The Food and Drug Administration’s decision to approve brexpiprazole (Rexulti) for the treatment of agitation related to Alzheimer’s disease in May was met with a mixed response. While some viewed the drug approval as a positive step for treating a common behavioral symptom of dementia, others questioned whether the benefits of the medication were worth the risk. Today, JAMA Neurology published the results of a key phase 3 clinical trial used in the FDA’s decision.
The trial of adults aged 55 to 90 with a diagnosis of probable Alzheimer’s disease who were experiencing agitation found that those who took brexpiprazole daily experienced a modestly greater drop in agitation behaviors over a 12-week period than those who took placebo. The study was funded by Otsuka Pharmaceutical and H. Lundbeck, co-developers of the drug.
“Treatment of agitation is essential to increase the comfort, quality of life, and safety of patients with Alzheimer dementia; to ease the burden on their caregivers; and to allow patients to live at home longer,” wrote Daniel Lee, M.D., of Otsuka and colleagues.
Lee and colleagues enrolled 345 adults with Alzheimer’s from clinical sites across Europe and the United States. The participants all had agitation symptoms that necessitated medication for at least two weeks prior to baseline screening. The participants also had to be living in a care facility or community-based setting and have a caregiver with enough contact to be able to describe the participant’s symptoms and behavior.
The participants were randomly assigned to 12 weeks of placebo (n=117), 2 mg brexpiprazole (n=75), or 3 mg brexpiprazole (n=153), taken orally once daily. The primary outcome was the participants’ change in Cohen-Mansfield Agitation Inventory (CMAI) scores after 12 weeks; the CMAI assesses the frequency of 29 physical and verbal agitation behaviors (such behaviors include kicking, pacing, and cursing), each on a 1 (never occurs) to 7 (occurs a few times an hour) scale. The CMAIs were filled out by clinicians following interviews with the participants’ caregivers.
The participants’ baseline CMAI scores were around 80. After 12 weeks, average CMAI scores dropped by 22.6 points in the combined brexpiprazole groups and 17.3 points in the placebo group, which was a statistically significant difference. Fifty-seven percent of participants taking brexpiprazole showed a meaningful change in agitation, defined as at least a 20-point CMAI reduction, compared with 37% of the placebo group.
Adverse side effects were reported by 40.7% of participants taking brexpiprazole and 31.0% of those taking placebo. Headache was the only side effect with an incidence of greater than 5% in the brexpiprazole group. “At week 12, weight gain of 7% or more from baseline was experienced by 3 of 196 patients (1.5%) in the brexpiprazole, 2 or 3 mg, group and 0 of 104 in the placebo group,” the authors added. Additionally, one patient taking brexpiprazole died of cardiac arrest, but an “autopsy revealed coronary atherosclerosis, and the death was considered unrelated to brexpiprazole,” the authors wrote.
“There are some clear pathways for further research that would build on the evidence provided by this study and inform the optimal use of brexpiprazole in people with AD,” wrote Clive Ballard, M.D., Ph.D., of the University of Exeter Medical School, United Kingdom, in an accompanying editorial. “The first will be to evaluate its efficacy and safety in the frailest patient groups with AD with more severe dementia and more serious comorbidities through studies in nursing home settings. This is particularly important as these individuals are at highest risk of neuropsychiatric symptoms and are most likely to be prescribed antipsychotic drugs.”
To read more on this topic, see the Psychiatric News article “FDA Approves Rexulti for Agitation Associated With Dementia Due to Alzheimer’s Disease.”
(Image: iStock/Tero Vesalainen)
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