FDA Approves the First Drug for Alzheimer’s Agitation: Rexulti

As many as half of people who develop Alzheimer’s dementia experience the symptom of agitation, which can lead to behaviors like pacing, restlessness, and aggression, both verbal and physical. Until now, there hasn’t been an FDA-approved treatment for these symptoms in people with Alzheimer’s. That changed last week, when the FDA gave its stamp of approval to new treatment for Alzheimer’s agitation Rexulti.

Generic name brexpiprazole, the drug is an antipsychotic, originally designed and FDA-approved to treat symptoms of clinical depression and schizophrenia. 

Up to this point, it has not been uncommon for clinicians to prescribe antipsychotics to address aggression in people living with Alzheimer’s and other forms of dementia. However, antipsychotics have never been FDA-approved for use in Alzheimer’s, make such prescriptions off-label usage — their safety and efficacy for Alzheimer’s symptoms hadn’t been tested in a controlled clinical study. Rexulti is now the exception. 

“Agitation is one of the most common and challenging aspects of care among patients with dementia due to Alzheimer’s disease,” said Tiffany Farchione, director of the division of psychiatry in the FDA’s Center for Drug Evaluation and Research, in the press release. “These symptoms are leading causes of assisted living or nursing home placement and have been associated with accelerated disease progression.”

“Anything that is safe and
effective is welcome.”
–Dr. Alireza Atri, Banner Sun
Health Research Institute

The approval comes a few weeks after an FDA advisory committee voted nine to one recommending Rexulti’s approval, based on the data from the drug’s successful clinical trial last year, The Phase 3 trial enrolled 345 participants who were randomized to receive a placebo, a 2-milligram dose of brexpiprazole (the generic name for the drug) or a 3-milligram dose of the brexpiprazole. The participants who received the placebo showed a 17-point improvement in symptoms over 12 weeks. Those who received either dose of brexpiprazole performed five points better, showing a 22-point improvement.

The downsides of antipsychotic prescription drugs

Rexulti doesn’t come without risks: Trial data also showed the drug increased mortality in the patient cohort from 0.3 percent to 0.9 percent.

The FDA’s briefing document said that the tripling in mortality was consistent with the known risks of antipsychotic drugs in older patients.

Alzheimer’s experts respond to Rexulti’s FDA approval

“Anything that is safe and effective is welcome,” said Dr. Alireza Atri, an institute director at the Banner Sun Health Research Institute in Arizona. Atri added that data on patient quality of life would be important to have moving forward as well.

University of Exeter professor of age-related diseases Clive Ballard noted that the trial participants were about a decade younger than typical nursing home residents with dementia. “I would like to see safety data in an older, frailer group,” he said.

Banner Sun Health Research Institute Director Dr. Pierre Tariot was more positive about the results. “We had efficacy without all the toxicity that has plagued the other drugs we’ve been studying for agitation,” he said. “This sounds like a major advance.” 

Improving care in nursing homes to treat agitation

At the 2022 CTAD conference, where Rexulti’s clinical trial data was presented, Suba Banerjee, a professor of dementia at the University of Plymouth presented another clinical trial which tested another drug called mirtazapine for agitation in Alzheimer’s. His trial found that both the placebo and drug group experienced a 12-point reduction in symptoms over 12 weeks.

“We had efficacy without all the toxicity
that has plagued the other drugs we’ve been
studying for agitation. This sounds
like a major advance.” –Dr. Pierre Tariot,
Banner Sun Health Research Institute

“The assumption that the agitation is caused by the dementia itself, rather than societal, family, or environmental factors to do with dementia, must be tested,” he said during his CTAD talk. “When you start looking at all of these causes of agitation, what is the likelihood that a drug of any kind would help with these unmet needs?”