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Alzheimer Agitation Therapy Brexpiprazole Proves Efficacy in Full Phase 3 Dataset
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Brexpiprazole was generally well tolerated over 12 weeks in this vulnerable patient population, with documented efficacy that supported its approval in early 2023.
George T. Grossberg, MD
Months after the FDA approved brexpiprazole (Rexulti; Otsuka/Lundbeck) as the first agent to treat patients with Alzheimer disease (AD) agitation, investigators have published the full dataset of the supportive phase 3 Study 331-12-283 (NCT01862640). In the study, patients on 2 or 3 mg brexpiprazole showed statistically significant improvement vs placebo in reducing agitation symptoms over a 12-week period.1
Published in JAMA Network Open, the trial featured 345 patients with AD agitation who were randomly assigned 2:1 to either brexpiprazole (n = 228) or placebo (n = 117) and assessed on change in Cohen-Mansfield Agitation Inventory (CMAI) total score, the primary end point. The mean age of the cohort was 74.0 (SD, 7.5) years, most patients were White (95.4%), and more than half (55.9%) had moderate cognitive impairment, defined as Mini-Mental State Exam scores of 13-18.
Led by George T. Grossberg, MD, Samuel W. Fordyce professor and director of Geriatric Psychiatry in the Department of Psychiatry at St. Louis University School of Medicine, the study spanned 123 across the US, Ukraine, Bulgaria, Serbia, Slovakia, Spain, and Hungary. During the trial, standard medications for AD (mostly memantine or donepezil) were taken by 184 patients (81.4%) receiving brexpiprazole and 95 (81.9%) receiving placebo, and concomitant medications for agitation were received at least once by 44 patients (19.5%) taking brexpiprazole and 17 (14.7%)) on placebo.
At the conclusion of the 12-week treatment period, those on brexpiprazole 2 or 3 mg demonstrated significantly greater improvement on CMAI total score, with a Cohen d effect size of 0.35. Throughout this time, the agent also demonstrated statistically greater improvement vs placebo on the change in Clinical Global Impression-Severity (CGI-S) score, a key secondary end point, with a Cohen d effect size of 0.31. Other secondary end points, CMAI factor scores, GCI-Improvement, and CMAI/GCI-I response rates, also favored brexpiprazole, with nominally greater changes over placebo.
Brexpiprazole, which acts as an antagonist at noradrenergic a1B and a2C and seotonergic 5-HT2A receptors, also performed well on exploratory end points. In comparison with placebo, the agent demonstrated nominally significant greater improvement on Neuropsychiatric Inventory-Nursing Home version, a validated assessment of neuropsychiatric symptoms and psychopathology of patients with AD and other dementias in extended care settings. On CGI-Severity score, brexpiprazole 2 and 3 mg demonstrated similar improvements at week 12, with nominal significance vs placebo for the 3 mg dosed group.
In terms of safety, treatment-emergent adverse events (TEAEs) occurred in 40.7% of those on brexpiprazole and 31.0% on placebo, with no apparent effect of dose. After 12 weeks of treatment, 1.5% (n = 3) of patients on brexpiprazole demonstrated a weight gain of 7% or more whereas no one on placebo experienced this. Mean change in Mini-Mental State Exam (MMSE) score from baseline to the end of the treatment period was 0.7 (SD, 2.8) in the brexpiprazole 2 or 3 mg group (n = 192) and 0.4 (SD, 2.1) in the placebo group (n = 103).
There was 1 death during the study, a 78-year-old patient in the brexpiprazole 3 mg group, who passed from cardiac failure. The patient was on the drug for 28 days before withdrawing because of an adverse event of hallucinations. An autopsy revealed coronary atherosclerosis, and the death was considered unrelated to brexpiprazole.
Brexpiprazole’s 2023 approval was also fueled by findings from the phase 3 Study 331-12-283 (NCT01922258), a similarly designed 12-week, randomized, double-blind, placebo-controlled trial. Also known as Study 284, the flexible-dose trial assessed brexpiprazole doses of 0.5-2 mg/day in a cohort of 270 patients with AD agitation. All told, brexpiprazole 0.5–2 mg/day did not achieve statistical superiority over placebo (CMAI total score change: –2.34; –5.49, 0.82; t(230) = −1.46; p = 0.15; MMRM). However, a benefit was observed in post hoc analyses among patients titrated to the maximum brexpiprazole dose of 2 mg/day compared with similarly titrated placebo patients (−5.06; −8.99, −1.13; t(144) = −2.54; p = 0.012; MMRM).
