliance on Third Parties .....................................................	112
1.5.4.	Risks Related to Operational Compliance and Risk Management ......................	115
1.5.5.	Risks Related to Regulatory Approvals for Our Product Candidates ..................	119
1.5.6.	Risks Related to Intellectual Property .......................................................................	125
1.5.7.	Risks Related to Human Capital................................................................................	131
1.5.8.	Risks Relating to Our Status as a Foreign Private Issuer or a French Company .......................................................................................................................	132
1.5.9.	Risks Related to Ownership of Our ADSs ................................................................	135
2. CORPORATE GOVERNANCE .............................................................................		138
2.1. ADMINISTRATIVE AND MANAGEMENT BODIES		138
2.1.1.	Composition of the Company's Executive and Supervisory Boards ....................	138
2.1.2.	Other corporate offices ................................................................................................	140
2.1.3.	Biographies of members of the Company’s corporate bodies ..............................	142
2.1.4.	Statements relating to members of the Executive Board and the Supervisory Board .............................................................................................................................	144
2.1.5.	Operation of the Executive and the Supervisory Boards .......................................	145
2.1.6.	Conflict of interests ......................................................................................................	148
2.1.7.	Agreements referred to in article L.225-37-4of the French Commercial Code ..	148
2.2. COMPENSATION AND BENEFITS FOR MEMBERS OF THE EXECUTIVE BOARD AND THE SUPERVISORY BOARD ...........................................................................		149
2.2.1.	Compensation and benefits paid to the Executive Board members ....................	149
2.2.2.	Compensation and benefits paid to the Executive and Supervisory Board members .......................................................................................................................	150
2.2.3.	Compensation and benefits allocated to Supervisory Board members ..............	154
2.2.4.	Directors' and employees' compensation ratios ......................................................	154
2.2.5.	Restriction on the sale by members of the Executive Board and the Supervisory Board of their stake in the Company ..................................................	156
2.2.6.	Summary of the operations of the managers and of the persons mentioned in article L.621-18-2 of the Monetary and Financial Code (“Code Monétaire et Financier”) on the Company's securities carried out during the financial year ended December 31, 2022 .........................................................................................	156
2.2.7.	Amounts provisioned by the Company for the payment of pensions, retirement and other benefits for the members of the Executive Board and the Supervisory Board .................................................................................................	156
2.2.8.	Warrants (BSA) and/or founders' warrants (BSPCE) allocated and free shares allocated to members of the Executive Board and the Supervisory Board .............................................................................................................................	156
2.2.9.	Compensation policy applicable to corporate officers for the 2023 financial year ................................................................................................................................	158

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2.3. GOVERNANCE .....................................................................................................................		165
2.4. INTERNAL CONTROL AND RISK MANAGEMENT PROCEDURES IMPLEMENTED BY THE COMPANY ........................................................................................		167
2.4.1.	General principles of internal control ........................................................................	167
2.4.2.	Internal control procedures relating to the preparation and processing of accounting and ﬁnancial information ........................................................................	167
2.5. ITEMS LIKELY TO HAVE AN IMPACT IN THE EVENT OF A PUBLIC OFFER ......		168
2.5.1.	Capital structure of the Company ..............................................................................	168
2.5.2.	Statutory restrictions on the exercise of voting rights and transfers of shares or clauses of agreements brought to the Company's attention in application of article L. 233-11 of the French Commercial Code ..............................................	168
2.5.3.	Direct or indirect shareholdings in the Company's capital of which it is aware pursuant to Articles L. 233-7 and L. 233-12 of the French Commercial Code ...	168
2.5.4.	List and description of holders of any securities with special control rights .......	168
2.5.5.	Control mechanisms provided for in any employee shareholding system, when the control rights are not exercised by the employee ..................................	168
2.5.6.	Shareholder agreements of which the Company is aware and which may result in restrictions on the transfer of shares and the exercise of voting rights	168
2.5.7.	Rules governing the appointment and replacement of members of the Supervisory Board or Executive Board and amendments to the Company's bylaws ......................................................................................................................................................	169
2.5.8.	Powers of the Executive board, in particular regarding the issuance or repurchase of shares ...................................................................................................	169
2.5.9.	Agreements entered into by the Company that are amended or terminated in the event of a change of control of the Company ...................................................	169
2.5.10.	Agreements providing for compensation for members of the Executive Board or employees if they resign or are dismissed without real and serious cause or if their employment is terminated due to a public offer ......................................	169
3. EXTRA-FINANCIAL REPORTING .......................................................................		170
3.1. SOCIAL IMPACT ..................................................................................................................		170
3.2. OUR PATIENTS ....................................................................................................................		170
3.2.1.	Patients’ safety during clinical trials ..........................................................................	170
3.3. OUR PEOPLE ........................................................................................................................		171
3.3.1	Employee Diversity ......................................................................................................	171
3.3.2	Employees’ health and safety ....................................................................................	172
4. 2021 ANNUAL FINANCIAL STATEMENTS .........................................................................		173
4.1. CONSOLIDATED FINANCIAL STATEMENTS FOR THE FISCAL YEAR ENDED DECEMBER 31, 2022 ...................................................................................................................		173
4.1.1.	Consolidated statement of financial position ...........................................................	173
4.1.2.	Consolidated income statement ................................................................................	174
4.1.3.	Consolidated statement of comprehensive loss .....................................................	174
4.1.4.	Statements of consolidated changes in shareholders’ equity ...............................	175
4.1.5.	Statements of consolidated cash flows ....................................................................	176

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4.1.6	Notes to the consolidated financial statements for the year ended December 31, 2022 .........................................................................................................................	177
4.2. STATUTORY AUDITOR'S REPORT ON THE 2022 CONSOLIDATED FINANCIAL STATEMENTS .........................................................................................................		228
4.3. ANNUAL FINANCIAL STATEMENTS (STATUTORY ACCOUNTS) FOR THE FISCAL YEAR ENDED DECEMBER 31, 2022 ........................................................................		235
4.3.1.	Balance sheet ...............................................................................................................	236
4.3.2.	Statement of Income ...................................................................................................	238
4.3.3.	Notes ..............................................................................................................................	239
4.4. STATUTORY AUDITOR'S REPORT ON THE 2022 COMPANY’S ANNUAL FINANCIAL STATEMENTS .........................................................................................................		266
5. COMPANY AND CAPITAL INFORMATION .......................................................		272
5.1. REGISTERED CAPITAL .....................................................................................................		272
5.1.1.	Amount of the share capital .......................................................................................	272
5.1.2.	Non-equity securities ...................................................................................................	272
5.1.3.	Acquisition by the Company of its own shares ........................................................	272
5.1.4.	Securities giving access to share capital .................................................................	273
5.1.5.	Authorized share capital .............................................................................................	285
5.1.6.	Information on the capital of any member of the Group who is the subject of an option or of a conditional or unconditional agreement to put it under option	291
5.1.7.	History of share capital ...............................................................................................	292
5.2. MAJOR SHAREHOLDERS ................................................................................................		297
5.2.1.	Allocation of capital and voting rights as of the date of the Universal Registration Document ...............................................................................................	297
5.2.2.	Significant shareholders not represented on the Executive Board and Supervisory Board .......................................................................................................	298
5.2.3.	Shareholders' voting rights .........................................................................................	298
5.2.4.	Control of the Company ..............................................................................................	298
5.2.5.	Agreements that may result in a change of control ................................................	298
5.2.6.	Pledges and collaterals ...............................................................................................	298
5.3. MEMORANDUM AND BYLAWS .......................................................................................		298
5.3.1.	Corporate purpose (article 3 of the Company’s bylaws) ........................................	298
5.3.2.	Provisions enabling a change of control to be delayed, postponed or prevented ......................................................................................................................	299
5.3.3.	Special provisions governing changes in capital ....................................................	299
5.4. INFORMATION AND HISTORY OF THE LEGAL LIFE OF THE COMPANY OVER THE FINANCIAL YEAR ...................................................................................................		299
5.4.1.	Corporate name of the Company ..............................................................................	299
5.4.2.	Place of registration and registration number ..........................................................	299
5.4.3.	Date of incorporation and term ..................................................................................	299
5.4.4.	Company headquarters, legal form, legislation governing its activities ..............	299
5.5. INFORMATION ABOUT THE SUBSIDIARIES ...............................................................		299

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5.6. REGULATED AGREEMENTS ...........................................................................................		300
5.6.1.	Related-party agreements ..........................................................................................	300
5.6.2.	Severance pay and employment agreements .........................................................	300
5.6.3.	Special report of the statutory auditors on regulated agreements and commitments ................................................................................................................	302
5.7. EMPLOYEES .........................................................................................................................		305
5.7.1.	Human Resources .......................................................................................................	305
5.7.2.	Employee share ownership ........................................................................................	306
6. FURTHER INFORMATION ....................................................................................		307
6.1. PERSON RESPONSIBLE FOR THE UNIVERSAL REGISTRATION DOCUMENT .		307
6.1.1.	Statement by the person responsible for the Universal Registration Document ......................................................................................................................	307
6.1.2.	Person responsible for the financial information .....................................................	307
6.2. STATUTORY AUDITORS ...................................................................................................		307
6.2.1.	Statutory Auditors .........................................................................................................	307
6.2.2.	Statement on the fees paid to the statutory auditors ..............................................	308
6.3. INFORMATION FROM THIRD PARTIES, STATEMENTS BY EXPERTS AND DECLARATION OF INTERESTS ...............................................................................................		308
6.4. PUBLICLY AVAILABLE DOCUMENTS ..........................................................................		308
6.5. CROSS-REFERENCE TABLE ..........................................................................................		308
6.6. GLOSSARY AND PRINCIPAL ABBREVIATIONS .......................................................		314
6.6.1.	Glossary .......................................................................................................................	314
6.6.2.	Principal abbreviations ............................................................................................	316

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1.NANOBIOTIX AND ITS ACTIVITIES PRESENTATION

1.1.SELECTED FINANCIAL INFORMATION

The main financial information below is extracted from the consolidated financial statements of the Company and

was prepared with IFRS standards as published by the IASB (International Accounting Standards Board) and

approved by the European Union on the date of preparation of these financial statements.

1.1.1.Indicators and key figures

Simplified balance sheet


	12/31/2022	12/31/2021	12/31/2020
Based on consolidated accounts (in thousands of euros)	Audited	Audited	Audited
Non current assets	7,412	8,709	8,782
Intangible assets	1	4	21
Property, plant and equipment	7,120	8,186	8,256
Financial assets	291	519	505
Current assets	52,358	93,060	125,248
Trade receivables	101	—	62
Other current assets	10,868	9,139	6,035
Cash and cash equivalents	41,388	83,921	119,151
Total assets	59,769	101,769	134,030
Equity	(27,045)	26,790	70,468
Non-current liabilities	48,878	38,134	44,522
incl. financial liabilities – non-current	48,608	37,816	44,107
Current liabilities	37,936	36,845	19,041
incl. financial liabilities - current	4,560	8,204	4,872
Total equity and liabilities	59,769	101,769	134,030

Simplified income statement


	2022	2021	2020
	12 months	12 months	12 months
Based on consolidated accounts (in thousands of euros)	Audited	Audited	Audited
Total revenues and other income	4,776	2,647	2,512,000
incl. Revenues	—	10	50
Operating loss	(46,702)	(52,579)	(36,428)
Financial loss	(10,329)	5,580	2,847
Net loss for the period	(57,041)	(47,003)	(33,590)
Total comprehensive loss	(56,983)	(46,915)	(33,469)

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Chapter 1. NANOBIOTIX AND ITS ACTIVITIES PRESENTATION

Operating expenses are divided between research and development costs and selling, general & administrative

costs. Details are presented below:

Research and development costs


	2022	2021	2020
	12 months	12 months	12 months
(in thousands of euros)	Audited	Audited	Audited
Purchases, sub-contracting and other expenses	(20,415)	(19,562)	(12,734)
Payroll costs (incl. Share-based payments)	(10,868)	(9,605)	(10,306)
Depreciation, amortization and provision expenses	(1,353)	(1,211)	(1,290)
Total research and development costs	(32,636)	(30,378)	(24,330)

Selling, general and administrative (SG&A) expenses


	2022	2021	2020
	12 months	12 months	12 months
(in thousands of euros)	Audited	Audited	Audited
Professional fees, rental and other expenses	(7,792)	(9,638)	(6,482)
Payroll costs (incl. Share-based payments)	(9,688)	(9,379)	(7,789)
Depreciation, amortization and provision expenses	(378)	(417)	(340)
Total selling, general and administrative expenses	(17,857)	(19,434)	(14,611)

Simplified cash flow


	2022	2021	2020
	12 months	12 months	12 months
Based on consolidated accounts (in thousands of euros)	Audited	Audited	Audited
Cash flows used in operations, before tax and changes in working capital	(39,403)	(41,412)	(33,300)
Changes in working capital	2,300	11,540	5,762
Cash flows from (used in) operating activities	(37,104)	(29,872)	(27,538)
Cash flows from (used in) investing activities	138	(242)	(112)
Cash flows from (used in) financing activities	(5,651)	(5,180)	111,769
Impact of exchange rates changes on cash	83	64	(63)
Net cash flow	(42,533)	(35,230)	84,056

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Chapter 1. NANOBIOTIX AND ITS ACTIVITIES PRESENTATION

1.1.2.Highlights of the financial year

2022 included several major developments for Nanobiotix in clinical, preclinical and financial areas.

Clinical

Local Control as a Single Agent Activated by Radiotherapy for Patients with Head and Neck Cancer

In January 2022, Nanobiotix randomized the first patient in pivotal Phase 3 study NANORAY-312, evaluating RT-

activated NBTXR3 with or without cetuximab in platinum-based chemotherapy-ineligible elderly patients with locally

advanced head and neck squamous cell carcinoma (LA-HNSCC). In the second half of 2022, enrollment was

expanded to include Asia, led by strategic partner Lian Oncology Limited (LianBio), and the United States.

In the first quarter of 2022, Nanobiotix completed enrollment in Study 102 and provided data as of February 2022

showing on-going median overall survival of 17.9 months in the all-treated population (n=56) and 23.0 months in the

evaluable patients (n=44). Study 102 Expansion is the expansion part of a Phase 1 study evaluating a single dose

of NBTXR3 at 22% of baseline tumor volume as a single agent activated by radiotherapy in cisplatin-ineligible locally

advanced HNSCC. The primary objectives of the expansion part are to confirm the safety of the Recommended

Dose and obtain preliminary evidence of efficacy.

Priming Immune Response for Combination with Anti-PD-1 Treatment

Nanobiotix presented updated safety and efficacy data from Study 1100, an ongoing, Phase 1 dose escalation and

dose expansion clinical trial evaluating RT-activated NBTXR3 in combination with an anti-PD-1 therapy (nivolumab

or pembrolizumab), at the 37th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) in November of

2022. These data showed that, as of the data cut-off date, NBTXR3 was feasible and well tolerated in the completed

dose escalation part of the study. The recommended Phase 2 dose (RP2D) was established at 33% of Gross Tumor

Volume (GTV) in each of the 3 cohorts.

The overall adverse event (AE) profile did not differ from what is expected with radiotherapy or anti-PD-1 agents. 53

NBTXR3-related AEs were observed during the dose escalation part, of them only 6 Grade 3 or higher AEs were

considered as related to NBTXR3 or tumor injection according to investigators. 4 NBTXR3-related SAEs were

observed; all in cohort 1 at dose level 1 – 22% of GTV. One patient in cohort 1 at dose level 1 (22% of GTV)

experienced 2 dose-limiting toxicities (DLTs). No other DLTs were observed in the study.

Consistent with prior data reporting from Study 1100, the SITC 2022 presentation continued to suggest local control

and systemic anti-cancer activity regardless of prior anti-PD-1 exposure. As of the cut-off date, the data showed

local control was achieved in all but one of 21 patients evaluable for efficacy assessment and an objective reduction

from baseline in all target lesions (objective reduction) was observed in 71.4% of evaluable patients (15/21). Of the

15 evaluable patients with cancer resistant to anti-PD-1, 13 had a documented radiological disease progression

before study entry. In this population,local disease control was demonstrated in 92.3% (12/13), with 30.7% (4/13)

achieving >30% reduction from baseline; local disease control rate in all evaluable patients was 95.2% (20/21).

Systemic disease control was observed in 71.4% of evaluable patients regardless of prior anti-PD-1 exposure,

suggesting that NBTXR3 plus radiotherapy could potentially stimulate immune response and convert anti-PD-1 non-

responders into responders. Further, systemic disease control was durable and sustained for more than 6 months in

38.1% of evaluable patients (8/21).

Following completion of the dose escalation phase, the dose expansion phase of Study 1100 was initiated at the

RP2D with a protocol amended to include one cohort focused on patients with R/M HNSCC that is resistant to anti-

PD-1; a second cohort focused on patients with R/M HNSCC that is naive to anti-PD-1; and a third cohort focused on

patients with lung, liver, or soft tissue metastases from primary non-small cell lung cancer (NSCLC), malignant

melanoma, hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), urothelial cancer, cervical cancer, or triple-

negative breast cancer (TNBC) that is resistant to a prior anti-PD-1 therapy.

Based on available outcomes from Study 1100, Nanobiotix initiated discussion with FDA and subsequently received

preliminary feedback in the first half of 2022 regarding a potential registrational program for patients with

unresectable relapsed or metastatic head and neck squamous cell carcinoma (R/M HNSCC) that developed primary

or secondary resistance to previous anti-PD-1/PD-L1 therapy. Feedback from the agency suggested a single,

randomized, controlled trial including a pre-specified comparative analysis of overall response rate (ORR) may be

suitable to support an accelerated approval, subject to confirmation of clinical benefit based on overall survival (OS)

results from the same trial.

Clinical Collaboration Results

Researchers from MD Anderson published a peer-reviewed clinical case study reporting preliminary data on the first-

in-human administration of NBTXR3 for the treatment of pancreatic cancer not eligible for surgery, demonstrating

feasibility with no treatment-related toxicity. At the end of the dose escalation phase, the RP2D for NBTXR3 in

pancreatic cancer was determined to be 42% of GTV. The ongoing dose expansion phase allows for enrollment of

patients with borderline resectable disease in addition to patients with unresectable disease.

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Data from a Phase 1b/2 head and neck cancer study in Asia evaluating RT-activated NBTXR3 combined with

concurrent weekly low-dose cisplatin-containing chemoradiation showed that, in 12 evaluable patients with stage 4

disease, the combination therapy was feasible, had a favorable safety profile for patients with LA-HNSCC, produced

a 100% disease control rate, and an overall response rate of 58.3%. (Study sponsored, executed, and reported by

former Nanobiotix collaborator PharmaEngine).

Data from a Phase 1b/2 rectal cancer study in Asia evaluating RT-activated NBTXR3 combined concurrent

chemoradiation showed that, in 31 evaluable patients with unresectable disease, the combination in the preoperative

setting was feasible, had a favorable safety profile, and enabled 96% of evaluable patients to undergo R0 surgery.

The combination therapy produced a 100% disease-control rate, a 35.5% overall response rate, and a 20%

pathological complete response rate in 25 patients who underwent surgery (Study sponsored, executed, and

reported by former Nanobiotix collaborator PharmaEngine.)

Preclinical

Published data from a preclinical study conducted in collaboration with MD Anderson in the International Journal of

Nanobiotechnology showed that adding NBTXR3 to a combination of radiotherapy, anti-PD-1, and anti-CTLA-4

produced significant antitumor effects against both primary and secondary tumors, improved the mouse survival rate

from 0 to 50%, and induced long term antitumor memory. These data further the hypothesis that the potential

immune priming effects of NBTXR3 could extend beyond anti-PD-1.

Presented new data from an open-label preclinical study evaluating the changes in immune-related genes induced

by multiple combinations of NBTXR3, anti-PD-1, anti-LAG-3, and anti-TIGIT at the 2022 Annual Meeting of the

American Association of Cancer Research (AACR) showing that groups receiving NBTXR3 along with checkpoint

inhibitors outperformed all other combinations in efficacy, survival, and induction of long-term anti-cancer memory.

This new analysis concluded that NBTXR3 plus a triple blockade of PD-1, LAG-3, and TIGIT (Combination therapy)

promotes immune activation at the irradiated site, abscopal responses at non-irradiated sites, and suggests that the

Combination therapy may be effective against metastatic cancers.

Scientific Advisory Board

In November 2022, Nanobiotix established a Scientific Advisory Board (SAB) of 12 multidisciplinary experts from the

United States and Europe. The SAB members is expected to provide independent advice and recommendations to

the Company regarding the development of its lead therapeutic candidate, NBTXR3. It integrates high level expertise

that is relevant to Nanobiotix business, including but not limited to medical, surgical and radiation oncology fields.

Leonard Farber, MD, Chief Clinical and Medical Affairs Officer at Nanobiotix was appointed as Chairman of the SAB.

See section 1.3.8. of the Universal Registration Document for additional details.

Finance

Proactive Prioritization of Registration Programs and Reduction of Operating Expenses

In May 2022, Nanobiotix implemented several initiatives intended to reduce operating costs while maintaining

targeted research efforts focused on the continued execution of its pivotal Phase 3 study in LA-HNSCC, the

continuation of I-O combination Study 1100, and the development of a registration pathway in I-O combination

therapy while leveraging its on-going strategic collaboration with MD Anderson to validate the feasibility of future

development opportunities.

Signing of Equity Line Financing

In May 2022, Nanobiotix established an equity line financing (PACEO) with Kepler Cheuvreux. This line of financing

provides financial optionality and near-term flexibility, if needed, as Nanobiotix continued efforts to reduce operating

expenses and to focus on its priority programs. In accordance with the terms of this agreement, Kepler Cheuvreux

committed to underwrite up to 5,200,000 shares over a maximum timeframe of 24 months starting from May 2022,

provided the contractual conditions are met. The shares will be issued based on the lower of the two daily volume

weighted average share prices for the two trading days preceding each issuance, less a maximum discount of 5.0%.

No warrant has been exercised by Kepler Cheuvreux as of December 31, 2022.

Restructuring of Existing Loan with the European Investment Bank (EIB)

In October 2022, Nanobiotix executed a final agreement with the European Investment Bank (EIB) to re-align

approximately €34.4 million in outstanding debt obligations with the Company’s expected development and

commercialization timelines. Details related to terms and conditions of the new agreement can be found in Section

1.3.14.4 EIB Finance Contract and Royalty Agreement.

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1.1.3.Recent events

Research and development updates

Curadigm

In January 2023, Curadigm received €300k from BPI France as part of the deep tech funding. Curadigm was

selected in July 2020 by BPI France to receive €1.0 million in non-dilutive funding from the Deep Tech program to

support the development of its Nanoprimer platform. The funding was divided in two parts: a first payment of €700k

received at the project start and a second one of €300k at project completion.

1.2.PRESENTATION AND EVOLUTION OF THE COMPANY

1.2.1.General presentation of the Company’s activities

Nanobiotix is a late-stage clinical biotechnology company pioneering disruptive, physics-based therapeutic

approaches to revolutionize treatment outcomes for millions of patients; supported by people committed to making a

difference for humanity. The company’s philosophy is rooted in the concept of pushing past the boundaries of what is

known to expand possibilities for human life.

Incorporated in 2003, Nanobiotix is headquartered in Paris, France. The company also has subsidiaries in

Cambridge, Massachusetts (United States), France, Spain and Germany. Nanobiotix has been listed on Euronext:

Paris since 2012 and on the Nasdaq Global Select Market in New York City since December 2020.

First-in-class radioenhancer NBTXR3, for which Nanobiotix has patented protection as summarized in the section

1.3.13.3 of the Universal Registration Document, aims to expand the benefits of radiotherapy for millions of patients

with cancer. In addition, the Company’s immuno-oncology program has the potential to bring a new dimension to

immunotherapies in oncology.

Milestones in the Company’s recent development

_2021

▪January:

◦Positive first results for novel NBTXR3 in rectal cancer study published at ASCO GI 2021;

◦Curadigm secured new collaboration agreement with Sanofi focused on gene therapy pipeline;

◦First patient injected with NBTXR3 in esophageal cancer.

▪March:

◦Agreement reached with PharmaEngine, Inc. to terminate the license and collaboration agreement

that the Company and PharmaEngine entered into in August 2012.

▪May:

◦Partnership with LianBio signed to develop and commercialize potential first-in-class radioenhancer

NBTXR3 across tumor types and therapeutic combinations in China and other Asian markets.

▪June:

◦Bart Van Rhijn joined as Chief Financial Officer and member of the Executive Board to support

global expansion;

◦New data published for potential first-in-class radioenhancer NBTXR3 in combination with anti-PD-1

showing local or distant tumor regression in 76.9% of evaluable patients regardless of prior anti-

PD-1 exposure (study 1100);

◦Initiation of new clinical study evaluating NBTXR3 in lung cancer within the MD Anderson

collaboration.

▪September:

◦Red Journal publication of preclinical data showing radioenhancer NBTXR3 may “reprogram” the

tumor microenvironment to overcome anti-PD-1 resistance and evoke abscopal effect.

▪October:

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◦Publication of first survival data in head and neck cancer: 18.1 month median overall survival for 41

evaluable elderly and frail patients with HNSCC in Phase 1 expansion evaluating NBTXR3 as a

single agent activated by radiotherapy (study 102).

_2022

▪January:

◦First patient enrolled in NANORAY-312, our global Phase 3 registrational study evaluating NBTXR3

for the treatment of head and neck cancer;

◦Completed enrollment in Study 102, a Phase 1 study of NBTXR3 in head and neck cancer.

▪February:

◦Publication of new clinical case study highlighting first patient experience of NBTXR3 treatment for

pancreatic cancer.

▪April:

◦New preclinical immunotherapy data show boosted anti-tumor immune activation via triple blockade

of PD-1, LAG-3, and TIGIT when combined with radiotherapy-activated NBTXR3.

▪June:

◦New data featuring NBTXR3 in combination with concurrent chemoradiation for the treatment of

head and neck cancer and rectal cancer presented at 2022 Annual Meeting of the American Society

for Clinical Oncology (ASCO).

▪September:

◦First patient enrolled in Asia in NANORAY-312, our global Phase 3 registrational trial evaluating

NBTXR3 for the treatment of head and neck cancer;

◦Determination of the recommended Phase 2 dose (RP2D) of NBTXR3 in combination with

pembrolizumab or nivolumab for the treatment of patients with advanced cancer, including patients

with inoperable locoregional recurrent (LRR) or recurrent and metastatic (R/M) head and neck

squamous cell carcinoma (HNSCC) that is resistant to prior immunotherapy (study 1100).

▪October:

◦Execution of a final agreement with the European Investment Bank (EIB) to re-align approximately

€34.4 million in outstanding debt obligations with the Company’s expected development and

commercialization timelines

▪November:

◦Appointed renowned global experts to comprehensive Scientific Advisory Board for potential first-in-

class radioenhancer NBTXR3

◦Reported updated Phase 1 anti-PD-1 combination data that may support the immune stimulation

potential of radioenhancer NBTXR3 at the 37th Annual Meeting of the Society for Immunotherapy of

Cancer (study 1100);

◦MD Anderson completed the dose escalation part of a Phase 1 study evaluating NBTXR3 in patients

with locally advanced (LA) or borderline resectable (BR) pancreatic cancer (PC), established RP2D

in pancreatic cancer at 42% of GTV, and initiated the dose expansion part of the study

▪December:

◦First patient enrolled in the United States in NANORAY-312, our global Phase 3 registrational study

evaluating NBTXR3 for the treatment of head and neck cancer.

1.2.2.Organizational chart

Nanobiotix headcount counts 102 employees (excluding trainees) at the end of the 2022 financial year, supervised

by a team of complementary and highly experienced management team as well as a Supervisory Board composed

of experts in their respective fields.

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1.2.2.1.Management

The management of the Company includes highly experienced professionals.

Executive Board (the “Executive Board”)

Laurent Levy, Ph.D., Co-founder, Chairman of the Executive Board


	Nationality: French Age: 51 Term of corporate office: at the end of the general shareholders meeting which shall approve the accounts for the financial year ended December 31, 2023

Biography

Laurent Levy is the co-founder of Nanobiotix and has served as our Chairman of our executive board since March

2003. He was first appointed as Chairman of the Executive Board of the Company on May 27, 2004. He has

extensive experience in sciences and techniques related to nanotechnologies. His research at the frontier of

biotechnology and nanotechnologies has resulted in the development of a number of concrete applications such as

NBTXR3, which could open a new method for cancer treatment.

Prior to founding Nanobiotix, he served from 2000 to 2003 as consultant for Altran Technologies and worked in the

development of the application of nanotechnologies with companies such as Sanofi S.A., Guerbet S.A., and Rhodia

S.A., as well as for early-stage biotechnology companies. He has served as president of the supervisory board of

Valbiotis S.A. (Euronext Paris: ALVAL) since March 2017, as a founding member of the Nanomedicine Translation

Advisory Board since June 2014 and as vice chairman of the executive board of the European Technology Platform

on Nanomedicine since December 2012. He is the author of more than 35 international scientific publications and

communications, has made several innovations that led to patent applications and patents granted, and regularly

speaks on the topic of using nanoparticles to fight cancer.

Laurent Levy holds a Doctorate in Physical Chemistry, specializing in nanomaterials, from the Pierre and Marie Curie

University (Université Paris VI Pierre et Marie Curie) in Paris and from the CEA (Commissariat à l’Énergie Atomique

et aux Énergies Alternatives), and a DEA (advanced studies and diplomas) in Physics of condensed matter from the

UPVI-ESPCI (Paris), followed by a post-doctoral fellowship at the Institute for Lasers, Photonics and Biophotonics,

SUNY (State University of New York), Buffalo, USA.

Bart Van Rhijn, Chief Financial Officer


	Nationality: Dutch Age: 50 Term of corporate office: at the end of the general shareholders meeting which shall approve the accounts for the financial year ended December 31, 2023

Biography

Bart Van Rhijn brings extensive experience in consultancy, technology, and life sciences industries and joined

Nanobiotix in 2021 after nearly 3 years as chief financial officer at Servier Pharmaceuticals, LLC (Servier US).

Prior to Servier US, he held leadership roles in prominent organizations in Europe and North America, including

PricewaterhouseCoopers, Philips and Galderma in Head of Tax, Senior Director of Mergers and Acquisitions, and

Head of Finance positions. Bart Van Rhijn’s track record reflects a relentless commitment to streamlining business

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operations, driving growth, and unlocking value. His varied experiences include the successful reorganization of a

healthcare technology-enabled services business, coordination of strategic financing transactions, and the efficient

scaling of commercial businesses. Bart Van Rhijn has a strong commitment to organizational health and empowers

his teams to embrace innovation, challenge the status quo, and drive optimal results while putting patients and

customers first. In addition, Bart Van Rhijn is a venture partner at an emerging technology fund and co-founder of a

podcast production start-up.

Bart Van Rhijn received master’s degrees in Civil Law and Tax Law at Leiden University, The Netherlands, obtained

his MBA with honors from Babson’s Olin School of Management, and his Certified Management Accountant (CMA)

certification from the Institute of Management Accountants.

Anne-Juliette Hermant, Chief People Officer


	Nationality: French Age: 49 Term of corporate office: at the end of the general shareholders meeting which shall approve the accounts for the financial year ended December 31, 2023

Biography

Anne-Juliette Hermant joined Nanobiotix in 2019 after more than 20 years in HR, Corporate Social Responsibility

and Public Affairs roles in both private and public sectors.

Prior to joining Nanobiotix, she had spent 15 years in AXA. She was at first the Founder and Head the AXA

Research Fund, a €100 million fund created to support frontier science in all fields related to an understanding of the

risks faced by human societies; she then served as the Chief Learning Officer of the AXA Group, before

contributing to the creation of a new AXA division, AXA Partners, as Global Head of Talent, Development, Culture &

Corporate Responsibility.

Prior to her AXA years, she had started her carrier supporting the evolution and transformation of various

organizations in government and non-government sectors.

A firm believer in education and research as critical foundations for the development of human societies, she served

on the Boards of some European research & higher education institutions, including HEC, the Toulouse School of

Economics, the Institut Mines-Telecom or the Ecole des Ponts. She is currently Vice-Chairman of the Board of the

Fondation Nationale Entreprise et Performance.

Anne-Juliette Hermant graduated from the Ecole Normale Supérieure and the Institut d‘Etudes Politiques de Paris.

She is also the holder of the Agrégation de Littérature Française and of a DEA (Certificate of Advanced Study/ABD)

in French Literature from the University Paris 3-Sorbonne Nouvelle.

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1.2.2.2.Legal Group chart

1.2.2.3.List of subsidiaries, branches, and secondary establishments

The Company holds a 100% interest in four subsidiaries: Nanobiotix Corp., a Cambridge, MA based company

incorporated in the state of Delaware, Nanobiotix Spain S.L.U., a Spanish company, Nanobiotix Germany GmbH, a

German company, and Curadigm SAS, a company incorporated under the laws of France. Curadigm SAS has a

wholly owned subsidiary located in Cambridge, MA in the United States.

For more information on these subsidiaries, see section 5.5 of the Universal Registration Document.

Nanobiotix also has a Swiss branch (succursale) as well as a secondary establishment located at 1, Mail of

Professor Georges Mathé, 94 800 Villejuif, France, where its manufacturing site is located.

1.2.2.4.Main intragroup transactions

In the course of business, the Company has set up agreements relating to the organization of financial and other

services within the Group according to the following structure:

▪Cash pooling agreement: entered into between the Company and each of its subsidiaries (US, Spain and

Germany), where cash advances made by and between any of the Group's entities, up to a maximum of €25

million, are paid for at the rate of EURIBOR 12 months + 1.25% ;

▪Service agreements: service agreements entered into between the Company and respectively its U.S.,

Spanish, and German subsidiaries, allowing subsidiaries to be remunerated for activities carried out for the

benefit of the parent company;

▪An agreement is also in place since 2019 between the Company and Curadigm SAS, to compensate Company

for use of office and laboratory space occupied by Curadigm SAS at the Company’s headquarters in Paris;

▪A Staff Loan agreement implemented in 2022 between the Company and its subsidiary Curadigm SAS allowing

employees of Curadigm SAS to work to the benefit of the parent company, provided all the legal conditions are

met.

Further details can be found in the Company’s annual financial statements set forth in the notes to the income

statement in the statutory accounts’ appendices in section 4.3 of the Universal Registration Document.

1.2.3.Property, plant and equipment

Our corporate headquarters is located in Paris, France, where we lease approximately 2,622 square meters of office

space. The lease of our Paris headquarters continues through June 30, 2027. Our headquarters, located at 60 rue

Wattignies in the 12th arrondissement of Paris, for which we signed a lease on July 1, 2017 for a term of 10 years

and an amendment pursuant to which we leased additional space, with retroactive effect from January 1, 2019.

Our approximately 1,195 square meter manufacturing facility is located in the Villejuif BioPark, a scientific research

and innovation center just outside of Paris, France. The lease for the facility, which began on July 1, 2017 and was

renewed in 2021, has a term of 9 years, ending June 30, 2030. The facility, which we opened in November 2017,

expanded our potential production capacity with the aim to produce NBTXR3 for our current and contemplated

clinical trials and the initial commercial phase.

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The Company owns equipment for its research, development and manufacturing activities. This equipment was

valued at €354 thousand (after depreciation) as of December 31, 2022 compared to €443 thousand at December 31,

2021.

We also rent office space for Nanobiotix Corp., our wholly owned U.S. subsidiary, in Cambridge, Massachusetts on a

month-to-month basis. We have no significant lease commitments with respect to our foreign subsidiaries.

Since January 1, 2019, following the application of IFRS 16 – Leases, the Company recognizes all eligible lease

contracts in its consolidated balance sheet (see Note 6. Property, plant and equipment).

We believe that our existing facilities are adequate for our near-term needs, and we believe that suitable additional

or alternative office and manufacturing space will be available as required in the future on commercially reasonable

terms.

Payments due per period at December 31, 2022


Contractual obligations (in thousands of euros)	Payments due per period
Contractual obligations (in thousands of euros)	At 1 year the most	At more than 1 year and up to 5 years	Over 5 years	Total
Simple leases	1,064	3,912	940	5,916

1.2.4.Investments

For the reporting period, the main net investments related to the Company’s business were as follows:

Nanobiotix’s net investments


	Dec 31, 2022	Dec 31, 2021	Dec 31, 2020
Based on consolidated accounts (in thousands of euros)	Audited	Audited	Audited
Intangible assets	1	4	21
Property, plant and equipment	7,120	8,186	8,256
Financial assets	291	519	505
Total	7,412	8,709	8,782

The main property, plant and equipment held by the Company consist mainly of fixtures and fittings and equipment in

premises leased by the Company, technical equipment for research, development and production, as well as office

and computer equipment. These fixed assets are shown in Note 6 to the consolidated financial statements for the

year ended December 31, 2022, prepared under IFRS in section 4.1 of the Universal Registration Document.

Investments underway

As of the date of the Universal Registration Document, the majority of the investments are made in France, given the

location of its head office and manufacturing facilities as well as the majority of its employees.

The Company does not have any short or long-term investments planned.

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1.3.DESCRIPTION OF ACTIVITIES

1.3.1.Overview

We are a late-stage clinical biotechnology company focused on developing first-in-class, physics-based product

candidates that use our proprietary nanotechnology to seek to improve treatment outcomes for millions of patients

around the world. Our lead product candidate, NBTXR3, is designed to improve local control of solid tumor by

increasing the tumor-killing effect of radiotherapy without increasing damage to surrounding healthy tissues, and to

improve systemic control through its potential immune priming effect subsequent to the physical destruction caused

by the physics-based mechanism of action (MoA). Through this approach we are advancing a strategy that initially

aims to build a potentially industry-leading head and neck cancer treatment franchise powered by NBTXR3, and then

to scale the franchise approach to other solid tumor indications.

Potential first-in-class radioenhancer NBTXR3 is an aqueous suspension of functionalized, crystalline hafnium oxide

nanoparticles designed for injection directly into a malignant tumor and is activated by radiotherapy. When exposed

to ionizing radiation, NBTXR3 increases the localized dose of radiotherapy delivered to the tumor cells where it is

present, significantly increasing tumor cell death without increasing the dose in surrounding healthy tissues.

Subsequent to the physical cellular destruction caused by radiotherapy-activated NBTXR3, the product candidate

may also prime adaptive immune response and create long-term anti-cancer memory. Given the physics-based

MoA, we believe that NBTXR3 could be developed as a tumor-agnostic treatment targeting all solid tumors that are

treated with radiotherapy and across therapeutic combinations, including immune checkpoints inhibitors.

Radiotherapy, also called radiation therapy (RT), involves the use of X-rays or other high-energy particles or rays to

kill cancer cells in tumors. It is among the most common cancer treatments, both as a standalone therapy and in

combination with surgery, chemotherapy or biological therapies. In developed countries with access to radiotherapy,

approximately 60% of all cancer patients will receive radiotherapy at least once, either alone or as a part of a more

complex treatment protocol. Nevertheless, many of these patients still die from the progression of their cancer

because, among other reasons, they are not able to receive a high enough radiation dose to completely destroy their

tumor without resulting in an unacceptable level of damage to surrounding healthy tissues. We believe that by

mitigating these limitations, NBTXR3 may improve the survival rate and quality of life for cancer patients.

Our pioneering approach uses nanophysics to bring a physics-based MoA that destroys cancer cells. Unlike

traditional targeted therapies or biologics, NBTXR3 has a broadly applicable mechanism of action that we believe to

have the potential to be used in the treatment of all solid tumor types in conjunction with radiotherapy. The

nanoparticles have a high electron density, which allows a tumor that contains NBTXR3 to absorb more energy than

could otherwise be absorbed by the cancer cells alone. This controlled concentration of energy leads to greater

localized cancer cell destruction. When exposure to radiation ceases, the nanoparticles return to their inactive, inert

state. However, the subsequent effect of improved physical cell destruction may allow for a greater exposition of

tumor antigens in the microenvironment. Preclinical data and early data from our ongoing clinical studies both

suggest that RT-activated NBTXR3 may allow for the priming of the immune system. This priming effect, if validated

through further clinical testing, may be due to the activation of complex causal mechanisms, referred to as pleiotropic

biological pathways, and increased exposition of antigens resulting in the activation of a patient’s own immune cells

to destroy cancer cells in the body. We believe that NBTXR3’s novel MoA and effect, when activated, on the tumor

microenvironment could enable better local control of tumors and may potentially enhance systemic control of

tumors.

We believe that NBTXR3’s MoA could improve outcomes for patient populations across all solid tumors that may be

treated with radiotherapy alone or in combination with other therapeutic agents. Consistent with the Company’s

strategic priorities, we intend to focus our resources on building a comprehensive treatment franchise across head

and neck cancer indications where radiotherapy is a part of the treatment protocol. It has been estimated that 74% of

head and neck cancer patients will receive radiotherapy treatment, making this patient population a significant

market opportunity for NBTXR3. Moreover, the Company believes this model can be replicated across any solid

tumor indication treated by radiotherapy that can be injected with NBTXR3, further expanding the market opportunity

of NBTXR3.

In addition, we believe NBTXR3 could bring new opportunities to patients with cancers that cannot currently be

treated with radiotherapy because of the radiosensitivity, or other characteristics, of the tissues near the tumor. The

three most advanced indications for which we have announced positive clinical trial results are locally advanced STS

of the extremity or the trunk wall, locally advanced head and neck cancers (for which the FDA has granted Fast

Track designation for the treatment of patients ineligible for platinum-based chemotherapies, the patient population

for our global Phase 3 clinical trial) and liver cancers.

We achieved a major proof-of-concept milestone for NBTXR3 with the completion of our randomized, controlled

Phase 2/3 clinical trial in the EU for the treatment of patients with locally advanced STS of the extremities and trunk

wall. Our Phase 2/3 clinical trial achieved its primary endpoint showing approximately twice as many STS patients

who received NBTXR3 activated by radiotherapy achieved a pathological complete response, which is defined as

less than 5% residual viable cancer cells in the tumor, compared to patients who received radiotherapy alone. This

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difference was statistically significant and served as the basis to obtain the right to legally commercialize the product

in the EU. In April 2019, we completed the regulatory process for the CE mark of NBTXR3, thereby allowing the

product to be commercialized in the 27 EU countries for the treatment of locally advanced STS of the extremity and

trunk wall under the brand name, Hensify®.

We are currently prioritizing the development of NBTXR3 in the United States and the EU for the treatment of head

and neck cancers, including locally-advanced as well as recurrent and/or metastatic (R/M) disease. Our most

advanced program is designed to enhance outcomes for patients with locally advanced head and neck cancers

ineligible for chemotherapy, which we believe presents a significant opportunity for NBTXR3 because of the high

incidence of these cancers and the high unmet medical need for such patients. More than half of locally advanced

head and neck cancers include large primary tumors which may invade underlying structures, spread to regional

nodes or both. Moreover, median overall survival is approximately 12-13 months in elderly patients with head and

neck squamous cell carcinoma (HNSCC) treated with radiotherapy alone. Further, because treatment of locally

advanced forms of head and neck cancer ordinarily requires aggressive, concerted measures, the subpopulation of

elderly patients generally suffers from limited therapeutic options. Accordingly, we believe NBTXR3 could represent a

significant benefit for this patient population with the potential to extend survival and improve quality of life.

In 2019, we concluded an initial dose escalation phase of Study 102, our Phase 1 clinical trial in frail or elderly

patients with locally advanced head and neck cancers who are ineligible for cisplatin or intolerant to cetuximab, a

patient population that is typically treated with radiotherapy alone. A review of preliminary data as of the February 22,

2022 cut-off date from Expansion Study 102 shows median overall survival (mOS) of 23 months in evaluable

patients (n=44) demonstrating continued improvement relative to the analysis presented at ASTRO 21 and

consistent with data reported from the dose escalation phase of Study 102. See “Our Clinical Programs—Locally

advanced head and neck cancers—Phase 1 (“Study 102 Escalation”) and Phase 1 Expansion (“Study 102

Expansion”) Trial” below.

We are conducting NANORAY-312, a global randomized open-label Phase 3 clinical trial evaluating RT-activated

NBTXR3 with or without cetuximab, for the treatment of elderly patients with locally advanced HNSCC who are not

eligible for platinum-based chemotherapy. The first patient of the study was randomized in January 2022, with sites

now active in the United States, Europe and Asia. The trial is expected to enroll approximately 500 patients. The trial,

which has been designated by the FDA as a Fast Track development program in 2020 is being conducted with our

partner Lian Oncology Limited (“LianBio”). LianBio has committed to enrolling 100 patients in their licensed territories

in Asia for participation in the study.

Alongside our NBTXR3 development program in locally advanced head and neck cancer, we are also pursuing a

robust development program to study the use of RT-activated NBTXR3 followed by immune checkpoint inhibitors

across several solid tumor indications. In recent years, significant attention has been focused on the potential of

immuno-oncology treatments, and in particular, checkpoint inhibitors. Checkpoint inhibitors are a type of

immunotherapy that function to block proteins that stop the immune system from attacking cancer cells. In doing so,

they enable the patient’s T cells to recognize cancer cells that would otherwise be invisible to immune attack.

However, many tumors exhibit little or no response to checkpoint inhibition (these tumors are referred to as “cold”

tumors). Our preclinical and early clinical results suggest that NBTXR3 plus radiotherapy may stimulate an immune

response, thereby rendering otherwise cold tumors more prone to recognition by the patient’s immune system

(making them “hot tumors”) and therefore potentially more responsive to I-O treatments such as checkpoint

inhibitors. Initially, we intend to leverage the data collected pursuant to our I-O Program to advance treatment for

patients with R/M HNSCC that is resistant to prior immunotherapy.

As part of our checkpoint inhibitor combination development program, we are conducting Study 1100, a multi-cohort

Phase 1 trial for NBTXR3 activated by radiotherapy followed by anti-PD-1 checkpoint inhibitors nivolumab (Opdivo)

or pembrolizumab (Keytruda) in patients with R/M HNSCC or with soft tissue, lung or liver metastases from any

primary cancer that is eligible for anti-PD-1 therapy. We presented updated clinical results from Study 1100 at SITC’s

Annual Meeting in November 2022. We believe that these early results suggest that NBTXR3 has the potential to

increase the proportion of patients that respond to immune checkpoint inhibitors, and we have commenced initial

discussions with regulatory authorities regarding the potential registration pathway, for this immunotherapy

combination for patients with R/M HNSCC that is resistant to prior immunotherapy. In early 2022, we amended the

Study 1100 protocol to add an expansion phase in three cohorts, including two cohorts focused on R/M HNSCC

patients that are either naïve to anti-PD-(L)-1 therapy or resistant to prior anti-PD-(L)-1 therapy and combining other

eligible patients with lung and/or liver and/or soft tissues metastases from anti-PD-(L)-1 resistant advanced cancers

into a third cohort. See “Our Clinical Programs—I-O Program— R/M HNSCC and lung, liver or soft tissue

metastases from any primary tumor—Multi-Cohort Phase 1 Trial (“Study 1100”)” below.

As of December 31, 2022, NBTXR3 has been administered to approximately 300+ patients. Given Nanobiotix’s

focus areas, and balanced against the scalable potential of NBTXR3, we have engaged in a strategic collaboration

strategy with large and reputable partners to expand development of the product candidate in parallel with our

priority development pathways, as discussed under the caption “—NBTXR3 Development Pipeline” below. In 2018

we entered into a broad, comprehensive clinical research collaboration with MD Anderson to sponsor several Phase

1 and Phase 2 studies in the United States to evaluate NBTXR3 across tumor types and therapeutic combinations,

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with a total of approximately 312 patients expected to be enrolled across these clinical trials. Four clinical trials under

this collaboration—a Phase 1 study in patients with locally advanced or borderline resectable pancreatic cancer, a

Phase 1 study in patients with esophageal cancer, a Phase 1 study in patients with non-small cell lung cancer and a

Phase 2 study in patients with head and neck cancer in combination with anti-PD-1—have commenced enrollment.

In May 2021, we entered into a collaboration agreement with LianBio to develop and commercialize NBTXR3 in key

countries in Asia, including Mainland China, Taiwan and South Korea, pursuant to which LianBio has undertaken to

contribute to enrollment in up to five global registrational studies for NBTXR3, beginning with NANORAY-312.

We were founded as a spin-off from the State University of New York, Buffalo, in 2003. Team members at

Nanobiotix, including our founder, Laurent Levy, have nearly two decades of experience developing Nanobiotix’s

technology and we believe Nanobiotix to be a pioneer and leader in the field of nanomedicine. We have built an

integrated, multidisciplinary team that combines expertise in physics, biology, chemistry and medicine as well as

operations and corporate finance. We believe that this unique expertise will allow us to expand our product pipeline

and to advance the development of our product candidates, either on our own or in collaboration with third parties.

Our corporate headquarters and manufacturing facilities are located in Paris, France, with U.S. operations in

Cambridge, Massachusetts.

NBTXR3 Development Pipeline

As a result of nearly two decades of experience developing our technology, and our broad collaboration with MD

Anderson, we have a robust development pipeline. The chart below highlights ongoing and planned clinical trials

portfolio, including those that are under Nanobiotix’s collaboration with MD Anderson. Nanobiotix is currently in

discussions with MD Anderson to determine the indications for the remaining trials. Additional detail regarding

Nanobiotix’s most advanced clinical trials is provided under the section “Our Clinical Programs”


(1)	NANORAY-312, a global Phase 3 clinical trial with NBTXR3 for elderly patients with locally-advanced head and neck cancer who are ineligible for platinum-based chemotherapy. NBTXR3 for the treatment of locally advanced head and neck cancers received Fast Track designation from the FDA in February 2020.
(2)	LianBio has been granted development and commercialization rights for NBTXR3 in key countries in Asia.
(3)	NBTXR3 activated by radiotherapy
(4)	Phase 1/2 study conducted in Asia by former partner, PharmaEngine. In conjunction with the termination of the license and collaboration agreement, PharmaEngine implemented the early termination and wind-down of the Phase 1 of this clinical trial in accordance with good clinical practice guidelines. The trial was deemed completed when all enrolled patients reached “end-of-study” and PharmaEngine issued a final study report. See “1.3.7. of the Universal Registration Document” for additional details.
(5)	Phase 1/2 study conducted in Asia by former partner, PharmaEngine. In conjunction with the termination of the license and collaboration agreement, PharmaEngine implemented the early termination and wind-down of the Phase 2 of this clinical trial in accordance with good clinical practice guidelines. The trial was deemed completed when all enrolled patients reached “end-of-study” and PharmaEngine issued a final study report. See “1.3.7. of the Universal Registration Document” for additional details.

The anticipated clinical milestones discussed in the pipeline chart above, and in our Universal Registration

Document generally, are subject to the potential impact of the COVID-19 pandemic on Nanobiotix’s business and

may be delayed as a result. The COVID-19 pandemic has caused some delays in site activation, study enrollment,

and the review of data. Despite these delays, Nanobiotix’s overall development plan continues to progress,

prioritizing head and neck cancer. The COVID-19 pandemic has not negatively impacted our liquidity and/or funding

sources. For more information about the ways in which we have been, and may be, impacted by COVID-19, please

the section titled “Risk Factors”.

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Strategy of Nanobiotix

The goal of Nanobiotix is to become a leader in the biotechnology industry using an approach that leverages the

universal principles of physics to deliver nanoparticle-based therapies designed for broad application across solid

tumors. Based on its proprietary, physics-based properties and its administration via intratumoral injection, we

believe that NBTXR3 could improve local control alone or in combination with other treatment modalities in any

indication where radiotherapy is a part of the treatment regimen. Due to the potential immune priming effect we have

observed subsequent to the physical tumor destruction caused by radiotherapy-activated NBTXR3, we also believe

that systemic treatment outcomes could be improved by expanding the benefits of immune checkpoint inhibitors to

more patients. Ultimately, our aim is to integrate NBTXR3 vertically within solid tumor indications, starting with head

and neck cancer, and then scale horizontally across solid tumor indications, revolutionizing the treatment of cancer

for millions of patients around the world. The key elements of this strategy include:

•Complete the development of, and satisfy applicable EU and US regulatory requirements for

NBTXR3 for the treatment of locally advanced head and neck cancers. Based on encouraging results

from Study 102 Escalation, Nanobiotix is conducting Study 102 Expansion to collect additional preliminary

efficacy data. See “Our Clinical Programs—Locally advanced head and neck cancers—Phase 1 (“Study

102 Escalation”) and Phase 1 Expansion (“Study 102 Expansion”) Trial” below for information regarding

preliminary clinical results for Study 102. In addition, we commenced NANORAY-312, a global Phase 3

clinical trial for elderly patients with locally advanced head and neck squamous cell carcinoma who are

ineligible for platinum-based chemotherapy, randomizing the first patient in January 2022. In the United

States, NBTXR3, classified as a drug, was granted Fast Track designation from the FDA in February 2020

for the treatment of locally advanced head and neck cancers, which Nanobiotix believes could allow for

expedited clinical development. See “Our Clinical Programs—Locally advanced head and neck cancers—

Phase 3 Registration Trial (“NANORAY-312”)” below for information regarding our NANORAY-312 Trial.

•Establish a second registration program in head and neck cancer leveraging I-O combination data

to advance treatment for patients with R/M HNSCC that is resistant to prior immunotherapy.

Nanobiotix is conducting, and continues to further develop a global I-O development program to explore

the use of RT-activated NBTXR3 as a complement to immune checkpoint inhibitors across several solid

tumor indications. In preclinical and clinical studies, RT-activated NBTXR3 followed by immune

checkpoint inhibitors demonstrated potential to convert checkpoint inhibitor non-responders into

responders, provide better local and systemic control and increase survival. Nanobiotix is conducting

Study 1100, a Phase 1 multi-cohort trial of RT-activated NBTXR3 followed by anti-PD-1 checkpoint

inhibitors in patients with LRR or R/M HNSCC or with soft tissue, lung or liver metastases from any

primary cancer eligible for anti-PD-1 therapy. Nanobiotix believes that preliminary clinical results suggest

that NBTXR3 could benefit this patient population with the potential to increase the proportion of patients

that respond to immune checkpoint inhibitors, and discussions have been initiated with regulatory

authorities regarding the potential registration pathway for this immunotherapy combination for patients

with R/M HNSCC that is resistant to prior immunotherapy. See “Our Clinical Programs—I-O Program— R/

M HNSCC and lung, liver or soft tissue metastases from any primary tumor— Multi-Cohort Phase 1 Trial

(“Study 1100”)” below for information regarding Study 1100.

•Expand the opportunity for NBTXR3 by replicating our head and neck cancer development

program in additional solid tumor indications. Nanobiotix believes that NBTXR3’s physical mode of

action could make it broadly applicable across a multitude of solid tumor indications. In addition to head

and neck cancers, Nanobiotix intends to continue to develop and pursue NBTXR3 for other indications,

and has already gathered data from clinical trials in liver cancers in the EU, prostate cancer in the United

States, and rectal cancer in Taiwan. In December 2018 Nanobiotix entered into a collaboration with MD

Anderson as part of which Nanobiotix is currently conducting four clinical trials in the United States to

evaluate RT-activated NBTXR3, either alone or in further combination with immuno-therapies or

chemotherapies, across several cancer types. If Nanobiotix is able to demonstrate the applicability of

NBTXR3 to solid tumor cancers in its current and planned clinical trials, Nanobiotix believes it would be

able to increase the addressable patient population of NBTXR3 to encompass a significant portion of the

patients who receive radiotherapy as part of their solid tumor cancer treatment.

•Build an effective clinical development program and establish a global commercial infrastructure

for NBTXR3. Nanobiotix has conducted clinical trials involving multiple therapeutic areas throughout the

United States and the EU. In addition, Nanobiotix’s global medical science liaison team has consulted

closely with a number of physicians, hospitals, clinics, and cancer treatment centers in the United States

and key European markets to better understand their needs as clinicians and institutions and to tailor

NBTXR3 accordingly. Nanobiotix plans to focus our commercialization and marketing efforts for NBTXR3

in Europe and the United States, subject to the grant of any marketing authorization by, among others,

health regulatory agencies. Nanobiotix has entered into an agreement with LianBio for the development

and potential commercialization of NBTXR3 in key countries in Asia. Nanobiotix retains development and

commercialization rights to NBTXR3 in all other geographies, and may develop and commercialize

NBTXR3 in other specific regions, independently or through collaboration agreements.

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1.3.2.Current cancer treatment options and limitations

In general, there are four major cancer treatment modalities: surgery, radiotherapy, chemotherapy and targeted

therapies (in which drugs target specific molecules of the tumor tissue). These treatments may be used individually

or in combination with one another.

Surgery remains the primary method for the eradication of solid cancers that are discovered at an early stage.

Surgery aims to remove not only the tumor, but also a ring of surrounding healthy tissues (referred to as the surgical

margin), to try to ensure that all cancer cells are removed. Surgery may not be a viable option based on a patient’s

health or the characteristics of the patient’s cancer. For example, when a patient’s cancer has spread, or

metastasized, surgery alone may not be adequate to remove the cancer. When surgery is an option, it is often

combined with radiotherapy or chemotherapy either before the surgery, in an effort to try to reduce the size of the

tumor so that it is easier to remove with clean margins, or after the surgery, in an effort to eliminate residual cancer

cells.

Radiotherapy is the administration of ionizing radiation, which are high-energy particles or rays such as X-rays,

gamma rays, electron beams or protons, to destroy or damage cancer cells by blocking their ability to grow, divide

and multiply. Radiotherapy is delivered over a period of several days to several weeks at a specific dose. Typically,

patients receive a fraction of the dose per day. The duration and dosage of radiotherapy are based on the standard

of care specific to the cancer indication.

Radiotherapy is typically measured in gray (‘‘Gy’’), a unit of ionizing radiation dose with one Gy representing the

absorption of one joule of energy per kilogram. In developed countries with access to radiotherapy, approximately

60%4 of all cancer patients will receive radiotherapy at least once, either alone or as a part of the more complex

treatment protocol.

The primary growth drivers for the radiotherapy market globally are technological advancements and the associated

growing adoption of radiotherapy devices and procedures. Improving the accuracy and precision of the delivery of

radiation enhances the efficacy of radiotherapy and reduces the side effects and damage to surrounding healthy

tissues, which has led to greater adoption of these techniques by the medical community and more widespread use

among cancer patients. Because high-dose radiotherapy can be delivered in a more precise way, it can be used to

target tumors that were previously inaccessible, such as brain tumors, thereby opening the radiotherapy market to

additional patient populations. In addition, new technologies that require lower doses of radiation to destroy cancer

cells can now be used in patients who may previously have been considered too fragile for higher-dose radiation.

Despite these technological advancements and the increasing use of radiotherapy in treating cancer, there remain

significant limitations to its use. Although radiotherapy is a local approach, it often causes damage to surrounding

healthy tissues, and may not be an effective treatment for cancers that have spread, or metastasized. As a result,

physicians may decide to withhold radiotherapy, because a high enough dose to kill the tumor cells would create

unacceptable damage to surrounding healthy tissues and cause other toxic side effects.

In addition, the I-O treatment approach has emerged as an option for cancer treatment. The I-O treatment approach

is a relatively new approach to fighting cancer that does not only directly target the tumor, but also aims to stimulate

and activate the patient’s own immune system, allowing it to recognize cancer cells and destroy them. I-O treatments

have demonstrated efficacy broadly in the treatment of many types of cancer, including among others leukemia,

melanoma, lung cancer, prostate cancer, skin cancer, cancer of the digestive system, gynecological cancers and

renal cancer. However, not all patients may benefit from I-O therapy. I-O therapy may be ineffective when a patient’s

tumor is “cold”, meaning that the cancer either has not been recognized or has not provoked a strong enough

response by the patient’s immune system. The challenge remains to find new ways to turn a cold tumor into a hot

tumor—one that will be responsive to I-O treatment approaches.

1.3.3.NBTXR3: Addressing the challenges of radiotherapy and immuno-oncology

We have designed NBTXR3 to address limitations inherent in radiotherapy, either alone or in combination with other

treatment approaches:

•By amplifying the intratumor killing effect of the radiation dose within cancer cells, NBTXR3 is designed to

give a radiation treatment dose greater efficacy.

•By intensifying the localized radiation dose within the tumor, NBTXR3 is designed to enhance the efficacy

of radiotherapy without resulting in additional toxicities on the surrounding healthy tissues.

With respect to I-O treatment approaches to fighting cancer, our preclinical and early clinical results suggest that

NBTXR3 plus radiotherapy may prime the immune response, thereby rendering otherwise cold tumors more prone to

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4 Morris ZS, Harari PM. Interaction of radiation therapy with molecular targeted agents. J Clin Oncol. 2014 Sep 10;32(26):2886-93. doi: 10.1200/JCO.2014.55.1366. Epub

2014 Aug 11. PMID: 25113770; PMCID: PMC4152717.

INTERNATIONAL ATOMIC ENERGY AGENCY, Radiotherapy in Cancer Care: Facing the Global Challenge, Non-serial Publications , IAEA, Vienna (2017)

recognition by the patient’s immune system and therefore potentially more responsive to I-O treatments such as

checkpoint inhibitors.

1.3.4.Our NBTXR3 technology

We are exploring the potential for nanotechnologies to provide solutions to unmet therapeutic needs in oncology. Our

pioneering approach uses nanophysics to bring a physical mode of action to destroy cancer cells from within. When

used in conjunction with radiotherapy, our NBTXR3 nanoparticles increase the absorption of the administered

radiation, thereby magnifying and focusing the dose locally within a malignant tumor, but without causing incremental

damage to surrounding healthy tissues. In magnifying the effect of the radiation, we believe our NBTXR3 technology

improves the benefit-risk ratio of radiotherapy for patients.

The amount of energy that can be deposited in a cell through radiotherapy is a function of the cell’s ability to absorb

the radiation, which depends on the amount and form of energy used and the electron density of the receiving

molecules. A cell is primarily composed of water, which has a very low electron density. At an average size of

approximately 50 nanometers in diameter, our nanoparticles are directly injected into a malignant tumor prior to

standard radiotherapy and can be internalized into the cell through endocytosis to function as radioenhancers. The

inert nanoparticles have an inorganic core of crystallized hafnium oxide, which has a high electron density. When

exposed to radiation, the high electron density of the nanoparticles allows the cancer cells to absorb more energy

than would otherwise be absorbed by the water molecules in the tumor. The high electron density of the

nanoparticles is essential for their effective interaction with radiation, while their physical and chemical properties do

not cause incremental damage to surrounding healthy tissues.

The following image is a transmission electron micrograph of a cross-section slice of a tumor with nanoparticles after

injection.

Clustered 50 nm Nanoparticles in cytoplasm

NBTXR3 is a novel approach to the local treatment of cancer that we believe provides a solution to the basic

limitation of radiotherapy - an inability to deliver sufficient amounts of radiation to eradicate the tumor because of the

low radiation tolerance of the surrounding healthy tissues.

The following illustration shows a representative increase in the radiation dose absorbed around the NBTXR3

nanoparticles administered into cancer cells.

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NBTXR3 Nanoparticles Amplifying the Effect of Radiation

Mechanism of Action of NBTXR3 nanoparticles

During radiotherapy, the interaction between the radiation and the targeted cell molecules ionizes atoms, freeing

electrons from the orbit of the atoms. These electrons dissipate their energy in multiple interactions with surrounding

molecules, producing free radicals, which are highly reactive ionized molecules in the cell. These free radicals are

primarily responsible for the effectiveness of radiotherapy in causing DNA damage, ultimately leading to cell death.

The MoA of NBTXR3 nanoparticles can be described in four stages:

Stage 1: Activity/Inactivity Principle

Our nanoparticles are inert, meaning that they produce no effect without ionizing radiation. When activated by

radiation, a number of phenomena occur. First, the radiation is absorbed by the hafnium oxide core of the

nanoparticles. Because the core of the nanoparticle has a significantly higher electron density than water, it can

absorb significantly more energy than a tumor cell could without the cluster of nanoparticles. Greater energy

absorption generates more electrons, and ultimately more free radicals.

Stage 2: Cell Damage

The electrons generated in the energy absorption disperse through the cancer cells and dissipate their energy in

multiple interactions with surrounding molecules, creating free radicals. The free radicals are highly reactive and tend

to destroy the covalent links of the molecules they interact with, such as DNA, RNA and proteins. Specifically, they

cause severe and irreparable DNA damage mainly responsible for the lethal effect of ionizing radiation on cells. The

free radicals therefore increase the localized cancer cell destruction.

Stage 3: Subsequent Action in the Cells

The destructive effect of free radicals is amplified and localized by the radiation-activated nanoparticles, which

generate a controlled concentration of energy within the tumor. Ionizing radiation can be applied to the nanoparticles

repeatedly because they return to their inactive, inert state after each exposure to radiation. Multiple courses of

radiotherapy can be administered to a tumor that has received a single injection of our nanoparticles.

Stage 4: Immune Activation

In our preclinical studies and our early clinical data, the treatment using radiation-activated nanoparticles has also

been observed to trigger destruction of metastatic cells due to the activation of the immune system. Based on these

observations we believe that our nanoparticles may prime the body’s immune response, rendering tumors more

prone to recognition by a patient’s immune system. In the illustration below, clusters of NBTXR3 nanoparticles are

injected into the cell and, when activated by radiotherapy, cause destruction of cancer cells due to the high energy

absorption. This destruction may include structural damage, DNA damage, stress to the cells, immunogenic cell

death (a specific form of cell death related to the immune system) and cGAS-STING pathway activation (an immune

sensing mechanism). This results in both direct cell death and activation of dendritic cells. Once activated, the

dendritic cells trigger lymphocyte activation (including cytotoxic T cells). This activation of lymphocytes has the effect

of “priming” the immune system to be able to better recognize and kill cancer cells.

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1.3.5.Overview of NBTXR3

NBTXR3, a sterile aqueous suspension of crystalline hafnium oxide nanoparticles, is administered through a one-

time image-guided local injection directly into the tumor prior to radiotherapy. In our clinical trials, the dosage of

injected NBTXR3 is based on a percentage of the baseline tumor volume and is determined during the initial phase

of the respective clinical trial for different indications. NBTXR3 nanoparticles have a negative-charge surface coating,

which allows them to interact with the surface of the tumor and accumulate inside the tumor cells. NBTXR3 is

designed to render the targeted tumor more operable or help destroy it completely.

NBTXR3 can easily be incorporated into the current standard of care in radiotherapy. Hospitals and medical facilities

where radiotherapy is delivered do not need any new equipment or to otherwise make significant capital investments

in new technology in order to treat patients with NBTXR3.

We are currently prioritizing the development of NBTXR3 in the United States and the EU for the treatment of head

and neck cancers, although we are also studying, or have studied, NBTXR3 across a broad range of indications,

including locally advanced soft tissue sarcoma, primary and secondary liver cancers, prostate cancer, pancreatic

cancer, esophageal cancer and non-small cell lung cancer. We believe NBTXR3 has the potential to treat all solid

tumors where radiotherapy can be used. We have also observed that NBTXR3 activated by radiotherapy could

modulate the antitumor immune response, supporting the rationale for its use as an in situ cancer vaccine,

potentially in combination with I-O treatments. With respect to our I-O development program, the initial cancer

indications for NBTXR3 in combination with immuno-oncology therapies - and, in particular, checkpoint inhibitor

combinations - are head and neck cancers (including R/M HNSCC).

1.3.6.Our clinical programs

NBTXR3 has been, and is currently being evaluated in several clinical trials worldwide in various cancer patient

populations, with a current focus on the treatment of head and neck cancers.

In December 2018, we entered into a large-scale comprehensive NBTXR3 clinical collaboration with MD Anderson.

The collaboration is expected to support multiple clinical trials with NBTXR3 for use in treating several cancer types

—including head and neck, pancreatic, lung, esophageal cancers—and is expected to involve approximately 312

patients. The first clinical trial under our collaboration with MD Anderson in patients with locally advanced or

borderline resectable pancreatic cancer was initiated in September 2020. Three additional trials were initiated in

2021, including trials in patients with: esophageal cancer; non-small cell lung cancer amenable to re-irradiation; and

R/M HNSCC (I-O program). Each of these four clinical trials is open and enrolling patients, although two of the trials

have experienced slower recruitment and enrollment than planned as a result of the COVID-19 pandemic. See “M.D.

Anderson Cancer Center of the University of Texas” for further detail regarding the terms of the collaboration.

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In May 2021, we entered into an exclusive license and collaboration agreement with LianBio for the development

and commercialization of NBTXR3 in key parts of Asia—Mainland China, Macau, Hong Kong, Thailand, Taiwan,

South Korea and Singapore. LianBio has committed to enrolling patients in the Territory in NANORAY-312 as well as

four additional registrational studies that we intend to conduct across indications and therapeutic combinations.

In August 2012, we entered into an exclusive license and collaboration agreement with PharmaEngine for the

development and commercialization of NBTXR3 in the Asia Pacific region. In March 2021, we and PharmaEngine

mutually agreed to terminate the agreement. Three NBTXR3 clinical trials conducted by PharmaEngine in Asia were

reported at the Annual Meeting of the American Society of Clinical Oncology in June 2022. See “Our Clinical

Programs—PharmaEngine Trials” for additional details.

