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)

• The supplemental new drug application (sNDA) for brexpiprazole in combination with sertraline for the treatment of adults with post-traumatic stress disorder (PTSD) has been accepted and filed by the FDA.
• The FDA target date (PDUFA date) for completion of the review is February 8, 2025.
• If approved, brexpiprazole and sertraline combination treatment would be the first FDA-approved pharmacological option for PTSD in more than 20 years.

PRINCETON, N.J. & DEERFIELD, Ill.--(BUSINESS WIRE)--Otsuka Pharmaceutical, Co. Ltd. (Otsuka) and H. Lundbeck A/S (Lundbeck) announce the U.S. Food and Drug Administration (FDA) has determined that the supplemental New Drug Application (sNDA) for brexpiprazole in combination with sertraline for the treatment of adults with post-traumatic stress disorder (PTSD) is sufficiently complete to permit a substantive review. The FDA has assigned the application for a Prescription Drug User Fee Act (PDUFA) target action date of February 8, 2025.

The sNDA submission is based on data from three randomized clinical trials evaluating the safety and efficacy of brexpiprazole in combination with sertraline in adult patients with PTSD. ^1,2

The primary endpoint for all three trials was the change from randomization (Week 1) to Week 10 in the Clinician-Administered PTSD Scale (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 (Phase II) and 071 (Phase III) were flexible dose trials, while Trial 072 (Phase III) 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 CAPS-5 total score from randomization (Week 1) to Week 10 (primary endpoint). In Trial 072, while the primary endpoint was not met, reductions in PTSD symptoms 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.^1,3

Across the three randomized trials, the combination of brexpiprazole and sertraline in adult patients with PTSD was 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

“Post-traumatic stress disorder is one of the most common mental health disorders in the United States. Approximately 13 million adults in the U.S. have PTSD during a given year, and between seven to eight out of every 100 will experience PTSD at some point in their lives,”^4-10 said John Kraus, M.D., Ph.D., executive vice president and chief medical officer, Otsuka. “This is a significant development, and we look forward to continuing our efforts to provide a treatment option that may benefit the millions of patients and caregivers who are impacted by the debilitating effects of PTSD.”

“Brexpiprazole in combination with sertraline could represent an important advancement over current standard of care, and we look forward to working with the FDA in the process of seeking approval of this combination,” said Johan Luthman, Ph.D., executive vice president, Lundbeck Research & Development. “We are grateful to the patients and caregivers who participated in these important trials.”

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.

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.^6-10 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.^11,12

Symptoms of PTSD are generally grouped into four clusters: intrusion (re-experiencing), avoidance, negative cognitions and mood, and marked alterations in arousal and reactivity.^7,12 Symptoms can vary over time or vary from person to person.¹² 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.⁷ Guideline recommended first-line treatment includes psychotherapy (e.g., cognitive behavioral therapy) and first line pharmacotherapy options include certain antidepressants.¹³

About REXULTI (brexpiprazole)

Brexpiprazole was approved in the U.S. 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.¹⁴

Brexpiprazole was discovered by Otsuka and is being co-developed by Otsuka and Lundbeck. The mechanism of action of brexpiprazole is unknown, however the efficacy of brexpiprazole may be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, antagonist activity at serotonin 5-HT2A receptors, as well as antagonism of alpha 1B/2C receptors.^14-16

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 (HLUNa / HLUNb, HLUNA DC / HLUNB DC) (“Lundbeck”), 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.

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.

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. Behl, S. Clinical Program of Brexpiprazole in Combination with Sertraline for Patients with Post-Traumatic Stress Disorder. Panel presentation at ASCP May 28, 2024.
4. Kilpatrick DG, Resnick HS, Milanak ME, Miller MW, Keyes KM, Friedman MJ. National estimates of exposure to traumatic events and PTSD prevalence using DSM-IV and DSM-5 criteria. J Trauma Stress. 2013;26(5):537-547.
5. Koenen KC, Ratanatharathorn A, Ng L, et al. Posttraumatic stress disorder in the World Mental Health Surveys. Psychol Med. 2017;47(13):2260-2274.
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. 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.
8. 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.
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. 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.
12. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association, 2013.
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. 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.
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 2023.

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