JAMA Neurology Publishes Complete Results of Positive Phase 3 Study of REXULTI® (brexpiprazole) for Agitation Associated with Dementia Due to Alzheimer’s Disease

New efficacy data reported for pivotal Study 213 shows significant, clinically meaningful improvements in agitation symptoms.

Agitation symptoms negatively impact functioning, disease progression, quality of life and care for about half of Alzheimer’s dementia patients – and are a consistent predictor of nursing home admission.^5,6

REXULTI^® is the first drug approved by the FDA for agitation associated with dementia due to Alzheimer’s disease.

PRINCETON, N.J. & DEERFIELD, Ill.--(BUSINESS WIRE)--Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) and Lundbeck Pharmaceuticals LLC (Lundbeck) announce that treatment with REXULTI^® (brexpiprazole) resulted in statistically significant and clinically meaningful improvements in adult patients with agitation associated with dementia due to Alzheimer’s disease, according to the complete results of the placebo-controlled pivotal phase 3 Study 213 (NCT03548584), published today in JAMA Neurology.¹ In May 2023, brexpiprazole became the first and only drug to receive approval from the Food and Drug Administration for this indication. REXULTI is not indicated as an as needed (“prn”) treatment for agitation associated with dementia due to Alzheimer’s disease.

Study 213 is the second pivotal phase 3 study, in addition to Study 283 (NCT01862640), to report positive efficacy and good tolerability for brexpiprazole, compared to a placebo, when used to treat patients with agitation associated with dementia due to Alzheimer’s disease.² The JAMA Neurology publication is the first to report the efficacy of brexpiprazole to significantly improve each of three classifications of agitation symptoms: aggressive behaviors, physically nonaggressive behavior and verbally agitated behavior.

“One of the most challenging aspects of caring for someone with Alzheimer’s dementia, whether it be a healthcare provider or loved one, is when they develop agitation symptoms that become increasingly difficult to manage alone,” said senior author George T. Grossberg, MD, Department of Psychiatry and Behavioral Neuroscience at Saint Louis University School of Medicine. “The findings of this study provide evidence that brexpiprazole meets the needs of patients and their caregivers and is an efficacious, well-tolerated treatment for the often-debilitating symptoms of agitation associated with dementia due to Alzheimer’s disease.”

Among the criteria required to enroll, trial participants had to have mild to severe dementia as defined by a score between 5 and 22 on the Mini Mental State Examination (MMSE), a validated screening tool for cognitive impairment in older adults.³ They also had to exhibit symptoms defined by the Cohen-Mansfield Agitation Inventory (CMAI) aggressive behavior subscale, which includes hitting, kicking, scratching, grabbing, pushing, hurting self or others, throwing things, cursing or verbal aggression, spitting, tearing things or destroying property, screaming, and biting.

Participants also required a diagnosis that met The International Psychogeriatric Association’s (IPA) provisional definition of agitation in patients with cognitive impairment or dementia. The definition requires evidence of emotional distress associated with excessive motor activity such as pacing, rocking, restlessness, verbal aggression, such as speaking excessively loudly, screaming, or physical aggression, such as, grabbing, pushing, throwing objects, which causes excess disability and cannot be attributed solely to suboptimal care or another disorder, such as psychiatric illness, medical illness, or effects of a substance.⁴

Brexpiprazole Demonstrated Significant Efficacy in Reducing Agitation Symptoms

In Study 213, the agitation symptoms of the group randomized to receive either a 2 or 3 milligram daily dose of brexpiprazole significantly improved after 12 weeks of treatment, compared to the placebo group, when measured using six efficacy endpoints.

“Agitation associated with dementia due to Alzheimer’s disease can be very challenging and emotionally distressing for patients and family members caring for them. With the publication of the complete Study 213 data, the evidence of brexpiprazole as an effective, well-tolerated treatment for this indication will help clinicians, families and caregivers make informed decisions about what is best for their patient or loved one who lives with this complex condition,” said John Kraus, M.D., Ph.D., executive vice president and chief medical officer at Otsuka.