Refer to the paragraph titled “NBTXR3 Development Pipeline” above for our ongoing and planned clinical trials,

including those being undertaken and contemplated by MD Anderson, our principal collaboration partner.

1.3.6.1.Locally advanced soft tissue sarcoma

Background and opportunity

Soft tissue sarcomas (STS) are rare cancers that develop in different types of soft tissues, including muscles, joint

structures, fat, nerves and blood vessels. Although STS can develop at any anatomic site, it occurs in the extremities

(arms and legs) in approximately 60% of cases. The American Cancer Society estimates that in 2023 in the United

States, approximately 13,400 patients will be diagnosed with STS, and approximately 5,140 STS patients died from

this cancer. In the EU, over 23,000 patients are diagnosed with STS each year. The National Cancer Institute

estimates that the five-year survival rate for STS patients is approximately 65%. Median overall survival for patients

with advanced, metastatic STS is estimated to be 18–19 months. Radiotherapy followed by surgery is part of the

typical treatment regimen for patients with non-metastatic advanced, resectable STS of the extremities in Europe.

Achieving local control of the tumor is critical to improving survival rates and reducing the need for limb amputations.

Patients with locally advanced STS are high-risk patients and have few therapeutic options capable of achieving

local control. Consequently, innovative treatments to improve cancer cell destruction and the feasibility of surgical

resection are needed. RT-activated NBTXR3 is designed to enhance the efficacy of radiation both by destroying

more tumor cells and rendering the tumor more susceptible to surgical resection, thereby improving patient

outcomes.

Clinical Development

Following the positive results of our Phase 1 trial , we commenced a Phase 2/3 trial for EU registration (Study 301),

which we also refer to as the Act.In.Sarc trial, to measure the anti-tumor activity of preoperative NBTXR3 activated

by radiotherapy, as compared to radiotherapy alone, in patients with locally advanced STS. The Act.In.Sarc trial was

conducted at more than 30 sites worldwide, including 23 sites in Europe and seven sites in the Asia-Pacific region.

The primary endpoint of the Phase 2/3 trial was an increase in the pathological complete response rate of

intratumoral injection of NBTXR3 activated by external beam radiation therapy (EBRT), as compared against EBRT

alone. The secondary endpoints were to evaluate the safety profile of RT-activated NBTXR3 and compare the rate of

tumor surgery with R0 margins (meaning no remaining cancer cells could be seen microscopically within a widely

accepted margin after resection), the percentage of tumor necrosis/infarction, limb amputation rates and tumor

response as measured by RECIST 1.1.

The trial achieved its primary endpoint, with 16.1% of patients in the NBTXR3 arm having a pathological complete

response (defined as less than 5% of residual viable cancer cells in the tumor) compared to 7.9% of patients in the

control arm. The difference was statistically significant, with a p-value of 0.0448. A p-value, or probability value, cited

in figures in the Universal Registration Document as “p”, is the likelihood of finding the observed, or more extreme,

outcome (e.g., a significant difference in terms of response for patients receiving NBTXR3 plus radiotherapy relative

to patients receiving radiotherapy alone) when a baseline outcome is assumed to be true (e.g., patients receiving

NBTXR3 plus radiotherapy and patients receiving radiotherapy alone both having an equal response). A p-value of

less than or equal to 0.05 is generally considered to demonstrate statistical significance, meaning that one would

accept the observed outcome as reasonable evidence to not accept the baseline outcome.

In addition, in the subgroup of patients with a higher histology grade (i.e., a more aggressive disease), which

represented the majority of patients in the trial, pathological complete response was achieved in four times as many

patients in the NBTXR3 arm (17.1%) compared to patients in the control arm (3.9%).

Patients in the NBTXR3 arm were more likely to have a pathological response (not limited to a complete response).

The proportion of patients with pathological “nearly” complete response (defined as less than 7% of residual viable

cancer cells in the tumor) and pathological response with 10% or less of residual viable cancer cells were 24.7% and

34.6%, respectively, in patients in the NBTXR3 arm as compared to 14.8% and 19.8%, respectively, in patients in the

control arm.

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The main secondary endpoint of the trial, the rate of tumor surgery with R0 margins, was also met. R0 resection

margin was observed in 77% of the patients in the NBTXR3 arm, compared to 64% of patients in the control arm.

This difference was statistically significant, with a p-value of 0.0424.

Similar safety profiles were observed in the NBTXR3 arm and the control arm, including the rate of postsurgical

wound complications. NBTXR3 did not impair the patients’ ability to receive the planned dose of radiotherapy. In the

NBTXR3 arm, 7.9% of patients experienced grade 3-4 acute immune reactions, which were manageable and of

short duration. Further, NBTXR3 showed a good local tolerance in patients and did not have any impact on the

severity or incidence of radiotherapy-related AEs.

Nanobiotix timely generated long-term follow up data for patients enrolled in the Act.In.Sarc Study, which reinforced

the favorable benefit-risk ratio of Hensify® plus RT in patients suffering from locally advanced STS of the extremity or

trunk wall. This long-term evaluation showed that NBTXR3 did not negatively affect safety or health related quality of

life (HRQoL). During the follow-up period, post-treatment SAEs (regardless of relationship) occurred in 13.5% of the

patients in the NBTXR3 arm, compared to 24.4% of patients in the control arm. During the follow-up period, there

was an improvement in scores across several instruments used for measuring health-related quality of life.

Commercialization

Based on these trial results, in April 2019, we completed the regulatory process for the CE mark of NBTXR3, thereby

allowing the product to be commercialized for the treatment of locally advanced STS of the extremities and trunk wall

under the brand name Hensify® in the 27 EU countries.

As the Company has no current plans to market or sell the product in the EU until after approval of NBTXR3 in a

second indication, the CE mark for the STS indication has no impact on expected cash inflow prior to approval in a

second indication. The Company has informed the GMED, the French Notified Body for the conformity assessment

of medical devices, of its revised development plans and its intention to seek revision of its post marketing

surveillance plan to be inclusive of the intended patient populations at the time of planned commercialization.

1.3.6.2.Locally advanced head and neck cancers

Background and opportunity

Squamous cell carcinoma of the head and neck cancers constitute more than 95% of head and neck cancers and

include cancers of the oral cavity, tongue and oropharynx, a part of the throat, larynx and hypopharynx. These

structures play a critical role in a human’s ability to swallow, eat, breathe and speak. The American Cancer Society

estimates that in 2022 in the United States, approximately 54,000 patients were diagnosed with oral or

oropharyngeal cancer and approximately 11,230 patients died from the cancer. The five-year survival rate for

patients with oral and oropharyngeal cancer is estimated at 68%. In 2020, according to estimates by the Global

Cancer Observatory, part of the World Health Organization’s International Agency for Research on Cancer, around

931,000 new patients were diagnosed globally with head and neck cancer. These cancers represent a major public

health concern.

Cisplatin-based chemotherapy in combination with concomitant definitive radiation is the standard treatment for

locally advanced head and neck cancers in both the United States and the EU which cannot be resected or for

patients who refuse surgery. However, it is often not an option for elderly or frail patients who are unable to endure

the physical strain inherent in chemoradiation treatment. The alternative treatment to chemoradiation is cetuximab in

combination with radiotherapy, but its efficacy is less well established in elderly patients. These patients are

estimated to account for approximately 25% of patients with head and neck cancers. In data presented at the

Multidisciplinary Head and Neck Cancers Symposium 2020, elderly patients treated with radiotherapy alone or

radiotherapy in combination with cetuximab had a median PFS of 7.3 months. Elderly patients with locally advanced

tumors who receive radiation only also generally have limited OS expectancy (median of 12 months following

diagnosis, based on our review and sub-group analysis of scientific literature relating to head and neck cancers) and

typically experience poor quality of life, as they have limited therapeutic options and a high unmet medical need and

are largely underrepresented in existing clinical trials.

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The following table summarizes data from certain published scientific literature relating to head and neck clinical

trials evaluating radiotherapy combined with the identified chemotherapies:


Patient Population / %		Best Observed Response (Overall Response)	Best Observed Response (Complete Response)	Best Observed Response (Partial Response)	Best Observed Response (Stable Disease)	Best Observed Response (Progressive Disease)
Patients receiving radiotherapy alone Bonner et al. 2006		64%	Not available	Not available	Not available	Not available
Median age (years)	58
KPS (Performance Score)
90-100	66
60-80	33
Unknown	1
Tumor Stage
T1-T3	72
T4	28
Patients receiving radiotherapy and cetuximab Bonner et al. 2006		74%	Not available	Not available	Not available	Not available
Median age (years)	56
KPS (Performance Score)
90-100	70
60-80	30
Unknown	1
Tumor Stage
T1-T3	70
T4	29
TX	<1
HPV negative patients with oropharyngeal HNSCC receiving radiotherapy and cisplatin Harrington et al. 2013 (evaluable patients)		58%	31%	27%	0%	42%
Median age (years)	57
ECOG (%)
0 (KPS 100)	52
1 (KPS 80-90)	48
2 (KPS 60-70)	0
Stage (%)
III	21
IVA/B	79
Primary tumor site (%)
Oral cavity	9
Oropharynx	61
Hypopharynx	21
Larynx	9
HPV status OPSCC (%)
HPV+	13
HPV-	87

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Patient Population / %		Best Observed Response (Overall Response)	Best Observed Response (Complete Response)	Best Observed Response (Partial Response)	Best Observed Response (Stable Disease)	Best Observed Response (Progressive Disease)
HPV positive patients with oropharyngeal HNSCC who received induction chemotherapy, radiotherapy and cetuximab Marur et al. 2017 (evaluable patients)		95%	49%	46%	1%	0%
Median age (years)	57
ECOG
0 (KPS 100)	91
1 (KPS 80-90)	9
0 (KPS 60-70)	—
Stage (%)
III	15
IVA/B	85
Primary tumor site ( %)
Oral cavity	—
Oropharynx	100
HPV status OPSCC (%)
HPV+	100
HPV-	—

Abbreviations: HPV (human papillomavirus); OPSCC (oropharyngeal squamous cell carcinoma); ECOG (a standardized measure–ranging from 5 to

0–of a patient’s level of functioning in terms of his/her ability to care for him/herself, carry out daily activity and engage in physical ability; a lower score

means the patient is better able to function); KPS (a standardized measure–ranging from 0 to 100–of a patient's level of functioning in terms of his/her

ability to care for himself/herself, carry out daily activity and engage in physical ability; a higher score means the patient is better able to function).

This historical literature is presented solely to illustrate the current market opportunity arising from existing application of the standard treatment—

chemotherapies in combination with concomitant radiation—for patients with locally advanced head and neck cancers. Because of the unique design

of such studies applied to specific patient populations, no comparison with any of our clinical trials is possible and none should be inferred from this

background data.

Phase 3 Registration Trial (“NANORAY-312”)

NANORAY-312 is a global Phase 3 clinical trial in elderly patients with locally-advanced head and neck cancer who

are ineligible for platinum-based (cisplatin) chemotherapy. As of the date of this report, patients in the NANORAY-312

study have been randomized in all planned major regions, with the first patient randomized in Europe in January

2022, the first patient randomized in Asia in August 2022, and the first patient randomized in the United States in

December 2022.

The clinical trial is a randomized (1:1), controlled, two-arm global registration trial including elderly head and neck

cancer patients who are ineligible for platinum-based chemotherapy. Patients in the control arm (arm B) will receive

definitive radiation therapy versus patients in the arm A will receive RT-activated NBTXR3. In both arms cetuximab

addition would be allowed as per investigator’s choice. The trial is expected to be conducted at more than 150 sites

worldwide and approximately 500 patients will be randomized.

The primary endpoint of the study is progression free survival (PFS) and the key secondary endpoint is overall

survival (OS). The study is designed to demonstrate a superiority of RT-activated NBTXR3 over control on PFS with

a statistical power of 89% and on OS with a statistical power of 80% (hazard ratio of 0.692 and 0.75 for PFS and

OS, respectively). The Hazard Ratio is a measure of the risk of a particular event occurrence in one group compared

to another group, over time. A median PFS of 9 months and median OS of 12 months is expected in the control arm

and an interim analysis aiming to demonstrate superiority of NBTXR3-containing arm over control on PFS and on

OS is planned. In addition, time to loco-regional and distant progression, head and neck cancer specific survival

outcomes, overall response rate, safety and quality of life will be evaluated as secondary endpoints.

A futility analysis is planned after approximately 25% of PFS events (i.e., disease progression or death), a pre-

specified interim efficacy analysis is planned after approximately 67% of planned PFS events, and the final analysis

after 424 PFS and 389 OS events. In the event of clinically meaningful PFS improvement (≥ 6 months PFS

difference) in the planned interim analysis with no detrimental OS effect having been observed, the Company plans

to submit a request to FDA for Accelerated Approval of NBTXR3 in the United States for this indication.

NANORAY-312 will utilize four stratification factors: (i) Investigator’s choice (cetuximab addition or not), (ii) HPV

status (HPV-positive oropharynx versus other), (iii) age-adjusted Charlson Comorbidity Index, or mCCI score at

screening (2 to 3 versus ≥ 4) and (iv) region (North America & Western Europe versus Rest of World).

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The Charlson Comorbidity Index (CCI) measures the burden of disease and predicts mortality in various diseases.

The CCI encompasses 19 medical conditions, each weighted according to its impact on mortality. The mCCI further

integrates the patient’s age as an additional scoring information to the CCI.

In February 2020, we received Fast Track designation from the FDA for NBTXR3 for the treatment of locally

advanced head and neck cancers that are not eligible for platinum-based chemotherapy. Fast Track designation is a

process designed to facilitate the development and accelerate the review of treatments for serious conditions and

that have the potential to address unmet medical needs.

Phase 1 (“Study 102 Escalation”) and Phase 1 Expansion (“Study 102 Expansion”) Trial

We are conducting a Phase 1 clinical trial of NBTXR3 activated by intensity-modulated radiation therapy in patients

with locally advanced squamous cell carcinoma of the oral cavity or oropharynx who are ineligible for cisplatin (the

frontline chemotherapy drug for advanced head and neck cancers) or intolerant to cetuximab (a monoclonal antibody

used as part of targeted cancer therapy in head and neck cancers).

The primary endpoint of Study 102 Escalation was to evaluate the safety of NBTXR3 and determine the

recommended Phase 2 dose of RT-activated NBTXR3. The primary endpoints of the Study 102 Expansion are to

confirm that the recommended dose is safe and to obtain preliminary evidence of efficacy by observing the objective

response rate and complete response rate of the NBTXR3-injected lesion by imaging according to RECIST 1.1.

The secondary endpoints of both phases were to evaluate the safety and tolerability of NBTXR3, to evaluate the

overall response rate and the complete response rate (based on the RECIST 1.1) of injected (target) and non-

injected lesions (non-target), to evaluate the local progression and PFS, assess the feasibility of local administration

by intratumoral injection of NBTXR3, and characterize the body kinetics of NBTXR3 administered by intratumoral

injection. Overall Survival was also planned to be analyzed.

Phase 1 Escalation

In Study 102 Escalation, the administered dosage was escalated, with 19 patients receiving an injection of NBTXR3,

followed by intensity-modulated radiation therapy (70 Gy in total, or 2 Gy per day, five days a week for seven weeks),

in accordance with standard medical practice, commencing one to five days after NBTXR3 injection. We initially

presented preliminary efficacy and safety results from Study 102 Escalation in February 2020 at the Multidisciplinary

Head and Neck Cancers Symposium. NBTXR3 was well tolerated in the trial and the recommended dose was

established as equivalent to 22% of tumor volume. Preliminary results included no observed serious side effects or

serious adverse events related to NBTXR3 observed, and feasibility of injection at all dose levels (5%, 10%, 15%

and 22%) with no leakage to surrounding healthy tissues.

The following graphic depicts shrinkage of the tumor in a representative patient in the trial over time following

treatment. The tumor continued to shrink after the end of treatment, with the patient achieving a complete response

at seven months.

As of April 2020, nine out of the 16, or 56%, evaluable patients who received the intended dose of NBTXR3 and

radiotherapy had achieved a complete response of the injected lesion, according to the RECIST 1.1., as assessed

by the investigator. Overall complete response (including non-injected lesions) was observed in five of the 16

patients, or 31%, and objective response rate was observed, as per Investigator’s assessment, in 11 of the 16

patients, or 68%. Of the seven patients who received the two highest doses of NBTXR3 plus radiotherapy and were

alive at the 12-month cut-off date, five patients were still alive at 24 months following treatment. Of the 13 evaluable

patients receiving the highest dose levels (therapeutic doses 10%, 15%, and 22%), nine patients, or 69%, achieved

a complete response of the injected lesion. Follow up of treated patients remains ongoing. We are encouraged by

the preliminary results, and we believe NBTXR3 has the potential to extend survival and improve quality of life in this

advanced cancer patient population. The following chart shows follow-up data of the 19 treated patients at the

various NBTXR3 dose levels as of the end of April 2020, including the type of cancer, tumor grade, age and human

papilloma virus status for each patient.

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Patient Follow-up in Study 102 Escalation Locally Advanced Head and Neck Cancers Trial

The following chart shows the best observed response by investigator’s assessment from baseline of each of the 16

evaluable patients as of April 30, 2020.

Patients’ Investigator’s assessed Best Response in Study 102 Escalation Locally Advanced Head and Neck

Phase 1 Expansion

As of January 2023, 56 patients were treated in the expansion cohort of which 44 were confirmed to be evaluable.

Therefore, patient accrual was completed and recruitment was closed.

The most recent updated efficacy and safety results from the ongoing Study 102 Expansion were presented at the

Annual Meeting of ASTRO in October 2021.

As of the September 3, 2021, cut-off date, 54 patients had received NBTXR3 and 41 patients were evaluable for

objective tumor response.

The expansion cohort utilizes the highest dose level (22%) from Study 102 Escalation in order to potentially

strengthen preliminary efficacy data from that initial escalation phase. Evaluability in Study 102 Expansion was

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determined based on the patient receiving at least 80% of the intended intratumoral dose of NBTXR3, at least 60 Gy

of radiotherapy, and the required imaging to assess the target lesion at baseline and at least once post treatment.

In the evaluable patient population, investigator-assessed response rates remained consistent with previously

reported results from the dose escalation and dose expansion study, showing the primary tumor objective response

rate according to RECIST 1.1, as per investigator assessment, was 85.4% (35 out of 41 patients), consisting of 26

patients with primary tumor complete response (63.4%) and 9 patients with primary tumor partial response (22.0%).

The other six patients were considered to have primary tumor stable disease. One patient, identified in the chart

below as having stable disease (as noted with a double asterisk), was recorded by the principal investigator on the

electronic case report form (eCRF) as having achieved an unconfirmed complete response of the injected lesion,

and we have included this patient in the 63.4% primary tumor complete response rate and the 85.4% primary tumor

objective response rate.

Among evaluable patients with oropharyngeal head and neck cancer with negative HPV status, objective response

rate of the target lesion was 100% (12 out of 12 patients), consisting of eight patients with complete response

(66.7%) and four patients with partial response (33.3%). In the subgroup composed of oropharyngeal head and neck

cancer patients with positive HPV status, objective response rate, as per investigator’s assessment, of the target

lesion was 100% (10 out of 10 patients) consisting of nine patients with complete response (90%) and one patient

with partial response.

Median follow up as of September 3, 2021 was 9.5 months since administration of NBTXR3.

In the evaluable population,the median overall survival was 18.1 months, and the median progression free survival

was 10.6 months. Among the 21 patients with best observed overall response of complete response, only one died

from disease progression while six patients died for non-oncologic reasons. The median overall survival was not

reached at the cut-off date (mean follow up of 16.1 months).

Based on an assessment under the mCCI, the patient population in the Study 102 Expansion is at higher risk of

early death than the global elderly head and neck cancer population.

In head and neck cancer, an mCCI ≥ 4 is correlated with higher risk of death relative to the broader population.

In the Study 102 Expansion “all patients treated” population (54 patients, including 13 non-evaluable patients), mOS

was 14.1 months, and median PFS was 9.4 months. Among the “all patients treated” population, 63% of all patients

included in the survival analysis, had an mCCI of four or more — an mCCI score associated with a risk of early death

(defined as death within 180 days after initiation of treatment), which is two to three times the prevalence of high

mCCI in the overall LA-HNSCC population that has been reported in the literature (Zumsteg ZS, et al. Cancer 2017;

123: 1345-53). Of the 13 non-evaluable patients, 69% had an mCCI of four or more. Of these 13 non-evaluable

patients, two were still pending evaluability assessment and of the 11 remaining, seven had early occurring death

(within 180 days after initiation of treatment). In contrast, in 41 evaluable patients, the mOS that was reached was

18.1 months as of the September 3, 2021 cut-off, suggesting the observed mOS in all treated patients could be

related to the high number of non-evaluable patients and a higher mCCI score observed in this subgroup which may

reflect a higher risk for early death as compared to lower mCCI scores.

Final results could differ from what has been reported at ASTRO’s Annual Meeting in October 2021.

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The following chart shows the best observed target lesion response from baseline of each of the 41 evaluable

patients as of September 3, 2021.

Patients’ Best Observed Target Lesion Response by RECIST 1.1 as per Investigator Assessment in Study

102 Expansion Locally Advanced Head and Neck Cancers Trial (Evaluable Population: N=41)

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The following charts show the survival of the 41 evaluable patients and the 54 patients in the “all patients treated”

population as of September 3, 2021.

Kaplan Meier Curve of Survival in Study 102 Expansion Locally Advanced Head and Neck Cancers Trial as

of September 3, 2021 cut-off date

Kaplan Meier Curve of Progression Free Survival in Study 102 Expansion Locally Advanced Head and Neck

Cancers Trial as of September 3, 2021 cut-off date

A subsequent review of data from Expansion Study 102 shows, as of February 22, 2022, an on-going median overall

survival (mOS) of 17.9 months in the all treated population (n=56) and 23.0 months in evaluable patients (n=44)

demonstrating continued improvement relative to the analysis presented at ASTRO 21 and consistent with data

reported from the dose escalation phase of Study 102.

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Kaplan Meier Curve of Survival in Study 102 Expansion Locally Advanced Head and Neck Cancers Trial as

of February 22, 2022 cut-off date

NBTXR3 has continued to be well tolerated in Study 102 Expansion. Five SAEs related to NBTXR3 were observed

across 5 patients: one Grade 4 tumor hemorrhage (also related to radiotherapy), one Grade 3 stomatitis (also related

to radiotherapy), one Grade 3 soft tissue necrosis (also related to radiotherapy), one Grade 4 dysphagia (also

related to radiotherapy) and one Grade 4 sepsis (also related to radiotherapy and disease). Of the SAEs, one death

from sepsis occurred, which the investigator assessed as possibly related to NBTXR3, radiotherapy, and cancer.

The AEs and SAEs as of September 3, 2021, are set forth in the graph below.

Percentage of all SAEs in Study 102 as of September 3, 2021

1.3.6.3.Immuno-Oncology (“I-O”) Program Trials

Background and opportunity

In recent years, significant attention has been focused on the potential of I-O treatments to treat cancer patients, and

in particular, with the approval of first checkpoint inhibitors anti-CTLA4 (ipilimumab) and anti-PD(L)1 (such as

pembrolizumab, nivolumab, durvalumab, or atezolizumab). Checkpoint inhibitors are a type of immunotherapy that

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function to block proteins that stop the immune system from attacking cancer cells. In doing so, they enable the T

cells to recognize cancer cells that would otherwise be hidden from the immune system. However, many cancers,

which are often referred to as “cold” tumors, exhibit little or no response to checkpoint inhibition.

Cancer immunotherapy is becoming a major treatment paradigm for a variety of cancers. Although immunotherapy,

especially the use of immune checkpoint inhibitors, has achieved clinical success, most cancer patients present

resistance to I-O treatments. In fact, published scientific data shows that only 15%-20% of non-small cell lung cancer

patients and 13%-22% of head and neck squamous cell carcinoma patients respond to immune checkpoint

inhibitors.

Recently, significant interest has been focused on the possibility of achieving improved response rate across cancers

using various therapies in combination with I-O. The figures below show data from a non-exhaustive selection of

published scientific literature relating to clinical trials evaluating I-O treatments in combination or alone for the

treatment of head and neck cancer in I-O naïve and I-O non-responder patients.

Outlook of Best Percentage Change from Baseline in HNSCC Trials

(Literature Data)

PD-1 Non-Responders (“NR”) Trials

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PD-1 Naïve Trials

This foregoing historical data survey is presented solely to illustrate the current market opportunity arising from

existing application of available I-O treatments—in combination or alone—for head and neck cancer patients that are

either naïve or non-responder patients. Because of the unique design of such studies applied to specific patient

populations, no comparison with any of our clinical trials is possible and none should be inferred from this

background data.

Supporting Rationale for I-O Combination Treatment Approach

We believe that RT-activated NBTXR3 in combination with immune checkpoint inhibitors has the potential to improve

the therapeutic response to I-O treatments by converting checkpoint inhibitor non-responders into responders and is

being explored in multiple settings.

Our preclinical and early clinical trial results suggest that RT-activated NBTXR3 may stimulate an immune response,

thereby rendering otherwise “cold” tumors more prone to recognition by the patient’s immune system and therefore

more responsive to I-O treatments such as checkpoint inhibitors. This effect is also referred to as causing a “cold”

tumor to become “hot.”

In preclinical experiments, we observed RT-activated NBTXR3 kill more cancer cells in vitro than radiotherapy alone,

leading to the release of a greater number of tumor-associated antigens. In addition, in in vitro experiments

performed on different human cancer cell lines, we observed RT-activated NBTXR3 enhance the expression of

markers of immunogenic cell death, as well as activation of the cGAS-STING pathway (a component of the immune

system that detects tumor-derived DNA and generates intrinsic anti-tumor immunity). These results suggest that RT-

activated NBTXR3 could modulate the immunogenicity of the cancer cells.

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We also observed RT-activated NBTXR3 in vivo generate an abscopal effect, which is a reduction of metastases

burden outside the irradiated area. This abscopal effect depends on the increase of CD8+ T cell lymphocyte

infiltrates (T lymphocytes that work to kill malignant tumor cells) in both treated and untreated tumors, induced by

RT-activated NBTXR3.

In our Phase 2/3 locally advanced STS clinical trial, based on immunohistochemistry analyses, we observed that RT-

activated NBTXR3 increased the density of CD8+ T cell lymphocytes and also decreased FOXP3+ (Treg) (regulatory

T cells that work to suppress immune response) compared to radiotherapy alone in the tumors, while macrophage

number remained relatively constant.

In March 2021, researchers from our collaborator MD Anderson shared preclinical data at the American Association

of Cancer Research (AACR) Virtual Special Conference on Radiation Science and Medicine. This study examined

RT-activated NBTXR3 in combination with anti-PD-1 along with TIGIT and LAG3 inhibitors in an in vivo anti-PD-1

resistant mouse model. The data showed that the Combo therapy (RT-activated NBTXR3 + anti-PD-1 + anti-LAG3 +

anti-TIGIT) significantly promoted the proliferation activity of CD8+ T cells, improved local and distant tumor control,

and increased survival rate. The data showed that the cured mice maintained significantly higher percentages of

memory CD4+ and CD8+ T cells, as well as stronger anti-tumor immune activities than control, and the cured mice

from the groups treated with the Combo therapy were immune to reinjections of tumor cells.

A subsequent analysis presented at the annual meeting of the AACR in April 2022, assessed immune gene

expression associated with multiple combinations of NBTXR3, anti-PD-1, anti-LAG-3, and anti-TIGIT. The data

showed that the Combo therapy outperformed all other tested treatment regimens in efficacy, survival, and induction

of long-term anti-cancer memory. The Combo therapy promoted immune activation at the irradiated site. Abscopal

immune responses were improved with the addition of LAG-3 and TIGIT to PD-1 and RT-activated NBTXR3,

suggesting that the Combination therapy may be effective against metastatic cancers.

Together, these data suggest that RT-activated NBTXR3 could be able to modulate the anti-tumor immune response

and transform the tumor into an in situ vaccine, which prompted the initial development of our I-O program.

Development in I-O

We are conducting, and continue to further develop, a global I-O development program to explore the use of

NBTXR3 as a complement to immune checkpoint inhibitors across several solid tumor indications. Initially, we intend

to leverage the data collected pursuant to our I-O Program to advance treatment for patients with R/M HNSCC that

is resistant to prior immunotherapy.

Study 1100, a multi-cohort Phase 1 trial of RT-activated NBTXR3 followed by an anti-PD-1 checkpoint inhibitor in

patients with R/M HNSCC or with lung,liver, or soft tissue metastases from selected solid tumors eligible for anti-

PD-1 therapy is ongoing. A clinical study protocol amendment was submitted to the FDA at the start of 2022, to

include three expansion cohorts of up to 35 patients each, in order to evaluate the safety and efficacy of the

combination in patients with either R/M HNSCC which failed a prior PD-(L)1 treatment (cohort 1), or in R/M HNSCC

patients that are PD-1 naive (who have never received I-O treatment before) (cohort 2) or in patients with selected

solid tumors (non-HNSCC cohort 3) resistant to prior PD-(L)1 treatment.

In addition, pursuant to our collaboration with MD Anderson, we are planning to evaluate NBTXR3 in combination

with various other checkpoint inhibitors (anti-PD-1, or anti-PD-L1) across several cancer indications. There is

currently one Phase 2 clinical trial evaluating RT-activated NBTXR3 followed by pembrolizumab for recurrent/

metastatic HNSCC patients with limited PD-L1 expression or refractory to PD-1 blockade being conducted as part of

our I-O program under the MD Anderson collaboration. The second, a randomized Phase 1/2 trial for NBTXR3

combined with an anti-PD-1 or PD-L1 +/- RadScopal™ in patients with lung or liver metastases from any advanced

solid tumors , is in the protocol development stage. We are conducting, and continue to further develop, a global I-O

development program to explore the use of NBTXR3 as a complement to immune checkpoint inhibitors across

several solid tumor indications.

1.3.6.4.I-O Program—R/M HNSCC and lung, liver or soft tissue metastases from any primary

tumor

Multi-Cohort Phase 1 Trial (“Study 1100”)

We initiated a Phase 1 prospective, multi-center, open-label, non-randomized clinical trial evaluating the safety and

efficacy of RT-activated NBTXR3 followed by anti-PD-1 checkpoint inhibitors (nivolumab or pembrolizumab). The trial

is being conducted in two consecutive phases: dose escalation followed by dose expansion. The dose escalation

part of the trial includes three patient populations:

•Patients with locoregional recurrent (LRR) or recurrent and metastatic (R/M) head and neck squamous

cell carcinoma (HNSCC) amenable to irradiation of the head and neck field that are anti-PD-1 therapy

naïve or non-responsive to an anti-PD-1 therapy (HNSCC Cohort),

•Lung metastases from any primary cancer eligible for anti-PD-1 therapy (“Lung Cohort”) or

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•Liver metastases from any primary cancer eligible for anti-PD-1 therapy (“Liver Cohort”).

The dose expansion part of the trial has the following treatment cohorts, which were introduced through a protocol

amendment in early 2022:

•Locoregional recurrent and/or metastatic HNSCC and that are resistant to a prior anti-PD-1/L1 therapy

with at least one lesion located in either head and neck region, lungs or liver, amenable for intratumoral

injection and irradiation.

•Locoregional recurrent and/or metastatic HNSCC naïve to anti-PD-1/L1 therapy and eligible for an anti-

PD-1 therapy with at least one lesion located in either head and neck region, lungs or liver amenable for

intratumoral injection and irradiation.

•Lung or liver or soft tissue metastases of primary tumor originating from either NSCLC, malignant

melanoma, HCC, RCC, urothelial cancer, cervical cancer or TNBC that are resistant to a prior anti-PD-1/

L1 therapy and eligible for anti-PD-1 therapy with at least one lesion located in either soft tissue, lungs or

liver that could be injected intratumorally and irradiated.

The trial’s main objective is to determine the recommended Phase 2 dose of RT-activated NBTXR3 in combination

with an anti-PD-1. The trial is ongoing and is being conducted at up to 20 sites in the United States; we intend to

enroll a total of approximately 141 evaluable patients in the trial.

Primary and secondary endpoints will determine the recommended Phase 2 dose of RT-activated NBTXR3 and

evaluate safety and efficacy, while exploratory endpoints will further characterize the treatment-induced gene

expression, including enriched cytokine activity and markers of adaptive immune response and T-cell receptor

signaling pathways.

Results

In September 2022, the Company established the recommended Phase 2 dose (RP2D) of NBTXR3, in combination

with pembrolizumab or nivolumab, at 33% of gross tumor volume (GTV) in each of the three cohorts from the

complete escalation part of Study 1100.

In November 2022, the Company reported updated Phase 1 anti-PD-1 combination data that may support the

immune stimulation potential of NBTXR3 at the 37th Annual Meeting of the Society for Immunotherapy of Cancer

(SITC).

As of the August 22, 2022 data cut-off date, there were 28 patients evaluable for safety and 21 patients evaluable for

early signs of efficacy.

Treatment remained feasible and well-tolerated, irrespective of injection site. The safety profile was consistent with

expectations from stereotactic body radiation therapy (a type of RT that uses special equipment to position the

patient and precisely deliver radiation to a tumor) followed by anti-PD-1 immune checkpoint inhibitors. One patient in

cohort 1 (H&N) at dose level 1 (22% GTV) experienced two dose-limiting toxicities (DLTs). No other DLTs were

observed in the study. The most prevalent adverse events observed in dose escalation were mild fatigue,

constipation, dyspnea (shortness of breath), and anemia; and the occurrence and severity did not differ greatly by

cohort. No relationship between dose and the occurrence or severity of toxicity was observed in any of the three

cohorts and no increase of stereotactic body RT or PD-1 related toxicity was observed in patients treated at the

RP2D in any cohort.

SAEs (Related To NBTXR3 Or Injection Procedure), Per Patient By Cohort And Dose Level

The data suggest local control and systemic anti-cancer activity regardless of prior anti-PD-1 exposure. Objective

reduction from baseline in target lesions (objective reduction) was observed in 71.43% of evaluable patients (15/21):

in 67.00 % of anti-PD-1 resistant patients (10/15) and in 83.00% of anti-PD-1 naïve patients (5/6). Among all

evaluable patients, 42.86% (9/21) showed objective reduction greater than 30%.

Out of the 15 evaluable anti-PD-1 resistant patients, 86.67% (13) had progressive disease when entering the study:

•30.77% (4/13) had a measurable reduction of at least 30% or more

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•15.38% (2/13) experienced a complete reduction of the target lesions

•only 1 patient experienced an increase of over 20% in measurable target lesions.

Best change in diameter sum from baseline and time progression (in all evaluable patients, N=21)

Out of the 16 evaluable patients with primary HNSCC:

•objective reduction in target lesions was observed in 75.00% (12/16), including

◦70% (7/10) of patients with primary HNSCC resistant to anti-PD-1; and

◦83.33% (5/6) patients with primary HNSCC naïve to anti-PD-1.

•43.75% (7/16) had a measurable reduction of at least 30% or more.

•31.25% (5/16) experienced a complete reduction of the target lesions.

Best change in diameter sum from baseline and time progression in primary HNSCC (16 of 21 all evaluable

patients, N=21)

As of the data cut-off, systemic disease control was durable and sustained for more than 6 months in 38.10% of

evaluable patients (8/21) and greater than 12 months in 23.81% of evaluable patients (5/21). Delayed objective

reduction has been observed in several patients, suggesting the potential for anti-cancer immune activity over time.

Local control in injected lesions occurred in all patients and remained in all patients except one.

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Percentage change from baseline over time: injected lesion/s vs all target lesion/s

The dose expansion part of the study is ongoing in the U.S. pursuant to an amended protocol, which provides for

evaluation of RT-activated NBTXR3 plus anti-PD1 in patients with LRR or R/M HNSCC that is either naïve or

resistant to prior anti-PD1 exposure.

The Company expects to provide an update on future interactions with the FDA, with respect to the design of the

Phase 3 registration protocol for the evaluation of RT-activated NBTXR3 plus anti-PD-1 in patients with LRR or R/M

HNSCC resistant to anti-PD-1, in Q3 2023.

1.3.6.5.Liver cancers

Background and opportunity

According to the World Health Organization, liver cancer is the fourth most common cause of cancer death in the

world and is estimated to have caused over 830,180 deaths in 2020. The American Cancer Society estimated that in

2023 in the United States, 41,210 people will be diagnosed with liver cancer and 29,380 patients will die of the

disease. In Europe, an estimated 47,000 patients died of liver cancer in 2020. The five-year survival rate for patients

with localized liver cancer is approximately 31%; once the cancer has spread to other organs or tissues, this survival

rate drops to approximately 3%.

Two types of liver cancer are hepatocellular carcinoma (HCC), the most common type of liver cancer, and secondary

liver cancer, or liver metastasis, which occurs when cancer from another part of the body spreads to the liver.

Surgical resection is often not an option for patients with either HCC or liver metastasis. Moreover, because patients

suffering from HCC or liver metastases typically have underlying liver dysfunction and concomitant malignancies,

local and systemic treatment options are few in number, with significant limitations. Stereotactic body radiation

therapy (SBRT)—a high-precision radiation therapy, delivered as high-energy dose fractions—is a prevalent

alternative therapy that has been shown to improve outcomes for these patients, as third-party clinical trials have

observed a direct correlation between higher doses of radiation and increased survival rates. However, SBRT

dosage is limited due to potential toxicity to surrounding tissues and the need to preserve liver function. Our clinical

trial described below evaluated NBTXR3 in patients with liver cancers in need of an alternative treatment, when

standard care protocols either could not be used or did not exist. By increasing the absorption of the administered

SBRT dose within the tumor itself, without causing additional damage to surrounding healthy tissues, and causing

more effective tumor destruction, we believe NBTXR3 can improve prognoses for this patient population.

Phase 1/2 trial (“Study 103”)

We completed Phase 1 of a Phase 1/2 clinical trial to evaluate the use of NBTXR3 activated by SBRT in liver

cancers. The Phase 1 trial was conducted at six sites in the EU. For this dose escalation phase of the clinical trial,

we recruited 23 patients, divided in two subgroups: patients with primary liver cancer (HCC) and patients with

secondary liver cancer (liver metastases)

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The endpoint of the Phase 1 part of the trial was to determine the recommended dose of NBTXR3 and to assess

early signs of anti-tumor activity. In this portion of the trial, patients received a single intra-lesional injection of

NBTXR3, at increasing dose levels, in each case activated by SBRT.

Final data with respect to the Phase 1 part of Study 103 was presented in October 2020 at the annual meeting of the

American Society for Radiation Oncology (ASTRO) and in January 2021 at the annual meeting of the

Gastrointestinal Cancers Symposium (ASCO-GI).

Results from the Phase 1 part of Study 103 showed feasibility of injection at each of the five tested dose levels

(10%, 15%, 22%, 33% and 42%) with no leakage to surrounding healthy tissues. One SAE of bile duct stenosis was

deemed to be related to NBTXR3 and no dose-limiting toxicities were observed. The recommended Phase 2 dose

(RP2D) has been set at 42%. In 11 patients evaluable for efficacy, early data showed a target lesion objective

response rate of 90.9% in evaluable HCC patients and a target lesion objective response rate of 71.4% in evaluable

patients with liver metastasis.

For HCC patients, preliminary results showed that out of 11 evaluable patients, 10 responded at least partially and 5

of the 11 patients (45.5%) reached complete response.

Out of the 7 patients evaluated for efficacy in the metastatic setting, 5 patients presented a partial response and 2

patients presented stable disease.

We believe these results suggest meaningful potential to address an unmet medical need in an indication with

typically extremely poor prognosis. Although this data is preliminary, it further supports the potential transferability of

NBTXR3 across multiple solid tumor indications.

1.3.6.6.Pancreatic cancer (MD Anderson acting as sponsor of this trial)

Background and opportunity

Pancreatic cancer is a rare, deadly disease. Worldwide, there were 495,773 new cases in 2020. Given that surgery

with R0 resection (i.e., macroscopically complete tumor removal with negative microscopic surgical margins)

remains the only hope for long-term survival, clinical trials have investigated various neoadjuvant strategies—

wherein patients receive anti-cancer drugs or radiation prior to surgery—to increase the surgery-eligible population

while also increasing the R0 resection rate. According to the American Cancer Society, in 2023, about 64,050 people

will be diagnosed with pancreatic cancer and about 50,550 people will die of pancreatic cancer; for all stages of

pancreatic cancer combined, the five-year relative survival rate is 12%.

In support of the rationale for neoadjuvant therapy, a retrospective analysis demonstrated a near doubling in OS in

pancreatic ductal adenocarcinoma (PDAC) patients who underwent surgery, which was attributed, at least in part, to

the increased proportion of borderline resectable pancreatic cancer (BRPC) patients who became eligible for surgery

as a result of neoadjuvant intervention. Importantly, there are also select cases of locally advanced pancreatic

cancer (LAPC) patients being considered for surgical resection based on their response to therapy. Given the poor

prognosis of PDAC, therapeutic regimens able to increase the proportion of BRPC and LAPC patients eligible for

surgery could improve survival outcomes in this population with unmet need.

Phase 1 Trial (“Study 2019-1001”)

The trial is an open-label, single-arm, prospective Phase 1 study consisting of two parts: (i) dose-escalation to

determine the RP2D and (ii) expansion at RP2D. The objectives of the study are the determination of the incidence

of dose-limiting toxicity, the maximum tolerated dose and determination of an RP2D.

The patient population will include adults (age ≥ 18 years) with BRPC or LAPC that are radiographically non-

metastatic at screening, having received between two to six months of chemotherapy prior to trial enrollment and

that have not previously received radiation therapy or surgery for pancreatic cancer. Up to 24 subjects will be

enrolled, including a maximum of 12 subjects with LAPC for the dose-finding part. 12 additional subjects with either

LAPC or BRPC will be enrolled for the RP2D expansion. The first patient was dosed in this trial in September 2020.

In the first quarter of 2022, researchers from MD Anderson published a peer-reviewed clinical case study reporting

preliminary data on the first-in-human administration of NBTXR3 for the treatment of pancreatic cancer not eligible

for surgery, demonstrating feasibility with no treatment-related toxicity. At the end of the dose escalation phase in the

fourth quarter of 2022, the RP2D for NBTXR3 in pancreatic cancer was determined to be 42% of GTV. The ongoing

dose expansion phase is currently enrolling patients with borderline resectable disease in addition to patients with

unresectable disease.

1.3.6.7.Lung cancer (MD Anderson acting as sponsor of this trial)

Background and opportunity

According to the World Health Organization, lung cancer is currently the most common cause of cancer death in the

world and is estimated to have caused over 1.7 million deaths in 2020. According to the American Cancer Society, in

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2023, approximately 238,240 new cases of lung cancer will be diagnosed in the United States and approximately

127,070 people will die of lung cancer. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer,

accounting for 80-85% of all lung cancer diagnoses. The five-year relative survival rate for NSCLC at all stages was

28%.

Phase 1 Trial (“Study 2020-0123”)

The trial is an open-label, two-cohort, prospective Phase 1 study consisting of two parts: (i) a radiation therapy safety

lead-in, and RT-activated NBTXR3 therapy dose-finding to determine the RP2D, and (ii) expansion at RP2D with

toxicity monitoring.

The patient population will include adults (age ≥ 18) with inoperable LRR NSCLC stage IA to IIIC that are

radiographically non-metastatic at screening and have previously received definitive radiation therapy. The number

of participants enrolled will be determined based on the maximum number required to establish the RP2D. Cohort 1

will evaluate the safety of intensity-modulated radiation therapy (IMRT) monotherapy in 10 patients using an

approach similar to a 3+3 design. If 45 Gy in 15 fractions is deemed safe, cohort 2 will test that regimen with

NBTXR3 activated by IMRT. Alternatively, if 45 Gy in 15 fractions is deemed to have excessive toxicity, a 30 Gy in 10

fractions regimen will be used in combination with NBTXR3 in cohort 2. Up to 24 subjects will be enrolled in cohort 2,

including a maximum of 12 subjects for the dose-finding part. Twelve additional subjects will be enrolled for the

NBTXR3 RP2D expansion.

Enrollment for this Phase 1 clinical trial of NBTXR3 with MD Anderson for patients with lung cancer receiving re-

irradiation is ongoing. The planned enrollment period is up to three years. The dose levels to be explored are 22%

and 33% of baseline GTV.

1.3.6.8.Esophageal cancer (MD Anderson acting as sponsor of this trial)

Background and opportunity

According to the World Health Organization, esophageal cancer is currently the sixth most common cause of cancer

death in the world and is estimated to have caused 544,076 deaths in 2020. The American Cancer Society estimates

that in 2023 in the United States, there will be approximately 21,560 new esophageal cancer cases diagnosed, and

approximately 16,120 deaths due to esophageal cancer. The five-year relative survival rate for esophageal cancer at

all stages is 21%.

Phase 1 Trial (“Study 2020-0122”)

This trial is an open-label, single-arm, prospective Phase 1 study consisting of two parts: (i) does-escalation to

determine the RP2D of RT-activated NBTXR3 with concurrent chemotherapy, and (ii) expansion at RP2D with

toxicity monitoring.

The patient population will include adults (age > 18 years) with stage II-III adenocarcinoma of the esophagus that are

treatment naïve and radiographically non-metastatic at screening. The number of participants enrolled will be

determined based on the maximum number required to establish the RP2D of RT-activated NBTXR3. Up to 24

subjects will be enrolled, including a maximum of 12 subjects for the dose-finding part. 12 additional subjects will be

enrolled for the RP2D expansion.

The first patient was dosed in this trial in January 2021. Enrollment is ongoing, and the planned enrollment period is

24 months. The objectives of the study are the determination of dose-limiting toxicity, the maximum tolerated dose

and RP2D.

1.3.7.PharmaEngine Trials

In August 2012, we entered into an exclusive license and collaboration agreement with PharmaEngine for the

development and commercialization of NBTXR3 in the Asia-Pacific region. In March 2021, in light of disagreements

over a number of issues with respect to the development of NBTXR3 in the Asia-Pacific region, we and

PharmaEngine mutually agreed to terminate the agreement. Three NBTXR3 clinical trials (including certain Asia-

Pacific sites for the Act.in.Sarc trial) conducted by PharmaEngine in Asia were concluded or terminated, and we

retain all rights to the development and commercialization of NBTXR3 in the Asia-Pacific region, pursuant to the

terms of a Termination and Release Agreement that we entered into with PharmaEngine in March 2021 (see

“PharmaEngine” below for additional information).

1.3.7.1.Head and Neck Cancers Treated with Radiotherapy plus Chemotherapy

Phase 1/2 Trial (“PEP503-HN-1002”)

In addition to our clinical trials of NBTXR3 in head and neck cancers, PharmaEngine conducted a Phase 1/2 clinical

trial of NBTXR3 for patients with locally advanced or recurrent HNSCC to be treated by radiotherapy plus cisplatin.

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The primary endpoints of the study were to determine the optimal NBTXR3 dose and to assess the preliminary

safety and efficacy of RT-activated NBTXR3 plus chemotherapy. The trial, conducted in Taiwan, recruited 12 patients

in the Phase 1 dose escalation part, was terminated early in conjunction with the termination of the license and

collaboration agreement with PharmaEngine. Accordingly, the RP2D was not determined due to the stoppage of the

trial. Data from this study was presented at the Annual Meeting of the American Society of Clinical Oncologists in

June 2022 and showed that, in the 12 evaluable patients, all of whom had stage 4 locally advanced disease, the

combination therapy was feasible and had a favorable safety profile. Of these 12 evaluable patients, 3 received

NBTXR3 at the 5% dose level, 6 received NBTXR3 at the 10% dose level, and 3 received NBTXR3 at the 15% dose

level. Serious adverse events were consistent with expectations for a low-dose chemoradiation regimen. Preliminary

efficacy data showed a disease control rate of 100%, and an overall response rate of 58.3% according to RECIST

1.1.

1.3.7.2.Rectal Cancer

Phase 1/2 Trial (“PEP503-RC-1001”)

PharmaEngine conducted an open-label Phase 1/2 clinical trial of RT-activated NBTXR3 in combination with

chemotherapy for patients with locally advanced or unresectable rectal cancer. Primary and secondary endpoints

were to assess the safety profile and determine the dose-limiting toxicity, evaluate the recommended dosage and

assess the anti-tumor activity by evaluating the response rate of RT-activated NBTXR3 with concurrent

chemotherapy (CCRT) treatment in patients with locally advanced or unresectable rectal cancer. The Phase 1 part of

this Phase 1/2 trial enrolled 32 adult and older patients at one site in Taiwan. The Phase 2 part of the trial was

stopped as a result of the conclusion of the collaboration between PharmaEngine and Nanobiotix in 2021.

PharmaEngine presented first clinical results from Study PEP503-RC-1001 at the Annual Meeting of the American

Society of Clinical Oncology in June 2022. Of the 32 patients enrolled in the Phase 1 study, 31 were deemed

evaluable patients. None of the evaluable patients had tumors eligible for surgery at the time of diagnosis. Of the 31

evaluable patients, 6, 4, 3, and 18 patients received NBTXR3 at the 5%, 10%, 15%, and 22% dose levels,

respectively. No NBTXR3-related SAEs or grade ≥ 3 AEs were observed. The most frequently reported AEs were

grade 1 or 2 decreased white blood cell count, diarrhea, increased C-reactive protein, urinary tract infection, and

decreased lymphocyte count which were all consistent with what would normally be expected from CCRT.

The study established the RP2D of NBTXR3 at 22% of GTV.

Preliminary efficacy results showed a disease control rate of 100%, with an overall response rate of 35.5% according

to RECIST 1.1. Pathological tumor downstaging was observed in 14 of 31 patients after therapy, 25 patients

underwent surgery, and 96% of those patients achieved R0 surgical margins. Pathological complete response was

observed in 20% of the patients who received surgery.

The study concluded that a single intratumoral injection of NBTXR3 in combination with CCRT is feasible and has a

favorable safety profile in the neoadjuvant setting for patients with locally advanced or unresectable rectal

adenocarcinoma.

1.3.8Scientific Advisory Board

The Scientific Advisory Board is an independent multidisciplinary board which includes twelve members from the

United States, Europe, and the United Kingdom. These experts support the Company regarding the development of

the lead therapeutic candidate NBTXR3. The Scientific Advisory Board integrates high level expertise that is relevant

to Nanobiotix business, including but not limited to medical, surgical and radiation oncology fields. Leonard A.

Farber, MD, Chief Clinical and Medical Affairs Officer at Nanobiotix, has been appointed as Chairman of the

Scientific Advisory Board.

Members of the Nanobiotix Scientific Advisory Board are:

–Sylvie Bonvalot, MD, PhD, HDR; Surgical Oncologist, Head of Sarcoma Surgery at Institut Curie, Paris, France

–Jared Marc Weiss, MD; Medical Oncologist, Professor, Medicine-Oncology at the University of North Carolina

Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, United States of America (USA)

–Robert L. Ferris, MD, PhD, FACS; Surgical Oncologist, Director at the UPMC Hillman Cancer Center, Hillman

Professor of Oncology, Associate Vice Chancellor for Cancer Research and Professor of Otolaryngology, of

Immunology and of Radiation Oncology at the University of Pittsburgh, Pittsburgh, Pennsylvania, USA

–Nancy Y. Lee, MD, FASTRO; Radiation Oncologist, Vice Chair, Department of Radiation Oncology; Service

Chief, Head & Neck Radiation Oncology; Service Chief, Proton Therapy at Memorial Sloan Kettering Cancer

Center, New York, New York, USA

–Silvia Chiara Formenti, MD, FASTRO; Radiation Oncologist, Chairman of the Department of Radiation

Oncology at Weill Cornell Medicine, Associate Director of the Meyer Cancer Center and Radiation Oncologist

in Chief at NewYork-Presbyterian Hospital, New York, New York, USA

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–Kevin Harrington, FRCP, FRCR, FRSB, PhD, Clinical Oncologist, Head of the Division of Radiotherapy and

Imaging at The Institute of Cancer Research (ICR)/Royal Marsden Hospital (RMH), United Kingdom

–Christophe Le Tourneau, MD, PhD; Medical Oncologist, Head of the Department of Drug Development (D3i) at

the Institut Curie and Professor of Medicine at Paris-Saclay University, Paris, France

–Hisham Mehanna, PhD, BMedSc, MBChB, FRCS; Surgical Oncologist, Deputy Pro-Vice Chancellor, Chair of

Head and Neck Surgery, and Director of the Institute of Head and Neck Studies and Education at the University

of Birmingham, United Kingdom

–Thierry De Baère, MD; Interventional Radiologist, Head of the Interventional Radiology Unit at Gustave Roussy

Cancer Centre and University Paris-Saclay in Paris, France, and Head of Interventional Radiology at Gustave

Roussy Cancer Center, Villejuif, France

–Chiaojung Jillian Tsai, MD, PhD; Radiation Oncologist, Incoming Site Lead, Palliative Radiation Oncology

Program, Radiation Medicine, Princess Margaret Cancer Centre, Toronto, Canada

–Stéphane Champiat, MD, MS, PhD; Medical Oncologist, Head of the Inpatient Unit at the Drug Development

Department of Gustave Roussy Cancer Campus, Paris, France

–Jean Bourhis, MD, PhD; Radiation Oncologist, Professor, Chief of Radiation Oncology at the Lausanne

University Hospital, Lausanne, Switzerland

1.3.9.The Curadigm Platform

Beyond NBTXR3, Nanobiotix is also evaluating several additional potential development programs in nanomedicine.

In July 2019, Nanobiotix formed a wholly-owned subsidiary — Curadigm SAS — with the mission of leveraging

Nanobiotix’s expertise and know-how beyond oncology to expand treatment benefits across multiple therapeutic

classes by increasing drug bioavailability while decreasing unintended off-target effects, specifically liver toxicity.

For most therapeutics today, only a small portion of the medicine administered is effective. After injection, the dose

moves through the patient’s circulatory system within the blood. While a small portion reaches the targeted tissue,

the remainder is either cleared from the body or accumulates—potentially with toxic effect—in organs such as the

liver or spleen.

Leveraging our deep expertise in nanotechnology, Curadigm is developing a nanoparticle, called Nanoprimer, that

primes the body to receive treatment. Injected intravenously prior to a therapeutic, the Nanoprimer has been

designed with specific physico-chemical properties that allow it to transiently occupy the liver cells responsible for

therapeutic clearance. By preventing the liver clearance, the Nanoprimer is intended to increase the blood

bioavailability and subsequent accumulation of therapeutics in the targeted tissues, thereby increasing therapeutic

action.

We believe that the Curadigm technology could have broad implications across the healthcare system by increasing

the efficacy of therapeutics at their current dose or lowering the necessary dose in order to decrease toxicity and

cost, thus allowing for novel therapeutic approaches. Preclinical in vivo data evaluating Curadigm’s concept has

been generated combining the Nanoprimer with different therapeutic agent families such as small molecules and

nucleic acids and has been published in scientific journals.

As the Nanoprimer is a combination product candidate that does not alter or modify the therapeutic it is paired with,

we expect that Curadigm will continue to seek partnerships across drug classes-particularly with nucleic acid-based

therapies. To support the development of its platform, Curadigm may pursue various funding opportunities, including,

without limitation, partnership and collaboration arrangements, licensing opportunities and/or sales of Curadigm

securities to third-party investors from time to time.

Curadigm Collaboration with Sanofi

In January 2021, a research project involving Curadigm’s Nanoprimer technology was selected for the Sanofi iTech

Awards Program for its potential to significantly improve gene therapy development. Curadigm entered into a

collaboration agreement with Sanofi that includes direct funding and scientific exchanges.

In September 2022, Curadigm finalized the experimental studies started in early 2021 in conjunction the

collaboration agreement. This project aims at establishing proof-of-concepts for the Nanoprimer as a combination

product to improve treatment outcomes for Sanofi’s gene therapy product candidates. Based on generated results

and final report provided by Curadigm, the parties are discussing the potential for further collaboration to pursue the

exploration of the impact of Curadigm’s Nanoprimer technology on the biodistribution and efficacy of product

candidates.

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1.3.10.Manufacturing

We contract the production of NBTXR3 to high-precision manufacturing partners. Our contracts with these contract

manufacturing organizations generally provide that the manufacturing partner may not transfer its rights or sub-

contract any of the services covered. The manufacturing partners are required to perform their obligations in

accordance with international professional standards, including the Good Manufacturing Practices guidelines issued

by the International Council for Harmonization.

In November 2017, we opened a facility to expand our manufacturing capabilities, increase production capacity of

NBTXR3 for our clinical trial needs and prepare for potential commercialization. This facility is located in the Villejuif

BioPark, a scientific research and innovation center just outside of Paris, France. We expect that the facility will

increase its production capacity as soon as 2024 with the aim to produce NBTXR3 for our ongoing clinical trials and

our initial commercial phase.

1.3.11.Commercialization

We have not yet developed commercial infrastructure in either the United States or the EU, and we are in the

process of defining our commercialization strategy. We intend to establish a global commercial infrastructure outside

the countries in which LianBio will commercialize NBTXR3, either alone or in combination with partners.

We believe that our commercial infrastructure, if and when established, will target the community of physicians who

are the key specialists in diagnosing and treating the patient populations for which NBTXR3 is being developed. We

may enter into additional development and commercialization agreements with third parties in select geographic

territories for any of our product candidates that successfully complete applicable pre-marketing regulatory

requirements in order to optimize sales.

1.3.12.Competition

The development of treatments for cancer is subject to rapid technological change. Many companies, academic

research institutions, governmental agencies and public and private research institutions are pursuing the

development of medicinal products, devices and other therapies that target the same conditions that we are

targeting, including in some cases in the same patient populations that we are targeting.

Approximately 60% of all cancer patients undergo radiotherapy at some point during their course of treatment5.

Current research in radiotherapy focuses primarily on (1) methods to increase sensitivity of tumors to radiation and

(2) methods to protect healthy tissues from radiation. In addition, many researchers believe that radiotherapy can

enhance the body’s immune response, thereby making a previously unsusceptible tumor susceptible to treatment.

Companies that are developing treatments to increase sensitivities of tumors to radiation and other sources of

energy include MagForce AG, Merck & Co., NH TherAguix, Nanospectra Biosciences, Inc., RiMO Therapeutics and

Coordination Pharmaceuticals, Inc. Like us, these companies are pursuing various technologies that involve the

delivery of a substance to a tumor that works to destroy the tumor cells without causing additional damage to

surrounding healthy tissues. Any product candidates that we or they develop and commercialize may compete with

existing therapies, as well as new therapies that may become available in the future, including therapies with a mode

of action similar to that of NBTXR3.

Many of our competitors, either alone or with their collaboration partners, may have significantly greater financial

resources and expertise in research and development, preclinical testing, clinical trials, manufacturing, and

marketing than we do. Future collaborations and mergers and acquisitions may result in further resource

concentration among a smaller number of competitors. These competitors also compete with us in recruiting and

retaining qualified research and development and management personnel and establishing clinical trial sites and

patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our

programs. Smaller or early stage companies may also prove to be significant competitors, particularly through

collaborative arrangements with more established companies.

The key competitive factors affecting the success of NBTXR3 and any other product candidates that we develop, if

approved, are likely to be their efficacy, safety, convenience, price and the availability of reimbursement from

government and other third-party payors. We must also protect our proprietary technology used in the development

of our product candidates. Our commercial opportunity could be reduced if our competitors develop and

commercialize products that are more effective or demonstrate a more favorable safety profile than any products that

we may develop. Our competitors may also successfully complete applicable pre-marketing regulatory requirements

for their products more rapidly than we do, which could impact our regulatory and commercialization strategies.

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5 Morris ZS, Harari PM. Interaction of radiation therapy with molecular targeted agents. J Clin Oncol. 2014 Sep 10;32(26):2886-93. doi: 10.1200/JCO.2014.55.1366. Epub

2014 Aug 11. PMID: 25113770; PMCID: PMC4152717.

INTERNATIONAL ATOMIC ENERGY AGENCY, Radiotherapy in Cancer Care: Facing the Global Challenge, Non-serial Publications , IAEA, Vienna (2017)

1.3.13.Research & Development and patents

1.3.13.1.Research & Development

Since the Company’s creation, most of the resources have been devoted to research and development activities.

These activities are described in detail in paragraph 1.3.1. for research and development (research, preclinical,

clinical, medical and regulatory) and production activities. In order to carry out their work, the research and

development teams use subcontractors with state-of-the-art technologies and/or the necessary expertise. In the

2022 workforce, 35 employees hold a doctorate in medicine, pharmacy or science. The research and development

function remains largely dominant, accounting for 73% of employees.

1.3.13.2.Publications

Nanomedicine is a very innovative field of research. A pioneer and major player in this sector, Nanobiotix has

developed technologies recognized by the international scientific and medical communities. The major work of our

researchers and the results of our clinical trials are regularly published and presented at international scientific

events (non-exhaustive list):

▪A new radio-enhancer, PEP503 (NBTXR3), in combination with concurrent chemoradiation in locally advanced

or unresectable rectal cancer: The dose-finding part of a Phase 1/II trial. Wang J-Y, Huang C-W, Huang M-Y,

Hu H-M, Hsu W-H, Shih H-Y, et al. Journal of Clinical Oncology. 2021;39(3_suppl):66-.

▪Abstract PO-040: Integration of anti-TIGIT and anti-Lag3 with NBTXR3-mediated immunoradiation therapy

improves abscopal effect and induces long-term memory against cancer. Hu Y, Paris S, Barsoumian H, Sezen

D, He KW, Wasley M, et al. Clinical Cancer Research. 2021;27(8 Supplement):PO-040-PO-.

▪Radiation enhancing hafnium oxide nanoparticles (NBTXR3) for the treatment of cisplatin-ineligible locally

advanced HNSCC patients: a phase I dose expansion study. Tourneau CL, Calugaru V, Moreno V, Calvo E,

Liem X, Salas S, et al. Oral Oncology. 2021;118:11.

▪NBTXR3 activated by SBRT combined with nivolumab or pembrolizumab in patients with advanced cancers:

phase I trial. Shen C, Frakes J, Niu J, Rosenberg A, Weiss J, Caudell J, et al. Oral Oncology. 2021;118:10.

▪A phase I study of radiation enhancing functionalized hafnium oxide nanoparticles in cisplatin-ineligible patients

with locally advanced HNSCC. Le Tourneau C, Calugaru V, Borcoman E, Takacsi-Nagy Z, Liem X, Papai Z, et

al. AHNS. 2021.

▪A phase I study evaluating NBTXR3 activated by radiotherapy in combination with nivolumab or

pembrolizumab in patients with advanced cancers. Shen C, Frakes J, Niu J, Weiss J, Caudell J, Jameson K, et

al. AHNS. 2021.

▪Phase I study of functionalized hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy in cisplatin-

ineligible locally advanced HNSCC patients. Le Tourneau C, Calugaru V, Takacsi-Nagy Z, Liem X, Papai Z,

Fijuth J, et al. Journal of Clinical Oncology. 2021;39(15_suppl):6051-.

▪Long-term evaluation of the novel radioenhancer NBTXR3 plus radiotherapy in patients with locally advanced

soft tissue sarcoma treated in the phase II/III Act.In.Sarc trial. Bonvalot S, Rutkowski P, Thariat J, Carrère S,

Ducassou A, Marie S, et al. Journal of Clinical Oncology. 2021;39(15_suppl):11544-.

▪A phase I trial evaluating NBTXR3 activated by radiotherapy in combination with nivolumab or pembrolizumab

in patients with advanced cancers. Journal of Clinical Oncology. Shen C, Frakes JM, Niu J, Rosenberg A,

Weiss J, Caudell JJ, et al. 2021;39(15_suppl):2590-.

▪Overcoming resistance to anti-PD-1 with tumor agnostic NBTXR3: From bench to bed side. Journal of Clinical

Oncology. Seiwert TY, Shen C, Frakes JM, Niu J, Weiss J, Caudell JJ, et al. 2021;39(15_suppl):2591-.

▪NBTXR3 Activated by SBRT Combined with Nivolumab or Pembrolizumab in Patients With Advanced Cancers:

Phase I Trial. Journal of Thoracic Oncology. Shen C, Frakes J, Niu J, Rosenberg A, Weiss J, Caudell J, et al.

MA03.032021;16(10):S893.

▪Study of Novel Radioenhancer NBTXR3 Plus Radiotherapy in Patients With Locally Advanced Soft Tissue

Sarcoma: Results of the Long-Term Evaluation in the Phase II/III Act.In.Sarc Trial. Bonvalot S, Rutkowski P,

Thariat JO, Carrere S, Ducassou A, Sunyach MP, et al. International journal of radiation oncology, biology,

physics. 2021;111(3):S40-S1.

▪Phase I Study of Novel Radioenhancer NBTXR3 Activated by Radiotherapy in Cisplatin-Ineligible Locally

Advanced HNSCC Patients. Le Tourneau C, Calugaru V, Takacsi-Nagy Z, Liem X, Papai Z, Fijuth J, et al.

International journal of radiation oncology, biology, physics. 2021;111(3):e392.

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Chapter 1. NANOBIOTIX AND ITS ACTIVITIES PRESENTATION

▪NBTXR3 Activated by Radiotherapy in Combination With Nivolumab or Pembrolizumab in Patients With

Advanced Cancers: A Phase I Trial. Shen C, Frakes JM, Niu J, Rosenberg AJ, Weiss J, Caudell JJ, et al.

International journal of radiation oncology, biology, physics. 2021;111(3):e361-e2.

▪Overcoming Resistance to Anti-PD-1 With Tumor Agnostic NBTXR3: From Bench to Bedside. Seiwert TY, Shen

C, Frakes JM, Hu Y, Niu J, Weiss J, et al. International journal of radiation oncology, biology, physics.

2021;111(3):S68-S9.

▪740 Radiotherapy-activated NBTXR3 nanoparticles Increase CD8+ T cell infiltration and diversity in tumors,

and modulate the immunopeptidome of cancer cells. Darmon A, Zhang P, silva JD, Paris S. Journal for

ImmunoTherapy of Cancer. 2021;9(Suppl 2):A771.

▪575 Dual blockade of LAG3 and TIGIT improves the treatment efficacy of a nanoparticle-mediated

immunoradiation in anti-PD1 resistant lung cancer in mice. Journal for ImmunoTherapy of Cancer. Hu Y, Welsh

J, Paris S, Bertolet G, Barsoumian H, Schuda L, et al. 2021;9(Suppl 2):A604.

▪SIOG2021-0035 - A phase I dose expansion study of NBTXR3, radiation enhancing hafnium oxide

nanoparticles, for the treatment of cisplatin-ineligible locally advanced HNSCC patients. Le Tourneau C,

Calugaru V, Moreno V, Calvo E, Liem X, Salas S, et al. Journal of Geriatric Oncology. 2021;12(8, Supplement

1):S9-S10.

▪NBTXR3, a first-in-class radioenhancer for pancreatic ductal adenocarcinoma: report of first patient experience.

Clinical and Translational Radiation Oncology. Bagley AF, Ludmir EB, Maitra A, Minsky BD, Li Smith G, Das P,

et al. 2022.

▪A radioenhancing nanoparticle mediated immunoradiation improves survival and generates long-term antitumor

immune memory in an anti-PD1-resistant murine lung cancer model. Hu Y, Paris S, Barsoumian H, Abana CO,

He K, Sezen D, et al. Journal of nanobiotechnology. 2021;19(1):416.

▪Radiation Therapy Enhanced by NBTXR3 Nanoparticles Overcomes Anti-PD1 Resistance and Evokes

Abscopal Effects. Hu Y, Paris S, Barsoumian H, Abana CO, He K, Wasley M, et al. International journal of

radiation oncology, biology, physics. 2021.

▪NBTXR3 Radiotherapy-Activated Functionalized Hafnium Oxide Nanoparticles Show Efficient Antitumor Effects

Across a Large Panel of Human Cancer Models. Zhang P, Marill J, Darmon A, Mohamed Anesary N, Lu B,

Paris S. Int J Nanomedicine. 2021;16:2761-73.

▪Phase I dose-escalation study of NBTXR3 activated by intensity-modulated radiation therapy in elderly patients

with locally advanced squamous cell carcinoma of the oral cavity or oropharynx. European Journal of Cancer.

Hoffmann C, Calugaru V, Borcoman E, Moreno V, Calvo E, Liem X, et al. 2021;146:135-44.

▪Results from the phase I dose-escalation study of the radiation enhancer NBTXR3 for the treatment of HCC

and liver metastases. Baere TD, Pracht M, Rolland Y, Durand-Labrunie J, Jaksic N, Nguyen F, et al. Journal of

Clinical Oncology. 2021;39(3_suppl):319-.

▪NBTXR3 nanoparticle with immunoradiation improves survival and generates long-term anti-tumor memory in

an anti-PD1 resistant murine lung cancer model. Hu Y, Welsh J, Paris S, Barsoumian H, Abana C, Gandhi S, et

al. Journal for ImmunoTherapy of Cancer. 2020;8(Suppl 3):A117-A8.

▪Modulation of TCR repertoire by radiotherapy-activated NBTXR3 nanoparticles. Darmon A, Zhang P, Paris S.

