P170: Safety and Tolerability of Brexpiprazole for the Treatment of Agitation in Alzheimer’s Dementia: Pooled Results From Three Phase III Trials

Abstract

Background: Despite the high burden of agitation in alzheimer's dementia (AAD) (1), there are no FDA-approved pharmacological treatments for the management of AAD. Certain medications, including antipsychotics, are commonly prescribed off-label to help control agitation symptoms. However, the use of off-label therapies is hindered by relatively poor adherence, and safety and tolerability concerns (2). Atypical antipsychotics carry an FDA boxed warning for mortality in elderly patients with dementia, due to analyses that show an increased risk of death versus placebo (3). Brexpiprazole, which has shown good tolerability in schizophrenia and major depressive disorder (4, 5), has been investigated as a potential therapy for AAD. Objectives: To assess the safety and tolerability of brexpiprazole in patients with AAD based on the combined results of three Phase III trials. Methods: Data were pooled from three 12-week, randomized, double-blind, placebO'Controlled, parallel-arm trials of brexpiprazole versus placebo in patients with AAD (ClinicalTrials.gov identifiers: NCT01862640 [6], NCT01922258 [6], NCT03548584). Two of the trials evaluated fixed doses of brexpiprazole (0.5, 1 or 2 mg/day [0.5 mg/day arm discontinued], and 2 or 3 mg/day), whereas the other trial investigated a flexible dose (0.5-2 mg/day). The primary objective of these trials was to assess efficacy on agitation symptoms (reported elsewhere). Safety was assessed as a secondary objective using standard variables, including treatment-emergent adverse events (TEAEs). For this post hoc analysis, data for all brexpiprazole groups were pooled, as were data for placebo groups. Results: Overall, 658 patients were randomized to brexpiprazole, and 389 patients randomized to placebo. At baseline, mean age was 73.5-74.2 years, and mean time since diagnosis of alzheimer's disease was 28.2-35.6 months, depending on the trial and randomized treatment group. A total of 655 patients were exposed to ≥1 dose of brexpiprazole, and 388 patients to ≥1 dose of placebo. The majority of patients had ≥42 days- exposure to study drug (95.1% for brexpiprazole, and 96.9% for placebo). Across all three trials, the incidence of TEAEs was 51.1% with brexpiprazole, with no notable differences between doses, and 45.9% with placebo. Serious TEAEs were experienced by 6.4% of patients receiving brexpiprazole and 4.1% of patients receiving placebo; TEAEs leading to discontinuation were experienced by 6.3% of patients receiving brexpiprazole compared with 3.4% receiving placebo. 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 in this patient population include falls (1.7% [brexpiprazole] versus 2.6% [placebo]), metabolism and nutrition disorders (3.5% versus 4.4%), sedation (0.3% versus 0%), and extrapyramidal disorder (0.8% versus 0%). No extrapyramidal symptom-related TEAEs occurred in ≥2% of patients receiving brexpiprazole and more than in placebo-treated patients. The mean change from baseline to last visit in body weight was 0.1 kg with brexpiprazole and -0.2 kg with placebo. The incidence of ≥7% increase in body weight from baseline was 1.7% with brexpiprazole and 0.8% with placebo. The mean change from baseline to last visit in Mini-Mental State Examination Total score was 0.21 with brexpiprazole (mean baseline 14.6) and 0.14 with placebo (mean baseline 14.9). Six patients receiving brexpiprazole (0.9%) and one patient receiving placebo (0.3%) died during the double-blind treatment period; none of these deaths were considered by the investigator to be related to brexpiprazole. Conclusion: Based on pooled results from three Phase III trials, brexpiprazole was well tolerated in patients with AAD, and had a clinical safety profile consistent with that of brexpiprazole in other indications. Brexpiprazole-treated patients had a similar incidence of sedation, extrapyramidal disorder, death, falls, and metabolic TEAEs compared with placebo, and no worsening of cognition.