FDA to Review Rexulti for PTSD Treatment Amidst PDUFA Delay
Key Insights
The FDA will convene a Psychopharmacologic Drugs Advisory Committee (PDAC) to review Rexulti (brexpiprazole) in combination with sertraline for treating PTSD (search) in adults.
The FDA's decision to host a PDAC meeting indicates a delay in the Prescription Drug User Fee Act (PDUFA) target action date, originally set for February 8, 2025.
Clinical trial data supports the combination of brexpiprazole and sertraline, showing statistically significant improvements in PTSD (search) symptoms compared to sertraline alone.
The FDA plans to host a Psychopharmacologic Drugs Advisory Committee (PDAC) meeting to review the supplemental new drug application (sNDA) for Rexulti (brexpiprazole) in combination with sertraline for the treatment of adults with post-traumatic stress disorder (search) (PTSD (search)). The announcement, made by Otsuka Pharmaceutical (search) and Lundbeck, indicates that the Prescription Drug User Fee Act (PDUFA) target action date, initially set for February 8, 2025, will be delayed. A final date for the PDAC meeting has yet to be determined, but it is anticipated to occur in the first half of 2025.
The decision to convene an advisory committee does not reflect a final decision on the approvability of the sNDA. The FDA is seeking expert input on the efficacy and safety data supporting the use of brexpiprazole in combination with sertraline for PTSD (search) treatment.
Clinical Trial Data
The sNDA submission is based on data from three randomized clinical trials. The primary endpoint for all three trials was the change from randomization (week 1) to week 10 in the Clinician-Administered PTSD (search) Scale (CAPS-5) total score for brexpiprazole and sertraline combination therapy versus sertraline plus placebo in patients diagnosed with PTSD. One phase III trial, published in JAMA Psychiatry, demonstrated that the combination of brexpiprazole and sertraline significantly improved PTSD symptoms compared to sertraline alone (mean change in CAPS-5 total score: -19.2 vs -13.6 points, P<0.001).
Mary Hobart, PhD, of Otsuka Pharmaceutical (search) Development & Commercialization, and co-authors noted that the -19.2 change in the brexpiprazole group "is above existing estimates of greater than or equal to 12 to 14 points for reliable change (i.e., beyond what may be attributed to measurement error)."
Current PTSD Treatment Landscape
PTSD (search) affects approximately five percent of the population in the United States annually. Symptoms are generally grouped into four clusters: intrusion, avoidance, negative cognitions and mood, and marked alterations in arousal and reactivity. Current guideline-recommended first-line treatments include psychotherapy (e.g., cognitive behavioral therapy) and pharmacotherapy options such as sertraline and paroxetine. However, many patients are left with residual symptoms or tolerability issues, highlighting the need for novel therapies.
John Krystal, MD, of Yale School of Medicine, who was not involved with the trial, emphasized the importance of new PTSD (search) treatments, stating, "New medications that might address the important 'effectiveness gap' in PTSD could help to reduce the remaining distress, disability, and suicide risk associated with PTSD."
Brexpiprazole Background
Brexpiprazole, discovered by Otsuka and co-developed by Otsuka and Lundbeck, is an atypical antipsychotic already approved for use as an adjunctive therapy to antidepressants in adults with major depressive disorder (search) (MDD), as a treatment for schizophrenia (search) in adults and children ages 13 years and older, and for agitation associated with dementia due to Alzheimer's disease (search). The mechanism of action of brexpiprazole is unknown, but it has high receptor binding affinity to norepinephrine, serotonin, and dopamine receptors. It functions as an antagonist at norepinephrine α1B (search) and α2C receptors and serotonin 5-HT2A receptors (search), as well as a partial agonist at serotonin 5-HT1A and dopamine D2 receptors (search).
Safety and Tolerability
Across the three trials, the combination of brexpiprazole and sertraline in adult patients with PTSD (search) was generally well-tolerated. The overall incidence of treatment-emergent adverse events (TEAEs) across the three trials was 55.5% with brexpiprazole plus sertraline, and 56.2% with sertraline plus placebo. Common TEAEs included nausea, fatigue, and weight increase.