FDA Raises Concerns Over Rexulti-Zoloft Combination for PTSD Treatment

The U.S. Food and Drug Administration (FDA) has expressed reservations about the efficacy of a proposed combination therapy for post-traumatic stress disorder (PTSD), developed by Lundbeck and Otsuka Pharmaceutical. The treatment, which combines Rexulti (brexpiprazole) with Viatris' Zoloft (sertraline), is currently under review by the agency's Psychopharmacologic Drugs Advisory Committee.

Conflicting Trial Results Prompt FDA Scrutiny

The FDA's concerns stem from "discordant results" observed in two pivotal Phase 3 trials. While one study demonstrated robust positive outcomes, the other failed to meet its primary endpoints, showing no statistical superiority over Zoloft monotherapy. This inconsistency has led the FDA to seek expert opinion on whether the positive findings from one Phase 3 trial and an exploratory Phase 2 study can outweigh the negative results of the second Phase 3 trial.

"This discordance complicates the interpretation of the overall efficacy evidence from these pivotal trials," FDA reviewers noted in a briefing document prepared for the upcoming advisory committee meeting.

Regulatory Implications and Market Impact

The conflicting data has resulted in a delay of the FDA's decision, originally scheduled for February 8. The agency is now relying on input from its advisory panel to help navigate the complex efficacy landscape presented by the trial results.

Despite these regulatory challenges, Rexulti continues to show strong market performance. Lundbeck reported first-quarter revenues of 1.5 billion Danish kroner ($233 million) for Rexulti, representing a 28% increase at constant exchange rates. The drug's growth is primarily attributed to increased U.S. demand for its use in Alzheimer's disease agitation.

Clinical Data and Future Outlook

In the successful Phase 3 trial, the Rexulti-Zoloft combination demonstrated a statistically significant reduction in PTSD symptoms compared to Zoloft alone. This was measured by changes in the clinician-administered CAPS-5 score from baseline to Week 10.

Otsuka and Lundbeck maintain that even in the failed Phase 3 study, reductions in PTSD symptom severity were consistent with the positive trials. However, the FDA's inability to identify an explanation for the differing outcomes, despite "extensive exploratory analyses," remains a significant hurdle for the drug's approval in this indication.

As the pharmaceutical industry awaits the FDA's final decision, the outcome of this review process could have far-reaching implications for the treatment landscape of PTSD and the future development strategies for combination therapies in psychiatric disorders.