Brexpiprazole for the Treatment of Agitation in Alzheimer Dementia

Abstract

ImportanceAgitation is a prevalent, distressing, and burdensome manifestation of Alzheimer dementia in need of an efficacious, safe, and well-tolerated treatment.ObjectiveTo confirm the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer dementia.Design, Setting, and ParticipantsThis randomized clinical trial was a 12-week, double-blind, placebo-controlled, fixed-dose, parallel-arm trial that ran from May 2018 to June 2022 at 123 clinical trial sites in Europe and the United States. Participants included patients with agitation in Alzheimer dementia in a care facility or community-based setting. Stable Alzheimer disease medications were permitted.InterventionsIn this 2-arm trial, patients were randomized to receive oral brexpiprazole or placebo (2:1 ratio) for 12 weeks. Within the brexpiprazole arm, patients were further randomized to receive fixed doses of 2 mg/d or 3 mg/d in a 1:2 ratio.Main Outcomes and MeasuresThe primary end point was change in Cohen-Mansfield Agitation Inventory total score (which measures the frequency of 29 agitated behaviors) from baseline to week 12 for brexpiprazole, 2 or 3 mg, vs placebo. Safety was assessed by standard measures, including treatment-emergent adverse events.ResultsA total of 345 patients were randomized to receive brexpiprazole (n = 228) or placebo (n = 117); completion rates were 198 (86.8%) for brexpiprazole and 104 (88.9%) for placebo. Mean (SD) age was 74.0 (7.5) years, and 195 of 345 patients were female (56.5%). Patients receiving brexpiprazole, 2 or 3 mg (n = 225), demonstrated statistically significantly greater improvement than those taking placebo (n = 116) in Cohen-Mansfield Agitation Inventory total score from baseline to week 12 (brexpiprazole baseline, 80.6, mean change, −22.6; placebo baseline, 79.2, mean change, −17.3; least-squares mean difference, −5.32; 95% CI, −8.77 to −1.87; P = .003; Cohen d effect size, 0.35). No treatment-emergent adverse events had an incidence of 5% or more with brexpiprazole and greater incidence than placebo. The proportion of patients who discontinued because of adverse events was 12 of 226 (5.3%) for brexpiprazole and 5 of 116 (4.3%) for placebo.Conclusions and RelevanceIn this study, patients with Alzheimer dementia who took brexpiprazole, 2 or 3 mg, showed a statistically significant improvement vs placebo in agitation over 12 weeks. Brexpiprazole was generally well tolerated over 12 weeks in this vulnerable patient population.Trial RegistrationClinicalTrials.gov Identifier: NCT03548584

Alzheimer's disease drug development pipeline: 2024

“…6 The atypical antipsychotic, brexpiprazole, was approved in 2023 for the treatment of agitation in dementia associated with AD, becoming the first approved therapy for any neuropsychiatric syndrome in AD. 8 Data are emerging that may allow plasma biomarkers to replace amyloid PET and CSF studies of AD markers for diagnosis. 19 This will facilitate patient recruitment and improve trial quality by confirming the presence of the target disease.…”

“… 5 , 6 , 7 Brexpiprazole is approved for the treatment of agitation in dementia associated with AD. 8 These successes have been influential for AD therapeutics including demonstrating the ability to slow disease progression through intervention in key pathological processes of AD, establishing biomarkers as a means of diagnosing AD and following therapeutic responses, providing experience with clinical outcome measures in trials of both DMTs and symptomatic agents, and constructing regulatory standards applicable to the development of DMTs and treatments for symptomatic aspects of AD. The preliminary foundation for future clinical trials for AD therapeutics is in place.…”

Navigating late‐stage dementia: A perspective from the Alzheimer's Association

“…However, if that route does not work, caregivers could consider talking to their loved one's doctor about using brexpiprazole (Rexulti), a recently US Food and Drug Administration-approved atypical antipsychotic for agitation associated with dementia due to AD. 10 An article titled "Response to Stanley Terman: Too Little, Too Late" in A&D: DADM presents a perspective advocating for euthanasia options for individuals in the early stages of AD or related dementia. 11 It is worth noting that euthanasia is legally permitted in the Netherlands (where the article's authors live) when specified in advance directives.…”

Neuroinflammation in Neurodegenerative Disorders: Current Knowledge and Therapeutic Implications

“…Brexpiprazole is the only FDAapproved atypical antipsychotic drug for AD patients for the management of agitation associated with dementia [30]. Symptomatic improvement by brexpiprazole is considered to result from antagonistic action in noradrenergic α1B and α2C and serotonergic 5-HT2A receptors and partial agonistic activity at 5-HT1A and dopaminergic D2 receptors [31,32]. Lecanemab and Aducanumab are monoclonal antibodies approved for AD treatments [26,33].…”