The FDA is raising efficacy questions over Lundbeck and Otsuka’s proposed combination of their Rexulti with Viatris’ Zoloft as a treatment for post-traumatic stress disorder (PTSD).
For an upcoming meeting of the FDA’s Psychopharmacologic Drugs Advisory Committee, the agency is asking an expert panel to weigh in on whether results from an exploratory phase 2 trial and a positive phase 3 study can overcome negative findings from a second phase 3 of the combination.
“Discordant results” from the two phase 3 trials have FDA reviewers worried, especially since the agency said it was unable to identify an explanation for the differing outcomes despite “extensive exploratory analyses.”
“This discordance complicates the interpretation of the overall efficacy evidence from these pivotal trials,” the FDA staff wrote in a document prepared for Friday’s meeting.
As the FDA typically requires, Otsuka and Lundbeck conducted two well-controlled phase 3 studies to support the Rexulti-Zoloft combo in PTSD. The agency and the drugmakers agreed that the combo needed to “consistently outperform” Zoloft monotherapy, a standard first-line medication, to show convincing evidence of efficacy.
One of the two studies, which tested Rexulti at 2 mg and 3 mg in separate cohorts, was “a clearly and convincingly negative study,” according to the FDA. The trial didn’t show statistical significance on its primary or secondary endpoints, the FDA noted, and neither dose was superior to Zoloft alone.
The other study, which evaluated flexible dosing of Rexulti at either 2 mg or 3 mg in one group, was “robustly positive,” according to the briefing document.
Given the conflicting results, Otsuka and Lundbeck submitted additional phase 2 results as supportive evidence and retrospectively selected three comparisons from the midstage, multi-arm study. The Rexulti-Zoloft combo showed statistical superiority against single-agent Zoloft using the drugmakers’ methods. But, as the FDA noted, the data cannot claim to demonstrate statistical significance under the study’s original design.
In the two positive trials, the Rexulti-Zoloft regimen was associated with a statistically significant reduction in PTSD symptoms versus Zoloft alone, as measured by the change in the clinician-administered CAPS-5 score from baseline to Week 10.
While the other phase 3 failed to meet its primary endpoint, reductions in PTSD symptom severity seen in the trial were consistent with the two positive studies, Otsuka and Lundbeck said when presenting the results last May.
To seek input from the advisory committee, the FDA has delayed its decision on Rexulti from its original target action date of Feb. 8. In the wake of the delay, it's not clear when the agency aims to make its its decision on the filing.
Meanwhile, Rexulti has delivered fast growth driven by increased U.S. demand in Alzheimer’s disease agitation. In the first quarter, Lundbeck recorded 1.5 billion Danish kroner ($233 million) of revenue from Rexulti, an increase of 28% at constant exchange rates. The atypical antipsychotic drug was cited alongside the CGRP migraine med Vyepti as Lundbeck’s main growth drivers during the period.