FDA Advisory Committee Recommends Against Rexulti-Sertraline Combo for PTSD

Otsuka and Lundbeck Face Setback in Bid to Expand Rexulti's Label

The prospect of Otsuka and Lundbeck's antipsychotic drug Rexulti (brexpiprazole) becoming part of a new treatment for post-traumatic stress disorder (PTSD) has been dealt a significant blow. An advisory panel to the U.S. Food and Drug Administration (FDA) overwhelmingly recommended against the proposed use of Rexulti in combination with sertraline for PTSD treatment, citing insufficient evidence of efficacy.

The Psychopharmacologic Drugs Advisory Committee voted 10-1 against recommending approval, with only the patient advocate voting in favor. This decision came after a thorough review of clinical data from two Phase III trials and a retrospective analysis of a Phase II study.

Mixed Trial Results Raise Concerns

The committee's decision was primarily influenced by discordant results from the two Phase III trials. One study showed significant evidence of efficacy, while the other was described by FDA reviewers as "clearly and convincingly a negative study that did not demonstrate statistical significance on its primary or secondary endpoints."

Dr. Rajesh Narendran, professor of radiology and psychiatry at the University of Pittsburgh School of Medicine, commented, "One trial looked so promising and the other was trying to find something in [a] Phase II trial that could convince me that [the combo] could work. It's just another Phase III trial is what's necessary."

The companies attempted to bolster their case with a post-hoc analysis of a Phase II study, which showed superiority of the Rexulti-sertraline combination. However, FDA reviewers expressed concerns about the retrospective selection of hypotheses and potential inflation of false positive rates.

Implications for Patients and Future Research

Despite the negative recommendation, some experts acknowledged the potential benefits of the combination therapy. Laura Block, the patient advocate who cast the sole vote in favor, cited accessibility and affordability issues that an approval could address. "While both of these individual component drugs are on the market, a third-party payer isn't likely to pay without an FDA-approved indication," she explained.

The committee's decision highlights the challenges in developing effective treatments for PTSD, a complex and heterogeneous condition. Dr. Pamela Shaw, a biostatistician with Kaiser Permanente, noted, "My overall assessment is that this is a heterogeneous condition, and that even by chance, trials could enroll quite different populations with respect to the underlying clinical heterogeneity."

Otsuka and Lundbeck remain committed to the potential of Rexulti in PTSD treatment. Dr. John Kraus, Otsuka's chief medical officer, stated, "We continue to believe in [Rexulti]'s potential to make a meaningful difference as a treatment option for the PTSD patient population."