FDA delays action on closely watched Alzheimer’s drug

The Food and Drug Administration has decided to delay action on a closely watched Alzheimer’s drug, donanemab, which was widely expected to approve this month. The FDA will instead require donanemab to be examined by a panel of independent experts, the drug’s maker, Eli Lilly and Company, said Friday.

“The FDA has informed Lilly that it wants to better understand topics related to evaluating the safety and efficacy of donanemab, including safety outcomes in donanemab-treated patients and the efficacy implications of the unique trial design,” said the company in a statement.

The decision will likely surprise many Alzheimer’s experts, doctors and patients who had expected the drug to hit the market soon. The FDA’s move was surprising for the company, which had planned to greenlight the drug in the first quarter of this year.

“We didn’t expect this,” Anne White, Lilly’s executive vice president and president of neuroscience, said in an interview. She said that while the FDA often turns to such independent advisory committees when it has questions about drugs, it was unusual to do so “at the end of the review cycle and after the action date that the FDA gave us.”

The FDA has not publicly said anything about this move, which will delay a decision on whether to approve donanemab until at least later this year. Lilly officials said they expected it would be a few months before the advisory committee held a hearing.

“The FDA has promised us that they will take action quickly, so we hope they will take action shortly after the advisory committee,” Ms. White said.

The decision to convene an advisory committee reflects the high stakes and troubled history of developing treatments for Alzheimer’s disease. The disease affects more than six million Americans and currently has no cure and no medications that can restore memory loss or reverse cognitive decline.

For years, the field was characterized by failed drug trials. But donanemab, a monthly infusion, belongs to a new class of drugs that experts hope can help patients by attacking a protein, amyloid, that clumps into plaques in the brains of people with Alzheimer’s disease.

Last year, the FDA approved another drug in this class, Leqembi, made by Eisai and Biogen. By giving an infusion every two weeks, Leqembi can somewhat slow cognitive decline in the early stages of Alzheimer’s disease.

The new drugs are considered only a first step in a potentially fruitful direction because they may not slow the decline enough to be noticeable to patients or families, experts say. The drugs also pose significant safety risks, including swelling and bleeding in the brain.

(The first drug approved in the anti-amyloid class, Aduhelm, was controversial because it had weak evidence; Biogen, the drug’s manufacturer, recently abandoned it.)

Donanemab was expected to gain approval easily because data showed the drug could also modestly slow cognitive decline in people with mild symptoms, and its safety risks were similar to those of Leqembi. Because donanemab’s study design was different from Leqembi’s and included some patients with more complex medical problems, the studies of the two drugs cannot be directly compared.

The donanemab study had two unusual aspects that the FDA indicated it would ask the advisory committee to review, said Dr. John Sims, medical director at Lilly and leader of the donanemab clinical trials.

One feature would be particularly attractive to patients: Study participants stopped receiving donanemab after their amyloid plaques cleared to a certain level — about a year for half of the participants who started donanemab — and their cognitive decline continued to slow . Lilly scientists estimate this would last almost four years so that the amyloid level rises above the threshold again.

Dr. Sims said he believed the FDA wanted to know more about stopping treatment because “it’s very unique” and that regulators might want to explore whether other anti-amyloid drugs could be stopped at some point.

Ms. White said there is a lot of enthusiasm among doctors and patients for this concept: once you achieve the goal you’re aiming for, you don’t have to put patients through additional infusions and visits.

The other unusual feature of the trial involved another protein, tau, which forms tangles in the brain after amyloid builds up. Higher tau levels are more closely linked to memory and thinking problems.

The donanemab study divided participants into groups with high tau levels and medium tau levels. People with moderate levels of tau showed greater slowing of cognitive decline – supporting a widely held theory that treating patients at the earliest possible stage of the disease process offers a better chance of slowing symptoms.

Dr. Sims said that measuring tau was “informative, but not necessary for initiating therapy for patients, and that we had treatment effects across the spectrum of tau.” He said the FDA had not indicated “the specifics of what they want to talk about” regarding tau, only that it was a topic the advisory committee would consider.

Ms White said: “There are a number of people here at Lilly who have been working on this for 35 years, so as you can imagine it was certainly a disappointment for them not to be able to bring this to patients now.” But she said the company was confident in its data and would consider in the coming months “additional analysis that we can do to answer any questions that someone might ask us.”