The trial’s primary efficacy endpoint, the change in the mean CMAI total scores from the study baseline to the end of treatment (Week 12), showed a significant decrease in agitation symptoms. Dr. Grossberg and team noted that an independent study previously reported that the “minimal clinically important difference” for trials of agitation associated with dementia due to Alzheimer’s disease interventions should be a change of 17 points in mean CMAI total scores at 12 weeks, a measure for a duration of time, rather than a comparison of outcomes between a drug and a placebo.⁵ In Study 213, brexpiprazole demonstrated significant efficacy as measured by a 22.6 point reduction in participants’ mean CMAI total scores. Their improvement also was significantly better (p=0.003) than that experienced by the placebo group, which reduced their mean CMAI total scores by 17.6 points. The CMAI is a validated standard measure of 29 agitated behaviors in elderly people widely used in clinical studies.^6-9 In Study 213, the investigators completed the CMAI based on an interview with the patient’s caregiver at each patient visit, which were every two weeks.

The brexpiprazole group also significantly improved as measured by the changes in mean scores of three CMAI subscales used as secondary efficacy endpoints: aggressive behavior (e.g., hitting, biting, kicking, hurting others, p= 0.004), physically nonaggressive behavior (e.g., pacing, inappropriate disrobing, handling things inappropriately, restlessness, p=0.03), and verbally agitated behavior (e.g., screaming, complaining, constant requests for attention, repetitive questions, swearing, p=0.01).

Brexpiprazole Well-Tolerated

Study 213 also documented that brexpiprazole was well-tolerated in the participants and had a clinical safety profile consistent with that of brexpiprazole when used for its other approved indications. The trial had high rates of patients completing the trial: 86.8% of the brexpiprazole group and 88.9% of the placebo group. Also, the mean change in MMSE scores from baseline to Week 12 was 0.7 in the brexpiprazole group (192), and 0.4 in the placebo group (103), indicating no worsening of the participants’ cognitive function during the study.

“The JAMA Neurology publication of Study 213 for brexpiprazole in the management of agitation associated with dementia due to Alzheimer’s disease further validates the clinical rigor of this pivotal Phase 3 trial within this patient population,” said Johan Luthman, executive vice president, Lundbeck Research & Development. “We greatly appreciate the efforts of those clinicians, patients, and their families that participated in this important clinical trial.”

During this study, brexpiprazole demonstrated the proportion of patients who discontinued due to adverse events was 5.3% for brexpiprazole (12 of 226) and 4.3% for placebo (5 of 116). The most common adverse events (>2% and greater than placebo) included weight increase, akathisia (uncontrolled body movements), headache, somnolence (sleepiness), anxiety and restlessness.

The incidence of Treatment Emergent Adverse Events (TEAEs) was 40.7% with brexpiprazole (40.7) and 31.0% with placebo (36), with no apparent effect of dose. The majority of TEAEs were mild or moderate in severity. Headaches occurred with an incidence ≥5% in the brexpiprazole group (6.6%, versus 6.9% with placebo). One patient died from cardiac failure unrelated to brexpiprazole 23 days after withdrawing from the trial, and the patient also had pneumonia and cachexia.

About the Trial 213

The 12-week Study 213 used a randomized, double-blind, placebo-controlled, fixed-dose, parallel-arm Phase 3 design. Investigators of the study, conducted from May 2018 to June 2022, randomized 345 patients 2:1 to receive either brexpiprazole (n=228) or a placebo (n=117).

Within the brexpiprazole group, patients were further randomized to fixed doses of 2 mg/day and 3 mg/day in a 1:2 ratio.

Of the participants, 42.1% of the brexpiprazole group and 46.2% of the placebo group resided in care facilities, with the remaining participants residing in community-based settings.

About Agitation Associated with Dementia Due to Alzheimer’s Disease

Agitation associated with dementia due to Alzheimer’s disease is a common neuropsychiatric symptom reported in approximately half of all patients with Alzheimer’s dementia. Based on the IPA definition, agitation is present in 45 to 61% of patients with dementia in community settings, and 53% in long-term care settings.^10,11 The condition has a negative impact on the quality of life for the patients, family members, and caregivers.^10,11

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.¹² Symptoms of agitation are also a consistent predictor of nursing home admission in patients with dementia, including those with Alzheimer’s disease. ^13,14,15

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 Pharmaceuticals LLC is a wholly owned subsidiary of H. Lundbeck A/S (HLUNa / HLUNb, HLUNA DC / HLUNB DC), a global biopharmaceutical 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 Pharmaceuticals LLC and 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

Contacts for Media

Otsuka in the U.S.

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Otsuka in Japan

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