Brexpiprazole

RSS Brexpiprazole in combination with sertraline demonstrated a statistically significant reduction in overall PTSD symptoms compared to sertraline plus placebo, as measured by change in CAPS-5 total score from Week 1 to Week 101 The safety profile of brexpiprazole in combination with sertraline was consistent with that of brexpiprazole in approved indications1 Otsuka and Lundbeck submitted an sNDA for brexpiprazole in combination with sertraline for the treatment of adults with PTSD in April 2024. The sNDA is currently under FDA review with a PDUFA target date of February 8, 2025 PTSD is a highly prevalent, trauma-based neuropsychiatric disorder that impacts approximately 13 million U.S. adults in a given year, and nearly 6 in 100 people will be diagnosed with PTSD in their lifetime2-6 Otsuka Pharmaceutical Co., Ltd. (Otsuka) announces that its US subsidiary Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) and Lundbeck Pharmaceuticals LLC (Lundbeck) today announced that the full results of a Phase 3 trial of brexpiprazole in combination with sertraline for the treatment of PTSD in adults have been published in JAMA Psychiatry. The results showed that in adults with PTSD, treatment with brexpiprazole in combination with sertraline resulted in statistically significant greater improvement of PTSD symptoms vs treatment with sertraline plus placebo, as measured by change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total score from Week 1 to Week 10.1 "About 6% of the United States population will have PTSD at some point in their lives, but around only half will seek treatment," said Lori Davis, M.D., clinical professor of psychiatry in the Department of Psychiatry and Behavioral Neurobiology, University of Alabama School of Medicine, who served as lead author on the JAMA Psychiatry manuscript. "The Phase 3 results are an important and encouraging step forward in the hopes of providing PTSD patients with a new therapeutic option in the future." About the Phase 3 Trial The Phase 3 randomized, double-blind, active-controlled, parallel-arm trial (NCT04124614) evaluated the efficacy, safety, and tolerability of brexpiprazole in combination with sertraline for the treatment of PTSD. The trial included 416 adult outpatients who were randomized to receive either brexpiprazole (2-3 mg/day) with sertraline (150 mg/day) or sertraline (150 mg/day) with a placebo. The primary endpoint was the change in CAPS-5 total score from randomization (Week 1) to Week 10. Patients receiving brexpiprazole with sertraline showed a statistically significant greater improvement in CAPS-5 total score (-19.2) compared to those receiving sertraline with placebo (-13.6), with a least squares (LS) mean difference of -5.59 (95% CI: -8.79 to -2.38; P<.001). Additionally, both secondary endpoints, the change in the Clinical Global Impression- Severity of Illness score (CGI-S) randomization (week 1) to week 10 and the change in the Brief Inventory of Psychosocial Function (B-IPF) from baseline (Day 0) to week 12, were also met.1 "The clinical trial results demonstrate the potential of brexpiprazole in combination with sertraline as a treatment option for patients with PTSD, a condition that affects millions within the United States," said John Kraus, M.D., Ph.D., executive vice president and chief medical officer, Otsuka Pharmaceutical Development & Commercialization, Inc. "The combination of brexpiprazole and sertraline demonstrated meaningful improvements in PTSD symptoms." The safety profile of brexpiprazole in combination with sertraline was consistent with that of brexpiprazole in approved indications. The proportion of treated participants who discontinued due to adverse events was 3.9% (8/205) for brexpiprazole + sertraline and 10.2% (20/196) for sertraline + placebo.1 The adverse events occurring in >=5% for brexpiprazole in combination with sertraline (n=205) compared to sertraline and placebo (n=196) were nausea (12.2% vs 11.7%), fatigue (6.8% vs 4.1%), weight increase (5.9% vs 1.5%), and somnolence (5.4% vs. 2.6%), respectively.1 "The outcome of this trial provides us with an opportunity to help patients with PTSD," said Johan Luthman, executive vice president and head of Research & Development at Lundbeck. "With these promising results, we are committed to working closely with the FDA to help bring brexpiprazole in combination with sertraline to the healthcare professionals serving the PTSD patient community." About CAPS-5 The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) is a structured interview designed to assess PTSD diagnostic status and symptom severity as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). The CAPS-5 consists of 30 items, with a higher score indicating a worse outcome.1 The CAPS-5 includes 20 DSM-5 PTSD-symptom items that are each scored from 0 (absent) to 4 (extreme/incapacitating). The total score is calculated by summing the 20 items, and symptom cluster scores by summing specific items: Intrusion (items 1-5); Avoidance (items 6-7); Negative cognitions and mood (items 8-14); and Arousal and reactivity (items 15-20).1 The CGI-S is a 7-point categorical scale, originally developed for mental disorders, but now applied to various illnesses, that requires a clinician to rate the severity of a patient's illness at the time of assessment, relative to the clinician's experience with patients who have the same diagnosis.7 The B-IPF is an abridged, 7-item version of the Inventory of Psychosocial Functioning (IPF) which assesses PTSD-related functional