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

• These data represent one of the largest clinical development programs to date for adults living with PTSD and a significant development in a therapy area that hasn’t seen a new approval for a pharmacological treatment in more than 20 years.^1,2,3

• These data showed that brexpiprazole in combination with sertraline improved symptoms of PTSD in two out of the three studies, based on the primary endpoint of change in CAPS-5 total scores from Week 1 to Week 10 compared to sertraline plus placebo.¹

• Brexpiprazole in combination with sertraline was associated with greater improvements across the four symptom clusters of PTSD (re-experiencing, avoidance, negative cognition/mood and arousal/reactivity symptoms), compared to sertraline plus placebo.⁴

• No new safety observations related to brexpiprazole were identified.²

• Based on these data, Otsuka and Lundbeck submitted a supplemental New Drug Application (sNDA) in April to the U.S. Food and Drug Administration (FDA) for brexpiprazole in combination with sertraline for the treatment of adults living with PTSD.

Otsuka Pharmaceutical Development & Commercialization, Inc. (Otsuka) and Lundbeck Pharmaceuticals LLC (Lundbeck) today presented results from the Phase II (Trial 061) and Phase III trials (Trial 071 and 072) evaluating the safety and efficacy of brexpiprazole in combination with sertraline for the treatment of adults with post-traumatic stress disorder (PTSD).^1,2 The findings were presented at the American Society of Clinical Psychopharmacology (ASCP) Annual Meeting in Miami.

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The primary endpoint for all three trials was the change from Week 1 to Week 10 in the CAPS-5 total score for brexpiprazole and sertraline combination therapy versus sertraline plus placebo in patients diagnosed with PTSD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).¹

The trials were randomized, double blind, active-controlled, and Trial 061 and 071 were flexible dose trials, while Trial 072 was a fixed dose trial.¹ In Trial 061 and 071, brexpiprazole in combination with sertraline was associated with a statistically significant reduction (p<0.05) in PTSD symptoms compared to sertraline plus placebo, as measured by the change in the Clinician-Administered PTSD Scale (CAPS-5) total score from baseline to Week 10 (primary endpoint). In Trial 072, while the primary endpoint was not met, reductions in PTSD symptom severity with brexpiprazole in combination with sertraline were consistent with Trials 061 and 071. Improvements were consistently observed across the Clinical Global Impression Severity (CGI-S) scale and the four CAPS-5 clusters of re-experiencing, avoidance, negative cognition/mood and arousal/reactivity symptoms in Trials 061 and 071.^1,4

“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,” said Lori Davis, M.D., clinical professor of psychiatry in the Department of Psychiatry and Behavioral Neurobiology, University of Alabama School of Medicine. “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.”

Across the three randomized trials, the combination of brexpiprazole and sertraline in adult patients with PTSD were generally well-tolerated, and no new safety observations were identified. The safety and tolerability results were consistent with the known profile of brexpiprazole in its approved indications and what has been observed in other clinical trials. The overall incidence of treatment-emergent adverse events (TEAEs) across the three trials was 55.5 percent with brexpiprazole plus sertraline, and 56.2 percent with sertraline plus placebo.²

In Trial 061, the least squares mean change from randomization (Week 1) in CAPS-5 total score was -16.4 with brexpiprazole in combination with sertraline (p=0.011 versus sertraline plus placebo), -12.2 with brexpiprazole plus placebo, -11.4 with sertraline plus placebo, and -10.5 with placebo. In Trial 071, the least squares mean change was -19.2 with brexpiprazole in combination with sertraline (p=0.0007 versus sertraline plus placebo) and -13.6 with sertraline plus placebo. In Trial 072, the least mean change was -16.5 with brexpiprazole 2 mg/day in combination with sertraline (p=0.52 versus sertraline plus placebo), -18.3 with brexpiprazole 3 mg/day in combination with sertraline (p=0.66 versus sertraline plus placebo), and -17.6 with sertraline plus placebo.¹

“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, Otsuka. “These findings represent a remarkable advancement in managing the PTSD symptoms of those affected by this chronically misunderstood and prevalent psychiatric disorder.”

