Brexpiprazole for Agitation in Patients with Alzheimer’s Dementia with and without Co-Occurring Psychosis: Post Hoc Analysis of Short- and Long-Term Trials

Pierre N Tariot,1,2 Sanjeda R Chumki,3 David Wang,4 Pedro Such,5 Anton M Palma,6 Zhen Zhang,6 C Brendan Montano7 1Banner Alzheimer’s Institute, Phoenix, AZ, USA; 2Department of Psychiatry, University of Arizona College of Medicine, Phoenix, AZ, USA; 3Global Medical Affairs, Otsuka Pharmaceutical Development & Commercialization Inc., Princeton, NJ, USA; 4Medical Affairs, Lundbeck LLC, Deerfield, IL, USA; 5Medical Affairs, H. Lundbeck A/S, Valby, Denmark; 6Medical and Real-World Data Analytics, Otsuka Pharmaceutical Development & Commercialization Inc., Princeton, NJ, USA; 7Connecticut Clinical Research, Cromwell, CT, USACorrespondence: Sanjeda R Chumki, Otsuka Pharmaceutical Development & Commercialization Inc., 508 Carnegie Center Drive, Princeton, NJ, 08540, USA, Email [email protected]: Patients with Alzheimer’s dementia may experience co-occurring agitation and psychosis symptoms. This exploratory post hoc analysis aimed to analyze the efficacy and safety of brexpiprazole for agitation in patients with Alzheimer’s dementia with and without co-occurring psychosis.Participants and Methods: Data were pooled from two Phase 3, 12-week, randomized, double-blind, placebo-controlled, fixed-dose trials of brexpiprazole versus placebo in participants with Alzheimer’s dementia and agitation, conducted in Europe, Russia, and the US (ClinicalTrials.gov identifiers: NCT01862640, NCT03548584). Post hoc, participants were stratified into subgroups with or without co-occurring psychosis at baseline, defined as a score ≥ 4 on the Neuropsychiatric Inventory Delusions domain, Hallucinations domain, or both. Efficacy was assessed by the Cohen-Mansfield Agitation Inventory Total score. Safety was assessed by treatment-emergent adverse events (TEAEs).Results: 142/607 participants (23.4%) had co-occurring psychosis at baseline. Brexpiprazole 2 or 3 mg/day was associated with greater improvement in agitation compared with placebo in participants with co-occurring psychosis (least squares mean difference at Week 12, − 9.18 [95% confidence interval − 15.2 to − 3.12]; P=0.004; Cohen’s d=0.52) and in participants without co-occurring psychosis (− 4.22 [− 6.91 to − 1.54]; P=0.002; Cohen’s d=0.29). In participants with co-occurring psychosis, for brexpiprazole and placebo respectively, 52.9% and 40.0% had TEAEs, and 3.4% and 9.1% discontinued due to TEAEs. No deaths occurred among participants with co-occurring psychosis. In participants without co-occurring psychosis, for brexpiprazole and placebo respectively, 49.3% and 38.2% had TEAEs, and 5.5% and 2.6% discontinued due to TEAEs. Two participants without co-occurring psychosis died; neither death was considered related to brexpiprazole treatment.Conclusion: In this post hoc analysis, brexpiprazole improved agitation and was generally well tolerated in patients with Alzheimer’s dementia with and without co-occurring psychosis. These exploratory data suggest that brexpiprazole may be of value to patients with Alzheimer’s dementia who present with agitation and psychosis in clinical practice.Plain Language Summary: Alzheimer’s dementia is a brain disorder in which people’s thinking and memory decline slowly over time. Many people with Alzheimer’s dementia experience agitation, which can emerge as movement symptoms (restlessness, wandering) or as spoken or physical aggression (swearing, hitting). People with Alzheimer’s dementia may also experience psychosis, which refers to fixed, false beliefs that are not based in reality, or hearing and seeing things that are not there. Agitation and psychosis can both be treated with antipsychotic medications. However, some antipsychotic medications are thought to cause serious harm, even death, in people with Alzheimer’s dementia. The antipsychotic, brexpiprazole, is the only medicine approved by the United States FDA for the treatment of agitation in people with Alzheimer’s dementia. In this report, researchers used information from previous clinical trials to explore whether brexpiprazole can safely treat agitation in people with Alzheimer’s dementia with both agitation and psychosis. The results showed that brexpiprazole improved agitation more than placebo (a dummy drug), with no new safety concerns compared with previous studies. This suggests that brexpiprazole may be able to help people with agitation and Alzheimer’s dementia, even if they also have psychosis.Keywords: Alzheimer’s disease, antipsychotic, clinical trial, efficacy, safety