• The flexible dose phase 3 trial met its primary endpoint, while the fixed dose phase 3 trial missed its primary endpoint 

  • Otsuka and Lundbeck will discuss these results with FDA to determine next steps 

Tokyo, Japan and Valby, Denmark – September 07, 2023 - Otsuka Pharmaceutical Co., Ltd. (Otsuka) and H. Lundbeck A/S (Lundbeck) announce results from two Phase 3 clinical trials of Otsuka’s brexpiprazole as combination therapy with sertraline for the treatment of post-traumatic stress disorder (PTSD).  

The first trial was a Phase 3, randomized, double-blind, 2-arm, flexible dose trial to evaluate the efficacy, safety, and tolerability of brexpiprazole (2 - 3 mg/day) as combination therapy with sertraline in 416 randomized adult subjects with PTSD. 

The second trial was a Phase 3, randomized, double-blind, 3-arm, fixed dose trial to evaluate the efficacy, safety, and tolerability of brexpiprazole (2 or 3 mg/day) as combination therapy with sertraline in 553 randomized adult subjects with PTSD. 

The primary endpoint for both trials was the change in the Clinician-Administered PTSD Scale (CAPS-5) total score for brexpiprazole + sertraline combination therapy versus sertraline + placebo at week 10 in patients diagnosed with PTSD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). 

The first trial met its primary endpoint by demonstrating improvements from baseline on the primary endpoint of CAPS-5 for patients receiving brexpiprazole 2-3 mg/day + sertraline combination therapy being statistically significantly greater than for those receiving sertraline + placebo (p<0.05). The second phase 3 trial missed its primary endpoint (p>0.05). 

Overall, the safety and tolerability results were consistent with the profile of brexpiprazole as observed in the clinical trials for schizophrenia, agitation associated with dementia due to Alzheimer’s disease (AADAD), and adjunctive treatment of major depressive disorder (MDD). The most common treatment-emergent adverse events in patients receiving combination therapy of brexpiprazole + sertraline versus sertraline + placebo (incidence at least 2% and greater than sertraline + placebo) were dyspepsia, fatigue, weight increase, akathisia (inability to remain still) and somnolence. Discontinuations due to adverse events occurred in 3.7% of patients treated with brexpiprazole + sertraline combination therapy and 7.6% of patients receiving sertraline + placebo. 

Further prespecified and exploratory analyses will be conducted to further assess brexpiprazole as combination therapy with sertraline for the treatment of PTSD. The trial results are planned to be submitted for scientific publication. 

“The results from the first trial indicate that brexpiprazole in combination with sertraline provides improvement of symptoms for people living with PTSD, whereas the second trial did not meet its primary endpoint,” said John Kraus, M.D., Ph.D., executive vice president and chief medical officer, Otsuka Pharmaceutical Development & Commercialization, Inc. “We will fully analyze these results and will discuss our findings with the FDA to determine next steps.” 

“PTSD is a serious mental health disorder with a wide range of symptoms with no new therapeutic options in more than 20 years,” Dr. Johan Luthman, executive vice president and head of Research & Development at Lundbeck. “The two trials constitute one of the largest clinical development programs ever conducted in PTSD. We will analyze the dataset to further determine the potential of brexpiprazole as combination therapy with sertraline in comprehensively addressing symptoms across the PTSD core domains.” 

Otsuka and Lundbeck are incredibly appreciative to all the patients with PTSD, their families, and the investigators who participated in the trial(s) and contributed greatly to this research.  

About the Trials 

Trials 331-201-00071 (NCT04124614) and 331-201-00072 (NCT04174170) were designed to evaluate the efficacy, safety and tolerability of brexpiprazole and sertraline combination treatment 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 (MINI). 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 331-201-00071 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 both trials was the change from randomization to week 10 in the CAPS-5 total score in those patients that met blinded criteria at the week 1 visit of the trial. 

 
About CAPS-5 

The Change in 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 a psychiatric disorder that 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.1 Examples include natural disasters, serious accidents, terrorist acts, war/combat, rape/sexual assault, historical trauma, intimate partner violence and bullying.1 

PTSD can occur in all people, of any ethnicity, nationality or culture, and at any age. It affects more than 13 million people in the U.S. and nearly 6 in 100 people will be diagnosed with PTSD in their lifetime.2 Women are twice as likely as men to have PTSD.1  

Symptoms of PTSD are generally grouped into four types: intrusive memories, avoidance, negative changes in thinking and mood, and changes in physical and emotional reactions. Symptoms can vary over time or vary from person to person.3 Symptoms usually begin within 3 months of the traumatic incident, but they sometimes emerge later.4 To meet the criteria for PTSD, symptoms must last longer than 1 month, and they must be severe enough to interfere with aspects of daily life, such as relationships or work.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. In May 2023, brexpiprazole was approved in the U.S. for the treatment of AADAD. 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. 

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. 

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 some people 24 years of age and younger, 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. 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. 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. Your healthcare provider should check your blood sugar before you start REXULTI and during treatment with REXULTI.  

  • 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 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. 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’ 2,000 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 Company, Ltd., which is a subsidiary of Otsuka Holdings Co., Ltd. headquartered in Tokyo, Japan. The Otsuka group of companies employed 47,000 people worldwide and had consolidated sales of approximately USD 13.1 billion in 2022. 

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 LLC is a wholly owned subsidiary of H. Lundbeck A/S (HLUNa / HLUNb, HLUNA DC / HLUNB DC), a global pharmaceutical company specialized in brain diseases. For more than 70 years, we have been at the forefront of neuroscience research. We are tirelessly dedicated to restoring brain health, so every person can be their best. 

We have approximately 5,400 employees in more than 50 countries, 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. 

In the United States, H. Lundbeck A/S subsidiaries, including Lundbeck LLC, employ more than 1,000 people focused solely on accelerating therapies for brain disorders. With a special commitment to the lives of patients, families and caregivers, Lundbeck US actively engages in a broad range of initiatives each year that support patient communities. 

For additional information, we encourage you to visit us at lundbeck.com/us and connect with us on LinkedIn and Twitter at @LundbeckUS. 

Citations 

  1. American Psychiatric Association. What is Posttraumatic Stress Disorder (PTSD). https://www.psychiatry.org/patients-families/ptsd/what-is-ptsd
  2. U.S. Department of Veteran Affairs. PTSD: National Center for PTSD. https://www.ptsd.va.gov/understand/common/common_adults.asp
  3. Mayo Clinic. Post-traumatic stress disorder (PTSD). https://www.mayoclinic.org/diseases-conditions/posttraumatic-stress-disorder/symptoms-causes/syc-20355967
  4. National Institute of Mental Health. Post-Traumatic Stress Disorder. https://www.nimh.nih.gov/health/publications/post-traumatic-stress-disorder-ptsd