A panel of independent advisors to the Food and Drug Administration voted unanimously Monday that the benefits outweigh the risks of the experimental new 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, produced 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, including swelling and bleeding in the brain.
The committee concluded, however, that the consequences of Alzheimer's are so dire that even a modest benefit may be worthwhile.
The FDA usually follows the advice of the agency's advisory committees, but not always.
The drug is based on a long-established hypothesis that Alzheimer's disease begins when hard, rough 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 cure Alzheimer's by attacking amyloid, eliminating it from the brain. Two similar amyloid drugs have been approved recently: Leqembi, made by Eisai and Biogen, was approved last year. The risks and modest benefits of this 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 would 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 review by an independent advisory panel, a surprise for 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 will hopefully stop the disease before symptoms even appear.
The panel on Monday discussed some unusual aspects of donanemab clinical trials, particularly the fact that study participants stopped taking the drug as soon as the amyloid was cleared. Some experts questioned whether discontinuation was the best strategy and whether clinical practice should include stopping treatment after the amyloid is cleared.
Donanemab, like Leqembi, is administered as intravenous infusions. Alzheimer's experts have said the drugs' effects in slowing cognitive decline are so modest that they may not be apparent to patients and families. Furthermore, some noted, patients and families would have no way of knowing how the disease would progress 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 approximately 4½-7½ months in subjects treated with donanemab compared to those treated with placebo. Nearly half of those who took donanemab remained at the same cognitive level a year into the study, compared with 29% of those who took the placebo.
But, the committee noted, 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 taking donanemab died due to swelling or bleeding in the brain linked to the drug. The FDA wanted a more detailed analysis of the study participants' deaths to check for other serious safety problems. Lilly complied and reported that no evidence suggested that further deaths had been caused by the drug.
Lilly's decision to stop treating patients as soon as a brain scan indicated that donanemab had eliminated amyloid had real appeal, committee members said. Patients could avoid monthly infusions and some of the risks of treatment. And the 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 treatment burden and potential risks,” the company wrote.
The committee liked the treatment interruption aspect but had questions.
Sarah Dolan, a member of the panel representing consumers, said the ability to stop treatment “could actually be a motivating factor for patients to remain compliant.” But she, she said, “there will always be a worry in the back of their head: Will he come back? Am I getting worse?”
Dr. Constantino Iadecola of Weill Cornell Medicine noted that it was unclear how to monitor patients after they stopped taking the drug. “Monitoring will be necessary,” he said. And, he added, “how soon should we intervene if there is a sign of increasing amyloid?”.
Lilly scientists estimated that it will take nearly four years for amyloid levels to cross the threshold again.
Another unusual feature involves the company's decision to scan patients' brains for tau, a noodle-like protein that appears in the brain after amyloid buildup. The more tau, the worse the cognitive decline.
Study participants with intermediate tau levels – which indicated an earlier stage of the disease – tapered off donanemab treatment more slowly than those whose levels were high, supporting a widely held theory that treating patients as early as possible offers greater chance of slowing down symptoms.
This has raised the question of whether patients should undergo tau brain scans before starting the drug.
In its briefing document, Lilly said it did not recommend requesting the tau scan. “The measurement of tau levels is not standardized and therefore cannot be easily implemented into routine clinical practice,” the company said. The FDA, in its review, said that, based on the evidence so far, there appeared to be no reason why patients needed to be tested for tau before receiving donanemab.
Committee members had the same reaction.
“From a practical standpoint I think it wouldn't be a wise thing to have as a barrier,” said Dr. Kathleen L. Poston, a professor of neurology at Stanford.
Ultimately, these drugs may just be a foothold in the search for an effective treatment. But, as the committee heard, for patients and their families, the possibility of slowing the progress of Alzheimer's, even by a few months, can be attractive.
“There is a huge unmet need here,” said Ms. Dolan, the panel's consumer representative.