FDA Panel Votes in Favor of Brexpiprazole as Potential Therapy for Alzheimer Agitation


The FDA is expected to make a decision by May 10, 2023, whether brexpiprazole will become the first approved therapy for Alzheimer disease agitation.

The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee has voted that the current data on brexpiprazole (Rexulti; Otsuka/Lundbeck), an agent under review for Alzheimer disease (AD) agitation, have shown enough evidence of benefit to outweigh its potential risks. The agent currently has a PDUFA date of May 10, 2023, and, if approved, would be the first agent specifically to treat AD agitation.1

The committee was asked to vote on whether the provided data was sufficient to allow the identification of a population in whom the benefits of treating agitation associated with Alzheimer dementia with brexpiprazole outweighed its risks. At the end of the hearing, the committee voted 9–1 (9 yes; 1 no; 0 abstain) in favor of the agent.

In the hearing, those involved were posed 2 discussion questions about the overall benefit/risk of the therapy, considering the increased risk of risk of death among elderly patients with dementia receiving antipsychotics, and the risks of medications that are often used off-label for the treatment of AD agitation without established evidence of efficacy.

Throughout the meeting, the safety of the drug, 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. Brexpiprazole’s supplemental new drug application (sNDA), accepted by the FDA in early January 2023, was based on 2 phase 3 studies—Study 331-12-283 (NCT01862640) and Study 331-14-213 (NCT03548584). Brexpiprazole was originally approved in July 2015 as an adjunctive therapy to antidepressants in adults with major depressive disorder and as a treatment for schizophrenia in adults.2

Do you agree with the FDA AdComm's assessment of brexpiprazole for treatment of Alzheimer agitation?


Throughout the trials, there were 7 recorded deaths, 6 of which were in brexpiprazole groups, and none of which were considered related to the drug in question. One case of intracranial hemorrhage and acute purulent meningoencephalitis were the reasons for death in the 0.5-mg group. Two patient deaths of aspiration pneumonia and airway obstruction were recorded in the 1-mg group, and 1 death of end-stage Alzheimer dementia was found in the 2-mg group. The final death of heart failure was in the 3-mg group. Throughout the hearing, presenters from Otsuka stressed that there were no patterns or trends in deaths, and that all of which were deemed unrelated to brexpiprazole.

Another point of contention was the potential unforeseen safety risks of the drug in the long term, considering none of the studies included treatment periods longer than 12 weeks. Like in many other neurodegenerative conditions, those who were involved in the hearing discussed and weighed the circumstances of this condition and the currently available options. Agitation affects approximately 45% of patients with AD dementia, with lasting impacts on family members and caregivers. It has been typically managed and treated using atypical antipsychotics, which include black box warnings for risks of stroke and death in this patient population.

While the agent’s mechanism of action is unknown, the reasons for its efficacy are thought to be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors along with antagonism at noradrenaline alpha1B/2C receptors and at serotonin 5-HT2A receptors.2

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.

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).3

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 of heart failure occurred in the 3-mg/day treatment group but was not related to the study drug.

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.4

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).

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 = .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 = .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%).

Safety, and specifically the use of atypical antipsychotics, has been a concern in the AD community for several years. A recently published study that included patients with dementia exposed (n = 8244) and unexposed (n = 24,730) added to the long evidence that antipsychotic treatment is associated with mortality. Using nationwide registry data, patients exposed to antipsychotics had a significantly higher adjusted risk of death (hazard ratio, 1.35; 95% CI, 1.27-1.43) than unexposed patients.5

1. FDA. Peripheral and Central Nervous System Drugs Advisory Committee Meeting. April 14, 2023. Accessed April 14, 2023. https://www.fda.gov/advisory-committees/advisory-committee-calendar/april-14-2023-joint-meeting-psychopharmacologic-drugs-advisory-committee-and-peripheral-and-central
2. Otsuka and Lundbeck announce FDA acceptance and priority review of sNDA for brexpiprazole for the treatment of agitation associated with Alzheimer’s dementia. January 7, 2023. Accessed April 14, 2023. https://www.otsuka-us.com/news/otsuka-and-lundbeck-announce-fda-acceptance-and-priority-review-snda-brexpiprazole-treatment
3. 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 April 14, 2023. 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
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
5. Norgaard A, Jensen-Dahm C, Wimberley T, et al. Effect of antipsychotics on mortality risk in patients with dementia with and without comorbidities. J Am. Geriat Soc. Published online January 22, 2022. doi:10.1111/jgs.17623
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