Journal for ImmunoTherapy of Cancer. 2020;8(Suppl 3):A349-A.

▪Overcoming resistance to anti-PD-1 with tumor agnostic NBTXR3: from bench to bed side. Welsh J, Shen C,

Frakes J, Niu J, Weiss J, Caudell J, et al. Journal for ImmunoTherapy of Cancer. 2020;8(Suppl 3):A241-A.

▪Phase I study of intratumoral NBTXR3 in combination with anti-PD-1 in patients with advanced cancers. Shen

C, Frakes J, Niu J, Weiss J, Caudell J, Jameson K, et al. Journal for ImmunoTherapy of Cancer. 2020;8(Suppl

3):A249-A.

▪PH-0159: NANORAY-103: Phase I/II trial of NBTXR3 activated by SBRT in patients with HCC and liver

metastases. De Baère T, Pracht M, Rolland Y, Durand-Labrunie J, Nguyen F, Bronowicki J, et al. Radiotherapy

and Oncology. 2020;152:S74-S5.

▪NBTXR3 Radiation Enhancing Hafnium Oxide Nanoparticles Activated By Radiotherapy In Combination With

Anti-PD-1 Therapy: A Phase I Study. Shen C, Frakes JM, Weiss J, Caudell J, Hackman T, Akulian J, et al.

International journal of radiation oncology, biology, physics. 2020;108(3):e851.

▪Phase I/II Study Of Radiation Enhancing Hafnium Oxide Nanoparticles NBTXR3 Activated by SBRT in HCC

and Liver Metastases Patients. De Baere T, Pracht M, Rolland Y, Durand-Labrunie J, Jaksic N, Nguyen TVF, et

al. International journal of radiation oncology, biology, physics. 2020;108(3):e577-e8.

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Chapter 1. NANOBIOTIX AND ITS ACTIVITIES PRESENTATION

▪NBTXR3 Radiation Enhancing Hafnium Oxide Nanoparticles Activated By Radiotherapy In Cisplatin-Ineligible

Patients With Locally Advanced HNSCC: A Phase I Trial. Le Tourneau C, Calugaru V, Borcoman E, Moreno V,

Calvo E, Liem X, et al. International journal of radiation oncology, biology, physics. 2020;108(3):e792.

▪NBTXR3 radiation enhancing hafnium oxide nanoparticles: RP2D for the treatment of HCC and liver

metastases. de Baere T, Pracht M, Rolland Y, Durand-Labrunie J, Jaksic N, Nguyen F, et al. Annals of

Oncology. 2020;31:S693.

▪Phase I study of NBTXR3 activated by radiotherapy in patients with advanced cancers treated with an anti-

PD-1 therapy. Shen C, Frakes J, Weiss J, Caudell JJ, Hackman TG, Akulian JA, et al. Journal of Clinical

Oncology. 2020;38(15_suppl):TPS3173-TPS.

▪Phase I trial of hafnium oxide nanoparticles activated by radiotherapy in cisplatin-ineligible locally advanced

HNSCC patients. Tourneau CL, Calugaru V, Borcoman E, Moreno V, Calvo E, Liem X, et al. Journal of Clinical

Oncology. 2020;38(15_suppl):6573-.

▪Hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy for the treatment of frail and/or elderly

patients with locally advanced HNSCC: a phase I/II study. Le Tourneau C, Calugaru V, Borcoman E, Moreno V,

Calvo E, Liem X, et al. International journal of radiation oncology, biology, physics. 2020;106(5):1142-3.

▪NANORAY-1100: A phase I study of NBTXR3 activated by radiotherapy in patients with advanced cancers

treated with anti-PD-1 therapy. Shen CJ, Jameson KL, Weiss J, Hackman T, Dixon R, Akulian JA, et al. Journal

of Clinical Oncology. 2020;38(5_suppl):TPS86-TPS.

▪Treatment of hepatocellular carcinoma and liver metastases with hafnium oxide nanoparticles activated by

SBRT: A phase I/II trial. Jaksic N, Pracht M, Rolland Y, Baere TD, Durand-Labrunie J, Nguyen F, et al. Journal

of Clinical Oncology. 2020;38(4_suppl):537-.

▪a Phase I Study of NBTXR3 Activated by Radiotherapy for Patients with Advanced Cancers Treated with an

Anti-PD-1 Therapy. Shen C, Jameson K, Weiss J, Hackman T, Corum D, Akulian JA, et al. Annals of Oncology.

2019;30:xi46.

▪Hafnium oxide nanoparticles activated by radiotherapy induce an anti-tumor immune response. Thariat J, Lae

M, Carrere S, Papai Z, Ducassou A, Rochaix P, et al. RSNA. 2019.

▪NBTXR3 for the treatment of locally advanced HNSCC in frail and/or elderly patients: a phase I/II study. Le

Tourneau C, Calugaru V, Garcia VM, Mirabel X, Doger B, Calvo E, et al. RSNA. 2019.

▪Combination of a radiation-enhancing nanoparticle, radiotherapy,and immune checkpoint inhibitors for treating

metastasized lungcancer in mice. Hu Y, Zhang P, Darmon A, Cortez MA, Paris S, Welsh J. Journal for

ImmunoTherapy of Cancer. 2019;7(Suppl 1:P508):283.

▪Phase I study of hafnium oxide nanoparticles activated by Intensity Modulated Radiation Therapy (IMRT) as a

new therapeutic option for elderly or frail HNSCC patients. Le Tourneau C, Garcia VM, Doger B, Urban A,

Bernois K, Liem X, et al. Journal of Geriatric Oncology. 2019;10(6):S32.

▪The radio-enhancer hafnium oxide nanoparticle, NBTXR3 activated by radiation therapy in patients with locally

advanced soft tissue sarcoma: a phase II/III trial. Bonvalot S, Rutkowski PL, Thariat J, Carrere S, Ducassou A,

Sunyach MP, et al. CTOS. 2019.

▪Phase I/II trial of NBTXR3 activated by SBRT in patients with hepatocellular carcinoma or liver metastasis.

Pracht M, Chajon E, Rolland Y, de Baere T, Nguyen F, Bronowicki JP, et al. Annals of Oncology. 2019;30:v291.

▪Hafnium Oxide Nanoparticles Activated By Radiotherapy: Potential for Local Treatment of a Wide Variety of

Solid Tumors. Dicker AP, Shen C, De Baere T, Hoffmann C, Welsh JW, Rolland Y, et al. International journal of

radiation oncology, biology, physics. 2019;105(1):S241.

▪NBTXR3 Activated By Radiotherapy Generates an Anti-Tumor Immune Response. Thariat JO, Laé M, Carrere

S, Papai Z, Ducassou A, Rochaix P, et al. International journal of radiation oncology, biology, physics.

2019;105(1):E651-E2.

▪Hafnium Oxide Nanoparticles Activated by SBRT for the Treatment of Hepatocellular Carcinoma and Liver

Metastasis: A Phase I/II Trial. Rodriguez EC, Pracht M, Rolland Y, De Baere T, Nguyen TVF, Bronowicki JP, et

al. International journal of radiation oncology, biology, physics. 2019;105(1):S110-S1.

▪NBTXR3 for the Treatment of Elderly Frail Patients with Locally Advanced HNSCC. Le Tourneau C, Calugaru V,

Garcia VM, Mirabel X, Doger B, Calvo E, et al. International journal of radiation oncology, biology, physics.

2019;105(1):S54-S5.

▪Enhancement of anti-PD1 and anti-CTLA4 efficacy by NBTXR3 exposed to radiotherapy. Yun Hu, Ping Zhang,

Audrey Darmon, Maria Angelica Cortez, Sebastien Paris, James Welsh. Poster presentation, AACR 2019;

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Chapter 1. NANOBIOTIX AND ITS ACTIVITIES PRESENTATION

▪Phase I/II trial of hafnium oxide nanoparticles activated by SBRT in the treatment of liver cancers. E. Chajon,

M. Pracht, T. De Baere, T.V.F Nguyen, J. P. Bronowicki, V. Vendrely, A. S. Braumann, V.V. Croisé-Laurent, E.

Rio, Y. Rolland, S. Le Sourd, P. Gustin, C. Perret, F. Mornex, D. Peiffert, P. Merle, and E. Deutsch. Oral

Presentation ESTRO 2019;

▪First randomized study of Hafnium nanoparticles activated by radiotherapy in soft tissue sarcoma. S. Bonvalot,

P.L. Rutkowski, J. Thariat, S. Carrere, M.-P. Sunyach, E. Saada-Bouzid, P. Agoston, A. Hong, A. Mervoyer, M.

Rastrelli, C. Le Pechoux, V. Moreno, R. Li, B. Tiangco, A. Casado Herraez, A. Gronchi, L. Mangel, P.

Hohenberger, M. Delannes, Z. Papai. Oral Presentation ESTRO 2019;

▪Hafnium oxide nanoparticles NBTXR3 activated by radiotherapy as a new therapeutic option for elderly/frail

HNSCC patients. Christophe Le Tourneau, Victor Moreno, Sebastien Salas, Xavier Mirabel, Emiliano Calvo,

Bernard Doger, Carmen Florescu, Juliette Thariat, Jacek Fijuth, Tomasz Rutkowski, Nicolas Magné, Xavier

Liem, Nicolas Fakhry, Stéphanie Wong-Hee-Kam, Valentin Calugaru, Caroline Hoffmann. Poster, ASCO 2019;

▪NBTXR3, a first-in-class radio-enhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy

alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, Phase II/ III,

randomised, controlled trial. Sylvie Bonvalot, Piotr L Rutkowski, Juliette Thariat, Sébastien Carrère, Anne

Ducassou, Marie-Pierre Sunyach, Peter Agoston, Angela Hong, Augustin Mervoyer, Marco Rastrelli, Victor

Moreno, Rubi K Li, Béatrice Tiangco, Antonio Casado Herraez, Alessandro Gronchi, László Mangel, Teresa Sy-

Ortin, Peter Hohenberger, Thierry de Baère, Axel Le Cesne, Sylvie Helfre, Esma Saada-Bouzid,Aneta

Borkowska, Rodica Anghel, Ann Co, Michael Gebhart, Guy Kantor, Angel Montero, Herbert H Loong, Ramona

Vergés, Lore Lapeire, Sorin Dema, Gabriel Kacso, Lyn Austen, Laurence Moureau-Zabotto, Vincent Servois,

Eva Wardelmann, Philippe Terrier, Alexander J Lazar, Judith V M G Bovée, Cécile Le Péchoux, Zsusanna

Papai. Lancet Oncology;

▪NBTXR3 for the treatment of elderly frail patients with locally advanced HNSCC. Christophe Le Tourneau,

Valentin Calugaru, Victor Moreno Garcia, Xavier Mirabel, Bernard Doger, Emiliano Calvo, Jacek Fijuth, Tomasz

Rutkowski, Nicolas Magné, Miren Sanz Taberna, Jorge Contreras, Irene Brana, Zsuzsanna Papai, Zoltán

Takacsi-Nagy, Xavier Liem, Sébastien Salas, Stéphanie Wong, Carmen Florescu, Juliette Thariat, and Caroline

Hoffmann. Oral presentation, ASTRO 2019;

▪Hafnium Oxide Nanoparticles Activated by SBRT for the Treatment of Hepatocellular Carcinoma and Liver

Metastasis: A Phase I/ II Trial. E. Chajon Rodriguez, M. Pracht, Y. Rolland, T. De Baere, T.V.F. Nguyen, J.P.

Bronowicki, V. Vendrely, A. Sa Cunha, A.S. Baumann, V. Croise ́-Laurent, E. Rio, S. Le Sourd, P. Gustin, C.

Perret, D. Peiffert, and E. Deutsch. Oral presentation, ASTRO 2019;

▪Phase I/II trial of NBTXR3 activated by SBRT in patients with hepatocellular carcinoma or liver metastasis. M.

Pracht, E. Chajon, Y. Rolland, T. de Baere, F. Nguyen, J-P. Bronowicki, V. Vendrely, A. Sa Cunha, A-S.

Baumann, V. Croise-Laurent, E. Rio, P. Said, S. Le Sourd, P. Gustin, C. Perret, D. Peiffert, E. Deutsch. Poster,

ESMO 2019 ;

▪Combination of a radiation-enhancing nanoparticle, radiotherapy, and immune checkpoint inhibitors for treating

metastasized lung cancer in mice. Yun Hu, James Welsh, Sébastien Paris, Angelica Cortez. Poster, SITC

2019 ;

▪DNA damage enhancement by radiotherapy-activated hafnium oxide nanoparticles improves cGAS-STING

pathway activation in human colorectal cancer cells. Julie Marill, Naeemunnisa Mohamed Anesary, Sébastien

Paris. Radiotherapy and Oncology;

▪Hafnium oxide nanoparticles activated by radiotherapy triggers an abscopal effect dependent on CD8 T cells.

Audrey Darmon, Ping Zhang, Sébastien Paris. Poster presentation, OncoRad 2018;

▪Phase I/ II trial: NBTXR3 activated by SABR for patients with advanced HNSCC or NSCLC in combination with

an anti-PD1 treatment. Seiwert T, Le Tourneau C, Paris S, Bonvalot S. Poster presentation, OncoRad 2018;

▪NBTXR3, hafnium oxide nanoparticles in the treatment of liver cancer: a Phase I/ II trial. Enrique Chajon, Marc

Pracht, Thierry De Baere, France Nguyen, Jean-Pierre Bronowicki, Véronique Vendrely, Anne-Sophie

Baumann, Valérie Croisé-Laurent, Emmanuel Rio, Yan Rolland, Samuel Le Sourd, Pierre Gustin, Christophe

Perret, Francoise Mornex, Didier Peiffert, Philippe Merle, Eric Deutsch. Online abstract, ASCO 2018;

▪Hafnium oxide nanoparticles and radiotherapy for solid tumors: a promising new treatment strategy. Le

Tourneau C, Le Pechoux C, Kantor G, Carrere S, Bonvalot S, Le Prise E, Nguyen F, Baumann A.S, Vendrely V,

Bronowicki J.P, Moreno-Garcia V, Delannes M, Thariat J, Papai Z, Ruthowski P, Tiangco B, Rastrelli M,

Agoston P, Sunyach M.P, Rubi Li K, Mervoyer A, Sy-Ortin T, Hong A, Anghel R, Gronchi A. Poster presentation,

ESTRO 2018;

▪Activation of the cGAS-STING pathway by NBTXR3 nanoparticles exposed to radiotherapy. Marill J, Darmon A,

Zhang P, Paris S. Poster presentation, AACR 2018;

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Chapter 1. NANOBIOTIX AND ITS ACTIVITIES PRESENTATION

▪Hafnium oxide nanoparticles as a promising emergent treatment for head and neck cancer. C. Le Tourneau, V.

Calugaru, T. Jouff roy, J. Rodriguez, C. Hoffmann, B. Dodger, V. Moreno, Laurent Levy, E. Calvo. Poster

presentation, Multidisciplinary Head and Neck Symposium 2018;

▪A Phase I/II trial of NBTXR3 nanoparticles activated by SBRT in the treatment of liver cancers. Chajon E,

Pracht M, De Baere T, Nguyen F, Bronowicki J-P, Vendrely V, Baumann A-S, Croisé-Laurent V, Deutsch E.

Poster presentation, ASCO GI 2018;

▪Hafnium Oxide Nanoparticles and Radiotherapy to Convert Immunologically “Cold” Tumor into “Hot” Tumor.

Tetreau R, Chateau MC and Bonvalot S. Oral Presentation Immuno-Oncology Summit 2018;

▪Transforming immunologically “Cold” tumor into “Hot” tumor with hafnium oxide nanoparticles and radiation

therapy. S. Paris, A. Darmon, P. Zhang, M. Bergère and L. Levy. Poster presentation SITC 2017;

▪Antitumor immunity in patients with locally soft tissue sarcoma treated with hafnium oxide nanoparticles and

radiation therapy. J. Galon, M. Laé, J. Thariat, S. Carrere, Z. Papai, M. Delannes, P. Rochaix, L. Mangel, F.

Hermitte, Z. Sapi, T. Tornoczky, V. Servois, I. Birtwisle Peyrottes, R. Tetreau, M-C. Château, S. Paris, H. Brisse,

and S. Bonvalot. Poster presentation SITC 2017;

▪A Phase I dose-escalation study of intratumoral injection of NBTXR3 in combination with IMRT in patients with

locally advanced HNSCC. Le Tourneau C, Moreno V, Calugaru V, Jouffroy T, Rodriguez J, Hoff man C, Dodger

B, Dimitriu M, Levy L and Calvo E. Oral Presentation THNO 2017;

▪Hafnium oxide nanoparticles as an emergent promising treatment for solid tumors. Dimitriu M, Pottier A, Le

Tourneau C, Sargos P, Le Pechoux C, Kantor G, De T, Baere, Le Cesne A, Moreno V, Garcia, Calvo E and

Bonvalot S. Oral Presentation Journées annuelles Cancéropole Grand Sud Ouest 2017;

▪First human study testing a new concept of radio enhancement using nanoparticles (NBTXR3) activated by

radiation therapy in patients with locally advanced soft tissue sarcomas (STS). Bonvalot S, Le Pechoux C,

Debaere T, Kantor G, Buy X, Stoeckle E, Sargos P, Terrier P, Coindre J-M, Lassau N, Ait Sarkouh R, Dimitriu

M, Borghi E, Levy L, Deutsch E et Soria J-C. Clinical Cancer Research, 6 October 2016,

10.1158/1078-0432.CCR-16-1297;

▪Hafnium oxide nanoparticles, a radiation-enhancer for in situ cancer vaccine. Paris S., Pottier A., Levy L., et Lu

B. Poster presentation, conference SITC 2016;

▪Metals as radio-enhancers in oncology: The industry perspective. Pottier A, Borghi E, Levy L. Biochem Biophys

Res Commun. 2015;

▪The future of nanosized radiation-enhancers. Pottier A, Borghi E, Levy L. Br J Radiol 2015 ; 88 : 20150171 ;

▪A Phase I/II study evaluating the impact of NBTXR3 nanoparticles activated by pre-operative radiotherapy in

locally advanced soft tissue sarcoma. Le Pechoux C, Kantor G, Deutsch E, Sargos P, Levy A, de Baere TJ,

Buy X, Martinetti F, Stoeckle E, Terrier P, Le Cesne A, Italiano A, Dimitriu M, Levy L, Soria JC, Bonvalot S.

Poster #PD0045, ESTRO 2015;

▪The impact of NBTXR3 nanoparticles combined with radiotherapy in advanced soft tissue sarcoma (STS): a

Phase I/ II study. Bonvalot S. Scientiﬁc presentation CTOS 2014;

▪Hafnium oxide nanoparticles: toward an in vitro predictive biological effect? Marill J, Mohamed Anesary N,

Zhang P, Vivet S, Borghi E, Levy L. Radiation Oncology 2014, 9: 150;

▪New Use of Metals as Nanosized Radio-enhancers: Hafnium Oxide for Local Treatment of Cancer. Pottier A,

Borghi E, Levy L. Anticancer Research 2014, 34: 443-454;

▪Phase I study OF NBTXR3 nanoparticles, in patients with advanced soft tissue sarcoma (STS). Bonvalot S, Le

Pechoux C, de Baere TJ, Buy X, Sargos P, Stoeckle E, Terrier P, Lassau N, Le Cesne A, Italiano A, Antoine M,

Lezghed N, Goberna A, Dimitriu M, Levy L, Soria JC, Deutsch E. Poster #10563, ASCO 2014;

▪MRI contrast variation of thermosensitive magnetoliposomes triggered by focused ultrasound: a tool for image-

guided local drug delivery. Lorenzato C, Cernicanu A, Meyre ME, Germain M, Pottier A, Levy L, de Senneville

BD, Bos C, Moonen C, Smirnov P. Contrast Media Mol Imaging 2013; 8 (2):185-92;

▪Nanoscale radiotherapy with hafnium oxide nanoparticles. Maggiorella L, Barouch G, Devaux C, Pottier A,

Deutsch E, Bourhis J, Borghi E, Levy L. Future Oncology, 2012 Sep; 8 (9):1167-1181 ;

▪One pot synthesis of new hybrid versatile nanocarrier exhibiting efficient stability in biological environment for

use in photodynamic therapy. Thienot E, Germain M, Piejos K, Simon V, Darmon A, Marill J, Borghi E, Levy L,

Hochepied JF, Pottier A. J Photochem Photobiol B 2010 2; 100 (1):1-9;

▪Overview of the main methods used to combine proteins with nanosystems: absorption, bioconjugation, and

encapsulation. Di Marco M, Shamsuddin S, Razak KA, Aziz AA, Devaux C, Borghi E, Levy L, Sadun C. Int J

Nanomedicine 2010; 5:37-49;

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Chapter 1. NANOBIOTIX AND ITS ACTIVITIES PRESENTATION

▪Pp IX silica nanoparticles demonstrate differential interactions with in vitro tumor cell lines and in vivo mouse

models of human cancers. Simon V, Devaux C, Darmon A, Donnet T, Thiénot E, Germain M, Honnorat J, Duval

A, Pottier A, Borghi E, Levy L, Marill J. Photochem Photobiol 2010; 86 (1):213-22.

▪NBTXR3, a first-in-class radioenhancer for pancreatic ductal adenocarcinoma: report of first patient experience.

Bagley AF, Ludmir EB, Maitra A, Minsky BD, Li Smith G, Das P, et al. Clinical and Translational Radiation

Oncology. 2022.

▪Final Safety and HRQoL Results of the Phase 2/3 Act.In.Sarc Study With Preoperative NBTXR3 Plus Radiation

Therapy Versus Radiation Therapy in Locally Advanced Soft-Tissue Sarcoma. Bonvalot S, Rutkowski PL,

Thariat J, Carrère S, Ducassou A, Sunyach MP, et al. International journal of radiation oncology, biology,

physics. 2022.

▪Radiotherapy-activated NBTXR3 nanoparticles modulate cancer cell immunogenicity and TCR repertoire.

Darmon A, Zhang P, Marill J, Mohamed Anesary N, Da Silva J, Paris S. Cancer Cell Int. 2022;22(1):208-.

▪Imaging Features of Intratumoral Injection of NBTXR3 for Head and Neck Squamous Cell Carcinoma Lymph

Node Metastases. Ginat DT, Juloori A, Vivar OI, Farber LA, Gooi Z, Rosenberg AJ. Diagnostics.

2022;12(9):2156.

▪Nanoparticle therapy for head and neck cancers. Hoffmann C, Shen C, Le Tourneau C. Current opinion in

oncology. 2022.

▪Combining a nanoparticle-mediated immunoradiotherapy with dual blockade of LAG3 and TIGIT improves the

treatment efficacy in anti-PD1 resistant lung cancer. Hu Y, Paris S, Bertolet G, Barsoumian HB, He K, Sezen D,

et al. Journal of nanobiotechnology. 2022;20(1):417.

▪NBTXR3 improves the efficacy of immunoradiotherapy combining nonfucosylated anti-CTLA4 in an anti-PD1

resistant lung cancer model. Hu Y, Paris S, Bertolet G, Barsoumian HB, Wang Q, Da Silva J, et al. Front

Immunol. 2022;13:1022011.

▪Trial in Progress: 2019-1001 A Phase I Study of NBTXR3 Activated by Radiotherapy for Locally Advanced or

Borderline Resectable Pancreatic Ductal Adenocarcinoma (LAPC or BRPC). Fuentes G, Rodriguez MJ,

Matthew G, De Gracia B, Katz MHG, Ikoma N, et al. International journal of radiation oncology, biology,

physics. 2022;114(3):e202.

▪Abstract 5516: Nanoparticle-enhanced radiotherapy combined with triple blockade of PD1, LAG3, and TIGIT

enhances anti-tumor immune activation. Hu Y, Bertolet G, Paris S, Barsoumian H, SILVA JD, Gandhi S, et al.

Cancer Research. 2022;82(12_Supplement):5516-.

▪869 NBTXR3-enhanced proton beam immunoradiotherapy reshapes tumor immune microenvironment and

improves abscopal effect in an anti-PD1-resistant lung cancer. Hu Y, Paris S, Sahoo N, Bertolet G, Wang Q,

Wang Q, et al. Journal for ImmunoTherapy of Cancer. 2022;10(Suppl 2):A906-A.

▪Phase 1b/ 2 study of a radio-enhancer, PEP503 (NBTXR3), in combination with concurrent chemo-radiation in

locally advanced or unresectable rectal cancer. Huang C-W, Wang J-Y, Chen C-P, Wei P-L, Hu H-M, Hsu W-H,

et al. Journal of Clinical Oncology. 2022;40(16_suppl):3603-.

▪International Guidelines for Intratumoral and Intranodal Injection of NBTXR3 Nanoparticles in Head and Neck

Cancers. Liem X, De Baere T, Seiwert TY, Shen C, Papai Z, Moreno V, et al. International Journal of Radiation

Oncology*Biology*Physics. 2022;114(3, Supplement):e310.

▪682 Changing the radiation and immune-oncology paradigm with the radioenhancer NBTXR3: overcoming

resistance to anti-PD-1 blockade from the bench to the clinic. Rosenberg A, Frakes J, Niu J, Weiss J, Caudell

J, Said P, et al. Journal for ImmunoTherapy of Cancer. 2022;10(Suppl 2):A712-A.

▪3-Dimensional Volumetric Distribution and Dispersion Analysis of the Radioenhancer NBTXR3 in Various Solid

Malignancies. Shen C, Ducassou A, Bonvalot S, Chajon E, Farber LA, Vivar OI, et al. International Journal of

Radiation Oncology*Biology*Physics. 2022;114(3, Supplement):S12-S3.

▪684 NBTXR3 activated by radiotherapy in combination with nivolumab or pembrolizumab in patients with

advanced cancers: results from an ongoing dose escalation phase I trial (Study 1100). Shen C, Frakes J, Niu J,

Weiss J, Caudell J, Seiwert T, et al. Journal for ImmunoTherapy of Cancer. 2022;10(Suppl 2):A714-A.

▪1122 Radiotherapy-activated NBTXR3 nanoparticles induce interferon beta secretion by cancer cells. Journal

for ImmunoTherapy of Cancer. Silva JD, Paris S. Journal for ImmunoTherapy of Cancer. 2022;10(Suppl

2):A1166-A.

▪NANORAY-312: A phase III pivotal study of NBTXR3 activated by investigator’s choice of radiotherapy alone or

radiotherapy in combination with cetuximab for platinum-based chemotherapy-ineligible elderly patients with

locally advanced head and neck squamous cell carcinoma. Tourneau CL, Hoffmann C, Takacsi-Nagy Z, Liem

X, Salas S, Debard A, et al. Journal of Clinical Oncology. 2022;40(16_suppl):TPS6110-TPS.

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▪PEP503 (NBTXR3), a radioenhancer, in combination with concurrent chemoradiation (CCRT) in locally

advanced or recurrent head and neck squamous cell carcinoma (HNSCC): Dose-finding of a phase 1b/2 trial.

Wang C-H, Chao KSC, Chen P-T, Yeh K-Y, Chen Y-C, Chen Y-L, et al. Journal of Clinical Oncology.

2022;40(16_suppl):e18041-e.

▪NANORAY-312: A Phase III Pivotal Study of NBTXR3 Activated by Investigator's Choice of Radiotherapy Alone

or Radiotherapy in Combination with Cetuximab for Platinum-Based Chemotherapy-Ineligible Elderly Patients

with Locally Advanced HNSCC. Yom SS, Takacsi-Nagy Z, Liem X, Salas S, Debard A, Finzi L, et al.

International Journal of Radiation Oncology*Biology*Physics. 2022;114(3, Supplement):e313.

1.3.13.3.Intellectual property

We are innovators in oncology-related nanotechnology. We rely on a combination of patent, trademark, copyright,

and trade secret laws in the United States and other jurisdictions to protect our intellectual property rights. No single

patent or trademark is material to our business as a whole.

We seek to protect and enhance our proprietary technology, product candidates, inventions and improvements that

are commercially important to the development of our business by seeking, maintaining, and defending patent rights,

whether developed internally or licensed from third parties. We will also seek to rely on regulatory protection afforded

through orphan drug designation, data exclusivity, market exclusivity and patent term extensions where available.

To achieve this objective, we maintain a strategic focus on identifying and licensing key patents that provide

protection and serve as an optimal platform to enhance our intellectual property and technology base. Our

technologies and product candidates are protected by more than 450 issued or pending patents and patent

applications in over 23 patent families across the world. We hold key patents and patent applications with respect to

the concepts, products and uses of nanoparticles activated by ionizing radiation through NBTXR3 technology and for

new applications in nanomedicine.

Summarized below are our material patents and patent applications in our own name:


Technology	Number of patent families	Expiration date for each patent family	Countries in which patents are issued
NanoXray Technology (1)	13	2025	Australia, United States (divisional (2))
NanoXray Technology (1)	13	2031	United States (parent (2))
†		2029	Australia, Brazil, Canada, China, Algeria, Eurasia (9 countries), Europe (parent + divisional, 34 countries), Indonesia, Israel, India, Japan, South Korea, Morocco, Mexico, New Zealand, South Africa, Macau, Hong Kong, Singapore
		2031	United States, **
		2030	Canada, China, Europe (6 countries and 5 countries in divisional), Israel, India, Japan, Mexico, United States (parent + divisional), Hong Kong, **
		2032	China, Europe (6 countries), Japan
		2035	United States
		2032	Australia, Canada, China, Eurasia (1 country), Europe (11 countries), Israel, India, Japan, South Korea, Mexico, New Zealand, Singapore, Ukraine, South Africa, **
		2035	United States
††		2034	Australia, China, Europe (36 countries), Indonesia, Japan, Mexico, New Zealand (parent + divisional), Israel, Ukraine, United States (parent + divisional), Eurasia (1 country), Hong Kong, South Africa, Singapore, South Korea (parent + divisional), **
		2034	Australia, Canada, China, Europe (9 countries), Israel, Japan, Mexico, Singapore, Hong Kong, South Korea, **

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Technology	Number of patent families	Expiration date for each patent family	Countries in which patents are issued
		2034	Japan, United States, Europe (Validated in 7 countries)
		2034	United States, Japan, **
†††		2036	Indonesia, Israel, Australia, United States, Ukraine, Eurasia (countries to be validated), New Zealand, **
		2041	**
		2041	**
Other technologies	10	2034 2035	Australia, Canada, Eurasia (1 country), Israel, India, Indonesia, Mexico, South Korea, Japan, New Zealand, Ukraine, United States (divisional), Singapore, South Africa, **, # United States
		2035 2036	Europe (23 countries), Japan, United States, #
		2035	Japan, Europe (validated in 23 countries), United States, **, #
		2035	Japan, United States (parents), United States (divisional), **, #
		2035	Australia, India, Japan, Mexico, New Zealand, Ukraine, United States, Singapore, Israel, **, #
		2037	United States, Mexico, **
		2037	United States, Mexico, **
		2037	Israel, Mexico, Singapore, United States, **
		2038	Russia, United States, **
		2038	United States, **
		2041	**

(1)The NanoXray technology covers, among other things, three product candidates, each of which is based on the same hafnium oxide core.

The goal of each of these three product candidates is to help patients receiving radiotherapy by enhancing the effect of radiotherapy within tumor

cells, without increasing the dose to surrounding healthy tissues. The three product candidates differ in the composition of the nanoparticle coating or

formulation, which have been developed for three different modes of administration to cover most oncology applications. The most advanced product

candidate in the NanoXray portfolio, and our current focus for development and commercialization, is injectable NBTXR3.

(2)“parent” and “divisional” refer to parent and divisional patents filed in a given country. A divisional (or daughter) application from any

application may be filed with respect to the parent. The same text is used as in the parent application, but the claims differ. A divisional application

may be filed to obtain a broader or different protection than what was obtained for the parent. The effective filing data of the divisional application is

the same as the parent application.

#Patent family owned by Curadigm.

*This expiration year does not take into account supplementary patent protection that could be obtained for some of our patents in the

United States, Europe and other countries. Expiration dates for US patents not yet granted may be subject to patent term adjustment.

**Patent application pending in at least one country/jurisdiction.

†Patent family covering the specific composition utilized in NBTXR3 (i.e., composition of matter). This patent family covers the injectable

use of metal oxide nanoparticles with a specific density for killing tumor cells, including cancer cells. The injectable use of an efficient dose of NBTXR3

in oncology is covered by this patent family.

††Patent family covering the specific composition utilized in injectable NBTXR3 (i.e., composition of matter). This patent family covers the

injectable use of metal oxide nanoparticles with a specific density for killing tumor cells and shrinking tumors where a certain number of electrons are

delivered to the targeted tumor. The injectable use of an efficient dose of NBTXR3 in oncology is covered by this patent family.

†††Patent family covering the specific composition utilized in NBTXR3 (i.e., composition of matter). This patent family covers the injectable

use of NBTXR3 as a therapeutic vaccine used to induce an immune response, including its use in immuno-oncology and its combination with other

checkpoint inhibitors.

In addition to patent protection, we have trademark protection in many countries for our “Nanobiotix” name and

Nanobiotix logo. We own over 300 trademark registrations and applications related to our products, product

candidates, processes and technology worldwide. Trademark registrations are generally granted for a period of ten

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years and are renewable. We anticipate we will apply for additional patents and trademark registrations in the future

as we develop new products, product candidates, processes and technologies.

We also rely on trade secrets to develop and maintain our proprietary position and protect aspects of our business

that are not amenable to, or that we do not consider appropriate for, patent protection. We seek to protect our

proprietary technologies, in part, through confidentiality agreements with our employees, consultants, scientific

advisors, contractors and others with access to our proprietary information. There can be no assurance, however,

that these agreements will provide meaningful protection or adequate remedies for any breach, or that our trade

secrets will not otherwise become known or be independently discovered by our competitors.

1.3.14.Our Major Contracts

We have entered into collaboration agreements in order to enable us to optimize our resources, expedite product

development, potentially generate revenue and maintain limited risk exposure outside of Europe.

1.3.14.1.M.D. Anderson Cancer Center of the University of Texas

On December 21, 2018, the Company entered into a clinical research collaboration agreement with the MD

Anderson Cancer Center of the University of Texas (“MD Anderson”) in the field of nanoparticles in order to improve

the efficiency of radiotherapy treatment for certain types of cancer. The agreement was amended and restated in

January 2020 and subsequently amended in June 2021.

Obligations of the Parties

Under the terms of the collaboration agreement, MD Anderson undertakes to lead several Phase 1 and Phase 2

clinical trials for NBTXR3 in various cancer indications to be agreed by us and MD Anderson, according to a

timetable and predefined recruitment thresholds. The Company expects to enroll approximately 312 patients across

the clinical trials covered by the agreement. For this purpose, MD Anderson provides the staff, equipment and the

premises required for each trial. As no exclusivity has been granted under the collaboration agreement, MD

Anderson can conduct similar clinical trials with third parties, simultaneously if need be. For more information on the

clinical trials conducted within the MD Anderson collaboration, see the paragraph titled “NBTXR3 Development

Pipeline” above.

The Company shall provide the required doses of NBTXR3 for each clinical trial and funds the clinical trials pursuant

to the following: the Company commits to pay a minimum amount of approximately US $11 million for and within the

conduct of the trials until the end of the collaboration. Accordingly, an initial payment of $0.96 million was paid upon

entering into the agreement and a payment of another $0.96 million was paid on February 3, 2020. Additional

payments will be paid semi-annually during the collaboration on the basis of patients enrolled during the relevant

period, with the balance payable upon enrollment of the final patient for all studies. The Company is also required to

make an additional one-time milestone payment upon (i) a first regulatory approval obtained from the FDA for

NBTXR3 and (ii) the enrollment of a certain number of patients in the United States. The amount of this one-time

milestone payment by the Company will increase significantly each year until payable upon the prerequisite

conditions being met. The amount for such milestone payment ranges from between $2.2 million (for the initial year

covered-2020) up to a maximum of $16.4 million (if the conditions are met in 2030).

The protocol, schedule, monitoring, termination and replacement of each trial will be determined by mutual

agreement between MD Anderson and the Company.

MD Anderson has made a number of representations for the benefit of the Company and has granted the Company

audit and information rights in connection with these clinical trials, in particular with respect to pharmacovigilance.

Intellectual Property

Each party retains ownership of its pre-existing or property rights generated outside the scope of the collaboration

agreement, it being specified that the Company licenses NBTXR3 to MD Anderson for use in the clinical trials under

the agreement.

The Company is the exclusive owner of any right, title or other interest in any invention or discovery made in a

clinical trial that incorporates NBTXR3 or any formulation relating to NBTXR3 (the “NBTXR3 Inventions”). As such,

MD Anderson agrees to transfer any rights it may have in the NBTXR3 Inventions. The Company grants MD

Anderson a non-exclusive, perpetual and irrevocable license, free of charge, for non-profit academic or research

purposes to use the NBTXR3 Inventions.

Any inventions and discoveries, other than a NBTXR3 Invention, made in the course of a clinical trial (the “Other

Inventions”) are the property of their inventor(s), MD Anderson and/or the Company, as the case may be.

MD Anderson grants the Company a non-exclusive license, free of charge, to any Other Invention it may own as well

as an exclusive option to negotiate an exclusive, remunerated license on this Other Invention (the “Option”). If the

Company does not exercise the Option or if the parties are unable to reach an agreement on the terms of the

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license, in each case within a specified period of time, MD Anderson would then be free to license the Other

Invention to any third party.

Finally, MD Anderson and the Company are co-owners of the data and clinical results generated in the conduct of

the trials performed within the collaboration agreement, it being specified that MD Anderson may use these data for

academic or non-profit research purposes. For each clinical trial, MD Anderson and the principal investigator decide

on the date, content and authors of the first publication of the clinical data and results, it being specified that the

Company has a right of review of such publications. Any unpublished data is considered confidential and may not be

transferred by one party to a third party without the written consent of the other party.

Responsibility

The Company shall be liable to MD Anderson, each principal investigator and their affiliates for any damages

resulting from NBTXR3 (whether due to the manufacture, design or use by a patient of the product candidate or to

the negligence of the Company in the performance of its obligations under the collaboration agreement), subject to

any gross negligence or willful misconduct of the indemnified party. In addition, the Company shall be liable for

medical costs reasonably incurred by a patient for any treatment resulting directly from the administration of

NBTXR3. Accordingly, the Company is required to maintain an insurance policy covering its liability for clinical trials

conducted by MD Anderson.MD Anderson is liable to the Company and its affiliates for any damages resulting from

(i) injury to a patient that is directly caused by the failure of MD Anderson or its personnel to comply with the trial

protocol or (ii) gross negligence or willful misconduct by MD Anderson in the conduct of the trial, subject to any gross

negligence or willful misconduct of the indemnified party.

Term and Termination

The collaboration agreement between MD Anderson and the Company is entered into for the duration of the clinical

trials, with a term of no less than 5 years.

The agreement may be terminated by either party in the event of a material breach of the other party’s obligations

under the agreement which is not remedied within 30 days of the first party’s notification of the breach to that party.

Termination of the contract shall not affect the conduct of ongoing clinical trials (other than with respect to the

termination of a specific trial, as described below), which shall be conducted in accordance with their original terms.

Either party may terminate a clinical trial (i) in the event of a material breach of the other party’s obligations (including

those under the trial protocols) which has not been remedied within 30 days of notification of the breach sent to that

party by the former party, (ii) due to health and safety issues related to NBTXR3 or the procedures applicable to that

clinical trial, or (iii) if the parties are unable to agree on the identity of the principal investigator to conduct the trial or

if the principal investigator does not agree to the terms of the collaboration agreement or trial protocol. In addition, a

clinical trial is automatically terminated in the event of withdrawal or rejection of the regulatory approvals required to

conduct the trial.

Pursuant to this agreement, the collaboration is implemented under the supervision of a steering committee,

comprising three representatives of each party, and provides a process for dispute resolution by a Senior Vice

President of MD Anderson and the chairman of the Company’s executive board.

1.3.14.2.Lian Oncology Limited

On May 11, 2021, the Company entered into a strategic License, Development and Commercialization Agreement

(the “LianBio Agreement”) with Lian Oncology Limited, a Hong Kong company, for the development and

commercialization of NBTXR3, as a product activated by radiotherapy in the field of oncology, in key parts of Asia—

the People’s Republic of China, Macau, Hong Kong, Thailand, Taiwan, South Korea and Singapore (collectively, the

“Territory”). The Company has granted LianBio an exclusive, royalty-bearing license which includes, subject to

certain conditions, the right for LianBio to grant sublicenses to its affiliates and/or third-party subcontractors involved

in the development of NBTXR3.

Obligations of the Parties

Under the LianBio Agreement, LianBio is exclusively responsible for the development and commercialization of

NBTXR3 throughout the Territory, except for specified ongoing trials that the Company will conclude. The Company

is responsible for the manufacturing of NBTXR3 and will be the exclusive supplier of NBTXR3 to LianBio.

Pursuant to the LianBio Agreement, LianBio will have to enroll a specified percentage of the worldwide total number

of patients in the Company’s global Phase 3 registrational study evaluating NBTXR3 for patients with locally

advanced head and neck squamous cell carcinoma (NANORAY-312) and each of four other specified global

registrational trials across indications and therapeutic combinations. For NANORAY-312, LianBio is expected to

enroll approximately 100 patients based on the Company’s current worldwide enrollment expectations. In the event

that LianBio does not meet its enrollment undertaking for these trials, LianBio will be responsible for covering certain

incremental costs incurred by the Company as a result. Otherwise, LianBio will fund all development and

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commercialization expenses in the Territory, and the Company will fund all development and commercialization

expenses in all other geographies.

For all non-registrational trials (i.e., Phase 1 or Phase 2 trials) undertaken to support the development and approval

of NBTXR3, the Company and LianBio have agreed to provide each other with rights to access all clinical efficacy

and safety data. For additional registrational trials, the Company and LianBio have agreed to provide each other with

rights to access all clinical safety data and to provide an opportunity to license and right of reference to efficacy data,

subject to certain cost-sharing and/or enrollment undertakings.

Pursuant to the LianBio Agreement, LianBio has sole control over commercialization in the Territory and is

responsible for all costs and expenses of such commercialization. LianBio, or its affiliates and/or sublicensees, is

solely responsible for all communications, filings with, as well as approvals sought from regulatory authorities to

obtain all marketing authorizations in relation to NBTXR3 in the Territory.

As consideration for entering into the LianBio Agreement, the Company received a non-refundable upfront payment

from LianBio of $20.0 million in June 2021.

As of the date of this report, the Company is also eligible to receive up to an aggregate of $205 million in potential

contingent, development and commercialization milestone payments. The Company will also be eligible to receive

tiered, low double-digit royalties based on net sales of NBTXR3 in the Territory, subject to downward adjustment

based on enrollment incentives and customary country-by-country competition- and intellectual property-related

triggers. Royalties will be payable on a product-by-product and country-by-country basis until the latest of (i) the

expiration of the last-to-expire valid claim of a licensed patent covering NBTXR3, (ii) the expiration of regulatory

exclusivity of NBTXR3, or (iii) the ten-year anniversary of the first commercial sale of NBTXR3. Upon the expiration

of the royalty term in a given country, LianBio shall be granted a perpetual, royalty-free, sublicensable license in such

country.

Responsibility

Pursuant to the LianBio Agreement, the collaboration is implemented under the supervision of a joint steering

committee, which will include an equal number of representatives of each party, including one member of senior

leadership of each of LianBio and the Company, and will meet on a regular basis to provide oversight and facilitate

information sharing between LianBio and the Company. In the event of a dispute among representatives at the joint

steering committee, the matters shall be escalated to appropriate senior officers of LianBio and the Company. In the

event such senior officers cannot reach an agreement on the matters at hand within a set timeframe, LianBio and the

Company have agreed that one of the parties shall have the final decision-making authority on certain specific

matters, without prejudice to any contractual obligations set out under the LianBio Agreement.

Pursuant to the LianBio Agreement, LianBio’s Territory-specific development and regulatory plan and

commercialization in the Territory will be conducted pursuant to LianBio’s Territory-specific plans, which will be

subject to periodic updates and joint steering committee review.

The Company retains the first right to prosecute, maintain and defend, at its expense, all of its licensed patents in the

Territory. In the event that the Company elects not to prosecute or maintain any such patent in the Territory or not to

defend a patent in the Territory, the Company has agreed to notify LianBio, and LianBio shall have the right, but not

the obligation, to assume such prosecution, maintenance or defense at its own expense. LianBio shall have the first

right to enforce, at its expense, the Company’s intellectual property against infringement in the Territory, except

where the Company is enforcing such intellectual property both within and outside the Territory against such

infringement. In the event that LianBio elects not to enforce the Company’s intellectual property against infringement

in the Territory, it has agreed to notify the Company, and the Company will have the right to enforce such intellectual

property at its expense.

The Company and LianBio have agreed to customary confidentiality obligations with respect to trade secrets and

confidential or proprietary information disclosed in connection with their respective performance under the LianBio

Agreement, subject to customary exceptions. The Company and LianBio have agreed to provide customary

indemnification to one another for claims relating to their respective obligations under the LianBio Agreement.

LianBio has agreed to maintain a customary liability insurance policy during the term of the LianBio Agreement.

LianBio has undertaken to conduct and ensure that all of its affiliates, sublicensees and subcontractors conduct their

business under the LianBio Agreement in accordance with applicable laws and to the extent applicable with respect

to certain development activities, FDA and EU medical device requirements.

Dispute Resolution

The LianBio Agreement provides a dispute resolution mechanism with respect to interpretation of rights or

obligations and any alleged breaches under the LianBio Agreement. The dispute resolution mechanism provides for

the escalation of such matters to the joint steering committee and, if unresolved following such escalation, further

escalation to the respective chief executive officers of the Company and LianBio to negotiate in good faith. If such

matter is unable to be resolved, the LianBio Agreement provides for arbitration, except that certain disputes relating

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to intellectual property matters are not subject to such an arbitration requirement and may be brought in courts of

competent jurisdiction.

Intellectual Property

The Company and LianBio retain ownership of their respective pre-existing intellectual property. Other inventions

and discoveries relating to NBTXR3 made in the course of performing obligations under the LianBio Agreement

made solely by the Company or LianBio, as the case may be, will be owned by the respective inventors. To the

extent an invention or discovery relating to NBTXR3 is made by LianBio and the Company together, such invention

and any related patents will be jointly owned by LianBio and the Company. The rights to file, prosecute and enforce

such jointly-owned patents will be determined by mutual agreement through the joint steering committee.

Termination

Unless terminated earlier, the LianBio Agreement will remain in effect for so long as royalties are payable under the

LianBio Agreement. The LianBio Agreement may be terminated earlier by either party if the other party commits an

uncured material breach. In any event where LianBio has a termination right based on a material breach by the

Company, LianBio may elect in lieu of termination to continue the LianBio Agreement, subject to a downward

percentage reduction in all milestone and royalty payments.

Either party may also terminate the agreement in the connection with the occurrence of certain insolvency or

bankruptcy events with respect to the other party. LianBio may terminate the agreement following a change in control

of the Company, subject to a specified notice period. The Company may terminate the agreement under certain

circumstances in connection with a change of control of LianBio. The Company may also terminate the LianBio

Agreement in the event that LianBio or its affiliates bring or join any challenge to the validity or enforceability of the

Company’s patents, subject to certain limited exceptions.

Termination of the LianBio Agreement will terminate all rights, licenses and sublicenses under the agreement,

subject to the Company’s agreement, in certain cases, to negotiate in good faith with sublicensees regarding a

potential direct license.

According to the LianBio Agreement, the Company and LianBio entered into a clinical supply agreement and a

related quality agreement for the purpose of the Company supplying LianBio and LianBio purchasing exclusively

from the Company all the required amount of NBTXR3 to to make and/or have made the product for clinical studies

conducted within the Territories.

1.3.14.3.PharmaEngine

In August 2012, the Company entered into a license and collaboration agreement with PharmaEngine, a Taiwan-

based company, for the development and commercialization of NBTXR3 (under the code name PEP503) in several

countries in the Asia-Pacific region. Under this agreement, PharmaEngine was responsible for the development

(non-clinical and clinical research) and marketing of NBTXR3 across the Asia-Pacific region. In return,

PharmaEngine was required to make payments to the Company based on the achievement of development and

commercialization milestones for NBTXR3. The Company received an upfront payment of $1 million upon signing

the agreement and, through December 31, 2020, received $2 million in two interim payments.

In March 2021, in light of disagreements over a number of issues with respect to the development of NBTXR3 in the

Asia-Pacific region, the Company and PharmaEngine mutually agreed to terminate the agreement. Accordingly, on

March 4, 2021, the Company and PharmaEngine entered into a Termination and Release Agreement. Under the

termination agreement the Company will retain all rights to the development and commercialization of NBTXR3 in

the Asia Pacific region. The Company has agreed to make total termination payments to PharmaEngine of up to

$12.5 million in aggregate. PharmaEngine was eligible for, and received, a $2.5 million payment from the Company

following the announcement of its collaboration with LianBio for the Asia-Pacific region. During the six months ended

June 30, 2021, PharmaEngine also received $4.0 million from the Company in conjunction with the completion of

various administrative steps in connection with the winding-up of the collaboration. In the second half of 2022,

PharmaEngine received an additional $1.0 payment following receipt and validation of certain clinical study reports.

PharmaEngine will be eligible to receive a final payment of $5 million upon a second regulatory approval of an

NBTXR3-containing product in any jurisdiction of the world for any indication. PharmaEngine is entitled to receive

from the Company a low-single digit percentage tiered royalty based on net sales of NBTXR3 in the Asia-Pacific

region for a 10-year period commencing on the corresponding first date of sales in the region.

As part of the termination agreement, PharmaEngine has re-assigned to the Company rights for the development,

manufacture, commercialization and exploitation of NBTXR3 in the Asia-Pacific region, as well as all development

data, regulatory materials, and all regulatory approvals that are in the name of PharmaEngine or its affiliates.

The Company and PharmaEngine also agreed to a mutual release of all claims against the other party and its

respective affiliates.

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1.3.14.4.EIB Finance Contract and Royalty Agreement

In July 2018, we and EIB entered into a finance contract and a royalty agreement. The EIB loan is comprised of

three potential disbursement tranches, each drawable in the absence of an event of default or prepayment event,

subject to our achieving specified documentary and/or performance criteria and making customary representations

and warranties.

As noted above, we drew the initial tranche in October 2018 and the second tranche in March 2019. The terms of the

EIB loan provide for a final €10.0 million third tranche if we satisfy the applicable performance criteria prior to July 26,

2021. The disbursement of the third tranche is dependent on conditions which were not met by July 31, 2021.

Consequently the Company has not requested the final tranche of the EIB loan, and the third tranche is no longer

available.

On October 18, 2022, the Company and the EIB amended the finance contract and the royalty agreement described

below (all together, the “Amendment Agreements”) to re-align the Company’s outstanding debt obligations with its

expected development and commercialization timelines.

Under the finance contract as amended, the final repayment date for the outstanding principal under the two drawn

tranches is fixed on the earliest of (i) June 30, 2029 and (ii) the third royalty payment date (being June 30 of the third

financial year starting after commercialization of NBTRX3, defined as the first Financial Year in which the Group first

achieves net sales in excess of EUR 5,000,000 (the “Commercialization”)) for the first tranche and the second

royalty payment date (being June 30 of the second financial year starting after Commercialization) for the second

tranche.

Prior to repayment at maturity (or earlier prepayment), interest on the first tranche shall accrue at the rate of 6%

annually, with such interest being capitalized and added to the outstanding principal. Interest on the second tranche

is payable semi-annually in arrears at a 5% fixed rate. Interest on any overdue amounts accrues at an annual rate

equal to the higher of the applicable rate plus 2% or EURIBOR plus 2%.

An amount of €5.4 million in interest accrued as payment-in-kind (“PIK”) on the first tranche shall be prepaid in

October 2024, except in the case of the closing of a collaboration agreement in which case the PIK will be subject to

an earlier redemption by October 2023. Going forward, principal on the first tranche will accrue interest at the

unchanged rate of 6% annually, with such interest being capitalized and due as PIK interest at maturity.

We may repay, in whole or in part, any tranche, together with accrued interest upon 30 days prior notice, subject to

the payment of a customary prepayment fee. EIB may require us to prepay all outstanding amounts under the EIB

loan in connection with certain events, including a substantial reduction in the anticipated cost of our NBTXR3

development program, a prepayment of certain non-EIB financing, certain change of control events, Dr. Laurent Levy

ceasing to be our principal executive officer or ceasing to hold a specified number of shares, or certain dispositions

of assets related to our NBTXR3 development program, in each case, subject to the payment of a customary

prepayment fee.

EIB may also require immediate repayment, together with accrued interest and a customary prepayment fee, in

connection with the occurrence of any event of default with respect to us or our subsidiaries, including failure to pay

any amounts due under the EIB loan, a determination of a material defect in any previously made representation or

warranty, any cross-default involving the acceleration or cancellation of an amount equal to at least €100,000 or

pursuant to any other loan from EIB, certain bankruptcy or insolvency events, the occurrence of any material

adverse change, or any failure to comply with any other provision under the Finance Contract that remains uncured

for 20 business days.

Prepayment fees, if required, are calculated as a percentage of the amount prepaid, which percentage decreases

over time.

The terms of the EIB loan impose restrictions on us and our subsidiaries that may impact the operation of our

business, including, among others, restrictions on (i) the disposition of any part of our business or assets outside of

arm’s length ordinary-course transactions, (ii) restructuring or making any substantial change to the nature of our

business, (iii) entering into certain merger or consolidation transactions, (iv) the disposition of our shareholdings in

our material subsidiaries, (v) pursuing acquisitions or investments, (vi) incurring any indebtedness in excess of €1.0

million in the aggregate, (vii) providing guarantees in respect of liabilities or other obligations, (viii) engaging in

certain hedging activities, (ix) granting security over our assets, (x) paying dividends or repurchasing our shares, or

(xi) impairing our intellectual property rights. Pursuant to these restrictions, we obtained EIB’s consent to the HSBC

PGE Loan (as defined below) and the Bpifrance PGE Loan, which represented an aggregate indebtedness of €10

million.

As part of the restructuring implemented by the Amended Agreements, Nanobiotix is subject to a financial covenant

that requires maintenance of a minimum cash balance equal to the outstanding principal owed to EIB, which totals

€25.3 million at December 31, 2022. However, Nanobiotix has obtained a 15 million euros temporary waiver, until

July 31, 2023, and has reached an agreement in principle with EIB to automatically extended it until January 31,

2024 should (a) a business development partnership, collaborative or strategic alliance have become effective

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before July 31, 2023 and (b) the contractual documentation is signed within fifteen days following the date of this

form 20-F. Failing this extension period, and except if it has obtained appropriate funding prior, the Company is

expected to be in breach of this temporary waiver as of July 31, 2023..

Any of our subsidiaries whose gross revenues, total assets or EBITDA represents at least 5% of our consolidated

gross revenues, total assets or EBITDA is required to guarantee our borrowings under the EIB loan.

Pursuant to the royalty agreement, we also committed to pay royalties to EIB calculated on an annual basis for a

period of six financial years starting on the first year of Commercialization and payable on each June 30 after closing

of the relevant financial year. The amount of royalties payable is calculated based on low single-digit royalty rates,

which vary according to the number of tranches that have been drawn and indexed on our annual sales turnover.

In the event that we elect to prepay a tranche of the EIB loan, EIB requires prepayment of the EIB loan in connection

with an event of default or other prepayment event under the Finance Contract, or a change of control event occurs

following the maturity of the EIB loan, EIB is entitled to request payment of an amount equal to the highest of (i) the

net present value of all future royalties, as determined by an independent expert, (ii) the amount required for EIB to

realize an internal rate of return of 20% on the EIB loan, and (iii) €35.0 million. Interest on any overdue amounts

accrues at an annual rate equal to 2%.

As part of the restructuring implemented by the Amended Agreements, Nanobiotix has agreed to pay an additional

milestone payment of €20 million to EIB at the latest on June 30, 2029. An accelerated payment schedule for this

additional milestone payment would be triggered calling for the repayment in two equal installments due one year

and two years after Commercialization, respectively. Further, should the Company secure non-dilutive capital

through the execution of any business development deal, this accelerated payment schedule for the additional

milestone payment would be triggered by reflecting a prorated payment amount not exceeding 10% of any upfront or

milestone payment received by Nanobiotix.

1.3.14.5.State-guaranteed loans

On June 5, 2020, the Company received initial approval from each of HSBC France and Bpifrance for two State-

guaranteed loans (prêts garantis par l’État) of €5.0 million each, representing a total amount of €10 million.

Accordingly, the Company entered into two agreements with HSBC France and Bpifrance Financement, respectively,

each providing for a €5 million State guaranteed loan.

The HSBC PGE Loan is 90% guaranteed by the French State and had an initial 12-month term during which it bore

no interest. At the end of this initial term, we (1) paid a guarantee fee equal to 0.25% of the €5 million principal

amount and (2) elected to amortize the principal amount of the loan over a period of five years during which the

HSBC PGE Loan will bear interest at a rate of 0.50% per annum for the first two years of amortization and 1% per

annum for the third, fourth and fifth year of amortization. The HSBC PGE Loan must be repaid upon the occurrence

of customary events of default.

The Bpifrance PGE Loan has a six-year term and is 90% guaranteed by the French State. The Bpifrance PGE Loan

bears no interest for the first 12-month period but, following such 12-month period and for the subsequent five years,

bore an interest rate of 2.25% per annum, inclusive of an annual State guarantee fee of 1.61% per annum. The

principal and interest of the Bpifrance PGE loan is repaid in 20 quarterly installments from October 31, 2021 until

July 26, 2026. The Bpifrance PGE Loan must be repaid upon the occurrence of customary events of default.

1.3.14.6.Bpifrance Advances and Loans

Except in the event we are unable to commercialize NBTXR3, we have undertaken to repay the total amount of our

€2.1 million advance under the Strategic Industrial Innovation program in 16 quarterly installments beginning

December 31, 2022 and ending September 2026.

We have undertaken to repay the €2.0 million interest-free innovation loan from 2016 in 16 quarterly installments of

€125 thousand each, beginning in September 2018. Accordingly, we repaid €0.3 million in 2018 and €0.5 million in

2019. Due to COVID-19, Bpifrance allowed us to defer two quarterly payments otherwise due in 2020, which will be

due, without fees or penalties, at the end of the initial reimbursement period. The 2016 innovation loan was fully

repaid as of December 31, 2022.

Curadigm’s €1.0 million financing agreement under Bpifrance’s Deep Tech program (the “Deep Tech Grant”), which

supports Curadigm’s development of Nanoprimer technology, comprises (i) a €500 thousand conditional advance,

the first €350 thousand of which was funded at signing and the remainder of which will be funded upon completion of

a project related to a nanomedicine therapy, at our request, and (ii) a €500 thousand grant, the first €350 thousand of

which was funded at signing and the remainder of which will be funded upon completion of a project related to a

nanomedicine therapy, at our request. Curadigm received (i) €350 thousand of the €500 thousand conditional

advance in June 2020, and (ii) €350 thousand of the €500 thousand grant, €187 thousand of which was recognized

as revenue in during the year ended December 31, 2020. The conditional advance component of the financing is

repayable each quarter, commencing March 31, 2023 and continuing through December 31, 2027.

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1.3.14.7.Equity Line

The Chairman of the Executive Board, acting under the authority of the Executive Board of Directors held on May 18,

2022, and in accordance with the 21st resolution from the Annual Shareholders’ Meeting of April 28, 2021, has

decided to set up an equity line financing agreement (PACEO).

In accordance with the terms of said agreement executed on May 18, 2022, Kepler Cheuvreux, acting as the

underwriter of this facility, committed to underwrite up to 5,200,000 shares, over a maximum timeframe of 24 months

starting from May 2022. Should Nanobiotix choose to use this facility, the shares will be issued based on the lower of

the two daily volume weighted average market price for the two trading days prior to each issue, minus a maximum

discount of 5.0%. (see section 5.1.4.5 of the URD Equity Line Agreement with Kepler Cheuvreux)

1.3.15.Our research agreements

We have established strategic collaborations with a number of hospitals, clinics and cancer treatment centers in

France and abroad. These agreements provide that we may negotiate certain commercial rights with such

collaborators with respect to joint inventions or inventions made by our collaborators that arise from the results of the

collaboration.

Under the preclinical research agreements for these collaborations, we retain exclusive ownership over any

inventions made solely by us. Any invention made solely by a research institution would be owned by the relevant

research institution, but would be subject to option to obtain an exclusive license, which would be free for research

purposes and royalty-bearing for commercial activities. Inventions made jointly by us and a research institution would

be jointly owned. As of December 31, 2022, no inventions under these programs have been made solely by a

research institution or jointly by us and a research institution.

We have entered into an agreement with Institut Gustave Roussy, one of the world’s leading cancer-research

institutes and the largest cancer center in France, for radiobiology research and preclinical development of NBTXR3.

Pursuant to the agreement, we conduct studies at Institut Gustave Roussy’s radiobiology lab to evaluate the

antitumor activity of nanoparticles activated by ionizing radiation. We maintain all rights to the products of our

studies; however, Institut Gustave Roussy may use the results without charge solely for the purposes of its own

academic research.

We have also partnered with The University of Texas MD Anderson Cancer Center in Houston, Texas, to conduct

immunotherapeutic preclinical research in lung cancer, combining NBTXR3 and immune checkpoint inhibitors. This

research collaboration is distinct from our clinical trial collaboration with MD Anderson and is intended to enable us to

generate preclinical data using NBTXR3 activated by radiotherapy plus anti-PD-1 nivolumab (murine version of

Opdivo) or other immune checkpoint inhibitors, such as anti-CTLA-4, anti-TIGIT and anti-LAG3.

1.3.16.Trademarks, trademark applications and domain names

We own various trademark registrations and applications, and unregistered trademarks and service marks.

“Nanobiotix”, “NBTXR3”, the Nanobiotix logo and other trademarks or service marks of Nanobiotix S.A. appearing in

the Universal Registration Document are the property of Nanobiotix or its subsidiaries. Solely for convenience, the

trademarks, service marks and trade names referred to in the Universal Registration Document are listed without the

® and ™ symbols, but such references should not be construed as any indicator that their respective owners will not

assert, to the fullest extent under applicable law, their rights thereto. All other trademarks, trade names and service

marks appearing in the Universal Registration Document are the property of their respective owners. We do not

intend to use or display other companies’ trademarks and trade names to imply any relationship with, or

endorsement or sponsorship of us by, any other companies.

The Company, in its trademark filing strategy, registers them domestically or internationally. Trademark registrations

are generally granted for a period of ten years and are renewable indefinitely. Some pay proof of use for the

maintenance of fees. In other countries, registrations remain valid unless a level is interested in suing forfeiture for

failure to use the mark. The Company holds various brands that are the main and most important:

Nanobiotix

The Company holds a number of domain names and different extensions, the main and most important of which are:

www.nanobiotix.com ; .fr .net ; .org ; .eu ; .biz ; www.actinsarc.com ; www.hensify.com

1.3.17.Government regulation, product approval and certification

Government authorities in the United States, at the federal, state and local level, in the European Union and in other

countries extensively regulate, among other things, the research, development, testing, manufacturing, quality

control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval

monitoring and reporting, marketing and export and import of products such as those we are developing. NBTXR3

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and any other therapeutic candidates that we develop must be approved by any relevant health authorities before

they may be legally marketed in the relevant country and, in the case NBTXR3 or any other therapeutic candidates

would be classified as medical device, must complete the conformity assessment procedure with the relevant

Notified Body before they may be legally marketed in the relevant country. In addition, in the European Union, the

Group is subject to data protection rules. Finally, the Group’s activities may be qualified as sensitive activities and

thus enter into the scope of the foreign investment control regime in France.

1.3.17.1Regulation in the United States

United States Drug Development Process

In the United States, the FDA regulates drugs under the Federal Food, Drug and Cosmetic Act and implementing

regulations. Drugs are also subject to other federal, state and local statutes and regulations. The process of

obtaining regulatory approvals and subsequent compliance with appropriate federal, state and local statutes and

regulations require the expenditure of substantial time and financial resources. Failure to comply with the applicable

US requirements at any time during the product development process, approval process or post approval may

subject an applicant to administrative and/or judicial sanctions. FDA sanctions may include, among other actions,

refusal to approve pending applications, withdrawal of an approval, a clinical hold, warning letters, product recalls or

withdrawals from the market, product seizures, total or partial suspension of production or distribution, injunctions,

fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties. Any agency or judicial

enforcement action could have a material adverse effect on us.

The process required by the FDA before a drug may be marketed in the United States generally involves the

following:

•Completion of extensive preclinical laboratory tests, preclinical animal studies and formulation studies in

accordance with applicable regulations, including good laboratory practice (GLP) regulations;

•Submission to the FDA of an investigational new drug (IND) application, which must become effective

before human clinical trials may begin;

•Performance of adequate and well-controlled human clinical trials in accordance with applicable

regulations, including current good clinical practice (GCP) regulations to establish the safety and efficacy

of the drug candidate for its proposed indication;

•Submission to the FDA of a new drug application (NDA) for a new drug product;

•A determination by the FDA within 60 days of its receipt of an NDA to accept the submitted NDA for filing

and thereafter begin a substantive review of the application;

•Satisfactory completion of an FDA inspection of the manufacturing facility or facilities where the drug is

produced to assess compliance with cGMP regulations to assure that the facilities, methods and controls

are adequate to preserve the drug’s identity, strength, quality and purity;

•Potential FDA inspection of the preclinical and/or clinical trial sites that generated the data in support of

the NDA; and

•FDA review and approval of the NDA prior to any commercial marketing or sale of the drug in the United

States.

Before testing any compounds with potential therapeutic value in humans, the drug candidate goes through a

preclinical testing stage. Preclinical tests include laboratory evaluations of product chemistry, toxicity and

formulation, as well as animal studies to assess the potential safety and activity of the drug candidate. The conduct

of the preclinical tests must comply with federal regulations and requirements including GLPs. The data sponsor

must submit the results of the preclinical tests, together with manufacturing information, analytical data, any available

clinical data or literature and a proposed clinical protocol, to the FDA as part of the IND. An IND is a request for

authorization from the FDA to administer an investigational drug product to humans. The central focus of an IND

submission is on the general investigational plan and the protocols for human studies. The IND automatically

becomes effective 30 days after receipt by the FDA, unless the FDA raises concerns or questions regarding the

proposed clinical trials and places the IND on clinical hold within that 30-day time period or issues an earlier notice

that the clinical trial may proceed. In the case of a clinical hold, the IND sponsor and the FDA must resolve any

outstanding concerns before the clinical trial can begin. The FDA may also impose a clinical hold on a drug

candidate at any time before or during clinical trials due to safety concerns or noncompliance. Accordingly, we

cannot be sure that submission of an IND will result in the FDA allowing clinical trials to begin, or that, once begun,

issues will not arise that cause us or FDA to suspend or terminate such trial.

Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing

procedures, subject selection and exclusion criteria, and the parameters to be used to monitor subject safety and

assess efficacy. Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as

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part of the IND. Further, each clinical trial must be reviewed and approved by an independent institutional review

board (IRB), at or servicing each institution at which the clinical trial will be conducted. An IRB is charged with

protecting the welfare and rights of trial participants and considers issues such as whether the risks to individuals

participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits. The IRB also

approves the informed consent form that must be provided to each clinical trial subject or his or her legal

representative and must monitor the clinical trial until completed. There are also requirements governing the

reporting of ongoing clinical trials and completed clinical trial results to public registries.

Human clinical trials are typically conducted in three sequential phases that may overlap or be combined:

•Phase 1. The drug is initially introduced into healthy human subjects and tested for safety, dosage

tolerance, absorption, metabolism, distribution and excretion, the side effects associated with increasing

doses, and if possible, to gain early evidence of effectiveness. In the case of some products for severe or

life-threatening diseases, especially when the product may be too inherently toxic to ethically administer

to healthy volunteers, the initial human testing is often conducted in patients.

•Phase 2. The drug is evaluated in a limited patient population to identify possible adverse effects and

safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases or

conditions and to determine dosage tolerance, optimal dosage and dosing schedule.

•Phase 3. Clinical trials are undertaken to further evaluate dosage, clinical efficacy and safety in an

expanded patient population at geographically dispersed clinical trial sites. These clinical trials are

intended to establish the overall benefit/risk ratio of the product and provide an adequate basis for product

approval. Generally, two adequate and well-controlled Phase 3 clinical trials are required by the FDA for

approval of an NDA. Phase 3 clinical trials usually involve several hundred to several thousand

participants.

Post-approval studies, or Phase 4 clinical trials, may be conducted after initial marketing approval. These studies are

used to gain additional experience from the treatment of patients in the intended therapeutic indication. In certain

instances, the FDA may mandate the performance of Phase 4 studies.

