The approval was based on 2, positive phase 3 studies in which brexpiprazole-treated patients demonstrated a 31% greater reduction in frequency of agitation symptoms vs those on placebo.
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The FDA has approved an expanded indication for brexpiprazole (Rexulti; Otsuka/Lundbeck) to include the treatment of agitation associated with dementia due to Alzheimer disease (AD). With the approval, it becomes the first marketed drug specific to treat AD agitation.1
"This approval is a testament to our commitment and unwavering support of patients and caregivers to lessen the symptoms of agitation associated with dementia due to Alzheimer’s disease,” Deborah Dunsire, chief executive officer and president, Lundbeck, said in a statement.1 "We look forward to offering this first FDA-approved treatment option to address this significant unmet need for patients. We are grateful to the patients and caregivers who participated in these important trials."
Brepiprazole was originally approved in 2015 as an adjunctive therapy to antidepressants in adults with major depressive disorder and as a treatment for schizophrenia in adults. The mechanism of action of brexpiprazole is unknown; however, the efficacy of the therapy is thought to be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT2A receptors.
The news of the expanded indication comes less than a month after the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted in favor of brexpiprazole as a potential therapy for AD agitation. The committee was asked to vote specifically on whether the provided data in the supplemental new drug application (sNDA), which comprised of 2, positive phase 3 studies, provided enough evidence of benefit of brexpiprazole to outweigh its potential risks.2
Brexpiprazole’s sNDA was supported by Study 331-12-283 (NCT01862640) and Study 331-14-213 (NCT03548584). In Study 331-12-213, also known as Trial 213, 345 individuals with AD agitation who received brexpiprazole 2- or 3-mg/day doses demonstrated statistically greater improvements from baseline to week 12 in the primary end point of Cohen-Mansfield Agitation Inventory (CMAI) total scores compared with those on placebo (P = .0026). 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.3
Patients aged 55 to 90 years who met the criteria for agitation based on the International Psychogeriatric Association were included in the study, which comprised those who were living at home and those in institutionalized settings. In addition to showing statical significance on its primary end point, the therapy showed promising benefit on the key secondary end point of Clinical Global Impression–Severity of Illness (CGI-S) score, as related to symptoms of agitation (P = .0055).
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"Today marks a major milestone for patients, caregivers, and families navigating the complexities of agitation associated with dementia due to Alzheimer’s disease,” Makoto Inoue, president and representative director, Otsuka, said in a statement.1 "Otsuka Pharmaceutical will continue its efforts to engage and provide options for those impacted by this devastating condition."
Data on the second study, Study 331-12-283, was released with another 12-week, randomized, double-blind placebo-controlled, parallel-arm study (NCT01922258), otherwise known as Study 284. Led by George Grossberg, MD, study 283 (n = 433) assessed brexpiprazole 1 or 2 mg/day or placebo (1:1:1) for 12 weeks while study 284 was a flexible-dose trial, with patients on brexpiprazole 0.5 to 2.0 mg/day or placebo (1:1) for 12 weeks. Both studies used CMAI and GCI-S as the main measurements, along with safety.
In study 283, 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).
Throughout the AdComm meeting, the safety of brexpiprazole, particularly the deaths recorded across the 3 trials, was a point of contention; however, panelists felt as though the evidence of efficacy, and the lack of available non-off-label treatments, was sufficient to support an approval. During the trial program, there were 7 recorded deaths, 6 of which were in the brexpiprazole group, and none of which were considered related to the therapy. Throughout the hearing, presenters from Otsuka continued to stress that there were no patterns or trends in deaths.
In its label, it states that brexpiprazole should not be used as an "as needed” treatment for agitation. Additionally, it may cause serious adverse events, including cerebrovascular problems, such as stroke, in elderly people with dementia-related psychosis, as we all as neuroleptic malignant syndrome, uncontrolled upper body movements, and issues with metabolism.