Otsuka and Lundbeck Issue Statement on U.S. Food and Drug Administration (FDA) Advisory Committee Meeting on REXULTI® (brexpiprazole) in Combination with Sertraline for the Treatment of Adults with Post-Traumatic Stress Disorder (PTSD)

PRINCETON, NJ and DEERFIELD, IL – July 18, 2025 – Otsuka Pharmaceutical Development & Commercialization, Inc. (Otsuka) and Lundbeck LLC (Lundbeck) announce the Psychopharmacologic Drugs Advisory Committee (PDAC) of the U.S. Food and Drug Administration (FDA) met to discuss the supplemental New Drug Application (sNDA) of REXULTI® (brexpiprazole) in combination with sertraline for the treatment of adults with post-traumatic stress disorder (PTSD). The committee voted 1-10, concluding that the efficacy of brexpiprazole, when initiated concurrently with sertraline, has not been established for the treatment of PTSD based on the available data presented. The feedback from the committee will be taken into consideration by the FDA as it reviews the application for REXULTI (brexpiprazole) in combination with sertraline for the treatment of adults with PTSD.

“Although today’s outcome was disappointing, we remain fully committed to collaborating with the FDA as they complete their review of this application,” said John Kraus, M.D., Ph.D., executive vice president and chief medical officer, Otsuka. “We continue to believe in REXULTI’s potential, in combination with sertraline, to make a meaningful difference as a treatment option for the PTSD patient population.”

The sNDA is based on previously disclosed data from two Phase 3 trials (NCT04124614 – flexible-dose trial, n=416 and NCT04174170 – fixed-dose trial, n=553), and one Phase 2 trial (NCT03033069 –flexible-dose trial, n=321). All three trials investigated the use of brexpiprazole in combination with sertraline versus sertraline plus placebo for the treatment of PTSD in adult subjects.

“Our dedication to patients and the broader PTSD community remains unwavering,” said Johan Luthman, executive vice president of Lundbeck Research & Development. “PTSD has long been a complex condition to treat, and we thank the patients, investigation sites and everyone who participated in the clinical trials.”

Otsuka and Lundbeck will continue to work closely with the FDA as it completes its review of the application.

About Post-Traumatic Stress Disorder
PTSD is one of the most common mental health disorders in the United States, impacting an estimated 13 million adults each year. ^{i, ii, iii, iv} Most patients (86%) with PTSD in the United States are in the civilian population.^{v, vi} 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 and 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.^{vii, viii}

Symptoms of PTSD are generally grouped into four symptom clusters: intrusion (re-experiencing), avoidance, negative alterations in mood and cognition, and heighted arousal and reactivity.^ix Individual symptom type and intensity can fluctuate over time and between individuals. The average time from index trauma to symptom presentation is typically 2.2 years, and the average time from index trauma to PTSD diagnosis is typically 8.7 years. 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. Guideline-recommended first-line treatment includes psychotherapy (e.g., trauma-focused cognitive behavioral and processing therapy). Pharmacotherapy with certain antidepressants is recommended when these trauma-focused psychotherapies are not available or feasible when patients prefer medications.^x

About Brexpiprazole
Brexpiprazole was approved in the U.S. by 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.

In 2024, Japan’s Ministry of Health, Labour and Welfare also approved brexpiprazole for the treatment of excessive motor activity or physically/verbally aggressive behavior due to rapid changes in mood, irritability, and/or outbursts associated with dementia due to Alzheimer’s disease.

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-HT_2A receptors, as well as a partial agonist at serotonin 5-HT_1A and dopamine D2 receptors.^{xi, xii}

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 total healthcare company that focuses on each individual’s potential to enhance their well-being. Our medical-related business provides treatments and diagnostics for both physical and mental health. Our nutraceutical business supports daily health maintenance and improvement. Otsuka’s unique products and services are based on scientific evidence, under the guidance of our corporate philosophy: Otsuka-people creating new products for better health worldwide. 

Otsuka established a presence in the U.S. in 1973 and today our 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 35,340 people worldwide and had consolidated sales of approximately USD 14.7 billion in 2024.

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.

Contacts

Otsuka in the U.S.
Robert Murphy
Corporate Communications
Otsuka America Pharmaceutical, Inc.
robert.murphy@otsuka-us.com
+1 609 249 7262

Otsuka outside the U.S.
Jeffrey Gilbert
Leader, Pharmaceutical PR
Otsuka Pharmaceutical Co., Ltd.
Gilbert.jeffrey.a@otsuka.co.jp

Lundbeck in the U.S.
Dyana Lescohier
Corporate Communications
Lundbeck US
dyle@lundbeck.com
+1 847 894 3586

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^x U.S. Department of Veterans Affairs. VA/DoD Clinical Practice Guidelines. Management of Posttraumatic Stress Disorder and Acute Stress Disorder. Provider Summary 2023. Version 4.0. www.healthquality.va.gov/guidelines/MH/ptsd/VA-DoD-CPG-PTSD-Provider-Summary.pdf
^xi REXULTI® (brexpiprazole). Prescribing Information. FDA.
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