JAMA Psychiatry Publishes Results of Otsuka and Lundbeck's Phase 3 Trial of Brexpiprazole in Combination with Sertraline in Treatment of Post-Traumatic Stress Disorder (PTSD) in Adults

• 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 lifetime^2-6

PRINCETON, N.J. & DEERFIELD, Ill.--(BUSINESS WIRE)--Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) and Lundbeck 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}

INDICATIONS and IMPORTANT SAFETY INFORMATION for REXULTI^® (brexpiprazole)

INDICATIONS:

REXULTI is a prescription medicine used:

• along with antidepressant medicines to treat major depressive disorder (MDD) in adults
• to treat schizophrenia in adults and children ages 13 years and older
• to treat agitation that may happen with dementia due to Alzheimer’s disease

REXULTI should not be used as an “as needed” treatment for agitation that may happen with dementia due to Alzheimer’s disease.

It is not known if REXULTI is safe and effective in children with MDD.

It is not known if REXULTI is safe and effective in children under 13 years of age with schizophrenia.

IMPORTANT SAFETY INFORMATION:

Increased risk of death in elderly people with dementia-related psychosis. Medicines like REXULTI can raise the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). REXULTI is not approved for the treatment of people with dementia-related psychosis without agitation that may happen with dementia due to Alzheimer’s disease. Increased risk of suicidal thoughts and actions. REXULTI and antidepressant medicines may increase suicidal thoughts and actions in pediatric patients and young adult patients, especially within the first few months of treatment or when the dose is changed. Depression and other mental illnesses are the most important causes of suicidal thoughts and actions. All patients on antidepressants and their families or caregivers should closely watch for new or worsening depression symptoms, especially sudden changes in mood, behaviors, thoughts, or feelings. Report any change in these symptoms immediately to the doctor.

Do not take REXULTI if you are allergic to brexpiprazole or any of the ingredients in REXULTI.

REXULTI may cause serious side effects, including:

• Cerebrovascular problems, including stroke, in elderly people with dementia-related psychosis that can lead to death.
• Neuroleptic malignant syndrome (NMS) is a serious condition that can lead to death. Call your healthcare provider or go to the nearest hospital emergency room right away if you have some or all of the following signs and symptoms of NMS: high fever; changes in your pulse, blood pressure, heart rate, and breathing; stiff muscles; confusion; increased sweating
• Uncontrolled body movements (tardive dyskinesia). REXULTI may cause movements that you cannot control in your face, tongue, or other body parts. Tardive dyskinesia may not go away, even if you stop taking REXULTI. Tardive dyskinesia may also start after you stop taking REXULTI.
• Problems with your metabolism such as:
  • high blood sugar (hyperglycemia) and diabetes. Increases in blood sugar can happen in some people who take REXULTI. Extremely high blood sugar can lead to coma or death. Your healthcare provider should check your blood sugar before you start, or soon after you start REXULTI and then regularly during long term treatment with REXULTI. Call your healthcare provider if you have any of these symptoms of high blood sugar during treatment with REXULTI:
    • feel very thirsty
    • feel very hungry
    • feel sick to your stomach
    • need to urinate more than usual
    • feel weak or tired
    • feel confused, or your breath smells fruity 
    • increased fat levels (cholesterol and triglycerides) in your blood. Your healthcare provider should check the fat levels in your blood before you start, or soon after you start REXULTI, and then periodically during treatment with REXULTI.
    • weight gain. You and your healthcare provider should check your weight before you start and often during treatment with REXULTI.
• Unusual and uncontrollable (compulsive) urges. Some people taking REXULTI have had strong unusual urges, to gamble and gambling that cannot be controlled (compulsive gambling). Other compulsive urges include sexual urges, shopping, and eating or binge eating. If you or your family members notice that you are having new or unusual strong urges or behaviors, talk to your healthcare provider.
• Low white blood cell count. Your healthcare provider may do blood tests during the first few months of treatment with REXULTI.
• Decreased blood pressure (orthostatic hypotension) and fainting. You may feel dizzy, lightheaded or pass out (faint) when you rise too quickly from a sitting or lying position.
• Falls. REXULTI may make you sleepy or dizzy, may cause a decrease in your blood pressure when changing position (orthostatic hypotension), and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries.
• Seizures (convulsions).
• Problems controlling your body temperature so that you feel too warm. Do not become too hot or dehydrated during treatment with REXULTI. Do not exercise too much. In hot weather, stay inside in a cool place if possible. Stay out of the sun. Do not wear too much clothing or heavy clothing. Drink plenty of water.
• Difficulty swallowing that can cause food or liquid to get into your lungs.
• Sleepiness, drowsiness, feeling tired, difficulty thinking and doing normal activities. Do not drive a car, operate machinery, or do other dangerous activities until you know how REXULTI affects you. REXULTI may make you feel drowsy.

