Otsuka Pharmaceutical Co., Ltd. (Otsuka) and H. Lundbeck A/S (Lundbeck) announced that the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) regarding the supplemental New Drug Application (sNDA) for the use of REXULTI® (brexpiprazole) in combination with sertraline for the treatment of adults with post-traumatic stress disorder (PTSD).
The FDA stated that while its review of the application is complete, it cannot approve the submission in its current form, noting that the data presented do not provide substantial evidence of effectiveness. The sNDA, accepted for review in June 2024, was supported by data from three randomized clinical trials evaluating the safety and efficacy of brexpiprazole with sertraline in adults with PTSD.
The decision follows the Psychopharmacologic Drugs Advisory Committee meeting on July 18, 2025, where the panel voted 1–10 against the evidence supporting efficacy of the treatment. The FDA highlighted that not all studies submitted could contribute to substantial evidence and indicated that additional positive, adequate, and well-controlled trials would be required to support future approval.
“While we respect the FDA’s decision, we continue to believe in the potential of REXULTI in combination with sertraline to help address this serious unmet need,” said John Kraus, M.D., Ph.D., executive vice president and chief medical officer at Otsuka. “Otsuka and Lundbeck will take time to review the contents of the letter with the FDA to determine the appropriate path forward.”
Johan Luthman, executive vice president of Lundbeck Research & Development, added, “Post-traumatic stress disorder places a significant and often overlooked burden on patients, their families, and society. We are grateful to the participants, their families, the clinical trial site investigators and staff, and the entire program team for their dedication and commitment to advancing care for those living with PTSD.”
PTSD is one of the most common mental health disorders in the United States, affecting around five percent of the population in a given year. More than 86% of U.S. cases occur in the civilian population. PTSD can arise after experiencing or witnessing traumatic events such as physical or sexual assault, natural disasters, serious accidents, terrorist acts, war, intimate partner violence, or bullying.
Brexpiprazole was first approved by the FDA in 2015 as an adjunctive therapy to antidepressants in adults with major depressive disorder (MDD) and as a treatment for schizophrenia. In May 2023, it also gained U.S. approval for the treatment of agitation associated with dementia due to Alzheimer’s disease. Globally, brexpiprazole is approved in more than 60 countries, including the European Union, Canada, and Japan.
Discovered by Otsuka and co-developed with Lundbeck, the drug’s mechanism of action is not fully understood. Brexpiprazole binds with high affinity to several receptors, including norepinephrine, serotonin, and dopamine. It acts as an antagonist at norepinephrine α1B and α2C receptors and serotonin 5-HT2A receptors, while functioning as a partial agonist at serotonin 5-HT1A and dopamine D2 receptors.