“With approximately 13 million people in the U.S. suffering from PTSD in a given year, these data are crucial to bringing forward a potential new treatment option,” said Johan Luthman, Ph.D., executive vice president, Lundbeck research & development. “We’re hopeful that brexpiprazole in combination with sertraline can become an approved treatment option for appropriate patients living with PTSD.”

About CAPS-5

The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) is a structured interview designed to assess PTSD diagnostic status and symptoms severity as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). The interview consists of 30 items, with a higher score indicating a worse outcome.⁴

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.^5,6,9-11 It may occur in people who have experienced or witnessed a traumatic event, series of events or set of circumstances. An individual may experience this as emotionally or physically harmful or life-threatening and may affect mental, physical, social, and/or spiritual well-being. Examples include physical/sexual assault, natural disasters, serious accidents, terrorist acts, war/combat, historical trauma, intimate partner violence and bullying.^7,12

Symptoms of PTSD are generally grouped into four types: intrusion (re-experiencing), avoidance, negative cognitions and mood, and marked alterations in arousal and reactivity.^5,8 Symptoms can vary over time or vary from person to person.⁷ Symptoms usually begin within 3 months of the traumatic incident, but they sometimes emerge later. 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 a medical condition.⁵ Guideline recommended first-line treatment includes psychotherapy (e.g., cognitive behavioral therapy) and first line pharmacotherapy options include certain antidepressants.¹³

About the Studies

Trials 331-201-061 (NCT03033069), 331-201-00071 (NCT04124614) and 331-201-00072 (NCT04174170) were designed to evaluate the efficacy, safety and tolerability of treatment with brexpiprazole in combination with sertraline in adults with PTSD. The trial populations included male and female patients, aged 18-65 years (inclusive), with a diagnosis of PTSD according to the DSM-5 and confirmed by the Mini International Neuropsychiatric Interview. The trials consisted of 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 a 21-day follow-up. Trial 331-201-061 was a 4-arm, double-blind, flexible-dose trial in which patients were randomized to receive flexible-dose brexpiprazole 1-3 mg/day plus sertraline 100-200 mg/day, flexible-dose brexpiprazole 1-3 mg/day plus placebo, flexible-dose sertraline 100-200 mg/day plus placebo, or placebo (double dummy) during the 11-week randomized treatment period. Trial 331-201-00071 was a 2-arm, double-blind, flexible-dose trial in which patients were randomized to receive either flexible-dose brexpiprazole 2-3 mg/day plus sertraline 150 mg/day or sertraline 150 mg/day plus placebo during the 11-week randomized treatment period. Trial 331-201-00072 was a 3-arm, double-blind, fixed-dose trial in which patients were randomized to receive either fixed-dose brexpiprazole 2 mg/day plus sertraline 150 mg/day, brexpiprazole 3 mg/day plus sertraline 150 mg/day, or sertraline 150 mg/day plus placebo during the 11-week randomized treatment period. The primary outcome in all trials was the change from randomization to week 10 in the CAPS-5 total score; in Trials 331-201-00071 and 331-201-00072 patients had to meet blinded criteria at the week 1 visit of the trial.⁴

About Brexpiprazole

Brexpiprazole was approved in the U.S. in 2015, as an adjunctive therapy to antidepressants in adults with 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. It was approved by the Ministry of Health, Labour and Welfare in Japan and by the European Medicines Agency in 2018 for the treatment of schizophrenia.³

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 activity at serotonin 5-HT1A and dopamine D2 receptors.^14,15

INDICATIONS and IMPORTANT SAFETY INFORMATION for REXULTI® (brexpiprazole)

INDICATIONS: REXULTI is a prescription medicine used to treat:

• Major depressive disorder (MDD): REXULTI is used with antidepressant medicines, when your healthcare provider determines that an antidepressant alone is not enough to treat your depression.
• Schizophrenia

It is not known if REXULTI is safe and effective in people under 18 years of age.

