FDA reviewers flag “discordant results” in a briefing document published ahead of Friday’s advisory committee meeting for the partners’ application for the antipsychotic in post-traumatic stress disorder.
FDA reviewers have flagged “discordant results” for Otsuka and Lundbeck’s antipsychotic Rexulti, suggesting a rough road for the companies’ bid to expand the drug into post-traumatic stress disorder.
Rexulti is already approved for use in schizophrenia and major depressive disorder.
Otsuka and Lundbeck are proposing to combine Rexulti with the selective serotonin reuptake inhibitor sertraline for the treatment of patients with post-traumatic stress disorder (PTSD). The companies conducted two Phase III trials to support the expansion: one used a flexible dosing regimen for Rexulti, while the other administered the drug at fixed doses. In both cases, controls were given sertraline plus placebo.
In a briefing document published ahead of a Friday advisory committee meeting, FDA reviewers called the results “discordant.” They noted that in the fixed-dose study, which used 2-mg and 3-mg doses of Rexulti, “neither active treatment group was superior to sertraline plus placebo.”
This study, they added, “was clearly and convincingly a negative study that did not demonstrate statistical significance on its primary or secondary endpoints.”
To bolster their application, Otsuka and Lundbeck also filed findings from a randomized, double-blinded and placebo- and active-controlled Phase II study. A post-hoc analysis of that trial’s results demonstrated the statistical superiority of Rexulti plus sertraline over sertraline plus placebo.
Reviewers were not convinced, however, noting that these retrospectively selected comparisons “do not align with the study’s primary objectives.”
“The retrospective selection of hypotheses and use of post hoc multiple testing procedures raises concerns about inflation of the overall Type I error [false positives] rate, which is crucial for demonstrating efficacy,” the briefing document read.
The FDA’s Psychopharmacologic Drugs Advisory Committee will convene on Friday with these concerns as a backdrop.
Available orally, Rexulti is an atypical antipsychotic that was first approved in July 2015 for schizophrenia and major depressive disorder. In mid-2024, Otsuka and Lundbeck applied to expand Rexulti’s label to PTSD, with the FDA assigning an initial decision target date of Feb. 8, 2025. In January, however, the regulator announced that it would hold an advisory committee meeting to discuss the application, and as a result would need to extend its review period. The agency has yet to provide a new target action date for Rexulti.
Beyond Rexulti, Otsuka continues to build out its pipeline and earlier this week acquired Cantargia’s investigational anti-IL-1RAP, CAN10, for several autoimmune conditions. Upon closing, Otsuka will make a $33 million upfront payment with $580 million in potential milestone payments, while also pledging future contingent payments in exchange for the exclusive global right to develop, manufacture and commercialize CAN10.
