FDA Approval of Antipsychotic Drug Sparks Alarm

The FDA granted fast-track approval to brexpiprazole, an antipsychotic drug for people with dementia, despite the medication failing to provide a clinically meaningful benefit and increasing mortality.

An investigation by journalist Robert Whitaker published in the British Medical Journal raises questions over the approval of Rexulti (brexpiprazole), manufacturers of which are forecasting an additional $1 billion in annual sales.

In 2005, the FDA warned over a 60% to 70% increased risk of death linked to off-label antipsychotic drug use in elderly patients with dementia. As a result, the U.S. Centers for Medicare and Medicaid Services (CMS) established the National Partnership to Improve Dementia Care in Nursing Homes. This collaboration aims to "reduce the use of antipsychotics" and enhance the use of non-pharmacological approaches instead.

However, in May 2023, the FDA approved Rexulti to treat agitation symptoms associated with Alzheimer’s dementia.

Whitaker writes that "serious questions remain" about the harm-benefit balance of the antipsychotic drug manufactured by Otsuka and Lundbeck. Rexulti carries a "boxed warning" — the FDA’s most serious warning over increased mortality risk.

The drug went through four safety evaluations across the three pre-licensure clinical trials. The highest efficacy observed was a 5.3-point improvement in symptoms over placebo on a 174-point scale, falling short of the 17-point minimal clinically important difference.

In the two trials assessing quality of life, Rexulti demonstrated no benefit for either the patient or the caregiver. At the same, the risk of death was four times higher in the patients taking brexpiprazole when compared with placebo over 16 weeks. Other safety concerns included the risk of urinary tract infections, drowsiness, insomnia, and cardiovascular events.

Addressing the FDA’s advisory committee at its 14 April meeting before the approval, Nina Zeldes, a health researcher at the consumer advocacy organization Public Citizen, said that the small benefits of brexpiprazole do not outweigh serious safety concerns.

"Like other antipsychotics, this is a drug that can kill patients without providing a meaningful benefit," she added.

Despite a lack of evidence on brexpiprazole benefits and safety concerns, the FDA concluded that the risk of death associated with the drug "appears to be consistent with the known risks with other antipsychotics in elderly patients with dementia."

Lon Schneider, professor of psychiatry, neurology, and gerontology at the Keck School of Medicine at the University of Southern California, noted that brexpiprazole outcomes mirrored the results from earlier trials of antipsychotics in patients with Alzheimer’s dementia. But unlike Rexulti, none of these medications have been approved to treat agitation symptoms in elderly patients.

Schneider said that the FDA has a "lower standard of approval" today than it did 20 years ago, and that applies to a wide range of drugs, including dementia medications such as lecanemab.

Nine of the committee’s 10 members voted to approve the drug. However, some expressed concern about using the drug in patients with mild symptoms, as the FDA did not exclude them from approval.

Several patient advocacy groups urged the FDA to approve brexpiprazole, while the Alzheimer’s Association "welcomed" the decision.

Whitaker notes that commercial interests partly fuel such public support. Leaders Engage on Alzheimer’s Research (LEAD), one of the organizations supporting the approval, includes Otsuka and other drug companies among its members. At the same time, the Alliance for Aging Research receives funding from Otsuka and other drug companies.

Erick Turner, former FDA reviewer and a professor of psychiatry at Oregon Health & Science University, said that for clinicians who are "on the fence" about antipsychotic drug use in dementia patients, the approval could undermine the message from the CMS and encourage them to prescribe antipsychotics in general and brexpiprazole in particular.

"To make that case, the company will want to get its KOLs [key opinion leaders] out on the trail with their slide decks, perhaps in the context of a dinner talk to more easily 'educate' the clinicians. I’m sure they’ve already curated a number of talking points addressing both efficacy and safety," he said.

Despite the fourfold higher mortality rate being much higher than the increased risk with other antipsychotics, Otsuka stated that the incidence of death in the patients taking brexpiprazole was lower "compared to other antipsychotics in [an] elderly population with dementia."

However, in the phase 3 trials, the participants were 74 years on average, which is seven years younger than patients in the earlier trials of antipsychotics. Moreover, most earlier trials had been conducted in nursing homes, whereas the brexpiprazole trials enrolled patients in institutional and residential settings. A combination of these factors could have produced a healthier population.

Whitaker writes: "Only one death in the placebo group was recorded in the brexpiprazole trials, a much lower incidence of death than in the placebo groups in the earlier trials."


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