Brexpiprazole Continues to Demonstrate Efficacy as Alzheimer Agitation Therapy Across Multiple Phase 3 Trials


Across 3 trials in patients with Alzheimer disease agitation, brexpiprazole doses of 2 or 3 mg/day was safe and showed a statistically significant improvement vs placebo in agitation.

Robert McQuade, PhD, executive vice president, chief strategy officer, Otsuka Pharmaceutical Development & Commercialization

Robert McQuade, PhD

After previously releasing positive findings from 2, phase 3 trials (NCT01862640; NCT01922258), new data from a third study presented at the 2022 Clinical Trials on Alzheimer Disease (CTAD) conference, held November 29 to December 2, in San Francisco, California, continued to highlight the significant impact of brexpiprazole (Rexulti; Otsuka Pharmaceutical/Lundbeck) as a potential therapeutic for Alzheimer disease (AD) agitation.1,2

After 12 weeks of treatment with brexpiprazole 2 or 3 mg/day, investigators observed a statistically significant improvement relative to placebo on the Cohen-Mansfield Agitation Inventory (CMAI) total (least square mean difference [LSMD], ­–5.32; P = .0026) and Clinical Global Impression-Severity (CGI-S) score (LSMD, –0.27; P = .0078). The study, known as Trial 213, had data readout in June 2022, and at the time, the companies noted they expect to file a supplemental new drug application later in the year to include findings from all 3 trials.

"Agitation in Alzheimer’s dementia represents an incredibly complex and challenging aspect of care in patients affected by the disease," Robert McQuade, PhD, executive vice president, chief strategy officer, Otsuka Pharmaceutical Development & Commercialization, said in a statement.1 "We’re proud to share this positive data from our Phase 3 double-blind trials that showcase our commitment to address current unmet needs and deliver a first-of-its-kind pharmacological treatment for agitation in Alzheimer’s dementia to patients and their caregivers."

All 3 studies were 12-week, randomized, double-blind, placebo-controlled, parallel-arm design; however, the third study differed in terms of the dose administered (2 or 3 mg/day) and agitation requirements, which comprised of the NPI criteria, the International Psychogeriatric Association (IPA) provisional definition, and a criterion based on CMAI factor 1. CMAI total score remained the primary end point throughout all the studies, with CGI-S score as related to agitation as the secondary end point.

In terms of safety, treatment-emergent adverse events (TEAEs) were observed in 51.1% of those on active therapy vs 45.9% of those on placebo. Across all 3 trials, no single TEAE had an incidence rate of at least 5% with brexpiprazole and more than in placebo-treated patients. Between the 2 groups, the TEAEs that occurred in at least 2% more of patients receiving brexpiprazole than placebo were insomnia (3.7% vs 2.8%), somnolence (3.4% vs 1.8%), nasopharyngitis (2.7% vs 2.6%), and urinary tract infection (2.6% vs 1.5%).

Additional safety data from the third trial showed a fall incidence of 1.7% for those on brexpiprazole vs 2.6% for those on placebo. There were 6 patient deaths in the brexpiprazole group and 1 on placebo; however, none of the deaths were considered related to active treatment. Discontinuation from the study because of TEAEs occurred in 6.3% of the brexpiprazole cohort and 3.4% for those on placebo.

Study 1 (n = 433) assessed brexpiprazole 1 or 2 mg/day or placebo (1:1:1) for 12 weeks while study 2 was a flexible dose trial, with patients on brexpiprazole 0.5 to 2.0 mg/day or placebo (1:1) for 12 weeks. In study 1, brexpiprazole 2 mg/day demonstrated statistically significant greater improvements in CMAI total score from baseline to week 12 than placebo (adjusted mean difference, –3.77; confidence limits, –7.38 to –0.17; t(316) = –2.06; = .040). Individuals in the 1-mg/day group did not show meaningful separation from placebo (adjusted mean difference, 0.23; confidence limits, –3.40 to 3.86; t(314) = 0.12; = .90).3

The flexible-dose group of brexpiprazole did not achieve statistical superiority over placebo (adjusted mean difference, –2.34; confidence limits, –5.49 to 0.82; t(230) = ­1.46; = .15) on CMAI total score; however, there were benefits observed among those titrated to the maximum brexpiprazole dose of 2 mg/day compared with similarly titrated patients on placebo (adjusted mean difference, –5.06; confidence limits, –8.99 to –1.13; t(144) = –2.54; = .012).

On the CGI-S, a greater numerical improvement than placebo was demonstrated for brexpiprazole 2 mg/day in Study 1 (adjusted mean difference, −0.16; confidence limits, −0.39 to 0.06; t(337) = −1.42; P = 0.16), and a greater improvement for brexpiprazole 0.5–2 mg/day in Study 2 (adjusted mean difference, −0.31; confidence limits, −0.55 to −0.06; t(222) = −2.42; P = 0.016). In study 1, TEAEs with an incidence of at least 5% among both placebo and those on brexpiprazole 2 mg/day were headache (9.3% vs 8.1% with placebo), insomnia (5.7% vs 4.4%), dizziness (5.7% vs 3.0%), and urinary tract infection (5.0% vs 1.5%).

"Agitation is a significant unmet need among the Alzheimer’s community, and these results bring us one step closer to providing a possible treatment option that addresses the needs of this vulnerable patient population" Johan Luthman, executive vice president and head of Research & Development, Lundbeck, said in a statement.1

1. Otsuka Pharmaceutical & Lundbeck Present Positive Data From Multiple Phase 3 Studies Showing Brexpiprazole Significantly Improved Symptoms of Agitation in Patients With Alzheimer’s Dementia at the 2022 Clinical Trials for Alzheimer’s Disease Congress. News release. Otsuka Pharmcaeuticals. December 1, 2022. Accessed December 1, 2022.
2. Grossberg G, Lee D, Slomkowski M, et al. Tackling agitation in Alzheimer’s dementia: brexpiprazole phase 3 trial results. Presented at: 2022 CTAD Conference; November 29 to December 2; San Francisco, CA. Readouts
3. Grossberg GT, Kohegyi E, Mergel V, et al. Efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer’s dementia: two 12-week, randomized, double-blind, placebo-controlled trials. Am J Geriatr Psychiatry. 2020;28(4):383-400. doi:10.1016/j.jagp.2019.09.009
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