Over a 12-week treatment period, brexpiprazole demonstrated statistically significant improvements on the primary and secondary end points compared with placebo.
Recently announced positive results from a phase 3 study (NCT03548584) showed that brexpiprazole (Rexulti; Otsuka/Lundbeck) met statistically significant changes in Cohen-Mansfield Agitation Inventory (CMAI) total score compared with placebo for the treatment of agitation amongst patients with Alzheimer disease (AD) dementia.1 The companies expect to file a supplemental new drug application later in 2022 using these findings and 2 previously successful studies.
In the study, known as Trial 213, patients who received brexpiprazole in 2- or 3-mg/day doses demonstrated statistically greater improvements from baseline to week 12 on the primary end point of CMAI compared with those on placebo (P = .0026). This result was also supported by statistically superior improvements on the key secondary end point of Clinical Global Impression–Severity of Illness (GCI-S) score, as related to symptoms of agitation (P = .0055).
Currently, there are no FDA-approved pharmacological treatments for agitation in AD. Although, other therapies are also being assessed for this indication. Recently, BioXcel Therapeutics initiated a phase 3 trial of BXCL501 (Igalmi), an orally dissolving thin-film formulation of dexmedetomidine, in AD-related agitation, consisting of 2 randomized, placebo-controlled, adaptive, parallel group pivotal trials—TRANQUILITY II (NCT05271552) and TRANQUILITY III (NCT05276830).2 Additionally, Suven Life Sciences initiated a phase 3 study in 2021 to further study its agent, masupirdine, and its effect on agitation with AD dementia, enrolling approximately 387 patients for a study period of 36 months. Topline results of that investigation are anticipated to be presented by the end of 2024.3
Brexpiprazole, a medication that received FDA approval in 2015 as an adjunctive therapy to antidepressants for patients with major depressive disorder and as a treatment for adults with schizophrenia, continued to show promising safety signals as well in this trial of AD agitation. Headache, reported in 6.6% of patients on brexpiprazole and 6.9% of those on placebo, was the only treatment-emergent adverse event (TEAE) with a greater than 5% incidence during the study. Somnolence, nasopharyngitis, dizziness, diarrhea, urinary tract infection, and asthenia, were among the other TEAEs with an incidence of at least 2% that were more common in the brexpiprazole group. One death occurred in the 3-mg/day treatment group but was not related to the study drug.1
In the study, 345 individuals, aged 55 to 90 years with a diagnosis of probable AD and who met criteria for agitation based on the International Psychogeriatric Association were treated with brexpiprazole or placebo in a 12-week double-blind period, with a 30-day follow-up. The study included both patients who were living at home and those in institutionalized settings. CMAI, a caregiver rated questionnaire that measures the frequency of manifestations of 29 agitated behaviors, has been used extensively for assessing agitation and has been adapted and validated for different patient settings.
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Brexpiprazole was previously assessed in two, 12-week, randomized, double-blind, placebo-controlled parallel-arm studies (NCT01862640; NCT01922258). Led by George Grossberg, MD, 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. Similar to the new study, these 2 used CMAI and GCI-S as the main measurements, along with safety.4
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; P = .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; P = .90). 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; P = .15); 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; P = .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%).