IND Annual reports must be submitted annually to the FDA and written IND safety reports must be submitted to the

FDA and the investigators for serious and unexpected adverse events or any finding from tests in laboratory animals

that suggests a significant risk for human subjects. Phase 1, Phase 2 and Phase 3 clinical trials may fail to be

completed successfully within any specified period, if at all. The FDA, the IRB or the sponsor may suspend or

terminate a clinical trial at any time on various grounds, including a finding that the research subjects or patients are

being exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial

at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has

been associated with unexpected serious harm to patients. Additionally, some clinical trials are overseen by an

independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring

board or committee. This group provides authorization for whether or not a trial may move forward at designated

checkpoints based on access to certain data from the study. We may also suspend or terminate a clinical trial based

on evolving business objectives and/or competitive climate.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop

additional information about the chemistry and physical characteristics of the drug as well as finalize a process for

manufacturing the product in commercial quantities in accordance with cGMP requirements. The manufacturing

process must be capable of consistently producing quality batches of the drug candidate and, among other things,

must include developed methods for testing the identity, strength, quality and purity of the final drug. Additionally,

appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the

drug candidate does not undergo unacceptable deterioration over its shelf life.

FDA Review and Approval Process

The results of product development, preclinical studies and clinical trials, along with descriptions of the

manufacturing process, analytical tests conducted on the chemistry of the drug, proposed labeling and other relevant

information are submitted to the FDA as part of an NDA requesting approval to market the product. The application

must include negative or ambiguous results of preclinical and clinical trials as well as positive findings. Data may

come from company-sponsored clinical trials intended to test the safety and effectiveness of a use of a product, or

from a number of alternative sources, including studies initiated by investigators. To support marketing approval, the

data submitted must be sufficient in quality and quantity to establish the safety and effectiveness of the

investigational drug product to the satisfaction of the FDA. The submission of an NDA is subject to the payment of

substantial user fees; a waiver of such fees may be obtained under certain limited circumstances.

In addition, under the Pediatric Research Equity Act (PREA), an NDA or supplement to an NDA must contain data to

assess the safety and effectiveness of the drug for the claimed indications in all relevant pediatric subpopulations

and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

The FDA may grant deferrals for submission of data or full or partial waivers. Unless otherwise required by

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regulation, PREA does not apply to any drug for an indication for which orphan designation has been granted.

However, if only one indication for a product has orphan designation, a pediatric assessment may still be required for

any applications to market that same product for the non-orphan indication(s).

The FDA reviews the completeness of each NDA submitted before accepting it for filing and may request additional

information rather than accepting the NDA for filing. The FDA must make a decision on accepting an NDA for filing or

refusing to file within 60 days of receipt. Once the submission is accepted for filing, the FDA begins an in-depth

review of the NDA. Under the goals and policies agreed to by the FDA under the Prescription Drug User Free Act

(PDUFA), the FDA has ten months from the 60-day filing date in which to complete its initial review of a standard

NDA and respond to the applicant, and six months from the 60-day filing date for a priority NDA. The FDA does not

always meet its PDUFA goal dates for standard and priority NDAs, and the review process is often significantly

extended by FDA requests for additional information or clarification.

The FDA reviews each NDA to determine, among other things, whether the proposed product is safe and effective

for its intended use, and whether the product is being manufactured in accordance with cGMP to assure and

preserve the product’s identity, strength, quality and purity. For novel drug products or drug products which present

difficult questions of safety or efficacy, FDA may decide to hold an advisory committee, typically a panel that includes

clinicians and other experts, to provide independent advice that will contribute to the quality of the agency's

regulatory decision-making and lend credibility to the product review process, including a recommendation as to

whether the application should be approved and under what conditions. The FDA is not bound by the

recommendations of an advisory committee, but it considers such recommendations carefully when making

decisions.

Before approving an NDA, the FDA will inspect the facilities at which the product is manufactured. The FDA will not

approve the product unless it determines that the manufacturing processes and facilities are in compliance with

cGMP requirements and adequate to assure consistent production of the product within required specifications.

Additionally, before approving an NDA, the FDA may inspect one or more clinical sites to assure compliance with

GCP requirements.

After the FDA evaluates the application, manufacturing process and manufacturing facilities, it may issue an

approval letter or a Complete Response Letter. An approval letter authorizes commercial marketing of the drug with

specific prescribing information for specific indications. A Complete Response Letter indicates that the review cycle

of the application is complete and the application is not ready for approval. A Complete Response Letter usually

describes all of the specific deficiencies in the NDA identified by the FDA. A Complete Response Letter may require

additional clinical data and/or an additional pivotal Phase 3 clinical trial(s), and/or other significant and time-

consuming requirements related to clinical trials, preclinical studies or manufacturing. If a Complete Response Letter

is issued, the applicant may either resubmit the NDA, addressing all of the deficiencies identified in the letter, or

withdraw the application. Even if such data and information is submitted, the FDA may ultimately decide that the

NDA does not satisfy the criteria for approval. Data obtained from clinical trials are not always conclusive and the

FDA may interpret data differently than we interpret the same data.

If a product receives regulatory approval, the approval may be significantly limited to specific diseases, patient

populations and dosages, or the indications for use may otherwise be limited, which could restrict the commercial

value of the product. Further, the FDA may require that certain contraindications, warnings or precautions be

included in the product labeling or may condition the approval of the NDA on other changes to the proposed labeling,

development of adequate controls and specifications, or a commitment to conduct one or more post-market studies

or clinical trials. For example, the FDA may require Phase 4 testing which involves clinical trials designed to further

assess a drug’s safety and effectiveness and may require testing and surveillance programs to monitor the safety of

approved products that have been commercialized. The FDA may also determine that a risk evaluation and

mitigation strategy (REMS) is necessary to assure the safe use of the drug. If the FDA concludes a REMS is needed,

the sponsor of the NDA must submit a proposed REMS, and the FDA will not approve the NDA without an approved

REMS. Depending on FDA’s evaluation of a drug’s risks, a REMS may include medication guides, physician

communication plans, or elements to assure safe use, such as restricted distribution requirements, patient registries

and other risk minimization tools. Following approval of an NDA with a REMS, the sponsor is responsible for

marketing the drug in compliance with the REMS and must submit periodic REMS assessments to the FDA.

Fast track, breakthrough therapy and priority review designations

The FDA is authorized to designate certain products for expedited development or review if they are intended to

address an unmet medical need in the treatment of a serious or life-threatening disease or condition. These

programs include fast track designation, breakthrough therapy designation and priority review designation.

To be eligible for a fast track designation, the FDA must determine that a product candidate is intended to treat a

serious or life threatening disease or condition and demonstrates the potential to address unmet medical needs for

the condition. Fast track designation provides opportunities for more frequent interactions with the FDA review team

to expedite development and review of the product candidate. The FDA may also agree to review sections of the

NDA for a fast track product candidate on a rolling basis before the complete application is submitted.

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A product candidate intended to treat a serious or life-threatening disease or condition may also be eligible for

breakthrough therapy designation. A product candidate can receive breakthrough therapy designation if preliminary

clinical evidence indicates that the product candidate, alone or in combination with one or more other drugs or

biologics, may demonstrate substantial improvement over existing therapies on one or more clinically significant

endpoints. The designation includes all of the fast track program features, as well as more intensive FDA interaction

and guidance beginning as early as Phase 1 and an organizational commitment to expedite the development and

review of the product candidate, including involvement of senior managers.

Finally, the FDA may designate an NDA for priority review if the product candidate treats a serious condition and, if

approved, would provide a significant improvement in safety or effectiveness. The FDA determines at the time that

the marketing application is submitted, on a case-by-case basis, whether the product candidate represents a

significant improvement when compared with other available therapies. Significant improvement may be illustrated

by, among other things, evidence of increased effectiveness, elimination or substantial reduction of a treatment-

limiting drug reaction, documented enhancement of patient compliance that may lead to improvement in serious

outcomes, or evidence of safety and effectiveness in a new subpopulation. A priority review designation is intended

to direct overall attention and resources to the evaluation of such applications and to shorten the FDA’s goal for

taking action on a marketing application from ten months to six months from the filing date for an NDA for a new

molecular entity.

Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer

meets the conditions for qualification or the time period for FDA review or approval may not be shortened.

Furthermore, fast track designation, priority review and breakthrough therapy designation do not change the

standards for approval and may not ultimately expedite the development or approval process.

Accelerated approval pathway

A drug product may also be eligible for accelerated approval if it is designed to treat a serious or life-threatening

disease or condition and provides a meaningful therapeutic benefit over existing treatments. Such product

candidates can be approved upon a determination that the product candidate has an effect on either a surrogate

endpoint that is reasonably likely to predict clinical benefit or on an intermediate clinical endpoint that can be

measured earlier than irreversible morbidity or mortality, or IMM, that is reasonably likely to predict an effect on IMM

or other clinical benefit, taking into account the severity, rarity, or prevalence of the disease or condition and the

availability or lack of alternative treatments. As a condition of approval, the FDA may require that a sponsor of a drug

receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials to verify and

describe the predicted effect on IMM or another clinical endpoint. If a post-approval study is required, FDA must

specify conditions, which may include enrollment targets, study protocol, and milestones, including the target date of

study completion. A failure to meet these conditions may result in a determination by the FDA that the sponsor failed

to conduct a required post-approval study with due diligence. FDA may require one or more post-approval studies to

be underway prior to approval, or within a specified time period after approval. The FDA may withdraw approval of a

drug or indication approved under accelerated approval on an expedited basis if, for example, the confirmatory trial

fails to meet the specified conditions of the accelerated approval, including the conduct of any required post-approval

study with due diligence.

Drugs granted accelerated approval must meet the same statutory standards for safety and effectiveness as those

granted traditional approval. In addition, all promotional materials for products approved under the accelerated

approval program are subject to prior review by the FDA.

Recently, the accelerated approval pathway has come under scrutiny within the FDA and by Congress. The FDA has

put increased focus on ensuring that confirmatory studies are conducted with diligence and, ultimately, that such

studies confirm the benefit. The Food and Drug Omnibus Reform Act of 2022 (FDORA) granted the FDA additional

enforcement authority FDA to take action for failure to conduct a required post approval study with due diligence,

including a failure to meet any required conditions specified by FDA or to submit timely reports. FDORA also created

a formal expedited withdrawal procedure for drugs approved through accelerated approval, including notice and

explanation of the proposed withdrawal, an opportunity for a meeting and written appeal, an opportunity for public

comment on the proposed withdrawal, and convening an advisory committee.

Post-Approval Requirements

Any drug products for which we receive FDA approvals are subject to continuing regulation by the FDA, including,

among other things, record-keeping requirements, reporting of adverse experiences with the product, providing the

FDA with updated safety and efficacy information, product sampling and distribution requirements, and complying

with FDA promotion and advertising requirements, which include, among other requirements, standards for direct-to-

consumer advertising, restrictions on promoting drugs for uses or in patient populations that are not consistent with

the drug’s approved labeling (known as “off-label use”), limitations on industry sponsored scientific and educational

activities, and requirements for promotional activities involving the Internet. Although physicians may prescribe

legally available drugs for off-label uses, manufacturers may not market or promote such off-label uses.

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In addition, quality control and manufacturing procedures must continue to conform to applicable manufacturing

requirements after approval. We rely, and expect to continue to rely, on third parties for the production of clinical and

commercial quantities of our products in accordance with cGMP regulations. cGMP regulations require, among other

things, quality control and quality assurance as well as the corresponding maintenance of records and

documentation and the obligation to investigate and correct any deviations from cGMP. Drug manufacturers and

other entities involved in the manufacture and distribution of approved drugs are required to register their

establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the

FDA and certain state agencies for compliance with cGMP and other laws. Accordingly, manufacturers must continue

to expend time, money and effort in the area of production and quality control to maintain cGMP compliance.

Discovery of problems with a product after approval may result in restrictions on a product, manufacturer or holder of

an approved NDA, including, among other things, recall or withdrawal of the product from the market. In addition,

changes to the manufacturing process are strictly regulated, and depending on the significance of the change, may

require prior FDA approval before being implemented. Other types of changes to the approved product, such as

adding new indications and additional labeling claims, are also subject to further FDA review and approval.

The FDA also may require Phase 4 testing and surveillance to monitor the effects of an approved product or place

conditions on an approval that could restrict the distribution or use of the product. Discovery of previously unknown

problems with a product or the failure to comply with applicable FDA requirements can have negative consequences,

including adverse publicity, judicial or administrative enforcement, warning letters from the FDA, mandated corrective

advertising or communications, and civil or criminal penalties, among others. Newly discovered or developed safety

or effectiveness data may require changes to a product’s approved labeling, including the addition of new warnings

and contraindications, and also may require the implementation of other risk management measures, such as a

REMS. Also, new government requirements, including those resulting from new legislation, may be established, or

the FDA’s policies may change, which could delay or prevent regulatory approval of our products under

development.

Coverage and Reimbursement

A pharmaceutical manufacturer’s ability to commercialize any approved drug product successfully depends in part

on the extent to which coverage and adequate reimbursement for such drug product and related treatments will be

available from third-party payors, including government health administration authorities, private health insurers,

health maintenance organizations and other organizations. Third-party payors determine which drug products and

treatments they will cover and establish reimbursement levels. Assuming coverage is obtained for a given product by

a third-party payor, the resulting reimbursement payment rates may not be adequate or may require co-payments

that patients find unacceptably high. Patients are unlikely to use a drug product, or agree to treatment using a drug

product, unless coverage is provided and reimbursement is adequate to cover all or a significant portion of the cost

of the drug product and associated treatment. Therefore, coverage and adequate reimbursement is critical to new

drug product acceptance. Coverage decisions may depend upon clinical and economic standards that disfavor new

drug products when more established or lower cost therapeutic alternatives are already available or subsequently

become available.

Third-party payors are developing increasingly sophisticated methods of controlling healthcare costs, such as by

limiting coverage and the amount of reimbursement for drug products and related treatments. In addition, the U.S.

government, state legislatures and foreign governments have continued implementing cost-containment programs,

including price controls, restrictions on reimbursement and requirements for substitution of generic products. Further,

no uniform policy requirement for coverage and reimbursement for drug products exists among third-party payors in

the United States.

Therefore, coverage and reimbursement for drug products can differ significantly from payor to payor and product to

product. As a result, the coverage determination process is often a time-consuming and costly process that requires

pharmaceutical manufacturers to provide scientific and clinical support for the use of its drug products to each payor

separately, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in

the first instance.

Healthcare Laws

Healthcare providers, physicians and others will play a primary role in the recommendation, and the incorporation

into treatment regimes, of drug products, if approved. A pharmaceutical manufacturer’s business operations in the

United States and its arrangements with clinical investigators, healthcare providers, consultants, third-party payors

and patients expose it to broadly applicable federal and state fraud and abuse and other healthcare laws. These

laws may impact, among other things, research, proposed sales, marketing and education programs for product

candidates that obtain marketing approval. Restrictions under applicable US federal and state and foreign healthcare

laws and regulations include, but are not limited to, the following:

•the U.S. federal Anti-Kickback Statute, which prohibits, among other things, persons or entities from

knowingly and willfully soliciting, offering, receiving or providing compensation, including any kickback,

bribe or rebate, directly or indirectly, in cash or in kind, to induce or reward, or in return for, either the

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referral of an individual for, or the purchase, lease, order or recommendation of, any item, good, facility or

service, for which payment may be made under federal healthcare programs such as Medicare and

Medicaid;

•U.S. federal civil and criminal false claims laws and civil monetary penalties laws, including the civil False

Claims Act, which can be enforced by individuals through civil whistleblower or qui tam actions, which

prohibit individuals or entities from, among other things, knowingly presenting, or causing to be presented,

claims for payment that are false or fraudulent or making a false statement to avoid, decrease, or conceal

an obligation to pay money to the federal government;

•HIPAA, which created additional federal criminal statutes which prohibit, among other things, executing or

attempting to execute a scheme to defraud any healthcare benefit program or knowingly and willingly

falsifying, concealing or covering up a material fact or making false statements relating to healthcare

matters;

•HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, and their

implementing regulations, which impose certain requirements on covered entities, including certain

healthcare providers, health plans and healthcare clearinghouses, and their business associates,

individuals and entities that perform functions or activities that involve individually identifiable health

information on behalf of covered entities, including mandatory contractual terms, with respect to

safeguarding the privacy, security and transmission of individually identifiable health information;

•US federal transparency requirements under the Physician Payments Sunshine Act, enacted as part of

the ACA, that require applicable manufacturers of covered drugs, devices, biologics and medical supplies

for which payment is available under Medicare, Medicaid, or the Children’s Health Insurance Program,

with specific exceptions, to track and annually report to CMS payments and other transfers of value

provided to physicians and teaching hospitals, and certain ownership and investment interests held by

physicians or their immediate family members; and

•analogous state or foreign laws and regulations, such as state anti-kickback and false claims laws, which

may apply to items or services reimbursed by any third-party payor, including commercial insurers, state

marketing and/or transparency laws applicable to manufacturers that may be broader in scope than the

federal requirements, state laws that require biopharmaceutical companies to comply with the

biopharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance

promulgated by the federal government, state and local laws that require the registration of

pharmaceutical sales representatives, and state laws governing the privacy and security of health

information in certain circumstances, many of which differ from each other in significant ways and may not

have the same effect as HIPAA, thus complicating compliance efforts.

Ensuring business arrangements with third parties comply with applicable healthcare laws and regulations is costly.

It is possible that governmental authorities will conclude that business practices do not comply with current or future

statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations. If a

pharmaceutical manufacturer’s operations are found to be in violation of any of these laws or any other

governmental regulations that may apply to it, it may be subject to significant civil, criminal and administrative

penalties, damages, fines, disgorgement, individual imprisonment, possible exclusion from government funded

healthcare programs, such as Medicare and Medicaid, additional reporting requirements and oversight if we become

subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these

laws, contractual damages, reputational harm, diminished profits and future earnings, and curtailment of operations.

Healthcare Reform

In the United States, the ACA is significantly impacting the provision of, and payment for, healthcare. Various

provisions of the ACA were designed to expand Medicaid eligibility, subsidize insurance premiums, provide

incentives for businesses to provide healthcare benefits, prohibit denials of coverage due to pre-existing conditions,

establish health insurance exchanges, and provide additional support for medical research. With regard to

therapeutic products specifically, the ACA, among other things, expanded and increased industry rebates for drugs

covered under Medicaid programs and made changes to the coverage requirements under the Medicare prescription

drug benefit.

Since its enactment there have been judicial and legislative challenges to certain aspects of the ACA, as well as

executive branch efforts to repeal or replace certain aspects of the ACA. Most recently, the executive branch has

sought to bolster the ACA through executive order.

While Congress has not passed comprehensive repeal legislation, two bills affecting the implementation of certain

taxes under the ACA have been signed into law. The Tax Cuts and Jobs Act included a provision which repealed,

effective January 1, 2019, the tax-based shared responsibility payment imposed by the ACA on certain individuals

who fail to maintain qualifying health coverage for all or part of a year that is commonly referred to as the “individual

mandate.” The Further Consolidated Appropriations Act, 2020, signed into law on December 19, 2019, repealed

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certain ACA-mandated fees, including the so-called “Cadillac” tax on certain high cost employer-sponsored

insurance plans, the medical device excise tax, and, effective for 2021, the annual fee imposed on certain health

insurance providers based on market share. The BBA, among other things, amended the ACA, effective January 1,

2019, to increase from 50% to 70% the point-of-sale discount that is owed by pharmaceutical manufacturers who

participate in Medicare Part D and to close the coverage gap in most Medicare drug plans, commonly referred to as

the “donut hole.” In July 2018, CMS published a final rule permitting further collections and payments to and from

certain ACA qualified health plans and health insurance issuers under the ACA risk adjustment program in response

to the outcome of federal district court litigation regarding the method CMS uses to determine this risk adjustment.

In addition, both the Budget Control Act of 2011 and the ATRA have instituted, among other things, mandatory

reductions in Medicare payments to certain providers.

Further, there has been heightened governmental scrutiny over the manner in which manufacturers set prices for

their marketed products, which has resulted in several recent US Congressional inquiries and proposed and enacted

federal and state legislation designed to, among other things, bring more transparency to drug pricing, review the

relationship between pricing and manufacturer patient programs, reduce the costs of drugs under Medicare and

reform government program reimbursement methodologies for drug products.

In August 2022, the United States enacted the Inflation Reduction Act of 2022 (IRA), which includes two policies that

are designed to have a direct impact on drug prices. The IRA requires the federal government to negotiate prices for

certain high-cost drugs covered under Medicare and requires drug manufacturers to pay rebates to Medicare if they

increase prices faster than inflation for drugs used by Medicare beneficiaries

Additionally, in May 2018, the Right to Try Act was signed into law. The law, among other things, provides a federal

framework for certain patients who have been diagnosed with life-threatening diseases or conditions who have tried

all approved treatment options and who are unable to participate in a clinical trial to access certain investigational

treatment options to access certain investigational new drug products that have completed a Phase 1 clinical trial

and that are undergoing investigation for FDA approval. Under certain circumstances, eligible patients can seek

treatment without enrolling in clinical trials and without obtaining FDA permission under the FDA expanded access

program. There is no obligation for a pharmaceutical manufacturer to make its drug products available to eligible

patients as a result of the Right to Try Act.

We cannot predict the ultimate content, timing or effect of any changes to the ACA or other federal and state reform

efforts, and there can be no assurance that any such health care reforms will not adversely affect our future business

and financial results.

1.3.17.2.Regulation in the EU

In the EU, health products qualify typically as medicinal products or as medical devices. Applicable regulations and

standards vary between each of these types of products, as well as the regulatory body counterparts and associated

regulatory processes for obtaining market authorizations.

The demarcation between the definitions of “medical device” and “medicinal product” can sometimes be blurred, or

difficult to draw, for some products referred to as “borderline products.” In order to determine whether a product

constitutes a medical device or a medicinal product, a number of factors must be taken into account, including the

claims regarding the function of the product, the mode of action on the human body and the primary intended

purpose of the product. The classification of our product, NBTXR3 as a medical device is supported by the

conformity assessment procedure applied by the relevant EC Notified Body, which led to the drawing up of the EU

Declaration of Conformity, as well as by the opinions released in 2009 and in 2011 by the national competent

authorities of Ireland and Spain, respectively.

Once established, the classification as “medical device” of NBTXR3 is technically applicable in all EU countries,

although dissenting views cannot be categorically ruled out in individual countries. For European countries which are

not part of the EU, classification decisions are taken at a national level by the relevant regulatory authorities.

An Evolving Regulatory Framework

On May 26, 2021, after a four year transition period, the Medical Devices Regulation (Regulation (EU) 2017/745, the

“MDR”) became fully applicable and introduced substantial changes to the previous regulatory regime applicable to

medical devices (including in particular Directive 93/42/EEC, the “MDD”).

Under the transitional provisions of the MDR, until May 26, 2021, the certification procedures underlying the CE

marking of medical devices could be carried out, at the manufacturer’s choice, either in accordance with the MDR or

in accordance with the MDD. Where a manufacturer elected to perform certification under the MDD - as we did in

connection with our NBTXR3 product for the treatment of STS - the related certificates originally remained valid until

their expiry date and at the latest until May 26, 2024 (for certificates issued on or after May 25, 2017, thereby

allowing sale of products until that date if they continue to comply with the MDD and provided that no significant

changes are brought to these devices’ design or intended purpose).

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However, on March 15, 2023, the European Parliament and the Council adopted an amendment to the MDR which

extends the validity of certificates issued under the MDD, under certain conditions, until December 31, 2027 for

medical devices of high risk class (class III and some class IIb) and December 31, 2028 for some medical devices of

lower risk class. This amendment will become applicable after publication in the Official Journal of the European

Union.

Manufacturers of those devices that are certified under the MDD have to comply with a number of requirements of

the MDR set out in its article 120 (e.g., those relating to post-market surveillance and vigilance).

Under the MDR, all devices incorporating or consisting of nanomaterials are classified as Class III if they present a

high or medium potential for internal exposure. The MDR introduced higher clinical data requirements for such Class

III devices.

The MDR also introduced increased scrutiny of conformity assessments by Notified Bodies for Medical Devices. For

certain high-risk devices, Notified Bodies must submit their clinical evaluation assessment report to the European

Commission for evaluation by an independent expert panel, except for the products which are exempted according

to Article 54(2) of the MDR.

In addition, under the MDR, manufacturers of Class III devices are subject to a new annual safety reporting

requirement called the Periodic Safety Update Report (PSUR), aimed at capturing the results and conclusions of the

analyses of the post-market surveillance data gathered as a result of the manufacturer’s post market surveillance

plan.

Additional guidance and legislation further specifying the applicable requirements and obligations under the MDR is

expected. We are in the process of assessing the impact of and preparing for compliance with, the MDR and

associated acts and guidance on our business. Due to these new regulatory requirements, conformity assessment

procedures in the EU may experience delays.

CE Marking Requirements

As manufacturers of medical devices, in the EU we are required under the MDR to affix a CE mark to our products in

order to sell our products in Member States of the EU. The CE mark is a symbol that indicates conformity with the

applicable regulatory requirements.

Medical Devices in the EU are classified in four different classes (I, IIa, IIb and III) depending on their inherent risk.

The MDR includes specific rules on classification of medical devices. Class III devices such as our NBTXR3 are

subject to a conformity assessment by a Notified Body designated for the evaluation of such device types.

EU Development Process

For Class III devices, such as NBTXR3, and for implantable devices, it is necessary, save for exceptions, to carry out

a clinical investigation to demonstrate that the product complies with the applicable regulatory requirements,

including as regards safety and performance.

Any clinical investigation must comply with all relevant legal, ethical and regulatory requirements. Clinical

investigations must take into account scientific principles underlying the collection of clinical data and be conducted

in accordance with the principles of good clinical practice. This means that, for example, all research subjects must

have provided their prior informed consent for participation in any clinical investigation.

A clinical investigation can be carried out only if the relevant competent national authorities have approved it and the

relevant ethics committee(s) have not issued a negative opinion in relation to it.

The MDR specifically requires that, subject to certain conditions, serious adverse events, device deficiencies and

related updates be recorded and notified to all competent authorities of the EU Member States in which the clinical

investigation is being performed. Termination of a clinical investigation must also be notified to such authorities and

be followed by a clinical investigation report, irrespective of the outcome of the investigation.

The MDR specifies conditions required for the collection of data from clinical investigations relating to medical

devices.

These requirements include rules on informed consent and the protection of vulnerable persons (e.g., persons under

18 years of age, pregnant women and disabled persons).

The conduct of a clinical investigation is subject to EU Member State national laws. For instance, in France, there

are specific rules governing the protection of patients (including, for example, regarding consent and insurance).

Tracking

The MDR introduced a system for the registration of devices and their manufacturers, importers and authorized

representatives, and allows EU Member States to also maintain or introduce registration obligations for distributors if

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they so wish. Moreover, in order to allow identification and to ensure the traceability of devices throughout the supply

chain, the MDR requires the establishment of a Unique Device Identification (UDI) system.

Notified Bodies and Conformity Assessment Procedures

To demonstrate compliance with the applicable regulatory requirements, manufacturers of medical devices must

follow a conformity assessment procedure which varies according to the type of medical device and its risk

classification. Except for certain Class I devices, a conformity assessment procedure typically requires the

intervention of an independent organization accredited to conduct conformity assessments, known as a “Notified

Body”. Under the conformity assessment procedure we have elected to follow for our products, the Notified Body

audits and examines the technical documentation and the quality system applied to the design, manufacture and

final inspection of our products. If we successfully complete the applicable procedure, the Notified Body issues an

EC certificate of conformity. These certificates entitle a manufacturer to affix the CE mark to its medical devices after

having also prepared and signed a “EU declaration of conformity” indicating that the product meets the applicable

regulatory requirements. The certificate of conformity is valid for a maximum of five years. While we have

successfully completed the applicable regulatory procedures for our NBTXR3 product for the treatment of STS under

the Medical Device Directive 93/42/EEC, we cannot guarantee that we will succeed in obtaining appropriate

certification under the MDR once the certificate issued under the MDD for NBTXR3 will expire, or that all our product

candidates will be equally successful.

The certificate of conformity can be suspended or withdrawn, e.g., where a Notified Body finds that pertinent

regulatory requirements are not met and the manufacturer has not implemented appropriate corrective measures

within the time limit set by the Notified Body. The same may be true for any new products that we may develop in the

future.

The MDR strengthened the rules on the designation, organization and surveillance of Notified Bodies. These must

meet the same high quality standards throughout the EU and have permanent availability of sufficient administrative,

technical and scientific personnel as is necessary to carry out their tasks. Notified Bodies must carry out inspections

of manufacturers’ premises, some of which are unannounced.

Post-Market Vigilance

Once CE-marked and placed on the European Economic Area (EEA) market, medical devices are subject to

vigilance requirements. In accordance with these requirements, manufacturers must report incidents to the

competent authorities and are required to take appropriate “field safety corrective actions” to prevent or reduce the

risk of serious incidents associated with devices made available on the market. Such actions must also be

communicated to users through field safety notices. Manufacturers must equally report statistically significant

increases in the frequency of certain incidents by means of trend reports.

In addition to reporting obligations for manufacturers regarding serious incidents and incident trends, the MDR

introduced an obligation for EU Member States to encourage and enable healthcare professionals, users and

patients to report suspicious incidents at national level.

Pricing and Reimbursement

Sales of our products in the EEA will be largely influenced by the outcome of our pricing and reimbursement

negotiations with the national authorities of each of the EEA Member States, such as government social security

funds. These third-party payors are increasingly limiting coverage and reimbursement for medical products and

services. In addition, EEA governments have continued implementing cost-containment programs, including price

controls, restrictions on reimbursement and requirements for substitution with cheaper products. Adoption of price

controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing

controls and measures, could further limit our net revenue and results. Decreases in third-party reimbursement for

our products or a negative outcome of our reimbursement negotiations could reduce physician usage of our products

once approved and have a material adverse effect on our sales, results of operations and financial condition.

Marketing, Advertising and Transparency

In the EU, the marketing and advertising of medical devices is subject to both legal and voluntary self-regulatory

rules at EU and national level including as regards the strict prohibition of misleading and unfair advertising of

medical devices. Moreover, under EU-wide voluntary self-regulatory rules, interactions between medical device

manufacturers and healthcare professionals and healthcare organizations – including in particular any transfers of

value that (a) such interactions cannot be misused to influence purchasing decisions through undue or improper

advantages and (b) cannot be contingent upon sales transactions, use or recommendation of any specific products.

Additional requirements may apply depending on the specific jurisdiction concerned.

Finally, increasing transparency requirements are mandated under national legislation and/or self-regulatory codes

of conduct. Under these requirements, manufacturers of health products can be required to publicly disclose any

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transfers of value (whether in kind or in cash) they provide to, e.g., healthcare professionals and healthcare

organizations.

As a result of the above requirements, manufacturers of medical devices are subject to increased monitoring of their

promotional activities as well as of their other interactions with healthcare professionals and organizations. Any

breach of the applicable rules can result in serious sanctions, including criminal, civil or administrative sanctions

depending on the affected jurisdiction.

Data Protection Rules

The Regulation 2016/679, known as the General Data Protection Regulation, or GDPR, as well as EU Member State

national legislations, apply to the collection and processing of personal data, including health-related information, by

companies located in the EU, or in certain circumstances, by companies located outside of the EU and processing

personal information of individuals located in the EU.

These laws impose strict obligations on the processing of personal data, including health-related information, in

particular in relation to their collection, use, disclosure and transfer.

Also, in certain countries, in particular France, the conduct of clinical trials is subject to compliance with specific

provisions of the Act No.78-17 of 6 January 1978 on Information Technology, Data Files and Civil Liberties, as

amended, and in particular Chapter IX relating to the processing of personal data in the health sector. These

provisions require, among others, the filing of compliance undertakings with “standard methodologies” adopted by

the French Data Protection Authority (the “CNIL”), or, if not complying, obtaining a specific authorization from the

CNIL.

The most common standard methodologies aimed at the processing of data in connection with research are the

following:

•Decision No. 2018-154 of May 3, 2018 concerning the approval of a standard methodology for processing

personal data in the context of research in the field of health, which does not require the express consent

of the person involved (methodology MR-003);

•Decision No. 2018-153 of May 3, 2018 concerning the approval of a standard methodology for the

processing of personal data carried out within the context of research in the field of clinical trials, which

requires the express consent of the person involved (standard methodology MR-001);

•Decision No. 2018-155 of May 3, 2018 concerning the approval of a standard methodology for the

processing of personal data carried out within the context of research in the field of non-human research

or of health studies and evaluations with high public relevance (standard methodology MR-004).

In certain specific cases, entities processing health personal data may have to comply with article L1111-8 of the

French Public Health Code which imposes certain certifications for the hosting service providers.

Foreign investment control regime in France

Over the past few years, the French government has strengthened its foreign investment control regime. Thus, as at

the date of the Universal Registration Document, any investment:

i.by (a) any non-French citizen, (b) any French citizen not fiscally residing in France, (c) any non-French

entity or (d) any French entity controlled by one of the aforementioned persons or entities;

ii.that will result in the relevant investor (a) acquiring control of an entity registered in France, (b) acquiring

all or part of a business line of an entity registered in France, or (c) for non-EU or non-EEA investors

crossing, directly or indirectly, alone or in concert, a 25% threshold of voting rights in an entity registered

in France; and

iii.where this entity registered in France is developing activities in certain strategic industries (sensitive

sectors or sensitive activities) related to (a) activity likely to prejudice national defense interests,

participating in the exercise of official authority or are likely to prejudice public policy and public security

(including weapons, double-use items, IT systems, cryptology, date capturing devices, gambling, toxic

agents or storage of data), (b) activities relating to essential infrastructure, goods or services (including

energy, water, transportation, space, telecom, public health, farm products or media), and (c) research

and development activity related to critical technologies (including biotechnology, cybersecurity, artificial

intelligence, robotics, additive manufacturing, semiconductors, quantum technologies or energy

storage…) or dual-use items, is subject to the prior authorization of the French Ministry of Economy, which

authorization may be conditioned on certain undertakings.

Additionally, within the scope of the article L151-3 of the French Monetary and Financial Code, in the context of the

ongoing COVID-19 pandemic, the Decree (décret) n°2020 892 dated July 22, 2020, as amended by the Decree

(décret) n°2020-1729 dated December 28, 2020, by the Decree (décret) n°2021-1758 dated December 22, 2021 and

by the Decree (décret) n°2022-1622 dated December 23, 2022, has created a new 10% threshold of the voting

rights applicable until December 31, 2023 for the non-European investments (i) in an entity governed by French law

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and (ii) whose shares are admitted to trading on a regulated market, replacing the 25% above-mentioned threshold

for certain activities.

On November 5, 2020, the French Ministry of Economy informed us that our activities are subject to the foreign

investment control regime described above. Therefore, investments in our Company meeting the above criteria are

subject to prior authorization by the French Ministry of Economy.

A fast-track procedure shall apply for any non-European investor exceeding this 10% threshold who will have to

notify the Minister of Economy who will then have 10 days to decide whether or not the transaction should be subject

to further examination.

If an investment requiring the prior authorization of the French Minister of Economy is completed without such

authorization having been granted, the French Minister of Economy might direct the relevant investor to nonetheless

(i) submit a request for authorization, (ii) have the previous situation restored at its own expense or (iii) amend the

investment.

In the absence of such authorization, the relevant investment shall be deemed null and void. The relevant investor

may be found criminally liable and may be sanctioned with a fine not to exceed the greater of the following amounts:

(i) twice the amount of the relevant investment, (ii) 10% of the annual turnover before tax of the target company or

(iii) €5 million (for a company) or €1 million (for a natural person).

1.3.17.3.Regulation in Asia

We have licensed to a partner our right to develop and commercialize NBTXR3 in some territories within the Asia-

Pacific region. We anticipate that the development and commercialization, if any, of NBTXR3 in the Asia-Pacific

region would initially target Taiwan, China and Japan.

Taiwan

In Taiwan, NBTXR3 has been classified as a drug for regulatory purposes. It is worth noting, however, that this

classification may be subject to change by the competent health authority up to the submission by the Company or,

as the case may be, by its licensee of a marketing authorization request.

Taiwan Drug Development Process

Under the Pharmaceutical Affairs Act (PAA), the competent authority at central government level is the Taiwan

Ministry of Health and Welfare (MOHW). The Taiwan Food and Drug Administration (TFDA) under the MOHW is in

charge of the administration, inspection and testing of pharmaceutical products (including drugs and medical

devices). Companies that plan to import drugs into or manufacture drugs in Taiwan must receive a prior drug permit

license from MOHW and comply with other applicable laws and regulations in Taiwan. Sale of drugs in Taiwan is also

subject to applicable laws and regulations. The drug development and marketing process in Taiwan mainly involves

preclinical tests, clinical trials, manufacturing and post-market monitoring. The said process is subject to scrutiny

and/or approval by the TFDA, such as IND, approval (which must be approved by the TFDA before human clinical

trials may begin) and NDA approval. Additionally, according to the PAA, unless otherwise announced by the MOHW,

for purposes of pharmaceutical products manufacture, the factory facilities, equipment, organization and personnel,

production, quality control, storage, logistics, handling of customer complaints, and other matters requiring

compliance shall comply with the Pharmaceutical Good Manufacturing Practice Regulations; the manufacture may

only begin after the MOHW has completed its inspection and granted approval and the pharmaceutical products

manufacture license has been obtained. After marketing, the pharmaceutical products are still subject to applicable

and regulations. For instance, with respect to the post-marketing monitoring, a manufacturer or an importer of a new

drug defined under the PAA shall collect safety information on drug use available both domestically and abroad

during the safety monitoring period; in addition to making report following the Regulations Governing the Reporting

of Severe Adverse Reactions of Medicines, such manufacturer or an importer shall also file periodic safety update

report to MOHW within the specified time period.

People’s Republic of China

In the People’s Republic of China (excluding Hong Kong, Macau and Taiwan), NBTXR3 has been classified as a

drug for regulatory purposes. It is worth noting, however, that this classification may be subject to change by the

competent health authority up to the submission by the Company or, as the case may be, by its licensee of a

marketing authorization request.

A market approval is required for its development and commercialization. Extensive data derived from preclinical

laboratory tests and studies meeting the requirements of Chinese law are required to support the granting of

approval by the National Medical Product Administration (NMPA) for a new drug product to proceed with clinical

trials. If clinical trials sufficiently establish that the product is safe and effective, the NMPA will issue approval for the

product to be marketed. Similar to the United States and the EU, the process for obtaining such marketing approval

is lengthy, although the Chinese government has recently made efforts to reduce the time required and to streamline

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the process. After obtaining marketing approval, the marketing approval holder must conduct post-marketing

approval studies to closely monitor the use of the product for purposes of reporting its demonstrated safety and

efficacy to the NMPA. Further, the marketing approval holder must closely monitor any adverse events or product

quality issues, and disclose any such events or issues to the NMPA, as well as potentially to other government

agencies and the public. An overseas entity must appoint a domestic agent in assisting it to apply for market

approval in China, and the approval holder and its domestic agent will be jointly liable for the aforementioned

obligations.

Japan

In Japan, NBTXR3 has been classified as a drug for regulatory purposes. It is worth noting, however, that this

classification may be subject to change by the competent health authority up to the submission by the Company or,

as the case may be, by its licensee of a marketing authorization request.

The Ministry of Health, Labour and Welfare (MHLW) regulates drugs and medical devices under the

Pharmaceuticals and Medical Devices Act (PMD Act) and its implementing regulations. The MHLW delegates part of

the oversight to the Pharmaceuticals and Medical Devices Agency (PMDA), an independent administrative

institution. In order to market a drug or a highly-controlled medical device in Japan, marketing authorization must be

obtained in advance. Foreign companies that plan to import drugs or medical devices into Japan must be registered

with the MHLW through a separate process. The process for obtaining marketing authorization includes preclinical

tests, clinical trials and compliance review of the application for marketing authorization by the PMDA. After

marketing authorization is obtained, drugs and medical devices are subject to continuing regulations under the PMD

Act. For example, a new drug is subject to periodic reexamination by the MHLW and the marketing authorization

holder must continue to collect clinical data during such specified reexamination period. In addition, the marketing

authorization holder must report to the MHLW when it learns of new information regarding the efficacy and safety of

its product, including occurrences of adverse events.

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Chapter 1. NANOBIOTIX AND ITS ACTIVITIES PRESENTATION

1.4.ANALYSIS AND COMMENTS ON THE GROUP’S FINANCIAL RESULTS

Readers are invited to read the following information on the Group’s financial position and results in conjunction with

the consolidated accounts established in IFRS standards for the years ended December 31, 2020, 2021 and 2022,

(i) in Chapter 4 of the Universal Registration Document on May 13, 2020 under number R. 20-010, (ii) in Chapter 4

of the Universal Registration Document on April 7, 2021 under number D. 21-0272 and (iii) in Chapter 4 of the

Universal Registration Document.

1.4.1.Income statement analysis

1.4.1.1.Revenues and other income

The Company’s ordinary activities revenues and other income were as follows:


(in thousands of euros)	2022	2021	2020
Services	—	5	50
Other sales	—	5	—
Total revenues	—	10	50
Research tax credit	4,091	2,490	1,927
Subsidies	135	126	526
Other	550	21	10
Total other income	4,776	2,638	2,462
Total revenues and other income	4,776	2,647	2,512

Revenues

All of our revenues for the years ended December 31, 2021 and 2020 were derived from the chargeback of external

contract research organization costs in connection with development support provided to PharmaEngine as part of

our license and collaboration agreement.There was no revenue recognized for the year ended December 31, 2022.

Other income

Total other income increased significantly to €4.8 million for the year ended December 31, 2022 compared to €2.6

million and €2.5 million for the years ended December 31, 2021 and 2020, respectively. The increase in each period

was mainly due to higher research tax credit.

Research tax credit

The French tax authorities grant a research tax credit (Crédit d’Impôt Recherche) to companies in order to

encourage them to conduct technical and scientific research. Companies demonstrating that they have incurred

research expenditures that meet the required criteria in France (or, since January 1, 2005, other countries in the EU

or the European Economic Area that have signed a tax treaty with France containing an administrative assistance

clause) receive a tax credit that may be used for the payment of their income tax due for the fiscal year in which the

expenditures were incurred and during the three fiscal years thereafter. If taxes due are not sufficient to cover the full

amount of the tax credit at the end of the three-year period, the difference is repaid in cash to the company by the

French tax authorities.

The main characteristics of the research tax credits are as follows:

•the research tax credits result in a cash inflow to us from the tax authorities, either through an offset

against the payment of corporate tax or through a direct payment to us for the portion that remains

unused;

•our income tax liability does not limit the amount of the research tax credit, as a company that does not

pay any income tax can request direct cash payment of the research tax credit; and

•the research tax credit is not included in the determination of income tax.

We apply for the research tax credit for research expenses incurred in each fiscal year and recognize the amounts

claimed in the same fiscal year. We have concluded that the research tax credits meet the definition of a government

grant as defined in IAS 20, Accounting for Government Grants and Disclosure of Government Assistance, and, as a

result, it has been classified as “Other income” within operating income in our statements of consolidated operations.

The Company has benefited from the research tax credit since its creation.

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Chapter 1. NANOBIOTIX AND ITS ACTIVITIES PRESENTATION

Research tax credit increased from €1,927 thousand in 2020 to €2,490 thousand in 2021 and to €4,091 thousand in

2022 due mainly to an increase of research and development expenses, and to the inclusion of additional eligible

expenses from contract research organizations for clinical trials, mainly related to the 312 study.

Subsidies

We have received various grants and other assistance from the government of France and French public authorities,

including through Bpifrance (formerly OSEO Innovation), since our inception. The funds are intended to finance our

operations or specific projects. Grants and subsidies are recognized in income as the corresponding expenses are

incurred independently of cash flows received.

The decrease of €400 thousand in subsidies between 2020 and 2021 is mainly due to the €312 thousand provided

by the French State as part of the ‘‘partial unemployment measure’’, a national plan allowing companies, facing

economic challenges posed by the COVID-19 pandemic to receive approximately 84% of specific employees’ net

salaries from the French State, that had been exceptionally granted in 2020.

Subsidies also included the Bpifrance Deep Tech Grant received by Curadigm SAS, €187 thousand of which was

recognized as other income in the year ended December 31, 2020, €126 thousand for the year ended December 31,

2021, and €135 thousand of which was recognized for the year ended December 31, 2022.

Other

The line item Other mainly includes income for supply services, in the framework of the clinical supply agreement

signed in May 2022 with LianBio (see Note 4.1 to the consolidated financial statements), amounting to €474

thousand for the year ended December 31, 2022. See note 4.1 and note 15 for further details.

1.4.1.2.Operating expenses

1.4.1.2.1 Research and development costs

Our operating expenses are primarily incurred for research and development and selling, general and administrative

purposes, for the most part in France.

Research and development activities are central to our business. Since our inception, most of our resources have

been allocated to research and development. These expenses include:

•sub-contracting, collaboration and consultant expenses that primarily consist of the cost of third-party

contractors, such as contract research organizations that conduct our non-clinical studies and clinical

trials;

•employee-related costs for employees in research and development functions;

•expenses relating to preclinical studies and clinical trials for NBTXR3;

•manufacturing costs for production of NBTXR3 to support clinical development;

•certain intellectual property expenses;

•expenses relating to regulatory affairs; and

•expenses relating to the implementation of our quality assurance system.

Product candidates in later stages of clinical development generally have higher development costs than those in

earlier stages, primarily due to the increased size and duration of later-stage clinical trials. We expect that our

research and development expenses will continue to increase in the foreseeable future as we advance the clinical

development of NBTXR3.

We cannot determine with certainty the duration and completion costs of the current or planned future clinical trials of

our product candidates or if, when, or to what extent we will generate revenue from the commercialization and sale

of any of our product candidates that obtain regulatory approval. We may not succeed in achieving regulatory

approval for any particular product candidate. The duration, costs and timing of clinical trials and development of our

product candidates will depend on a variety of factors, including:

•the scope, rate of progress and expense of our ongoing and planned preclinical studies, clinical trials and

other research and development activities;

•clinical trial and early-stage results;

•the terms and timing of regulatory approvals;

•the expense of filing patent applications and maintaining and enforcing patents and other intellectual

property rights and defending against claims or infringements raised by third parties; and

•the ability to market, commercialize and achieve market acceptance for NBTXR3 or any other product

candidate that we may develop in the future.

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A change in the outcome of any of these variables with respect to the development of NBTXR3 or any other product

candidate that we develop could mean a significant change in the costs and timing associated with the development

of NBTXR3 or such other product candidates. For example, if the FDA or other comparable regulatory authority were

to require us to conduct preclinical studies and clinical trials beyond those which we currently anticipate will be

required for the completion of clinical development, or if we experience significant delays in enrollment in any clinical

trials, we could be required to spend significant additional financial resources and time on clinical development.

All of these research and development expenses (R&D) incurred to date have been recorded as expenses, with the

Company considering that the technical feasibility of its development projects will not be demonstrated until the

issuance of the approvals necessary for the marketing of its products, which is also the time at which substantially all

of the development costs will have been incurred.

The breakdown of research and development costs is as follows:


	2022	2021	2020
	12 months	12 months	12 months
(in thousands of euros)	Audited	Audited	Audited
Purchases, sub-contracting and other expenses	(20,415)	(19,562)	(12,734)
Payroll costs (incl. Share-based payments)	(10,868)	(9,605)	(10,306)
Depreciation, amortization and provision expenses	(1,353)	(1,211)	(1,290)
Total R&D costs	(32,636)	(30,378)	(24,330)

The total amount of expenses incurred with respect to research and development activities increased by €2.3 million,

or 7.4%, from €30.4 million for the year ended December 31, 2021 to €32.6 million for the year ended December 31,

2022. This net increase was mainly due to:

•Purchases, sub-contracting and other expenses increased by €0.9 million, or 4.4% for the year ended

December 31, 2022 as compared with the same period in 2021. This reflects the increase of the clinical

development activities, especially driven by our global Phase 3 clinical trial for elderly head and neck

cancer patients ineligible for platinum-based (cisplatin) chemotherapy (NANORAY-312).); and

•an increase of €1.3 million, or 13% in payroll costs, which was mainly due to cost of living adjustments

and higher bonus expenses.

The total amount of expenses incurred with respect to research and development activities increased by €6.1 million,

or 25.0%, from €24.3 million for the year ended December 31, 2020 to €30.4 million for the year ended December

31, 2021. This net increase was mainly due to:

•Purchases, sub-contracting and other expenses increased by €6.8 million, or 54% for the year ended

December 31, 2021 as compared with the same period in 2020. This reflects the increase of the clinical

development activities, especially our clinical trial NANORAY-312;

•a decrease of €0.7 million, or 6.8%, in payroll costs, which was mainly due to a change in the mix and in

the location of research and development staff; and

•a decrease of €79 thousand in depreciation, amortization and provision expenses primarily due to the

application of the IFRS 16 standard.

1.4.1.2.2 Selling, general and administrative (SG&A) expenses

SG&A expenses mainly comprise administrative payroll costs, overhead costs relating to our headquarters in Paris,

and costs such as accounting, legal, human resources, communications and market access activities.. Their total

amount was as follows during the reported period:


	2022	2021	2020
	12 months	12 months	12 months
(in thousands of euros)	Audited	Audited	Audited
Professional fees, rental and other expenses	(7,792)	(9,638)	(6,482)
Payroll costs (incl. Share-based payments)	(9,688)	(9,379)	(7,789)
Depreciation, amortization and provision expenses	(378)	(417)	(340)
Total SG&A costs	(17,857)	(19,434)	(14,611)

Our SG&A expenses decreased by €1.6 million, or 8.1%, from €19.4 million for the year ended December 31, 2021

to €17.9 million for the year ended December 31, 2022. This was primarily due to:

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Chapter 1. NANOBIOTIX AND ITS ACTIVITIES PRESENTATION

•a decrease in purchases, fees and other expenses of €1.8 million, or 19%. This variation reflects the

Company’s actions to reduce reliance on external support for core activities as well as rationalization of

and cost savings achieved relative to the services procured.

•an increase of €0.3 million or 3.3% in payroll costs mainly driven by the recruitment of a General Counsel

in 2022.

Our SG&A expenses increased by €4.8 million, or 33.0%, from €14.6 million for the year ended December 31, 2020

to €19.4 million for the year ended December 31, 2021. This was primarily due to:

•an increase in purchases, fees and other expenses of €3.1 million or 48.7%. This variation reflects two

main impacts, first the legal expenses relating to partnership agreements as well as consulting fees, legal

and compliance expenses as a result of being a US public company. The second main impact relates to

recruitment expenses;

•an increase of €1.6 million or 20.4% in payroll costs due to a change in the mix and location changes of

SG&A staff (more US based employees); and

•Depreciation, amortization and provision expenses increased from €340 thousand in 2020 to €417

thousand in 2021, primarily due to the to the extension of Villejuif leases.

1.4.1.4.Net income

1.4.1.4.1.Financial income and expenses

Net financial income (loss) decreased by €15.9 million, from an income of €5.6 million for the year ended December

31, 2021 to a €10.3 million loss for the year ended December 31, 2022. This decrease was primarily attributable to

the restructuring of the EIB financing with a negative one-off IFRS9 valuation impact of €6.9 million, higher interest

costs on the EIB loan by €4.9 million, and lower foreign exchange gains by €2.0 million. See note 12.1 and note 18

for further details.

Net financial income (loss) increased by €2.7 million, from a €2.8 million income for the year ended December 31,

2020 to an income of €5.6 million for the year ended December 31, 2021. The increase was primarily attributable to

the increase in foreign exchange gains as a result of gross proceeds of our global offering, which included our U.S.

initial public offering in a US dollar bank account.

1.4.1.4.2.Income tax

Due to the losses incurred during the reporting period, the Company did not record any significant corporate tax

expense. According to current legislation, the Company has tax deficits that can be carried forward in France for a

total amount of €331.3 million. For financial years ending on or after December 31, 2013, carried forward losses are

capped at €1 million, on top of which 50% of the profits above that amount can be included.

1.4.1.4.3.Net loss and net loss per share

The loss per share (average weighted number of shares during the year) amounted to €1.98 in 2022, €1.35 in 2021

and €1.38 in 2020.

1.4.2.Balance sheet analysis

1.4.2.1.Non-current assets


(in thousands of euros)	As of December 31, 2022	As of December 31, 2021
Intangible assets	1	4
Property, plant and equipment	7,120	8,186
Financial assets	291	519
Total non-current assets	7,412	8,709

From 1 January 2019, the Company has adopted IFRS 16 – Leases, increasing its non-current, tangible assets. The

rights of use related to these contracts relate primarily to the leases of the head office in Paris and the manufacturing

site in Villejuif in France.

The decrease in of €1.2 million in Property, plant and equipment from €8.2 million as of December 31, 2021

compared to €7.1 million mainly corresponds to the amortization of the period.on the right of use of buildings.

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Chapter 1. NANOBIOTIX AND ITS ACTIVITIES PRESENTATION

1.4.2.2.Current assets


(in thousands of euros)	As of December 31, 2022	As of December 31, 2021
Research tax credit receivable	4,091	2,490
VAT receivable	1,055	1,058
Prepaid expenses	2,981	2,213
Other receivables	2,741	3,378
Other current assets	10,868	9,139

As of December 31, 2022, prepaid expenses mainly relate to the to MD Anderson collaboration agreement for

€1.5 million (see Note 4.4), as compared to €1.0 million for the year ended December 31, 2021, to the AON

insurance contracts for €0.7 million (as compared to the CRF insurance contracts for €0.6 million in 2021), and to

Myonex prepayment on purchased Cetuximab for €0.1 million (nil in 2021).

Other receivables decrease by €0.6 million is mainly explained by decrease of suppliers prepayment, amounting to

€2.6 million as of December 31, 2022 and €3.0 million as of December 31, 2021. These advance payments are

mainly related to ICON and Imaging EndPoints, vendors for clinical trial services.


(in thousands of euros)	As of December 31, 2022	As of December 31, 2021
Cash and bank accounts	38,576	83,921
Short-term bank deposits	2,813	—
Net cash and cash equivalents	41,388	83,921

As of December 31, 2022, net cash and cash equivalents decreased by €42,533 thousand as compared with

December 31, 2021

In the framework of the Amendment Agreement with the EIB, the Company has agreed to maintain a minimum cash

and cash equivalents balance equal to the outstanding principal owed to EIB €25.3 million as of December 31, 2022

the debt reimbursement related to the EIB loan and PGE loans to HSBC and Bpifrance, the payments made to

PharmaEngine and other cash flows used in operating activities.


(in thousands of euros)	2022	2021
Cash flows from (used in) operating activities	(37,104)	(29,872)
Cash flows from (used in) investing activities	138	(242)
Cash flows from (used in) financing activities	(5,651)	(5,180)
Impact of exchange rates changes on cash	83	64
Net cash flow	(42,533)	(35,230)

(see note 1.4.4 Cash flow, capital financing)

1.4.2.3.Equity

The Company’s equity on December 31, 2021 was €26,790 thousand compared to €(38,839) thousand on

December 31, 2022. The decrease is primarily due to the net losses of €68,835 thousand in 2022.

1.4.2.4.Non-current liabilities

Non-current liabilities of €60,672 thousand at December 31, 2022 mostly include financial liabilities related to the

loans and advances granted to the Company, including the fair value of the EIB loan for a nominal value of €47.5

million.

Details of the remaining amounts to be repaid as of December 31, 2021 can be found in Note 12 to the consolidated

financial statements for the year ended December 31, 2022, prepared under IFRS, in Section 4.1. of the Universal

Registration Document.

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1.4.2.5.Current liabilities


(in thousands of euros)	As of December 31, 2022	As of December 31, 2021
Current provisions	327	110
Current financial liabilities	4,560	8,204
Trade payables and other payables	9,621	6,482
Other current liabilities	6,855	5,277
Deferred income	55	254
Current contract liabilities	16,518	16,518
Total current liabilities	37,936	36,845

Under Sections L. 441-6-1 and D. 441-4 of the French Code of Commerce, the breakdown of the Company's

supplier debts on the closing date of the last two financial years based on their respective maturity dates is

presented below.

2022

Unpaid invoices received at the end of the financial year:


	1 to 30 days	31 to 60 days	61 to 90 days	91 days and more	Total (1 day and more)
(A) Late payment tranche
Number of invoices					76
Total (incl. VAT)	€462k	€32k	€71k	€55k	€621k
Percentage of total purchases for the year (incl. VAT)	1.60%	0.11%	0.25%	0.19%	2.15%
(B) Invoices excluded from (A) related to disputed or unrecognized debts and receivables
Number of invoices excluded	—	—	—	—	—
Total amount of invoices excluded (incl. VAT)	—	—	—	—	—
(C) Reference payment terms used (contractual or legal deadline - article L. 441-6 or article L. 443-1 of the French Commercial Code)
Payment period used to calculate late payments	Contractual deadlines: deadlines for each invoice

Unpaid invoices issued at the end of the financial year:


	1 to 30 days	31 to 60 days	61 to 90 days	91 days and more	Total (1 day and more)
(A) Late payment tranche
Number of invoices					—
Total (incl. VAT)	—	—	—	—	—
Percentage of total purchases for the year (incl. VAT)
Percentage of the financial year revenue (incl. VAT)	—	—	—	—	—
(B) Invoices excluded from (A) related to disputed or unrecognized debts and receivables
Number of invoices excluded	—	—	—	—	—
Total amount of invoices excluded (incl. VAT)	—	—	—	—	—
(C) Reference payment terms used (contractual or legal deadline - article L. 441-6 or article L. 443-1 of the French Commercial Code)
Payment period used to calculate late payments	Contractual deadlines: deadlines on each invoice

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Chapter 1. NANOBIOTIX AND ITS ACTIVITIES PRESENTATION

2021

Unpaid invoices received at the end of the financial year:


	1 to 30 days	31 to 60 days	61 to 90 days	91 days and more	Total (1 day and more)
(A) Late payment tranche
Number of invoices					155
Total (incl. VAT)	€61k	€139k	€177k	€753k	€1,130k
Percentage of total purchases for the year (incl. VAT)	0.17%	0.39%	0.49%	2.10%	3.14%
(B) Invoices excluded from (A) related to disputed or unrecognized debts and receivables
Number of invoices excluded	—	—	—	—	—
Total amount of invoices excluded (incl. VAT)	—	—	—	—	—
(C) Reference payment terms used (contractual or legal deadline - article L. 441-6 or article L. 443-1 of the French Commercial Code)
Payment period used to calculate late payments	Contractual deadlines: deadlines for each invoice

Unpaid invoices issued at the end of the financial year:


	1 to 30 days	31 to 60 days	61 to 90 days	91 days and more	Total (1 day and more)
(A) Late payment tranche
Number of invoices					0
Total (incl. VAT)	—	—	—	—	—
Percentage of total purchases for the year (incl. VAT)
Percentage of the financial year revenue (incl. VAT)	—	—%	—	—%	—%
(B) Invoices excluded from (A) related to disputed or unrecognized debts and receivables
Number of invoices excluded	—	—	—	—	—
Total amount of invoices excluded (incl. VAT)	—	—	—	—	—
(C) Reference payment terms used (contractual or legal deadline - article L. 441-6 or article L. 443-1 of the French Commercial Code)
Payment period used to calculate late payments	Contractual deadlines: deadlines on each invoice

1.4.3.Outlook and subsequent events

1.4.3.1.Trends

To find out the main trends since December 31, 2022, see paragraph 1.1.3. of the Universal Registration Document.

1.4.3.2.Known trend, uncertainty, commitment request or reasonably sensitive event to affect the

Company’s outlook

For details about the impact of COVID-19 and the ongoing conflict between Ukraine and Russia on the Group, see

paragraphs 1.5.1.4 and 1.5.1.7 of the Universal Registration Document, respectively.

1.4.3.3.Profit forecasts or estimates

The Company does not intend to forecast or estimate profits.

1.4.3.4.Significant change in financial or business situation

To the Company’s knowledge, there has been no significant change in the Company’s financial or commercial

position since December 31, 2022.

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Chapter 1. NANOBIOTIX AND ITS ACTIVITIES PRESENTATION

1.4.4.Cash flow, capital financing

Information about the Group’s capital, liquidity and sources of financing.

As of December 31, 2022, the amount of cash and cash equivalents held by the Company was €41.4 million

compared to €83.9 million as of December 31, 2021. Cash and cash equivalents include the Company’s current

availability and financial instruments (mainly composed of paid short-term bank deposits). These availability and

investment securities are used to fund the Company's activities, including its research and development costs.

As of March 31, 2023, Nanobiotix had €30.2 million in cash and cash equivalents, and continues to explore options

to obtain additional funding, including through third part collaborations related to the future potential development

and/or commercialization of our product candidates, that could significantly extend the cash horizon. With utilization

of the equity line it has in place with Kepler Cheuvreux, the Company expects to finance its operations into Q1 2024.

This is subject to the EIB cash covenant that requires the Company to maintain a cash balance equal to the principal

debt outstanding to the EIB of EUR 25.3 million. However, Nanobiotix has obtained a 15 million euros temporary

waiver, until July 31, 2023, and has reached an agreement in principle with EIB to automatically extended it until

January 31, 2024 should (a) a business development partnership, collaborative or strategic alliance have become

effective before July 31, 2023 and (b) the contractual documentation is signed within fifteen days following the date

of this form 20-F. Failing this extension period, and except if it has obtained appropriate funding prior, the Company

is expected to be in breach of this temporary waiver as of July 31, 2023..

Capital financing

Refer to chapter 4 of the Universal Registration Document.

Financing through advances

See paragraph 1.4.2.4. of the Universal Registration Document.

Research Tax Credit financing

See Note 8.2 to the consolidated financial statements for the year ended December 31, 2022, prepared under IFRS,

in Section 4.1. of the Universal Registration Document.

Off-balance sheet of commitment

See Note 23 to the consolidated financial statements for the year ended December 31, 2022, prepared under IFRS,

in Section 4.1. of the Universal Registration Document.

Source and amount of cash flow

During the period presented, net cash flows are presented as shown in the table below.


(in thousands of euros)	2022	2021
Cash flows from (used in) operating activities	(37,104)	(29,872)
Cash flows from (used in) investing activities	138	(242)
Cash flows from (used in) financing activities	(5,651)	(5,180)
Impact of exchange rates changes on cash	83	64
Net cash flow	(42,533)	(35,230)

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Chapter 1. NANOBIOTIX AND ITS ACTIVITIES PRESENTATION

Cash flows from / used in operating activities

Net cash consumption at operating activities is primarily divided into cash flow over the period and changes in

working capital requirements.


(in thousands of euros)	2022	2021
Net loss for the period	(57,041)	(47,003)
Elimination of other non-cash, non-operating income and expenses
Depreciation and amortization	1,500	1,560
Provisions	305	152
Expenses related to share-based payments	3,174	3,201
Cost of net debt	2,042	2,224
Loss on disposal	3	—
Impact of deferred income related to financial liabilities discounting effect	10,649	(1,554)
Other charges with no impact on treasury	(36)	8
Cash flows used in operations, before tax and changes in working capital	(39,403)	(41,412)
Changes in operating working capital	2,300	11,540
Cash flows from (used in) operating activities	(37,104)	(29,872)

Our net cash flows used in operating activities was €37.1 million and €29.9 million for the years ended December 31,

2022 and 2021, respectively.

The net cash flows used in operating activities for the year ended December 31, 2022 (€37.1 million), increased by

€7.2 million compared to the net cash used in operating activities in 2021 (€29.9 million), primarily due to a €2.0

million improvement of cash-flows used in operating activities, reflecting a strict monitoring of or clinical studies

operating expenses and a reduction of cash outflows related to SG&A activities, which is fully offset by a €9.2 million

negative change in working capital compared to 2021, but only due to the one-off favorable impact in 2021 (€16.5

million LianBio upfront payment received). Without this one-off impact, working capital variance would be favorable

by €7.3 million in 2022 compared to 2021.

Cash flow from / used in investing activities

Cash consumption related to investment activities should be analysed by distinguishing flows directly related to the

Company’s operating activity and those related to its cash management policy.


(in thousands of euros)	2022	2021
Acquisitions of intangible assets	(1)	(5)
Acquisitions of property, plant and equipment	(92)	(228)
(Increase) / Decrease in non-current financial assets	230	(9)
Net cash flows from (used in) investing activities	138	(242)

Our net cash flows received from investing activities was an inflow of €138 thousand for the year ended December

31, 2022, is composed by a €230 thousand positive cash effect on non-current financial assets corresponding to a

deposit repayment received from Paris offices lessor amounting to €133 thousand and the end of our liquidity

contract with Gilbert Dupont amounting to €97 thousand, offset by a €92 thousand outflow for fixed asset

acquisitions.

Cash flows from / used in financing activities

Net flows from financing activities are mainly related to:


(in thousands of euros)	2022	2021
Capital increases	—	—
Warrants subscription	—	43
Transaction costs	—	(349)
Decrease in conditional advances	(3,642)	(2,833)
Repayment of lease liabilities	(1,093)	(909)
Interest paid related to loans	(915)	(1,132)
Net cash flows from (used in) financing activities	(5,651)	(5,180)

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Chapter 1. NANOBIOTIX AND ITS ACTIVITIES PRESENTATION

The net cash flows used in financing activities slightly increased by €0.5 million between 2022 and 2021 and are

mainly composed of bank and leasing debt reimbursements

Our net cash flows from (used in) financing activities were €(5.7) million and €(5.2) million for the periods ended

December 31, 2022 and 2021 respectively. The cash used in financing activities for the periods ended December 31,

2022 and 2021 mainly relate to the loans repayments and interests paid.

Information on repayable advance conditions and financing structure

The main terms of the repayable advances granted to the Company as of December 31, 2022 are described in

paragraph 1.4.2. of the Universal Registration Document.

Restrictions to the use of Equity


(in thousands of euros)	2022	2021
Treasury share - cash account	—	97
Deposits paid	291	421
TOTAL	291	519

Funding sources needed for the future

As outlined in paragraphs 1.5.1.5 and 1.5.1.6. and in the note 6.2 of the Universal Registration Document, events

and conditions indicate that a material uncertainty exists that may cast significant doubt about the Company’s ability

to have a sufficient cash position to cover operating needs for at least the next 12 months following the date of the

Universal Registration Document.

1.4.5.Accounting and reporting on allocation of the profit

Important factors, including unusual or infrequent events or new developments, significantly affecting the

issuer’s operating income, indicating the measure in the world is affected.

In terms of the development stage of the Company’s business, the main factors affecting the business and

profit are:

•the scope of the R&D programs and compliance with their timetable; the existence of tax incentives for

companies involved in technical and scientific research activities such as the research tax credit for which

it benefits;

•entering into development agreements and/or licenses on part of its technology, or;

•obtaining grants and repayable advances.

In addition, the Company regularly grants financial instruments giving access to its capital to its employees, be they

corporate officers or not, as well certain business partners. The Company’s results are affected by the corresponding

expense, recorded in the financial statements established according to the IFRS repository prepared under IFRS.

The Company did not find any unusual or infrequent events that could affect its operating income.

When financial statements show significant changes in net sales or net revenues, explain the reasons for

these changes.

Not Applicable.

Mention any measures or factors of an administrative, economic, budgetary, monetary or political nature

that have significantly or could have significant impact, directly or indirectly, on the issuer’s operations.

Given the great uncertainty regarding the evolution of COVID-19 pandemic, global confinement measures and the

resulting economic downturn, the potential impact of the pandemic on the Group’s activities and future results

remains highly uncertain. In addition, enrollment and retention of patients in clinical trials could be disrupted by

geopolitical events, including civil or political unrest (such as the ongoing conflict between Ukraine and Russia),

terrorism, insurrection or war, man-made or natural disasters, or public health pandemics or epidemics or other

business interruptions, including, the current COVID-19 pandemic and future outbreaks of the disease.

1.4.6.Information on dividends

Dividends paid in the last three years

None.

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Chapter 1. NANOBIOTIX AND ITS ACTIVITIES PRESENTATION

Dividend distribution policy

There are no plans at this time to initiate a dividend payment policy given the Company’s stage of development.

1.4.7.Non-tax-deductible expenses

In accordance with the provisions of Article 223 quarter of the General Tax Code, the General Meeting of

Shareholders approved, among other things, non-tax-deductible expenses and expenses covered by Section 39-4 of

the same Code.

We indicate that the corporate accounts for the past year do not show any tax-deductible expenses or expenses as

covered by section 4 of section 39 of the French General Tax Code.

1.4.8.Results for the last five years of Nanobiotix SA


INDICATORS (in thousands of euros)	2018	2019	2020	2021	2022
I. Financial position at the end of the year
a) Share Capital	589	672	1,033	1,045	1,046
b) Weighted average number of shares	19,633,373	21,631,514	24,385,827	34,733,418	34,851,868
c) Number of equity options that may be converted in shares	3,176,910	2,338,013	2,414,654	2,972,860	3,513,246

II. Overall results
a) Turnover (excl VAT)	209,000	444,000	231,000	125,000	624,000
b) Loss before tax, depreciation and provisions	(30,751)	(44,772)	(36,734)	(46,788)	(45,617)
c) Research Tax credit	3,251	2,373	1,858	2,273	3,884
d) Profit/ (loss) after tax, amortization and depreciation	(28,117)	(43,574)	(35,720)	(45,146)	(42,667)
e) Dividends	—	—	—	—	—

III. Results assessed for one share
a) Loss before tax, depreciation and provisions	(1.57)	(2.07)	(1.51)	(1.35)	(1.31)
b) Net loss	(1.43)	(2.01)	(1.46)	(1.30)	(1.22)
c) Dividend per share	—	—	—	—	—

IV. Employees
a) Number of employees at the end of the year	89	85	71	75	77
b) Payroll cost	7,649	8,307	7,375	7,826	7,877
c) Social benefit expense during the year	3,044	3,439	3,551	4,091	4,045

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1.5.RISK FACTORS

Our business and our industry are subject to significant risks. You should carefully consider all the information set

forth in this Universal Registration Document, including the following risk factors. Our business, financial condition or

results of operations could be materially adversely affected by any of these risks. Additional risks not currently known

to us or that we currently deem immaterial may also affect our business operations.

