FDA Raises Concerns Over Rexulti-Zoloft Combination for PTSD Treatment

The U.S. Food and Drug Administration (FDA) has expressed concerns regarding the efficacy of a proposed combination therapy for post-traumatic stress disorder (PTSD) developed by Lundbeck and Otsuka. 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 primary concern stems from "discordant results" observed in two pivotal phase 3 trials. While one study demonstrated robust positive outcomes, the other failed to meet its primary endpoint, showing no statistical superiority over Zoloft monotherapy. This inconsistency has led the FDA to seek expert input on whether the positive findings from one phase 3 trial and supportive data from an exploratory phase 2 study can outweigh the negative results of the second phase 3 trial.

According to the FDA briefing document, agency reviewers were unable to identify a clear explanation for the differing outcomes despite "extensive exploratory analyses." The document states, "This discordance complicates the interpretation of the overall efficacy evidence from these pivotal trials."

Regulatory Implications and Next Steps

As a result of these concerns, the FDA has delayed its decision on Rexulti beyond the original target action date of February 8. The agency is now seeking input from its advisory committee to help resolve the conflicting data and determine the path forward for the combination therapy.

Lundbeck and Otsuka had initially agreed with the FDA that the Rexulti-Zoloft combination needed to "consistently outperform" Zoloft monotherapy to demonstrate convincing efficacy. The companies have submitted additional phase 2 results as supportive evidence, retrospectively selecting three comparisons from a multi-arm midstage study. However, the FDA noted that while these data showed statistical superiority using the drugmakers' methods, they cannot claim statistical significance under the original study design.

Rexulti's Market Performance and Future Prospects

Despite the regulatory hurdles in PTSD treatment, Rexulti continues to show strong growth in other indications. In the first quarter, Lundbeck reported Rexulti revenues of 1.5 billion Danish kroner ($233 million), representing a 28% increase at constant exchange rates. The drug's growth is primarily driven by increased U.S. demand for Alzheimer's disease agitation treatment.

As the pharmaceutical industry awaits the FDA's final decision on the Rexulti-Zoloft combination for PTSD, the outcome of this review could have significant implications for future combination therapies and the treatment landscape for post-traumatic stress disorder.