Otsuka and Lundbeck Announce FDA Acceptance and Priority Review of sNDA for Brexpiprazole for the Treatment of Agitation Associated With Alzheimer’s Dementia

• The supplemental new drug application (sNDA) for brexpiprazole in the treatment of agitation associated with Alzheimer’s dementia has been accepted and filed by the FDA under Priority review
• The FDA target date (PDUFA date) for completion of the review is May 10, 2023
• FDA is currently planning to hold a Psychopharmacologic Drugs Advisory Committee
• If approved, brexpiprazole would be the first pharmacological treatment indicated for agitation in patients with Alzheimer’s dementia in the U.S.

PRINCETON, N.J. & DEERFIELD, Ill.--(BUSINESS WIRE)-- Otsuka Pharmaceutical Co., Ltd. (Otsuka) and H. Lundbeck A/S (Lundbeck) announce the U.S. Food and Drug Administration (FDA) has determined that the supplementary New Drug Application (sNDA) for brexpiprazole for the use in the treatment of agitation associated with Alzheimer’s dementia (AAD) is sufficiently complete to permit a substantive review.

The FDA has assigned the application priority review and a Prescription Drug User Fee Act (PDUFA) target action date of May 10, 2023. The FDA also indicated that they are currently planning to hold a Psychopharmacologic Drugs Advisory Committee meeting to discuss the application.

The sNDA submission includes data from two positive clinical phase III studies that investigated the treatment of brexpiprazole in patients with AAD. Study 331-12-283 demonstrated brexpiprazole 2 mg/day was statistically superior to placebo for the primary endpoint of mean change in Cohen-Mansfield Agitation Inventory (CMAI) Total Score from baseline to Week 12 (p < 0.05). In Study 331-14-213, treatment with brexpiprazole 2 and 3 mg/day showed statistically significant improvement compared with placebo for the primary efficacy endpoint, the mean change in CMAI Total Score from baseline to Week 12 (p < 0.05).

“Agitation associated with Alzheimer’s dementia is complex and difficult to navigate for both patients and caregivers,” said John Kraus, M.D., Ph.D., executive vice president and chief medical officer, Otsuka Pharmaceutical Development & Commercialization, Inc. “New treatments in this area are desperately needed. Our commitment to patients is unwavering as we work to provide them and their caregivers with an option to help lessen the symptoms of agitation.”

“This milestone is important in our efforts to bring patients with Alzheimer’s dementia and their caregivers one step closer to having a potential treatment option that may address a major disabling neuropsychiatric symptom of the disease,” said Johan Luthman, executive vice president, Lundbeck Research & Development.

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.^1-4

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.^5-6 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.⁷

Symptoms of agitation are also a consistent predictor of nursing home admission in patients with dementia.^8-10

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. Brexpiprazole was also approved in 2017 in Health Canada and by the EMA in Europe 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 antagonism at noradrenaline alpha1B/2C receptors and at serotonin 5-HT2A receptors. In addition, brexpiprazole is an antagonist at noradrenaline alpha 1a, 1b, 1d and 2c receptors and partial agonist activity at serotonin5-HT1A and dopamine D2 receptors all at pharmacologically relevant potencies.^11-12

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.

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/

Citations
1. Brodaty H, Hadzi-Pavlovic D. Psychosocial effects on carers of living with persons with dementia. Aust NZ J Psychiatry 1990; 24: 351–361
2. Kales HC et al. Assessment and management of behavioral and psychological symptoms of dementia. BMJ 2015; 350: h369
3. 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
4. Brodaty H, Donkin M. Family caregivers of people with dementia. Dialogues Clin Neurosci 2009; 11: 217–228
5. 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
6. 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
7. Cummings J et al. Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition. Int Psychogeriatr 2015; 27: 7–17
8. Gaugler JE et al. Predictors of nursing home admission for persons with dementia. Med Care 2009; 47: 191–198
9. 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
10. Yaffe K et al. Patient and caregiver characteristics and nursing home placement in patients with dementia. JAMA 2002;287:2090 -2097
11. 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.
12. 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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