Summary of Risk Factors Associated with Our Business

Our business and our industry are subject to numerous risks described in “Risk Factors” and elsewhere in this

Universal Registration Document. You should carefully consider these risks before making a decision to invest in our

securities.

The main risk factors relating to the Group and its business are grouped into nine categories listed below.

The most important risk factors have been identified and assessed considering the likelihood of occurrence and the

possible negative effect on the Company, in each case also taking into account corrective actions and risk

management measures that have been put in place. The occurrence of new events, whether internal or external to

the Company, is therefore likely to modify this ranking in the future.


	Risk	Likelihood	Impact
1.5.1.	Risks Related to Our Business
1.5.1.5.	We have a history of losses and require additional funding to support ongoing operational needs and to meet debt covenant requirements.	High	High
1.5.1.2.	We have incurred significant losses since our inception and anticipate that we will continue to incur significant losses for the foreseeable future.	High	Medium
1.5.1.6.	We are limited in our ability to raise additional share capital, which may make it difficult for us to fund our operations.	Medium	High
1.5.2.	Risks Related to the Discovery, Development and Commercialization of Our Product Candidates
1.5.2.1.	Our product candidate development programs are in various phases of development and may be unsuccessful.	High	High
1.5.2.3.	We may encounter substantial delays in our clinical trials, including clinical studies of NBTXR3, or we may fail to demonstrate safety and efficacy to the satisfaction of applicable regulatory authorities.	High	High
1.5.2.5.	Our business is highly dependent on the success of our lead product candidate NBTXR3, and we cannot be certain that we, directly or through any partner with which we may conclude a development agreement, will be able to obtain regulatory approval for, or successfully commercialize, NBTXR3.	Medium	High
1.5.2.8.	Difficulty enrolling patients could delay or prevent clinical studies of NBTXR3.	Medium	High
1.5.2.10.	If our product candidates do not achieve projected development milestones and commercialization in the announced or expected timeframes, further development or commercialization of our product candidates may be delayed, and our business may be harmed.	High	High
1.5.2.12.	Even if NBTXR3 is commercialized, NBTXR3 may not be accepted by physicians, patients, or others in the medical community.	Medium	High
1.5.2.14.	Our future profitability, if any, depends, in part, on our ability to penetrate global markets, where we would be subject to additional regulatory burdens and other risks and uncertainties.	Medium	High
1.5.3.	Risks Related to Our Reliance on Third Parties

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	Risk	Likelihood	Impact
1.5.3.2.	Third parties on whom we rely to conduct, supervise and monitor clinical studies may not perform satisfactorily.	Medium	High
1.5.3.3.	We are party to strategic development and commercialization relationships, which may not advance or be successful and may delay or harm further development or commercialization of our product candidates.	High	High
1.5.3.4.	Access to raw materials, starting material and products necessary for the conduct of clinical trials and manufacturing of our product candidates is not and cannot be guaranteed.	Medium	High
1.5.4.	Risks Related to Operational Compliance and Risk Management
1.5.4.1.	We will need to develop and expand our company, and we may encounter difficulties in managing this development and expansion, which could disrupt our operations.	High	High
1.5.4.2.	Product liability lawsuits could divert our resources, result in substantial liabilities and reduce the commercial potential of our product candidates.	Medium	High
1.5.4.4.	We identified a material weakness in our internal control over financial reporting as of December 31, 2022 related to a lack of supervisory personnel with the appropriate level of technical accounting experience and training to comply with International Financial Reporting Standards and with SEC reporting obligations, and sufficient processes and procedures, particularly in the areas of complex, judgmental areas such as assessing the Company’s ability to continue as a going concern and the valuation of complex debt instruments	Medium	High
1.5.4.7.	Because our consolidated financial statements rely on estimates and assumptions, actual results may vary significantly from estimates that we make.	Medium	High
1.5.5.	Risks Related to Regulatory Approvals for Our Product Candidates
1.5.5.1.	The regulatory landscape that governs our product candidates is uncertain as it is subject to both drug & device regulations, depending on the country involved, and changes in regulatory requirements could result in delays or discontinuation of development of our product candidates or unexpected costs in obtaining regulatory approval and/or CE-marking.	High	High
1.5.5.3.	The regulatory approval processes of the FDA and comparable foreign authorities are lengthy, time consuming and inherently unpredictable, and if we are ultimately unable to obtain regulatory approval for our product candidates, our business will be substantially harmed.	High	High
1.5.5.6.	Government restrictions on pricing and reimbursement, as well as other healthcare payor cost-containment initiatives, may negatively impact our ability to generate revenues if we obtain regulatory approval for any of our product candidates.	Medium	High
1.5.6.	Risks Related to Intellectual Property
1.5.6.1	Our ability to compete may decline if we do not adequately protect our proprietary rights.	High	High

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	Risk	Likelihood	Impact
1.5.6.2.	If we are unable to protect the confidentiality of our trade secrets, our business and competitive position would be harmed.	Medium	High
1.5.6.9.	A dispute concerning the infringement or misappropriation of our proprietary rights or the proprietary rights of others could be time consuming and costly, and an unfavorable outcome could harm our business.	Medium	High
1.5.7.	Risks Related to Human Capital
1.5.7.1.	We depend on key management personnel and attracting and retaining other qualified personnel, and our business could be harmed if we lose key management personnel or cannot attract and retain other qualified personnel.	High	High
1.5.8.	Risks Relating to Our Status as a Foreign Private Issuer or a French Company
1.5.8.2.	The rights of shareholders in companies subject to French corporate law differ in material respects from the rights of shareholders of corporations incorporated in the United States.	High	High
1.5.9.	Risks Related to Ownership of Our ADSs
1.5.9.6.	Share ownership is concentrated in the hands of our principal shareholders and management, who will continue to be able to exercise substantial influence on us.	Medium	High

Risks Related to Our Business (see “Risks Factors — Risks Related to Our Business” for additional details):

•We have incurred significant losses since our inception and anticipate that we will continue to incur

significant losses for the foreseeable future.

•We face substantial competition from companies, many of which have considerably more resources and

experience than we have.

•We will need to raise additional funding, which may not be available on acceptable terms, or at all. Failure

to obtain this necessary capital when needed may force us to delay, limit or terminate our product

development efforts or other operations.

•We are subject to various risks related to public health crises, including the COVID-19 pandemic, that

could have material and adverse impacts on our business, financial condition, liquidity, and results of

operations.

Risks Related to the Discovery, Development and Commercialization of Our Product Candidates (see “Risks

Factors — Risks Related to the Discovery, Development and Commercialization of Our Product Candidates”

for additional details):

•Our product candidate development programs are in various phases of development and may be

unsuccessful.

•Initial, interim and preliminary data from our clinical trials that we announce or publish from time to time

may change as more patient data becomes available and are subject to audit and verification procedures

that could result in material changes in the final data.

•We may encounter substantial delays in our clinical trials, including clinical studies of NBTXR3, or we may

fail to demonstrate safety and efficacy to the satisfaction of applicable regulatory authorities.

•Even if we or our strategic development and commercialization partners successfully complete clinical

trials of NBTXR3, NBTXR3 may not be successfully commercialized for other reasons.

•Any issues that arise in the highly complex manufacturing process for our product candidates could have

an adverse effect on our business, financial position or prospects.

•Difficulty enrolling patients could delay or prevent clinical studies of NBTXR3.

•If our product candidates do not achieve projected development milestones and commercialization in the

announced or expected timeframes, further development or commercialization of our product candidates

may be delayed, and our business may be harmed.

•Our product candidates may cause undesirable side effects that could halt their clinical development,

delay or prevent their regulatory approval, limit their commercial potential, or result in other significant ,

negative consequences.

•Our future profitability, if any, depends, in part, on our ability to penetrate global markets, where we would

be subject to additional regulatory burdens and other risks and uncertainties.

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Risks Related to Our Reliance on Third Parties (see “Risks Factors — Risks Related to Our Reliance on

Third Parties” for additional details):

•Third parties on whom we rely to conduct, supervise and monitor clinical studies may not perform

satisfactorily.

•We are party to strategic development and commercialization relationships, which may not advance or be

successful and may delay or harm further development or commercialization of our product candidates.

•Access to raw materials, starting material and products necessary for the conduct of clinical trials and

manufacturing of our product candidates is not and cannot be guaranteed.

Risks Related to Operational Compliance and Risk Management (see “Risks Factors — Risks Related to

Operational Compliance and Risk Management” for additional details):

•We will need to develop and expand our company, and we may encounter difficulties in managing this

development and expansion, which could disrupt our operations.

•Product liability lawsuits could divert our resources, result in substantial liabilities and reduce the

commercial potential of our product candidates.

•We identified a material weakness in our internal control over financial reporting. If we are not able to

remediate the material weakness and otherwise maintain an effective system of internal control over

financial reporting, the reliability of our financial reporting, investor confidence, and the value of our

securities could be adversely affected.

•Our internal computer systems, or those of our third-party contractors or consultants, may fail or suffer

security breaches, which could result in a material disruption of our product development programs or

loss of personal data.

•Because our consolidated financial statements rely on estimates and assumptions, actual results may

vary significantly from estimates that we make.

Risks Related to Regulatory Approvals for Our Product Candidates (see “Risks Factors — Risks Related to

Regulatory Approvals for Our Product Candidates” for additional details):

•Our business is governed by a rigorous, complex and evolving regulatory framework, including pre-

marketing regulatory requirements, pricing, reimbursement and cost-containment regulations, and

rigorous ongoing regulation of approved products. This regulatory framework results in significant

compliance costs, makes the development and approval of our product candidates time intensive and

unpredictable, and may reduce the ultimate economic value and prospects for our product candidates.

•A Fast Track, Breakthrough Therapy, Priority Review or Accelerated Approval designation by the FDA,

may not lead to a faster development or regulatory review or approval process and does not increase the

likelihood that our product candidates will receive or maintain regulatory approval. See more specifically

for Accelerated approval pathway section “Government regulation, product approval and certification” of

this URD for additional details.

•Government restrictions on pricing and reimbursement, as well as other healthcare payor cost-

containment initiatives, may negatively impact our ability to generate revenues if we obtain regulatory

approval for any of our product candidates.

Risks Related to Intellectual Property (see “Risks Factors — Risks Related to Intellectual Property” for

additional details):

•Our ability to compete may decline if we do not adequately protect our proprietary rights.

•If we are unable to protect the confidentiality of our trade secrets, our business and competitive position

would be harmed.

•Patents and patent applications involve highly complex legal and factual questions, which, if determined

adversely to us, could negatively impact our competitive position.

•A dispute concerning the infringement or misappropriation of our proprietary rights or the proprietary rights

of others could be time-consuming and costly, and an unfavorable outcome could harm our business.

Risks Related to Human Capital (see “Risks Factors — Risks Related to Human Capital” for additional

details):

•We depend on key management personnel and attracting and retaining other qualified personnel, and our

business could be harmed if we lose key management personnel or cannot attract and retain other

qualified personnel.

Risks Relating to Our Status as a Foreign Private Issuer or a French Company (see “Risks Factors — Risks

Relating to Our Status as a Foreign Private Issuer or a French Company” for additional details):

•The rights of shareholders in companies subject to French corporate law differ in material respects from

the rights of shareholders of corporations incorporated in the United States.

•Our By-laws and French corporate law contain provisions that may delay or discourage a takeover

attempt and investments in the Company may be subject to prior governmental authorization under the

French foreign investment control regime.

•Our failure to maintain certain tax benefits applicable to French technology companies may adversely

affect our results of operations.

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102

•Although not free from doubt, we do not believe we were a “passive foreign investment company,” or

PFIC, for U.S. federal income tax purposes for the taxable year ended December 31, 2022. However, we

cannot assure you that we will not be classified as a PFIC for the taxable year ending December 31, 2023

or any future taxable year, which may result in adverse U.S. federal income tax consequences to U.S.

holders.

•As a foreign private issuer under U.S. Securities law, we are exempt from a number of rules under the

U.S. securities laws and we follow certain home country practices in relation to corporate governance

matters that differ significantly from Nasdaq corporate governance standards.

Risks Related to Ownership of Our ADSs (see “Risks Factors — Risks Related to Ownership of Our ADSs”

for additional details):

•Holders of our ADSs do not directly hold our ordinary shares.

•Share ownership is concentrated in the hands of our principal shareholders and management, who will

continue to be able to exercise substantial influence on us.

1.5.1.Risks Related to Our Business

1.5.1.1.We are a clinical-stage biotechnology company pioneering disruptive, physics-based

therapeutic approaches, which makes it difficult to evaluate our current business and

future prospects and may increase the risk of your investment.

We are a clinical-stage biotechnology company pioneering disruptive, physics-based therapeutic approaches

focused on developing first-in-class product candidates that use its proprietary nanotechnology to transform cancer

treatment by increasing the efficacy of radiotherapy. Investment in biotech development is a highly speculative

endeavor. Biotech product development entails substantial upfront capital expenditures, and there is significant risk

that any potential product candidate will fail to demonstrate adequate efficacy or an acceptable safety profile, to gain

required regulatory approvals or to become commercially viable. While there have been significant advances in

nanotechnology, our product candidates are new and unproven, and our most advanced product candidate NBTXR3

is in clinical development except for the STS indication, and we have not yet generated any revenue from product

sales to date, including STS.

Our operating history to date may make it difficult to evaluate our current business and our future prospects. We

have encountered, and will continue to encounter, risks and difficulties frequently experienced by growing companies

in rapidly evolving industries, such as the biotechnology industry. Consequently, the ability to predict our future

operating results or business prospects is more limited than if we had a portfolio of approved products on the market.

We may not be able to fully implement or execute on our commercial strategy or realize, in whole, in part, or within

our expected time frames, the anticipated benefits of our strategies. You should consider our business and prospects

in light of the risks and difficulties we face as a company focused on developing products in the field of physics-

based therapeutic approaches and advancing clinical trials.

1.5.1.2.We have incurred significant losses since our inception and anticipate that we will

continue to incur significant losses for the foreseeable future.

We devote most of our financial resources to research and development relating to our NBTXR3, including the

advancement of our clinical trials. We finance our current operations primarily through loans such as from the

European Investment Bank, as well as by obtaining public funding, reimbursements of research tax credit claims,

and milestones on our licensed technology pursuant to strategic licensing relationships such as LianBio.

We have not yet built a commercial organization and do not currently market or sell any commercial products.

Notwithstanding the European CE marking enabling the Company to commercialize NBTXR3 within the European

Economic Area, under the brand name Hensify®, for the treatment of locally advanced soft tissue sarcoma of the

extremities and trunk wall, the Company has no current plans to market or sell the product in the EU until after

approval of NBTXR3 in a second indication to the extend a marketing authorization approval would be granted by

competent health authorities. It will be several years, if ever, before we complete the required clinical studies and

obtain regulatory approval for, or are ready for commercialization of, a biotech or medical product candidate, in

particular NBTXR3.

Even if we or our strategic licensees successfully complete clinical studies and obtain regulatory approval to market

a product candidate, any future revenues will depend upon the size of any markets in which the product candidates

are approved for sale as well as the market share captured by such product candidates, market acceptance of such

product candidates and levels of reimbursement from third-party payors.

We expect to continue to incur significant expenses and operating losses for the foreseeable future. We expect our

losses and our cash utilization to substantially increase in the near term as we conduct our clinical studies for

elaborating the relevant file and submit a NDA and/or foreign equivalent filings for additional product candidates,

conduct research and development for product candidates, invest in deploying and scaling our manufacturing

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103

capabilities, seek regulatory and marketing approvals, and establish necessary infrastructure for the

commercialization of any products for which we obtain marketing approval.

The net losses we incur may fluctuate significantly from year to year and quarter to quarter, such that a period-to-

period comparison of our results of operations may not be a good indication of our future performance. In any

particular period or periods, our operating result could be below the expectations of securities analysts or investors

which could cause the price of our common shares, including under ADSs, to decline.

1.5.1.3.We face substantial competition from companies many of which have considerably more

resources and experience than we have.

The biotechnology industry, and the oncology industry in particular, is characterized by intense competition and rapid

innovation. We face competition from new and established biotechnology and pharmaceutical companies, academic

research institutions, government agencies and public and private research institutions. Many of our competitors,

either alone or with strategic partners, have substantially greater financial, technical and other resources, such as

larger research and development staff, greater expertise in large scale pharmaceutical manufacturing, and/or well-

established marketing and sales teams. In addition, smaller or early-stage companies may compete with us through

collaborative arrangements with more established companies. Our competitors, either alone or with partners, may

succeed in developing, acquiring or licensing compounds, drugs, biologic products or medical device that are more

effective, safer, more easily commercialized, or less costly than our product candidates. Further, competitors may

develop proprietary technologies or secure patent protection that we may need for the development of our

technologies and products. Our competitors also compete with us in recruiting and retaining qualified scientific and

management personnel.

Even if we obtain regulatory approval of our product candidates, the availability and price of our competitors’

products may limit demand for, or the price that we are able to charge for our product candidates. We may not be

able to implement our business plan if the acceptance of our product candidates is inhibited by price competition or

the reluctance of physicians to switch from existing methods of treatment to our product candidates, or if physicians

switch to other new drug, medical device or biologic products or choose to reserve our product candidates for use in

limited circumstances.

1.5.1.4.We are subject to various risks related to public health crises, including the COVID-19

pandemic, that could have material and adverse impacts on our business, financial

condition, liquidity, and results of operations.

Any outbreaks of contagious diseases and other adverse public health developments could have a material and

adverse impact on our business, financial condition, liquidity, and results of operations. As has occurred with the

COVID-19 global pandemic, a regional epidemic or a global pandemic could cause disruptions to national and global

economies and financial markets as well as raw materials supply chains, and could have a negative impact on our

clinical trials, including with respect to patient recruitment. In the case of the COVID-19 pandemic, the most

significant impact on our business were delays in protocol development and review processes for the initiation of

clinical trials, clinical trial delays resulting from patient enrollment disruptions, increased patient withdrawals from

clinical trials, and tighter restrictions imposed on patients participating in clinical trials.

While we believe that global health systems and patients have largely adapted to the impacts of COVID-19, the

advancement of our clinical trials relies on physician-administered product candidates and in-person patient follow-

up, which could be adversely affected by the pandemic if it continues or worsens. The continued duration and

severity of the COVID-19 pandemic is uncertain and difficult to predict. The degree to which COVID-19-related

disruptions impact our business in 2023 will depend on future developments, beyond our knowledge or control. In

addition, any future pandemic, epidemic or similar public health threat could present similar risks to our business,

results of operations, financial condition and prospects.

1.5.1.5. We have a history of losses and require additional funding to support ongoing operational

needs and to meet debt covenant requirements.

We have incurred recurring losses since inception of €227.3 million, including net losses of €57.0 million for the year

ended December 31, 2022. As of December 31, 2022, we had cash and cash equivalents of €41.4 million.

We expect to continue to incur significant expense related to the development and manufacturing of nanotechnology

product candidates such as NBTXR3 and conducting clinical studies. Additionally, we may encounter unforeseen

difficulties, complications, development delays and other unknown factors that require additional expense. As a

result of these expenditures, we expect to continue to incur significant losses in the near term. Additionally, the

Company’s debt instruments contain covenants that require maintenance of minimum cash and cash equivalent

balances that limit the availability of cash resources to pursue operational needs.

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The Company has not yet established a source of revenues sufficient to cover its operating costs, and as such, has

financed its growth through successive capital increases, collaboration and license agreements and receipt of

research tax credit applicable in France.

These facts and conditions raise substantial doubt about our ability to continue as a going concern, and our

independent registered public accounting firm has included an explanatory paragraph regarding going concern

qualification in its audit report. The failure to raise additional funding may have a material adverse effect on our

business, results of operations and financial position, and may adversely affect our ability to continue as a going

concern. If we do not become consistently profitable, our accumulated deficit will grow larger and our cash balances

will decline further, and we will require further financings to continue operations. Any such financings may not be

accessible on acceptable terms, if at all.

Our ability to raise additional capital may be limited.

Under French law, our extraordinary general shareholders’ meeting may decide to increase our share capital at a

majority vote of at least two-thirds of the shareholders present, represented by proxy. Alternatively, it may delegate to

our executive board the authority to carry out such increase. Accordingly, we may not be in position to issue

additional share capital if we are unable to obtain the required majority at our shareholders’ meetings.

If we raise additional capital through the sale of additional equity or convertible securities, including through the

equity line we implemented with Kepler Cheuvreux, current ownership interests may be diluted, and the terms of

these securities may include liquidation or other preferences that adversely affect stockholders’ rights. Debt

financing, if available, would result in increased fixed payment obligations and a portion of our operating cash flows,

if any being dedicated to the payment of principal and interest on such indebtedness. In addition, debt financing may

involve agreements that include restrictive covenants that impose operating restrictions, such as restrictions on the

incurrence of additional debt, the making of certain capital expenditures or the declaration of dividends. Furthermore,

to the extent we raise additional funds through arrangements with research and development partners or otherwise,

we may be required to relinquish some of our technologies, product candidates or revenue streams, license our

technologies or product candidates on unfavorable terms, or otherwise agree to terms unfavorable to us.

Finally, we cannot guarantee that future financing will be available in sufficient amounts or on terms acceptable to us,

if at all. Even if we believe we have sufficient funds for our current or future operating plans, we may seek additional

capital if market conditions are favorable or in light of specific strategic considerations.

The Group entered into several loan agreements in particular with the European Investment Bank, Bpifrance

Financement and HSBC France (for a description of these agreements, see Section 1.3.14 of the Universal

Registration Document). A default in payment or a breach of certain covenants of all or part of these loans, in

particular due to a request for early repayment by the European Investment Bank, could result in other loans

contracted by the Group becoming due and payable and have an adverse effect on the Group’s reputation and

financial position.

If we are unable to obtain funding on a timely basis, we may be required to significantly curtail, delay or discontinue

one or more of our research and development programs of our product candidate, or the commercialization of any

product candidate that may receive regulatory approval.

1.5.1.6.We are limited in our ability to raise additional share capital, which may make it difficult for

us to fund our operations.

Under French law, our share capital generally may be increased subject to the approval of a majority vote of at least

two-thirds of the shareholders present, represented by proxy at an extraordinary general shareholders’ meeting.

Alternatively, the shareholders may delegate to our executive board the authority to carry out any increase in the

share capital. Accordingly, our executive board may be precluded from issuing additional share capital if this

prerequisite approval of the shareholders is not duly obtained.

1.5.1.7.We are subject to various risks related to geo-political crises, including the Ukraine-

Russia war, that could have material and adverse impacts on our business, financial

condition, liquidity, and results of operations.

In February 2022, Russia launched an invasion of Ukraine, which, in addition to creating humanitarian concerns,

may have an adverse impact on the global healthcare ecosystem in the form of delayed clinical trials. Clinical trial

sites originally identified in Russia and Ukraine for the NANORAY-312 clinical trial were not opened or active at the

start of the conflict and, consequently, did not recruit patients. However, certain trial preparation and start-up fees

and expenses that the Company had incurred are not recoverable. While alternate clinical sites in other countries

have since been identified, there is currently insufficient information about start-up costs timing in these countries to

exclude the possibility of any delays to NANORAY-312 as a direct result of the conflict.

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1.5.2.Risks Related to the Discovery, Development and Commercialization of Our

Product Candidates

1.5.2.1.Our product candidate development programs are in various phases of development and

may be unsuccessful.

Our product candidates are in various phases of development. At each stage of development, there is typically an

extremely high rate of attrition from the failure of product candidates advancing to subsequent stages of

development.

Because some of our product candidates are in the early stages of discovery or preclinical development, there can

be no assurance that our research and development activities will result in these product candidates advancing into

clinical development. Product candidates in these development phases undergo testing in animal studies, and the

results from these animal studies may not be sufficiently compelling to warrant further advancement. Moreover, even

if results from animal studies are positive, such results are not necessarily predictive of positive results in clinical

studies.

Even where product candidates do progress into and through clinical studies, these product candidates may fail to

show the desired safety and efficacy in clinical development despite demonstrating positive preliminary clinical data

and/or results in animal studies. Although we are a late-stage clinical development company, the safety, specificity

and clinical benefits of NBTXR3 has not yet been fully demonstrated in all indications, and we cannot assure you

that the results of current and future clinical trials will demonstrate the value and efficacy of our platform. The results

of clinical studies are subject to a variety of factors, and there can be no assurance that any current or future product

candidate will advance to regulatory approval, be approved by applicable regulatory agencies or be successfully

commercialized.

Although there are a large number of drugs, biologics, and medical devices in development globally, only a very

small percentage obtain regulatory approval, even fewer are approved for commercialization, and only a small

number of these achieve widespread physician and consumer acceptance. Accordingly, despite expending

significant resources in pursuit of their development, our product candidates may never achieve commercial

success, and any time, effort and financial resources we expend on development programs that we pursue may

adversely affect our ability to develop and commercialize our product candidates.

1.5.2.2.Initial, interim and preliminary data from our clinical trials that we announce or publish

from time to time may change as more patient data become available and are subject to

audit and verification procedures that could result in material changes in the final data.

From time to time, we, or our strategic development and commercialization partners such as MD Anderson and

LianBio, may publish initial, interim or preliminary data from clinical studies. Interim and preliminary data from clinical

trials are subject to the risk that one or more of the clinical outcomes may materially change as patient enrollment

continues and more patient data become available. For instance, while we and our strategic development partners

have published preliminary data from past and ongoing clinical studies, because such data is preliminary in nature,

they have not established statistical significance, and should not be viewed as predictive of the ultimate success of

the respective clinical trials. It is possible that such results will not continue or may not be repeated in ongoing or

future clinical trials for our product candidates, in particular NBTXR3. Particular caution should be exercised when

interpreting preliminary results and results relating to a small number of patients or individually presented case

studies--such results should not be viewed as predictive of future results.

Preliminary data also remain subject to audit and verification procedures that may result in the final data being

materially different from the preliminary data we previously published (according, among others, the applicable new

response evaluation criteria in solid tumors). As a result, initial, interim and preliminary data should be viewed with

caution until the final data are available. Adverse differences between initial, preliminary or interim data and final data

could significantly harm our business prospects.

1.5.2.3.We may encounter substantial delays in our clinical trials, including clinical studies of

NBTXR3, or we may fail to demonstrate safety and efficacy to the satisfaction of

applicable regulatory authorities.

Clinical trials are long, expensive and unpredictable processes that can be subject to extensive delays. We cannot

guarantee that any clinical trials will be conducted as planned or completed on schedule, if at all. It will take several

years to complete the clinical development necessary to obtain adequate data to file for a marketing authorization or

to commercialize a product candidate, and failure can occur at any stage.

Positive interim or preliminary results of clinical trials do not necessarily predict positive final results, and success in

early clinical trials does not ensure that later clinical trials will be successful. Product candidates in later stages of

clinical trials such as NBTXR3 may still fail to show the desired safety and efficacy profile despite having

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successfully progressed through initial clinical trials. A number of pharmaceutical and biotechnology companies have

suffered significant setbacks—lack of efficacy, insufficient durability of efficacy or unacceptable safety issues in

advanced clinical trials, even after promising results in earlier trials.

We cannot be certain that our product candidates will not face similar setbacks. An unfavorable outcome in one or

more clinical trials would be a major setback for our product candidates and for us and may require us or our

strategic development and commercialization partners to delay, reduce or redefine the scope of, or eliminate one or

more product candidate development programs, any of which could have a material adverse effect on our business,

financial condition and prospects.

In addition, a number of events, including any of the following, could delay clinical trials, negatively impact the ability

to obtain regulatory approval for, and to market and sell, a particular product candidate, or result in suspension or

termination of a clinical trial:

•conditions imposed by the FDA, or, as the case may be, EMA, or any other regulatory authority regarding

the scope or design of clinical trials;

•inability to generate sufficient preclinical, toxicology or other in vivo or in vitro data to support initiation of

clinical studies;

•delays in obtaining, or the inability to obtain, regulatory agency approval for the conduct of the clinical

trials or required approvals from institutional review boards, or institutional review boards (IRBs), or other

reviewing entities at clinical sites selected for participation in our clinical trials;

•the identification of flaws in the design of a clinical trial;

•changes in regulatory requirements and guidance that necessitate amendments to clinical trial protocols;

•recommendations from independent data monitoring committees to modify or discontinue ongoing studies

due to unforeseen safety issues or lack of effectiveness;

•delays in sufficiently developing, characterizing or controlling manufacturing processes suitable for clinical

trials;

•insufficient supply or deficient quality of the product candidates or other materials necessary to conduct

the clinical trials, including as a result of manufacturing issues at our in-house manufacturing facilities or

at the facilities of our external partners;

•lower-than-anticipated enrollment and retention rate of subjects in clinical trials for a variety of reasons,

including size of patient population, sites selection, nature of trial protocol, the availability of approved

treatments for the relevant disease and competition from other clinical trial programs for similar indications

and competition from approved products;

•delays in reaching agreement on acceptable terms with prospective contract research organizations

(CROs) and clinical study sites and obtaining required IRB approval at each clinical study site;

•the placing of a clinical hold on our or our strategic licensees’ clinical trials;

•unfavorable interpretations by FDA, or similar foreign regulatory authorities of interim data;

•determinations by the FDA, or similar foreign regulatory authorities that a clinical trial protocol is deficient

in design to meet its stated objectives;

•failure to conduct the clinical trial in accordance with regulatory requirements or our clinical protocols;

•serious and unexpected safety issues, including related side effects experienced by patients in clinical

trials;

•failure of our or our strategic development third-party contractors to meet their contractual obligations in a

timely manner; or

•lack of, or failure to, demonstrate efficacy of our products candidate.

1.5.2.4.Our product candidates are based on a novel technology, which makes it difficult to

predict the time and cost of product candidate development and obtaining regulatory

approval.

The nanotechnology underlying the Group’s product candidates, specifically the use of nanosized radiation

enhancers as a cancer treatment method, is a relatively new technology. We have concentrated our research,

development and manufacturing efforts on our nanotechnology-based product candidate NBTXR3, and our future

success depends on the successful development of this therapeutic approach using a physical mode of action.

There can be no assurance that any development problems we experience in the future will not cause significant

delays or unanticipated costs, or that such development problems can be overcome. We may also experience

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delays in developing a sustainable, scalable manufacturing process, or effectively implementing such process at our

manufacturing facility, which may prevent us from completing our clinical studies or commercializing our products on

a timely or profitable basis, if at all. Our expectations with regard to the scalability and cost of manufacturing may

change significantly as we further progress the development of our NBTXR3.

In addition, the clinical study requirements of the FDA, EMA and other regulatory agencies and the criteria these

regulators use to determine the safety and efficacy of a product candidate are determined according to the type,

complexity, novelty and intended use and market of the potential products. The regulatory approval process for novel

product candidates such as ours can be more complex and consequently more expensive and can take longer than

for other, better known or extensively studied pharmaceutical or other product candidates, as corroborated by the

dual classification of NBTXR3, considered as a drug by the FDA and a medical device by the EMA. Approvals by any

regulatory agency may not be indicative of what any other regulatory agency may require for approval or what such

regulatory agencies may require for approval in connection with our product candidates, in particular NBTXR3.

1.5.2.5.Our business is highly dependent on the success of our lead product candidate NBTXR3,

and we cannot be certain that we, directly or through any partner with which we may

conclude a development agreement, will be able to obtain regulatory approval for, or

successfully commercialize, NBTXR3.

Our business and future success depends on our ability to successfully develop, obtain regulatory approval for, and

successfully commercialize NBTXR3. Preliminary results to date may not predict results for our ongoing or planned

clinical studies. If NBTXR3 fails, it may impede our ability to develop our future product candidates, and significantly

influence physicians’ and regulators’ opinions in regard to our nanotechnology-based products. If serious adverse

events (SAEs) are observed with the administration of our NBTXR3, our ability to develop other therapies using

nanotechnology-based products may be significantly harmed.

NBTXR3 will require substantial additional clinical development, testing, and regulatory review and approval in

multiple jurisdictions, substantial investment, implementation and scaling of our commercial manufacturing

capabilities, and significant marketing efforts before we can generate any revenue from product sales. Before

obtaining regulatory approvals for the commercial sale of any product candidate, we must demonstrate, with

substantial evidence gathered in well-controlled clinical trials and to the satisfaction regulatory authorities (including

the FDA in the United States and the competent authority or notified body in the EU) that the product candidate is

safe and effective for use in each target indication. Following this extensive regulatory process, the manufacturing

and marketing of our product candidates, including NBTXR3, will be subject to extensive and rigorous review and

regulation by numerous government authorities in the United States and in other countries where we intend to

pursue commercialization.

Satisfaction of these and other regulatory requirements is costly, time consuming, uncertain and subject to

unanticipated delays. The process can take many years and may include post-marketing studies and surveillance,

which will require the expenditure of substantial resources beyond our existing cash on hand. There can be no

assurance that any of our product candidates including NBTXR3 will successfully complete the foregoing regulatory

approval processes. We do not expect any of the product candidates including NBTXR3 we or our strategic

development and commercialization partners develop to be commercially available for another few years and some

or all may never become commercially available.

1.5.2.6.Any issues that arise in the highly complex manufacturing process for our product

candidates could have an adverse effect on our business, financial position or prospects.

Our nanotechnology-based products undergo a complex, highly regulated manufacturing process. The process is

subject to strict controls and procedures to ensure minimal batch-to-batch variability. As a result, our manufacturing

process is subject to multiple risks.

We may encounter difficulties in production, particularly in scaling out and validating initial production and ensuring

the absence of contamination. These problems include difficulties with production costs and yields, quality control,

including stability of the product, quality assurance testing, improper installation or operation of equipment, operator

error, shortages of qualified personnel, shortage of raw material or starting material and other procurement issues,

as well as compliance with strictly enforced federal, state and foreign regulations.

Even minor deviations from normal manufacturing processes could result in reduced production yields, product

defects, and other supply disruptions. If microbial, viral, or other contaminations are discovered in our supply of

product candidates or in the manufacturing facilities in which product candidates are made, such supply may have to

be discarded and the manufacturing may be stopped or such manufacturing facilities may need to be closed for an

extended period of time to investigate and remedy the contamination.

While we currently use third-party contract manufacturing organizations, or CMOs, to manufacture NBTXR3, we

completed construction of an in-house manufacturing facility in Villejuif, France. This manufacturing facility is now

operational and dedicated to the manufacturing of drug substance for our investigational products. We have very

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limited experience in operating a manufacturing infrastructure for clinical or commercial pharmaceutical products,

and we may never be successful in effectively exploiting such in-house manufacturing capabilities. In addition to all

the challenges discussed above regarding manufacturing, we may face potential problems associated with scaling to

the level required for advanced clinical trials or commercialization, including, among others, cost overruns, process

scale-up and/or scale-out, process reproducibility, stability issues, lot consistency, and timely availability of reagents

or raw materials. Further, the application of new regulatory guidelines or parameters, such as those related to

release testing, may also adversely affect our ability to manufacture NBTXR3.

Even as we successfully deploy and scale our in-house manufacturing capabilities, we may be adversely affected by

cost-overruns, unexpected delays, equipment failures, labor shortages, natural disasters, power failures, regulatory

issues and numerous other factors that could prevent us from realizing the intended benefits of our internalized

manufacturing capabilities and have a material adverse effect on our business. We may ultimately be unable to

reduce the cost of goods for NBTXR3 to levels that will allow for an attractive return on investment if and when those

product candidates are commercialized. In addition, we may never obtain the regulatory approvals to manufacture

our commercial products in our in-house manufacturing facility.

1.5.2.7.Any changes to manufacturing processes may result in additional regulatory approvals.

The manufacturing process for any products that we may develop is subject to FDA, and any other regulatory

authority approval or notified body for the jurisdictions in which we or our strategic development and

commercialization partners will seek marketing approval for commercialization as well as ongoing compliance

requirements. If the manufacturing process is changed during the course of product development or subsequent to a

product’s commercialization, FDA, or foreign regulatory authorities could require us to repeat some or all previously

conducted trials or conduct additional bridging trials, which could delay or impede our ability to obtain marketing

approval. If we, or our CMOs, are unable to reliably produce NBTXR3 or products to specifications acceptable to the

FDA, or other regulatory authorities, we may not obtain or maintain the approvals we need to further develop,

conduct clinical trials for, and commercialize such products in the relevant territories.

1.5.2.8.Difficulty enrolling patients could delay or prevent clinical studies of NBTXR3.

Identifying and qualifying patients to participate in clinical studies is critical to the success of the relevant product

candidate. The timing of clinical studies depends, in part, on the speed of recruitment of patients to participate in

testing such product candidates such as NBTXR3 as well as completion of required follow-up periods. We or those

evaluating NBTXR3 pursuant to licenses from us may not be able to identify, recruit and enroll a sufficient number of

patients or patients with required or desired characteristics to achieve the objectives of the study. If patients are

unable or unwilling to participate in such studies, the timeline for recruiting patients, conducting studies and obtaining

regulatory approval of potential products may be delayed. These delays could result in increased costs, delays in

advancing NBTXR3, delays in testing the effectiveness of our technology, failure to meet study endpoints or

objectives or termination of the clinical studies altogether.

In addition, competition among clinical trials in the same therapeutic areas may reduce the number and types of

patients available to participate in our clinical trials or clinical trials conducted by our strategic development partners.

Because the number of qualified clinical investigators is limited, we expect to conduct some clinical trials at the same

sites as our competitors, which may reduce the number of patients available for our clinical trials at such sites.

Certain of our competitors may have greater success than us in enrolling patients as a result of a variety of factors.

Moreover, because of the novel nature of NBTXR3, potential patients and their doctors may be less likely to enroll in

our clinical trials relative to clinical trials for more conventional therapies.

Patient enrollment is affected by a variety of factors, including:

•severity of the disease under investigation;

•incidence and prevalence of the disease under investigation;

•design of the clinical trial protocol;

•size and nature of the patient population;

•eligibility criteria for the trial in question;

•perceived risks and benefits of the product candidate under trial, including relative to other available

therapies;

•proximity and availability of clinical trial sites for prospective patients;

•availability of competing therapies and clinical trials;

•patient referral practices of physicians;

•our ability to monitor patients adequately during and after treatment, and

•ability of the clinical sites to have sufficient resources and avoid any backlogs.

If we, or our strategic development partners, are unable to enroll a sufficient number of patients to conduct clinical

studies as planned, it may be necessary to delay, limit or terminate such clinical studies, which could have a material

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adverse effect on our business and financial condition. Even if we are able to enroll a sufficient number of patients in

our clinical trials, delays in patient enrollment may result in increased costs or may affect the timing or outcome of

the planned clinical trials, which could prevent completion of these trials and adversely affect our ability to advance

the development of the product candidates we develop.

1.5.2.9.Our product candidates may cause undesirable side effects that could halt their clinical

development, delay or prevent their regulatory approval, limit their commercial potential,

or result in other significant negative consequences.

Undesirable or unacceptable side effects caused by our product candidates could cause us or regulatory authorities

to interrupt, delay, suspend or halt clinical trials, could result in the delay or denial of regulatory approval by the FDA,

EMA or other comparable foreign regulatory authorities, or could lead to a more restrictive label for our product

candidates.

Our product candidates have only had limited clinical trial application, and results of our clinical trials could reveal a

high and unacceptable incidence and severity of side effects or unexpected characteristics. Additionally, as more

patients are included in our and our strategic development partners’ clinical trials, previously less common, side

effects may also emerge.

Any undesirable side effects could cause us, our strategic development partners or regulatory authorities to interrupt,

delay, halt or terminate clinical trials and could result in a more restrictive label or the delay or denial of regulatory

approval by the FDA, EMA or other regulatory authorities. Treatment-related side effects could also adversely affect

patient recruitment or the ability of enrolled subjects to complete the trial or result in potential product liability claims.

Although we provide training to medical personnel involved in clinical trials for NBTXR3, failure of medical personnel

to recognize or manage potential side effects of NBTXR3 could exacerbate adverse outcomes and potentially result

in patient deaths.

Any of these occurrences could prevent our product candidates, including NBTXR3 from achieving or maintaining

market acceptance and could increase the cost of development and commercialization, and may harm our business,

financial condition and prospects significantly.

1.5.2.10.If our product candidates do not achieve projected development milestones and

commercialization in the announced or expected timeframes, further development or

commercialization of our product candidates may be delayed, and our business may be

harmed.

We sometimes estimate, or may in the future estimate, for planning purposes, the timing of the accomplishment of

various scientific, clinical, manufacturing, regulatory and other product development objectives. These milestones

may include our expectations regarding the commencement or completion of scientific studies, clinical trials, the

submission of regulatory filings, and the receipt of marketing approval or commercialization objectives.

The achievement of many of these milestones may be outside of our control. All of these milestones are based on a

variety of assumptions, including assumptions regarding capital resources and constraints, progress of development

activities, and the receipt of key regulatory approvals or actions, any of which may cause the timing of achievement

of the milestones to vary considerably from our estimates.

If we, or our strategic development and commercialization partners, fail to achieve announced milestones in the

expected timeframes, the commercialization of the product candidates, in particular NBTXR3, may be delayed, our

credibility may be undermined, and our business and results of operations may be harmed.

1.5.2.11.Even if we or our strategic development and commercialization partners successfully

complete clinical trials of NBTXR3, NBTXR3 may not be successfully commercialized for

other reasons.

Even if we or our strategic licensees successfully complete clinical trials for NBTXR3, NBTXR3 may not be

commercialized for other reasons, including:

•failing to receive regulatory approvals required to market them as drug or medical device;

•being subject to proprietary rights held by others;

•failing to comply with GMP requirements;

•being difficult or expensive to manufacture on a commercial scale;

•having adverse side effects that make their use less desirable;

•being inferior to existing approved drugs or therapies;

•failing to compete effectively with existing or new products or treatments commercialized by competitors;

•failing to show long-term benefits sufficient to offset associated risks.

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In addition, for product candidates developed by a strategic development partner or other collaboration partner

pursuant to a licensing or commercialization agreement, we will depend entirely upon such party for marketing and

sales of that product. These parties may not devote sufficient time or resources to the marketing and

commercialization, or may determine not to pursue marketing and commercialization at all, which could prevent the

affected products from reaching milestones or sales that would trigger payments to Nanobiotix.

1.5.2.12.Even if NBTXR3 is commercialized, NBTXR3 may not be accepted by physicians, patients,

or others in the medical community.

Even if NBTXR3 receives marketing approval, the medical community may not accept such products as adequately

safe and efficacious for their indicated use. Moreover, physicians may choose to restrict the use of the product, if,

based on experience, clinical data, side-effect profiles and other factors, they are not convinced that the product is

preferable to alternative drugs or treatments.

Additional factors that may influence whether NBTXR3 is accepted in the market, include:

•the clinical indications for which NBTXR3 is approved;

•the potential and perceived advantages and risks of NBTXR3 relative to alternative treatments;

•the prevalence and severity of side effects;

•the demonstration of the clinical efficacy and safety of the product;

•the approved labeling for the product and any required limitations or warnings;

•the timing of market introduction of the product candidate as well as of competing products;

•the effectiveness of educational outreach to the medical community about the product;

•the coverage and reimbursement policies of government and commercial third-party payors pertaining to

the product; and

•the market price of the product relative to competing treatments.

We cannot predict the degree of market acceptance of any product candidate that receives marketing approval. If

NBTXR3 is approved but fails to achieve market acceptance in the medical community, we will not be able to

generate significant revenue. Even if our products achieve market acceptance, we may not be able to maintain that

market acceptance over time if new products or technologies are introduced that are more favorably received than

our products, are more cost effective or render our products obsolete.

1.5.2.13.Coverage and reimbursement may be limited or unavailable in certain market segments

for our product candidates, including NBTXR3, which could make it difficult for us to sell

our product candidates, including NBTXR3, profitably.

Successful sales of NBTXR3, if approved, depends, in part, on the availability of adequate coverage and

reimbursement from third-party payors. Patients who are provided medical treatment for their conditions generally

rely on third-party payors to reimburse all or part of the costs associated with their treatment. Adequate coverage

and reimbursement from governmental healthcare programs, such as Medicare and Medicaid in the United States,

and commercial third-party payors, such as private health insurers and health maintenance organizations, are critical

to new product acceptance. Coverage and reimbursement may depend upon a number of factors, including

determinations as to whether a product is:

•a covered benefit under applicable policies or plans;

•safe, effective and medically necessary;

•appropriate for the specific patient;

•cost-effective; and

•neither experimental nor investigational.

Coverage and reimbursement policies vary, and obtaining coverage and reimbursement approval of a product from a

government or other third-party payor is a time-consuming and costly process that could require us or our strategic

development and commercialization partners to furnish on a payor-by-payor basis supporting scientific, clinical and

cost-effectiveness data for the use of our products, with no assurance that coverage or adequate reimbursement will

be obtained.

Even if coverage for a product is obtained, reimbursement rates may be inadequate to achieve profitability or may

require co-payments that patients find unacceptably high.

If coverage is unavailable or reimbursement rates are inadequate, patients may not use our products. Because

NBTXR3 represents a new approach to treatment, it may have a higher cost than conventional therapies and may

require long-term follow-up evaluations, which may increase the risk that coverage and/or reimbursement rates may

be inadequate for us to achieve profitability.

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1.5.2.14.Our future profitability, if any, depends, in part, on our ability to penetrate global markets,

where we would be subject to additional regulatory burdens and other risks and

uncertainties.

Our future profitability, if any, will depend, in part, on our ability and the ability of our strategic development and

commercialization partners to commercialize the product candidates we develop in markets throughout the world.

Commercialization of our product candidates in various markets could subject us to additional risks and

uncertainties, including:

•obtaining, on a country-by-country basis, the applicable marketing authorization from the competent

regulatory authority;

•the burden of complying with complex and changing regulatory, tax, accounting and legal requirements in

each jurisdiction that we pursue;

•differing medical practices and customs affecting acceptance in the marketplace;

•import or export licensing requirements;

•country specific requirements related manufacturing;

•language barriers for technical training, healthcare professionals and patients documents;

•reduced protection of intellectual property rights in some foreign countries;

•foreign currency exchange rate fluctuations;

•potential imposition of governmental controls; and

•patients’ ability to obtain reimbursement for products in various markets.

1.5.3.Risks Related to Our Reliance on Third Parties

1.5.3.1.Third parties on whom we rely to conduct some aspects of our development programs

may not perform satisfactorily.

We do not, and do not expect in the future to, independently conduct all aspects of our development programs. For

example, LianBio, our development and commercialization partner in the Asia-Region, has undertaken to contribute

to enrollment in certain number of global registrational studies for NBTXR3 (see Section 1.3.14. of the Universal

Registration Document). We are also collaborating with MD Anderson on the development of NBTXR3 in various

indications (e.g. head and neck, pancreatic, esophageal and lung cancers, etc.). We rely, and will continue to rely, on

third parties for certain aspects of manufacturing, quality control, protocol development, material supply, research

and preclinical development, translational activities, and clinical testing, clinical trial conduct and distribution

activities. With respect to the clinical trials that we sponsor, we rely on CROs, medical institutions and clinical

investigators to conduct our clinical studies. Such reliance on third parties reduces our control over these activities,

but does not relieve us of our responsibility to ensure compliance with all required regulations and study and trial

protocols.

If these third parties do not successfully carry out their contractual duties, meet expected deadlines or conduct their

activities in accordance with regulatory requirements and our stated study and trial plans and protocols, or if there

are disagreements between us and these third parties, we may not be able to complete, or may be delayed in

completing, the preclinical studies and clinical trials required to support future regulatory submissions and approval

of the product candidates we develop.

Reliance on such third parties entails additional risks to which we would not be subject if we conducted the above-

mentioned activities ourselves, including:

•that we may be unable to negotiate agreements with third parties under reasonable terms or that

termination or non-renewal of an agreement occurs in a manner or time that is costly or damaging to us;

•that such third parties may have limited experience with our or comparable products and may require

significant support from us in order to implement and maintain the infrastructure and processes required

to manufacture, test or distribute our product candidates;

•that such third parties may not perform as agreed or in compliance with applicable laws and

requirements, or may not devote sufficient resources to our products;

•that we may not have sufficient rights or access to the intellectual property or know how relating to

improvements or developments made by our third-party service providers in the course of their providing

services to us;

•that regulators object to or disallow the performance of specific tasks by certain third parties or disallow

data provided by such third parties; and

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•that such third parties may experience business disruptions, such as bankruptcy or acquisition, or failures

or deficiencies in their supply chains, that disrupt their ability to perform their obligations to us.

Under certain circumstances, service providers, such as CROs, which has contracted with the Company, may be

entitled to terminate their engagements with us. In such circumstances, product development activities could be

delayed while we seek to identify, validate, and negotiate an agreement with a replacement service provider. In some

such cases an appropriate replacement may not be readily available or available on acceptable terms, which could

cause additional delays to our development process.

Any of these events could lead to manufacturing, supply and/or clinical study delays or failure to obtain regulatory

approval, or impact our ability to successfully commercialize future products, which could, in each case, have a

material adverse effect on our business, financial condition, results of operations and prospects.

1.5.3.2.Third parties on whom we rely to conduct, supervise and monitor clinical studies may not

perform satisfactorily.

We and our strategic licensees rely on medical institutions, clinical investigators, CROs and contract laboratories to

carry out, or otherwise assist with, clinical trials or to perform data collection and analysis. For example, these third

parties are tasked with monitoring toxicities and managing adverse events, which may be particularly challenging

due to a number of factors including personnel changes, inexperience, shift changes, house staff coverage or related

issues. While we and our strategic development partners have agreements governing these services, we and our

strategic development partners have limited control over such third parties’ actual performance. Nevertheless, we or

our strategic development partners, as applicable, are responsible for ensuring that such clinical trial is conducted in

accordance with the applicable protocol, legal, regulatory, ethical and scientific standards. Reliance on a third party

does not relieve the sponsor of a clinical trial of any regulatory responsibilities, including compliance with the FDA’s

and other regulatory authorities’ good clinical practices, or GCP, good manufacturing practices, or GMP, good

laboratory practices, or GLP, and other applicable requirements for conducting, recording and reporting the results of

clinical trials to assure that the data and reported results are credible and accurate and that the rights, integrity and

confidentiality of clinical trial participants are protected.

If we, our strategic licensees, our respective CROs, or our respective investigators or trial sites fail to comply with

applicable GCP, GLP, GMP or other applicable regulatory requirements, the clinical data generated in the applicable

clinical trial may be deemed unreliable or otherwise not usable by the regulatory authorities and they may require the

performance of additional clinical trials before issuing any marketing authorizations for the relevant product

candidates.

Third party performance failures may increase our costs, delay our ability to obtain regulatory approval, and delay or

prevent starting or completion of clinical trials and delay or prevent commercialization of our product candidates.

While we believe that there are numerous alternative sources to provide these services, in the event that we seek

such alternative sources, we may not be able to enter into replacement arrangements without incurring delays or

additional costs.

1.5.3.3.We are party to strategic development and commercialization relationships, which may

not advance or be successful and may delay or harm further development or

commercialization of our product candidates.

We have entered into a strategic licensing agreement with LianBio, under which this latter has exclusive

development and commercialization rights with respect to certain product candidates, including NBTXR3 within

certain Asia territories, including Great China. We may, in the future, enter into additional strategic relationships.

All of the risks relating to product development, regulatory approval and commercialization described in this

Universal Registration Document apply to the activities of our strategic licensees.

Our reliance on strategic licensing arrangements may pose a number of risks, including the following:

•strategic licensees may not perform or prioritize their obligations as expected;

•clinical trials conducted pursuant to strategic licensing agreements may not be successful;

•strategic licensees may not pursue development and commercialization of product candidates including

NBTXR3 that achieve regulatory approval or may elect not to pursue development or commercialization

of product candidates, including NBTXR3 based on clinical trial results, changes in the partners’ focus or

available funding, or external factors, such as an acquisition, that divert resources or create competing

priorities;

•strategic licensees may delay clinical trials, provide insufficient funding for clinical trials, stop a clinical

trial, or abandon a product candidate;

•strategic licensees could develop, independently or with third parties, products that compete directly or

indirectly with our product candidates, including NBTXR3;

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•product candidates, including NBTXR3 developed pursuant to strategic licensing agreements may be

viewed by our partners as competitive with their independently developed product candidates or products,

which may cause them to devote limited resources to the product candidate’s development or

commercialization;

•a partner may not commit sufficient resources to the commercialization, marketing and distribution of any

product candidate;

•disagreements with strategic licensees, including over proprietary rights, contract interpretation, or the

preferred course of development, may cause delays or termination of the development or

commercialization of such product candidates, or may result in time-consuming and expensive legal

proceedings;

•strategic licensees may not properly obtain, maintain, protect, defend or enforce intellectual property

rights or may improperly use proprietary information;

•disputes may arise with respect to the ownership of intellectual property developed pursuant to our

strategic licensing agreements;

•strategic licensees may infringe, misappropriate or otherwise violate third-party intellectual property rights,

which may expose us to litigation and potential liability;

•strategic licensing agreements may be terminated for convenience by the collaborator and, if terminated,

the development of product candidates may be delayed or stopped;

•the negotiation of strategic licensing agreements may require substantial attention from our management

team; and

•we could face significant competition in seeking appropriate strategic licensees, and the negotiation

process is time-consuming and complex.

We rely on these strategic licensing arrangements to help us finance the development and commercialization of our

own product candidates. Our success depends, in part, on our ability to collect milestone and royalty payments from

our strategic licensees. To the extent our strategic licensees do not aggressively and effectively pursue product

candidates such as NBTXR3 for which we are entitled to such payments, we will not realize these significant

revenue streams, which may slow our overall development progress and could have an adverse effect on our

business and future prospects.

In addition, our strategic license agreements are generally terminable at will upon specified prior notice. If one or

more collaborator terminates a strategic license agreement, this could have an adverse effect on our revenues. If we

do not receive anticipated payments, our development of product candidates could be delayed and we may need

additional resources to develop our product candidates, including NBTXR3.

1.5.3.4.Access to raw materials, starting material and products necessary for the conduct of

clinical trials and manufacturing of our product candidates is not and cannot be

guaranteed.

We are dependent on third parties for the supply of various of materials, including Hafnium, that are necessary to

produce certain of our product candidates, including NBTXR3. The supply of these materials could be reduced or

interrupted at any time. In such case, we may not be able to find other acceptable suppliers or on acceptable terms.

If key suppliers or manufacturers are lost or the supply of the materials is diminished or discontinued, we may not be

able to develop, manufacture, and market our product candidates in a timely and competitive manner. In addition,

these are subject to stringent manufacturing process and rigorous testing.

Delays in the completion and validation of manufacturing processes for these materials could adversely affect the

ability to complete trials and commercialize our products candidates. In addition, our suppliers or manufacturers may,

from time to time, change their internal manufacturing or testing processes and procedures. Such changes may

require us to perform or have performed studies to demonstrate equivalence of the materials produced or tested

under such new procedures. Such equivalence testing may impose significant delays in the development of our

product candidates, including NBTXR3.

Furthermore, our suppliers may face quality issues or findings from regulatory authorities’ inspections that could lead

to delays or interruption of the supply of our product candidates, including NBTXR3.

1.5.3.5.We may enter into agreements with third parties to sell, distribute and/or market any of

the products candidates we develop for which we obtain regulatory approval, which may

adversely affect our ability to generate revenues.

Given the development stage of our product candidates, we have no experience in sales, marketing and distribution

of biotech products. However, if any of our product candidates, including NBTXR3, obtain marketing approval, we

intend to develop sales and marketing capacity, either alone or with partners. Outsourcing sales, distribution and

marketing may subject us to a variety of risks, including:

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•our inability to exercise direct control over sales, distribution and marketing activities and personnel;

•potential failure or inability of contracted sales personnel to successfully market our products to

physicians; and

•potential disputes with third parties concerning distribution, sales and marketing expenses, calculation of

royalties, and sales and marketing strategies.

If we are unable to partner with a third party that has adequate sales, marketing, and distribution capabilities, we

may have difficulty commercializing our product candidates, including NBTXR3, which would adversely affect our

business, financial condition, and ability to generate product revenues.

1.5.3.6.Our reliance on third parties and our strategic licensees requires us to share our trade

secrets, which increases the possibility that a competitor will discover them or that our

trade secrets will be misappropriated or disclosed.

Because we rely on third-party service providers for certain activities in our development process, we must, at times,

share trade secrets with them.

In addition, we are required to share certain trade secrets with our strategic licensees pursuant to the terms of our

strategic licensing agreements. We also conduct joint research and product development that may require us to

share trade secrets under the terms of our research and development partnerships or similar agreements.

We seek to protect our proprietary technology in part by entering into confidentiality agreements and, if applicable,

material transfer agreements, collaborative research agreements, licensing agreements, consulting agreements or

other similar agreements with our strategic licensees, subcontractors, advisors, employees and consultants prior to

beginning research, services or disclosing proprietary information. These agreements typically limit the rights of the

third parties to use or disclose our confidential information, such as trade secrets. Despite these contractual

provisions, the need to share trade secrets and other confidential information increases the risk that such trade

secrets become known by our competitors, are incorporated into the technology of others, or are disclosed or used

in violation of these agreements. Parties with whom we share confidential information may also be acquired by

competitors, which may increase the risk that these entities might breach their confidentiality obligations and share

our confidential information with the acquirer.

Given that our proprietary position is based, in part, on our know-how and trade secrets, a competitor’s discovery of

our trade secrets or other unauthorized use or disclosure would impair our competitive position and may have a

material adverse effect on our business.

1.5.4.Risks Related to Operational Compliance and Risk Management

1.5.4.1.We will need to develop and expand our company, and we may encounter difficulties in

managing this development and expansion, which could disrupt our operations.

As our development, manufacturing and commercialization programs develop, and as we continue to comply with

our obligations as a public company in both France and the United States, we expect our employee base to continue

to grow. To manage our anticipated continued development and expansion, including the operation of our

manufacturing facilities and the commercialization of our product candidates, we must continue to implement and

improve our managerial, operational and financial systems, expand our facilities and continue to recruit and train

additional qualified personnel.

Current and future growth imposes significant responsibility on our management team, including:

•identifying, recruiting, integrating, maintaining and motivating additional employees;

•effectively managing our internal development efforts, including the clinical and regulatory review process

for our product candidates; and

•improving our operational, financial and management controls, reporting systems and procedures.

Our future financial performance and our ability to commercialize our product candidates including NBTXR3, if

approved, and compete effectively will depend, in part, on our ability to effectively manage the future development

and expansion of our company. To achieve this, our management may need to divert a disproportionate amount of

its attention away from its day-to-day activities and devote a substantial amount of time to managing these activities.

If our management is unable to effectively manage our expected development and expansion, our expenses may

increase more than expected, our ability to generate or increase our revenue could be reduced and we may not be

able to implement our business strategy.

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1.5.4.2.Product liability lawsuits could divert our resources, result in substantial liabilities and

reduce the commercial potential of our product candidates.

The risk that we may be sued on product liability claims is inherent in the development and commercialization of

biotechnology products.

Side effects of, or manufacturing defects in, products that we develop could result in the deterioration of a patient’s

condition, injury or even death. For example, our liability could be sought by patients participating in the clinical trials

for our product candidates, including NBTXR3 as a result of unexpected side effects resulting from the administration

of these product candidates. Once a product is approved for sale and commercialized, the likelihood of product

liability lawsuits increases. Criminal or civil proceedings might be filed against us by patients, regulatory authorities,

our strategic licensees, biopharmaceutical or biotechnology companies and any other third party using or marketing

our products. These actions could include claims resulting from acts by our partners, licensees and subcontractors,

over which we have little or no control.

In addition, regardless of merit or eventual outcome, product liability claims may result in: impairment of our business

reputation; withdrawal of clinical trial participants; initiation of investigations by regulators; costs due to related

litigation; distraction of management’s attention from our primary business; substantial monetary awards to trial

participants, patients or other claimants; loss of revenue; exhaustion of any available insurance and our capital

resources; the inability by us and our strategic licensees to commercialize our product candidates, including

NBTXR3; and decreased demand for our product candidates, including NBTXR3, if approved for commercial sale.

We maintain product liability insurance coverage for damages caused by our product candidates NBTXR3, including

clinical trial insurance coverage, with coverage limits that we believe are customary for companies in our industry.

This coverage may be insufficient to reimburse us for any expenses or losses we may suffer. In addition, in the

future, we may not be able to obtain or maintain sufficient insurance coverage at an acceptable cost or to otherwise

protect against potential product or other legal or administrative liability claims by us or our partners, licensees or

subcontractors, which could prevent or inhibit the commercial production and sale of any of our product candidates,

including NBTXR3 that receive regulatory approval, which could adversely affect our business.

1.5.4.3.We may use hazardous chemicals and biological materials in our business. Any claims

relating to improper handling, storage or disposal of these materials could be time

consuming and costly.

We are subject to numerous environmental, health and safety laws and regulations, including those governing

laboratory procedures and the handling, use, storage, treatment, manufacture and disposal of hazardous materials

and wastes. Our research and development processes may involve the controlled use of hazardous materials,

including chemicals and biological materials.

We cannot eliminate the risk of accidental contamination or discharge and any resultant injury from these materials.

We may be sued for any injury or contamination that results from our use or the use by third parties of these

materials, and our liability may exceed any insurance coverage and our total assets. European Union regulation,

French law, Federal, state, local or any other foreign laws and regulations govern to use, manufacture, storage,

handling and disposal of these hazardous materials and specified waste products, as well as the discharge of

pollutants into the environment and human health and safety matters. Compliance with environmental laws and

regulations may be expensive and may impair our research and development efforts. If we fail to comply with these

requirements, we could incur delays, substantial costs, including civil or criminal fines and penalties, clean-up costs

or capital expenditures for control equipment or operational changes necessary to achieve and maintain compliance.

In addition, we cannot predict the impact on our business of new or amended environmental laws or regulations or

any changes in the way existing and future laws and regulations are interpreted and enforced. These current or

future laws and regulations may impair our research, development or production efforts.

1.5.4.4.We identified a material weakness in our internal control over financial reporting as of

December 31, 2022 related to a lack of supervisory personnel with the appropriate level of

technical accounting experience and training to comply with International Financial

Reporting Standards and with SEC reporting obligations, and sufficient processes and

procedures, particularly in the areas of complex, judgmental areas such as assessing the

Company’s ability to continue as a going concern and the valuation of complex debt

instruments

As a U.S. public company, the Sarbanes-Oxley Act requires, among other things, that we assess the effectiveness of

our disclosure controls and procedures and the effectiveness of our internal control over financial reporting at the

end of each fiscal year. The rules governing the standards that must be met for our management to assess our

internal control over financial reporting pursuant to Section 404 of the Sarbanes Oxley Act are complex and require

significant documentation, testing and possible remediation. These stringent standards require that our audit and

finance committee be advised and regularly updated on management’s review of internal control over financial

reporting.

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In connection with our fiscal 2022 audit, we identified a material weakness in our internal controls over financial

reporting related to a lack of supervisory personnel with the appropriate level of technical accounting experience and

training to comply with International Financial Reporting Standards and with SEC reporting obligations, and sufficient

processes and procedures, particularly in the areas of complex, judgmental areas such as assessing the Company’s

ability to continue as a going concern and determining the average discount rate used to measure the fair value of

the EIB loan Amendment agreement signed on October 18, 2022.

In response to the material weakness described above, our management is implementing a remediation plan, which

it believes will remediate the material weakness that have been identified. We cannot assure that the measures we

have taken to date and may take in the future, will be sufficient to remediate the control deficiencies that led to our

material weakness in internal control over financial reporting or that we will prevent or avoid potential future material

weaknesses. Effective internal controls are necessary for us to provide reliable financial reports. These remediation

measures may be time consuming and costly and there is no assurance that these initiatives will ultimately have the

intended effects.

If we fail to staff our accounting and finance function adequately or maintain internal control over financial reporting

adequate to meet the requirements of the Sarbanes-Oxley Act, our business and reputation may be harmed.

Moreover, if we are not able to comply with the applicable requirements of Section 404 in a timely manner, we may

be subject to sanctions or investigations by regulatory authorities, including the SEC and Nasdaq.

If we identify any new material weakness in the future, any such newly identified material weakness could limit our

ability to prevent or detect a misstatement of our accounts or disclosures that could result in a material misstatement

of our annual or interim financial statements. In such case, we may be unable to maintain compliance with securities

law requirements regarding timely filing of periodic reports in addition to applicable stock exchange listing

requirements, investors may lose confidence in our financial reporting, our ADSs could decline and our access to the

capital markets could be restricted. The occurrence of any of the foregoing would also require additional financial

and management resources. .We cannot assure you that the measures we have taken to date, or any measures we

may take in the future, will be sufficient to avoid potential future material weaknesses.

Our compliance with applicable provisions of Section 404 requires that we incur substantial accounting expense and

expend significant management attention and time on compliance-related issues as we implement additional

corporate governance practices and comply with reporting requirements. In addition, our independent registered

public accounting firm will be required to attest to the effectiveness of our internal controls over financial reporting

beginning with our Universal Registration Document following the date on which we are no longer an emerging

growth company, which may extend until December 31, 2025.6

1.5.4.5Our internal computer systems, or those of our third-party contractors or consultants,

may fail or suffer security breaches, which could result in a material disruption of our

product development programs or loss of personal data.

In the ordinary course of our business, we may collect, process, store and transmit proprietary, confidential and

sensitive information, including personal data (including health information), intellectual property, trade secrets, and

proprietary business information owned or controlled by ourselves or other parties. We may also share or receive

sensitive information with our partners, CROs, CMOs, or other third parties. Our ability to monitor these third parties’

information security practices is limited, and these third parties may not have adequate information security

measures in place.

Despite the implementation of security measures, our internal computer systems and those of our third-party

contractors and consultants are vulnerable to damage from computer viruses, cyber-attacks, unauthorized access,

natural disasters, terrorism, war and telecommunication and electrical failures. Cyberattacks, malicious internet-

based activity, and online and offline fraud are prevalent and are increasing in their frequency, sophistication and

intensity, and have become increasingly difficult to detect. These threats come from a variety of sources, including

traditional computer “hackers,” threat actors, personnel (such as through theft or misuse), sophisticated nation-

states, and nation-state-supported actors. Some actors now engage and are expected to continue to engage in

cyber-attacks, including without limitation nation-state actors for geopolitical reasons and in conjunction with military

conflicts and defense activities. During times of war and other major conflicts, we, and the third parties upon which

we rely, may be vulnerable to a heightened risk of these attacks, including retaliatory cyber-attacks, that could

materially disrupt our systems and operations, supply chain, and ability to produce and distribute our product

candidates. Cyberattacks could include, but are not limited to, the deployment of harmful malware (including as a

result of advanced persistent threat intrusions), denial-of-service (such as credential stuffing), credential harvesting,

social engineering attacks (including through phishing attacks), viruses, ransomware, supply chain attacks,

personnel misconduct or error and other similar threats. We may also be the subject of software bugs, server

malfunction, software or hardware failures, loss of data or other information technology assets, adware,

telecommunications failures or other similar issues. In particular, ransomware attacks are becoming increasingly

prevalent and severe and can lead to significant interruptions, delays, or outages in our operations, disruptions to our

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6 According to SEC definition, a material weakness is a deficiency, or combination of deficiencies, in internal control over financial reporting, such that there is a reasonable

possibility that a material misstatement of the Company’s annual or interim financial statements will not be prevented or detected on a timely basis.

clinical trials, loss of data (including data related to clinical trials), significant expense to restore data or systems,

reputational loss and the diversion of funds. Extortion payments may alleviate the negative impact of a ransomware

attack, but we may be unwilling or unable to make such payments due to, for example, applicable laws or regulations

prohibiting such payments. Similarly, supply chain attacks have increased in frequency and severity, and we cannot

guarantee that third parties and infrastructure in our supply chain have not been compromised or that they do not

contain exploitable defects or bugs that could result in a breach to our information technology systems or the third-

party information technology systems that support us and our services. Future or past business transactions (such

as acquisitions or integrations) could expose us to additional cybersecurity risks and vulnerabilities, as our systems

could be negatively affected by vulnerabilities present in acquired or integrated entities’ systems and technologies.

