Post Hoc Analysis Highlights Brexpiprazole’s Efficacy and Tolerability in Alzheimer Agitation

Kara Keilman, PharmD, senior medical science liaison at Lundbeck

In a new post-hoc analysis presented at the 4th Annual Advanced Therapeutics in Movement and Related Disorders (ATMRD) Congress, held by the PMD Alliance from June 27-30, 2025, brexpiprazole (Rexulti, Otsuka/Lundbeck), an FDA-approved therapy for agitation associated with Alzheimer dementia, showed a favorable balance of efficacy and safety. Overall, the data demonstrated its potential to ease agitation in patients living with the neurodegenerative disorder.¹

Presented by Kara Keilman, PharmD, senior medical science liaison at Lundbeck, the analysis evaluated clinical benefit versus risk of brexpiprazole 2 or 3 mg/day using a number of different outcomes, including Number Needed to Treat (NNT), Number Needed to Harm (NNH), how many needed to be treated for one to be harmed, and Likelihood to be Helped or Harmed (LHH). In the findings, the medication showed efficacy in reducing agitation symptoms, with statistically meaningful NNT values. Overall, it was well tolerated, with minimal differences in discontinuation rates related to adverse effects (AEs) compared with placebo.

The post-hoc analysis had data from two 12 week trials (Study 283 [NCT01862640] and Study 213 [NCT03548584]) of which that led to the therapy's 2023 approval. Among 610 patients (brexpiprazole, n = 363, placebo = 247), response rates were higher in brexpiprazole in multiple categories: 20-point reductions in Cohen-Mansfield Agitation Inventory (CMAI; 50.1% vs 37.7%; NNT = 9, 95% CI: 5-22); 58.1% vs 42.9% met a greater than or equal to 17-point reduction (NNT = 12).

For safety, discontinuation because of treatment-emergent adverse events (TEAEs) was similar between groups. There was 4.9% discontinuation rate with brexpiprazole vs 4.8% with placebo (NNH = 730; not significant). Mild TEAEs occurred in 38.8% of brexipiprazole-treated patients vs 30.3% of those on placebo (NHH=12). Moderate TEAEs occurred in 17.2% vs 13.9% (1.24x higher) of those respective groups while severe TEAEs occurred in 5.2% vs 3.2% (1.63x higher).

The most common specific TEAEs also occurred more frequently with brexpiprazole vs placebo: somnolence and sedation (3.8% vs 0.8%), extrapyramidal symptoms excluding akathisia (3.3% vs 1.2%), urinary tract infections (3.3% vs 1.2%), and akathisia (1.7% vs 0%). Despite these differences, the LHH was favorable at 81:1 (based on a greater than or equal to 20-point CMAI reduction vs TEAE discontinuation), showing brexpiprazole is more likely to benefit patients with agitation in AD.

Brexpiprazole, an atypical antipsychotic, was the first FDA-approved treatment to address Alzheimer’s-related agitation in 2023. It was originally approved in the U.S. in 2015 for schizophrenia and as an adjunctive treatment for major depressive disorder (MDD) but later had its indication expanded to include agitation associated with dementia due to AD.²

The FDA approval was based on the two aforementioned studies, both of which were randomized, double-blind, and placebo-controlled in design, featuring patients aged 51 to 90 with probable AD and clinically significant agitation. Coming into the study, participants required Mini-Mental State Examination (MMSE) scores of 5 to 22 and caregiver-confirmed agitation behaviors. Both studies used the CMAI as the primary endpoint, with results that showed statistically and clinically meaningful improvements after 12 weeks of treatment with brexpiprazole 2 or 3 mg.³

The drug works by targeting multiple neurotransmitter systems. It is a novel serotonin-dopamine activity modulator that acts as a partial agonist of serotonin 1A (5-HT1A) and dopamine D2 receptors, as well as a potent antagonist of 5-HT2A receptors and noradrenergic α1B and α2C receptors.⁴

Agitation in Alzheimer’s dementia is a distressing common neuropsychiatric symptom. Agitation occurs in approximately 45% of individuals with AD and may manifest as verbal outbursts, pacing, inappropriate gesturing, or physical aggression. These symptoms are associated with earlier transition to residential care, lower patient quality of life, and increased distress in caregivers.⁵

REFERENCES:
1.Citrome L, Chumlaki S, Such P, et al. Brexpiprazole for agitation associated with dementia due to Alzheimer’s disease: number needed to treat, number needed to harm, and likelihood to be helped or harmed. Advanced Therapeutics in Movement & Related Disorders (ATMRD) Congress; June 27–30, 2025; P-19.
2.Siwek M, Wojtasik-Bakalarz K, Krupa AJ, Chrobak AA. Brexpiprazole—Pharmacologic Properties and Use in Schizophrenia and Mood Disorders. Brain Sciences. 2023;13(3):397-397. doi:https://doi.org/10.3390/brainsci13030397
3.Commissioner O of the. FDA Approves First Drug to Treat Agitation Symptoms Associated with Dementia due to Alzheimer’s Disease. FDA. Published May 11, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treat-agitation-symptoms-associated-dementia-due-alzheimers-disease
4.Greig SL. Brexpiprazole: First Global Approval. Drugs. 2015;75(14):1687-1697. doi:https://doi.org/10.1007/s40265-015-0462-2
5.Alzheimer's Association. Alzheimer’s Association Statement on FDA Approval of Brexpiprazole. Alzheimer’s Association. Published May 11, 2023. Accessed July 1, 2025. https://www.alz.org/news/2023/alzheimer-s-association-statement-on-fda-approval-of-brexpiprazole