Otsuka Pharmaceutical & Lundbeck Present Positive Data From Multiple Phase 3 Studies Showing Brexpiprazole Significantly Improved Symptoms of Agitation in Patients With Alzheimer’s Dementia at the 2022 Clinical Trials for Alzheimer’s Disease Congress

• Researchers highlight efficacy and safety data across three Phase 3 studies of brexpiprazole for agitation in Alzheimer’s dementia
• Agitation is a highly prevalent clinical manifestation in Alzheimer’s dementia and one of the most complex and stressful aspects of care in patients affected by the disease. It is associated with greater caregiver burden, earlier nursing home placement, increased morbidity and mortality, and a substantial economic burden
• There are no FDA-approved pharmacological treatments for agitation in Alzheimer’s dementia

Otsuka America Pharmaceutical, Inc., (Otsuka) and Lundbeck US (Lundbeck) today presented positive efficacy and safety data from multiple Phase 3 studies of brexpiprazole in the treatment of agitation in patients with Alzheimer's dementia at the Clinical Trials for Alzheimer’s Disease (CTAD) Congress in San Francisco, CA.

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Data from two Phase 3 studies showed that brexpiprazole 2 mg or 3 mg doses significantly (p<0.05) improved symptoms of agitation in patients with Alzheimer’s dementia compared to placebo. The primary endpoint across the studies was improvement from baseline in the Cohen-Mansfield Agitation Inventory (CMAI) total score while the key secondary endpoint was an improvement from baseline to week 12 in the Clinical Global Impression-Severity (CGI-S) score related to agitation. Brexpiprazole also demonstrated a favorable safety and tolerability profile in all three studies.

“Agitation in Alzheimer’s dementia represents an incredibly complex and challenging aspect of care in patients affected by the disease,” said Robert McQuade, PhD, executive vice president, chief strategy officer, Otsuka Pharmaceutical Development & Commercialization, Inc. “We’re proud to share this positive data from our Phase 3 double-blind trials that showcase our commitment to address current unmet needs and deliver a first-of-its-kind pharmacological treatment for agitation in Alzheimer’s dementia to patients and their caregivers.”

All studies were 12-week, randomized, double-blind, placebo-controlled, parallel-arm trials of brexpiprazole versus placebo in patients with agitation in Alzheimer’s dementia. Based on the results of the first two studies with 0.5-2mg/day doses, the third trial investigated higher doses (2 or 3 mg/day) in an enriched patient population that had higher baseline agitation. The primary endpoint in all three trials was the change in CMAI total.

In the third trial, brexpiprazole 2 or 3 mg/day demonstrated statistically-significant improvement versus placebo from baseline to week 12 in the CMAI total (LSMD, -5.32; p=0.0026) and CGI-S score as related to agitation (LSMD, -0.27; p=0.0078). Across all three trials, treatment emergent adverse events (TEAEs) that occurred in ≥2% of patients receiving brexpiprazole and more than in placebo-treated patients were insomnia (3.7% versus 2.8%), somnolence (3.4% versus 1.8%), nasopharyngitis (2.7% versus 2.6%), and urinary tract infection (2.6% versus 1.5%). The incidence of falls was 1.7% (brexpiprazole) versus 2.6% (placebo). Overall, 6.3% of patients receiving brexpiprazole discontinued treatment due to TEAEs, versus 3.4% receiving placebo. The safety and tolerability profile of brexpiprazole in agitation in Alzheimer’s dementia is consistent with that observed for currently approved indications. Deaths in both arms were less than 1%.

“Agitation is a significant unmet need among the Alzheimer’s community, and these results bring us one step closer to providing a possible treatment option that addresses the needs of this vulnerable patient population,” said Dr. Johan Luthman, executive vice president and head of Research & Development at Lundbeck.

