FDA Panel Rejects Combo Drug for PTSD

An FDA advisory panel has resoundingly rejected the supplemental new drug application for the atypical antipsychotic brexpiprazole (Rexulti, Otsuka Pharmaceutical Co., Ltd.), in combination with the selective serotonin reuptake inhibitor (SSRI) sertraline, for the treatment of adults with posttraumatic stress disorder (PTSD).

Based on the data at hand, in a 10 to 1 vote, the Psychopharmacologic Drugs Advisory Committee felt that the efficacy of brexpiprazole, when started concurrently with sertraline, has not been established in PTSD.

In a briefing document released ahead of the FDA committee meeting, FDA reviewers flagged “discordant” results from the two phase 3 trials.

They noted that while study “071” was “robustly positive,” study “072” was “clearly and convincingly” negative and failed to demonstrate statistical significance on its primary or secondary endpoints.

Given the conflicting phase 3 results, the company also provided the FDA with data from the “061” phase 2 study. However, the reviewers cited statistical and methodologic concerns with this study. The data from this study were “retrospectively analyzed with post hoc multiplicity control methods to provide additional efficacy evidence, raising concerns about type I error inflation,” the reviewers cautioned. The committee also had concerns about the 061 data analysis.

Taken together, the data “is not crossing that bar in my head,” said committee member Jess Fiedorowicz, MD, PhD, head of the Department of Mental Health, The Ottawa Hospital, Ottawa, Ontario, Canada.

Walter Dunn, MD, PhD, director, Mood Disorders Section, West Los Angeles Veterans Affairs Medical Center, Los Angeles, agreed. Dunn said while he is a “strong advocate” for increasing treatment options for PTSD, he was “not convinced” of the efficacy of the combination given the conflicting data.

Murray Raskind, MD, professor, Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, felt it would be “hard to translate the confusing contradictory datasets to my clinical practice.”

Raskind also said he is not convinced the combination offers clinicians a new tool.

Brexpiprazole is currently approved as adjunctive treatment of major depressive disorder in adults, treatment of schizophrenia in adults and adolescents aged 13 years or older, and treatment of agitation associated with Alzheimer’s dementia.

“We already have sertraline, and we already have brexpiprazole. The prescribing physician can make the decision to progress to the combination or start with it in the patient with PTSD,” Raskind said. Other committee members agreed.

Committee members in general felt that in the real world, co-initiation of both drugs may not be the preferred approach. It’s more likely that clinicians would opt to start sertraline first, then add brexpiprazole if needed. “Third-party payers may require that,” Dunn predicted.

During the public comment period, Michael Abrams, PhD, MPH, senior health researcher with Public Citizen, said the data supporting the use of this combination for treatment of PTSD is “weak at best, based on two conflicting phase 3 trials and a questionable post hoc analysis of data from a phase 2 trial,” and he urged the committee and the FDA to reject the combination.

The lone “yes” vote for the brexpiprazole-sertraline combination in PTSD came from the patient advocate on the committee, Laura Block, PharmD, clinical pharmacist (retired), Cary, North Carolina.

Block noted that 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. “That means that there are those who are going to have difficulty accessing,” Block commented.

At the same time, Block said she would not want to offer patients “destructive false hope,” and whether it is approved, she would like to see either a phase 3 or phase 4 study.

Currently, the SSRI sertraline and paroxetine are the only FDA-approved medications for PTSD, and while these medications can be effective, many patients fail to achieve remission or discontinue treatment due to side effects or lack of response.

The proposed upfront co-initiation of brexpiprazole with sertraline is a novel treatment paradigm. If approved by the FDA, it would be the first new treatment for PTSD in more than 20 years.

The FDA is not required to follow the advice of its advisory committees, but it often does.