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 who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). REXULTI is not approved for the treatment of patients with dementia-related psychosis.

Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment. Depression and other serious mental illnesses are the most important causes of suicidal thoughts or actions. Some people may have a particularly high risk of having suicidal thoughts or actions. Patients on antidepressants and their families or caregivers should watch for new or worsening depression symptoms, especially sudden changes in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. Report any changes in these symptoms immediately to the doctor. REXULTI is not approved for the treatment of people younger than 18 years of age.

Contraindication: Do not take REXULTI if you are allergic to brexpiprazole or any of the ingredients in REXULTI. Allergic reactions have included rash, facial swelling, hives and itching, and anaphylaxis, which may include difficulty breathing, tightness in the chest, and swelling of the mouth, face, lips, or tongue.

REXULTI may cause serious side effects, including:

• Stroke in elderly people (cerebrovascular problems) that can lead to death.
• Neuroleptic Malignant Syndrome (NMS): Tell your healthcare provider right away if you have some or all of the following symptoms: high fever, stiff muscles, confusion, sweating, changes in pulse, heart rate, and blood pressure. These may be symptoms of a rare and serious condition that can lead to death. Call your healthcare provider right away if you have any of these symptoms.
• 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): Increases in blood sugar can happen in some people who take REXULTI. Extremely high blood sugar can lead to coma or death. If you have diabetes or risk factors for diabetes (such as being overweight or having a family history of diabetes), your healthcare provider should check your blood sugar before you start taking REXULTI and during your treatment.
    
    Call your healthcare provider if you have any of these symptoms of high blood sugar while taking REXULTI:
    • feel very thirsty
    • feel very hungry
    • feel sick to your stomach
    • feel weak or tired
    • need to urinate more than usual
    • feel confused, or your breath smells fruity
  • increased fat levels (cholesterol and triglycerides) in your blood.
  • weight gain. You and your healthcare provider should check your weight regularly.
• Low white blood cell count
• Decreased blood pressure (orthostatic hypotension). You may feel lightheaded or faint when you rise too quickly from a sitting or lying position.
• Seizures (convulsions)
• Problems controlling your body temperature so that you feel too warm. Avoid getting over-heated or dehydrated while taking REXULTI.
  • Do not over-exercise.
  • Stay out of the sun. Do not wear too much or heavy clothing.
  • In hot weather, stay inside in a cool place if possible.
  • Drink plenty of water.
• Difficulty swallowing that can cause food or liquid to get into your lungs.

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.

Avoid drinking alcohol while taking REXULTI.

Before taking REXULTI, tell your healthcare provider if you:

• have diabetes or high blood sugar or a family history of diabetes or high blood sugar. Your healthcare provider should check your blood sugar before you start REXULTI and during your treatment.
• have high levels of cholesterol, triglycerides, LDL-cholesterol, or low levels of HDL cholesterol
• have or had seizures (convulsions)
• have or had low or high blood pressure
• have or had heart problems or a stroke
• have or had a low white blood cell count
• are pregnant or plan to become pregnant. It is not known if REXULTI may harm your unborn baby. Using REXULTI in the last trimester of pregnancy may cause muscle movement problems, medicine withdrawal symptoms, or both of these in your newborn.
  • If you become pregnant while taking REXULTI, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. 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. You and your healthcare provider should decide if you will take REXULTI or breastfeed.

Tell your healthcare provider about all the medicines you take or recently have taken, including prescription medicines, 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 while taking REXULTI without talking to your healthcare provider first.

The most common side effects of REXULTI include weight gain and an inner sense of restlessness such as feeling like you need to move.

Tell your healthcare provider if you experience abnormal muscle spasms or contractions, which may be a sign of a condition called dystonia.

These are not all the possible side effects of REXULTI. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about your health or medicines, including side effects.