About CMAI

The Cohen-Mansfield Agitation Inventory (CMAI) measures the frequency of manifestations of 29 agitated behaviors in elderly persons, such as pacing, restlessness, yelling, and hitting.¹

About Agitation in Alzheimer’s Dementia

Neuropsychiatric symptoms (NPS) of Alzheimer’s dementia, such as agitation are associated with poor caregiver outcomes, including reduced quality of life and poorer health.^2-5

Agitation is a common neuropsychiatric symptom of Alzheimer’s dementia. It is reported in approximately 45 percent of patients with Alzheimer’s dementia and has a large impact on quality of life for the patients, family members, and caregivers.^6-7 Agitation covers a large group of behaviors occurring in patients with Alzheimer’s dementia, and it is an excessive/inappropriate manifestation of “normal” human emotions and behaviors. Such behaviors include pacing, gesturing, profanity, shouting, shoving, and hitting.⁸

Symptoms of agitation are also a consistent predictor of nursing home admission in patients with dementia.^9-11

Agitation in Alzheimer’s dementia is thought to be associated with underlying pathophysiological circuit level dysfunctions in noradrenergic, serotonergic, and dopaminergic neurotransmission.¹²

About Brexpiprazole

Brexpiprazole was approved in the U.S. on July 10, 2015, as an adjunctive therapy to antidepressants in adults with major depressive disorder and as a treatment for schizophrenia in adults and children ages 13 years and older. Brexpiprazole was also approved in 2017 in Health Canada and by the EMA in Europe in 2018 for the treatment of schizophrenia. In addition, brexpiprazole has been approved in multiple other countries across the world. Brexpiprazole is distributed and marketed under the brand name REXULTI^®. In Europe, brexpiprazole is distributed and marketed under the brand name Rxulti^®.

Brexpiprazole was discovered by Otsuka and is being co-developed by Otsuka and Lundbeck. The efficacy of brexpiprazole may be mediated through a combination of antagonism at noradrenaline alpha1B/2C receptors and serotonin 5-HT2A receptors and partial agonist activity at serotonin5-HT1A and dopamine D2 receptors all at pharmacologically relevant potency.^13-14

INDICATIONS and IMPORTANT SAFETY INFORMATION for REXULTI^® (brexpiprazole)

INDICATIONS

REXULTI is indicated for:

• Use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults
• Treatment of schizophrenia in adults and pediatric patients ages 13 years and older

IMPORTANT SAFETY INFORMATION

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death. REXULTI is not approved for the treatment of patients with dementia-related psychosis.

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Antidepressants increased the risk of suicidal thoughts and behaviors in patients aged 24 years and younger. Monitor for clinical worsening and emergence of suicidal thoughts and behaviors. The safety and effectiveness of REXULTI have not been established in pediatric patients with MDD.

Contraindication: In patients with known hypersensitivity reaction to brexpiprazole or any of its components. Reactions have included: rash, facial swelling, urticaria and anaphylaxis.

Cerebrovascular Adverse Events, Including Stroke: In clinical trials, elderly patients with dementia randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. REXULTI is not approved for the treatment of patients with dementia-related psychosis.

Neuroleptic Malignant Syndrome (NMS): NMS is a potentially fatal symptom complex reported in association with administration of antipsychotic drugs including REXULTI. Clinical signs of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability. Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Manage NMS with immediate discontinuation of REXULTI, intensive symptomatic treatment, and monitoring.

Tardive Dyskinesia (TD): Risk of TD, and the potential to become irreversible, are believed to increase with duration of treatment and total cumulative dose of antipsychotic drugs. TD can develop after a relatively brief treatment period, even at low doses, or after discontinuation of treatment. For chronic treatment, use the lowest dose and shortest duration of REXULTI needed to produce a clinical response. If signs and symptoms of TD appear, drug discontinuation should be considered.

Metabolic Changes: Atypical antipsychotic drugs have caused metabolic changes including:

• Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication, and monitor periodically during long-term treatment.
• Dyslipidemia: Atypical antipsychotics cause adverse alterations in lipids. Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment.
• Weight Gain: Weight gain has been observed in patients treated with REXULTI. Monitor weight at baseline and frequently thereafter.

Pathological Gambling and Other Compulsive Behaviors: Intense urges, particularly for gambling, and the inability to control these urges have been reported while taking REXULTI. Other compulsive urges have been reported less frequently. Prescribers should ask patients or their caregivers about the development of new or intense compulsive urges. Consider dose reduction or stopping REXULTI if such urges develop.

Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia and neutropenia have been reported with antipsychotics. Agranulocytosis (including fatal cases) has been reported with other agents in this class. Monitor complete blood count in patients with pre-existing low white blood cell count (WBC)/absolute neutrophil count or history of drug-induced leukopenia/neutropenia. Discontinue REXULTI at the first sign of a clinically significant decline in WBC and in severely neutropenic patients.

Orthostatic Hypotension and Syncope: Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. Monitor in patients vulnerable to hypotension, and those with cardiovascular and cerebrovascular diseases.

Falls: Antipsychotics may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls causing fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating treatment and recurrently during therapy.

Seizures: REXULTI may cause seizures and should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold.

Body Temperature Dysregulation: Use REXULTI with caution in patients who may experience conditions that increase body temperature (e.g., strenuous exercise, extreme heat, dehydration, or concomitant use with anticholinergics).

Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotics, including REXULTI, and should be used with caution in patients at risk for aspiration.

Potential for Cognitive and Motor Impairment: REXULTI has the potential to impair judgment, thinking, or motor skills. Patients should not drive or operate hazardous machinery until they are reasonably certain REXULTI does not affect them adversely.

Concomitant Medication: Dosage adjustments are recommended in patients who are known cytochrome P450 (CYP) 2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers.

Most commonly observed adverse reactions: In clinical trials of adults, the most common adverse reactions were:

• Major Depressive Disorder (MDD) (adjunctive treatment to antidepressant therapy; ≥5% incidence and at least twice the rate of placebo for REXULTI vs. placebo): akathisia and weight increased
• Schizophrenia (≥4% incidence and at least twice the rate of placebo for REXULTI vs. placebo): weight increased. Adverse reactions in patients 13 to 17 years of age were generally similar to those observed in adult patients.

Dystonia: Symptoms of dystonia may occur in susceptible individuals during the first days of treatment and at low doses.

Pregnancy: Adequate and well-controlled studies to assess the risks of REXULTI during pregnancy have not been conducted. REXULTI should be used during pregnancy only if the benefit justifies the risk to the fetus.

Lactation: It is not known if REXULTI is excreted in human breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).

Please click here FULL PRESCRIBING INFORMATION, including BOXED WARNING.

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, nephrology, and cardiology, 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 13.6 billion in 2021.

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 H. Lundbeck A/S

Lundbeck is 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 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. 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.

For additional information, we encourage you to visit our corporate site www.lundbeck.com and connect with us on Twitter at @Lundbeck and via LinkedIn.

Citations

1. Cohen-Mansfield J. Agitated behavior in persons with dementia: the relationship between type of behavior, its frequency, and its disruptiveness. J Psychiatr Res 2008; 43: 64–69

2. Brodaty H, Hadzi-Pavlovic D. Psychosocial effects on carers of living with persons with dementia. Aust NZ J Psychiatry 1990; 24: 351–361

3. Kales HC et al. Assessment and management of behavioral and psychological symptoms of dementia. BMJ 2015; 350: h369

4. Karttunen K et al. Neuropsychiatric symptoms and quality of life in patients with very mild and mild Alzheimer’s disease. Int J Geriatr Psychiatry 2011; 26: 473–482

5. Brodaty H, Donkin M. Family caregivers of people with dementia. Dialogues Clin Neurosci 2009; 11: 217–228

6. 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

7. 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

8. Cummings J et al. Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition.

Int Psychogeriatr 2015; 27: 7–17

9. Gaugler JE et al. Predictors of nursing home admission for persons with dementia. Med Care 2009; 47: 191–198

10. 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

11. Yaffe K et al. Patient and caregiver characteristics and nursing home placement in patients with dementia. JAMA 2002;287:2090 -2097

12. Liu, K. Y. et al. The neurochemistry of agitation in Alzheimer’s disease: a systematic review. Ageing Research Reviews. 2018;43:99–107

13. 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. 2014a;350(3):589–604.

14. Maeda K, Lerdrup L, Sugino H, et al. Brexpiprazole II: antipsychotic-like and procognitive effects of a novel serotonin–dopamine activity modulator. J Pharmacol Exp Ther. 2014b;350(3):605–614.

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