FDA Advisory Committee Votes Against Recommending Brexpiprazole Plus Sertraline for PTSD

The US Food and Drug Administration Advisory Committee voted not to recommend brexpiprazole (Rexulti) in combination with sertraline for posttraumatic stress disorder (PTSD). The panel believed the efficacy was not well-enough established to recommend its approval. The vote was 10-1.

According to Arash Javanbakht, MD, the founding director of the Stress, Trauma, Anxiety, and Research Clinic at Wayne State University School of Medicine, approximately 13 million adult Americans experience PTSD in a given year, and approximately 6 of 100 will have PTSD in their lifetimes. The age group of 39-50 has the highest prevalence, and women are 2 times more likely to have PTSD. Additionally, 86% of the US population with PTSD is civilian, not military—despite popular belief. Upon receiving a PTSD diagnosis, 41% of patients receive polypharmacy as their first line of treatment; then 70% need to switch medications within their first 2 years of treatment. The. most common reason for changing treatment is “inadequate/suboptimal management of PTSD symptoms with prior treatment.”

With only 2 approved treatments in the past 25 years for PTSD, both with modest and inconsistent efficacy in managing PTSD symptoms, investigators hoped to meet this severe unmet need with brexpiprazole.

Brexpiprazole, while new to the PTSD space, is already on the market for several other disease states. It was approved by the FDA in 2015 as an adjunctive therapy to antidepressants in adults with major depressive disorder (MDD) and as a monotherapy treatment for schizophrenia in adults, and was most recently approved in May 2023 for the treatment of agitation associated with Alzheimer disease dementia—the first FDA-approved treatment option for this indication.

In clinical trials, brexpiprazole plus sertraline underwent 2 phase 3 studies (071 and 072). Study 071 was a flexible-dose (2 to 3 mg/day), 2-arm, randomized, controlled, double-blind, multicenter, 12-week study. Study 072 was a fixed-dose (2 to 3 mg/day), 3-arm, randomized, controlled, double-blind, multicenter, 12-week study. Study 071 was robustly positive, with statistically significant results that brexpiprazole plus sertraline is superior to sertraline alone. Study 072 was clearly negative, in which brexpiprazole plus sertraline did not separate from sertraline alone. Investigators were “unable to identify a reason for these discordant results despite extensive exploratory analyses.” There was also 1 phase 2 study (061) that was similar in design to the phase 3 studies: it was a flexible-dose (1 to 3 mg/day), 4-arm, randomized, controlled, double-blind, multicenter, 12-week study. It was initially designed as an exploratory study to generate hypotheses for the design of the phase 3 program. The statistical significance cannot be claimed due to retrospective selection of the hypothesis and the use of post hoc multiple testing procedures. However, it does provide strong supportive evidence that was replicated in study 071. Overall, a greater proportion of patients taking brexpiprazole plus sertraline met clinically meaningful improvement thresholds and achieved greater than 30% clinical response.

The enrollment criteria were generally consistent across the 3 studies: participants were 18-65 years of age and had a diagnosis of PTSD, defined by the DSM-5 and confirmed by the Mini International Neuropsychiatric Interview. They had to be symptomatic for 6 months or more prior to screening and have a CAPS-5 total score of 33 or higher at screening and day 0. There were no trauma types excluded.

Brexpiprazole plus sertraline showed itself to be more effective than sertraline alone in 2 of these 3 studies. It was well-tolerated, and its safety profile was consistent with the large database from clinical trials and the real-world usage in other psychiatric disorders.

The discussion attempted to balance the disappointment in the phase 3 results with the potential hope this treatment could offer. Discussion participants cited “confusing, contradictory datasets” and “discordant results,” while at the same time questioning, “Is study 061 enough to overcome study 072? We are here today because these are difficult questions.”

“I would be disappointed if 1 trial with an unusually large response to sertraline obstructs our ability to discuss and assess the entirety of the data presented today for a critically important disorder for which there are significant unmet clinical needs,” shared Kathleen Brady, MD, PhD.

This is the second PTSD treatment to receive a negative advisory committee vote. In August 2024, the FDA issued a complete response letter for MDMA-AT for PTSD, requesting an additional phase 3 trial to examine safety and efficacy, rather than the approving the psychedelic.

“I know people have been through a lot and this vote may be disappointing,” said one panelist, who voted against recommending brexpiprazole plus sertraline. For now, further data will be needed to convince the FDA to recommend a treatment for this disease state.

In a Psychiatric Times Drug Watch Special Report, Editor in Chief John J. Miller, MD, spoke with Michael Asbach, DMSc, PA-C, Psych-CAQ, and Erin Crown, MHS, PA-C, Psych-CAQ, about their immediate reactions to the July 18 vote and the implications for practice.