Rexulti for PTSD: “Discordant Results” Flagged by FDA Reviewers

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Ahead of the July 18 US Food and Drug Administration (FDA) advisory committee meeting to discuss the supplemental New Drug Application (sNDA) for brexpiprazole (Rexulti) tablets in combination with sertraline for the treatment of adults with posttraumatic stress disorder (PTSD),FDA reviewers have flagged “discordant results” for the potential treatment.^1,2 This may indicate trouble for expanding Rexulti’s label to include PTSD.

FDA reviewers published a briefing document ahead of this Friday’s advisory meeting, in which they call the results “discordant” and note 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.” Additionally, they concluded that the study “was clearly and convincingly a negative study that did not demonstrate statistical significance on its primary or secondary endpoints.”¹

The sNDA also contains findings from a randomized, double-blinded, and placebo- and active-controlled phase 2 study. A post-hoc analysis of that trial’s results demonstrated that Rexulti in combination sertraline was statistically superior to sertraline plus placebo. However, reviewers were not convinced, instead noting that the selected comparisons “do not align with the study’s primary objectives.”¹

If this briefing is any indication of how the advisory committee will vote, there could be more bad news for potential PTSD treatments. Just last year, the FDA issued a complete response letter for MDMA-AT for PTSD, which received a lot of positive buzz, requesting an additional phase 3 trial to examine safety and efficacy instead of approving the psychedelic.³ With no new treatments for PTSD in over 20 years, there is a severe unmet need, but no one has managed to sway the FDA yet.

Rexulti has the benefit of preestablished efficacy in several other disease states, including as an adjunctive therapy to antidepressants in adults with major depressive disorder (MDD), as a monotherapy treatment for schizophrenia in adults, and for the treatment of agitation associated with Alzheimer disease dementia. Although the mechanism of action of Rexulti is unknown, it has high receptor binding affinity to norepinephrine, serotonin, and dopamine receptors, and is 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.

The FDA advisory committee will discuss these concerns in Friday’s meeting.⁴ 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.

Stay tuned for more coverage on the outcome of the advisory committee meeting, right here at PsychiatricTimes.com.

References

1. FDA Briefing Document: Brexpiprazole. Psychopharmacologic Drugs Advisory Committee Meeting. July 16, 2025. Accessed July 17, 2025. https://www.fda.gov/media/187617/download

2. Otsuka, Lundbeck’s PTSD bid for Rexulti hits speedbump as FDA questions efficacy. Biospace. July 17, 2025. Accessed July 17, 2025. https://www.biospace.com/drug-development/otsuka-lundbecks-ptsd-bid-for-rexulti-hits-speedbump-as-fda-questions-efficacy

3. Lykos Therapeutics announces complete response letter for midomafetamine capsules for PTSD. August 9, 2024. Accessed July 15, 2025. https://news.lykospbc.com/2024-08-09-Lykos-Therapeutics-Announces-Complete-Response-Letter-for-Midomafetamine-Capsules-for-PTSD

4. July 18, 2025: Meeting of the Psychopharmacologic Drugs Advisory Committee Meeting Announcement. US Food and Drug Administration. Accessed July 15, 2025. https://www.fda.gov/advisory-committees/advisory-committee-calendar/july-18-2025-meeting-psychopharmacologic-drugs-advisory-committee-meeting-announcement-07182025