FDA Accepts Brexpiprazole-Sertraline Combination for PTSD Review, Marking First Potential New Treatment in Over 20 Years
核心洞察
The FDA has accepted Otsuka and Lundbeck's supplemental New Drug Application for brexpiprazole combined with sertraline to treat adults with PTSD (搜索), with a target review completion date of February 8, 2025.
Clinical trials showed the combination therapy significantly reduced PTSD (搜索) symptoms compared to sertraline alone in two of three studies, with improvements observed across all four symptom clusters of re-experiencing, avoidance, negative cognition/mood, and arousal/reactivity.
If approved, this would represent the first FDA-approved pharmacological treatment for PTSD (搜索) in more than 20 years, addressing a critical unmet need for the approximately 13 million Americans affected by PTSD annually.
The U.S. Food and Drug Administration has accepted for review a supplemental New Drug Application for brexpiprazole in combination with sertraline for treating adults with post-traumatic stress disorder (搜索), potentially marking the first new pharmacological treatment approval for PTSD (搜索) in over two decades. Otsuka Pharmaceutical (搜索) and H. Lundbeck A/S announced that the FDA has assigned a Prescription Drug User Fee Act target action date of February 8, 2025, for completing its review of the combination therapy.
The regulatory submission is supported by data from three randomized clinical trials evaluating the safety and efficacy of brexpiprazole combined with sertraline in adult patients with PTSD (搜索). According to the companies, approximately 13 million adults in the United States have PTSD during a given year, with seven to eight out of every 100 people experiencing the condition at some point in their lives.
Clinical Trial Results Demonstrate Efficacy
The comprehensive clinical development program included one Phase II trial (Trial 061) and two Phase III trials (Trial 071 and 072). All three studies used the same primary endpoint: change from randomization at Week 1 to Week 10 in the Clinician-Administered PTSD (搜索) Scale (CAPS-5) total score for brexpiprazole and sertraline combination therapy versus sertraline plus placebo.
In Trials 061 and 071, both flexible-dose studies, brexpiprazole in combination with sertraline demonstrated statistically significant reductions in PTSD (搜索) symptoms compared to sertraline plus placebo (p<0.05). Trial 072, a fixed-dose study, did not meet its primary endpoint, though reductions in PTSD symptoms with the combination therapy were consistent with the other two trials.
Specific efficacy data showed meaningful improvements across studies. In Trial 061, the least squares mean change from randomization in CAPS-5 total score was -16.4 with brexpiprazole in combination with sertraline (p=0.011 versus sertraline plus placebo), compared to -11.4 with sertraline plus placebo. Trial 071 demonstrated even greater separation, with a least squares mean change of -19.2 for the combination therapy (p=0.0007 versus sertraline plus placebo) compared to -13.6 with sertraline plus placebo.
Improvements Across All PTSD Symptom Clusters
The combination therapy showed consistent improvements across the Clinical Global Impression Severity scale and all four CAPS-5 symptom clusters defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. These clusters include re-experiencing, avoidance, negative cognition/mood, and arousal/reactivity symptoms.
"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 (搜索) as defined by the DSM-5," said Lori Davis, M.D., clinical professor of psychiatry in the Department of Psychiatry and Behavioral Neurobiology at the University of Alabama School of Medicine.
Safety Profile Consistent with Known Drug Characteristics
Across the three randomized trials, the combination of brexpiprazole and sertraline was generally well-tolerated, with no new safety observations identified. The safety and tolerability results aligned with the known profile of brexpiprazole in its approved indications. The overall incidence of treatment-emergent adverse events across the three trials was 55.5 percent with brexpiprazole plus sertraline, compared to 56.2 percent with sertraline plus placebo.
Addressing a Critical Treatment Gap
The potential approval represents a significant development in PTSD (搜索) treatment, where therapeutic options have remained limited. "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," said John Kraus, M.D., Ph.D., executive vice president and chief medical officer at Otsuka.
Current guideline-recommended first-line treatments include psychotherapy such as cognitive behavioral therapy and certain antidepressants as first-line pharmacotherapy options. However, only approximately half of people living with PTSD (搜索) seek treatment, despite it being one of the most common mental health conditions in the United States, affecting approximately five percent of the population during a given year.
About the Combination Therapy
Brexpiprazole, marketed as REXULTI, was originally approved in the U.S. in 2015 as an adjunctive therapy to antidepressants in adults with major depressive disorder (搜索) and as a treatment for schizophrenia (搜索) in adults. The drug was most recently approved for treating agitation associated with dementia (搜索) due to Alzheimer's disease (搜索) in May 2023.
The mechanism of action of brexpiprazole is unknown, though its efficacy may be mediated through a combination of partial agonist activity at serotonin 5-HT1A (搜索) and dopamine D2 receptors (搜索), antagonist activity at serotonin 5-HT2A receptors (搜索), and antagonism of alpha 1B/2C receptors (搜索). Brexpiprazole was discovered by Otsuka and is being co-developed by Otsuka and Lundbeck.
Johan Luthman, Ph.D., executive vice president of Lundbeck Research & Development, emphasized the potential impact: "With approximately 13 million people in the U.S. suffering from PTSD (搜索) in a given year, these data are crucial to bringing forward a potential new treatment option."