An independent advisory committee to the U.S. Food and Drug Administration unanimously decided Monday that the benefits of a new experimental drug for Alzheimer's disease outweigh the risks.
Alzheimer's disease afflicts more than six million Americans. There is no cure, and no treatments or lifestyle changes that can reverse memory loss or reverse cognitive decline.
The drug, made by Eli Lilly and Co., is called donanemab and slightly slows cognitive decline in patients in the early stages of the disease but also carries significant safety risks, including brain swelling and bleeding.
But the committee concluded that the effects of Alzheimer's are so severe that even small benefits are worth it.
The FDA typically follows the advice of the agency's advisory committees, but it doesn't always follow it.
The drug is based on the long-held hypothesis that Alzheimer's disease occurs when hard clumps of amyloid, a type of protein, build up in a patient's brain, setting off a chain reaction that causes neurons to die.
The idea is to treat Alzheimer's by attacking amyloid and removing it from the brain. Two similar amyloid-inhibiting drugs have been approved recently. Requenvi, made by Eisai and Biogen, was approved last year. The drug's risks and modest benefits are similar to donanemab. Aduherm, made by Biogen, is another drug that was approved in 2021 but was discontinued due to insufficient evidence that it would benefit patients.
Donanemab was expected to be approved earlier this year, but the FDA decided in March to instead require donanemab to be vetted by an independent advisory committee, a surprise to Eli Lilly.
Lilly's chief scientific officer, Dr. Daniel Skovronski, said the vote validates a 25-year quest to find a way to intervene in Alzheimer's, and that the company is now beginning research in the hope of halting the disease before symptoms appear.
At issue before the committee on Monday were some unusual aspects of the donanemab clinical trial, particularly the fact that participants stopped taking the drug as soon as amyloid was cleared. Some experts questioned whether stopping was the best strategy, and whether clinical practice should be to stop treatment once amyloid is cleared.
Donanemab, like Lukembi, is given by infusion. Alzheimer's experts say the drug's effect on slowing cognitive decline may be so small that it goes unnoticed by patients and their families. And some say there's no way for them to know how the disease would have progressed without the treatment.
Lilly submitted data from a 76-week study of 1,736 people with mild cognitive impairment or the early stages of mild dementia. Participants were randomly assigned to receive either donanemab or a placebo. To measure efficacy, Lilly researchers assessed patients' performance on cognitive tests.
Patients who took donanemab slowed the decline in cognitive function by about 4.5 to 7.5 months compared with patients who took a placebo. Nearly half of the patients who took donanemab maintained their level of cognitive function one year after starting the study, compared with 29 percent of patients who took a placebo.
However, the research committee noted that nearly all of the study participants were white.
“I would like to see more data on underrepresented groups,” said Colette C. Johnson, a patient representative on the committee.
Three patients who took donanemab died from side effects of the drug that caused brain swelling and bleeding. The FDA asked for a more detailed analysis of the trial participants' deaths to see if there were any other serious safety issues. Lilly responded by reporting that there was no evidence that the drug was responsible for any additional deaths.
Committee members said Lilly's decision to stop treating patients as soon as brain scans showed that donanemab had cleared amyloid was very attractive: Patients could avoid monthly infusions and some of the risks of treatment, and it might even be cheaper.
In a statement, Lilly suggested that continuing to give the drug after the amyloid has cleared would not help patients and may even be harmful: “Once the target has been cleared from the brain, continuing to give donanemab is likely not beneficial and would only increase the burden and potential risks of treatment,” the company wrote.
The committee agreed with stopping the treatment but had doubts.
Sarah Dolan, a member of the committee that represents consumers, said the possibility of stopping treatment “may be an incentive for patients to continue taking their medication,” but added that “there's always that worry in the back of their mind: Is it going to come back? Is it going to get worse?”
Dr. Constantino Iadecola of Weill Cornell Medical College noted that it's unclear how to monitor patients after they stop taking the drug. “Monitoring will be necessary,” he said, adding, “If there are signs of an increase in amyloid, how soon do we have to intervene?”
Lilly scientists estimate that it could take nearly four years for amyloid levels to cross that threshold again.
Another unusual feature is that the company decided to scan patients' brains for tau, a tangled, spaghetti-like protein that appears in the brain after amyloid builds up. The more tau there is, the more severe the cognitive decline.
Study participants with intermediate tau levels (indicating an early stage of the disease) experienced a slower deterioration with donanemab than those with higher tau levels, supporting the widely held theory that treating patients as early as possible increases the chances of slowing the progression of the disease.
This raised the question of whether patients should undergo tau brain scans before taking the drug.
Lilly said in its report that it is not recommending that tau scanning be mandatory. “Measurement of tau concentrations is not standardized and therefore cannot be easily implemented in routine clinical practice,” the company said. The FDA said that based on the evidence to date, there appears to be no reason to test patients for tau before administering donanemab.
Committee members had a similar reaction.
“From a practical standpoint, I don't think it's wise to have this as a barrier,” said Dr. Kathleen L. Poston, a professor of neurology at Stanford University.
Ultimately, these drugs may only be stepping stones in the search for effective treatments, but as the committee heard, for patients and their families, the possibility of slowing the progression of Alzheimer's, even if only by a few months, is appealing.
“There's a huge unmet need,” said Dolan, the committee's consumer representative.