Improvements in Alzheimer Agitation, Response Rates Seen Through Brexpiprazole

Denise Chang, MD

Pooled data from 2 fixed-dose, phase 3 trials of patients with agitation associated with dementia due to Alzheimer disease (AD) revealed that a greater number of those treated with brexpiprazole (Rexulti: Otsuka) 2 or 3 mg/day vs placebo achieved pre-defined criteria for agitation response. Overall, these data continued to highlight the effects of brexpiprazole, which became the first approved treatment for AD agitation in May 2023.¹

The analysis included 363 patients randomized to brexpiprazole 2 or 3 mg/day and 247 patients randomized to placebo from Study 283 (NCT01862640) and Study 213 (NCT03548584), the studies that served as the basis for the therapy’s approval. After 12 weeks of treatment, 25.1% of those on brexpiprazole achieved at least a 40% reduction in Cohen-Mansfield Agitation Inventory (CMAI), the primary efficacy end point, vs 14.2% of those on placebo (P = .0003).

These data were presented at the 2024 American Academy of Neurology (AAN) Annual Meeting, held April 13-18, in Denver, Colorado, by senior author Denise Chang, MD, medical director of the Behavioral Health Integration Program at the University of Washington. In addition to being used as the primary end point, investigators used response rates of at least 40%, 30%, or 20% reduction on CMAI as secondary/exploratory end points. In this post-hoc analysis, data for the FDA-approved recommended-to-maximum dose of brexpiprazole was compared with pooled placebo data.

A greater than 30% or 20% reduction in agitation symptoms, defined by CMAI scores, was found in 42.7% and 65.3% of patients, respectively, on brexpiprazole. In comparison, only 30.8% (P = .0023) and 50.6% (P = .0014) of those on placebo achieved these response rates. At week 12, the pooled Clinical Global Impression-Improvement response rates were 51.2% with brexpiprazole vs 43.3% with placebo (P = .047).

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Brexpiprazole, which acts as an antagonist at noradrenergic a1B and a2C and seotonergic 5-HT2A receptors, had the full dataset of Study 293 published in JAMA Network Open earlier this year. During the trial, standard medications for AD (mostly memantine or donepezil) were taken by 184 patients (81.4%) receiving brexpiprazole and 95 (81.9%) receiving placebo, and concomitant medications for agitation were received at least once by 44 patients (19.5%) taking brexpiprazole and 17 (14.7%) on placebo. The mean age of the cohort was 74.0 (SD, 7.5) years, most patients were White (95.4%), and more than half (55.9%) had moderate cognitive impairment, defined as Mini-Mental State Exam scores of 13-18.²

At the conclusion of the 12-week treatment period, those on brexpiprazole 2 or 3 mg in Study 283 demonstrated significantly greater improvement on CMAI total score, with a Cohen d effect size of 0.35. Throughout this time, the agent also demonstrated statistically greater improvement vs placebo on the change in CGI-Severity score, a key secondary end point, with a Cohen d effect size of 0.31. Other secondary end points, CMAI factor scores, GCI-Improvement, and CMAI/GCI-I response rates, also favored brexpiprazole, with nominally greater changes over placebo.

In its label, it states that brexpiprazole should not be used as an "as needed” treatment for agitation. Additionally, it may cause serious adverse events, including cerebrovascular problems, such as stroke, in elderly people with dementia-related psychosis, as we all as neuroleptic malignant syndrome, uncontrolled upper body movements, and issues with metabolism.

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REFERENCES
1. Behl S, Lee D, Aggarwal J, Hefting N, Chen D, Chang D. Effects of brexpiprazole on agitation associated with dementia due to Alzheimer’s disease: analysis of pooled response data from two phase 3 fixed-dose trials. Presented at: 2024 AAN Annual Meeting; April 13-18; Denver, CO.
2. Lee D, Slomkowski M, Hefting N, et al. Brexpiprazole for the treatment of agitation in Alzheimer dementia: a randomized clinical trial. JAMA Neurol. 2023;80(12):1307-1316. doi:10.1001/jamaneurol.2023.3810