Agitation in Alzheimer’s dementia (AAD) is prevalent, distressing, and burdensome. Medications for agitation are commonly prescribed off-label, although use is hindered by safety and tolerability concerns. This pooled analysis evaluates the safety and tolerability of brexpiprazole in patients with AAD.

Data were pooled from three Phase 3, 12-week, placebo-controlled trials (NCT01862640, NCT01922258, NCT03548584) (overall, and by brexpiprazole dose). The primary objective of each trial was to assess the efficacy of brexpiprazole on agitation. Safety was a secondary objective.

658 patients were randomized to brexpiprazole (0.5–3 mg/day, depending on the trial; n=655 treated), and 389 patients were randomized to placebo (n=388 treated). Mean baseline age was 73.5–74.2 years, and mean time since diagnosis of Alzheimer’s disease was 28.2–35.6 months. The pooled incidence of treatment-emergent adverse events (TEAEs) was 51.1% with brexpiprazole, with no notable differences between doses, and 45.9% with placebo. The incidence of serious TEAEs was 6.4% (brexpiprazole) versus 4.1% (placebo), and the incidence of TEAEs leading to discontinuation was 6.3% versus 3.4%, respectively. TEAEs that occurred in ≥2% of patients receiving brexpiprazole and more than in placebo-treated patients were insomnia (3.7% versus 2.8%), somnolence (3.4% versus 1.8%), nasopharyngitis (2.7% versus 2.6%), and urinary tract infection (2.6% versus 1.5%). Other TEAEs of interest included falls (1.7% versus 2.6%) and sedation (0.3% versus 0.0%). TEAE categories of interest included extrapyramidal symptom (EPS)-related TEAEs (5.3% versus 3.1%), cardiovascular TEAEs (3.7% versus 2.3%), and cerebrovascular TEAEs (0.5% versus 0.3%). The mean change from baseline to last visit in Mini–Mental State Examination score was 0.21 (brexpiprazole) and 0.14 (placebo). Six patients receiving brexpiprazole (0.9%) and one patient receiving placebo (0.3%) died; none of the deaths was considered related to brexpiprazole.

Based on pooled data, brexpiprazole was well tolerated in patients with AAD, and had a clinical safety profile consistent with that of brexpiprazole in other indications. Patients receiving brexpiprazole had a similar incidence of sedation, EPS events, falls, cardiovascular events, and cerebrovascular events compared with placebo, and no worsening of cognition. The incidence of death was low, and no deaths were considered related to study treatment.