Concern As FDA Approves Antipsychotic Drug For Dementia

Brexpiprazole (Rexulti), an antipsychotic medication, failed to demonstrate a clinically significant improvement in studies and raised mortality risk. Rexulti is now the first antipsychotic approved by the US Food and Drug Administration (FDA) to treat agitation in elderly dementia patients.

Rexulti’s manufacturers, Otsuka and Lundbeck, are estimating an additional $1 billion in sales for the drug, but there are significant concerns regarding the drug’s harm-benefit ratio, according to investigative journalist Robert Whitaker’s article in The BMJ today.

The US Centers for Medicare and Medicaid Services’ (CMS) decades-long efforts to curtail the extensive off-label use of antipsychotics in residential care facilities may be undone by the judgment.

The medication, like other antipsychotics, carries a “boxed warning,” the FDA’s most severe sort of caution, alerting prescribers to a higher chance of passing away. Additionally, the FDA found that in the three pre-approval trials, those who received brexpiprazole died at a rate that was four times greater than that of those who received a placebo.

On a 174-point efficacy scale, the medicine only improved over placebo by a maximum of 5.3 points, well below the 17 points deemed clinically significant.

“The small benefits do not outweigh serious safety concerns,” Public Citizen health researcher Nina Zeldes told the FDA’s Advisory Committee prior to the approval. “Like other antipsychotics, this is a drug that can kill patients without providing a meaningful benefit.”

Although none of these other antipsychotics have been approved for treating behavioral symptoms in elderly dementia patients, Professor Lon Schneider at the Keck School of Medicine of the University of Southern California noted that the brexpiprazole outcomes mirrored those from earlier trials of antipsychotics in patients with Alzheimer’s.

Schneider says the FDA has a “lower standard of approval” today than it did 20 years ago, a theme echoed by Zeldes, who said, “We are very disappointed that the FDA approved this additional label indication for brexpiprazole on such weak data. The FDA has set a dangerous precedent about the data it may require for future drug approvals for this vulnerable patient group.”

Nine of the 10 members of the FDA committee agreed in a vote that there was enough information to pinpoint a group of people for whom the drug’s advantages exceeded its hazards. However, even among those who voted in favor, a few experts had reservations regarding its use to patients with minor symptoms. Some emphasized the importance of doing personalized risk-benefit analyses in conjunction with patients’ families.

Rajesh Narendran, the advisory committee’s chair, declined several requests for an interview to address issues brought up 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 would be unable to respond.

According to Whitaker, a number of patient advocacy organizations, including Us Against Alzheimer’s, Leaders Engage on Alzheimer’s Research (LEAD), and the Alliance for Aging Research, pushed the FDA to approve brexpiprazole.

He claims that commercial motives are a contributing factor to this public backing.

LEAD, for instance, is a “coalition of more than 200 organizations” that 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 “non-branded health education and advocacy on neuropsychiatric symptoms of dementia.”

According to Erick Turner, a professor of psychiatry at Oregon Health & Science University and a former FDA reviewer, physicians’ reactions to the approval will probably differ depending on how they currently feel about giving antipsychotics to people with Alzheimer’s disease and dementia

He added, “On the topic of marketing, I do think it will come down to KOLs [key opinion leaders] and drug reps ‘educating’ clinicians.”

Whitaker claims that even though this positive safety comparison was incorporated into Otsuka’s phase III trial design, if the company’s presentation to the drug advisory council is any indication, it will utilize the talking point that brexpiprazole is considerably safer than other antipsychotics to sell the medicine.

Such marketing efforts will likely be at odds with ongoing efforts by the CMS. “Antipsychotic medications are especially dangerous among the nursing home population because of their potentially devastating side effects, including death,” a CMS spokesperson said. “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.”

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