Although we have implemented security measures designed to protect against security incidents, there can be no

assurance that these measures will be effective. We have experienced attempts to compromise our information

technology systems or otherwise cause a security incident. While we do not believe that we have experienced any

significant system failure, accident, or security breach to date, if such an event were to occur and cause interruptions

in our operations, it could result in unauthorized, unlawful, or accidental acquisition, modification, destruction, loss,

alteration, encryption, disclosure of, or access to our sensitive information. A security incident or other interruption

could disrupt our ability (and that of third parties upon whom we rely) to manufacture or deliver our product

candidates. For example, the loss of clinical trial data for our product candidates could result in delays in our

regulatory approval efforts and significantly increase our costs to recover or reproduce the data. To the extent that

any disruption or security breach results in a loss of or damage to our data or applications or other data or

applications relating to our technology or product candidates, or inappropriate disclosure of confidential or

proprietary information, we could incur liabilities and the further development of our product candidates could be

delayed.

We may be unable to detect vulnerabilities in our information technology systems because such threats and

techniques change frequently, are often sophisticated in nature, and may not be detected until after a security

incident has occurred. Despite our efforts to identify and remediate exploitable critical vulnerabilities, if any, in our

information technology systems, our efforts may not be successful. Further, we may experience delays in developing

and deploying remedial measures designed to address any such identified vulnerabilities. Any failure to prevent or

mitigate security incidents or improper access to, use of, or disclosure of our clinical data or patients’ personal data

could result in significant liability under state, federal, and international law and may cause a material adverse impact

to our reputation, affect our ability to conduct our clinical trials and potentially disrupt our business.

1.5.4.6.Data privacy regulations could adversely affect our business, results of operations and

financial condition.

We are subject to data privacy and protection laws and regulations that impose requirements relating to the

collection, transmission, storage and use of personally-identifying information, including comprehensive regulatory

systems in the U.S. and EU. The legislative and regulatory landscape for privacy and data protection continues to

evolve in jurisdictions worldwide, and there has been an increasing focus on privacy and data protection issues with

the potential to affect our business. Failure to comply with any of these laws and regulations could result in

enforcement action against us, including fines, imprisonment of company officials and public censure, claims for

damages by affected individuals, damage to our reputation and loss of goodwill, any of which could have a material

adverse effect on our business, financial condition, results of operations or prospects.

There are numerous regulation as European Union General Data Protection Regulation (GDPR), US federal and

state laws and regulations related to the privacy and security of personal information, including regulations

promulgated pursuant to GDPR and Health Insurance Portability and Accountability Act (HIPAA) that establish

privacy and security standards for the use and disclosure of individually identifiable health information and require

the implementation of administrative, physical and technological safeguards to protect the privacy of such protected

health information.

Determining whether protected health information has been handled in compliance with applicable privacy standards

and our contractual obligations can be complex and may be subject to changing interpretation. We cannot be sure

how these regulations will be interpreted, enforced or applied to our operations. If we fail to comply with applicable

privacy laws, including applicable GDPR HIPAA privacy and security standards, we could face civil and criminal

penalties.

More specifically, in the EU, we are subject to the European Regulation (EU) No. 2016/679, known as the General

Data Protection Regulation (GDPR), as well as EU Member State legislations complementing the GDPR. GDPR and

EU Member State legislation apply to the collection and processing of personal data, including health-related

information, of individuals in the EU by companies established in the EU and, in certain circumstances established

outside of the EU. These laws impose strict obligations on the ability to process personal data, including health-

related information, in particular in relation to their collection, use, disclosure and transfer. These include several

requirements relating to (i) obtaining, in some situations, the informed consent of the individuals to whom the

personal data relates, (ii) the information provided to the individuals about how their personal information is used, (iii)

ensuring the security and confidentiality of the personal data, (iv) the obligation to notify personal data breaches to

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regulatory authorities and, as applicable, to communicate such breaches to affected individuals, (v) extensive

internal privacy governance obligations, and (vi) obligations to honor rights of individuals in relation to their personal

data (for example, the right to access, correct and delete their data). The GDPR also imposes restrictions on the

transfer of personal data to most countries in the world outside of the European Economic Area (EEA), including the

U.S., unless the parties to the transfer have implemented specific safeguards to protect the transferred personal

information. One of the primary safeguards allowing US companies to import personal information from the EEA has

been the European Commission’s Standard Contractual Clauses (SCCs). However, the Court of Justice of the EU

(CJEU) issued a decision that called into question whether the SCCs can lawfully be used for transfers of personal

information from Europe to the United States or most other countries. At present, there are few, if any, viable

alternatives to the SCCs, on which we have relied for personal information transfers from Europe to the United

States and other countries outside of the EEA. Following this CJEU judgment, new sets of SCCs were published on

June 4, 2021. Most importantly, the use of SCCs no longer automatically ensures compliance with the GDPR.

Instead, companies remain required to conduct a data transfer impact assessment for each transfer, which adds a

compliance burden. The GDPR has thus increased our responsibility and liability in relation to personal data that we

process, and we may be required to put in place additional potential mechanisms to ensure compliance with the new

EU data protection rules. Also, some uncertainty remains around the legal and regulatory environment for these

evolving privacy and data protection laws and regulations. Potential pecuniary fines for noncompliant companies

may be up to €20 million or 4% of annual global revenue, whichever is higher.

We may become the subject of investigations and/or claims in respect of privacy matters and unfavorable outcomes

in any of such matters could preclude the commercialization of products, harm our reputation, negatively affect the

profitability of our products and subject us to substantial fines. In addition, our ongoing efforts to comply with evolving

laws and regulations in the U.S., EU and elsewhere may be costly and require ongoing modifications to our policies,

procedures and systems.

1.5.4.7 Because our consolidated financial statements rely on estimates and assumptions, actual results

may vary significantly from estimates that we make.

The preparation of the consolidated financial statements in accordance with IFRS requires the use of estimates and

assumptions that affect the amounts and information disclosed in the financial statements. The estimates and

judgments used by management are based on historical information and on other factors, including expectations

about future events considered to be reasonable given the circumstances. These estimates may be revised where

the circumstances on which they are based change. In connection with our period-end closing process, which

includes review by management and our audit and finance committee and discussions with our independent

registered public accounting firm,we reassess and evaluate our estimates and assumptions and the circumstances

on which they are based and may determine that certain estimates or assumptions should be revised or adjusted.

We have in the past, and expect in the future, to make such revisions and adjustments to our estimates and

assumptions prior to their issuance of our financial statements in light of these ordinary course reassessments.

Because our financial statements require the use of estimates and assumptions, actual results—particularly with

respect to going concern, share-based payments, deferred tax assets, clinical trials accruals, revenue recognition

and the fair value of financial instruments—may vary significantly from these estimates under different assumptions

or conditions.

1.5.5.Risks Related to Regulatory Approvals for Our Product Candidates

1.5.5.1.The regulatory landscape that governs our product candidates is uncertain as it is subject

to both drug & device regulations, depending on the country involved, and changes in

regulatory requirements could result in delays or discontinuation of development of our

product candidates or unexpected costs in obtaining regulatory approval and/or CE-

marking.

The development and manufacturing of therapeutic solutions for cancer treatment are governed by a rigorous,

complex and evolving global regulatory environment (for more information on such environment, see Section 1.3.17.

of the Universal Registration Document). Regulatory authorities, including the ANSM, EMA and the FDA, have

imposed stringent requirements on the amount and types of data required to demonstrate the safety and efficacy of

products prior to their marketing and sale. Increase in costs of obtaining and maintaining the necessary marketing

authorizations or CE-marking for NBTXR3 may limit its economic value and thus lessen the prospects for growth in

this field, and consequently the prospects of NBTXR3 or any other Group’s product candidates.

NBTXR3 has been classified as a ‘‘Class III medical device’’ in the EU and as a ‘‘drug’’ in the United States. As a

result, the Group must meet various specific requirements and deadlines, particularly in terms of CE-marking (or

equivalents in all non-EU jurisdictions where the Group intends to market its products) and in terms of marketing

authorization for drugs in other countries around the globe (chiefly deadlines and conditions for registration, as,

where no single authority exists, deadlines tend to be longer) and related transparency requirements. As soon as a

product is classified as a drug candidate or medical device as appropriate, a competent authority or a notified body

must approve or certify the conformity of said drug candidate or medical device before it can be commercialized,

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marketed, promoted or sold in those jurisdictions. The Group must provide these regulatory authorities with data

from preclinical studies and clinical trials that demonstrate that its product candidates are safe and effective for a

defined indication before they can be approved or certified for commercial distribution. It must provide data to ensure

the strength, quality and purity of the product and its components. It must also assure the regulatory authorities that

the characteristics and performance of the clinical batches will be replicated consistently in the commercial batches.

The regulatory framework may also change, particularly in key markets such as the EU, where rules on medical

devices are set to be significantly tightened following the adoption of the MDR regulation.

In light of the regulatory evolutions, the competent authorities of EU Member States could reconsider the

classification of NBTXR3 as a medical device in the EU and decide to reclassify it as a drug (see Section 1.3.17.2. of

the Universal Registration Document). If Hensify® or the other Group product candidates were to be classified as

drugs in the EU, their clinical development would be subject to different regulatory framework. As a result, the

development and commercialization process would be longer and more costly than expected. To minimize the

impact of a potential reclassification of our product candidates, we are designing our clinical development programs

so as to generate clinical evidence we believe will constitute a robust scientific basis, irrespective of classification.

Delay or failure to obtain, or unexpected costs in obtaining, the regulatory approval and/or the CE-marking

necessary to bring a potential product to market could decrease our ability to generate sufficient product revenue to

maintain our business.

1.5.5.2.Once we obtain a regulatory approval for a product candidate, our products will remain

subject to ongoing regulatory requirements.

Obtaining marketing authorizations approval or medical device certification for a product in a specific indication is not

a gauge of effectiveness, job security, or the ability to obtain marketing authorizations approvals or medical device

certification for a product in another indication, regardless of scientific rational connection. Even after obtaining

regulatory approval in a jurisdiction for the product candidates we develop, including NBTXR3, they will be subject to

ongoing regulatory requirements for manufacturing, labeling, packaging, storage, advertising, promotion, sampling,

record-keeping, and submission of safety and other post-market information.

Any regulatory approvals received for the product candidates may also be subject to limitations:

•on the approved indicated use(s) for which the product may be marketed; or

•to the conditions of approval, such as an accelerated approval subject to a further confirmation of the

effectiveness of the product to be based on confirmatory study, and requirements for potentially costly

post-marketing testing, including Phase 4 clinical trials, and surveillance to monitor the safety and efficacy

of the product. In addition, potential accelerated approvals are limited by the risk of withdrawal in the

event that confirmatory studies do not confirm the benefits of the product.

Moreover, following its initial approval or certification, any product approved for commercialization is reassessed on a

regular basis in terms of risk/benefit ratio for the patient. The potential discovery of new defects or side effects which

were not detected during development and clinical trials can result in restrictions on sale, the suspension or

withdrawal of the product from the market and an increased risk of litigation. For example, the holder of an approved

NDA in the United States is obligated to monitor and report adverse events and any failure of a product to meet the

product’s specifications approved in the NDA. Similarly, in the EU, any marketing authorization approval or medical

device certification holder has legal obligations to continuously collect data and conduct safety vigilance, i.e., the

activities relating to the detection, assessment, understanding and prevention of adverse reactions and other

medicine or product-related problems. Data must be transmitted to the authorities within defined timelines, and any

emerging concern about the benefit-risk balance has to be notified immediately. If necessary, competent authorities

may request further investigations, including formal studies. Regulatory procedures exist for updating product

information and implementing other safety measures. In the United States, the holder of an approved NDA must also

submit new or supplemental applications and obtain FDA approval for certain changes to the approved product,

including product labeling or manufacturing process. Similar provisions apply in the EU. Advertising and promotional

materials must comply with any competent health authorities rules and are subject to health authorities review, in

addition to other potentially applicable laws.

In addition, product manufacturers and their facilities are subject to periodic inspections by Regulatory Authorities for

compliance with cGMP requirements and/or others quality and manufacturing standards and adherence to

commitments made in compliance with approved regulatory dossiers. If we or a regulatory authority is made aware

of previously unknown problems with a product, such as adverse events of unanticipated severity or frequency, or

problems with the facility where the product is manufactured or if a regulatory authorities disapprove the promotion,

marketing or labeling of that product, a regulatory authority may impose restrictions relative to that product, the

manufacturing facility or us, including requiring batch or product recall or withdrawal of the product from the market,

suspension or revocation of the marketing authorization or medical device certification or partial or full suspension of

manufacturing activities.

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If we or our strategic licensees fail to comply with applicable regulatory requirements following approval of any of the

product candidates we develop, regulatory authorities may:

•issue a warning letter asserting a violation of the law;

•seek an injunction or impose civil or criminal penalties or monetary fines;

•suspend or withdraw regulatory approval;

•suspend or terminate any ongoing clinical trials;

•refuse to approve a pending marketing authorizations, medical device certifications or comparable foreign

marketing application (or any supplements thereto) submitted by us or our strategic licensees;

•restrict the marketing, distribution or manufacturing of the product;

•seize or detain product or otherwise require the withdrawal or recall of product from the market;

•destroy or require destruction of products;

•refuse to permit the import or export of products; or

•refuse to allow us to enter into supply contracts, including government contracts.

Any of the foregoing regulatory actions could require us to expend significant time and resources in response and

could generate negative impact on the company. The occurrence of any event or penalty described above may

inhibit the ability to commercialize products and generate revenues. In addition, the FDA’s policies, and policies of

foreign regulatory agencies, may change and additional government regulations may be enacted that could prevent,

limit or delay regulatory approval of product candidates. We cannot predict the likelihood, nature or extent of

government regulation that may arise from future legislation or administrative action, either in the United States or

abroad. If we or our strategic licensees are unable to adapt to changes in existing requirements or the adoption of

new requirements or policies, or if we or our strategic licensees are not able to maintain regulatory compliance,

marketing approval or medical device certification that has been obtained may be suspended or withdraw and we

may not achieve or sustain profitability, which would adversely affect our business, prospects, financial condition and

results of operations.

Finally, even though the Group has obtained the CE-marking for Hensify®, the name of NBTXR3 in the indication of

locally advanced STS, it cannot be certain that NBTXR3 will receive regulatory approvals in other indications or in

other territories or successfully complete the necessary conformity assessment procedures, as applicable, or be

successfully commercialized, for any cancer indications, even if the Group successfully completes applicable pre-

marketing regulatory requirements.

1.5.5.3.The regulatory approval processes of the FDA and comparable foreign authorities are

lengthy, time consuming and inherently unpredictable, and if we are ultimately unable to

obtain regulatory approval for product candidates, our business will be substantially

harmed.

We must obtain regulatory approval to market and sell our product candidates, including NBTXR3. For example, in

the U.S., we must obtain FDA approval for each product candidate in each specific indication that we intend to

commercialize, and in the EU we must obtain approval from the European Commission (EC), based on the opinion

of the EMA. The approval processes are typically expensive, and the time required to obtain approval by the FDA,

the EC and comparable foreign authorities is inherently unpredictable but typically takes many years following the

commencement of clinical trials and depends upon numerous factors, including the discretion of the regulatory

authorities. In addition, approval policies, regulations, or the type and amount of clinical data necessary to gain

approval may change during the course of a product candidate’s clinical development and may vary among

jurisdictions. Save with regard to the CE-marking above mentioned relating to the STS indication, we have not

obtained regulatory approval for the commercialization of any product candidate and it is possible that none of our

existing product candidates including NBTXR3 or any product candidates we may seek to develop in the future will

ever obtain such regulatory approval.

The FDA or other regulatory authority, as applicable, may delay, limit or deny approval of our product candidates for

many reasons, including disagreement with clinical trial design or implementation, determinations that a product

candidate is not sufficiently safe or efficacious, objections to the statistical significance of data or our interpretation of

data, objections to the production, formulation or labeling of our product candidates, and any other discretionary

factors such regulators deem relevant.

This lengthy approval process as well as the unpredictability of future clinical trial results may result in our failing to

obtain regulatory approval to market the product candidates we develop, including NBTXR3, which would

significantly harm our business, results of operations and prospects. In addition, even if we or our strategic licensees

were able to obtain approval, regulatory authorities may approve any of our product candidates for fewer or more

limited indications than we request, may not approve the price we intend to charge for our products, may grant

approval contingent on the performance of costly post-marketing clinical trials, or may approve a drug candidate with

a label that does not include the labeling claims necessary or desirable for the successful commercialization of that

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product candidate. Any of the foregoing scenarios could materially harm the commercial prospects for the product

candidates we develop.

1.5.5.4.Although we may seek fast track designation from the FDA for some or all of the

indications that NBTXR3 may potentially address, there is no assurance that such

designation will be granted or, if granted that it will lead to a faster development or

regulatory review or approval process.

We may seek fast track designation and review for some or all of the indications that NBTXR3 may potentially

address. In February 2020, the Company received Fast Track designation from the FDA for NBTXR3 for the

treatment of locally advanced head and neck cancers. If a product is intended for the treatment of a serious or life

threatening condition or disease, the sponsor may apply for FDA fast track designation. The FDA has broad

discretion whether or not to grant this designation. Thus, even if we believe a particular product candidate is eligible

for this designation, we cannot assure that the FDA would decide to grant it. Moreover, even if we do receive fast

track designation, we may not experience a faster development process, review or approval compared to

conventional FDA procedures and such designation does not assure ultimate approval. In addition, the FDA may

withdraw fast track designation if it believes that the designation is no longer supported by data from our clinical

development program. Moreover, the FDA may change its fast track designation program or guidance.

1.5.5.5.Even if we or our strategic licensees obtain and maintain approval for product candidates

in the United States or another jurisdiction, we or our strategic licensees may never

obtain approval for the same product candidates in other jurisdictions, which would limit

market opportunities and adversely affect our business.

Approval of a product candidate in the United States by the FDA or in another jurisdiction by the requisite regulatory

agencies in such other jurisdiction does not ensure approval of such product candidate by regulatory authorities in

other countries or jurisdictions, and approval by one foreign regulatory authority does not ensure approval by

regulatory authorities in other foreign countries or by the FDA. The approval process varies among countries and

may limit our or our strategic licensees’ ability to develop, manufacture, promote and sell our product candidates

including NBTXR3 internationally. Failure to obtain marketing approval in international jurisdictions would prevent the

product candidates from being marketed outside of the jurisdictions in which regulatory approvals have been

received. In order to market and sell product candidates in the EU and many other jurisdictions, we and our strategic

licensees must obtain separate marketing approvals and comply with numerous and varying regulatory

requirements. The approval procedure varies among countries and may involve additional preclinical studies or

clinical trials both before and post approval. In many countries, a product candidate must be approved for

reimbursement before it can be approved for sale in that country. In some cases, the intended price for the product is

also subject to approval. Further, while regulatory approval of a product candidate in one country does not ensure

approval in any other country, a failure or delay in obtaining regulatory approval in one country may have a negative

effect on the regulatory approval process in others. If we or our strategic licensees fail to comply with the regulatory

requirements in international markets and/or receive applicable marketing approvals, the target market will be

reduced and the ability to realize the full market potential of the subject product candidates will be harmed and our

business may be adversely affected. For the sake of clarity, this risk factor is applicable whether it is about marketing

approval or CE-marking.

Depending on the results of clinical trials and the process for obtaining regulatory approvals in other countries, we or

our strategic licensees may decide to first seek regulatory approvals of a product candidate in countries other than

the United States, or we or our strategic licensees may simultaneously seek regulatory approvals in the United

States and other countries, in which case we or our strategic licensees will be subject to the regulatory requirements

of health authorities in each country in which we seek approvals. Obtaining regulatory approvals from health

authorities in countries outside the United States and the EU is likely to subject us or our strategic licensees to risks

in such countries that are substantially similar to the risks associated with obtaining approval in the United States or

the EU described herein.

1.5.5.6.Government restrictions on pricing and reimbursement, as well as other healthcare payor

cost-containment initiatives, may negatively impact our ability to generate revenues if we

obtain regulatory approval for any of our product candidates.

Third-party payors, whether domestic or foreign, or governmental or commercial, are developing increasingly

sophisticated methods of controlling healthcare costs. The continuing efforts of various governments, insurance

companies, managed care organizations and other payors to contain or reduce healthcare costs may adversely

affect our ability or our strategic licensees’ ability to set a price for our products that we believe is fair, to achieve

profitability, and to obtain and maintain market acceptance by patients and the medical community. In both the

United States and certain foreign jurisdictions, there have been a number of legislative and regulatory initiatives to

contain healthcare costs. By way of example, in the United States, the Patient Protection and Affordable Care Act, as

amended by the Health Care and Education Reconciliation Act (collectively, the ACA) was enacted in March 2010.

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The ACA expanded health care coverage through Medicaid expansion and the implementation of a tax penalty for

individuals who do not maintain mandated health insurance coverage (the so-called ‘individual mandate’). The ACA

also contains a number of provisions that affect coverage and reimbursement of drug products. Uncertainty remains

regarding the implementation and impact of the ACA. There have been sustained congressional and legal efforts to

modify or repeal all or certain provisions of the ACA. For example, tax reform legislation was enacted at the end of

2017 that eliminated the individual mandate beginning in 2019. Additionally, in the United States, the Inflation

Reduction Act of 2022 (IRA), enacted on August 16, 2022, includes several provisions to lower prescription drug

costs for people with Medicare and reduce drug spending by the federal government. We cannot predict the ultimate

content, timing or effect of any changes to the ACA, the IRA or other federal and state reform efforts, and there can

be no assurance that any such health care reforms will not adversely affect our future business and financial results.

U.S. federal and state governments have shown significant interest in implementing cost-containment programs to

limit the growth of government-paid healthcare costs, including price controls, waivers from Medicaid drug rebate law

requirements, restrictions on reimbursement and requirements for substitution of generic products for branded

prescription drugs. The private sector has also sought to control healthcare costs by limiting coverage or

reimbursement or requiring discounts and rebates on products. We are unable to predict what additional legislation,

regulations or policies, if any, relating to the healthcare industry or third-party coverage and reimbursement may be

enacted in the future or what effect such legislation, regulations or policies would have on our business. Any cost

containment measures could significantly decrease the available coverage and the price we might establish for our

potential products, which would have an adverse effect on our net revenues and operating results.

Likewise, in many EU Member States, legislators and other policymakers continue to propose and implement

healthcare cost-containing measures in response to the increased attention being paid to healthcare costs in the EU.

Certain of these changes could impose limitations on the prices we will be able to charge for our products and any

approved product candidates or the amounts of reimbursement available for these products from governmental and

private third-party payers, may increase the tax obligations on pharmaceutical companies or may facilitate the

introduction of generic competition with respect to our products.

Further, an increasing number of EU countries Member States and other non-U.S. countries use prices for medicinal

products established in other countries as “reference prices” to help determine the price of the product in their own

territory. If the price of one of our products decreases substantially in a reference price country, that could impact the

price for such product in other countries. Consequently, a downward trend in prices of our products in some

countries could contribute to similar downward trends elsewhere, which would have a material adverse effect on our

revenues and results of operations. Also, in order to obtain reimbursement for our products in some countries, we

may be required to conduct clinical trials that compare the cost-effectiveness of our products to other available

therapies.

Moreover, this political and legislative uncertainty could harm our and our strategic licensees’ ability to market any

products and generate revenues. Cost containment measures that healthcare payors and providers are instituting

and the effect of further healthcare reform could significantly reduce potential revenues from the sale of any of our

product candidates approved in the future, and could cause an increase in our compliance, manufacturing, or other

operating expenses.

In some countries, the proposed pricing for a biopharmaceutical product must be approved before it may be lawfully

marketed. In addition, in certain foreign markets, the pricing of a biopharmaceutical product is subject to government

control and reimbursement may in some cases be unavailable. The requirements governing drug pricing vary widely

from country to country. For example, the EU provides options for its Member States to restrict the range of

medicinal products for which their national health insurance systems provide reimbursement and to control the prices

of medicinal products for human use. An EU Member State may approve a specific price for the medicinal product or

it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal

product on the market. There can be no assurance that any country that has price controls or reimbursement

limitations for biopharmaceutical products will allow favorable reimbursement and pricing arrangements for any of

our products. Historically, biopharmaceutical products launched in the EU do not follow price structures of the United

States and generally tend to have significantly lower prices.

We believe that pricing pressures will continue and may increase, which may make it difficult for us to sell our

potential products that may be approved in the future at a price acceptable to us or any of our future collaborators.

1.5.5.7.We are subject to healthcare laws and regulations, which could expose us to the potential

for criminal sanctions, civil penalties, exclusion from government healthcare programs,

contractual damages, reputational harm and diminished profits and future earnings.

Healthcare providers, physicians and others will play a primary role in the recommendation, prescription, and

administration of our products. Our arrangements with such persons and third-party payors must be structured in

accordance with the broadly applicable fraud and abuse and other healthcare laws and regulations that may

constrain the business or financial arrangements and relationships through which we research, market, sell and

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distribute our products, if we obtain marketing approval. Restrictions under applicable federal, state and foreign

healthcare laws and regulations include but are not limited to the following:

•The federal Anti-Kickback Statute, which prohibits, among other things, persons from knowingly and

willfully soliciting, offering, receiving or providing remuneration (including any kickback, bribe or rebate),

directly or indirectly, in cash or in kind, to induce or reward either the referral of an individual for, or the

purchase or lease, order or recommendation of, any item, good, facility or service, for which payment may

be made under federal healthcare programs such as Medicare and Medicaid.

•The federal civil and criminal false claims laws and civil monetary penalties laws, which impose criminal

and civil penalties, including those from civil whistleblower or qui tam actions, against individuals or

entities for knowingly presenting, or causing to be presented, claims for payment that are false or

fraudulent or making a false statement to avoid, decrease, or conceal an obligation to pay money to the

federal government.

•The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created new

federal criminal statutes that prohibit executing a scheme to defraud any healthcare benefit program or

knowingly and willingly falsifying, concealing or covering up a material fact or making false statements

relating to healthcare matters.

•HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, or

HITECH, and its implementing regulations, which impose certain requirements on covered entities and

their business associates, including mandatory contractual terms, with respect to safeguarding the

privacy, security and transmission of individually identifiable health information.

•The federal transparency requirements under the Physician Payments Sunshine Act, enacted as part of

the ACA, that require applicable manufacturers of covered drugs, devices, biologics and medical supplies

to track and annually report to CMS payments and other transfers of value provided to physicians and

teaching hospitals and certain ownership and investment interests held by physicians or their immediate

family members.

•Analogous laws and regulations in various U.S. states, such as state anti-kickback and false claims laws,

which may apply to items or services reimbursed by any third-party payor, including commercial insurers,

state marketing and/or transparency laws applicable to manufacturers that may be broader in scope than

U.S. federal requirements, state laws that require biopharmaceutical companies to comply with the

biopharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance

promulgated by the U.S. government, and state laws governing the privacy and security of health

information in certain circumstances, many of which differ from each other in significant ways and may not

have the same effect as HIPAA.

Similar legislation is applicable in other countries, including by way of example and without limitation: the UK’s

Bribery Act 2010 or Article D1453-1 to D1453-9 of the French Public Health Code on Transparency of Benefits Given

by Companies Manufacturing or Marketing Health and Cosmetic Products for Human Use. Furthermore, in the EU,

harmonized rules prohibit gifts, pecuniary advantages or benefits in kind to Health Care Professionals (HCPs) unless

they are inexpensive and relevant to the practice of medicine or pharmacy.

Similarly, strict rules apply to hospitality at sales promotion events. Based on these rules, a body of industry

guidelines and sometimes national laws in force in individual EU Member States has been introduced to fight

improper payments or other transfers of value to HCPs, and in general inducements that may have a broadly

promotional character.

Ensuring that our business practices and that our business arrangements with third parties comply with applicable

healthcare laws and regulations could be costly. It is possible that governmental authorities will conclude that our

business practices do not comply with current or future statutes, regulations or case law involving applicable fraud

and abuse or other healthcare laws and regulations. If our operations were found to be in violation of any laws or any

other governmental regulations that may apply to us, we may be subject to significant civil, criminal and

administrative penalties, damages, fines, disgorgement, individual imprisonment and exclusion from government

funded healthcare programs, such as Medicare and Medicaid, any of which could substantially disrupt our

operations. If the physicians or other providers or entities with whom we expect to do business are found not to be in

compliance with applicable laws, they may be subject to criminal, civil or administrative sanctions, including

exclusions from government funded healthcare programs.

1.5.5.8.Significant regulation applies to the manufacturing of our products and the manufacturing

facilities on which we rely may not meet regulatory requirements or may have limited

capacity.

All entities involved in the preparation of products for clinical studies or commercial sale, including our existing

contract manufacturers for our product candidates, including NBTXR3 as well as our in-house manufacturing facility

in Villejuif, France, are subject to extensive regulations.

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For example, in the United States, a drug product approved for commercial sale or used in clinical studies must be

manufactured in accordance with the current Good Manufacturing Practices (cGMP) requirements. In the EU,

NBTXR3 is classified as a medical device and must be manufactured in accordance with ISO13485 requirements.

Nevertheless, due to the classification of NBTXR3 as a drug product in other regions, notably, the United States, the

development and manufacturing of NBTXR3 is made in accordance with the more stringent cGMP requirements. As

a result, each of the facilities involved in the manufacturing NBTXR3 must comply with cGMP. Also, applicants for a

marketing authorization are responsible for ensuring that the proposed manufacturing sites included in the marketing

authorization application comply with cGMP.

The FDA’s cGMP regulations and comparable regulations in other jurisdictions govern manufacturing processes and

procedures (including record keeping) and the implementation and operation of quality systems to control and

assure the quality of investigational products and products approved for sale. Poor control of production processes

can lead to the introduction of contaminants, or to inadvertent changes in the properties or stability of the product

candidates including NBTXR3 we develop that may not be detectable in final product testing. In the United States, in

the framework of the potential upcoming NDA, we or our contract manufacturers must supply all necessary

documentation in support of registration on a timely basis and must adhere to the cGMP requirements enforced by

the FDA and/or by other Competent Regulatory Authorities through its facilities inspection program. Our facilities and

Quality Management Systems as well as the facilities and Quality Management Systems of our third-party

contractors must pass a pre-approval inspection for compliance with the applicable regulations as one of a condition

of regulatory approval of our product candidates. In addition, the FDA may, at any time, inspect a manufacturing

facility involved with the preparation and/or control of our product candidates as well as the associated quality

systems for compliance with the regulations applicable to the activities being conducted.

If we or any of our third-party manufacturers fail to provide appropriate products and data (as per GxP requirements)

or maintain regulatory compliance, the regulator can impose regulatory sanctions including, among other things, the

imposition of a hold on clinical trials, the refusal to permit a clinical trial to commence, the refusal to use certain

batches of product candidates intended to be used in the clinical trials, the refusal to approve a pending application

for a new product, the revocation or non-renewal of a pre-existing approval - including the withdrawal of GMP license

in case of major findings, or the refusal to accept some non-clinical and/or clinical data generated with material for

which that third-party was responsible. As a result, our business, financial condition and results of operations may be

materially harmed.

Manufacturing and increasing manufacturing scale at our in-house manufacturing facility will require significant

resources and substantial regulatory engagement. Our manufacturing facility in Villejuif, France, will be subject to

ongoing periodic unannounced inspection by the FDA, as well as regular inspections by the ANSM for GMP

certificate renewal (every 3 years), and other foreign agencies to ensure strict compliance with cGMPs, and other

government regulations. Accordingly, operating our own manufacturing facilities and maintaining compliant

manufacturing capabilities at scale may be costlier than we anticipate or may result in delays.

In addition, if supply from one approved manufacturer or supplier, including our own in-house manufacturing facility,

is interrupted, there could be a significant disruption in commercial and/or clinical supply of our products. Identifying

and engaging an alternative manufacturer or supplier that complies with applicable regulatory requirements could

result in further delay. Applicable regulatory agencies may also require additional studies if a new manufacturer or

supplier is relied upon in connection with commercial production. Switching manufacturers or suppliers may involve

substantial costs and time and is likely to result in a delay in our desired clinical and commercial timelines.

These factors could cause commercialization of our product candidates including NBTXR3 to be delayed, cause us

to incur higher costs, or prevent us from commercializing our products successfully. Furthermore, if our

manufacturing facilities are unable to produce high quality product for our clinical and commercial needs, and we are

unable to secure one or more replacement suppliers capable of production at a substantially equivalent cost, our

clinical studies may be delayed, or we could lose potential revenue.

1.5.6.Risks Related to Intellectual Property

1.5.6.1.Our ability to compete may decline if we do not adequately protect our proprietary rights.

Our commercial success depends, in part, on obtaining and maintaining proprietary rights to our and our licensors’

intellectual property estate, including with respect to our NBTXR3 product candidates, as well as successfully

defending these rights against third-party challenges. We will only be able to protect our product candidates from

unauthorized use by third parties to the extent that valid and enforceable patents, or effectively protected trade

secrets, cover them. Our ability to obtain and maintain patent protection for all aspects of our product candidates is

uncertain due to a number of factors, including:

•we or, as the case may be, our licensors may not have been the first to invent the technology covered by

our or their pending patent applications or issued patents;

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•we cannot be certain that we or our licensors were the first to file patent applications covering our product

candidates, including their compositions or methods of use, as patent applications in the United States

and most other countries are confidential for a period of time after filing;

•others may independently develop identical, similar or alternative products or compositions or methods of

use thereof;

•the disclosures in our or our licensors’ patent applications may not be sufficient to meet the statutory

requirements for patentability and the plausibility case law requirements that may exist in certain

jurisdictions;

•any or all of our or our licensors’ pending patent applications may not result in issued patents;

•we or our licensors may not seek or obtain patent protection in countries or jurisdictions that may

eventually provide us a significant business opportunity;

•any patents issued to us or our licensors may not provide a basis for commercially viable products, may

not provide any competitive advantages, or may be successfully challenged by third parties, which may

result in our or our licensors’ patent claims being narrowed, invalidated or held unenforceable;

•our compositions and methods may not be patentable;

•others may design around our or our licensors’ patent claims to produce competitive products that fall

outside of the scope of our or our licensors’ patents; and

•others may identify prior art or other bases upon which to challenge and ultimately invalidate our or our

licensors’ patents or otherwise render them unenforceable.

Even if we own, obtain or in-license patents covering our product candidates or compositions, we may still be barred

from making, using and selling our product candidates or technologies because of the patent rights or other

intellectual property rights of others. Others may have filed, and in the future may file, patent applications covering

compositions, products or methods that are similar or identical to ours, which could materially affect our ability to

successfully develop and, if approved, commercialize our product candidates. In addition, because patent

applications can take many years to issue, there may be currently pending applications unknown to us that may later

result in issued patents that our product candidates or compositions may infringe. These patent applications,

including intermediate documents, may have priority over patent applications filed by us or our licensors.

Obtaining and maintaining a patent portfolio entails significant expense. Part of such expense includes periodic

maintenance fees, renewal fees, annuity fees and various other governmental fees on patents and/or applications

due over the course of several stages of prosecuting patent applications, and over the lifetime of maintaining and

enforcing issued patents. We may or may not choose to pursue or maintain protection for particular intellectual

property in our portfolio. If we choose to forgo patent protection or to allow a patent application or patent to lapse

purposefully or inadvertently, our future competitive position could suffer. We employ reputable law firms and other

professionals to help us comply with the various procedural, documentary, fee payment and other similar provisions

we are subject to and, in many cases, an inadvertent lapse can be cured by payment of a late fee or by other means

in accordance with the applicable rules.

There are situations, however, in which failure to make certain payments or noncompliance with certain requirements

in the patent prosecution and maintenance process can result in lapse of a patent or patent application, resulting in

partial or complete loss of patent rights in the relevant jurisdiction. In such an event, our competitors might be able to

enter the market, which would have a material adverse effect on our business.

Legal action that may be required to enforce our patent rights can be expensive and may involve the diversion of

significant management time. In addition, these legal actions could be unsuccessful and could also result in the

invalidation or transfer of ownership of our patents or a finding that they are unenforceable. We may or may not

choose to pursue litigation or other actions against those that have infringed our patents, or have used them without

authorization, due to the associated expense and time commitment of monitoring these activities. In addition, some

of our competitors may be able to sustain the costs of such litigation or proceedings more effectively than we can

because of their greater financial resources. Accordingly, despite our efforts, we may not be able to prevent third

parties from infringing or misappropriating or from successfully challenging or claiming ownership over our

intellectual property rights. If we fail to protect or to enforce our intellectual property rights successfully, our

competitive position could suffer, which could harm our results of operations.

1.5.6.2.If we are unable to protect the confidentiality of our trade secrets, our business and

competitive position would be harmed.

In addition to patent protection, because we operate in the highly technical field of nanotherapeutics, we rely in part

on trade secret protection in order to protect our proprietary technology and processes. However, trade secrets are

difficult to protect. Monitoring unauthorized uses and disclosures is difficult, and we do not know whether the steps

we have taken to protect our proprietary technologies will be effective or sufficient.

In addition to contractual measures that we implement in our agreements with third-party service providers and in

strategic licensing agreements, we try to protect the confidential nature of our proprietary information using physical

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and technological security measures. Such measures may not provide adequate protection for our proprietary

information. For example, our security measures may not prevent an employee, consultant, or collaborator with

authorized access from misappropriating our trade secrets and providing them to a competitor, and the recourse we

have available against such misconduct may not provide an adequate or sufficiently swift remedy to protect our

interests fully. Enforcing a claim that a party illegally disclosed or misappropriated a trade secret can be difficult,

expensive and time consuming, and the outcome is unpredictable. In addition, courts outside the United States may

be less willing to protect trade secrets. Furthermore, our proprietary information may be independently developed or

lawfully reverse-engineered by others in a manner that could prevent legal recourse by us.

We cannot guarantee that our trade secrets and other proprietary and confidential information will not be disclosed

or that competitors will not otherwise gain access to our trade secrets. If any of our confidential or proprietary

information, including our trade secrets, were to be disclosed or misappropriated, or if any such information was

independently developed by a competitor, our competitive position could be harmed.

1.5.6.3.Patents and patent applications involve highly complex legal and factual questions,

which, if determined adversely to us, could negatively impact our competitive position.

The patent positions of biotechnology and nanotherapeutic companies and other actors in our fields of business can

be highly uncertain and typically involve complex scientific, legal and factual analyses. In particular, the interpretation

and breadth of claims allowed in some patents covering, for example, compositions may be uncertain and difficult to

determine, and are often affected materially by the facts and circumstances that pertain to the patented compositions

and the related patent claims. The standards of the United States Patent and Trademark Office, or USPTO, and

foreign patent offices are sometimes uncertain and could change in the future. Consequently, the issuance and

scope of patents cannot be predicted with certainty. Patents, if issued, may be challenged, invalidated, narrowed or

circumvented. U.S. patents and patent applications may also be subject to interference proceedings, and U.S.

patents may be subject to reexamination proceedings, post- grant review, inter partes review, or other administrative

proceedings in the USPTO. Foreign patents as well may be subject to opposition or comparable proceedings in the

corresponding foreign patent offices. Challenges to our patents and patent applications, if successful, may result in

the denial of our patent applications or the loss or reduction in their scope. In addition, any interference,

reexamination, post-grant review, inter partes review, opposition proceedings and other administrative proceedings

may be costly and involve the diversion of significant management time. Accordingly, rights under any of our or our

licensors’ patents may not provide us with sufficient protection against competitive products or processes and any

loss, denial or reduction in scope of any such patents and patent applications may have a material adverse effect on

our business.

Furthermore, even if not challenged, our patents and patent applications may not adequately protect our product

candidates, including NBTXR3 or technology or prevent others from designing their products or technology to avoid

being covered by our patent claims. If the breadth or strength of protection provided by the patents we own or

license with respect to our product candidates is threatened, it could dissuade companies from collaborating with us

to develop, and could threaten our ability to successfully commercialize, our product candidates. Furthermore, for

U.S. patent applications in which claims are entitled to a priority date before March 16, 2013, an interference

proceeding can be provoked by a third party or instituted by the USPTO in order to determine who was the first to

invent any of the subject matter covered by such patent claims.

In addition, changes in, or different interpretations of, patent laws in the United States and other countries may

permit others to use our discoveries or to develop and commercialize our technology and products without providing

any notice or compensation to us, or may limit the scope of patent protection that we or our licensors are able to

obtain. The laws of some countries do not protect intellectual property rights to the same extent as U.S. laws and

those countries may lack adequate rules and procedures for defending our intellectual property rights.

If we fail to obtain and maintain patent protection and trade secret protection of our product candidates and

technology, we could lose our competitive advantage and competition we face would increase, reducing any

potential revenues and have a material adverse effect on our business.

1.5.6.4.The lives of our patents may not be sufficient to effectively protect our products and

business.

Patents have a limited lifespan. In the United States, the natural expiration of a patent is generally 20 years after its

first effective filing date.

Although various extensions may be available, the life of a patent, and the protection it affords, is limited. Our issued

patents and pending patent applications will expire on dates ranging from 2025 to 2041, subject to any patent

extensions that may be available for such patents. In addition, although upon issuance in the United States a

patent’s life can be increased based on certain delays caused by the USPTO, this increase can be reduced or

eliminated based on certain delays caused by the patent applicant during patent prosecution. In the EU, for patents

related to authorized drug products, Supplementary Protection Certificates (SPCs) are available to extend a patent

term for up to five years to compensate for patent protection lost during regulatory review. In the case our

candidates’ products are registered as a medical device in a particular European country, we will not benefit from the

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supplementary patent protection afforded by an SPC in that country. Although all EU Member States must provide

SPCs, SPCs must still be applied for and granted on a country-by-country basis and their protection is subject to

exceptions. If we do not have sufficient patent life to protect our products, our business and results of operations will

be adversely affected.

1.5.6.5.We will not seek to protect our intellectual property rights in all jurisdictions throughout

the world and we may not be able to adequately enforce our intellectual property rights

even in the jurisdictions where we seek protection.

Filing, prosecuting and defending patents on our product candidates in all countries and jurisdictions throughout the

world would be prohibitively expensive, and our intellectual property rights in some countries outside the United

States could be less extensive than those in the United States, assuming that rights are obtained in the United

States. In addition, the laws of some foreign countries do not protect intellectual property rights to the same extent as

federal and state laws in the United States. Consequently, we may not be able to prevent third parties from practicing

our inventions in all countries outside the United States, or from selling or importing products made using our

inventions in and into the United States or other jurisdictions.

Competitors may use our technologies in jurisdictions where we or our licensors do not pursue and obtain patent

protection to develop their own products and further, may export otherwise infringing products to territories where we

have patent protection, but where the ability to enforce our patent rights is not as strong as in the United States.

These products may compete with our products and our intellectual property rights and such rights may not be

effective or sufficient to prevent such competition.

The laws of some foreign countries do not protect intellectual property rights to the same extent as the laws of the

United States. Patent protection must be sought on a country-by-country basis, which is an expensive and time-

consuming process with uncertain outcomes. Accordingly, we may choose not to seek patent protection in certain

countries, and we will not have the benefit of patent protection in such countries. In addition, the legal systems of

some countries, particularly developing countries, do not favor the enforcement of patents and other intellectual

property protection, , and the requirements for patentability differ, in varying degrees, from country to country, and

the laws of some foreign countries do not protect intellectual property rights, including trade secrets, to the same

extent as federal and state laws of the United States. As a result, many companies have encountered significant

problems in protecting and defending intellectual property rights in certain foreign jurisdictions. Such issues may

make it difficult for us to stop the infringement, misappropriation or other violation of our intellectual property rights.

For example, many foreign countries, including the EU countries, have compulsory licensing laws under which a

patent owner must grant licenses to third parties. In addition, many countries limit the enforceability of patents

against third parties, including government agencies or government contractors. In these countries, patents may

provide limited or no benefit. In those countries, we may have limited remedies if patents are infringed or if we are

compelled to grant a license to a third party, which could materially diminish the value of those patents. This could

limit our potential revenue opportunities. Accordingly, our efforts to enforce intellectual property rights around the

world may be inadequate to obtain a significant commercial advantage from the intellectual property that we own or

license. Similarly, if our trade secrets are disclosed in a foreign jurisdiction, competitors worldwide could have access

to our proprietary information and we may be without satisfactory recourse. Such disclosure could have a material

adverse effect on our business. Moreover, our ability to protect and enforce our intellectual property rights may be

adversely affected by unforeseen changes in foreign intellectual property laws.

Furthermore, proceedings to enforce our patent rights and other intellectual property rights in foreign jurisdictions

could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our

patents at risk of being invalidated or interpreted narrowly, could put our patent applications at risk of not issuing and

could provoke third parties to assert claims against us. We may not prevail in any lawsuits that we initiate, and the

damages or other remedies awarded to us, if any, may not be commercially meaningful, while the damages and

other remedies we may be ordered to pay such third parties may be significant. Accordingly, our efforts to enforce

our intellectual property rights around the world may be inadequate to obtain a significant commercial advantage

from the intellectual property that we develop or license.

1.5.6.6.Third parties may assert rights to inventions we develop or otherwise regard as our own.

Third parties may in the future make claims challenging the inventorship or ownership of our or our licensors’

intellectual property. We have written agreements with collaborators that provide for the ownership of intellectual

property arising from our strategic licensing arrangements. These agreements provide that we must negotiate certain

commercial rights with such collaborators with respect to joint inventions or inventions made by our collaborators that

arise from the results of the strategic arrangement. In some instances, there may not be adequate written provisions

to clearly address the allocation of intellectual property rights that may arise from the respective strategic licensing

arrangement. If we cannot successfully negotiate sufficient ownership and commercial rights to the inventions that

result from our use of a third-party collaborator’s materials when required, or if disputes otherwise arise with respect

to the intellectual property developed through the use of a collaborator’s samples, we may be limited in our ability to

capitalize on the full market potential of these inventions. In addition, we may face claims by third parties that our

agreements with employees, contractors, or consultants obligating them to assign intellectual property to us are

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ineffective, or are in conflict with prior or competing contractual obligations of assignment, which could result in

ownership disputes regarding intellectual property we have developed or will develop and could interfere with our

ability to capture the full commercial value of such inventions. Litigation may be necessary to resolve an ownership

dispute, and if we are not successful, we may be precluded from using certain intellectual property and associated

products and technology, or may lose our rights in that intellectual property. Either outcome could have a material

adverse effect on our business.

1.5.6.7.We may not identify relevant third-party patents or may incorrectly interpret the relevance,

scope or expiration of a third-party patent which might adversely affect our ability to

develop and market our products.

We cannot guarantee that any of our patent searches or analyses, including but not limited to the identification of

relevant patents, the scope of patent claims or the expiration of relevant patents, are complete or thorough, nor can

we be certain that we have identified each and every third party patent and pending application in the European

countries, Japan, United States and abroad that is relevant to or necessary for the commercialization of our product

candidates, including NBTXR3, in any jurisdiction.

The scope of a patent claim is determined by an interpretation of the law, the written disclosure in a patent and the

patent’s prosecution history.

Our interpretation of the relevance or the scope of a patent or a pending application may be incorrect, which may

negatively impact our ability to market our products. We may incorrectly determine that our products are not covered

by a third-party patent or may incorrectly predict whether a third party’s pending application will issue with claims of

relevant scope. Our determination of the expiration date of any patent in the United States or abroad that we

consider relevant may be incorrect, which may negatively impact our ability to develop and market our product

candidates. Our failure to identify and correctly interpret relevant patents may negatively impact our ability to develop

and market our products.

1.5.6.8.Third parties may assert that our employees or consultants have wrongfully used or

disclosed confidential information or misappropriated trade secrets.

We currently employ, and may in the future employ, individuals who were previously employed or worked as an

intern at universities or other biotechnology, biopharmaceutical or nanotherapeutic companies, including our

competitors or potential competitors. Although we try to ensure that our employees and consultants do not use the

proprietary information or know-how of others in their work for us, we may be subject to claims that we or our

employees, consultants or independent contractors have inadvertently or otherwise used or disclosed intellectual

property, including trade secrets or other proprietary information, of a former employer or other third parties.

Litigation may be necessary to defend against these claims. If we fail in defending any such claims, in addition to

paying monetary damages, we may lose valuable intellectual property rights or personnel. Even if we are successful

in defending against such claims, litigation could result in substantial costs and be a distraction to management and

other employees.

1.5.6.9.A dispute concerning the infringement or misappropriation of our proprietary rights or the

proprietary rights of others could be time consuming and costly, and an unfavorable

outcome could harm our business.

There is significant litigation in the biopharmaceutical and biotechnology industry regarding patent and other

intellectual property rights. Although we are not currently subject to any material pending intellectual property

litigation, and are not aware of any such threatened litigation, we may be exposed to future litigation by third parties

based on claims that our product candidates, technologies or activities infringe the intellectual property rights of

others.

Our success will depend in part on our ability to operate without infringing, misappropriating or otherwise violating

the intellectual property and proprietary rights of third parties. Other parties may allege that our or our collaborators’

products or product candidates or the use of our or our collaborators’ technologies infringe, misappropriate or

otherwise violate patent claims or other intellectual property rights held by them or that we or our collaborators are

employing their proprietary technology without authorization.

If our development activities are found to infringe any such patents or other intellectual property rights, we may have

to pay significant damages or seek licenses to such patents or other intellectual property. A patentee could prevent

us from using the patented drugs or compositions. We may need to resort to litigation to enforce a patent issued to

us, to protect our trade secrets, or to determine the scope and validity of third-party proprietary rights.

If we become involved in litigation, it could consume a substantial portion of our managerial and financial resources,

regardless of whether we win or lose. Any adverse ruling or perception of an adverse ruling in defending ourselves

against these claims could have a material adverse impact on our cash position. Patent and other types of

intellectual property litigation can involve complex factual and legal questions, and their outcome is uncertain.

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Any legal action against us or our collaborators could lead to:

•payment of damages, potentially including treble or punitive damages if we are found to have willfully

infringed a party’s patent rights;

•injunctive or other equitable relief that may effectively block our ability to further develop, commercialize,

and sell products;

•our or our collaborators being required to obtain a license under third-party intellectual property, and such

license may not be available on an exclusive basis, on commercially acceptable terms, or at all; or

•extensive discovery in which our confidential information could be compromised.

Any of these outcomes could have a material adverse impact on our cash position and financial condition and our

ability to develop and commercialize our product candidates.

1.5.6.10.Issued patents covering our product candidates could be found invalid or unenforceable

if challenged in court.

If we or one of our licensing partners initiated legal proceedings against a third party to enforce a patent covering our

product candidate, the defendant could counterclaim that the patent covering our product candidate is invalid and/or

unenforceable. In patent litigation in the United States, defendant counterclaims alleging invalidity and/or

unenforceability are commonplace. Furthermore, third parties may petition courts for declarations of invalidity or

unenforceability with respect to our patents or individual claims. If successful, such claims could narrow the scope of

protection afforded our product candidates, including NBTXR3, and future products, if any. Grounds for a validity

challenge include alleged failures to meet any of several statutory requirements, including lack of novelty,

obviousness or non-enablement. Grounds for unenforceability assertions include allegations that someone

connected with prosecution of the patent withheld relevant information from the USPTO, or made a misleading

statement, during prosecution. Third parties may also raise similar claims before administrative bodies in the United

States or abroad, even outside the context of litigation. Such mechanisms include re-examination, post grant review

and equivalent proceedings in foreign jurisdictions. Such proceedings could result in revocation or amendment of our

patents in such a way that they no longer cover our product candidates or competitive products. The outcome

following legal assertions of invalidity and unenforceability is unpredictable. With respect to validity, for example, we

cannot be certain that there is no invalidating prior art, of which we and the patent examiner were unaware during

prosecution. If a defendant were to prevail on a legal assertion of invalidity and/or unenforceability, we would lose at

least part, and perhaps all, of the patent protection on our product candidates. Such a loss of patent protection would

have a material adverse impact on our business.

1.5.6.11.We may be unsuccessful in licensing or acquiring third-party intellectual property that

may be required to develop and commercialize our product candidates.

We have rights, through patents that we own, to the intellectual property to develop our product candidates, including

NBTXR3.

Because our programs may involve additional product candidates or improved formulations of existing product

candidates, including NBTXR3, that may require the use of intellectual property or proprietary rights held by third

parties, the growth of our business may depend in part on our ability to acquire, in-license or use such intellectual

property and proprietary rights. We may be unable to acquire or in-license any third-party intellectual property or

proprietary rights or to do so on commercially reasonable terms. For example, we sometimes collaborate with public

or private academic institutions to accelerate our research or development under written agreements with these

institutions. Typically, these institutions provide us with an option to negotiate a license to any of the institution’s

rights in technology resulting from the strategic collaboration. Regardless of such option, we may be unable to

negotiate a license within the specified time frame or under terms that are acceptable to us, and the institution may

license such intellectual property rights to third parties, potentially blocking our ability to pursue our development and

commercialization plans. The same situation may occur with a present or future development partner.

The licensing and acquisition of third-party intellectual property and proprietary rights is a competitive area, and a

number of more established companies are also pursuing strategies to license or acquire third-party intellectual

property and proprietary rights that we may consider attractive or necessary. These established companies may

have a competitive advantage over us due to their size and greater capital resources and development and

commercialization capabilities. In addition, companies that perceive us to be a competitor may be unwilling to assign

or license intellectual property and proprietary rights to us.

If we are unable to successfully acquire or in-license rights to required third-party intellectual property and proprietary

rights or maintain our intellectual property and proprietary rights, we may have to cease development of the relevant

the relevant program, product or product candidate, which could have a material adverse effect on our business.

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1.5.6.12.If we fail to comply with our obligations in any agreements under which we may license

intellectual property rights from third parties or otherwise experience disruptions to our

business relationships with any licensors, we could lose license rights that are important

to our business.

We may, in the future, be a party to intellectual property license agreements that may be important to our business.

Such future license agreements will impose, various diligence, milestone payment, royalty and other obligations on

us. If in the future we were to fail to comply with our obligations under these agreements, or we were subject to a

bankruptcy, our licensors may have the right to terminate the license, in which event we would not be able to market

products or NBTXR3 covered by the license.

In addition, in the case we in-license intellectual property rights, disputes may arise regarding the payment of the

royalties or other consideration due to licensors in connection with our exploitation of the rights we license from

them. Licensors may contest the basis of payments we had retained and claim that we are obligated to make

payments under a broader basis. In addition to the costs of any litigation we may face as a result, any legal action

against us could increase our payment obligations under the respective agreement and require us to pay interest

and potentially damages to such licensors.

In some cases, patent prosecution of an in-licensed technology is controlled solely by the licensor. If such licensor

fails to obtain and maintain patent or other protection for the proprietary intellectual property we in-licensed from

such licensor, we could lose our rights to such intellectual property or the exclusivity of such rights, and our

competitors could market competing products using such intellectual property. In addition, these patents and

applications may not be prosecuted and enforced in a manner consistent with the best interests of our business. In

that event, we may be required to expend significant time and resources to develop or license replacement

technology. If we are unable to do so, we may be unable to develop or commercialize the affected products and

NBTXR3, which could harm our business significantly. In other cases, for example we may control the prosecution of

patents resulting from licensed technology. In the event we were to breach any of our obligations related to such

prosecution, we could incur significant liability to our eventual licensing partners. We may also require the

cooperation of our licensors to enforce any licensed patent rights, and such cooperation may not be provided.

Moreover, we would have obligations under these license agreements, and any failure to satisfy those obligations

could give our licensor the right to terminate the agreement. Termination of a necessary license agreement could

have a material adverse impact on our business.

Disputes may arise regarding intellectual property subject to a licensing agreement, including:

•the scope of rights granted under the license agreement and other interpretation-related issues;

•the basis of royalties and other consideration due to our licensors;

•the extent to which our products, NBTXR3, technology and processes infringe on intellectual property of

the licensor that is not subject to the licensing agreement;

•the sublicensing of patent and other rights under our collaborative development relationships;

•our diligence obligations under the license agreement and what activities satisfy those diligence

obligations;

•the ownership of inventions and know-how resulting from the joint creation or use of intellectual property

by our licensors and us and our partners; and

•the priority of invention of patented technology.

If disputes over intellectual property that we have licensed from third parties prevent or impair our ability to maintain

any future licensing arrangements on acceptable terms, we may be unable to successfully develop and

commercialize the affected NBTXR3.

1.5.7.Risks Related to Human Capital

1.5.7.1.We depend on key management personnel and attracting and retaining other qualified

personnel, and our business could be harmed if we lose key management personnel or

cannot attract and retain other qualified personnel.

Our success depends to a significant degree upon the technical skills and continued service of certain members of

our management team, including Laurent Levy, our co-founder and Chairman of the executive board of the

Company. Although we have taken out and maintain “key person” insurance policies on the lives of Laurent Levy and

the principal executives, and such individuals are also subject to a non-competition clause, the loss of the service of

Laurent Levy or other key executive officers could nevertheless have a material adverse effect on us.

Our success also will depend upon our ability to attract and retain additional qualified management, regulatory,

medical, and development executives and personnel. The failure to attract, integrate, motivate, and retain additional

skilled and qualified personnel or to find suitable replacements upon departure (including due to movements in the

price of the Company’s ordinary shares that are beyond our control and may significantly affect free shares and

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stock options granted to employees that vest over time) could have a material adverse effect on our business. We

compete for such personnel against numerous companies, including companies with significantly greater financial

resources than we possess. In addition, failure to successfully develop our product candidates, including NBTXR3,

development may make it more challenging to recruit and retain qualified personnel.

In addition, the ability of our executive board’s authority to grant equity incentive instruments is subject to an

approval of a two-thirds majority of the votes cast of our shareholders and any failure to reach such prerequisite

would preclude the executive board from granting such equity awards. Further, the volatility in the price of our

ordinary shares and its impact on the value of the free shares and stock options that are granted to employees may

limit our ability to adequately incentivize current or new employees.

1.5.8. Risks Relating to Our Status as a Foreign Private Issuer or a French Company

1.5.8.1.Our By-laws and French corporate law contain provisions that may delay or discourage a

takeover attempt and investments in the Company may be subject to prior governmental

authorization under the French foreign investment control regime.

Over the past few years, the French government has strengthened its foreign investment control regime. Thus, as at

the date of the Universal Registration Document, any investment: by any non-European Union or non-European

Economic Area’s investor that will result in the relevant investor (a) acquiring at least a 10% threshold of voting rights

of the Company or (b) acquiring all or part of a business line of the Company where the Company is developing

research and development activity related to biotechnology listed by the French Ministry of Economy as included in

the critical technologies, is subject to the prior authorization of the French Ministry of Economy, which authorization

may be conditioned on certain undertakings.

In such circumstances, the Company cannot guarantee that such investor will obtain the necessary authorization in

due time. The authorization may also be granted subject to conditions that may deter a potential purchaser. The

existence of such conditions to an investment in the Company could have a negative impact on the ability of the

Company to raise the funds necessary to its development.

Similarly, certain existing investors could be subject to this control regime if regulatory thresholds are crossed due to

the allocation of double voting rights in their favor. Provisions contained in our By-laws and French corporate law

could make it more difficult for a third party to acquire us, even if doing so might be beneficial to our shareholders. In

addition, provisions of French law and our By-laws impose various procedural and other requirements, which could

make it more difficult for shareholders to effect certain corporate actions. These provisions include the following:

•a merger (i.e., in a French law context, a stock-for-stock exchange after which our company would be

dissolved without being liquidated into the acquiring entity and our shareholders would become

shareholders of the acquiring entity) of our company into a company incorporated in the European Union

would require the approval of our board of directors as well as a two-thirds majority of the votes cast of

the shareholders present, represented by proxy or voting by mail at the relevant meeting;

•a merger of our company into a company incorporated outside of the European Union would require the

unanimous approval of our shareholders;

•under French law, a cash merger is treated as a share purchase and would require the consent of each

participating shareholder;

•our shareholders have granted and may in the future grant to our executive board broad authorizations to

increase our share capital or to issue additional ordinary shares or other securities (for example, warrants)

to our shareholders, the public or qualified investors, which could be used as a possible defense following

the launching of a tender offer for our shares;

•our shareholders may have been granted with preferential subscription rights proportional to their

shareholding in our company on the issuance by us of any additional shares or securities giving the right,

immediately or in the future, to new shares for cash or a set-off of cash debts, which rights may only be

waived by the extraordinary general meeting (by a two-thirds majority vote) of our shareholders or on an

individual basis by each shareholder;

•our shares take the form of bearer securities or registered securities, if applicable legislation so permits,

according to the shareholder’s choice. Issued shares are registered in individual accounts opened by us

or any authorized intermediary (depending on the form of such shares), in the name of each shareholder

and kept according to the terms and conditions laid down by the legal and regulatory provisions;

•approval of at least a majority of the votes cast of the shareholders present, represented by a proxy, or

voting by mail at the relevant ordinary shareholders’ general meeting is required to remove supervisory

board member with or without cause;

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•advance notice is required for nominations to the supervisory board or for proposing matters to be acted

upon at a shareholders’ meeting, except that a vote to remove and replace a supervisory board member

can be proposed at any shareholders’ meeting without notice;

•transfers of shares shall comply with applicable insider trading rules; and

•in the event where certain ownership thresholds would be crossed, a number of disclosures should be

made by the relevant shareholder in addition to other certain obligations; more specifically, according to

French legal and regulatory provisions, insofar the Company is a publicly-listed company into a regulated

stock exchange, shareholders must make a declaration to us and to the French financial regulatory AMF

no later than the fourth trading day after such shareholder crosses the following thresholds: 5%, 10%,

15%, 20%, 25%, 30%, 33.33%, 50%, 66.66%, 90% and 95%. The above obligations of declaration apply

when crossing each of the above-mentioned thresholds in an upward or downward direction.

Furthermore, and subject to certain exemptions, any shareholder crossing, alone or acting in concert, the

50% threshold must file a mandatory public tender offer.

1.5.8.2.The rights of shareholders in companies subject to French corporate law differ in material

respects from the rights of shareholders of corporations incorporated in the United

States.

We are a French company with limited liability. Our corporate affairs are governed by our By-laws and by the laws

governing companies incorporated in France. The rights of shareholders and the responsibilities of members of our

board (whether supervisory or executive board members) are in many ways different from the rights and obligations

of shareholders in companies governed by the laws of U.S. jurisdictions. For example, in the performance of its

duties, our board of directors is required by French law to consider the interests of our company, its shareholders, its

employees and other stakeholders, rather than solely our shareholders and/or creditors. It is possible that some of

these parties will have interests that are different from, or in addition to, the interests of our shareholders.

1.5.8.3.French law may limit the amount of dividends we are able to distribute, and we do not

currently intend to pay dividends.

We have never declared or paid any cash dividends on our share capital and do not currently intend to do so for the

foreseeable future. We currently intend to invest our future earnings, if any, to fund our growth. Therefore, holders of

our ordinary shares and ADSs are not likely to receive any dividends for the foreseeable future and any increase in

value will depend solely upon any future appreciation. Consequently, holders of our equity securities may need to

sell all or part of their holdings after price appreciation, which may never occur, as the only way to realize any future

gains.

Further, under French law, the determination of whether we have been sufficiently profitable to pay dividends is

made on the basis of our statutory financial statements prepared and presented in accordance with standard

applicable in France. Therefore, we may be more restricted in our ability to declare dividends than companies not

based in France.

1.5.8.4.Our failure to maintain certain tax benefits applicable to French technology companies

may adversely affect our results of operations.

As a French biotechnology company, we have benefited from certain tax advantages, including the French research

tax credit (Crédit d’Impôt Recherche), or CIR. The CIR is a French tax credit aimed at stimulating research and

development. The CIR can be offset against French corporate income tax due and the portion in excess (if any) may

be refunded at the end of a three fiscal-year period (or, sooner, in certain cases). The CIR is calculated based on our

claimed amount of eligible research and development expenditures in France. The French tax authority with the

assistance of the Research and Technology Ministry may audit each research and development program in respect

of which a CIR benefit has been claimed and assess whether such program qualifies in their view for the CIR benefit,

in accordance with the French tax code (code general des impôts) and the relevant official guidelines.

Furthermore, if the French Parliament decides to eliminate, modify, or reduce the scope of the CIR benefit, which it

could decide to do at any time, our results of operations could be adversely affected.

1.5.8.5.Future use of tax loss carryforwards could be called into question.

Tax losses in France (i) can be carried forward for an unlimited period of time to be computed against any upcoming

benefit-making result, being noted that (ii) such computation is capped annually at €1 million, plus 50% of the portion

of profits in excess of that limit. The unused loss balance can be carried forward to upcoming periods under the

same conditions.

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It is possible that, due to upcoming changes in corporate taxation in France, in the United States, or in any other

relevant country, previous tax loss carryforwards to future revenues are called into question, in part or in whole, or, if

it is not already the case, limited in time. In addition, tax losses would in principle be voided if ever the Company

undertakes a “change of activity” under the meaning of French tax law, defined as any addition, cessation or transfer

of an activity resulting in a variation of (i) the turnover or (ii) the average number of employees and the gross amount

of the Company’s fixed assets, of more than 50% (in the fiscal year of its occurrence or in the following fiscal year,

compared to the fiscal year preceding that of such addition, cessation or transfer).

1.5.8.6.We may be exposed to significant foreign exchange risk, which may adversely affect our

financial condition, results of operations and cash flows.

We incur portions of our expenses and may in the future derive revenues in currencies other than the euro,

including, in particular, the U.S. dollar.

As a result, we are exposed to foreign currency exchange risk as our results of operations and cash flows are

subject to fluctuations in foreign currency exchange rates. We currently do not engage in hedging transactions to

minimize the impact of uncertainty in future exchange rates on cash flows. We cannot predict the impact of foreign

currency fluctuations, and foreign currency fluctuations in the future may adversely affect our financial condition,

results of operations and cash flows.

1.5.8.7.Although not free from doubt, we do not believe we were a “passive foreign investment

company,” or PFIC, for U.S. federal income tax purposes for the taxable year ended

December 31, 2022. However, we cannot assure you that we will not be classified as a

PFIC for the taxable year ending December 31, 2023 or any future taxable year, which may

result in adverse U.S. federal income tax consequences to U.S. holders.

A non-U.S. corporation will be considered a PFIC for any taxable year if either (1) at least 75% of its gross income

for such year is passive income or (2) at least 50% of the value of its assets (based on an average of the quarterly

values of the assets during such year) is attributable to assets that produce or are held for the production of passive

income. Although the matter is not free from doubt, we do not believe that we were a PFIC for U.S. federal income

tax purposes for the taxable year ended December 31, 2022. Because certain aspects of the PFIC rules are not

entirely certain and because this determination is dependent upon a number of factors, there can be no assurance

that we were not a PFIC for such taxable year or that the IRS will agree with any position we take regarding our

PFIC status.

Further, no assurances may be given at this time as to our PFIC status for the current or future taxable years. The

determination of PFIC status is fact-specific, and a separate determination must be made each taxable year as to

whether we are a PFIC (after the close of each such taxable year). It is possible that we could be classified as a

PFIC for the taxable year ending December 31, 2023 or future taxable years due to changes in the composition of

our assets or income, as well as changes to the market value of our assets. If we are a PFIC for any taxable year

during which a U.S. holder holds ADSs, the U.S. holder may be subject to adverse tax consequences, including (1)

the treatment of all or a portion of any gain on disposition of the ADSs as ordinary income, (2) the application of an

interest charge with respect to such gain and certain dividends and (3) compliance with certain reporting

requirements. Each U.S. holder is strongly urged to consult its tax advisor regarding these issues and any available

elections to mitigate such tax consequences.

1.5.8.8.As a foreign private issuer under U.S. Securities law, we are exempt from a number of

rules under the U.S. securities laws and we follow certain home country practices in

relation to corporate governance matters that differ significantly from Nasdaq corporate

governance standards.

We are a “foreign private issuer,” as defined in the SEC’s rules and regulations and, consequently, we are not

subject to all of the disclosure requirements applicable to public companies organized within the United States.

Accordingly, there may be less publicly available information concerning our company than there would be if we

were a U.S. domestic issuer.

Further, as a foreign private issuer that is listed on the Nasdaq Global Market, we are subject to Nasdaq’s corporate

governance standards. However, Nasdaq rules provide that foreign private issuers are permitted to follow home-

country corporate governance practices in lieu of Nasdaq’s corporate governance standards as long as notification is

provided to Nasdaq of the intention to take advantage of such exemptions. As a result, our shareholders may be

afforded less protection than they otherwise would have under Nasdaq’s corporate governance standards applicable

to U.S. domestic issuers.

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1.5.8.9.We may lose our foreign private issuer status in the future, which could result in

significant additional cost and expense.

Based on our determination made on June 30, 2022 (the last business day of our most recently completed

semester), we qualify as a foreign private issuer. The next determination as to foreign private issuer status will be

made on June 30, 2023.

We may lose our foreign private issuer status if, as of the relevant determination date, more than 50% of our

securities are held by U.S. residents and (i) more than 50% of our executive officers or more than 50% of the

members of our board of directors are residents or citizens of the United States, (ii) more than 50% of our assets are

located in the United States, or (iii) our business is principally administered within the United States.

As of June 30, 2022, approximately 87% of our outstanding ordinary shares (including in the form of ADSs) were

held by persons who were not U.S. residents.

The regulatory and compliance costs to us under U.S. securities laws as a U.S. domestic public company would be

significantly more than the costs we currently incur as a foreign private issuer.

1.5.8.10.The Company’s dual listing shares requires the implementation of costly and complex

compliance procedures.

