The US Food and Drug Administration (FDA) is preparing to convene its Psychopharmacologic Drugs Advisory Committee (PDAC) on July 18 to assess whether conflicting clinical trial results justify approval of Otsuka Pharmaceutical’s Rexulti (brexpiprazole) with Viatris’ Zoloft (sertraline) combination therapy for post-traumatic stress disorder (PTSD).
At the heart of the deliberations is whether a single positive Phase III study, bolstered by an exploratory Phase II trial, can outweigh a negative Phase III trial in establishing the combination’s efficacy for PTSD, a debilitating psychiatric disorder.
The US FDA postponed its decision on the Rexulti and Zoloft combination to convene the advisory committee, affecting the review timeline for brexpiprazole in combination with sertraline for PTSD treatment. The original Prescription Drug User Fee Act (PDUFA) date was set for 8 February, marking the deadline for the FDA to complete its review of the supplemental New Drug Application (sNDA).
Conflicting Evidence
Otsuka submitted a supplemental new drug application (sNDA) proposing Rexulti, an atypical antipsychotic, combined with sertraline, a selective serotonin reuptake inhibitor (SSRI), as a novel treatment for PTSD. The proposed approach involves co-initiating both drugs, aiming to address the limited response rates and side effects of current therapies.
The US FDA guidance typically requires evidence from at least two adequate and well-controlled trials to support a finding of substantial effectiveness. While Otsuka’s Phase III Study 00071 showed a statistically significant benefit of the combination over sertraline alone, Phase III Study 00072 failed to demonstrate superiority.
The US regulatory agency’s reviewers noted in their briefing document that Study 00071 was a “robustly positive study,” but Study 00072 was “clearly and convincingly negative,” showing no statistical difference on primary or secondary endpoints.
To strengthen its case, Otsuka also submitted Phase II Study 00061, which initially had exploratory objectives but showed positive outcomes in post hoc analyses. However, FDA statisticians expressed concerns about the retrospective selection of endpoints and the lack of prespecified multiplicity controls, warning of potential inflation in Type I error rates.
PTSD Treatment Gap
The deliberations come amid a persistent gap in effective PTSD treatments. Currently, only two SSRIs—sertraline and paroxetine—are FDA-approved for PTSD. Response rates to these medications hover between 37% and 62%, leaving many patients inadequately treated.
Rexulti, already approved for schizophrenia and as an adjunct for major depressive disorder, is thought to act through partial agonism of serotonin and dopamine receptors. Its combination with Zoloft aims to improve symptom control in PTSD patients without the need to demonstrate prior inadequate response to monotherapy.
“There remains an unmet need for additional safe and effective PTSD treatments,” the US FDA briefing document states. But reviewers caution that enthusiasm for new options must be balanced against rigorous evidence requirements.
Key Questions for the Panel
The PDAC will be asked to weigh three key considerations:
- The strength of evidence from Studies 00071 and 00072, especially given their conflicting outcomes.
- Whether exploratory Phase II data from Study 00061 can independently substantiate efficacy.
- The benefit-risk balance of initiating Rexulti and Zoloft concurrently, considering their known safety profiles.
The US FDA reviewers emphasized that Study 00061 was not designed to serve as pivotal evidence and cautioned about the reliability of post hoc analyses. “Retrospective changes in the analysis plan raise concerns about Type I error and bias,” the document notes.
Additionally, the agency flagged methodological differences between the studies, including dosing strategies and population criteria, as complicating factors in interpreting results.
No new safety signals emerged in the development program beyond the known risks of the two agents. Rexulti carries warnings about weight gain, akathisia, and sedation, while sertraline is associated with gastrointestinal effects and sexual dysfunction.
The panel will be asked whether the known risks are acceptable in light of the potential benefits for PTSD patients.
Regulatory Context
While the advisory committee’s meeting decision is not binding, it usually acts as a reliable indicator of how the agency will review a submission. However, there have been rare cases when the US FDA has approved or rejected drugs contrary to the committee’s recommendations.
The July 18 meeting will include presentations from US FDA reviewers, Otsuka representatives, and public commenters. The committee’s vote will provide a crucial indicator of whether Rexulti and Zoloft combination treatment is likely to gain regulatory approval.
