Alert as the FDA fast-tracks the first antipsychotic drug for agitation in dementia

In trials, the antipsychotic drug brexpiprazole (Rexulti) failed to provide clinically meaningful benefit and increased the risk of death. But the US Food and Drug Administration (FDA) quickly tracked its approval, making Rexulti the first antipsychotic to treat agitation in elderly patients with dementia.

Costing about $1,400 per month, Rexulti makers Otsuka and Lundbeck estimate an additional $1 billion in annual sales, but there are serious questions about the benefit-harm balance of the drug, writes investigative journalist Robert Whitaker in BMJ Today.

The decision could also reverse years of efforts by the US Centers for Medicare and Medicaid Services (CMS) to reduce the widespread use of off-label antipsychotics in residential care homes.

Like other antipsychotics, it carries a “box warning,” the most serious type of FDA warning, informing prescribers of an increased risk of death. And in three pre-approved trials, the FDA concluded that the death rate was four times higher in those given brexpiprazole compared with those given a placebo.

On efficacy, the drug showed a maximum improvement of 5.3 points over placebo on a 174-point scale, far from the 17 points considered clinically important.

“The small benefits do not outweigh the serious safety concerns,” Public Health researcher Nina Zeldes told the FDA Advisory Committee prior to approval. “Like other antipsychotics, this is a drug that can kill the patient without providing any significant benefit.”

Professor Lon Schneider at the Keck School of Medicine of the University of Southern California noted that the results of brexpiprazole mirror those of previous antipsychotic trials in Alzheimer’s patients, but that neither of these other antipsychotics have been approved to treat behavioral symptoms in elderly patients with dementia. .

Schneider said the FDA has “lower approval standards” today than they did 20 years ago, a theme echoed by Zeldes, who said, “We are very disappointed that the FDA approved an additional label indication for brexpiprazole on such weak data. The FDA has determined dangerous precedent about the data that may be needed for future drug approval for this vulnerable patient group.”

In the vote, nine out of 10 members of the FDA committee believed there was sufficient data to identify the population for which the benefits outweigh the risks of the drug. But even among those who voted yes, some advisers expressed concern about its use in patients with mild symptoms. Some emphasize the need for individual risk-benefit evaluation in collaboration with the patient’s family.

The chairman of the advisory committee, Rajesh Narendran, did not respond to multiple requests for interviews to address questions raised by this approval, while a spokesperson for the FDA’s Center for Drug Evaluation and Research stated that “due to conflicting schedules and competing priorities,” the FDA will not be able to respond.

Whitaker notes that a number of patient advocacy groups, such as the Alliance for Aging Research, Leaders Engage on Alzheimer’s Research (LEAD), and Us Against Alzheimer’s, are pressing the FDA to approve brexpiprazole.

This public support was partly driven by commercial interests, he wrote.

LEAD, for example, is a “coalition of more than 200 organizations” which includes, among its members, Otsuka and other pharmaceutical companies, while the Alliance for Aging Research, which lists 31 partners, receives funding from Otsuka and other pharmaceutical companies for “unhealthy education”. branding and advocacy on neuropsychiatric symptoms of dementia.”

Erick Turner, a former FDA reviewer and professor of psychiatry at Oregon Health & Science University, said doctors’ responses to the approval would likely vary according to their current beliefs about prescribing antipsychotics to Alzheimer’s patients.

He added, “On the topic of marketing, I think it will get to KOL [key opinion leaders] and drug reps ‘educating’ physicians.”

Whitaker writes that if Otsuka’s presentation to the drug advisory committee is any guide, the talking point he will use to market brexpiprazole is that it is far safer than other antipsychotics, even though that favorable safety comparison is built into Otsuka’s phase III trial design.

Such marketing efforts are likely to conflict with ongoing CMS efforts. “Antipsychotic medications are especially dangerous among the nursing home population because of their potentially devastating side effects, including death,” said a CMS spokesperson. “We cannot talk about a hypothetical future use of brexpiprazole; however, CMS will continue its efforts to reduce unnecessary antipsychotic prescriptions in nursing homes.”