Questions have been raised after the US Food and Drug Administration (FDA) recently fast-tracked its approval of brexpiprazole (Rexulti), an antipsychotic for treating agitation in dementia patients, when clinical studies demonstrated an increased risk of death and no meaningful benefit.
The FDA can designate drugs for fast-tracking after being requested by the drug company. It's a process designed to facilitate the development and expedite the review of drugs for serious conditions – Alzheimer’s disease is deemed a serious condition – if they fill an “unmet medical need.”
To receive FDA marketing approval, a ‘sponsor’ – in this case the manufacturers of Rexulti, Otsuka Pharmaceutical Company, Ltd. and Lundbeck Inc. – must show that a new drug is safe and effective. That is, its benefits outweigh any known risks.
In an investigative feature published in The BMJ, journalist Robert Whitaker has raised concerns surrounding brexpiprazole’s fast-tracked approval in May this year, especially considering the evidence about the drug's safety and efficacy following clinical trials.
Clinical trials: issues of safety and efficacy
For drugs that treat agitation in people with Alzheimer’s dementia, the Cohen-Mansfield Agitation Inventory (CMAI) is used as a benchmark. Caregivers assess the weekly frequency of 29 behaviors, giving each a score between one and seven, which results in a total score of 29 to 203. An international group of researchers reported in 2021 that the “minimal clinically important difference” at 12 weeks using the CMAI scale was a reduction of 17 points.
The first two placebo-controlled clinical trials of brexpiprazole failed to convince the FDA to approve the drug, even though the second trial produced statistically significant results (the first did not). The third trial found that the drug produced a 5.3-point reduction on the CMAI scale, far short of the 17 points required to demonstrate clinical importance. Nonetheless, in their May 2023 press release, the FDA stated that “In both studies, patients … showed statistically significant and clinically meaningful improvements in total CMAI scores compared to patients in the placebo group at 12 weeks.”
Whitaker points to some irregularities seen with the results of the clinical trials. Namely, in the third trial, brexpiprazole produced no benefit at US sites, which enrolled 44% of patients. The reported 5.3-point improvement occurred because of a nine-point drug-placebo difference in 125 patients given the drug across five eastern European countries and Spain. If no benefit was seen in US patients in the one study that provided the FDA with evidence for approval, why was approval granted?
And then there’s the trials’ mortality data. In patients taking brexpiprazole over a 16-week period, the risk of death was four times higher than the placebo group. Despite this, the FDA concluded that that risk was on par with the risk attached to other antipsychotics, and to address the issue they included a ‘boxed warning’ on the product label, informing of the risk. Other safety concerns included the risk of urinary tract infections, insomnia, drowsiness, and cardiovascular events.
“The small benefits do not outweigh serious safety concerns,” said Nina Zeldes, a health researcher at consumer advocacy organization Public Citizen, who addressed a meeting of the FDA’s advisory committee prior to Rexulti’s approval. “Like other antipsychotics, this is a drug that can kill patients without providing a meaningful benefit.”
Because the FDA fast-tracked approval of brexpiprazole, the public would be entitled to assume it’s more effective than other antipsychotic drugs. But that’s not necessarily the case, especially when brexpiprazole is compared with previous trials of antipsychotics in patients with Alzheimer’s disease.
“There are the same small points of difference on the [CMAI scale] that you see with every other drug,” said Lon Schneider, professor of psychiatry, neurology and gerontology at the Keck School of Medicine at the University of Southern California. “With brexpiprazole, you get the same level of side effects, the same black box warning, the same concern about a whole range of adverse effects.”
Antipsychotic drugs like risperidone, olanzapine and quetiapine were trialed more than 20 years ago and none were approved for treating agitation in dementia patients.
Who supported Rexulti's approval?
At the April 2023 meeting of the FDA’s Advisory Committee to discuss the use of brexpiprazole, nine out of 10 committee members indicated that they believed the sponsor had provided sufficient clinical data to identify a population where the benefits of the drug outweighed its risks. But despite the overwhelming ‘yes’ vote, several members expressed concern about using brexpiprazole in patients with mild symptoms, with some pushing for individualized risk-benefit evaluations to be undertaken in collaboration with patient’s families.
“There is a lot of variability in presentation and the severity of agitation, and I think the risk-benefit equation is very difficult to make in broad strokes,” said Jess Fiedorowicz, a professor of psychiatry at the University of Ottawa who voted for the drug’s approval. “Ultimately, I think the risk-benefit depends on the context, the nature of the behaviors, and what sort of resources or options a person has for their ongoing care. We have some sense of what the risks are with these agents, and as long as people aren’t exaggerating the potential benefit, and not continuing the [treatment] if there is no benefit, it seems potentially prudent to give clinicians a tool they can use to make that determination.”
A number of patient advocacy groups also urged the FDA to approve brexpiprazole, including the Alliance for Aging Research, Leaders Engage on Alzheimer’s Research (LEAD), and Us Against Alzheimer’s. But Whitaker says this support was fueled partly by commercial interests. LEAD, for example, includes Otsuka and other drug companies as its members, and the board of the Alliance for Aging Research includes representatives from Otsuka and other drug companies.
With Rexulti costing around US$1,400 (£1,096; AUD2,181) a month and annual sales of the drug predicted to hit US$1 billion, it’s hard to ignore the commercial angle.
How does Rexulti fit with current practices?
The answer is it doesn’t, really. Based on evidence of serious side effects from the use of antipsychotics, including an increased risk of death, in 2005 and 2008 the FDA issued a boxed warning for the use of these drugs in people with dementia. This prompted the US Centers for Medicare and Medicaid Services (CMS) to establish the National Partnership to Improve Dementia Care in Nursing Homes. This public-private collaboration is committed to reducing the ‘off-label’ use of antipsychotic medications and, instead, employing non-drug approaches. Off-label means prescribing a drug whose use is approved for a certain medical condition to treat a condition for which it’s not approved.
In keeping with the goals of the National Partnership, the practice guideline of the American Psychiatric Association, published in 2016, urges practitioners to start with non-drug options first. And a 2019 meta-analysis of 163 studies assessing drug and non-drug interventions found that non-drug interventions like multidisciplinary care, massage and touch therapy, and music were clinically more efficacious than usual care in treating agitation and aggression in adults with dementia.
While brexpiprazole is now the only FDA-approved antipsychotic for the treatment of agitation in dementia patients, therefore side-stepping the current, widespread off-label use of these drugs, its approval appears to undermine the current therapeutic approach.
“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 speak to the hypothetical future use of brexpiprazole; however, CMS will continue its efforts to reduce the prescribing of unnecessary antipsychotics in nursing homes.”
Clinicians’ responses to the approval will likely vary based on their beliefs about prescribing antipsychotics to dementia patients and on the marketing strategies adopted by drug reps.
“On the topic of marketing, I do think it will come down to KOLs [key opinion leaders] and drug reps ‘educating’ clinicians,” said Erick Turner, a former FDA reviewer and professor of psychiatry at Oregon Health and Science University.
It is perhaps telling that the chair of the FDA’s Advisory Committee, Rajesh Narendran, did not respond to multiple requests by Whitaker for an interview to answer the question raised by brexpiprazole’s approval.
Time will tell if the FDA’s decision was a good one.
The investigative piece was published in The BMJ.
