FDA’s outside experts weren’t sold on the trial data for brexpiprazole (Rexulti) as an adjunctive treatment for post-traumatic stress disorder (PTSD), sinking its prospects for approval in this setting.
In a 10-1 vote on Friday, members of the agency’s Psychopharmacologic Drugs Advisory Committee said the efficacy of the atypical antipsychotic in combination with sertraline (Zoloft), which is already approved for PTSD, was not established by the data package from Otsuka Pharmaceutical that included a positive phase III trial, a negative phase III trial, and a phase II study.
The studies fell short of FDA’s typical standard of two adequate and well-controlled studies, said Jess Fiedorowicz, MD, PhD, of the University of Ottawa in Ontario.
“I may have been swayed if this represented a major advance in the field,” said panelist Walter Dunn, MD, PhD, of the University of California Los Angeles and the West Los Angeles VA Medical Center. “At best I think it’s potentially incremental.”
Brexpiprazole is an atypical antipsychotic that is currently approved for schizophrenia, as adjunctive therapy for major depressive disorder, and for agitation associated with dementia. Sertraline is a selective serotonin reuptake inhibitor (SSRI) that along with PTSD is approved for depression, panic disorder, and several other psychiatric conditions.
In the positive phase III trial, sertraline plus brexpiprazole led to a significant improvement in PTSD symptoms as measured by the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) versus sertraline plus placebo (-19.2 vs -13.6 points, P=0.0007). CAPS-5 ranks the severity of 20 PTSD symptoms from 0 to 80 (not present to most severe).
Dunn called that 5.6-point difference potentially not clinically significant.
“Even if [the combination] was unequivocally advantageous … I would still be hesitant about changing my practice guidelines,” he continued. “I can’t imagine that the VA … would recommend starting with a combination treatment, especially in a population that has not been shown to be treatment resistant.”
PTSD affects about 3.6% of U.S. adults each year, with a higher prevalence in women. It’s characterized by intrusive memories, hyperarousal, and avoidant behavior after exposure to actual or threatened death, serious injury, or sexual violence.
While no new safety signals emerged in the trials, panel members were concerned with starting patients off on a powerful duo containing an antipsychotic, which is associated with weight gain and potentially serious side effects, including suicidal ideation.
There’s an unmet need for effective treatments in PTSD, as current options include psychotherapy and the SSRIs sertraline and paroxetine (Paxil). These options carry various adverse effects, and the response rate for SSRIs is 37% to 62%, according to the FDA. Many treatments, including atypical antipsychotics, are prescribed off-label.
Jacob Ballon, MD, MPH, of Stanford University in California, said that while there was some evidence the sertraline-brexpiprazole combination may be effective, the studies weren’t “a slam dunk that I would want to start both of these medicines together — nor do I think that that’s a really safe and purposeful treatment.”
Ballon did praise the trial data for providing some evidence for prescribing brexpiprazole off-label in a step-wise fashion.
However, patient representative and retired clinical pharmacist Laura Block, PharmD, argued that not approving brexpiprazole in PTSD could lead to accessibility issues or high out-of-pocket costs for patients.
“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,” said Block, who was the only “yes” vote on the committee.
Murray Raskind, MD, of the University of Washington in Seattle, encouraged Otsuka to assess the subgroup of veterans with combat trauma PTSD, saying the sponsor “may be pleasantly surprised.”
The FDA isn’t required to follow the recommendations of its advisory committees, but it typically does.
