A committee of independent advisors to the Food and Drug Administration voted unanimously Monday that the benefits outweigh the risks of the newest experimental drug for Alzheimer’s disease.
Alzheimer’s affects more than six million Americans. There is no cure and there is no treatment or lifestyle modification that can restore memory loss or reverse cognitive decline.
The drug, manufactured by Eli Lilly, is donanemab. It modestly slowed cognitive decline in patients in the early stages of the disease, but also had significant safety risks, such as swelling and bleeding in the brain.
However, the committee concluded that the consequences of Alzheimer’s are so dire that even a modest benefit may be worth it.
The FDA often follows the advice of the agency’s advisory committees, but not always.
The drug is based on a long-standing hypothesis that Alzheimer’s disease begins when hard balls of amyloid, a protein, build up in patients’ brains, followed by a cascade of reactions that lead to the death of neurons.
The idea is to treat Alzheimer’s by attacking amyloid and eliminating it from the brain. Two similar drugs were recently approved to combat amyloid: Leqembi, made by Eisai and Biogen, was approved last year. The modest risks and benefits of that drug are similar to those of donanemab. Aduhelm, made by Biogen, is the other drug and was approved in 2021, but was stopped because there was not enough evidence that it could benefit patients.
Donanemab was expected to be approved earlier this year, but in March, the FDA decided that it would instead require donanemab to undergo scrutiny by an independent advisory committee, a surprise to Eli Lilly.
The vote, said Dr. Daniel Skovronsky, Lilly’s chief scientific officer, confirmed his 25-year quest to find a way to intervene in Alzheimer’s disease. Now, he said, the company is launching a study that, he hopes, will stop the disease before symptoms even begin.
What was discussed before the committee on Monday were some unusual aspects of the donanemab clinical trials, notably that study participants stopped taking the drug as soon as their amyloid was cleared. Some experts questioned whether stopping was the best strategy and whether clinical practice should include stopping treatment after amyloid clearance.
Donanemab, like Leqembi, is administered as intravenous infusions. Alzheimer’s experts said the effects of drugs to slow cognitive decline are so modest that they may not be noticeable to patients and their families. Additionally, some noted that patients and families would have no way of knowing how the disease would have progressed without treatment.
Lilly presented data from a 76-week study of 1,736 people in the early stages of the disease, with mild cognitive impairment or mild dementia. Participants were randomly assigned to receive donanemab or a placebo. To measure effectiveness, Lilly researchers evaluated patients’ performance on cognitive tests.
Cognitive decline slowed by 4½ to 7½ months in those taking donanemab compared to those receiving placebo. Nearly half of those taking donanemab remained at the same cognitive level one year into the study, compared with 29 percent who received the placebo.
But, the committee noted, almost 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 taking donanemab died with drug-related brain swelling or hemorrhage. The FDA wanted a more detailed analysis of the deaths of trial participants to look for other serious safety problems. Lilly complied and reported that there was no evidence to suggest the drug caused additional deaths.
Lilly’s decision to stop treating patients as soon as a brain scan indicated that donanemab had cleared their amyloid had real appeal, committee members said. Patients could avoid monthly infusions and some of the risks of treatment. And costs could be lower.
In a briefing paper, Lilly suggested that continuing the drug after the amyloid disappears would not help patients and could be harmful. “Once the target is cleared from the brain, continued dosing of donanemab is likely not beneficial and only increases the treatment burden and potential risks,” the company wrote.
The committee liked the aspect of stopping treatment, but had questions.
Sarah Dolan, a member of the panel representing consumers, said the possibility of stopping treatment “could actually be a motivating factor for patients to remain compliant.” But she, she said, “will always have a worry in the back of their heads: Will he come back? Am I getting worse?
Dr. Constantino Iadecola of Weill Cornell Medicine said it was unclear how to monitor patients after they stop taking the drug. “Follow-up is going to be necessary,” he said. And, he added, “how soon will you have to intervene if you have an amyloid signal going up?”
Lilly scientists have estimated that it would take almost four years for amyloid levels to rise above the threshold again.
Another unusual feature involved the company’s decision to scan patients’ brains for tau, a tangled, spaghetti-like protein that appears in the brain after amyloid builds up. The more tau, the worse the cognitive decline.
Trial participants with intermediate levels of tau (indicating an earlier stage of the disease) declined more slowly with donanemab than those whose levels were high, supporting a widespread theory that treating patients as early as possible provides better best chance of slowing symptoms.
That raised the question of whether patients should undergo tau brain scans before starting the drug.
In its briefing paper, Lilly said it did not recommend that tau scanning be required. “Measurement of tau levels is not standardized and therefore could not be easily implemented in routine clinical practice,” the company stated. The FDA, in its review, said that based on the evidence so far, there did not appear to be a reason for patients to have a tau test before receiving donanemab.
Committee members had the same reaction.
“From a practical perspective, I think it would be unwise to have this as a barrier,” said Dr. Kathleen L. Poston, a professor of neurology at Stanford.
In the end, these drugs can only be a support point in the search for an effective treatment. But, as the committee heard, for patients and their families, the chance to slow the progress of Alzheimer’s, even by a few months, can be tempting.
“There is a huge unmet need here,” said Ms. Dolan, a consumer representative on the panel.