FDA reviewers have raised significant concerns about Otsuka Pharmaceutical Company's supplemental New Drug Application for brexpiprazole (Rexulti) tablets in combination with sertraline for treating adults with posttraumatic stress disorder (PTSD), ahead of a critical advisory committee meeting scheduled for July 18, 2025.
Critical Efficacy Concerns Emerge
In a briefing document published prior to the advisory meeting, FDA reviewers flagged "discordant results" for the potential PTSD treatment, describing findings that may jeopardize the drug's path to approval for this indication. The reviewers noted that in the fixed-dose study, which utilized 2 mg and 3 mg doses of Rexulti, "neither active treatment group was superior to sertraline plus placebo."
More concerning for Otsuka, FDA reviewers concluded that the study "was clearly and convincingly a negative study that did not demonstrate statistical significance on its primary or secondary endpoints." This assessment represents a significant hurdle for the supplemental application, which had an original Prescription Drug User Fee Act target action date of February 8, 2025, now postponed pending the advisory committee discussion.
Post-Hoc Analysis Fails to Convince Regulators
The supplemental New Drug Application also included findings from a randomized, double-blinded, and placebo- and active-controlled phase 2 study. While a post-hoc analysis of that trial's results demonstrated that Rexulti in combination with sertraline was statistically superior to sertraline plus placebo, FDA reviewers remained unconvinced.
The reviewers noted that the selected comparisons "do not align with the study's primary objectives," suggesting that the post-hoc analysis may not provide sufficient evidence to support approval.
Broader Context of PTSD Treatment Challenges
This potential setback comes at a time when there is a severe unmet need for PTSD treatments. Approximately 13 million Americans currently struggle with the disorder, and no new treatments have been approved in over 20 years. The situation became more challenging following the FDA's complete response letter for MDMA-assisted psychotherapy (MDMA-AT) for PTSD in August 2024, which requested an additional phase 3 trial to examine safety and efficacy rather than approving the psychedelic treatment.
The rejection of MDMA-AT disappointed many advocates, including federal veterans advocates at the Heroic Hearts Project, who stated: "The FDA's decision is a missed opportunity to embrace groundbreaking science, save countless Veteran lives, and honor the sacrifices made by those who served our country. If this critical treatment remains inaccessible, we face losing an additional 6000 Veterans to suicide this year alone—and every year thereafter."
Rexulti's Established Profile in Other Indications
Despite the challenges in PTSD, Rexulti has demonstrated efficacy across several other disease states. The drug was approved by the FDA in 2015 as an adjunctive therapy to antidepressants in adults with major depressive disorder and as a monotherapy treatment for schizophrenia in adults. Most recently, it received approval in May 2023 for the treatment of agitation associated with Alzheimer disease dementia—the first FDA-approved treatment option for this indication.
Although the mechanism of action of Rexulti is unknown, it has high receptor binding affinity to norepinephrine, serotonin, and dopamine receptors. The drug functions as an antagonist at norepinephrine α1B and α2C receptors and serotonin 5-HT2A receptors, as well as a partial agonist at serotonin 5-HT1A and dopamine D2 receptors.
Advisory Committee Decision Ahead
The FDA advisory committee will address these efficacy concerns during Friday's meeting. Even if the committee votes against recommending approval for Rexulti in combination with sertraline for PTSD, the FDA is not required to adhere to their recommendation, though such votes typically carry significant weight in final regulatory decisions.
