Controversy Surrounds Brexpiprazole's FDA Approval, a New Alzheimer's Agitation Drug

When the FDA granted fast-track approval to brexpiprazole (Rexulti) in May, experts heralded it as the first drug approved specifically for treating agitation in Alzheimer’s patients. With more than six million Americans living with Alzheimer’s disease, a medication to safely address episodes of aggression, irritability, and disinhibition seemed like a welcome development.

But a troubling new British Medical Journal (BMJ) investigation suggests that the drug’s benefits are questionable at best, and extremely hazardous at worst. 

Questionable Benefits and Hazards

In clinical trials, brexpiprazole failed to deliver meaningful improvements in agitation symptoms compared to placebo. On a 174-point symptom scale, the maximum difference was just 5.3 points, This is well below the 17 point threshold experts generally agree signals a real-world change, according to the BMJ investigation. At the same time, the drug increased the chances of death four-fold compared to placebo over 16 weeks.

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The report also suggested that the drug got the green light because the US Food and Drug Administration (FDA) has lowered its standards compared to past antipsychotic approvals. 

“We are seeing that for a wide range of drugs. This is an example of that,” said Lon Schneider, MD, professor of psychiatry, neurology, and gerontology at the Keck School of Medicine at the University of Southern California. Schneider has researched antipsychotic drugs in Alzheimer’s patients extensively, including co-authoring past meta-analyses on safety and efficacy. 

Lowered FDA Standards?

The report referenced Aduhelm as another controversial Alzheimer’s drug that the FDA approved in 2021. It was the first new Alzheimer’s drug in nearly 20 years. But experts hotly debated about whether standards were lowered to approve it.

Aduhelm is a monoclonal antibody that targets and removes amyloid beta plaques in the brain, which are a hallmark of Alzheimer’s disease. The drug’s clinical trial results returned mixed outcomes. They showed only very small effects on cognitive decline while also escalating safety risks like brain swelling. 

Brexpiprazole, on the other hand, functions as a dopamine D2 receptor partial agonist. It was approved in the US in 2015 as an adjunctive treatment for major depression in people who did not have an adequate response with a first-line medication. bears the agency’s most severe black box warning on mortality. Critics argue its approval will expand prescriptions among clinicians hoping for better outcomes rather than older, less expensive generics used for Alzheimer’s agitation, despite the minimal advantage seen in trials.

“We are very disappointed that the FDA approved this additional label indication for brexpiprazole on such weak data,” the article quoted Nina Zeldes, a health researcher at the consumer advocacy organization, Public Citizen, as saying. “The FDA has set a dangerous precedent about the data it may require for future drug approvals for this vulnerable patient group.” 

Economics and Outcomes

As the BMJ article noted, Otsuka, which markets brexpiprazole, has a lot at stake. With sales forecasts topping $1 billion annually, the drugmaker stands to benefit handsomely.

In its presentation to the FDA advisory committee, Otsuka argued that brexpiprazole is much safer than other antipsychotics. Although the fourfold higher mortality rate was actually much higher than the increased risk with other antipsychotics, the incidence of death in the patients taking brexpiprazole, as one of Otsuka’s slides stated, was lower “compared to other antipsychotics in [an] elderly population with dementia.”

However, the BMJ report pointed out that Otsuka had built that favorable safety comparison into the design of phase 3 trials. The mean age of enrolled patients was 74, seven years younger than the average age of patients in the earlier trials of antipsychotics. Additionally, researchers had conducted most of the earlier trials in nursing homes. The brexpiprazole trials enrolled patients in institutional and residential settings, where a healthier population was more likely. The brexpiprazole trials recorded only one death in the placebo group. This was a much lower incidence of death than in the placebo groups in its earlier trials.

CMS’s Stance and Future Use

The BMJ investigation expressed concerns that the new drug will put vulnerable Alzheimer’s patients in harm’s way. The  push for brexpiprazole also appears to be at odds with current efforts to reduce antipsychotic use in nursing homes.

Indeed, in a statement included in the report, a Centers for Medicare & Medicaid Services (CMS) spokesperson said, “Antipsychotic medications are especially dangerous among the nursing home population because of their potentially devastating side effects, including death. We cannot speak to the hypothetical future use of brexpiprazole; however, CMS will continue its efforts to reduce the prescribing of unnecessary antipsychotics in nursing homes.”