A committee of independent advisers to the US Food and Drug Administration voted unanimously last week that the benefits outweigh the risks of the newest experimental drug made by Eli Lilly for Alzheimer’s disease.
The committee concluded that although donanemab, which modestly slowed cognitive decline in patients in the early stages of the disease, also had significant safety risks, including swelling and bleeding in the brain, the consequences of Alzheimer’s are so dire that even a modest benefit could be worthwhile.
The FDA usually follows the advice of the agency’s advisory committees but not always, reports The New York Times.
The treatment is based on a long-held hypothesis that Alzheimer’s disease begins when rough hard balls of amyloid, a protein, pile up in patients’ brains, followed by a cascade of reactions leading to the death of neurons.
The idea is to treat Alzheimer’s by attacking amyloid, clearing it from the brain. Two similar amyloid-fighting drugs approved recently were Leqembi, made by Eisai and Biogen, and which has risks and modest benefits similar to those of donanemab, and Aduhelm, from Biogen, which was approved in 2021 but discontinued because of insufficient evidence that it could benefit patients.
Donanemab was expected to be approved earlier this year, but in March, the FDA decided that, instead, it would require the treatment to undergo the scrutiny of an independent advisory committee.
At issue before the committee last week were some unusual aspects of donanemab’s clinical trials, especially 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 halting the treatment after amyloid clearance.
Donanemab, like Leqembi, is given as intravenous infusions. Alzheimer’s experts said that the drug’s effects in slowing cognitive decline are so modest that they might not be noticeable to patients and families. Also, some noted, patients and families would have no way of knowing how the disease would have progressed without the treatment.
Lilly submitted data from a 76-week study of 1 736 people in the early stages of the disease, with either mild cognitive impairment or mild dementia. The participants were randomly assigned to get donanemab or a placebo. To measure effectiveness, the Lilly researchers assessed the patients’ performance on cognitive tests.
Cognitive decline slowed by about 4½ to 7½ months in those taking donanemab compared with those who got the placebo. Nearly half who took donanemab stayed at the same cognitive level one year into the study, compared with 29% who got the placebo.
But, the committee noted, nearly all study participants were white, and some would like to see more data on under-represented groups.
Three patients taking donanemab died with brain swelling or bleeding that was linked to the drug, and the FDA asked for a more detailed analysis of the deaths of trial participants to check for other serious safety problems. Lilly complied and reported that no evidence suggested additional deaths were caused by the drug.
Lilly’s decision to stop treating patients as soon as a brain scan indicated 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 might be lower.
In a briefing document, Lilly suggested that continuing the drug after amyloid has gone would not help patients and might be harmful. “Once the target is cleared from the brain, continued dosing of donanemab is not likely to be beneficial and only adds to treatment burden and potential risks,” the company wrote.
The committee liked the aspect of halting treatment but one said that the possibility of stopping treatment “could actually be a motivational factor for patients to stay compliant”. However, there might always be a concern about “is it coming back? Am I getting worse?”
Dr Constantino Iadecola of Weill Cornell Medicine noted that it was not clear how to monitor patients after they stop taking the drug. “Monitoring is going to be necessary,” he said. And, he added, “how soon will you have to intervene if you have a signal of amyloid going up?”
Lilly scientists have estimated it would take nearly four years for amyloid levels to bump up over 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 brains after amyloid accumulates. The more tau, the worse the cognitive decline.
Trial participants with intermediate tau levels – indicating an earlier stage of the disease – declined more slowly on donanemab than those whose levels were high, supporting a widespread theory that treating patients as early as possible provides a better chance of slowing symptoms.
That raised a question of whether patients should have tau brain scans before starting the drug.
In its briefing document, Lilly said it was not recommending that tau scanning be required. “The measurement of tau levels is not standardised and therefore could not be readily implemented in routine clinical practice,” it said.
In its review, the FDA said that based on the evidence so far, there did not seem to be a reason for patients to be tested for tau before receiving donanemab, and committee members had the same reaction.
“From a practical perspective I think this would not be a wise thing to have as a barrier,” Dr Kathleen Poston, a neurology professor at Stanford, said.
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