FDA Advisory Committee Casts Nearly Unanimous Vote Against Otsuka's PTSD Combination

The FDA's Psychopharmacologic Drugs Advisory Committee voted 1-10 against recommending approval of brexpiprazole (Rexulti) combined with sertraline (Zoloft) for treating post-traumatic stress disorder (PTSD) in adults. The July 18 meeting concluded that efficacy had not been established based on the available clinical trial data.

Otsuka Pharmaceutical and Lundbeck submitted the supplemental new drug application (sNDA) to the FDA in June 2024, based on 3 clinical trials: one phase 2 study (n=321) and 2 phase 3 studies (n=416 and n=553). All trials compared the brexpiprazole-sertraline combination against sertraline plus placebo in adults with PTSD.

"Although today's outcome was disappointing, we remain fully committed to collaborating with the FDA as they complete their review of this application," John Kraus, MD, PhD, executive vice president and chief medical officer at Otsuka, said in a statement.

The committee's recommendation is non-binding, but the FDA typically follows advisory panel guidance when making final approval decisions.

Clinical Trial History

The combination therapy met its primary endpoint in the phase 2 trial and one phase 3 study, showing statistically significant reductions in PTSD symptoms as measured by the CAPS-5 score at 10 weeks. However, the second phase 3 study failed to demonstrate superiority over sertraline alone.

FDA reviewers had previously characterized these as "discordant results" and noted that exploratory analyses did not provide a satisfactory explanation for the different outcomes between studies.

The failed phase 3 trial used fixed doses of brexpiprazole (2 mg and 3 mg) and showed no benefit on primary or secondary endpoints. The positive phase 3 trial employed flexible dosing and demonstrated what the FDA called a "robustly positive" effect.

Agency reviewers also questioned whether the observed treatment effects, even in positive trials, would translate to clinically meaningful benefits for patients. The sponsors submitted retrospective analyses of phase 2 data, but the FDA noted these findings did not align with the study's original design.

The sNDA was originally scheduled for FDA decision by February 8, 2025. The agency delayed this timeline to seek advisory committee input, indicating uncertainty about the supporting data.

If approved, the combination would have been the first new FDA-approved PTSD treatment since sertraline and paroxetine received approval over 30 years ago. Brexpiprazole is currently approved for treatment of schizophrenia and as adjunctive therapy for major depressive disorder.

References

1. Otsuka and Lundbeck issue statement on U.S. Food and Drug Administration (FDA) advisory committee meeting for the treatment of post-traumatic stress disorder (PTSD). News release. Lundbeck LLC. July 18, 2025. Accessed July 21, 2025. https://news.cision.com/h--lundbeck-a-s/r/otsuka-and-lundbeck-issue-statement-on-u-s--food-and-drug-administration--fda--advisory-committee-me,c4208413

2. Halsey G. Otsuka and Lundbeck will face scrutiny over investigational PTSD therapy at July 18 FDA AdComm meeting. Patient Care. July 17, 2025. https://www.patientcareonline.com/view/otsuka-and-lundbeck-will-face-scrutiny-over-investigational-ptsd-therapy-at-july-18-fda-adcomm-meeting