FDA Accepts sNDA for Brexpiprazole-Sertraline Combo in Adult PTSD Treatment

The U.S. Food and Drug Administration (FDA) has accepted the supplemental new drug application (sNDA) for brexpiprazole in combination with sertraline for treating adults with post-traumatic stress disorder (PTSD). This application, submitted by Otsuka Pharmaceutical Co., Ltd. (Otsuka) and H. Lundbeck A/S (Lundbeck), aims to provide the first FDA-approved pharmacological treatment for PTSD in over two decades. The FDA has set a target review date of February 8, 2025.

This submission is grounded in data from three randomized clinical trials that evaluated the safety and efficacy of the brexpiprazole-sertraline combination in adult PTSD patients. The trials employed the Clinician-Administered PTSD Scale (CAPS-5) as the primary endpoint to measure changes in PTSD symptoms from the start of the trial to ten weeks. The participants were diagnosed with PTSD based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).

The clinical trials were designed as randomized, double-blind, and active-controlled. Trials 061 (Phase II) and 071 (Phase III) used a flexible dosing regimen, while Trial 072 (Phase III) adopted a fixed dosing regimen. In Trials 061 and 071, the combination treatment significantly reduced PTSD symptoms compared to sertraline plus placebo. Although Trial 072 did not meet its primary endpoint, the reduction in PTSD symptoms was consistent with the other trials. Improvements were observed in the Clinical Global Impression Severity (CGI-S) scale and the four CAPS-5 symptom clusters: re-experiencing, avoidance, negative cognition/mood, and arousal/reactivity.

Safety profiles from the trials indicated that the combination treatment was generally well-tolerated with no new safety concerns. The incidence of treatment-emergent adverse events (TEAEs) was comparable between the brexpiprazole-sertraline group and the sertraline-plus-placebo group, with rates of 55.5 percent and 56.2 percent, respectively.

John Kraus, M.D., Ph.D., Executive Vice President and Chief Medical Officer at Otsuka, emphasized the significant impact of PTSD in the United States, affecting approximately 13 million adults annually. He expressed optimism about the potential benefits this new treatment could offer to patients and caregivers dealing with PTSD.

Johan Luthman, Ph.D., Executive Vice President of Lundbeck Research & Development, highlighted the potential of brexpiprazole combined with sertraline to improve existing treatment standards. He expressed gratitude to the patients and caregivers who participated in the trials and looked forward to working with the FDA towards approval.

The CAPS-5 is a structured interview designed to assess PTSD diagnostic status and symptom severity, consisting of 30 items with higher scores indicating worse outcomes.

PTSD is a prevalent mental health disorder in the U.S., affecting about five percent of the population annually. It can follow traumatic experiences such as assault, natural disasters, accidents, and combat. Symptoms, which typically begin within three months of the traumatic event, are categorized into intrusion, avoidance, negative cognitions and mood, and arousal/reactivity. For a PTSD diagnosis, symptoms must persist for more than one month and significantly impact daily life. First-line treatments include psychotherapy and certain antidepressants.

Brexpiprazole, marketed as Rexulti, was first approved in the U.S. in 2015 for adjunctive therapy in major depressive disorder (MDD) and schizophrenia. It recently received approval for treating agitation associated with Alzheimer's disease. The drug, co-developed by Otsuka and Lundbeck, was discovered by Otsuka. It operates through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors and antagonist activity at serotonin 5-HT2A and alpha 1B/2C receptors.

Otsuka Pharmaceutical Co., Ltd. is a global healthcare leader specializing in mental, renal, and cardiovascular health. Lundbeck, a biopharmaceutical company, focuses on neurological and psychiatric diseases, striving to develop transformative treatments for brain diseases.