Otsuka and Lundbeck Announce U.S. Food and Drug Administration (FDA) Approval of Supplemental New Drug Application (sNDA) for REXULTI® (brexpiprazole) for the Treatment of Agitation Associated with Dementia Due to Alzheimer’s Disease

REXULTI is the first and only pharmacological treatment approved in the U.S. for agitation associated with dementia due to Alzheimer’s disease

PRINCETON, N.J. & DEERFIELD, Ill.--(BUSINESS WIRE)-- Otsuka Pharmaceutical, Co. Ltd. (Otsuka) and Lundbeck LLC (Lundbeck) announce the U.S. Food and Drug Administration (FDA) has approved the supplemental New Drug Application (sNDA) of REXULTI^® (brexpiprazole) for use in the treatment of agitation associated with dementia due to Alzheimer’s disease.

This approval makes REXULTI the first and only pharmacological treatment approved in the U.S. for agitation associated with dementia due to Alzheimer’s disease. Agitation is a common neuropsychiatric symptom in Alzheimer’s dementia and one of the most complex and stressful aspects of caring for people living with the condition. It is reported in approximately half of people with Alzheimer’s dementia and is associated with earlier nursing home placement.^1,2 REXULTI is not indicated as an as needed (“prn”) treatment for agitation associated with dementia due to Alzheimer’s disease.

Makoto Inoue, president and representative director of Otsuka, commented, “Today marks a major milestone for patients, caregivers, and families navigating the complexities of agitation associated with dementia due to Alzheimer’s disease. Otsuka Pharmaceutical will continue its efforts to engage and provide options for those impacted by this devastating condition.”

Deborah Dunsire, CEO and president, Lundbeck, said, “This approval is a testament to our commitment and unwavering support of patients and caregivers to lessen the symptoms of agitation associated with dementia due to Alzheimer’s disease. We look forward to offering this first FDA-approved treatment option to address this significant unmet need for patients. We are grateful to the patients and caregivers who participated in these important trials.”

The FDA previously granted priority review for the sNDA, a designation for a drug application that represents a significant improvement in the safety and/or effectiveness of the treatment, diagnosis, or prevention of a serious medical condition.

The submission was based on two Phase 3, 12-week, randomized, double-blind, placebo-controlled fixed-dose studies that evaluated the frequency of agitation symptoms in patients with dementia due to Alzheimer’s disease based on the Cohen-Mansfield Agitation Inventory (CMAI) total score. The primary endpoint was a change in agitation symptom frequency (CMAI total score) from baseline at Week 12 in both studies. Brexpiprazole patients with agitation associated with dementia due to Alzheimer’s disease achieved a 31% greater reduction from baseline in frequency of agitation symptoms vs. placebo.

Overall, the data showed brexpiprazole as being well-tolerated with a low incidence of discontinuations, and with a safety profile consistent with the known safety profile of brexpiprazole in other indications. ³

About Agitation Associated with Dementia Due to Alzheimer’s Disease

Agitation associated with dementia due to Alzheimer’s disease is a common neuropsychiatric symptom that is reported in approximately half of all patients with Alzheimer’s dementia. The condition has a large impact on the quality of life for the patients, family members, and caregivers.^1,4

Agitation associated with dementia covers a large group of behaviors occurring in patients with Alzheimer’s disease, such as pacing, gesturing, profanity, shouting, shoving, and hitting.⁵Symptoms of agitation are also a consistent predictor of nursing home admission in patients with dementia, including those with Alzheimer’s disease.^6,7,8

About 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. 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 (EMA) 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, and antagonist activity at serotonin 5-HT2A 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:

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 Halpern R et al. Using electronic health records to estimate the prevalence of agitation in Alzheimer disease/dementia. Int J Geriatr Psychiatry 2019; 34: 420–431
² Gaugler JE et al. Predictors of nursing home admission for persons with dementia. Med Care 2009; 47: 191–198
³ Fillit H et al. Impact of agitation in long-term care residents with dementia in the United States. Int J Geriatr Psychiatry 2021; 36: 1959–1969
⁴ Fillit H et al. Impact of agitation in long-term care residents with dementia in the United States. Int J Geriatr Psychiatry 2021; 36: 1959–1969
⁵ Cummings J et al. Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition. Int Psychogeriatr 2015; 27: 7–17
⁶ Gaugler JE et al. Predictors of nursing home admission for persons with dementia. Med Care 2009; 47: 191–198
⁷ Kales HC et al. Rates of clinical depression diagnosis, functional impairment, and nursing home placement in coexisting dementia and depression. Am J Geriatr Psychiatry 2005;13:441-449
⁸ Yaffe K et al. Patient and caregiver characteristics and nursing home placement in patients with dementia. JAMA 2002;287:2090 -2097

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