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 U.S. 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 Pharmaceuticals LLC is a wholly owned US subsidiary of H. Lundbeck A/S (HLUNa / HLUNb, HLUNA DC / HLUNB DC), a global biopharmaceutical company focused exclusively on neuroscience, with more than 70 years of experience in 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 challenges. We develop transformative medicines targeting people for whom there are few, if any, treatment options. Our goal is to create long term value and make a positive contribution to people and societies, everywhere we operate. We are committed to fighting stigma and discrimination, and we act to improve health equity for the people we serve and the communities we are part of.

Too many people worldwide live with brain diseases – complex conditions often invisible to others that nonetheless take a tremendous toll on individuals, families and societies. We are committed to fighting stigma and discrimination against people living with brain diseases and advocating for broader social acceptance of people with brain health conditions. Every day, we strive for improved treatment and a better life for people living with brain disease.

We have approximately 5,700 employees, and our products are available in more than 100 countries. Our research programs tackle some of the most complex challenges in neuroscience, and our pipeline is focused on bringing forward transformative treatments for brain diseases for which there are few, if any therapeutic options. We have research facilities in Denmark and the United States, and our production facilities are located in Denmark, France, and Italy.

Lundbeck US comprises the wholly owned US subsidiaries of H. Lundbeck A/S, including Lundbeck LLC and Lundbeck Pharmaceuticals LLC. With a workforce of more than 1,000 colleagues, Lundbeck US is deeply committed to enhancing the lives of patients, families, and caregivers through focused innovation in neuroscience. For additional information, please visit Lundbeck.com/us and connect with us on LinkedIn and X at @LundbeckUS.

References

1. Behl S et al. Efficacy of Brexpiprazole in Combination with Sertraline for Patients with Post-Traumatic Stress Disorder: Summary of Data from Phase 2 and Phase 3 Randomized Clinical Trials. Presented at ASCP 2024 (May 28-31).
2. Behl S et al. Safety and Tolerability of Brexpiprazole in Combination with Sertraline for Patients with Post-Traumatic Stress Disorder: Summary of Data from Phase 2 and Phase 3 Randomized Clinical Trials. Presented at ASCP 2024 (May 28-31).
3. Otsuka. Otsuka Pharmaceutical and Lundbeck Announce Topline Results from Two Phase 3 Trials of Brexpiprazole as Combination Therapy with Sertraline for the Treatment of Post-Traumatic Stress Disorder in Adults. Last accessed: May 20, 2024. Available at: https://www.otsuka-us.com/news/otsuka-pharmaceutical-and-lundbeck-announce-topline-results-two-phase-3-trials-brexpiprazole.
4. Behl, S. Clinical Program of Brexpiprazole in Combination with Sertraline for Patients with Post-Traumatic Stress Disorder. Panel presentation at ASCP May 28, 2024.
5. 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.
6. 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.
7. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association, 2013.
8. Wang PS, Berglund P, Olfson M, Pincus HA, Wells KB, Kessler RC. Failure and delay in initial treatment contact after first onset of mental disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):603-613.
9. U.S. Department of Veterans Affairs. How Common Is PTSD in Adults? Last updated: Feb. 3, 2023. Last accessed: April 30, 2024. Available at: https://www.ptsd.va.gov/understand/common/common_adults.asp.
10. US Census Bureau 2022 Data.
11. 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.
12. American Psychiatric Association. What is Posttraumatic Stress Disorder (PTSD)? Last updated: November 2022. Last accessed: April 30, 2024. Available at: https://www.psychiatry.org/patients-families/ptsd/what-is-ptsd.
13. VA/DoD Clinical Practice Guideline for Management of PTSD – Provider Summary 2023. Version 4.0. US Department of Veterans Affairs, US Department of Defense; 2023. Last accessed May 22, 2024. https://www.healthquality.va.gov/guidelines/MH/ptsd/VA-DoD-CPG-PTSD-Provider-Summary.pdf.
14. 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.
15. REXULTI^® (brexpiprazole). Prescribing Information. FDA. Reference ID: 4911319. May 2023.

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