FDA Raises Concerns Over Rexulti's Efficacy in PTSD Treatment

The U.S. Food and Drug Administration (FDA) has expressed significant concerns regarding the efficacy of Rexulti (brexpiprazole) in the treatment of post-traumatic stress disorder (PTSD), casting doubt on Otsuka and Lundbeck's application to expand the drug's label. This development comes as the pharmaceutical industry closely watches the potential for new therapies in the challenging field of mental health disorders.

Conflicting Clinical Trial Results

At the heart of the FDA's concerns are what reviewers termed "discordant results" from two Phase III clinical trials conducted by Otsuka and Lundbeck. These trials aimed to evaluate the efficacy of combining Rexulti with sertraline, a selective serotonin reuptake inhibitor, for PTSD treatment.

The first study, which employed a flexible dosing regimen for Rexulti, showed promising results. However, the second trial, using fixed doses of 2 mg and 3 mg, failed to demonstrate superiority over sertraline plus placebo. FDA reviewers described this second study as "clearly and convincingly a negative study that did not demonstrate statistical significance on its primary or secondary endpoints."

To bolster their application, the companies submitted additional data from a Phase II study. A post-hoc analysis of this trial suggested statistical superiority of the Rexulti-sertraline combination over sertraline alone. However, FDA reviewers expressed skepticism about these retrospectively selected comparisons, noting that they "do not align with the study's primary objectives."

Regulatory Implications and Next Steps

The FDA's Psychopharmacologic Drugs Advisory Committee is set to convene on Friday to discuss these concerns. This meeting comes after the agency delayed its decision on Rexulti's label expansion beyond the original target date of February 8, 2025.

The regulatory body is specifically seeking expert input on whether the positive results from one Phase III trial and the exploratory Phase II study can outweigh the negative findings from the second Phase III trial. The FDA's inability to identify an explanation for the differing outcomes, despite "extensive exploratory analyses," further complicates the situation.

This regulatory hurdle represents a significant challenge for Otsuka and Lundbeck, who are seeking to expand Rexulti's approved indications beyond its current use in schizophrenia and major depressive disorder. The outcome of this application could have far-reaching implications for the treatment landscape of PTSD, a condition for which there remains a significant unmet medical need.