Circuitry / neuronal biology
Brexpiprazole in Post-Traumatic Stress Disorder
(PTSD)
On 25 June 2024, Lundbeck announced that a
supplemental new drug application (sNDA) for
brexpiprazole in combination with sertraline for the
treatment of adults with PTSD was accepted and filed
by the U.S. FDA.
The sNDA is based on data from three randomized
clinical trials evaluating the safety and efficacy of
brexpiprazole in combination with sertraline in adult
patients with PTSD, namely the phase II trial 061 and
the two phase III trials 071 and 072.
The primary endpoint for all three trials was the change
from week 1 to week 10 in the Clinician-Administered
PTSD Scale (CAPS-5) total score for brexpiprazole and
sertraline combination therapy versus sertraline plus
placebo in patients diagnosed with PTSD according to
the Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition (DSM-5).
The trials were randomized, double blind, and active-
controlled, and trials 061 and 071 were flexible-dose
trials, while trial 072 was a fixed-dose trial. In both
trials 061 and 071, brexpiprazole in combination with
sertraline was associated with a statistically
significant reduction (p<0.05) in PTSD symptoms
compared to sertraline plus placebo, as measured by
the change in the CAPS-5 total score from week 1 to
week 10 (primary end-point). In trial 072, while the
primary endpoint was not met, reductions in PTSD
symptom severity with brexpiprazole in combination
with sertraline were consistent with trials 061 and 071.
Across the three randomized trials, the combination of
brexpiprazole and sertraline in adult patients with
PTSD was generally well-tolerated, and no new safety
observations were identified.
U.S. FDA has communicated the date for
brexipiprazole PTSD Psychopharmacologic Drugs
Advisory Committee (PDAC) meeting as 18 July 2025. If
approved, the brexpiprazole and sertraline
combination treatment will be the first U.S. FDA-
approved pharmacological treatment for PTSD in more
than 20 years.
Brexpiprazole – phase III in adolescent patients (13-
17 years old) with schizophrenia
A Type II variation to apply for a pediatric schizophrenia
indication (for adolescents aged 13 to 17 years) was
successfully submitted to the European Medicines
Agency (EMA) on 26 June 2024 and was followed by a
positive opinion from the Committee for Medicinal
Products for Human Use (CHMP) on 30 January 2025.
The CHMP recommendation was recently ratified by
European Commission on 7 March 2025.
The submission is based on the phase III trial 331-10-
234 in adolescent patients with schizophrenia
(NCT03198078), which demonstrated a significant
improvement for brexpiprazole compared to placebo.
In the trial, brexpiprazole was generally well tolerated,
and the safety profile was similar to that observed in
adult patients with schizophrenia. The trial forms part
of the brexpiprazole EMA Paediatric Investigation Plan.
Bexicaserin in Developmental and Epileptic
Encephalopathies (DEEs) – Phase III
In 2024, Lundbeck acquired Longboard with the lead
asset bexicaserin which holds blockbuster potential.
In September 2024, a global phase III trial was initiated
by Longboard, evaluating bexicaserin for the treatment
of seizures associated with Dravet Syndrome (DEEp
SEA trial), one of the rare epilepsies, and in November
2024 Longboard initiated a second phase III trial to
evaluate the efficacy of bexicaserin in Developmental
and Epileptic Encephalopathies (DEEs), including
Lennox-Gastaut Syndrome (LGS) (DEEp Ocean trial).
There is a strong unmet need across a broad range of
epilepsy indications, including DEEs. Among many
types of DEEs, only 4 have approved treatments so far.
Bexicaserin has shown encouraging anti-seizure
effects to date in preclinical and clinical studies, with
its next-generation super agonist mechanism
specifically targeting 5-HT2C receptors, supporting
bexicaserin’s potential to offer a highly differentiated
and best-in-class profile, and emphasized by having
U.S. FDA Break-Through Designation, while being
afforded Orphan Drug designation in both Dravet
Syndrome and Lennox-Gastaut Syndrome in the U.S.
Bexicaserin has the potential to address all DEEs, and
compared to the treatments currently available, e.g.,
fenfluramine, bexicaserin has greater selectivity,
designed to only bind 5-HT2C receptors.