Before taking REXULTI, tell your healthcare provider about all of your medical conditions, including if you:

• have or have had heart problems or a stroke
• have or have had low or high blood pressure
• have or have had diabetes or high blood sugar or a family history of diabetes or high blood sugar.
• have or have had high levels of total cholesterol, LDL cholesterol, or triglycerides, or low levels of HDL cholesterol
• have or have had seizures (convulsions)
• have or have had kidney or liver problems
• have or have had a low white blood cell count
• are pregnant or plan to become pregnant. REXULTI may harm your unborn baby. Taking REXULTI during your third trimester of pregnancy may cause your baby to have abnormal muscle movements or withdrawal symptoms after birth. Talk to your healthcare provider about the risk to your unborn baby if you take REXULTI during pregnancy.
  • Tell your healthcare provider if you become pregnant or think you are pregnant during treatment with REXULTI.
  • There is a pregnancy exposure registry for women who are exposed to REXULTI during pregnancy. If you become pregnant during treatment with REXULTI, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychiatric Medications. You can register by calling 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.
• are breastfeeding or plan to breastfeed. It is not known if REXULTI passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with REXULTI.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. REXULTI and other medicines may affect each other causing possible serious side effects. REXULTI may affect the way other medicines work, and other medicines may affect how REXULTI works. Your healthcare provider can tell you if it is safe to take REXULTI with your other medicines. Do not start or stop any medicines during treatment with REXULTI without first talking to your healthcare provider.

The most common side effects of REXULTI include weight gain, sleepiness, dizziness, common cold symptoms, and restlessness or feeling like you need to move (akathisia).

These are not all the possible side effects of REXULTI. For more information, ask your healthcare provider or pharmacist.

You are encouraged to report side effects of REXULTI (brexpiprazole). Please contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).

Please read FULL PRESCRIBING INFORMATION, including BOXED WARNING, and MEDICATION GUIDE for REXULTI

About Otsuka

Otsuka Pharmaceutical Co., Ltd. is a global healthcare company with the corporate philosophy: Otsuka–people creating new products for better health worldwide. Otsuka researches, develops, manufactures, and markets innovative products, with a focus on pharmaceutical products to meet unmet medical needs and nutraceutical products for the maintenance of everyday health.

In pharmaceuticals, Otsuka is a leader in the challenging areas of mental, renal, and cardiovascular health and has additional research programs in oncology and on several under-addressed diseases including tuberculosis, a significant global public health issue. These commitments illustrate how Otsuka is a “big venture” company at heart, applying a youthful spirit of creativity in everything it does.

Otsuka established a presence in the U.S. in 1973 and today its U.S. affiliates include Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) and Otsuka America Pharmaceutical, Inc. (OAPI). These two companies’ 2,250 employees in the U.S. develop and commercialize medicines in the areas of mental health and nephrology, using cutting-edge technology to address unmet healthcare needs.

OPDC and OAPI are indirect subsidiaries of Otsuka Pharmaceutical Co., Ltd., which is a subsidiary of Otsuka Holdings Co., Ltd. headquartered in Tokyo, Japan. The Otsuka group of companies employed 34,400 people worldwide and had consolidated sales of approximately USD 14.2 billion in 2023.

All Otsuka stories start by taking the road less traveled. Learn more about Otsuka in the U.S. at www.otsuka-us.com and connect with us on LinkedIn and Twitter at @OtsukaUS. Otsuka Pharmaceutical Co., Ltd.’s global website is accessible at https://www.otsuka.co.jp/en/.

About Lundbeck

Lundbeck is a global biopharmaceutical company focusing exclusively on brain health. With more than 70 years of experience in neuroscience, we are committed to improving the lives of people with neurological and psychiatric diseases.

As a focused innovator, we strive for our research and development programs to tackle some of the most complex neurological challenges. We develop transformative medicines targeting people for whom there are few or no treatments available, expanding into neuro-specialty and neuro-rare from our strong legacy within psychiatry and neurology. We strive to create long-term value for our shareholders by making positive contributions to patients, their families and society as a whole.

Lundbeck US comprises the wholly owned US subsidiaries of H. Lundbeck A/S (HLUNa / HLUNb, HLUNA DC / HLUNB DC) (“Lundbeck”), including Lundbeck LLC and Lundbeck Pharmaceuticals LLC.

For additional information on Lundbeck US, please visit Lundbeck.com/us and connect with us on LinkedIn and X at @LundbeckUS.

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.