PTSD Treatment: Brexpiprazole plus Sertraline May be First New Option for Patients in 2 Decades

_{©Feng Yu/AdobeStock}

A new pharmacologic treatment option for post-traumatic stress disorder (PTSD) may become available as early as February 2025.

In June 2024, the US Food and Drug Administration (FDA) determined that the supplemental new drug application (sNDA) for brexpiprazole in combination with sertraline (Otsuka, Lundbeck) for the treatment of PTSD in adults was “sufficiently complete to permit a substantive review,” according to an Otsuka press release.¹

The FDA has set a Prescription Drug User Fee Act target action date of February 8, 2025, to complete its review. If approved, brexpiprazole plus sertraline would be the first treatment to receive FDA approval for PTSD in over 20 years.¹

The sNDA submission for brexpiprazole in combination with sertraline was based on data from 3 double-blind randomized clinical trials that examined the safety and efficacy of the treatment in adults with PTSD. The results from the phase 2 (#061) and phase 3 trials (#071 and #072) were recently presented at the American Society of Clinical Psychopharmacology annual meeting, held May 28-31, 2024, in Miami, FL.¹

The Studies

The primary endpoint for all 3 studies was the change from week 1 to week 10 in the Clinician-Administered PTSD Scale (CAPS-5) total score for brexpiprazole in combination with sertraline compared to sertraline plus placebo in patients aged 18 to 65 years diagnosed with PTSD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). CAPS-5 is a structured interview consisting of 30 items designed to analyze PTSD status and symptom severity, with a higher score indicating a worse outcome, according to Otsuka.¹

Also, all 3 studies had a 1-week double-blind placebo run-in period followed by 11 weeks of double-blind randomized treatment for a continuous 12-week double-blind treatment period with 21 days of follow-up.¹

Trial 061 (NCT03033069) was a 4-arm, flexible-dose phase 2 study. Participants received either brexpiprazole 1-3 mg/day plus sertraline 100-200 mg/day, brexpiprazole 1-3 mg/day plus placebo, sertraline 100-200 mg/day plus placebo, or placebo.²

Trial 071 (NCT04124614) was a 2 arm, flexible-dose phase 3 study in which participants received either brexpiprazole 2-3 mg/day plus sertraline 150 mg/day or sertraline 150 mg/day plus placebo.²

Trial 072 (NCT04174170) was a 3-arm fixed-dose phase 3 trial where participants received either brexpiprazole 2 mg plus sertraline 150 mg daily, brexpiprazole 3 mg plus sertraline 150 mg per day, or sertraline 150 mg/day plus placebo.²

Findings. Trial 061 and 071 met the primary endpoint, with data showing that brexpiprazole in combination with sertraline was associated with a statistically significant reduction (P < .05) in PTSD symptoms compared to sertraline plus placebo. While trial 072 did not meet the primary endpoint, results showed that the reductions in symptom severity with brexpiprazole in combination with sertraline were consistent with trials 061 and 071, according to the company.²

In addition, in trials 061 and 071, researchers observed consistent improvements across the Clinical Global Impression Severity (CGI-S) scale as well as the 4 CAPS-5 clusters of re-experiencing, avoidance, negative cognition/mood, and arousal/reactivity symptoms of PTSD.²

“Only approximately half of people living with PTSD seek treatment, even though it is one of the most common mental health conditions in the United States,” Lori Davis, MD, clinical professor of psychiatry, Department of Psychiatry and Behavioral Neurobiology, University of Alabama School of Medicine, said in a May 2024 press release.² “For the first time, we now have data from a comprehensive clinical trial program that show a combination of medicines can help improve the four symptom clusters of PTSD as defined by the DSM-5.”

Brexpiprazole in combination with sertraline in patients with PTSD was generally well-tolerated and no new safety observations were noted across the 3 studies. The overall incidence of treatment-emergent adverse events across all studies was 55.5% with brexpiprazole plus sertraline and 56.2% with sertraline plus placebo, according to Otsuka.²

“Lack of recognition and misdiagnosis of PTSD can result in ineffective management, with the average time from onset of symptoms to treatment being 12 years,” John Kraus, MD, PhD, executive vice president and chief medical officer, Otsuka, said in the press statement.² “These findings represent a remarkable advancement in managing the PTSD symptoms of those affected by this chronically misunderstood and prevalent psychiatric disorder.”

Brexpiprazole was first approved in the US in 2015 as an adjunctive therapy to antidepressants in adults with major depressive disorder as well as for schizophrenia in adults. In May 2023, brexpiprazole received FDA approval for the treatment of agitation associated with dementia due to Alzheimer disease.²

References:

1. Otsuka and Lundbeck announce FDA acceptance of sNDA filing for brexpiprazole in combination with sertraline for the treatment of adults with post-traumatic stress disorder (PTSD). News item. Otsuka. June 25, 2024. Accessed August 15, 2024. https://www.otsuka-us.com/news/otsuka-and-lundbeck-announce-fda-acceptance-snda-filing-brexpiprazole-combination-sertraline-0
2. Otsuka and Lundbeck present results from three clinical trials of brexpiprazole in combination with sertraline for the treatment of post-traumatic stress disorder (PTSD) in adults. News item. Otsuka. May 28, 2024. Accessed August 15, 2024. https://www.otsuka-us.com/news/otsuka-and-lundbeck-present-results-three-clinical-trials-brexpiprazole-combination-sertraline