Due to the listing of our shares, in the form of ADSs, in the United States on the NASDAQ Global Select Market, the

Company is subject to a number of additional laws, rules and regulations, including the Securities Exchange Act and

the reporting requirements thereunder, the Sarbanes-Oxley Act, the NASDAQ corporate governance requirements

and other applicable securities laws, rules and regulations.

Compliance with these laws, rules and regulations requires the implementation of costly and complex compliance

procedures that increases our legal and financial compliance costs, make some activities more difficult, time-

consuming, or costly, increase demand on our systems and resources and may divert the management’s attention

from the Group’s other concerns.

In addition, the dual listing of the Company’s shares on the regulated market of Euronext in Paris and on the

NASDAQ Global Select Market in the United States requires compliance with both regulations and thus entails an

increase in the legal requirements applicable to the Group, particularly in terms of disclosures of regulated

information. The Company may not be able to ensure an equivalent level of disclosure in the information disclosed

and published on the two stock exchanges. This may lead to uncertainty as to the determination of the applicable

rules and regulations and increase costs related, in particular, to the implementation of good disclosure and

corporate governance practices.

Legal actions may be initiated by competitors or third parties on the basis of the regulated information. In addition to

the costs and consequences of the Group’s potential loss of the legal actions, the legal proceedings themselves and

the time and resources required to address them may force the Group to divert significant resources that would have

been allocated to its business.

1.5.9. Risks Related to Ownership of Our ADSs

1.5.9.1.Holders of our ADSs do not directly hold our ordinary shares.

Holders of ADSs are not treated as one of our shareholders and do not have ordinary shareholder rights. French law

governs shareholder rights.

The depositary, through the custodian or the custodian’s nominee, is the holder of the ordinary shares underlying all

ADSs. Holders of ADSs have only ADS holder rights. Among other things, ADS holder rights do not provide for

double voting rights, which otherwise would be available to holders of ordinary shares held in a shareholders’ name

for a period of at least two years. The deposit agreement among us, the depositary and purchasers of ADSs in the

U.S. offering, as an ADS holder, and all other persons directly and indirectly holding ADSs, sets out ADS holder

rights, as well as the rights and obligations of us and the depositary.

1.5.9.2.Holders of our ADSs may not be able to exercise their right to vote the ordinary shares

underlying such ADSs.

Holders of ADSs may exercise voting rights with respect to the ordinary shares represented by the ADSs only in

accordance with the provisions of the deposit agreement and not as a direct shareholder. The deposit agreement

provides that, upon receipt of notice of any meeting of holders of our ordinary shares, the depositary will fix a record

date for the determination of ADS holders who shall be entitled to give instructions for the exercise of voting rights.

Upon timely receipt of notice from us, if we so request, the depositary shall distribute to the holders as of the record

date (i) the notice of the meeting or solicitation of consent or proxy sent by us and (ii) a statement as to the manner

in which instructions may be given by the holders.

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Holders of ADSs may instruct the depositary of the ADSs to vote the ordinary shares underlying such ADSs.

Otherwise, holders of our ADSs will not be able to exercise their right to vote, unless they withdraw the ordinary

shares underlying such ADSs. However, holders of our ADSs may not know about the meeting far enough in

advance to withdraw those ordinary shares. If we ask for instructions, the depositary, upon timely notice from us, will

notify holders of our ADSs of the upcoming vote and arrange to deliver our voting materials to such holders. We

cannot guarantee that holders of our ADSs will receive the voting materials in time to ensure that they can instruct

the depositary to vote such ordinary shares or to withdraw such ordinary shares so as to vote them directly. If the

depositary does not receive timely voting instructions from holders of our ADSs, it may give a proxy to a person

designated by us to vote the ordinary shares underlying such ADSs in accordance with the recommendation of our

board of directors. In addition, the depositary and its agents are not responsible for failing to carry out voting

instructions or for the manner of carrying out voting instructions. This means that holders of our ADSs may not be

able to exercise their right to vote, and there may be nothing such holders can do if the ordinary shares underlying

such ADSs are not voted as requested.

1.5.9.3.The right of holders of our ADSs to participate in any future preferential subscription

rights or to elect to receive dividends in shares may be limited, which may cause dilution

to holders of ADSs.

According to French law, if we issue additional shares or securities for cash, current shareholders will have

preferential subscription rights for these securities proportionally to their shareholding unless they waive those rights

at an extraordinary meeting of our shareholders (by a two-thirds majority vote) or individually by each shareholder.

However, our ADS holders in the United States will not be entitled to exercise or sell such rights unless we register

the rights and the securities to which the rights relate under the Securities Act or an exemption from the registration

requirements is available. In addition, the deposit agreement for our ADSs provides that the depositary will not make

rights available to holders of our ADSs unless the distribution to ADS holders of both the rights and any related

securities are either registered under the Securities Act or exempted from registration under the Securities Act.

Further, if we offer holders of our ordinary shares the option to receive dividends in either cash or shares, the

depositary may require satisfactory assurances from us that extending the offer to holders of ADSs does not require

registration of any securities under the Securities Act before making the option available to holders of ADSs. We are

under no obligation to file a registration statement with respect to any such rights or securities or to endeavor to

cause such a registration statement to be declared effective. Moreover, we may not be able to establish an

exemption from registration under the Securities Act. Accordingly, ADS holders may be unable to participate in our

rights offerings or to elect to receive dividends in shares and may experience dilution in their holdings and may

receive no value for these rights.

1.5.9.4.Holders of our ADSs may be subject to limitations on the transfer of such ADSs and the

withdrawal of the underlying ordinary shares.

ADSs, which may be evidenced by American Depositary Receipts, or ADRs, are transferable on the books of the

depositary. However, the depositary may close its books at any time or from time to time when it deems expedient in

connection with the performance of its duties. The depositary may refuse to deliver, transfer or register transfers of

ADSs generally when our books or the books of the depositary are closed, or at any time if we or the depositary think

it is advisable to do so because of any requirement of law, government or governmental body, or under any provision

of the deposit agreement, or for any other reason subject to an ADS holders’ right to cancel such ADSs and withdraw

the underlying ordinary shares.

Temporary delays in the cancellation of such ADSs and withdrawal of the underlying ordinary shares may arise

because the depositary has closed its transfer books or we have closed our transfer books, the transfer of ordinary

shares is blocked to permit voting at a shareholders’ meeting or we are paying a dividend on our ordinary shares. In

addition, holders of our ADSs may not be able to cancel such ADSs and withdraw the underlying ordinary shares

when such holders owe money for fees, taxes and similar charges and when it is necessary to prohibit withdrawals

in order to comply with any laws or governmental regulations that apply to ADSs or to the withdrawal of ordinary

shares or other deposited securities.

1.5.9.5.The market price for our ADSs may be volatile or may decline regardless of our operating

performance.

The trading price of the ADSs has fluctuated, and is likely to continue to fluctuate, substantially. Since the ADSs were

sold in our initial public offering in December 2020 at a price of $13.50 per share, the price per ADS has ranged as

low as $2.32 and as high as $19.68 through April 24, 2023. The market price of the ADSs may fluctuate significantly

in response to numerous factors, including those described in this “Risk Factors” section, many of which are beyond

our control. The market price and demand for our ADSs may also fluctuate substantially, regardless of our actual

operating performance, which may limit or prevent holders from readily selling their ADSs and may otherwise

negatively affect the liquidity of our capital shares. Pharmaceutical, biotechnology and nanomedicine companies, in

particular, have experienced extreme price and volume fluctuations that have often been unrelated or

disproportionate to the operating performance of these companies.

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1.5.9.6.Share ownership is concentrated in the hands of our principal shareholders and

management, who will continue to be able to exercise substantial influence on us.

Our executive officers, directors and current 5% or greater shareholders beneficially own approximately 22.0% of our

ordinary shares outstanding (including those underlying our ADSs, but excluding shares that may be acquired upon

exercise of stock options or warrants) as of December 31, 2022. As a result, these shareholders have significant

influence over all matters that require approval by our shareholders, including the election of directors and approval

of significant corporate transactions. These shareholders may be able to take corporate action even if other

shareholders oppose them. This concentration of ownership might also have the effect of delaying or preventing a

change of control of our company that other shareholders may view as beneficial.

Lastly, If our existing shareholders sell, or indicate an intent to sell, substantial amounts of their ordinary shares or

ADSs, the trading price of our ADSs and ordinary shares could decline significantly. Such secondary sales may also

impair our ability to raise capital through the sale of additional equity securities.

1.5.9.7. We are an emerging growth company and we cannot be certain if the reduced disclosure

requirements applicable to us will make our ADSs less attractive to investors.

We are an “emerging growth company,” as defined in the JOBS Act. As an emerging growth company, we intend to

take advantage of certain exemptions from various reporting requirements that are applicable to other public

companies that are not “emerging growth companies,” including, but not limited to, not being required to comply with

the auditor attestation requirements of Section 404(b) of the Sarbanes-Oxley Act, and exemptions from the

requirements of holding a non-binding advisory vote on executive compensation and shareholder approval of any

golden parachute payments not previously approved.

We cannot predict if investors will find our ADSs less attractive because we rely on these exemptions. If some

investors find our ADSs less attractive as a result, there may be a less active trading market for our ADSs and the

price of our ADSs may be more volatile. We intend to take advantage of these reporting exemptions until we are no

longer an emerging growth company. We will remain an emerging growth company until the earliest of (i) the last day

of the fiscal year in which we have total annual gross revenue of $1.07 billion or more; (ii) December 31, 2025; (iii)

the date on which we have issued more than $1.0 billion in non-convertible debt during the previous three years; and

(iv) the date on which we are deemed to be a large accelerated filer under the rules of the SEC. Once we cease to

be an emerging growth company, we may continue to avail ourselves of the accommodations available to us as a

foreign private issuer for as long as we qualify.

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2.CORPORATE GOVERNANCE

2.1.ADMINISTRATIVE AND MANAGEMENT BODIES

2.1.1.Composition of the Company’s Executive and Supervisory Boards

As of the date of the Universal Registration Document, the Executive Board and supervisory board of the company

(the “Supervisory Board”) consist of:

2.1.1.1.Executive Board composition

As of the date of the Universal Registration Document, the Executive Board’s composition is as follows:


Name	Corporat e office	Main role in the Company	Main role outside the Company	Date of first appointme nt	End date of corporate office
Laurent LEVY	Chairman, Executive Board	Company Officer	None	05/27/04	Reappointed by the Supervisory Board on March 13, 2020, for a four-year term starting on April 28, 2020 and expiring at the end of the shareholders’ meeting called to approve the financial statements for the financial year ending December 31, 2023.
Bart VAN RHIJN	Member of Executive Board	Financial & Administrative Officer	None	05/31/21	Appointed by the Supervisory Board on May 31, 2021, for the duration of the Executive Board’s term of office, i.e. until the end of the shareholders’ meeting called to approve the financial statements for the financial year ending December 31, 2023.
Anne- Juliette HERMANT	Member of Executive Board	Human Resources Officer	None	07/01/19	Reappointed by the Supervisory Board on March 13, 2020, for a four-year term starting on April 28, 2020 and expiring at the end of the shareholders’ meeting called to approve the financial statements for the financial year ending December 31, 2023.

The professional address of Laurent Levy and Anne-Juliette Hermant is the registered office of the Company and

Bart Van Rhijn’s is the registered office of Nanobiotix Corp.

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2.1.1.2.Supervisory Board composition

As of the date of the Universal Registration Document, the Supervisory Board comprises four members and one

observer (censeur).


Name	Corporate office	Main role in the Company	Main role outside the Company	Date of first appointment	End date of corporate office
Gary PHILLIPS	Chairman (Independent Member*)	None	Chief Business Officer of Anaveon AG	Nominated by the Supervisory Board held 05/25/2021, ratified by the ordinary shareholders’ meeting held 06/23/2022	At the end of the shareholders’ meeting held to approve the financial statements of the financial year ended on December 31, 2022
Anne-Marie GRAFFIN	Vice- Chairwoman (Independent Member*)	None	Expert consultant for the pharmaceutical industry	Nominated by the Supervisory Board held 12/18/2013, ratified by the shareholders’ meeting held 06/18/2014	At the end of the shareholders’ meeting held to approve the financial statements of the financial year ended on December 31, 2023
Alain HERRERA	Independent Member	None	Managing Director of AOC	Nominated by the Supervisory Board held 12/18/2013, ratified by the shareholders’ meeting held 06/23/2013	At the end of the shareholders’ meeting held to approve the financial statements of the financial year ended on December 31, 2023
Enno SPILLNER	Independent Member*	None	Chief Financial Officer at Formycon AG	06/18/2014	At the end of the shareholders’ meeting held to approve the financial statements of the financial year ended on December 31, 2025
Christophe DOUAT	Observer	None	Chief Executive Officer at Medincell	06/14/2017	At the end of the shareholders’ meeting held to approve the financial statements of the financial year ended on December 31, 2022

* Within the meaning of the Middlenext Code of corporate governance as amended in September 2021.

The addresses of Supervisory Board members and of the observer are as follows:

▪Gary PHILLIPS, OrphoMed Inc., 50 Francisco Street, Suite 245, San Francisco, CA 94133, USA;

▪Anne-Marie GRAFFIN: registered office of the Company;

▪Alain HERRERA, Alain Oncology Consulting (AOC), 77 rue de Vaugirard 75006 Paris, France;

▪Enno SPILLNER, registered office of the Company; and

▪Christophe DOUAT, Medincell SA, 1 rue Charles Cros, 34830 Jacou, France.

The expertise and management experience of the members of the Executive and Supervisory Boards stems from

the various salaried and management positions they previously held.

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Observers to the Supervisory Board

The shareholders’ meeting may appoint observers or censors (“Observers”) to the Supervisory Board. The

Supervisory Board may also appoint observers directly, subject to the ratification of the appointment by the next

shareholders’ meeting.

Observers are appointed for a term of 6 years, ending at the end of the shareholders’ meeting called to approve the

financial statements for the past financial year and held in the year during which the appointment expires. Observers

may be reelected.

The Observers review any questions the Supervisory Board, its Chairman, or the Executive Board may submit to

them. They attend the Supervisory Board meetings and take part in the deliberations in a strictly advisory capacity.

Their absence does not impact the validity of the Supervisory Board’s decisions.

The Observers are convened to Supervisory Board meetings under the same conditions as the Supervisory Board

members.

Observers are bound by the same duties and obligations as the members of the Supervisory Board, including a duty

of loyalty.

The Supervisory Board may compensate the Observers by deducting their compensation from the global amount of

compensation allocated to the Supervisory Board members by the shareholders’ meeting.

2.1.2.Other corporate offices

2.1.2.1.Other current corporate offices outside the Group

As of the date of the Universal Registration Document, the members of the Executive Board exercise the following

corporate offices outside the Group:


	Other existing corporate offices
	Nature of corporate office	Company or Public Institution
Laurent LEVY	Chairman of the Supervisory Board	VALBIOTIS*
Bart VAN RHIJN	Treasurer and Secretary	Slice of Media, Inc.
Bart VAN RHIJN	Venture Partner	1414 Ventures
Anne-Juliette HERMANT	Member of the Board of Directors Member of the Scientific Council Member of the Board of Directors	Mines-Telecom Institute Ecole des Ponts Paris Tech ISEP - Ecole d’ingénieurs du numérique

*Listed Company

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Members of the Supervisory Board

As of the date of the Universal Registration Document, the Supervisory Board members exercise the following

corporate offices outside the Group:


	Other existing corporate offices
	Nature of corporate office	Company
Gary PHILLIPS (Independent member)*	Chief Business Officer and member of the Execuive Committee	Anaveon AG
	Member of the Board of Directors	Aldeyra Therapeutics
	Member of the Board of Directors	Rheon Medical SA
	Member of the Board of Directors	Zyla Life Sciences
Anne-Marie GRAFFIN (Independent Member)*	Member of the Supervisory Board	VALNEVA SE**
	Member of the Board of Directors	SARTORIUS STEDIM BIOTECH SA**
	Managing Director	SMAG CONSULTING
	Member of the Board of Directors	VETOQUINOL SA**
Alain HERRERA (Independent Member)*	Member of the Board of Directors	IDDI (Belgium)
	Member of the Board of Directors	FONDATION ARCAD
	Member of the Board of Directors	ISOFOL**
	Member of the Board of Directors	PDC' LINE PHARMA
	Managing Director	AB BIO CONSULTING
	Chief Medical Officer & Member of the Board of Directors	ONWARD Therapeutics SA
	President	Onward Therapeutics France SAS
	Member of the Board of Directors	EMERCell
	Independent Member of the Board of Directors	ERVACCINE Technologies
	Managing Director	ALAIN ONCOLOGIE CONSULTING
	Member of the Board of Directors	Gustave Roussy Transfert
Enno SPILLNER (Independent Member)**	Chief Financial Officer and member of the Executive Board	Formycon AG **
Enno SPILLNER (Independent Member)**	Member of the Supervisory Board	Leon Nanodrugs
Christophe DOUAT (Observer)	Chairman of the Executive Board	Medincell SA **
Christophe DOUAT (Observer)	Member of the Board of Directors	CM Biomaterials BV

*Within the meaning of the Middlenext Code of corporate governance as amended in September 2021 (see Section 2.1.6.1 of the Universal Registration Document).

**Listed Company.

2.1.2.2.Corporate offices exercised in the past five years, but which have ceased to date

Members of the Executive Board


Name	Nature of corporate office	Company
Laurent LEVY	None
Bart VAN RHIJN	Member of Board of Directors	Stynt, Inc.
Bart VAN RHIJN	Member of Board of Advisors	BlocHealth, Inc.
Anne-Juliette HERMANT	None

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Members of the Supervisory Board


Name	Nature of corporate office	Company
Gary PHILLIPS (Independent Member*)	President, CEO & Member of the Board of Directors	OrphoMed, Inc.
	Executive Vice President & Chief Strategy Officer	Mallinckrodt Pharmaceuticals
	Member of the Board of Directors	Inotek Pharmaceuticals
	Member of the Board of Directors	Envisia Therapeutics
Anne-Marie GRAFFIN (Independent Member*)	Member of the Board of Directors	M2 Care
Alain HERRERA (Independent Member*)	Managing Director	PharmaEngine Europe SARL (in liquidation proceedings)
Enno SPILLNER (Independent Member*)	Financial Officer Member of the Management Board	EVOTEC**
Christophe DOUAT (Observer)	None

* Within the meaning of the Code of corporate governance as amended by MiddleNext in September 2017 (see section 2.1.6.1 of the Universal Registration Document).

**Listed Company.

2.1.3.Biographies of members of the Company’s corporate bodies

2.1.3.1.Biographies of Members of the Executive Board

The biographies of the members of the Executive Board can be found in Section 1.2.2. of the Universal Registration

Document.

2.1.3.2.Biographies of Members of the Supervisory Board

The biographies of the members of the Supervisory Board are as follows:


	GARY PHILLIPS – Chairman of the Supervisory Board (independent member) Nationality: American Age: 57 Corporate office term: At the end of the general meeting held to approve the financial statements for the financial year ended on December 31, 2022 Committee Member: Member of the audit committee and the appointments and compensation committee

BIOGRAPHY

Dr. Gary Phillips has served as Chairman of our supervisory board since May 2021. Dr. Phillips has over 30 years of

experience in the pharmaceutical and healthcare industries, leading commercial operations, clinical medicine,

business strategy and development functions. Dr. Phillips serves as the Chief Business Officer of the Swiss oncology

biotech company Anaveon AG. Before joining Anaveon in 2022, he was president and chief executive officer of

OrphoMed, Inc. in the United States. Dr. Phillips previously worked with Mallinckrodt Pharmaceuticals, where he had

served as Executive Vice President and Chief Strategy Officer and President of their Autoimmune and Rare

Diseases business. Prior to that role, he was Head of Global Health & Healthcare Industries at the World Economic

Forum, served as President of Reckitt Benckiser Pharmaceuticals North America (now Indivior), and held dual roles

as President, U.S. Surgical and Pharmaceuticals and Global Head of Pharmaceuticals at Bausch & Lomb. In

addition, Dr. Phillips has served in executive roles at Merck Serono, Novartis, and Wyeth. Dr. Phillips earned a B.A.

in Biochemistry summa cum laude from the College of Arts and Sciences at the University of Pennsylvania, an MBA

from the Wharton School at the University of Pennsylvania, and an M.D. with Alpha Omega Alpha distinction from

the School of Medicine at the University of Pennsylvania. Dr. Phillips maintains an active medical license and

practiced as a general medicine clinician/officer in the U.S. Navy, from which he was honorably discharged as a

lieutenant commander.

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	ANNE-MARIE GRAFFIN – Vice President of the Supervisory Board (independent member) Nationality: French Age: 61 Corporate office term: At the end of the general meeting held to approve the financial statements for the financial year ended on December 31, 2023 Committee Member: Chairwoman of the appointments and compensation committee

BIOGRAPHY

Ms. Anne-Marie Graffin has served as a supervisory board member since 2013, as chairwoman of the appointments

and compensation committee since 2017 and as Vice Chairwoman of the supervisory board since July 2017. She

has over 20 years of experience in life sciences and pharmaceutical companies. She has served as a non-executive

board member of Valneva SE (Nantes, FR – Vienna, AT) since 2013 of Sartorius Stedim Biotech SA (Aubagne, FR –

Goëttingen, Ger) since 2015 and of Vetoquinol SA since September 2022. Ms. Graffin has expertise in both

developing market access strategies and driving biotechnology companies’ growth. She has been a consultant to the

pharmaceutical industry since 2011, developing many initiatives within the innovation and startups fields, connecting

biotech and medtech startups with major EU venture capital firms and investors. Previously, she was an executive

vice president at Sanofi Pasteur MSD, a European leader in the vaccine field, and acted as a member of the

Executive Committee. Prior to working at Sanofi Pasteur MSD, she worked for five years at ROC as international

group manager and at URGO Laboratories as brand manager for 3 years. Ms. Graffin graduated from ESSEC

Business School Paris.


	ALAIN HERRERA – Supervisory Board Member Nationality: French Age: 72 Corporate office term: At the end of the general meeting held to approve the financial statements for the financial year ended on December 31, 2023 Committee Member: Member of the appointments and compensation committee

BIOGRAPHY

Dr. Alain Herrera, M.D. has served as a supervisory board member since 2013. Dr. Herrera has more than 25 years

of experience in the pharmaceutical industry with a strong focus in oncology drug development and marketing. Dr.

Herrera currently works at Alain Oncologie Consulting, an oncology consultancy company he started and at Onward

Therapeutics SA as co-founder and CMO. Previously, Dr. Herrera has served as Head of Corporate Development

PharmaEngine and Managing Director of PharmaEngine Europe Sarl, as well as the head of the Oncology business

at Sanofi-Aventis for 10 years. He also served as Vice President for the Global Oncology Business Strategy and

Development from 2007-2008 and Head of the Global Oncology Franchise from 1998-2007. While at Sanofi-Aventis,

he contributed to the worldwide registration of Oxaliplatin (Eloxatin®) and Rasburicase (Fasturtec®/Elitek®), as well

as the Gastric and Head & Neck indications for Docetaxel (Taxotere®). Prior to Sanofi-Aventis, he served as

Chairman of Chiron Therapeutics Europe, Managing Director at Pierre Fabre Oncology Laboratories and Head of the

Oncology Platform at Roger Bellon (Rhône Poulenc). He serves as a non-executive board member of Emercell SAS

(Montpellier, Fr), ErVaccine SA (Lyon, Fr), Onward Therapeutics SA (Lausanne, Sw), IDDI (Ottignies, Belg),

PDC’Line (Liège, Belg). Dr. Herrera has also served as a Hematologist Consultant at Antoine Beclere Hospital until

2019.

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	ENNO SPILLNER – Member of the Supervisory Board (independent member) Nationality: German Age: 53 Corporate office term: At the end of the general meeting held to approve the financial statements for the financial year ended on December 31, 2025 Committee Member: Chairman of the audit committee

BIOGRAPHY

Enno Spillner has served as a Supervisory Board member and chairman of the audit committee since 2014. He has

24 years of experience in the life science industry and currently serves as Chief Financial Officer and Member of the

Executive Board at Formycon AG. From July 2016 to March 2023, he served as Chief Financial Officer and Member

of the Management Board at German biotech company Evotec SE. From March 2013 until June 2016, he served as

Chairman of the Management Board, Chief Executive Officer and Chief Financial Officer of 4SC AG. From

September 2005 to March 2013 he acted as Chief Financial Officer of 4SC AG. Enno Spillner started his life science

industry career as Head of Finance and Managing Partner of the Munich-based biotech venture fund, BioM AG. He

was also Managing Director of two portfolio companies, ACTIPAC Biosystems GmbH and Munich innovative

Biomaterials GmbH. Currently he also serves as Member of the Supervisory Board of Leon Nanodrugs GmbH and

supports Fox Corporate Finance in his role as Member of the Life Science Advisory Board. Prior to moving into the

life science field, he was engaged in the media and marketing industry. Enno Spillner earned his Dipl.-Kaufmann

degree (Masters in Business) at the University of Bamberg, Germany.


	CHRISTOPHE DOUAT - Observer Nationality: French Age: 60 Corporate office term: At the end of the general meeting held to approve the financial statements for the financial year ended on December 31, 2022 Committee Member: Member of the audit committee (as an observer)

BIOGRAPHY

Mr. Christophe Douat serves as a supervisory board observer and is entitled, in this capacity, to attend all meetings

of the supervisory board in a non-voting capacity. Mr. Douat previously served as member of the supervisory board

from 2011 until 2017 and from 2006 to 2009 when he was the lead investor. He is currently CEO of Medincell

(MEDCL, Euronext), a pharmaceutical company that specializes in drug delivery technologies. Mr. Douat worked at

the venture capital company Matignon Investissement & Gestion from 2001 to 2009. Mr. Douat is also an alumnus of

the Boston Consulting Group. He graduated from École des Mines de Paris, an engineering French “Grande Ecole”,

and holds a master’s of science in engineering (U.S.A.) and an MBA (Canada).

2.1.4.Statements relating to members of the Executive Board and the Supervisory Board

There are no family connections between the persons listed above.

In the past five years, none of these persons:

▪Have been convicted of fraud;

▪Have been involved as an officer or director in any bankruptcy, sequestration or liquidation;

▪Have been barred by a court from acting as a member of an administrative, management or

supervisory body of an issuer or from participating in the management or conduct of the affairs of an

issuer;

▪Have been the subject of official public incrimination or sanctions by statutory or regulatory

authorities (including designated professional bodies).

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2.1.5.Operation of the Executive and the Supervisory Boards

Nanobiotix is a public limited Company (société anonyme) with an Executive Board and Supervisory Board whose

memberships are listed in Section 2.1.1. above.

2.1.5.1.Executive Board

During the financial year ended on December 31, 2022, the Executive Board met fourteen (14) times, it being

specified that the Executive Board members meet informally on a weekly basis.

2.1.5.2.Supervisory Board

During the past financial year, the Supervisory Board of the Company met height (8) times with a members’

attendance rate of 100%.

2.1.5.2.1.Tasks of the Supervisory Board

The Supervisory Board is subject to the provisions of the French Commercial Code, Articles 15 to 17 of the Bylaws

of the Company and the internal rules that it has adopted. In particular, the Supervisory Board:

▪Continuously oversees the Executive Board’s management of the Company

▪Verifies and monitors the corporate and consolidated financial statements prepared by the Executive

Board

▪Appoints and dismisses members of the Executive Board, who are in charge of managing the Company

and defining its strategy, and sets their compensation

▪Authorizes the agreements and undertakings referred to in Articles L. 225-86 and L. 225-90-1 of the

French Commercial Code

▪Recommends the appointment of the statutory auditors to the shareholders’ meeting

▪Prepares the Corporate Governance Report referred to in Article L. 225-68 of the French Commercial

Code

▪Prepares the draft resolutions referred to in Article L. 22-10-8 of the French Commercial Code, and the

associated report

The Supervisory Board ensures the quality of information provided to the shareholders and the market.

In addition and based on recommendation n°14 of the MiddleNext code, the Supervisory Board intends to conduct a

yearly review of the voting results of each of the shareholders’ meetings of the Company on any decision submitted

to its shareholders. The Supervisory Board will pay particular attention to how the majority of the Company’s minority

shareholders express themselves especially as regards negative votes, if any, and discuss whether any measures

should be taken as a result.

2.1.5.2.2.Conditions for preparing and organizing the work of the Supervisory Board

The Executive Board regularly informs the Supervisory Board of the financial position, cash flow, financial

commitments and significant events of the Company. Any new member of the Supervisory Board may ask for

training on the speciﬁc characteristics of the Company and its Group, their business lines and sector activities. The

Supervisory Board meets at least once per quarter.

Every year, a provisional calendar of annual meetings is set. Members of the Supervisory Board are convened by

letter, fax or email at least five (5) business days before each meeting. The board may also be convened by any

other means, even verbally, if all the board members are present or represented at the meeting. All documents or

draft documents are sent, submitted or made available to members of the Supervisory Board a reasonable amount

of time before the meeting, so as to inform them of the agenda and of any matters that are submitted to the board for

review. To participate effectively in the work and deliberations of the Supervisory Board, each member of the

Supervisory Board is sent the documents that he or she considers to be useful. Requests to this end are made to the

Executive Board or any other officer, as the case may be.

Furthermore, the Supervisory Board is informed during its meetings of the Company’s ﬁnancial position, cash flow

situation and commitments. Each member of the Supervisory Board has the right to meet with the Company’s main

officers, provided that he/she notifies the Executive Board beforehand. Members of the Executive Board can attend

these meetings, unless the relevant member of the Supervisory Board objects to their presence. Members of the

Executive Board may be heard at any meeting of the Supervisory Board.

Members of the Supervisory Board may participate in the board meeting through videoconferencing or

telecommunication technology. However, this method of participation is not valid when adopting decisions in relation

with the verification and monitoring of the financial year’s financial statements, including the consolidated accounts

prepared in accordance with the IFRS norms, and the review of the management report and the Group’s

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management report7. Moreover, the members of the Supervisory Board are allowed to take certain specific decisions

by written consultation, such as convening a shareholders’ meeting or making provisional appointments to the

Supervisory Board in accordance with Article L. 225-78 of the French Commercial Code.

The technology used must allow for the identification of the participants and ensure their effective participation.

The minutes of the meeting must mention the participation of Supervisory Board members by means of

videoconferencing or telecommunications technology, if any.

In accordance with the recommendations of the Code of corporate governance as amended in September 2021 by

MiddleNext (the “MiddleNext Code”), the Supervisory Board shall conduct a yearly assessment of the operating

methods of the board and committees, as well as on the preparation of its work. The assessment of the year 2022

was conducted and the Supervisory Board took note of it during its discussions on April 24, 2023.

2.1.5.2.3.Balanced gender representation

The principle of balanced gender representation on the Supervisory Board (Law No. 2011–103 of January 27, 2011 –

loi du 27 janvier 2011 relative à la représentation équilibrée des femmes et des hommes au sein des conseils

d’administration et de surveillance et à l’égalité professionnelle) is also respected by the Company, as the

Supervisory Board is composed of one woman and three men.

The Company continues to pursue a diversity and equity policy at all hierarchical levels. As of the date of the

Universal Registration Document, women are represented at all levels of the Company. In particular, in addition to

the Supervisory Board being composed of one woman and three men, the Executive Board is composed of two men

and one woman. Overall, women represent 59% of the Company’s employees.

2.1.5.3.Specialized Committees

At the date of the Universal Registration Document, the Company has two specialized committees set up by the

Supervisory Board: an audit committee and an appointments and compensation committee.

2.1.5.3.1.Audit Committee

2.1.5.3.1.1.Composition

The Supervisory Board dated September 9, 2010 set up an audit committee, whose members adopted new internal

rules of procedure, detailed below, on April 11, 2012, which were approved by the Supervisory Board on the same

day. In the context of the Company’s initial public offering on the Nasdaq Global Select Market, the Supervisory

Board voted to amend the audit committee’s internal rules of procedure (règlement intérieur) on November 20, 2020

in order to ensure compliance with all applicable requirements of the French Commercial Code, the United States

Securities Exchange Act and the Nasdaq Global Market, as well as the rules and regulations of the United States

Securities Exchange Commission.

The audit committee monitors the questions relating to the processing and control of accounting and financial

information. To this end, it ensures the quality of the Company’s internal controls and the reliability of information

provided to shareholders and financial markets.

The duties specifically assigned to the audit committee by the Supervisory Board include, but are not limited to:

▪monitoring the financial reporting process;

▪monitoring the effectiveness of internal control and risk management systems;

▪monitoring the legal audit of the annual and consolidated accounts of the statutory auditors;

▪making recommendations regarding the selection of the Company’s statutory auditors to be appointed by

its shareholders, determining their compensation and ensuring their independence;

▪making recommendations regarding the selection of any accounting firm, other than the Company’s

statutory auditors, to be appointed for non-audit services;

▪examining the Company’s procedures for the receipt, retention and treatment of complaints received by

the Company regarding accounting, internal accounting controls or auditing matters, as well as for the

confidential, anonymous submissions by its employees of concerns regarding questionable accounting or

auditing matters; and

▪generally advising the Supervisory Board and making recommendations with respect to all of the areas

above.

The audit committee may meet or consult with any member of the Executive Board and may conduct internal or

external due diligence reviews with respect to any matter that may be relevant to the performance of its duties, so

long as the Supervisory Board and the chairman of the Executive Board are informed in advance. In particular, the

audit committee has the right to interview the persons involved in the preparation or control of the Company’s

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7 It being specified that such restriction has been temporally lifted in the context of the COVID-19 pandemic until July 31, 2022.

financial statements, including the Chief Financial Officer and those persons responsible for significant areas within

the Company’s financial department.

The audit committee shall be comprised of at least two members from, and appointed by, the supervisory board,

after consultation with the appointments and compensation committee. Members shall be independent in

accordance with Nasdaq’s listing rules and Rule 10A-3 of the United States Securities Exchange Act as well as the

criteria established by the MiddleNext Code. At least one member shall have specific financial and accounting skills.

No member of the audit committee may be a person exercising any management function within the Company and

its subsidiaries.

Further, under French law an audit committee may only have two members, whereas Nasdaq requires a three-

member audit committee. We currently have two members on our audit committee in accordance with French law.

We also have one non-voting observer to the audit committee.

Currently, the audit committee is comprised of two members: Enno Spillner (chairman and independent member)

and Gary Phillips (independent member), and one observer, Christophe Douat, who attends in a non-voting capacity.

The Supervisory Board has determined that Enno Spillner is an “audit committee financial expert,” as defined by

SEC rules and regulations, and that each member qualifies as financially sophisticated under the Nasdaq listing

rules.

The audit committee met five (5) times during the 2022 financial year.

2.1.5.3.2.Appointments and Compensation Committee

On February 28, 2019, to replace the former compensation committee, the Supervisory Board set up an

appointments and compensation committee, whose members adopted internal rules of procedure, detailed below, on

the same day, which were approved by the Supervisory Board. In the context of the Company’s initial public offering

on the Nasdaq Global Select Market, the Supervisory Board voted to amend the appointments and compensation

committee’s internal rules of procedure (règlement intérieur) on November 20, 2020 in order to ensure compliance

with all applicable requirements of the French Commercial Code, the United States Securities Exchange Act and the

Nasdaq Global Market, as well as the rules and regulations of the United States Securities Exchange Commission.

The appointments and compensation committee provides recommendations and proposals to the Executive and

Supervisory Board members on the composition and compensation policies of the Executive and Supervisory

Boards, and also prepares any related reports to be provided by the Company.

The principal duties and responsibilities of the appointments and compensation committee include, but are not

limited to:

▪making recommendations on the composition of the Executive and Supervisory Boards and the

Supervisory Board’s committees;

▪annually evaluating independence and submitting to the Supervisory Board a list of its members who may

qualify as independent members based on Nasdaq's listing rules and Rule 10A-3 of the United States

Securities Exchange Act as well as the criteria set forth in the MiddleNext Code;

▪establishing a succession plan for the Company’s executive officers and assisting the Supervisory Board in

the selection and evaluation of Executive and Supervisory Board members;

▪reviewing the main objectives recommended by management regarding the compensation granted to the

non-executive officers of the Company, including under free share and stock option plans;

▪reviewing equity incentive plans, including free share plans and stock options or stock purchase options,

pension and contingency schemes and benefits in kind for non-executive officers;

▪making recommendations to the Supervisory Board regarding:

◦the compensation, pension and contingency schemes, benefits in kind and other various

pecuniary rights, including termination, of the members of the Executive Board. The committee

makes recommendations on the amount and structure of Executive Board member compensation,

taking into account strategy, objectives, outcomes, and general market practice, and

◦the free share and stock option plans, as well as any similar equity incentive instrument and in

particular, the allocation to members of the Executive Board,

▪making recommendations to the Supervisory Board regarding compensation, including equity-based

compensation and expense reimbursement, for the members of the Supervisory Board, taking into account

corporate goals and objectives and performance of Supervisory Board members in light of such goals and

objectives;

▪preparing and presenting the reports provided for in the Supervisory Board internal rules of procedure

(règlement intérieur);

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▪making any other recommendation that might be requested by the Supervisory Board regarding

compensation; and

▪generally advising the Supervisory Board and making recommendations with respect to all of the areas

above.

The appointments and compensation committee shall be comprised of at least two members from and appointed by

the Supervisory Board. No member of the appointments and compensation committee may be a person exercising

any management function within the Company and its subsidiaries. Currently, the appointments and compensation

committee is comprised of three members: Anne-Marie Graffin (chairman and independent member), Dr. Alain

Herrera and Gary Phillips (independent members).

The Appointments and Compensation Committee met seven (7) times during the 2022 financial year.

2.1.6.Conflict of interests

2.1.6.1.Review of the members’ independence and potential conflicts of interest

The MiddleNext Code sets out the following five criteria to be used to evaluate the independence of supervisory

board members, which are characterized by the absence of any significant financial, contractual or family

relationship likely to affect a member’s independence of judgment. Each supervisory board member:

▪must not be a salaried employee or corporate officer of us or any of our affiliates and must not have held

such a position within the last five years;

▪must not be in a significant business relationship with us or any of our affiliates (e.g., client, supplier,

competitor, provider, creditor, banker, etc.) and must not have been in such a relationship within the last two

years;

▪must not be a reference shareholder or hold a significant number of voting rights;

▪must not have close relationships or family ties with any of our corporate officers or reference shareholders;

and

▪must not have been our auditor within the last six years.

The Supervisory Board is tasked with examining the situation of its members on a case by case basis in light of

these criteria. Subject to the justification of its position, the Supervisory Board may consider one of its members to

be independent when he or she does not meet all of these criteria; conversely, the Board may also consider one of

its members not to be independent when he or she does meet all of these criteria.

The Supervisory Board believes that all of its current members are independent with regard to the MiddleNext Code.

In addition, under US listing requirement and the rules of Nasdaq, the Company is not required to have independent

members on the Supervisory Board, except with respect to the audit committee. The Supervisory Board has

undertaken a review of the independence of its members and determined that all of its members qualify as

“independent directors” as defined under applicable rules of Nasdaq and the independence requirements

contemplated by Rule 10A-3 under the United States Securities Exchange Act.

2.1.6.2.Conﬂicts of interest of the Executive Board and Supervisory Board

Members of the Executive Board who make up the executive team as well as some Supervisory Board members are

shareholders of the Company and/or hold securities giving them access to the Company’s capital. See Section 2.2.8

of the Universal Registration Document for more information.

2.1.6.3.Information on service agreements binding members of the Executive Board and

Supervisory Board with the Group

There is no service agreements between members of the Executive Board and any of the Group Companies or

between members of the Supervisory Board and any of the Group Companies. As far as the Company is aware,

there is no contract, arrangement or agreement whatsoever with the shareholders, customers, suppliers or others

according to which a member of the Executive Board or the Supervisory Board has been appointed.

2.1.7.Agreements referred to in article L.225-37-4 of the French Commercial Code

In order to fulfill the legal requirements regarding current agreements, the Executive Board shall inform the

Supervisory Board on an annual basis on current agreements entered into during the past financial year. It shall

review the purpose and financial conditions of these agreements and confirm or deny their classification as current

agreements. In the 2022 financial year, current agreements related to the cash pooling and service level agreement

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were entered into by and between the Company as parent company of the Group, and each of its fully-owned

affiliate.

2.2.COMPENSATION AND BENEFITS FOR MEMBERS OF THE EXECUTIVE BOARD

AND THE SUPERVISORY BOARD

The information is based on the MiddleNext Code. The tables in Appendix 2 of AMF position and recommendation

no. 2021-02 are presented below.

The composition of both the Supervisory Board and the Executive Board has not evolved in the course of 2022.

The reader may refer to the details, if any, provided in the tables below.

2.2.1.Compensation and benefits paid to the Executive Board members

Table No. 1: Summary of compensation and dilutive instruments allotted to each executive board member


Summary table of compensation and stock-options and free shares granted to each corporate officer
Corporate officer	2022 Financial Year	2021 Financial Year
Laurent LEVY - Chairman of the Executive Board
Compensation due for the financial year (1)	€635,145	€553,065
Value of the free shares granted during the financial year (2)	€546,000	€2,417,400
Value of the stock options granted during the financial year (2)	€212,000	€763,920
TOTAL	€1,393,145	€3,734,385
Bart VAN RHIJN – Chief Financial Officer
Compensation due for the financial year (1)(4)	€563,444	€268,885
Value of the free shares granted during the financial year (2)	€218,400	—
Value of the stock options granted during the financial year (2)	€84,800	€458,400
TOTAL	€866,644	€727,285
Anne-Juliette HERMANT – Chief People Officer
Compensation due for the financial year (1)	€309,750	€287,543
Value of the free shares granted during the financial year (2)	€127,400	€1,208,700
Value of the stock options granted during the financial year (2)	€49,467	€254,640
TOTAL	€486,617	€1,750,883
Philippe MAUBERNA(3) – Chief Financial Officer
Compensation due for the financial year (1)	€—	€381,615
Value of the free shares granted during the financial year (2)	—	—
Value of the stock options granted during the financial year (2)	—	—
TOTAL	€—	€381,615
TOTAL	€2,746,406	€6,594,168

(1) See Table no. 2 “ Summary of the compensation of each corporate officer” below

(2) The valuation of the stock option and/or free shares according to the IFRS2 fair value method used for the consolidated financial statements.

(3) Philippe Mauberna resigned from his corporate office as Executive Board member, effective on May 31, 2021, it being specified that Philippe Mauberna continued to

receive compensation under his employment agreement until his departure from the Company, i.e. until June 30, 2021. The above amounts reflect his compensation for the

first six months of the 2021 financial year.

(4) The euro to dollar exchange rate used to convert the compensation of Bart Van Rhijn is equal to 1€ = $1,0539

No multi-year variable compensation was granted to Executive Board members during the 2021 and 2022 fiscal

years.

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2.2.2.Compensation and benefits paid to the Executive and Supervisory Board members

Table No. 2: Summary of compensation for each corporate executive officer


Summary table of compensation for each corporate officer
Corporate officer	2022 Financial Year		2021 Financial Year
Corporate officer	Amounts due (1)	Amounts paid (2)	Amounts due (1)	Amounts paid (2)
Laurent LEVY - Chairman of the Executive Board
Annual fixed compensation (3)	€380,000	€380,000	€380,000	€380,000
Annual variable compensation (4)	€237,120	€155,040	€155,040	€165,000
Exceptional compensation (5)	—	—	—	—
In kind benefits (corporate officer private unemployment insurance or “Garantie Sociale du Chef d’entreprise”)	€18,025	€18,025	€18,025	€18,025
TOTAL	€635,145	€553,065	€553,065	€563,025
Bart VAN RHIJN – Chief Financial Officer(8)
Annual fixed compensation (6,7,8)	€370,687	€370,687	€195,715	€195,715
Annual variable compensation (4, 6, 8)	€192,757	73,170	€73,170	—
Exceptional compensation	—	—	—	—
In kind benefits	—	—	—	—
TOTAL	€563,444	€443,857	€268,885	€195,715
Anne-Juliette HERMANT – Chief People Officer
Annual fixed compensation (6,7)	€210,000	€210,000	€210,000	€210,000
Annual variable compensation (4)	€99,750	€77,543	€77,543	€100,000
Exceptional compensation	—	—	—	—
In kind benefits	—	—	—	—
TOTAL	€309,750	€287,543	€287,543	€310,000
Philippe MAUBERNA – Chief Financial Officer (9)
Annual fixed compensation (6,7)	€—	€—	€100,741	€100,741
Annual variable compensation	€—	€—	€25,874	€108,900
Exceptional compensation (9)	€—	€—	€255,000	€255,000
In kind benefits	—	—	—	—
TOTAL	€—	€—	€381,615	€464,641
TOTAL EXECUTIVES BOARD MEMBERS	€1,508,339	€1,284,465	€1,491,108	€1,533,381

(1) For the financial year, the amount of which is unlikely to change regardless of the payment date, on a gross basis before tax.

(2) During the financial year, on a gross basis before tax.

(3) Laurent Levy is compensated solely for his corporate office as Chairman of the Executive Board. His fixed compensation is set annually by the Supervisory Board.

(4) Variable compensation corresponds to an annual bonus equal for each executive board member to a percentage of his/her annual fixed compensation decided by the

Supervisory Board in light the actual achievement of (i) individual performance criteria that are linked to specified individual criteria and individual leadership qualities (together,

the “strategic goals”), as well as (ii) company‐wide, performance criteria. Based on recommendations of the Appointments and Compensation Committee, the Supervisory

Board decided, subject to the approval of the 2023 annual shareholders’ meeting of the Company, to set the final variable compensation of Laurent Levy, Bart Van Rhijn and

Anne-Juliette Hermant for 2022 to, respectively, 104%, 104% and 94.5% of their initial bonus. It is specified that the Supervisory Board exceptionally decided to de-cap the

variable compensations of Laurent Levy and Bart Van Rhijn, due to their leadership in the renegotiation of the loan granted by the EIB in order to extend the maturity date.

(5) The exceptional compensation, if applicable, might relate, among others, to newly filed patented inventions or performance leading to exceptional event impacting

significantly the business of the Company.

(6) Compensation granted under an employment agreement.

(7) The variations between the amounts due and amounts paid are due to the treatment of paid leave.

(8) Bart Van Rhijn entered into an employment agreement with the Company on May 11, 2021, effective on June 1, 2021, and was appointed as a member of the Executive

Board by the Supervisory Board on May 31, 2021, effective June 1st, 2021. His fixed yearly salary amounts to $380,000, to which is added variable compensation of up to 50%

of his fixed compensation, i.e., up to $190,000. His fixed salary in 2021 amounted (on a prorate basis and with a euro to dollar exchange rate equal to €1 = $1.1326) to

$221,666, to which was added variable compensation of up to 50% of his fixed salary, i.e., up to $110, 833, i.e. a total of €268,885. His fixed salary in 2022 amounted (on the

basis of a euro to dollar exchange rate equal to 1€ = $1,0539, i.e. the average exchange rate for the 2022 period) to $390,667 to which was added a variable compensation of

€192.757, ie, a total of €563,444.

(9) Philippe Mauberna entered into an employment agreement with the Company on April 1, 2019 and was appointed as a member of the Executive Board by the Supervisory

Board on June 20, 2019, effective July 1st, 2019. He resigned from his corporate office as Executive Board member, effective on May 31, 2021. The Company and Philippe

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Mauberna, mutually agreed to terminate his employment agreement, effective June 30, 2021 and, in this context, entered into a termination agreement on May 19, 2021, the

terms of which were approved by the Supervisory Board on April 6, 2021. Pursuant to this agreement, Philippe Mauberna is in particular entitled to an exceptional indemnity of

€255,000. He shall also keep the benefit of his 2021 variable compensation (on a prorata basis), subject however to the achievement of the performance objectives set by the

Executive Board.

Table No. 3: Compensation (e.g. attendance fees) and other compensation received by non-Executive Board

members

This table is included in Section 2.2.3. of this Universal Registration Document.

Table No. 4: Stock options (Options de Souscription d’Actions, OSA) awarded during the financial year to

each corporate officer by the Company and any company of Group


Stock-options granted during the financial year to each Executive Board member by the Company and any Group company
Name of the Executive Board member	Plan name and date	Nature of the stock options (purchase or subscription)	Value of the options (1)	Number of options awarded during the financial year	Exercise price	Exercise period
Laurent LEVY	Name: OSA 2022-06- Ordinary	subscription	€212,000	150,000	€4.16	10 years(2)
	Date: June 22, 2022
Bart VAN RHIJN	Name: OSA 2022-06- Ordinary	subscription	€84,800	60,000	€4.16	10 years(2)
	Date: June 22, 2022
Anne-Juliette HERMANT	Name: OSA 2022-06- Ordinary	subscription	€49,467	35,000	€4.16	10 years(2)
	Date: June 22, 2022
TOTAL			€346,267	245,000	—	-

(1) Valuation of the options according to the method used for consolidated financial statements

(2) The OSA 2022-06 Ordinary may be exercised as follows:

• up to one-third of the OSA 2022-06 Ordinary as from June 22, 2023;

• an additional one-third of the OSA 2022-06 Ordinary as from June 22, 2024; and

• the balance, i.e., one-third of the OSA 2022-06 Ordinary as from June 22, 2025, subject to, for each increment, a continued service condition.

Pursuant to Article L. 225-185 of the French Commercial Code, the Supervisory Board of the Company decided that

Laurent Levy, Bart Van Rhijn and Anne-Juliette Hermant must keep 10% of the shares resulting from the exercise of

the OSA 2022-06-Ordinary in registered form until they cease to hold office.

Between December 31, 2022 and the date of the Universal Registration Document, the Company has not granted

any stock-options to members of the Executive Board.

Table No. 5: Stock options exercised during the financial year by each corporate officer

None

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Table No. 6: Free shares awarded by the Company to Executive Board members


Free shares awarded by the Company to each Executive Board member during the financial year
	Plan name and date	Number of shares awarded during the financial year	Valuation of the shares (1)	Acquisition date	Availability date	Performan ce conditions
Laurent LEVY	Name: AGA 2022	150,000	€546,000	06/22/24	06/22/25	(2)(3)
	Date: June 22, 2022
Bart VAN RHIJN	Name: AGA 2022	60,000	€218,400	06/22/24	06/22/25	(2)(3)
	Date: June 22, 2022
Anne-Juliette HERMANT	Name: AGA 2022	35,000	€127,400	06/22/24	06/22/25	(2)(3)
	Date: June 22, 2022
Total		245,000	€891,800	-	-	-

(1) Valuation of the shares according to the method used for consolidated financial statements.

(2) The acquisition of the AGA 2022 granted to members of the executive board are conditioned upon the achievement of three of the six below events in the next 24 months

upon attribution:

•RP2D defined in Pancreatic Cancer Trial with data of such quality that it enabling the next step (expansion part of trial or subsequent trial);

•Esophageal cancer trial outcome indicates that product is well tolerated, injection treatment feasible and RP2D defined;

•1100 trial escalation phase show an ORR that is higher than SOC of naïve patients treated with PD1 (keynote 048);

•Establish a collaboration / development deal with a pharma or industry (signed term sheet);

•Submission to FDA of a Ph2 or Ph3 protocol for IO combo with R3;

•EIB debt restructuring completed.

The satisfaction of each of this condition must be acknowledged by the executive board, with the prior approval of the supervisory board. Furthermore, the AGA 2022 will be

subject to a one-year holding period starting at the end of the two-year acquisition period, i.e. starting June 22, 2024.

(3) See also “Continued Service Condition” and “Change of Control” in Section 5.1.4.4. of the Universal Registration Document.

Pursuant to Article L. 225-197-1 of the French Commercial Code, the Supervisory Board of the Company decided

that Laurent Levy, Bart Van Rhijn and Anne-Juliette Hermant must keep 10% of the shares resulting from the

exercise of the OSA 2022-06-Ordinary in registered form until they cease to hold office.

No stock options have been granted to Philippe Mauberna during the 2022 financial year, as he definitely left the

Company on June 30, 2021.

Between December 31, 2022 and the date of the Universal Registration Document, the Company has not granted

free shares to members of the Executive Board.

Table No. 7: Free shares that became available for each member of the Executive Board


Free shares that became available for each member of the Executive Board member during the financial year
Free shares that became available for each member of the Executive Board	Plan name and date	Number of shares that became available and that were exercised during the financial year	Acquisition condition
Anne- Juliette HERMANT	Name : AGA 2020	50,000	(1)
	Date: March 11, 2022
	Name: AGA 2021	90,000	(2)
	Date: Date: April 20, 2023
Laurent LEVY	Name: AGA 2021	180,000	(2)
	Date: Date: April 20, 2023
TOTAL		320,000

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(1) The definitive acquisition of the AGA 2020 granted to Anne-Juliette HERMANT as member of the Executive Board was subject to the achievement of clinical and strategic

objectives in the head and neck indication, the completion of which was acknowledged by the Executive Board, under the approval of the Supervisory Board, on March 17,

2020. The AGA 2020 were subject to a one-year conservation period from their acquisition date that expired on March 11, 2023.

(2) The definitive acquisition of the AGA 2021 granted to Anne-Juliette HERMANT and Laurent LEVY as member of the Executive Board was subject to the determination of

the recommended dose for two of the three cohorts of patients enrolled in the NBTXR3-1100 clinical study, in order to be able to define the continuation of the io development

plan, the completion of which was acknowledged by the Executive Board in March 28th, 2023 under the approval of the Supervisory Board. The AGA 2021 are subject to a

one-year conservation period from their acquisition date that will expire on April 20, 2024.

Table No. 8: History of allotments of securities giving access to capital

The history of allotments of securities giving access to capital can be found in Section 5.1.4. of this Universal

Registration Document.

Table No. 9: Securities giving access to capital granted to the top ten employees who are not corporate

officers and options exercised by them

This table can be found in paragraph 5.7.1.2. of this Universal Registration Document.

Table No. 10: Free share grants

The history of free shares grants can be found in Section 5.1.4.4. of this Universal Registration Document.

Table No. 11: Terms of compensation and other benefits granted solely to corporate officers


	Employment Agreement		Additional pension plan		Indemnity or benefits due or likely to be due in the event of termination or change in position		Indemnity due to a non-compete clause
Executive Board members	YES	NO	YES	NO	YES	NO	YES	NO
Laurent LEVY
Chairman of the Executive Board		X		X	X (1)			X
Corporate office Start Date	May 27, 2004
Term of corporate office	At the shareholders’ meeting held to approve the financial statements for the financial year ended December 31, 2023
Anne-Juliette HERMANT
Executive Board member	X (2)			X	X		X (3)
Corporate office Start Date	July 1st, 2019
Term of corporate office	At the shareholders’ meeting called to decide on the financial statements for the financial year ended December 31, 2023
Bart VAN RHIJN
Executive Board member	X (4)			X	X		X (5)
Corporate office Start Date	June, 1st, 2021
Term of corporate office	At the shareholders’ meeting held to approve the financial statements for the financial year ended December 31, 2023

(1)On July 2, 2013, the Supervisory Board re-specified the terms of a previous decision from May 27, 2004, under the terms of which Laurent Levy would be entitled to a

severance payment in case of a forced departure from the Company (see Section 5.6.2. of the Universal Registration Document).

(2)On April 1, 2019, Anne-Juliette Hermant entered into an employment agreement with the Company. Following her appointment as a member of the Executive Board of

the Company, the Supervisory Board held on June 20, 2019 authorized the combination of Anne-Juliette Hermant’s employment agreement with her corporate office.

(3)Anne-Juliette Hermant is bound by a non-competition clause for a period of 12 months from the termination of her employment agreement. During this non-compete

period, Anne-Juliette Hermant is entitled to a monthly compensation amounting to 66% of her annual base salary.

(4)On May 11, 2021 Mr. Bart Van Rhijn entered into an employment agreement with Nanobiotix Corp, effective June 1, 2021.

(5)Bart Van Rhijn is bound by a non-competition clause for a period of 12 months from the termination of his employment agreement. During this non-compete period, Bart

Van Rhijn is entitled to a monthly compensation amounting to 80% of his annual base salary and his variable compensation.

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2.2.3.Compensation and benefits allocated to Supervisory Board members

Table No. 3: Compensation (e.g. Director fees) and other compensation received by Supervisory Board

members


Non-executive corporate officers		2022 Financial year		2021 Financial year
		Amounts due	Amount paid	Amounts due	Amount paid
Laurent CONDOMINE(1)		€0	€26,250	€26,250	€49,000
	Compensation
	Value of the BSA awarded during the financial year(2, 3)	€0	€0	€0	€0
	Other compensation	—		—
Gary PHILLIPS(4)		€63,000	€36,750	€36,750(5)	€0
	Compensation
	Value of the BSA awarded during the financial year(2)	€0	€0	€0	€0
	Other compensation	—		—
Alain HERRERA		€35,000	€35,000	€35,000	€30,000
	Compensation
	Value of the BSA awarded during the financial year(2)	€0	€0	€0	€0
	Other compensation	—		—
Anne-Marie GRAFFIN		€42,000	€42,000	€42,000	€36,000
	Compensation
	Value of the BSA awarded during the financial year(2)	€0	€0	€0	€0
	Other compensation	—		—
Enno SPILLNER		€50,000	€50,000	€50,000	€40,000
	Compensation
	Value of the BSA awarded during the financial year(2)	€0	€0	€0	€0
	Other compensation	—		—
Christophe DOUAT(6) (Observer)		€35,000	€35,000	€35,000	€30,000
	Compensation
	Value of the BSA awarded during the financial year(2)	€0	€0	€0	€0
	Other compensation	—		—

(1)On May 25, 2021, Laurent Condomine, member and president of the Supervisory Board, resigned with immediate effect.

(2)The members of the Supervisory Board members and the observer were granted warrants (BSA) during the 2020 and 2021 financial years, the subscription price of which

reflects the market value of those warrants at their grant date, according to the Black-Scholes model. Once subscribed, and if the exercise conditions are met, these BSA

allow their holder to subscribe to the underlying shares at a price defined at the grant date (see Section 5.1.4.2 of the Universal Registration Document for more details on

these BSA).

(3)Laurent Condomine subscribed the BSA he was granted in 2021, at an issue price of €2.95 per BSA, with payment made to the Company an amount of €42,571.45.

(4)On May 25, 2021, the Supervisory Board named Dr. Gary Phillips as a member of the Supervisory Board to replace Laurent Condomine for the remainder of Laurent

Condomine’s term of office, subject to the ratification of the appointment by the next ordinary shareholders’ meeting, and elected him as chairman of the Supervisory

Board.

(5)prorated over 7 months.

(6)As part of his role as observer, Christophe Douat is granted compensation for his contribution to the Supervisory Board. Such compensation is calculated on the same

basis as the compensation granted to the Supervisory Board members.

2.2.4.Directors’ and employees’ compensation ratios

In accordance with articles L. 22-10-9 6° and L. 22-10-78 of the French Commercial Code, the below ratios are

calculated based on the fixed and variable compensation due for each executive officers and chairman of the

Supervisory Board (as detailed in Sections 2.2.2 and 2.2.3 of the Universal Registration Document, annualized for

those who left during the year), divided by the average or median compensation of all of the Company’s employees,

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excluding corporate officers. The valuation of dilutive instruments such as free shares and stock options has not

been taken into account as per the uncertainty on the valuation of such long term incentives for the whole Company.

The average compensation of employees is calculated on a full-time basis, excluding the compensation of the

Executive Board members.

Comparisons between the level of compensation of executive officers, the chairman of the Supervisory

Board and that of Group employees


Laurent LEVY - Chairman of the Executive Board	2022	2021	2020	2019	2018
Ratio(1) vs. average employee compensation	5.46	4.87	4.87	5.72	5.46
Ratio(1) vs. median employee compensation	8.01	7.76	7.53	7.45	7.59


Anne-Juliette HERMANT - Chief People Officer	2022	2021	2020	2019	2018
Ratio(1) vs. average employee compensation	2.83	2.57	2.95	2.16	-
Ratio(1) vs. median employee compensation	4.15	4.09	4.56	2.81	-


Bart Van RHIJN - Chief Financial Officer	2022	2021	2020	2019	2018
Ratio(1) vs. average employee compensation	4.99	4.11	-	-	-
Ratio(1) vs. median employee compensation	7.33	6.54	-	-	-

(1) Calculations are based on theoretical level of compensation of executive officers as if each were paid fully during the fiscal year for those having started or finished

employment during the fiscal year.


Gary PHILLIPS – Chairman of the Supervisory Board	2022	2021	2020(1)	2019(1)	2018(1)
Ratio vs. average employee compensation	0.63	-	0.21	0.26	0.26
Ratio vs. median employee compensation	0.92	-	0.33	0.33	0.36

(1) Laurent CONDOMINE served as chairman prior Gary Phillips nomination

Annual changes in the compensation of Executive Board members and Company employees in light

of Company performance over the last five years

As a key performance indicator for a biotechnology company, the Company monitors rigorously the resources

allocated to research and development (R&D) compared to the total operating expenses incurred.


	2022 vs. 2021	2021 vs. 2020	2020 vs. 2019	2019 vs. 2018	2018 vs. 2017
Laurent LEVY
Compensation	€635,185	€553,065	€513,025	€479,757	€464,530
Evolution (in absolute numbers)	€82,120	€40,040	€33,268	€15,227	€79,985
Evolution (in %)	14.85%	7.80%	6.96%	3.28%	20.80%
Bart VAN RHIJN
Compensation(2)(3)	€553,584	€268,885	-	-	-
Evolution (in absolute numbers)(2)	€284,699	-	-	-	-
Evolution (in %)	105.88%	-	-	-	-
Anne-Juliette HERMANT
Compensation	€309,750	€287,543	€300,000	€144,000	-
Evolution (in absolute numbers)	€22,207	€(12,457)	€156,000	-	-
Evolution (in %)	7.72%	(4.15)%	108.33%	-	-
Average employee compensation(1)
Compensation(1)(2)	€111,010	€107,053	€101,695	€93,761	€93,283
Evolution (in absolute numbers)(2)	€3,957	€5,358	€7,934	€478	€7,554
Evolution (in %)	3.70%	5.27%	8.46%	0.51%	8.81%

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Proportion of resources allocated to R&D compared to the total operating expenses incurred (1)
Proportion	73%	73%	73%	74%	77%
Evolution (in %)	—%	12%	-19%	33%	22%

(1) Average gross salary, including variable pay, on a full-time basis.

(2) The euro to dollar exchange rate used to convert the compensation of Bart Van Rhijn and of the US-based employees is equal to 1€ = $1,0539

(3) 2021 compensation based on 7 months of presence in the Company

2.2.5.Restriction on the sale by members of the Executive Board and the Supervisory

Board of their stake in the Company

There is no such restriction, other than (i) the one applicable to free shares during their holding period and (ii)

pursuant to articles L. 225-185 and L. 225-197-1 of the French Commercial Code, whereby members of the

Executive Board are required to keep at least 10% of the free shares they were granted or of the shares resulting

from the exercise of the options they were granted, in registered form until the termination of their duties within the

Company.

2.2.6.Summary of the operations of the managers and of the persons mentioned in article

L.621-18-2 of the Monetary and Financial Code (“Code Monétaire et Financier”) on the

Company’s securities carried out during the financial year ended December 31, 2022

At 31 December 2022, to the best of the Company’s knowledge, a total of 959,060 shares whose registration is

managed by a financial institution were pledged by Laurent Levy, accounting for 2.72% of the issued capital. To the

best of the Company’s knowledge, this pledge is serving as collateral to the benefit of the financial institution for a

three-year maturity loan granted to Laurent Levy so as to enable him to subscribe to the shares of the Company

issued from stock-option previously granted to him.

2.2.7.Amounts provisioned by the Company for the payment of pensions, retirement and

other benefits for the members of the Executive Board and the Supervisory Board

The Company has not provisioned any amounts for the payment of pensions, retirements and other benefits for

members of the Executive Board and Supervisory Board, except for the sums allotted for corporate officer private

unemployment insurance (“Garantie Sociale du Chef d’entreprise”), taken out at the benefit of Laurent Levy for the

2021 and 2022 financial years, with a premium amounting to €18,025 and €18,025, respectively, and the statutory

retirement benefits of Philippe Mauberna and Anne-Juliette Hermant.

The Company has not granted any new hiring or severance bonuses or other severance or benefits to these

persons, with the exception of the departure indemnity Laurent Levy is entitled to (see Section 5.6.2. of the Universal

Registration Document).

2.2.8.Warrants (BSA) and/or founders’ warrants (BSPCE) allocated and free shares

allocated to members of the Executive Board and the Supervisory Board

As of the date of the Universal Registration Document, the direct and indirect shareholdings of the members of the

Executive Board and the Supervisory Board, as well as the number of financial securities giving access to the

Company’s share capital that they hold, are as follows:

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Executive Board


Name	Shares		Securities granting access to capital
	Number	% of capital
Laurent LEVY Chairman of the Executive Board	1,139,060	3.23%	A total of 1,250,400 potential shares derived from the exercise of:
			* 21,000 BSPCE 09-2014 founders' warrants granting the right to subscribe to 21,000 shares at a price per share of €18.68

			* 24,000 BSPCE 2015-1 granting the right to subscribe to 24,000 shares at a price per share of €18.57

			*23,500 BSPCE 2016 Ordinary granting the right to subscribe to 23,500 shares at a price per share of €14.46

			*23,500 BSPCE 2016 Performance granting the right to subscribe to 23,500 shares at a price per share of €14.46

			*26,400 BSPCE 2017 Ordinary granting the right to subscribe to 26,400 shares at a price per share of €15.93

			*32,000 BSPCE 2017 granting the right to subscribe to 32,000 shares at a price per share of €15.93

			*500,000 OSA LLY 2019 (stock options) granting the right to subscribe to 500,000 shares at a price per share of €6.41

			*120,000 OSA 2020 granting the right to subscribe to 120,000 shares at a price per share of €6.25

			180,000 OSA 2021-04 Performance granting the right to subscribe to 180,000 shares at a price per share of €13.74

			150,000 OSA 2022-06 Ordinary granting the right to subscribe to 150,000 shares at a price per share of €4.16

			*150,000 AGA 2022 (free shares)
Bart VAN RHIJN Member of the Executive Board	0	0.00%	A total of 240,000 potential shares derived from the exercise of:
			* 60,000 OSA Ordinary 2021-06 granting the right to subscribe to 60,000 shares at a price per share of €12.99

			* 60,000 OSA Performance 2021-06 granting the right to subscribe to 60,000 shares at a price per share of €12.99

			* 60,000 OSA Ordinary 2022-06 granting the right to subscribe to 60,000 shares at a price per share of €4.16

			*60,000 AGA 2022 (free shares)
Anne-Juliette HERMANT Member of the Executive Board	140,000	0.40%	A total of 190,000 potential shares derived from the exercise of:

			*60,000 OSA 2020 granting the right to subscribe to 60,000 shares at a price per share of €6.25

			*60,000 OSA 2021-04 Performance granting the right to subscribe to 60,000 shares at a price per share of €13.74

			*35,000 OSA 2022-06 Ordinary granting the right to subscribe to 35,000 shares at a price per share of €4.16

			*35,000 AGA 2022 (free shares)

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Supervisory Board


Name	Shares		Securities granting access to capital
	Number	% of capital
Gary PHILLIPS Chairman of the Supervisory Board	0	0.00%	None.
Anne-Marie GRAFFIN Vice-Chairman of Supervisory Board	0	0.00%	A total of 11,743 potential shares derived from the exercise of:
			* 5,000 BSA 2015-1 granting the right to subscribe to 5,000 shares at a price of €17.67 per share
			*2,900 BSA 2019-1 granting the right to subscribe to 2,900 shares at a price of €11.66 per share
			*3,843 BSA 2020 granting the right to subscribe to 3,843 shares at a price of €6.59 per share
Alain HERRERA Member of the Supervisory Board	0	0.00%	A total of 15,095 potential shares derived from the exercise of:
			* 4,000 BSA 2014 granting the right to subscribe to 4,000 shares at a price of €17.67 per share
			* 5,000 BSA 2015-1 granting the right to subscribe to 5,000 shares at a price of €17.67 per share
			*2,900 BSA 2019-1 granting the right to subscribe to 2,900 shares at a price of €11.66 per share
			*3,195 BSA 2020 granting the right to subscribe to 3,195 shares at a price of €6.59 per share
Enno SPILLNER Member of the Supervisory Board	0	0.00%	A total of 7,829 potential shares derived from the exercise of:
			*4,000 BSA 2019-1 granting the right to subscribe to 2,900 shares at a price of €11.66 per share
			*3,829 BSA 2020 granting the right to subscribe to 3,829 shares at a price of €6.59 per share
Christophe DOUAT Observer	0	0.00%	A total of 6,057 potential shares derived from the exercise of:
			*2,900 BSA 2019-1 granting the right to subscribe to 2,900 shares at a price of €11.66 per share
			*3,157 BSA 2020 granting the right to subscribe to 3,157 shares at a price of €6.59 per share

For more information on the securities held by the Executive and Supervisory Board members, including their

exercise conditions, see Section 5.1.4 of the Universal Registration Document.

