4 August 2022 - - Japan-based pharmaceutical company Otsuka Pharmaceutical Development and Commercialization, Inc. and Danish pharmaceutical company H. Lundbeck A/S (OTC: HLUYY) have presented positive results from a Phase 3 clinical trial of brexpiprazole in the treatment of agitation in patients with Alzheimer's dementia at the 2022 Alzheimer's Association International Conference, the companies said.

The double-blind, randomized, placebo-controlled trial of 345 male and female participants with a diagnosis of probable Alzheimer's disease 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.

All participants in the treatment group (N=228) and placebo group (N=117), aged 55–90 years (inclusive), met criteria of agitation as defined by the International Psychogeriatric Association.

The primary outcome was the change in the Cohen-Mansfield Agitation Inventory 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.

In the study, the improvements from baseline on the primary endpoint of CMAI for patients receiving brexpiprazole 2 mg/day or 3 mg/day were statistically greater than for those receiving placebo (brexpiprazole = -22.6, placebo = -17.3; 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). When analyzed individually, both 2 mg and 3 mg doses showed statistically significant improvements vs. placebo on the CMAI.

In the study, there were no adverse events with more than 5 % incidence in all patients treated with brexpiprazole with an incidence greater than placebo; asthenia (extreme, chronic weakness and fatigue), diarrhea, somnolence, dizziness, urinary tract infections and nasopharyngitis occurred in more than 2 % of brexpiprazole-treated patients with an incidence greater than placebo.

In addition, adverse events such as falls, akathisia, and extrapyramidal disorder occurred at a rate of less than 2% in the patients treated with brexpiprazole.

Discontinuations due to adverse events occurred in 5.3% of patients treated with brexpiprazole and 4.3% of patients receiving placebo.

The Supplemental New Drug Application 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.

The Cohen-Mansfield Agitation Inventory 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.

Neuropsychiatric symptoms of Alzheimer's dementia, such as agitation are associated with poor caregiver outcomes, including reduced quality of life and poorer health.

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, family members, and caregivers.

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.

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

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

Brexpiprazole was approved in the US 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.