Updated: Sep 15
Investigation by BMJ Questions Antipsychotic's Approval for Agitation in AD
How the FDA approved an antipsychotic that failed to show a meaningful benefit but raised the risk of death
The US Food and Drug Administration (FDA) approved the antipsychotic drug brexpiprazole (Rexulti) for agitation due to Alzheimer’s disease despite questionable efficacy data and a known higher risk of death, alleges a new investigation in the BMJ.
Journalist Robert Whitaker took a deep dive into the safety and efficacy data soon after the FDA approved the new indication for the drug in May of this year. After sifting through the data and watching the agency's April 14 advisory panel meeting, he concluded that brexpiprazole presented no advance, despite winning the backing of both the advisory committee and the FDA.
The advisory panel meeting "just seemed like a rubber-stamp exercise rather than a probing of really what are the risks and benefits of this drug," Whitaker told Medscape Medical News.
Whitaker wrote that "no benefit was seen at the US sites in the one study that provided the primary evidence for approval." And yet, the lack of efficacy in the US was never discussed by any of the advisers, he told Medscape.
Brexpiprazole, along with other antipsychotics such as aripiprazole, risperidone, and olanzapine have long been used off label to treat dementia-related agitation. But in 2005, the FDA warned against this use, noting that older patients were at higher risk for death, primarily due to strokes and other cardiovascular events. Indeed, all the antipsychotics — including the new label for brexpiprazole — carry boxed warnings on the increased risk of death.
Whitaker reported that the mortality risk with brexpiprazole was four times higher than with placebo.
Meanwhile, the US Centers for Medicare and Medicaid Services (CMS) has campaigned against the inappropriate use of antipsychotics in nursing homes at least since the start of an initiative in 2012.
Not 'Statistically Persuasive'
Still, Otsuka and Lundbeck, the manufacturers of brexpiprazole, decided to pursue FDA approval for agitation. Such an approval would allow the companies to essentially rebrand the medication and specifically market it for agitation — at an estimated monthly cost of $1400, noted Whitaker in his article.
Whitaker reported that the FDA was skeptical of the manufacturers' first two pivotal controlled studies, telling them in a 2017 meeting that the agency did not consider a 3.8-point reduction in symptoms on the Cohen-Mansfield Agitation Inventory (CMAI) scale with the 2-milligram dose when compared with placebo to be "statistically persuasive."
An international group determined in 2021 that a "minimal clinically important difference" on the CMAI scale was 17 points, Whitaker reported.
The FDA ordered Otsuka and Lundbeck to conduct a third trial. In that study, there was a maximum 5.3-point improvement over placebo on the 174-point CMAI, far short of the 17 points considered to be clinically important, Whitaker noted.
And yet, in its approval, the FDA wrote that "patients who received 2 mg or 3 mg of Rexulti showed statistically significant and clinically meaningful improvements in total CMAI scores compared to patients in the placebo group at week 12."
Whitaker told Medscape that he asked FDA why the results were considered "clinically meaningful." First, the agency said it could not respond in time for his deadline. It later told him that he would have to file a Freedom of Information Act request to get answers.
The reporter also said he received no response to multiple requests for comment from Rajesh Narendran, MD, a professor of psychiatry at the University of Pittsburgh, Pittsburgh, Pennsylvania, and the chair of the FDA advisory committee that weighed the approval.
Lon Schneider, MD, a professor of psychiatry, neurology, and gerontology at the University of Southern California's Keck School of Medicine, Los Angeles, told Whitaker that brexpiprazole was no different than other antipsychotics. It offers the "same small points of difference on the CMAI scale," and "the same level of side effects, the same black box warning," he said.
The FDA has a "lower standard of approval" than it did two decades ago, Schneider told the BMJ reporter.
FDA: Drug Fills Unmet Need
But in a response to Medscape Medical News, the FDA defended the approval process. The agency granted brexpiprazole a fast-track approval — signaling that it was an advance over existing therapies and that it fills an unmet medical need. The agency also gave it a priority review.
"Both fast track and priority review are programs intended to help ensure that therapies for serious conditions are approved and available to patients as soon as it can be concluded that the therapies' benefits justify their risks," an FDA spokesperson told Medscape. "The clinical benefits of Rexulti are stated in the prescribing information," he added.
"This submission was discussed at an advisory committee meeting on April 14; the overwhelming majority of the advisory committee members agreed with FDA's conclusion that the drug is effective and that the benefit risk assessment was favorable for the use of Rexulti in the treatment of agitation in patients with dementia due to Alzheimer's disease," said the spokesperson.
Whitaker said the approval "is going to open the floodgates for the use of this antipsychotic," adding that "the FDA is saying this drug is different from the drugs that are being prescribed off label right now. That's the message to the prescribing population and that's exactly the message that Otsuka and Lundbeck are going to market their drug with."
The BMJ reporter also noted that a number of patient advocacy groups — including the Alzheimer's Association, the Alliance for Aging Research, Leaders Engaged on Alzheimer's Disease, and Us Against Alzheimer's — have backed brexpiprazole. Many of these organizations also receive funding from Otsuka and other drug makers, Whitaker reported.
Medscape sought comment from Otsuka but received no response.
Medicare Coverage a Given
A CMS spokesperson told Whitaker that the agency still posits that, "Antipsychotic medications are especially dangerous among the nursing home population because of their potentially devastating side effects, including death," and that the agency would "continue its efforts to reduce the prescribing of unnecessary antipsychotics in nursing homes."
However, the spokesperson also told Whitaker that Medicare already covers brexpiprazole. Part D drug plan formularies must include brexpiprazole since it was previously FDA-approved for schizophrenia, the spokesperson said.
The drug plans can, however, "add limits to this medication to prevent inappropriate use," the spokesperson told Whitaker.
A CMS spokesperson confirmed to Medscape Medical News the quotes given to Whitaker.