2.2.9.Compensation policy applicable to corporate officers

Pursuant to Article L. 22-10-26 of the French commercial code, the Supervisory Board submits for approval to the

shareholders’ meeting convened to approve the financial statements of the year ended December 31, 2022 to

approve compensation policy for corporate officers with regard to the 2023 financial year, which must be consistent

with the Company's corporate interest and contribute to its long-term viability and be in line with its strategy. This

policy describes all the components of the fixed and variable compensation payable to members of the Executive

Board and of the Supervisory Board for the performance of their duties for the 2023 financial year (in each case

whether currently in office or, as the case may be, appointed in the future). It also explains the decision-making

process followed for its determination, review and implementation.

The principles and criteria of this compensation policy, determined by the Supervisory Board upon the

recommendation of the appointments and compensation committee, are presented in sections 2.2.9.1 to 2.2.9.6

below.

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2.2.9.1.Executive Board

Severance payment in case of Change of Control

After evaluation of the implications of a change of control event on the Company, the Supervisory Board held on April

24, 2023 decided that each of the Executive Board members would benefit from a severance package in case of

occurrence of any of the following events:

•a dismissal or non-renewal of the concerned member in the context of a change of control of the

Company to the benefit of one or more persons, acting alone or in concert within the meaning of article L.

233-10 of the French commercial code, where the “change of control” would be defined as follows: (a) a

merger of the Company, in which said person(s) would hold more than 50% of the share capital and/or

voting rights of the surviving entity, or (b) a transfer to such person(s) (by way of sale, contribution

(apport) or otherwise) of more than 50% of the share capital and/or voting rights of the Company, or (c)

the power granted to such person(s) to dismiss (“révoquer”) and/or appoint a majority of the member of

the Executive Board or of the board of directors of the Company (as applicable), or (d) [the decision of the

Supervisory Board or the board of directors of the Company (as applicable) to cease all research and

development activities of the Company, or (e) the transfer (by way of sale, contribution (apport) or

otherwise) of all or substantially all of the assets owned by the Company to the benefit of such person(s)

(a “Change of Control”);

•a resignation of the concerned Executive Board member following (a) the dismissal by the person(s)

controlling the Company of the majority of the members of the Executive Board or the board of directors

of the Company (as applicable) within the 12-month period following a Change of Control,or (b) a

significant reduction in duties and responsibilities or compensation (including fixed compensation, benefits

in kind, variable compensation or severance pay) or transfer of workplace to another country, within the 9-

month period following a Change of Control, in each case, without consent (a “Following Event”).;

•the economic metric of the severance package of each member of the Executive Board is specified in the

paragraph applicable to him/her in section 2.2.9.1 above.

Subject to the occurrence of a Following Event or a Change of Control, the Company shall pay a severance package

to the concerned member of the Executive Board equal to 12 or 18 months of his/her fixed salary (as applicable),

increased by an amount equal to the annual performance bonus to which the concerned member of the Executive

Board may be entitled for the year of his/her departure but deducted of any legal and conventional payments owed

to the concerned member in his/her quality of officer and/or employee of the Company under applicable law in the

context of his/her departure (including any compensation of his/her non-compete undertaking). The severance

package shall in no event exceed two years of the fixed and variable compensation of the concerned member of the

Executive Board (including, as the case may be, any of the above-mentioned legal or conventional payments).

By exception to the foregoing, if the Following Event occurs (a) within the 6-month period following the effective date

of the employment contract of the concerned Executive Board member, the severance package shall be equal to six

months of his/her fixed salary, (b) from the 7-month period until the end of 12-month period following the effective

date of the employment contract of such member, the severance package shall be equal to his/her prorated fixed

salary.

Pursuant to Article L. 22-10-34 of the French Commercial code, such severance packages will be submitted for

shareholder approval during the shareholders’ meeting called to approve the Company’s financial statements for the

2022 financial year.

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Laurent Levy, Chairman of the Executive Board


Compensation elements	Principles	Determining criteria
Fixed compensation	The chairman receives fixed compensation	The gross annual amount of this fixed compensation has been set at €411,000 for the 2023 financial year.
Variable compensation	The Chairman is eligible to a variable compensation, the base of which is set at 50% of his fixed compensation, subject to the terms provided in in section 2.2.9.1.4 below.	The final amount of the variable compensation due to the chairman will be determined by the supervisory board in accordance with the principles described in section 2.2.9.1.4 below.
Exceptional compensation	The Chairman may be awarded exceptional compensation.	This exceptional compensation would be intended to compensate specific performance on one or more projects that have a major impact on the Company's development, such as acquisitions, mergers or change of control.
Benefits in kind	The Chairman benefits from a GSC Insurance (Corporate officer unemployment insurance)	-
Supplementary retirement plan	The Chairman does not benefit from any supplementary retirement plan.	-
Severance Payment in case of Change of Control	18 months of base salary +annual performance bonus to which Laurent Levy may be entitled for the year of his departure (without such severance payment exceeding two years of his fixed and variable compensation, including, as the case may be, any payment to be made pursuant to a non-compete undertaking)	See section 2.2.9.1 above

As Nanobiotix operates as a late-stage biotech on different job markets, the compensation structure has been

aligned on a comparable benchmark performed by an independent expert, resulting in an adaptation of the structure

of the remuneration (fixed and variable compensation) for the Chairman of the Executive Board.

In addition, Laurent Levy will be entitled to a termination indemnity in the event of forced departure from the

Company.

The Chairman of the Executive Board may be granted stock options and/or free shares subject to continued service

and performance conditions.

Finally, it is specified that Laurent Levy does not receive any compensation of any kind whatsoever in respect of his

duties within the Company’s subsidiaries, and does not benefit from a long-term multi-annual compensation

mechanism, other than, on a case-by-case basis, the granting of stock options and/or free shares subject to

continued service and/or performance conditions.

Pursuant to Article L. 22-10-34 of the French Commercial code, the amounts resulting from implementation of the

aforementioned compensation policy will be submitted for shareholder approval during the shareholders’ meeting

called to approve the Company’s financial statements for the 2023 financial year, with payment of variable and

exceptional compensation remaining subject to the shareholders’ approval during the next annual shareholders’

meeting.

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2.2.9.1.1.Bart Van Rhijn, member of the Executive Board

It should be noted that all compensation received by Bart Van Rhijn is in respect of his salaried duties. For more

information on Bart Van Rhijn’s employment agreement with Nanobiotix Corp., including its term and termination

conditions, see Section 5.6.2. of the Universal Registration Document:


Compensation elements	Principle	Determining criteria
Fixed compensation	Bart Van Rhijn receives a fixed compensation granted as part of an employment agreement.	The gross annual amount of this fixed compensation has been set at €415,599 (USD 438,000) for the 2023 financial year.(*)
Variable compensation	Bart Van Rhijn is eligible to a variable compensation, the base of which is set at 40% of his fixed compensation, subject to the terms provided in in section 2.2.9.1.4 below.	The final amount of the variable compensation due to Bart Van Rhijn, if any, will be determined by the supervisory board in accordance with the principles described in section 2.2.9.1.4 below.
Non-competition clause	Bart Van Rhijn is bound by a non-competition clause for a period of 12 months from termination of his employment agreement.	Payment of compensation during the non-compete period at a rate equal to 80% of his annual base salary and variable compensation.
Exceptional compensation	Bart Van Rhijn may be awarded exceptional compensation.	Such exceptional compensation may be used to provide compensation for exceptional performance on one or more projects that have had a major impact on the Company’s development.
Benefits in kind	N/A	N/A
Supplementary retirement plan	Bart Van Rhijn does not benefit from any supplementary retirement plan.	-
Severance Payment in case of Change of Control	12 months of base salary +annual performance bonus to which Bart Van Rhijn may be entitled for the year of his departure (without such severance payment exceeding two years of his fixed and variable compensation, including, as the case may be, any payment to be made as per his non-compete undertaking and/or his employment agreement)	See section 2.2.9.1 above.

(*) applicable amount according to the employment agreement is in USD. The euro to dollar exchange rate used is $ 1.0539, (i.e. the average exchange rate for the 2022)

period).

As Nanobiotix operates as a late-stage biotech on different job markets, the compensation structure has been

aligned on a comparable benchmark performed by an independent expert, resulting in an adaptation of the structure

of the remuneration (fixed and variable compensation) for the CFO.

Additionally, Bart Van Rhijn may be granted stock options and/or free shares subject to continued service and

performance conditions.

Finally, it is specified that Bart Van Rhijn does not receive any compensation of any kind whatsoever in respect of his

duties within the Company’s subsidiaries other than Nanobiotix Corp., and does not benefit from a long-term multi-

annual compensation mechanism, other than, on a case-by-case basis, the granting of stock options and/or free

shares subject to continued service and/or performance conditions.

Pursuant to Article L. 22-10-34 of the French Commercial code, the amounts resulting from implementation of the

aforementioned compensation policy will be submitted for shareholder approval during the shareholders’ meeting

called to approve the Company’s financial statements for the 2023 financial year, with payment of variable and

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exceptional compensation remaining subject to the shareholders’ approval during the next annual shareholders’

meeting.

2.2.9.1.2.Anne-Juliette Hermant, member of the Executive Board

It should be noted that all compensation received by Anne-Juliette Hermant is in respect of her salaried duties. For

more information on Anne-Juliette Hermant’s employment agreement, including its term and termination conditions,

see Section 5.6.2. of the Universal Registration Document.


Compensation elements	Principle	Determining criteria
Fixed compensation	Anne-Juliette Hermant receives a fixed compensation granted as part of an employment agreement.	The gross annual amount of this fixed compensation has been set at €210,000 for the 2023 financial year.
Fixed compensation
Variable compensation	Anne-Juliette Hermant is eligible to a variable compensation, the base of which is set at 50% of her fixed compensation, subject to the terms provided in in section 2.2.9.1.4 below..	The final amount of the variable compensation due to Anne-Juliette Hermant, if any, will be determined by the supervisory board in accordance with the principles described in section 2.2.9.1.4 below.
Non-competition clause	Anne-Juliette Hermant is bound by a non-competition and loyalty clause for a period of 12 months from termination of her employment agreement.	Payment of a special fixed monthly indemnity equal to 2/3 of her gross monthly compensation for her last month of service with the Company.
Exceptional compensation	Anne-Juliette Hermant may be awarded exceptional compensation.	Such exceptional compensation may be used to provide compensation for exceptional performance on one or more projects that have had a major impact on the Company’s development.
Benefits in kind	N/A	N/A
Supplementary retirement plan	Anne-Juliette Hermant does not benefit from any supplementary retirement plan.	-
Severance Payment in case of Change of Control	12 months of base salary +annual performance bonus to which Anne-Juliette Hermant may be entitled for the year of his departure (without such severance payment exceeding two years of her fixed and variable compensation, including, as the case may be, any payment to be made as per her non-compete undertaking and/or her employment agreement)	See section 2.2.9.1 above.

Additionally, Anne-Juliette Hermant may be granted stock options and/or free shares subject to continued service

and performance conditions.

Finally, it is specified that Anne-Juliette Hermant does not benefit from a long-term multi-annual compensation

mechanism, other than, on a case-by-case basis, the granting of stock options and/or free shares subject to

continued service and/or performance conditions.

Pursuant to Article L. 22-10-34 of the French Commercial code, the amounts resulting from implementation of the

aforementioned compensation policy will be submitted for shareholder approval during the shareholders’ meeting

called to approve the Company’s financial statements for the 2023 financial year, with payment of variable and

exceptional compensation remaining subject to the shareholders’ approval during the next annual shareholders’

meeting.

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2.2.9.1.3.Executive Board’s members variable compensation calculation principles

The final amount of the variable compensation due to each member of the Executive Board for the 2023 financial

year shall be determined by the Supervisory Board in accordance with the following principles:

•A percentage of the bonus (comprised between 0% and 150%) will be earned by the concerned member

based on the achievement by such member of specific individual criteria. This percentage shall be based

on a matrix combining:

◦the ‘What’: a percentage of the bonus will be earned by the achievement of specific operational

individual criteria determined, at the beginning of the concerning financial year, by the Supervisory

Board based on recommendation of the appointments and compensation committee, it being

specified that these criteria are not made public for confidentiality reasons, and

◦the ‘How’: the remaining percentage will be the individual ability to role-model Nanobiotix

leadership values.

At the beginning of the 2024 financial year, the Supervisory Board will assess, based on recommendations of the

appointments and compensation committee, the level of completion of each of such criteria through a 5-level scale

(significantly under expectations, under expectations, meets expectations, above expectations, significantly above

expectations). Based on such assessment, the Supervisory Board will determine the final percentage of the bonus

earned by the concerned member between 0% (significantly under expectations) and 150% (significantly above

expectations).

The percentage set forth above shall be multiplied by the ‘Company performance factor’, corresponding to a certain

percentage of the bonus (comprised between 0% and 150%) established based on the achievement of Company-

wide yearly performance criteria. These criteria, which fully derived from the Company’s strategic plan (defined as

the ‘critical path’), are meant to measure the performance of the Company in light of the achievement of such plan

and are organized around four pillars that are expected to sustain the Company’s development and progress:


Pillars	KPIs	Weight
Advance the development pathway towards commercialization for NBTXR3	based on progress of the patient enrollment in the context of the 312 Study	35%
Advance the development pathway of NBTXR3 in other indications	based on the progress of the IO pathway, including the progress of the 1100 Study	10%
Be a sustainable organization with efficient operating models	based on the optimizations made on the Company’s financing and manufacturing progress	35%
Be a performing company relying on top skills, capabilities, culture & behaviors	based on the implementation of continuous business improvement initiatives as well as achievements of people metrics	20%

The Company considers that such Company’s performance multiplier aligns the risk-sharing between Executive

Board members and shareholders in the light of the Company’s development by ensuring a strong correlation

between each Executive Board member’s compensation and the achievement of the Company-wide yearly

performance criteria. Accordingly, an underachievement of the Company performance factor (i.e., the achievement of

the Company-wide yearly performance criteria below the expectation set forth by the Supervisory Board), if and

when assessed as such by the Supervisory Board, will proportionally decrease the variable compensation of each

Executive Board member, even if such member has fully achieved or over-achieved his/her personal performance

criteria.

The degree of achievement of the Company’s performance multiplier shall be assessed by the Supervisory Board in

the same way as for the individual criteria, as described above.

•Due to the multiplier mechanism, the over achievement of the personal performance criteria and/or of the

Company-wide yearly performance criteria, may result in a payable amount superior to 100% of the

defined variable remuneration for the Executive Board member at stake, it being specified that this

payable amount shall not exceed 150% of said defined variable compensation.

•The appointments and compensation committee may be assisted by the chairman of the Executive Board

in its assessment of the other members of the Executive Board’s ability to role-model Nanobiotix

leadership values.

2.2.9.2.Members of the Supervisory Board

The members and observers, if any, of the supervisory board are entitled to compensation within the limits of the

global annual amount(compensation for serving on the Supervisory Board and each of the committees set up by the

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Supervisory Board – formerly known as attendance fees) or for special assignments that may be delegated to them

by the supervisory board.

The amount of such compensation will be set by the supervisory board based on the nature of the specific

assignment entrusted to the concerned member or observer, as applicable.

Furthermore, travel expenses are reimbursed for each physical attendance upon presentation of an expense report.

Lastly, the members of the supervisory board may be offered the option of subscribing, under market conditions, for

warrants, the issue price of which will be determined on the day of issuance of the warrants on the basis of their

characteristics, if necessary with the assistance of an independent expert.

The shareholders’ general meeting dated June 23, 2022 set such compensation to an annual aggregate amount of

up to €260,000 for the 2022 financial year and for each subsequent financial year, until a decision to the contrary is

made by the shareholders of the Company at an ordinary shareholders’ meeting.

The Supervisory Board determines (within the range of limits voted on by the shareholders’ meeting) the amount

awarded to each member and observer, if any, based on the principles described below:

(i)an amount not exceeding €63,000 may be granted to the Chairman of the Supervisory Board;

(ii)an amount not exceeding €35,000 may be granted to each member of the Supervisory Board (excluding

the Chairman but including the observer(s), if any);

(iii)an additional amount not exceeding €7,000 may be granted to the chairperson of the appointments and

compensation committee; and

(iv)an additional amount not exceeding €15,000 may be granted to the chairperson of the audit committee.

Each of the members and observers, if any, of the Supervisory Board must attend 80% of all meetings of the

Supervisory Board and committees of the Supervisory Board, as applicable, in order to receive this compensation.

2.2.9.3.Compensation paid or due by a company within the consolidation scope in line with

article L. 233-16 of the Code of Commerce

No compensation of this kind is provided for in the compensation policy.

2.2.9.4.Explanation of how total compensation complies with the adopted compensation policy,

including the way it contributes to the Company’s long-term performance and how

performance criteria have been applied

The compensation of the Executive Board members is determined by the Supervisory Board, based on proposals

from its appointments and compensation committee.

With regard to the 2022 financial year, each member of the Executive Board received a fixed compensation, the

chairman in respect of his duties and the other members of the Executive Board in respect of an employment

contract. In addition, in accordance with the compensation policy approved by the shareholders’ meeting of June 23,

2022, the Supervisory Board granted, subject to the approval of the next shareholders’ meeting, variable annual

compensation to each member of the Executive Board, based on its review and evaluation of the achievement of the

Company’s objectives for the 2022 financial year, including its assessment of the quality of the leadership of each

such member. . This variable remuneration was determined as follows: the assessment of specified individual criteria

(representing 50% of said bonus) and the assessment of individual leadership qualities by the supervisory board

(representing the balance of said bonus, i.e. 50%) (together, the “strategic goals”), multiplied by company‐wide,

performance criteria. The Company’s objectives have been set by the Executive Board, reviewed by the

appointments and compensation committee and approved by the Supervisory Board. The achievement of these

objectives has been assessed on April 24, 2023 according to the same procedure. Such Supervisory Board decided

that Laurent Levy, Bart Van Rhijn and Anne-Juliette Hermant would receive respectively, 104%, 104% and 94.5% of

their initial bonus. The Supervisory Board exceptionally decided to de-cap the variable compensations of Laurent

Levy and Bart Van Rhijn, due to their leadership in the renegotiation of the loan granted by the EIB in order to extend

its maturity date (for more information, see section 2.2.2. of the Universal Registration Document).

The same principles apply to the other Nanobiotix employees, each of whom is eligible for variable compensation

linked, in part, to the objectives of his or her department and, in part, to personal objectives. Performance criteria are

applied on the basis of the achievement of departmental objectives assessed by the executive board, on the one

hand, and on the basis of the achievement of personal objectives assessed by the managers concerned and

reported to each member of their team during annual interviews, on the other.

Each year, the Company asks its shareholders to grant it the necessary authorizations and delegations of authority

to proceed, where appropriate, with the granting of instruments giving access to the Company’s capital (stock

options and/or free shares) to all Group employees. The Executive Board, after authorization by the Supervisory

Board, on the advice of the appointments and compensation committee, shall decide on the granting of such

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instruments when these bodies deem it appropriate, in particular with regard to market conditions.For the 2023

financial year, the shareholders’ meeting called to approve the financial statements for the year ended December 31,

2022 will be asked to vote to modify the principles used for the calculation of the Executive Board members’ variable

compensation. See Section 2.2.9.1 of the Universal Registration Document for more information.

2.2.9.5.Way in which the last shareholders’ ordinary meeting vote, as provided for in section II of

article L. 225-100 of the French commercial code has been taken into account

The shareholders’ meeting dated June 23, 2022 approved a new compensation policy for the 2022 financial year.

The Supervisory Board held on April 24, 2023 fixed the compensation of each member of the Executive and

Supervisory Board in accordance with the compensation policy approved by the shareholders’ meeting and all

payment done in 2022 to such members have been done in compliance therewith (subject to the de-cap of the

variable compensation of Laurent Levy and Bart Van Rhijn, due to their leadership in the renegotiation of the loan

granted by the EIB in order to extend its maturity date).

2.2.9.6.Deviation from the procedure for implementing the compensation policy and any waiver

applied in accordance with the second paragraph of III of Article L. 225-37-2, including an

explanation of the nature of the exceptional circumstances and an indication of the

specific elements from which a waiver is made

No deviation was identified during the reference period (see section 2.2.9.5 of the Universal Registration Document

above).

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2.3.GOVERNANCE

The Supervisory Board, during its meeting held on April 11, 2012, decided to refer to the MiddleNext Code, as

amended, which is available on the MiddleNext website (www.middlenext.com), as the Company’s corporate

governance reference code.

Implementation of the “ comply or explain” rule

The Company’s objective is to comply with all of the recommendations of the MiddleNext Code.

According to the requirements of Article L. 22-10-10 of the Code of Commerce, the Company regularly reviews its

governance in relation to the recommendations of this Code. The table below showcases the Company’s position on

all of the recommendations issued by the MiddleNext Code as of the date of this Universal Registration Document:


Middlenext Code Recommendations	Adopted	Will be adopted	Under consideration
Supervisory power
R1: Code of conduct for board members	X
R2: Conflicts of interest	X
R3: Composition of the board - Attendance by independent members	X
R4: Information of the board members	X
R5: Training of the board members			X(1)
R6: Organization of board and committee meetings	X
R7: Setting up of committees	X
R8: Implementation of a specialized Corporate Social and environmental Responsibility (CSR) committee			X(2)
R9: Setting up internal board regulations[3]	X
R10: Selection of each board member	X
R11: Length of board members’ terms of office	X
R12: Compensation for board members	X
R13: Establishing an assessment of the board’s work	X
R14: Shareholders relations		X(3)
Executive power
R15: Company diversity and equity policy	X(4)
R16: Definition and transparency of executive directors' compensation	X
R17: Preparation for the succession of directors		X(5)
R18: Combination of employment agreements and corporate offices	X
R19: Severance packages	X(6)
R20: Supplementary retirement plans	X
R21: Stock options and free shares	X(7)
R22: Review of points to be watched	X

(1)The Company intends to reflect on the implementation of a three-year training plan for its Supervisory Board and will set up an annual follow-up of this process.

(2)The Company intends to reflect on the implementation of a specialized Corporate Social and environmental Responsibility (CSR) committee of the Supervisory

Board and will set up an annual follow-up of this process.

(3)Starting after the shareholders’ meeting held to approve the financial statements for the year ended December 31, 2022, the Supervisory Board intends to

conduct a yearly review of the voting results of each of the shareholders’ meetings of the Company, especially as regards the negative votes on any decision

submitted to its shareholders. The Board would in particular pay attention on how the majority of the Company’s minority shareholders expressed themselves,

and discuss whether any measures should be taken as a result.

(4)The Company continues to pursue a diversity and equity policy at all hierarchical levels. As of the date of the Universal Registration Document, women are

represented at all levels of the Company. In particular, the Executive Board is composed of two men and one woman, and the Supervisory Board is composed of

three men and one woman (see Section 2.1.5.2.3 for more information on the balanced gender representation on the Supervisory Board). Overall, women

represent 59% of the Company’s employees (see Section 3.3.1 for more information on the balanced gender representation among the Group’s employees).

(5)The Company intends to continue its reflection on the succession of its executives in 2023 and has set up an annual follow-up of this process.

(6)The Company has granted Laurent Levy a severance indemnity in the event of forced departure from the Company, it being specified that such severance

payments, as well as any non-competition payments that Laurent Levy may be entitled to receive, cannot exceed twice the amount of his total compensation

during the year in which his duties were terminated. See Section 5.6.2 of the Universal Registration Document for more information. The Company has granted

each other Executive Board member a severance package if an Event occurs following a Change of Control, see section 2.2.9 of the Universal Registration

Document for more information.

(7)The exercise of a portion of the BSPCEs that have been granted in the past by the Company to some members of the Executive Board is not subject to

performance conditions. However, the Company has since granted dilutive instruments to its corporate officers for which the exercise and/or acquisition is subject

to performance conditions. See Section 5.1.4 for more information on the dilutive instruments granted to corporate officers of the Company.

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2.4.INTERNAL CONTROL PROCEDURES IMPLEMENTED BY THE COMPANY

2.4.1.General principles of internal control

Our Executive Board, under supervision of the Supervisory Board, is responsible for establishing and maintaining

adequate internal controls over financial reporting and for the assessment of the effectiveness thereof.

Furthermore, and in respect of its role, the Audit Committee, established by the Company, does not perform audit

work, rather it considers that its core duties are to oversee the work performed by internal and external auditors, to

understand and monitor how the Chairman of the Executive board and the Chief Financial Officer of the Company

are assessing the adequacy and effectiveness of internal control systems.

However, because of its inherent limitations, internal control over financial reporting may not prevent or detect

misstatements. Also, projections of any evaluation of effectiveness to future periods are subject to the risk that

controls may become inadequate because of changes in conditions, or that the degree of compliance with the

policies or procedures may deteriorate.

2.4.2.Internal control procedures relating to the preparation and processing of accounting

and ﬁnancial information

Since the Company’s accounting activities have largely been internalized, the use of external accounting firms is

now primarily limited to the review of its internal control framework, the preparation of the accounts of Nanobiotix

Corp. and Curadigm SAS, as well as the preparation and review of the Company’s consolidated ﬁnancial

statements. Similarly, management of tax obligations is also handled by this firm next to an administrative review in

connection with payroll through the use of payroll audits, auditing of monthly and quarterly social security

contributions, end-of-contract documents, etc.

As the Company is also listed on a U.S. exchange, the Company is required to establish and maintain internal

controls over its financial reporting in accordance with Sarbanes Oxley in its version applicable to foreign private

issuer and as defined in Rules 13a-15(f) and 15d-15(f) under the Exchange Act, Internal Control Over Financial

Reporting SOX-ICOFR. Pursuant to Section 404(a) of the United States Sarbanes- Oxley Act it is required to furnish

a report by its management that assesses its internal control over financial reporting as of year-end in its Annual

Reports on Form 20-F.

Under the supervision and with the participation of our chairman of the executive board and Chief Financial Officer,

management conducted an assessment of the effectiveness of our internal control over financial reporting as of

December 31, 2022 based on the guidelines of the framework in Internal Control — Integrated Framework (2013)

issued by the Committee of Sponsoring Organizations of the Treadway Commission (COSO).

A material weakness is a deficiency, or a combination of deficiencies, in internal control over financial reporting, such

that there is a reasonable possibility that a material misstatement of our financial statements will not be prevented or

detected on a timely basis.

Based on our assessment as of December 31, 2022, our management concluded that our internal control over

financial reporting was not effective because of the existence of a material weakness in internal control over financial

reporting related to a lack of supervisory personnel with the appropriate level of technical accounting experience and

training to comply with International Financial Reporting Standards and with SEC reporting obligations, and sufficient

processes and procedures, particularly in the areas of complex, judgmental areas such as assessing the company’s

ability to continue as a going concern and the valuation of complex debt instruments.

Notwithstanding this material weakness and management’s assessment that internal control over financial reporting

was ineffective as of December 31, 2022, our management, including our Chairman of the Executive Board

(principal executive officer) and our chief financial officer (principal financial officer), believe that the consolidated

financial statements contained in this Universal Registration Document as of December 31, 2022 present fairly, in all

material respects, our financial position, results of operations and cash flows for the periods presented in conformity

with IFRS.

Management’s Plan for Remediation

In response to the material weakness described above, the Company’s management will implement a remediation

plan, which includes the following:

•will continue to improve our level of analysis and provide further monitoring of our key topics, including

financial risk, or other areas impacting the assessment of the going concern, or significant judgment and

estimates, or impacts of financial debts covenants;

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•will continue to train our accounting and finance team, to develop and implement stronger internal

controls and appropriate level of supervision, together with appropriate reporting procedures, particularly

in the areas of complex and judgmental areas;

•in particular, improve the review and monitoring control over the measurement of fair value of financial

instruments;

•implement systematic reviews of proposed valuation underlying assumptions provided by by third-party

valuation experts.

As the Company continues to evaluate and work to improve its internal control over financial reporting, it may

determine to take additional measures to address control deficiencies or determine to modify certain of the

remediation measures described above. We cannot assure that the measures we have taken to date and may take

in the future, will be sufficient to remediate the control deficiencies that led to our material weakness in internal

control over financial reporting or that we will prevent or avoid potential future material weaknesses. Effective internal

controls are necessary for us to provide reliable financial reports. These remediation measures may be time

consuming and costly and there is no assurance that these initiatives will ultimately have the intended effects.

If we identify any new material weaknesses in the future, any such newly identified material weaknesses could limit

our ability to prevent or detect a misstatement of our accounts or disclosures that could result in a material

misstatement of our annual or interim financial statements. In such case, we may be unable to maintain compliance

with securities law requirements regarding timely filing of periodic reports in addition to applicable stock exchange

listing requirements, investors may lose confidence in our financial reporting and our stock price may decline as a

result. We cannot assure you that the measures we have taken to date, or any measures we may take in the future,

will be sufficient to avoid potential future material weaknesses.

2.4.3.Changes in Control over Financial Reporting

There were no changes in our internal control over financial reporting identified in connection with the evaluation

required by Rules 13a-15(d) and 15d-15(d) of the Exchange Act that occurred during the three months ended

December 31, 2022 that have materially affected, or are reasonably likely to materially affect, our internal control

over financial reporting.

2.5.ITEMS LIKELY TO HAVE AN IMPACT IN THE EVENT OF A PUBLIC OFFER

2.5.1.Capital structure of the Company

See Section 5.1. of the Universal Registration Document.

2.5.2.Statutory restrictions on the exercise of voting rights and transfers of shares or

clauses of agreements brought to the Company’s attention in application of article L.

233-11 of the French Commercial Code

None.

2.5.3.Direct or indirect shareholdings in the Company’s capital of which it is aware

pursuant to Articles L. 233-7 and L. 233-12 of the French Commercial Code

See Section 5.2. of the Universal Registration Document.

2.5.4.List and description of holders of any securities with special control rights

The Company is not aware of the existence of any special control rights.

2.5.5.Control mechanisms provided for in any employee shareholding system, when the

control rights are not exercised by the employee

The Company has not set up an employee shareholding system that may contain control mechanisms when control

rights are not exercised by employees.

2.5.6.Shareholder agreements of which the Company is aware and which may result in

restrictions on the transfer of shares and the exercise of voting rights

The Company is not aware of any such agreement.

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2.5.7.Rules governing the appointment and replacement of members of the Supervisory

Board or Executive Board and amendments to the Company’s bylaws

Members of the Executive Board are appointed in accordance with French law by the Supervisory Board.

Members of the Supervisory Board are appointed in accordance with French law by the shareholders of the

Company at shareholders’ meetings. By exception, if a member of the Supervisory Board dies or resigns between

annual meetings, the Supervisory Board may appoint a temporary member to fill the vacancy, subject to ratification

at the next ordinary general meeting. If such vacancy results in a number of Supervisory Board members below

three, the Executive Board must call an ordinary shareholders’ meeting in order to fill the vacancy.

The bylaws are amended by shareholders during shareholder’s meetings.

2.5.8.Powers of the Executive board, in particular regarding the issuance or repurchase of

See Sections 5.1.3.1. and 5.1.5 of the Universal Registration Document.

2.5.9.Agreements entered into by the Company that are amended or terminated in the

event of a change of control of the Company

The Group has entered into several agreements to finance its operations, some of which provide for the possibility of

early repayment in the event of a change of control.

In addition, the rights to exercise certain dilutive instruments issued by the Company are accelerated in the event of

a change of control of the Company (see Section 5.1.4. of the Universal Registration Document).

2.5.10.Agreements providing for compensation for members of the Executive Board or

employees if they resign or are dismissed without real and serious cause or if their

employment is terminated due to a change of control

Laurent Levy may be entitled to severance payment in the event of forced departure from the Company and Anne-

Juliette Hermant and Bart Van Rhijn may be entitled to indemnities in the context of termination of their employment

agreement (see Section 5.6.2. of the Universal Registration Document).

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3.EXTRA-FINANCIAL REPORTING

3.1. Social Impact

Nanobiotix approach to social impact is reflected in our business model detailed in 1.2.1 and 1.3.1 above and in its

commitment to building a sustainable business so that we can deliver on our mission to improve the lives of patients.

It is also reflected in our commitment to our employees and stakeholders who make our mission possible. Our

approach to extra-financial reporting focuses on our efforts in two areas: Patients and People.

This chapter contains disclosures related to non-financial key performance indicators including information relating to

matters of social impact that are relevant to Nanobiotix business strategy. To that end, this chapter describes the

activities led by the Company, including its subsidiaries, in terms of patient safety as well as the health, well-being

and diversity of its people.

As of the date of this URD, Nanobiotix has not reached the threshold described in article L.225-102-1 of the French

commercial code requiring issuance of extra-financial performance reporting and undertakes such disclosure

voluntarily.

3.2.Our Patients

Since its creation, most of the Company’s resources have been devoted to the development of therapeutic product

candidates, including NBTXR3, intended to provide an unprecedented approach to the treatment of cancer and other

significant unmet medical needs with the express intent of favorably impacting the lives of millions of patients.

We believe the nanotherapeutics we are developing for the treatment of cancer have the potential to significantly

enhance patients’ response to radiotherapy and increase the number of patients that may benefit from systemic

cancer treatments, including targeted therapeutics and chemotherapy.

3.2.1.Patients’ safety during clinical trials

NBTXR3 is currently being evaluated in several clinical trials worldwide and the care and safety of our patients is our

number one priority.

All Clinical Trials sponsored by Nanobiotix or business partners are executed with respect to the highest standards in

the industry according to the national and international Regulations, Directives, Guidance and Recommendations.

The main guidelines supporting clinical trials compliance are developed within the guidance for good clinical practice

ICH E6(R2) (which discusses approaches to clinical trial design, conduct, oversight, recording, and reporting as well

as updated standards regarding electronic records and essential documents), “Good Clinical Practice” (GCP) being

an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that

involve the participation of human subjects.

Compliance with this standard provides Nanobiotix assurance that the rights, safety, and well-being of patients

enrolled in the clinical trials are protected, consistent with the principles coming from the Declaration of Helsinki, and

that the clinical trial data are credible, meaning that quality and integrity of the data gathering during the trials can be

demonstrated during and after the trial termination.

In addition, clinical trials and then protection of patients during the activities is framed by additional guidance

established in the same concept and outlines within ICH E2A regarding “clinical safety data management” and ICH

E8 “general consideration for clinical trials”, which sets out the general scientific principles for the conduct,

performance and control of clinical trials. The Guideline addresses a wide range of subjects in the design and

execution of clinical trials.

As the goal of the Clinical Trial Regulation framework is to create an environment that is favorable to conducting

clinical trials, with the highest standards of safety for participants and increased transparency of trial information,

Nanobiotix has identified several processes with objectives driving continuous compliance towards those regulations.

While Clinical research associates work closely with the hospitals, ensuring sites’ compliance and meeting ICH-GCP

guidelines, the Safety Vigilance department is specifically dedicated to the collection, review and evaluation of all

Adverse Events/Effects. All these events are duly reported to the appropriate national competent authorities, ethic

committees and all parties involved in the clinical trials.

Oversight of clinical trials compliance and execution are defined through numerous procedures within the

organization which are currently evaluated for Clinical Risk Management.

An annual audit program established on a risk-based approach also supports GCP compliance during the trials,

including audits of the contract research organization (CROs) involved in Nanobiotix projects, investigational sites,

the Principal Investigators’ responsibilities for the site as well as internal audits.

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Although Nanobiotix tracks SAEs (clinical trial-related injury and serious adverse events), this indicator not deemed

to be as relevant as the actions taken in order to address these SAEs and, more importantly, whether these SAEs

have been communicated to the appropriate regulatory authorities, the Independent Ethics Committees and the

Company’s Safety Management Plan, established at the beginning of each trial.

The deadlines differ, depending on the country and whether the product is a drug or a medical device amongst the

factors. Typically, depending on the severity of the event and the factors mentioned above, the deadline for

submission could be 24 hours, 2 calendar days, 7 calendar days or longer.


Indicator	2022	2021	2020	2019	2018
% of SAEs (clinical trial-related injury and serious adverse events) reported on time	100%	96%	100%	99%	100%

3.3.Our People

The strength of Nanobiotix is embodied in its employees, their well-being, and their diversity. We are committed to a

policy of non-discrimination and equal opportunity for all employees and qualified applicants without regard to race,

color, religion, gender and gender identity, pregnancy, sexual orientation, national origin, ancestry, age, disability,

genetic information, or any other status protected by law.

3.3.1.Employee Diversity

Nanobiotix counts 102 employees at the end of 2022, including highly experienced management, and is supported

by a Supervisory Board consisting of experts in their respective fields.

As at December 2022, 74 employees were dedicated to research and development, while 28 were working in

supporting departments.

The workforce at as December 31, 2022, was as follows:


	2022	2021	2020	2019	2018
Cadres	92	90	77	99	93
Non cadres	10	10	11	11	9
Total headcount	102	100	88	110	102

Split men/ women	42/58	38/62	32/68	30/70	34/66
Number of men	43	38	28	33	35
Number of women	59	62	60	77	67

Split R&D/ SG&A	73/27	73/27	66/24	81/29	79/23
Number of R&D staff	74	73	66	81	79
Number of SG&A staff	28	27	24	29	23

Women consistently represent a large majority of the workforce, representing 58% of the total employee headcount

and 20% of Nanobiotix Supervisory Board as of December 31, 2022. Nanobiotix workforce is highly qualified and

includes 92 cadres8 as of December 31, 2022, representing 90% of the workforce. In addition, 36 employees held a

PhD, MD or PharmD.

With an average age of 42 years old, Nanobiotix maintains well-balanced workforce by age.

The workforce’s age was as follows:


	Number	Percentage
Less than 26 years old	3	3%
From 26 to 35 years old	32	31%
From 36 to 45 years old	30	29%
More than 46 years old	37	36%

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8 see section 6.6. Glossary

3.3.2.Employees’ health and safety

As a biotechnology company, our commitment to improving human health begins with promoting and protecting the

physical health of our employees. Our key objectives include:

▪Informing employees, including new starters about health and safety risks,

▪Maintaining our health and safety training efforts at work, and

▪Reducing the number of accidents at work or during employees’ commute as recognized by health

authorities.

The Human Resource Department collaborates tightly with the Quality Assurance Department, meeting on a bi-

yearly basis during the management review to discuss the KPIs, and the employees’ representative body, the Comité

Social et Économique (CSE), which meets once every two months. KPIs are reviewed with the CSE every six

months.

Risks and key attention points related to health and safety for each type of position are defined in the Document

Unique (DUERP), available as soon as a new starter joins the Company and all along their employment agreement.

In 2022, the Company noted:

(i)In terms of training:

◦4.5 days dedicated to health & security at work.

(ii)In terms of accidents on the premises or during employees’ commute:

◦2 accidents at the workplace as recognized by health authorities

◦1 accident during commuting as recognized by health authorities

◦No leave due to work-related sickness;

◦No collective agreement was signed in 2022 regarding health and safety at work.


Indicator	2022	2021	2020	2019	2018
Health and safety-related trainings (days)	4,5	1,5	—	3.3	2
Number of accidents	3	—	—	6	—

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4.2022 ANNUAL FINANCIAL STATEMENTS

4.1.CONSOLIDATED FINANCIAL STATEMENTS FOR THE FISCAL YEAR ENDED

DECEMBER 31, 2022

4.1.1.Consolidated statement of financial position

Amounts in thousands of euros


	Notes	2022	2021
Non-current assets
Intangible assets	5	1	4
Property, plant and equipment	6	7,120	8,186
Non-current financial assets	7	291	519
Total non-current assets		7,412	8,709
Current assets
Trade receivables	8.1	101	—
Other current assets	8.2	10,868	9,139
Cash and cash equivalents	9	41,388	83,921
Total current assets		52,358	93,060
TOTAL ASSETS		59,769	101,769

Shareholders’ equity
Share capital	10.1	1,046	1,045
Premiums related to share capital	10.1	255,760	255,767
Accumulated other comprehensive income		700	643
Treasury shares		(228)	(202)
Reserve		(227,282)	(183,459)
Net loss for the period		(57,041)	(47,003)
Total shareholders’ equity		(27,045)	26,790
Non-current liabilities
Non-current provisions	11.2	270	318
Non-current financial liabilities	12	48,608	37,816
Total non-current liabilities		48,878	38,134
Current liabilities
Current provisions	11.1	327	110
Current financial liabilities	12	4,560	8,204
Trade payables and other payables	13.1	9,621	6,482
Other current liabilities	13.2	6,855	5,277
Deferred income	13.3	55	254
Current contract liabilities	13.3	16,518	16,518
Total current liabilities		37,936	36,845
TOTAL LIABILITIES AND SHAREHOLDERS’ EQUITY		59,769	101,769

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4.1.2.Consolidated income statement

Amounts in thousands of euros (except per share numbers)


		For the year ended December 31, 2022
	Notes	2022	2021
Revenues and other income
Revenues	15	—	10
Other income	15	4,776	2,637
Total revenues and other income		4,776	2,647
Research and development expenses	16.1	(32,636)	(30,378)
Selling, general and administrative expenses	16.2	(17,857)	(19,434)
Other operating income and expenses	16.5	(985)	(5,414)
Total operating expenses		(51,478)	(55,226)
Operating income (loss)		(46,702)	(52,579)
Financial income	18	3,533	6,360
Financial expenses	18	(13,863)	(780)
Financial income (loss)		(10,329)	5,580
Income tax	19	(10)	(5)
Net loss for the period		(57,041)	(47,003)
Basic loss per share (euros/share)	21	(1.64)	(1.35)
Diluted loss per share (euros/share)	21	(1.64)	(1.35)

4.1.3.Consolidated statement of comprehensive loss

Amounts in thousands of euros


		For the year ended December 31,
	Notes	2022	2021
Net income (loss) for the period		(57,041)	(47,003)
Actuarial gains and losses on retirement benefit obligations (IAS 19)	11.1	126	182
Tax impact		—	—
Other comprehensive income (loss) that will not be reclassified subsequently to income (loss)		126	182
Currency translation adjustment		(68)	(94)
Tax impact		—	—
Other comprehensive income (loss) that may be reclassified subsequently to income (loss)		(68)	(94)
Total comprehensive income (loss)		(56,983)	(46,915)

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4.1.4.Statements of consolidated changes in shareholders’ equity

Amounts in thousands of euros (except number of shares)


		Share capital Ordinary shares
	Note s	Number of shares	Amou nt	Premium s related to share capital	Accumulated other comprehensi ve income (loss)	Treasur y shares	Reserve	Net loss for the period	Total shareholder s’ equity
As of December 31, 2020		34,432,122	1,033	255,735	555	(196)	(153,070)	(33,590)	70,468
Net loss for the period		—	—			—	—	(47,003)	(47,003)
Currency translation adjustments		—	—	—	(94)	—	—	—	(94)
Actuarial gains and losses (IAS 19)	11.2	—	—	—	182	—	—	—	182
Total comprehensive loss		—	—	—	88	—	—	(47,003)	(46,915)
Allocation of prior period loss		—	—	—	—	—	(33,590)	33,590	—
Capital increase	10.1	393,750	12	—	—	—	(12)	—	—
Subscription of warrants	10.3	—		32	—	—	11	—	43
Share based payment	17	—	—	—	—	—	3,201	—	3,201
Treasury shares	10.2	—	—	—	—	(6)	—	—	(6)
As of December 31, 2021		34,825,872	1,045	255,767	643	(202)	(183,460)	(47,003)	26,790
Net loss for the period		—	—	—	—	—	—	(57,041)	(57,041)
Currency translation adjustments		—	—	—	(68)	—	—	—	(68)
Actuarial gains and losses (IAS 19)	11.2	—	—	—	126	—	—	—	126
Total comprehensive loss		—	—	—	57	—	—	(57,041)	(56,983)
Allocation of prior period loss		—	—	—	—	—	(47,003)	47,003	—
Capital increase	10.1	50,000	2	—	—	—	(2)	—	—
Subscription of warrants	10.3	—	—	(7)	—	—	7	—	—
Share based payment	17	—	—	—	—	—	3,174	—	3,174
Treasury shares	10.2	—	—	—	—	(26)	—	—	(26)
As of December 31, 2022		34,875,872	1,046	255,760	700	(228)	(227,284)	(57,041)	(27,045)

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4.1.5.Statements of consolidated cash flows

Amounts in thousands of euros


		For the year ended December 31,
	Notes	2022	2021
Cash flows used in operating activities
Net loss for the period		(57,041)	(47,003)
Elimination of other non-cash, non-operating income and expenses
Depreciation and amortization	16.4	1,500	1,560
Provisions	16.4	305	152
Expenses related to share-based payments	17	3,174	3,201
Cost of net debt	18	2,042	2,224
Impact of deferred income related to financial liabilities discounting effect	18	10,649	(1,554)
Other charges with no impact on treasury		(36)	8
Loss on disposal		3	—
Cash flows used in operations, before tax and changes in working capital		(39,403)	(41,412)
(Increase) / Decrease in trade receivables	8.1	(101)	62
(Increase) / Decrease in Research tax credit receivable	8.2	2,490	1,927
Increase in other receivables	8.2	(4,215)	(5,034)
Increase in trade and other payables	13.1	2,905	(281)
Increase / (Decrease) in other current liabilities	13.2	1,220	(1,652)
Increase in deferred income and contract liabilities	13.3		16,518
Changes in operating working capital		2,300	11,540
Net cash flows used in operating activities		(37,104)	(29,872)
Cash flows from (used in) investing activities
Acquisitions of intangible assets	5	(1)	(5)
Acquisitions of property, plant and equipment	6	(92)	(228)
(Increase) / Decrease in non-current financial assets	7	230	(9)
Net cash flows from (used in) investing activities		138	(242)
Cash flows from financing activities
Capital increases	10.1	—	—
Warrants subscription	10.1	—	43
Transaction costs	10.1	—	(349)
Increase in loans and conditional advances	12	—	—
Loans repayments	12	(3,642)	(2,833)
Payment of lease liabilities	12	(1,093)	(909)
Interest paid	12	(915)	(1,132)
Net cash flows from financing activities		(5,651)	(5,180)
Effect of exchange rates changes on cash		83	64
Net increase (decrease) in cash and cash equivalents		(42,533)	(35,230)
Net cash and cash equivalents at beginning of period		83,921	119,151
Net cash and cash equivalents at end of period	9	41,388	83,921

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4.1.6.Notes to the consolidated financial statements for the year ended December 31, 2022

4.1.6.1.Information related to the Company

4.1.6.1.1.Presentation of the Company

Nanobiotix, a Société Anonyme registered with the Paris registry of trade and companies under number 447 521 600

and having its registered office at 60 rue de Wattignies, 75012, Paris (“Nanobiotix” or the “Company” and, with its

subsidiaries, the “Group”), is a late-stage clinical biotechnology company pioneering disruptive, physics-based

therapeutic approaches to the treatment of cancer and other significant unmet medical needs with the express intent

of favorably impacting the lives of millions of patients.

We believe the nanotherapeutics we are developing for the treatment of cancer have the potential to significantly

enhance patients’ response to radiotherapy and increase the number of patients that may benefit from systemic

cancer treatments, including targeted therapeutics and chemotherapy.

Incorporated in 2003, Nanobiotix is headquartered in Paris, France. The Company also has subsidiaries in

Cambridge, Massachusetts (United States), France, Spain, and Germany. The Group has been listed on Euronext:

Paris under the ticker symbol “NANO” since 2012 (ISIN: FR0011341205, Bloomberg Code: NANO:FP) and on the

Nasdaq Global Select Market under the ticker symbol “NBTX” in the United States since December 2020.

The Group is the owner of more than 23 patent families associated with three (3) nanotechnology platforms with

applications in 1) oncology; 2) bioavailability and biodistribution; and 3) disorders of the central nervous system. The

company's resources are primarily devoted to the development of its lead product candidate–NBTXR3—which is the

product of its proprietary oncology platform.

4.1.6.1.2.Key events of the fiscal year ended December 31, 2022

Significant events of the period

Considerations arising from the Russia-Ukraine war

In February 2022, Russia launched an invasion of Ukraine, which may have an adverse impact on the global

healthcare ecosystem in the form of delayed clinical trials. Clinical trial sites originally identified in Russia and

Ukraine for the NANORAY-312 clinical trial were not opened or active at the start of the conflict and, consequently,

did not recruit patients. However, certain trial preparation and start-up fees and expenses that the Company had

incurred are not recoverable. While alternate clinical sites in other countries have since been identified, there is

currently insufficient information about start-up costs timing in these countries to exclude the possibility of any delays

to NANORAY-312 as a direct result of the conflict.

Share capital increase

On March 11, 2022, the share capital of the Company was increased by a nominal amount of €1,500, through the

issuance of 50,000 new ordinary shares with a nominal value of €0.03 each, increasing the Company’s share capital

from €1,044,776 to €1,046,276 as a result of the definitive vesting of 50,000 AGA 2020. Such acquisition was

acknowledged by the Executive Board on March 11, 2022. See Note 10 - Share Capital.

Termination of the licensing and collaboration agreement with PharmaEngine

As part of the termination of the licensing and collaboration agreement entered into with PharmaEngine in August

2012, the Company paid $1 million to PharmaEngine on August 18 2022, in compliance with terms and conditions of

the termination agreement. See Note 4 - Significant Transactions.

Restructuring of the existing loan agreement with the European Investment Bank (“EIB”)

On October 18, 2022, the Company and the EIB amended the set of financing and royalties’ agreements (together

the “Amendment Agreement to the Finance Contract” or “Amendment Agreement”) relating to the EIB loan to re-align

the Company’s outstanding debt obligations with its expected development and commercialization timelines. The

main terms and conditions of the Amendment Agreement are as follows:

Under the Amendment Agreement, the repayment of the remaining €25.3 million in principal for both tranches is due

at the earliest of the third royalty payment (four years after commercialization of NBTXR3) for the first tranche and

the second royalty payment (three years following commercialization of NBTXR3) for the second tranche, or on

June 30, 2029 irrespective of the commercialization date of NBTXR3. Commercialization date corresponds to the

first fiscal year during which net sales will exceed €5 million.

Under these main terms and conditions, an amount of €5.4 million in interest accrued as payment-in-kind (“PIK”) on

the first tranche shall be prepaid in October 2024, except in the case of the closing of a collaboration agreement in

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which case the PIK will be subject to an earlier redemption by October 2023. Going forward, principal from the first

tranche will accrue interest at the unchanged rate of 6% annually, with such interest being capitalized and due as

PIK interest at maturity. Interest on the remaining €9.3 million in principal from the second tranche will continue to

accrue at the unchanged 5% fixed rate paid in semi-annual installments through the repayment date.

The annual royalty payment remains in the low single digits and indexed on our net sales turnover, and continues to

cover a six-year period but has been re-aligned to begin as of the first year of NBTXR3 commercialization meaning,

when the Company achieves annual net sales in excess of €5.0 million.

In addition to the royalty fees, the Amendment Agreement also includes a “milestone” payment of €20 million, which

can be considered as due at the latest in June 2029. An accelerated redemption schedule for this new milestone

payment would be triggered calling for the repayment in two equal installments due one year and two years after

commercialization, respectively. Further, should the company secure non-dilutive capital through the execution of

any business development deal, an accelerated redemption of this new milestone payment would be triggered

resulting in a prorated payment amount not exceeding 10% of any upfront or milestone payment received by the

Company.

As part of the Amendment Agreement, the Company has agreed to maintain a minimum cash and cash equivalents

balance equal to the outstanding principal owed to EIB which is €25.3 million as of December 31, 2022. All other

covenants included in the 2018 finance contract remain unchanged.

Accounting treatment of the Amendment Agreement is described in Note 12 - Financing Liabilities

Termination of the liquidity agreement

Consistent with customary practices in the French securities market, the Company entered in 2012 into a liquidity

agreement with Gilbert Dupont, an investment service provider established in France, which agreement allowed

Gilbert Dupont to carry out market purchases and sales of Nanobiotix shares on the regulated market of Euronext in

Paris, in accordance with the authorizations granted by the Company’s shareholders meeting and in compliance with

the French and EU regulations, in order to provide liquidity for the trading market. Effective on December 20, 2022,

the Company terminated its Liquidity Agreement with Gilbert Dupont.

4.1.6.2.General Information, Statement of Compliance and Basis of Presentation

4.1.6.2.1.General principles

The statement of consolidated financial position as of December 31, 2022, 2021 and 2020 and the statements of

consolidated operations, the statements of consolidated comprehensive loss, the consolidated changes in

shareholders’ equity and statements of consolidated cash flows for the years ended December 31, 2022, 2021 and

2020 were prepared under management’s supervision and were approved by the Executive Board of the Company

(the “Executive Board”) and reviewed by the Supervisory Board of the Company (the “Supervisory Board”) on April

24, 2023.

All amounts presented in the consolidated financial statements are presented in thousands of euros, unless stated

otherwise. Some figures have been rounded. Accordingly, the totals in some tables may not be the exact sums of

component items.

The preparation of the consolidated financial statements in accordance with International Financial Reporting

Standards (‘‘IFRS’’) requires the use of estimates and assumptions that affect the amounts and information disclosed

in the financial statements (see Note 3.2 for additional information).

The consolidated financial statements have been prepared using the historical cost measurement basis, with the

exception of some financial assets and liabilities, which are measured at fair value.

4.1.6.2.2.Statement of Compliance and Basis of Presentation

The consolidated financial statements have been prepared in accordance with IFRS, International Accounting

Standards (“IAS”) as issued by the International Accounting Standards Board (“IASB”) as well as interpretations

issued by the IFRS Interpretations Committee (“IFRS-IC”) and the Standard Interpretations Committee (the “SIC”),

which application is mandatory as of December 31, 2022. The consolidated financial statements are also compliant

with IFRS as adopted by the European Union.

Those are available on the European Commission website:

https://eur-lex.europa.eu/eli/reg/2002/1606/oj

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The accounting principles used to prepare the consolidated financial statements for the fiscal year ended December

31, 2022 are identical to those used for the previous year except for the standards listed below that required

adoption in 2022.

Application of New or Amended Standards and Interpretations

The Company adopted the following standards, amendments and interpretations, whose application was mandatory

for periods beginning on or after January 1, 2022:

•Amendment to IFRS 3 - update of a reference to the conceptual framework

•Amendment to IAS 16 Property, Plant and Equipment - related to proceeds before intended use.

•Amendment to IAS 37 related to onerous contracts and the cost of Fulfilling a contract

The application of these standards had no impact on the consolidated financial statements of the Company.

Assessment of the impacts of the Application of the standards, amendments and interpretations which will come into

force subsequently

The application of the following new standards, amendments and interpretations was not yet mandatory for the year

ended December 31, 2022 :

•Amendments to IAS 1 – Classification of Liabilities as Current or Non-current (issued in October 2022 and

Effective for the accounting periods as of January 1, 2024)

•Amendments to IAS 8 – Definition of Accounting Estimates (issued on 12 February 2021 and Effective for

the accounting periods as of January 1, 2023)

•Amendments to IAS 1 and IFRS Practice Statement 2 –Disclosure of Accounting Policies (issued in

March 2021 and Effective for the accounting periods as of January 1, 2023)

•Amendments to IAS 12 – Income Taxes: Deferred Tax related to Assets and Liabilities arising from a

Single Transaction (issued in May 2021 and Effective for the accounting periods as of January 1, 2023)

No significant impact is expected on the consolidated financial statements following the application of the above

amendments.

The Company elected to early adopt no new standards, amendments or interpretations which application was not yet

mandatory for the year ended December 31, 2022.

4.1.6.2.3 Going concern

We have prepared our consolidated financial statements assuming that we will continue as a going concern. We

experienced net losses of €57.0 million in 2022 and a net decrease in cash and cash equivalents of €42.5 million in

2022. At December 31, 2022, our accumulated deficit was €227.3 million and we had negative working capital of

€22.7 million. We expect to continue to incur significant expense related to the development and manufacturing of

nanotechnology product candidates such as NBTXR3 and conducting clinical studies. Additionally, we may

encounter unforeseen difficulties, complications, development delays and other unknown factors that require

additional expense. As a result of these expenditures, we expect to continue to incur significant losses in the near

term. Additionally, the Company’s debt instruments contain covenants that require maintenance of minimum cash

and cash equivalent balances that limit the availability of cash resources to pursue operational needs.

The Company’s covenant obligations entail that the current cash and cash equivalents are only sufficient to fund our

operating expenses into the third quarter of 2023. Violation of the covenant would result in immediate repayment of

all or part of the loan outstanding (if and when requested by the bank), together with accrued interest, prepayment

fees and all other accrued or outstanding amounts. However, Nanobiotix has obtained a 15 million euros temporary

waiver, until July 31, 2023, and has reached an agreement in principle with EIB to automatically extend it until

January 31, 2024 should (a) a business development partnership, collaborative or strategic alliance have become

effective before July 31, 2023 and (b) the contractual documentation is signed within fifteen days following the date

of this form 20-F. Failing this extension period, and except if it has obtained appropriate funding prior, the Company

is expected to be in breach of this temporary waiver as of July 31, 2023.

The Company is also pursuing additional funding through one or more possible new partnerships, collaborative or

strategic alliances; or from the use of the use of the equity line (PACEO) signed with Kepler Cheuvreux, financing

from institutional or strategic investors, from the capital markets, or a combination of the above. However, the

Company cannot guarantee if or when any such transactions will occur or whether they will be on satisfactory terms.

While the Company has taken and will continue to take actions to obtain new funding and manage costs through

operating expense reduction plans, as necessary, the above factors indicate substantial doubt about the Company’s

ability to continue as a going concern as there is no assurance that the Company will be successful in satisfying its

future cash needs.

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Subsequently, the Executive Board determined it is appropriate to prepare consolidated financial statements as of

and for the period ended December 31, 2022, applying a going concern basis, assuming the Company will continue

to operate for the foreseeable future.

4.1.6.3.Consolidation principles and methods

4.1.6.3.1.Basis of consolidation

Accounting policy

In accordance with IFRS 10 – Consolidated Financial Statements, the Group controls an entity when it is exposed or

has rights to variable returns due to its links with the entity and has the ability to influence these returns due to the

power it holds on this one.. Accordingly, each of the Company’s subsidiaries has been fully consolidated from the

date on which the Company obtained control over it. A subsidiary would be deconsolidated as of the date on which

the Company no longer exercises control.

All intra-Company balances, transactions, unrealized gains and losses resulting from intra-Company transactions

and all intra-Company dividends are eliminated in full.

The accounting methods of the Company’s subsidiaries are aligned with those of the Company.

The consolidated financial statements are presented in euros, which is the reporting currency and the functional

currency of the parent company, Nanobiotix S.A. The financial statements of consolidated foreign subsidiaries whose

functional currency is not the euro are translated into euros for statement of financial position items at the closing

exchange rate at the date of the statement of financial position and for the statement of operations, statement of

comprehensive loss and statement of cash flow items at the average rate for the period presented, except where this

method cannot be applied due to significant exchange rate fluctuations during the applicable period. The dollar to

euro exchange rate used in the consolidated financial statements to convert the financial statements of the U.S.

subsidiary was $1.0666 as of December 31, 2022 and an average of $1.0539 for the year ended December 31,

2022 (source: Banque de France) compared with $1.1326 and $1.1835 for 2021 and $1.2271 and $1.1413 for 2020,

respectively. The resulting currency translation adjustments are recorded in other comprehensive income (loss) as a

cumulative currency translation adjustment.

Consolidated entities

As of December 31, 2022, the Company is comprised of one parent entity, “Nanobiotix S.A.,” and five wholly owned

subsidiaries:

•Nanobiotix Corp., incorporated in the State of Delaware in the United States in September 2014;

•Nanobiotix Germany GmbH, incorporated in Germany in October 2017;

•Nanobiotix Spain S.L.U., incorporated in Spain in December 2017;

•Curadigm S.A.S., incorporated on July 3, 2019 and located in France; and

•Curadigm Corp., a wholly-owned subsidiary of Curadigm S.A.S., incorporated in the State of Delaware on

January 7, 2020 and headquartered in Cambridge, Massachusetts.

The consolidated financial statements as of and for the year ended December 31, 2022 include the operations of

each of these subsidiaries from the date of their incorporation.

4.1.6.3.2.Use of judgement, estimates and assumptions

The preparation of consolidated financial statements in accordance with IFRS requires the use of estimates and

assumptions that affect the amounts and information disclosed in the financial statements. The estimates and

judgments used by management are based on historical information and on other factors, including expectations

about future events considered to be reasonable given the circumstances. These estimates may be revised where

the circumstances on which they are based change. Consequently, actual results may vary significantly from these

estimates under different assumptions or conditions. The main items affected by the use of estimates are going

concern, share-based payments, deferred tax assets, clinical trials accruals, revenue recognition and the fair value

of financial instruments.

Measurement of share-based payments

The Company measures the fair value of stock options (OSA), founders’ warrants (BSPCE), warrants (BSA) and free

shares (AGA) granted to employees, members of the Supervisory Board and consultants based on actuarial models.

These actuarial models require that the Company use certain calculation assumptions with respect to characteristics

of the grants (e.g., vesting terms) and market data (e.g., expected share volatility) (see Note 17).

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Deferred tax assets

Deferred taxes are recognized for temporary differences arising from the difference between the tax basis and the

accounting basis of the Company’s assets and liabilities that appear in its financial statements. The primary

temporary differences are related to the tax losses that can be carried forward or backward, depending on the

jurisdiction. Enacted tax rates are used to measure deferred taxes (see Note 19).

The deferred tax assets are recorded in the accounts only to the extent that it is probable that the future profits will

be sufficient to absorb the losses that can be carried forward or backward. Considering its stage of development,

which does not allow income projections judged to be sufficiently reliable to be made, the Company has not

recognized deferred tax assets in relation to tax losses carryforwards in the Statements of Consolidated Financial

Position.

Clinical trial accruals

Clinical trial expenses, although not yet billed in full, are estimated for each study and a provision accrual is

recognized accordingly. See Note 13.1 for information regarding the clinical trial accruals as of December 31, 2022

and 2021.

Revenue recognition

In order to determine the amount and timing of revenue under the contract with customers, the Company is required

to use significant judgments, mainly with respect to identifying performance obligations of the Company and

determining the timing of satisfaction of support services provided to customers

Determining the distinctiveness of performance obligations — A promised good or service will need to be recognized

separately in revenue if it is distinct as defined in IFRS 15. In determining whether the performance obligation is

separate, the Company analyses if (i) the good or service is distinct in absolute terms, i.e. it can be useful to the

customer, either on its own or in combination with resources that the customer can obtain separately; and if (ii) the

good or service is distinct in the context of the contract, i.e. it can be identified separately from the other goods and

services in the contract because there is not a high degree of interdependence or integration between this element

and the other goods or services promised in the contract. If either of these two conditions is not met, the good or

service is not distinct, and the Company must group it with other promised goods or services until it becomes a

distinct group of goods or services.

Allocation of transaction price to performance obligations — A contract’s transaction price is allocated to each distinct

performance obligation and recognized as revenue when, or as, the performance obligation is satisfied. To determine

the proper revenue recognition method, the Company evaluates whether the contract should be accounted for as

more than one performance obligation. This evaluation requires significant judgment; some of the Company’s

contracts have a single performance obligation as the promise to transfer the individual goods or services is not

separately identifiable from other promises in the contracts and, therefore, not distinct. For contracts with multiple

performance obligations, the Company allocates the contract’s transaction price to each performance obligation

using our best estimate of the standalone selling price of each distinct good or service in the contract.

Variable consideration — Due to the nature of the work required to be performed on many of the Company’s

performance obligations, the estimation of total revenue and cost at completion is complex, subject to many

variables and requires significant judgment. It is common for the collaboration and license agreements to contain

variable consideration that can increase the transaction price. Variability in the transaction price arises primarily due

to milestone payments obtained following the achievement of specific milestones (e.g., scientific results or regulatory

or commercial approvals). The Company includes the related amounts in the transaction price as soon as their

receipt is highly probable. The effect of the increase of the transaction price due to milestones payments is

recognized as an adjustment to revenue on a cumulative catch‑up basis.

Revenue recognized over time and input method — Some of the Company’s performance obligations are satisfied

over time as work progresses, thus revenue is recognized over time, using an input measure of progress as it best

depicts the transfer of control to the customers.

See Note 15 for additional detail regarding the Company’s accounting policies for its additional sources of revenue.

Fair value of financial assets and liabilities

The fair value measurement of the loan granted by European Investment Bank (“EIB”) requires the Company to

determine:

–the average discount rate of the new liability executed in October 2022. The average discount rate reflects

the company’s credit risk at the Amendment Agreement date as well as a premium to reflect uncertainties

associated with the timing and the amount of the royalties’ payment. The company involved external

specialists to support in determining the average discount rate;

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–the amount of additional interest (“royalties”, as defined by the royalty agreement with EIB) that will be due

according to the loan agreement during a royalty calculation period commencing upon commercialization.

The royalties due during this period will be determined and calculated based on the number of tranches that

have been withdrawn and will be indexed to the Company’s annual sales turnover. For the purpose of

measuring the fair value of the EIB loan, the Company forecasts the sales that it expects to generate during

the royalty period, taking into consideration the operational assumptions such as market release dates of

the products, growth and penetration rate in each market. (see notes 4.3 and 12 for details about this loan

and the accounting treatment applied).

4.1.6.4.Significant transactions

4.1.6.4.1.LianBio

In May 2021, Nanobiotix announced a partnership with Lian Oncology Limited (LianBio) a biotechnology company

dedicated to bringing paradigm-shifting medicines to patients in China and major Asian markets, to develop and

commercialize NBTXR3 into Greater China (mainland China, Hong Kong, Taiwan, and Macau), South Korea,

Singapore and Thailand.

LianBio has started to collaborate in the development of NBTXR3 in the Asia-Pacific region in the frame of the study

NANORAY-312 and will contribute to patient enrollment in four other future global registrational studies across

several tumor types and therapeutic combinations. LianBio will also participate in the global Phase 3 registrational

study in head and neck cancer into Greater China and South Korea, while supporting longer term strategic alignment

across multiple tumor indications and therapeutic combinations.

As of December 31, 2021, a non-refundable upfront payment of $20 million has been collected by the Company at

the signature of the LianBio Agreement. Additionally, the Company is entitled to receive up to an aggregate of

$205 million in potential contingent, development and commercialization milestone payments. Nanobiotix will also be

eligible to receive tiered, low double-digit royalties based on net sales of NBTXR3 in the licensed territories.

In May 2022 and according to the License Agreement executed in May 2021, the Company entered into a clinical

supply agreement and a related quality agreement with LianBio for the purpose of the Company supplying LianBio

and LianBio purchasing exclusively from the Company fall the required quantities of NBTXR3 for the global clinical

study NANORAY-312 and any other studies conducted within the Territories.

As of December 31, 2022, the Company has collected €0.4 million from LianBio pursuant to this clinical supply

agreement. Furthermore, LianBio is required to order and purchase NBTXR3 product from the Company according

to quantities specified in binding forecasts prepared by LianBio.

See Note 15 for discussion of the accounting analysis of the partnership with Lianbio.

4.1.6.4.2.PharmaEngine

In August 2012, the Company entered into a license and collaboration agreement with PharmaEngine, which

provided for the development and commercialization of NBTXR3 by PharmaEngine throughout the covered Asia-

Pacific countries. In March 2021, the Company and PharmaEngine mutually agreed to terminate the License and

Collaboration agreement.

As of December 31, 2021, the Company had paid a total of $6.5 million to PharmaEngine in accordance with the

termination agreement signed between the parties. During the period ended December 31, 2022, PharmaEngine

became eligible for an additional $1 million payment following receipt and validation of certain clinical study reports,

this additional payment was made in August 2022.

PharmaEngine is entitled to receive an additional payment of $5 million upon the second regulatory approval of

NBTXR3 in any jurisdiction of the world for any indication. The Company has also agreed to pay royalties to

PharmaEngine at low single-digit royalty rates with respect to sales of NBTXR3 in the Asia-Pacific region for a 10-

year period beginning at the date of the first sales in the region. As of December 31, 2022, these future payments

were not accrued because the triggering events have not occurred.

4.1.6.4.3.Financing agreement with the European Investment Bank (“EIB”)

In July 2018, the Company signed a non-dilutive financing agreement with the EIB to borrow up to €40 million in

order to fund its research, development and innovation activities related to NBTXR3 in various therapeutic

indications, subject to achieving a set of agreed-upon performance criteria. This financing is divided in three

tranches:

•a first tranche of €16 million, received in October 2018, subject to a 6% fixed rate and that will be fully

repaid in 2023 at the latest;

•a second tranche of €14 million, received in March 2019, subject to a 5% fixed rate, with repayments

beginning in 2021 and continuing into 2024; and,

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•a last tranche of €10 million, however the Company did not meet the criteria to request this tranche prior

to the contractual deadline for requesting this third tranche. Accordingly the third tranche is no longer

available to the Company.

In connection with this financing agreement, the Company also entered into a royalty agreement with EIB pursuant

to which the Company is required, during a six-year royalty calculation period commencing on January 1, 2021, to

pay (on each June 30 with respect to the preceding year within the calculation period) royalties to EIB. The amount

of royalties payable is calculable based on low single digit royalties indexed on our net sales turnover, which vary

according to the number of tranches that have been drawn, and indexed on the Company’s annual sales turnover.