impairment in the prior 30 days across the same domains that are assessed by the 80-item version of the IPF; each item on the B-IPF corresponds to one IPF functional domain.8 About Post-Traumatic Stress Disorder PTSD is one of the most common mental health disorders in the United States, with approximately five percent of the population affected during a given year.2, 4, 9, 10 Most patients (>80%) with PTSD in the United States are in the civilian population.4, 11 It may occur in people who have experienced or witnessed a traumatic event, series of events or set of circumstances. An individual may experience an event that is emotionally or physically harmful or life-threatening which may affect mental, physical, social, and/or spiritual well-being. Examples of traumatic events include physical/sexual assault, natural disasters, serious accidents, terrorist acts, war/combat, historical trauma, intimate partner violence and bullying.12, 13 Symptoms of PTSD are generally grouped into four symptom clusters: intrusion (re-experiencing), persistent avoidance of stimuli, negative alterations in cognitions and mood, and marked alterations in arousal and reactivity. Individual symptom type and intensity can fluctuate over time and between individuals. To meet the criteria for PTSD diagnosis, symptoms must last longer than one month, and they must be severe enough to interfere with aspects of daily life, such as relationships or work. Symptoms also must not be due to medications, substance use, or another medical condition.10, 12 The average time from index trauma to symptom presentation is 2.2 years, and the average time from index trauma to PTSD diagnosis is 8.7 years.14 About Brexpiprazole Brexpiprazole was approved in the U.S. by the FDA in 2015, as an adjunctive therapy to antidepressants in adults with major depressive disorder (MDD) and as a treatment for schizophrenia in adults. Most recently, brexpiprazole was approved in the U.S. for the treatment of agitation associated with dementia due to Alzheimer's disease, in May 2023. Brexpiprazole was also approved by Health Canada for schizophrenia and adjunctive treatment of MDD in 2017 and 2019, respectively, and for agitation associated with dementia due to Alzheimer's disease in 2024. It was approved by the European Medicines Agency in 2018 for the treatment of schizophrenia and the Ministry of Health, Labour and Welfare in Japan for the treatment of schizophrenia and MDD in 2018 and 2023, respectively. Brexpiprazole was discovered by Otsuka and is being co-developed by Otsuka and Lundbeck. The mechanism of action of brexpiprazole is unknown. Brexpiprazole has high receptor binding affinity to norepinephrine, serotonin and dopamine receptors. It is an antagonist at norepinephrine α1B and α2C receptors and serotonin 5-HT2A receptors, as well as a partial agonist at serotonin 5-HT1A and dopamine D2 receptors.15, 16 References 1. Davis LL, Behl S, Lee D, et al. Brexpiprazole and Sertraline Combination Treatment in Posttraumatic Stress Disorder. JAMA Psychiatry. Published online December 18, 2024. doi:10.1001/jamapsychiatry.2024.3996 2. U.S. Department of Veterans Affairs. How Common Is PTSD in Adults? Accessed September 2024. www.ptsd.va.gov/understand/common/common_adults.asp. 3. US Census Bureau. (2022). National Population by Characteristics: 2020-2022. Retrieved from www.census.gov/data/tables/time-series/demo/popest/2020s-national-detail.html. 4. Lehavot K, Katon JG, Chen JA, Fortney JC, Simpson TL. Post-traumatic Stress Disorder by Gender and Veteran Status [published correction appears in Am J Prev Med. 2019 Oct;57(4):573]. Am J Prev Med. 2018;54(1):e1-e9. 5. Goldstein RB, Smith SM, Chou SP, et al. The epidemiology of DSM-5 posttraumatic stress disorder in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions-III. Soc Psychiatry Psychiatr Epidemiol. 2016;51(8):1137-1148. 6. Schein J, Houle C, Urganus A, et al. Prevalence of post-traumatic stress disorder in the United States: a systematic literature review. Curr Med Res Opin. 2021;37(12):2151-2161. 7. Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont). 2007;4(7):28-37. 8. U.S. Department of Veterans Affairs. Inventory of Psychosocial Functioning (IPF). Accessed December 2024. https://www.ptsd.va.gov/professional/assessment/functioning-other/ipf_psychosocial_function.asp 9. Kessler RC, Petukhova M, Sampson NA, Zaslavsky AM, Wittchen H -U. Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatr Res. 2012;21(3):169-184. 10. Lancaster CL, Teeters JB, Gros DF, Back SE. Posttraumatic Stress Disorder: Overview of Evidence-Based Assessment and Treatment. J Clin Med. 2016;5(11):105. 11. Davis LL, Schein J, Cloutier M, et al. The Economic Burden of Posttraumatic Stress Disorder in the United States From a Societal Perspective. J Clin Psychiatry. 2022;83(3):21m14116. 12. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association, 2013 13. American Psychiatric Association. What is Posttraumatic Stress Disorder (PTSD)? Last updated: November 2022. Last accessed: August 28, 2024. Available at: www.psychiatry.org/patients-families/ptsd/what-is-ptsd. 14. Davis LL, Urganus A, Gagnon-Sanschagrin P, et al. Patient journey of civilian adults diagnosed with posttraumatic stress disorder-A chart review study. Curr Med Res Opin. 2024;40(3):505-516. 15. Maeda K, Sugino H, Akazawa H, et al. Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator. J Pharmacol Exp Ther. 2014;350(3):589-604. 16. REXULTI® (brexpiprazole). Prescribing Information. FDA. Reference ID: 4911319. May 2024.