Alzheimer Agitation Therapy Brexpiprazole Maintains Safe Profile in Longitudinal Analysis

Using data from a double-blind, phase 3 trial (NCT03548584) and its long-term extension (NCT03594123), results showed that brexpiprazole (Rexulti; Otsuka/Lundbeck), an FDA-approved treatment for patients with Alzheimer disease (AD) agitation, was safe over a 24-week period, with a low incidence of treatment-emergent adverse events (TEAEs) observed. Of note, this post-hoc analysis was restricted to patients who enrolled in the extension trial, which may have resulted in a sample better able to tolerate brexpiprazole.

Presented at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 29-November 1 in Madrid, Spain, the analysis included 163 patients who were treated with brexpiprazole 2 or 3 mg/day over the 12-week double-blind core study and 12-week extension. Throughout the pooled 24-week period, TEAEs were experienced by 48.5% (n = 79) of treated patients. Most notably, a Kaplan-Meier estimate revealed that among patients who had not experienced a TEAE in the randomized trial, TEAEs were rare throughout the extension study.

Led by Anton P. Porsteinsson, MD, director of the Alzheimer’s Disease Care, Research, and Education Program at the University of Rochester, the analysis was geared towards building a greater understanding of the long-term safety profile of brexpiprazole, which received FDA approval last May. In the randomized trial, patients were randomized 2:1 to brexpiprazole (2 or 3 mg/day; titration: Days 1–7, 0.5 mg/day; Days 8–14, 1 mg/day; Days 15–28, 2 mg/day; Day 29 onwards, assigned dose) or placebo. Upon completion, patients entered the 12-week open-label extension.

In the analysis, results showed that the incidence of all TEAEs in 2-week intervals was 2.5-12.9% during the first 12 weeks and 1.3-8.9% in the second 12 weeks. In addition, the median time to first TEAE was 7.4 days (IQR, 3-12), while the median duration of all TEAEs was 3 days (IQR, 1-8). Overall, these results suggest that longer-term treatment with brexpiprazole was not associated with increased risk of TEAEs.

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Brepiprazole was originally approved in 2015 as an adjunctive therapy to antidepressants in adults with major depressive disorder and as a treatment for schizophrenia in adults. It later had its indication expanded in 2023 to include the treatment of AD agitation, making it the first FDA-approved therapy specific for that condition. The mechanism of action of brexpiprazole is unknown; however, the efficacy of the therapy is thought to be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT2A receptors.

The 12-week study used in the analysis presented at CTAD 2024 was otherwise known as study 213. This trial, which served as one of the major studies in brexpiprazole’s approval, randomly assigned 345 individuals with AD agitation to brexpiprazole 2- or 3-mg/day doses or placebo for a 12-week period. At the conclusion of the treatment period, those on the therapy demonstrated statistically greater improvements in the primary end point of Cohen-Mansfield Agitation Inventory (CMAI) total scores compared with those on placebo.²

Patients aged 55 to 90 years who met the criteria for agitation based on the International Psychogeriatric Association were included in the study, which comprised those who were living at home and those in institutionalized settings. In addition to showing statical significance on its primary end point, the therapy showed promising benefit on the key secondary end point of Clinical Global Impression–Severity of Illness (CGI-S) score, as related to symptoms of agitation (P = .0055).

In study 213, headache, reported in 6.6% of patients on brexpiprazole and 6.9% of those on placebo, was the only TEAE with a greater than 5% incidence during the study. Somnolence, nasopharyngitis, dizziness, diarrhea, urinary tract infection, and asthenia, were among the other TEAEs with an incidence of at least 2% that were more common in the brexpiprazole group. One death occurred in the 3-mg/day treatment group but was not related to the study drug.

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REFERENCES
1. Porteinsson AP, Brubaker M, Chumki SR, et al. Timing and duration of adverse events during 24 weeks of brexpiprazole treatment in patients with agitation associated with dementia due to Alzheimer disease: results from a randomized trial and an extension trial. Presented at: Clinical Trials on Alzheimer’s Disease (CTAD) conference; October 29-November 1; Madrid, Spain. ABSTRACT LB28
2. Otsuka Pharmaceuticals and Lundbeck announce positive results showing reduced agitation in patients with Alzheimer’s dementia treated with brexpiprazole. News release. June 27, 2022. Accessed October 31, 2024. https://www.businesswire.com/news/home/20220627005184/en/Otsuka-Pharmaceutical-and-Lundbeck-Announce-Positive-Results-Showing-Reduced-Agitation-in-Patients-with-Alzheimer%E2%80%99s-Dementia-Treated-with-Brexpiprazole