Tokyo, Japan and Valby, Denmark – JUNE 27, 2022 - Otsuka Pharmaceutical Co., Ltd. (Otsuka) and H. Lundbeck A/S (Lundbeck) announce positive results of the Phase 3 clinical trial of brexpiprazole in the treatment of agitation in patients with Alzheimer's dementia (NCT03548584). The analysis concluded that there is a statistically significant difference (p=0.0026) in the mean change from baseline to Week 12 in the Cohen-Mansfield Agitation Inventory (CMAI) total score between brexpiprazole and placebo.
Full study results are not yet available. Further prespecified and exploratory analyses of the data set will be conducted to determine the full potential of brexpiprazole in the treatment of agitation in patients with Alzheimer's dementia.
Based on this outcome Otsuka and Lundbeck are planning a regulatory filing to the U. S. Food and Drug Administration (FDA) later in 2022. The Supplemental New Drug Application (sNDA) will be comprised of this study as well as two earlier trials.1 In February 2016, the FDA granted fast track designation for brexpiprazole for treatment of agitation in patients with Alzheimer’s dementia.
Otsuka and Lundbeck are incredibly grateful to all the patients with Alzheimer´s dementia, their families and the investigators who participated in the trials and contributed greatly to this research.
The trial results are planned to be submitted for scientific publication at a later date.
Trial 331-14-213 (NCT03548584; Trial 213) was designed to assess the safety, tolerability and efficacy of two fixed doses of brexpiprazole (2 mg/day and 3 mg/day) in the treatment of patients with agitation in Alzheimer’s dementia. The trial consisted of a continuous 12-week double-blind treatment period with a 30-day follow-up. The randomized trial population included 345 male and female patients, aged 55–90 years (inclusive), with a diagnosis of probable Alzheimer’s disease, and meeting criteria of agitation as defined by the International Psychogeriatric Association (IPA). The primary outcome was the change in the CMAI total score at week 12 for all patients treated with brexpiprazole versus those treated with placebo. The key secondary outcome was the change in the Clinical Global Impression – Severity of Illness (CGI-S) score, as related to symptoms of agitation. Participating countries include Bulgaria, Hungary, Serbia, Slovakia, Spain, Ukraine, and USA. The study included both patients who were living at home and those living in institutionalized settings.
In the study, the improvements from baseline on the primary endpoint of CMAI for patients receiving brexpiprazole or 2 mg/day or 3 mg/day were statistically greater than for those receiving placebo (p=0.0026). This result was supported by a statistically superior improvement on the key secondary endpoint of CGI-S, as related to agitation (p=0.0055).
Brexpiprazole was generally well tolerated, and no new safety signals were observed. The only treatment emergent adverse event (TEAE) with more than 5% incidence in patients treated with brexpiprazole was headache (6.6% vs. 6.9% for placebo). The following TEAEs occurred at an incidence of at least 2% in the brexpiprazole treatment group and greater than that of placebo: somnolence, nasopharyngitis, dizziness, diarrhea, urinary tract infection, and asthenia. There was one death observed in the 3 mg/day treatment group, assessed as not related to treatment by the investigator.
The Cohen-Mansfield Agitation Inventory (CMAI) is a caregiver rated questionnaire that measures the frequency of manifestations of 29 agitated behaviors in elderly persons, such as pacing, restlessness, yelling, and hitting.2 It has been used extensively for assessing agitation and has been adapted and validated for different patient settings.2-5
Neuropsychiatric symptoms (NPS) of Alzheimer’s dementia, such as agitation are associated with poor caregiver outcomes, including reduced quality of life and poorer health.6-9
Agitation is a common neuropsychiatric symptom of Alzheimer’s dementia. It is reported in approximately 45% of patients with Alzheimer’s dementia and has a large impact on quality of life for the patients and their loved ones.10-11 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.12
Symptoms of agitation are also a consistent predictor of nursing home admission in patients with dementia.13-15
Agitation in Alzheimer’s dementia is thought to be associated with underlying pathophysiological circuit level dysfunctions in noradrenergic, serotonergic, and dopaminergic neurotransmission.16
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 in adults with schizophrenia. 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 several 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 partial agonist activity at noradrenaline alpha1B/2C receptors, serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT2A receptors, all at pharmacologically relevant potency.17-18
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.
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’ 1,700 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 13.3 billion in 2020.
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