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Brexpiprazole Demonstrates Positive Impact on Alzheimer Agitation, NDA Submission on the Horizon

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.

READ MORE: Fosgonimeton Fails to Reach End Points, but Shows Mechanistic Potential in Alzheimer Disease

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%).

1. Otsuka Pharmaceuticals and Lundbeck announce positive results showing reduced agitation in patients with Alzheimer’s dementia treated with brexpiprazole. News release. June 27, 2022. Accessed June 28, 2022. https://www.businesswire.com/news/home/20220627005184/en/Otsuka-Pharmaceutical-and-Lundbeck-Announce-Positive-Results-Showing-Reduced-Agitation-in-Patients-with-Alzheimer%E2%80%99s-Dementia-Treated-with-Brexpiprazole
2. BioXcel Therapeutics initiates pivotal phase 3 program of BXCL501 for acute treatment of agitation in patients with Alzheimer’s disease. News release. BioXcel Therapeutics Inc. December 15, 2021. Accessed June 28, 2022. https://www.biospace.com/article/releases/bioxcel-therapeutics-initiates-pivotal-phase-3-program-of-bxcl501-for-acute-treatment-of-agitation-in-patients-with-alzheimer-s-disease/
3. Suven Life Sciences announces phase 3 clinical trial of SUVN-502 (Masupirdine) a 5-HT6 antagonist for treatment of agitation and aggression in Alzheimer type dementias. News release. Suven Life Sciences. August 17, 2021. Accessed June 28, 2022. https://www.firstwordpharma.com/node/1855886
4. 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