Otsuka and Lundbeck Will Face Scrutiny Over Investigational PTSD Therapy at July 18 FDA AdComm Meeting

A FDA advisory committee will convene July 18 to consider whether to recommend approval of a novel combination therapy, brexpiprazole (Rexulti) and sertraline (Zoloft), for the treatment of post-traumatic stress disorder (PTSD).

At issue is whether the evidence presented by sponsors Otsuka and Lundbeck is sufficiently robust and consistent to support efficacy of the combination over sertraline monotherapy, currently a standard of care.

The FDA’s Psychopharmacologic Drugs Advisory Committee will evaluate results from 3 pivotal trials: one phase 2 exploratory study and 2 confirmatory phase 3 studies. The combination met its primary endpoint, a statistically significant reduction in PTSD symptoms measured by the CAPS-5 score at 10 weeks, in the phase 2 trial and in one of the phase 3 studies. However, the second phase 3 study failed to show a significant benefit for the brexpiprazole-sertraline combination compared with sertraline alone. The FDA has called these “discordant results” and noted that extensive exploratory analyses did not yield a satisfactory explanation for the divergent outcomes.

FDA reviewers highlighted that the failed phase 3 trial, which tested fixed doses of brexpiprazole (2 mg and 3 mg), showed no superiority on either primary or secondary endpoints. In contrast, the positive phase 3 trial used a flexible dosing strategy and showed what the FDA termed a “robustly positive” effect. The sponsors also submitted retrospective analyses of the phase 2 data to support the application, but the agency pointed out that the positive findings did not conform to the study’s original design and thus cannot be relied on for statistical confirmation.

Beyond the inconsistencies, the FDA expressed concern about the modest size of the observed treatment effect. Even in the trials where the combination demonstrated statistical significance, the absolute magnitude of improvement in PTSD symptoms may not translate into a clinically meaningful benefit. This raises the question of whether the added complexity and cost of combination therapy is justified in routine practice.

The application, submitted as a supplemental new drug application (sNDA) for Rexulti, was originally scheduled for an FDA decision by February 8, 2025. That decision was delayed to allow for advisory committee input, signaling the agency's uncertainty about whether the data support approval.

If ultimately approved, the brexpiprazole-sertraline combination would represent the first FDA-approved therapy for PTSD in more than 30 years, following the approvals of sertraline and paroxetine. This historical context underscores the clinical need and the significance of the upcoming committee vote.

The advisory committee’s discussion will center on whether the positive findings in 2 of the 3 three trials, despite methodological limitations, are sufficient to overcome the failed study and justify regulatory approval. The panel's recommendation, while nonbinding, will likely guide the FDA’s final decision.