FDA delays Alzheimer’s drug for further review in surprise move

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The U.S. Food and Drug Administration delayed regulatory action on an experimental Alzheimer’s drug that was widely expected to be approved this month, citing a need for more review to establish its safety and effectiveness, drugmaker Eli Lilly said Friday.

The FDA plans to hold an advisory committee meeting to further scrutinize donanemab, one of the few treatments developed for Alzheimer’s disease, a debilitating and incurable affliction that affects some 6 million Americans.

The agency’s action reflects a cautious approach, experts said. The FDA drew criticism in 2021 after approving a different Alzheimer’s drug that showed conflicting results about its effectiveness. And it comes as public pressure mounts for therapies to fend off the memory-robbing disease, after decades of research have produced only a handful of drugs that aim to slow Alzheimer’s progression or treat its symptoms.

The call for additional scrutiny surprised Eli Lilly executives, who said it is unusual for such a review to occur after the FDA has given an anticipated date to make a decision on approval.

“We are confident in donanemab’s potential to offer very meaningful benefits to people with early symptomatic Alzheimer’s disease,” Anne White, an executive vice president at Lilly, said in a statement. The company noted that the FDA held similar reviews for the two other amyloid-targeting drugs it previously approved.

The two approved drugs, known by their brand names as Aduhelm and Leqembi, drew heightened attention because of complications such as bleeding in the brain, with particular risk for patients who have a certain genetic variation and those taking blood thinners. Cambridge, Mass.-based Biogen, which developed the two drugs with Japan’s Eisai, said in January it would cease marketing Aduhelm, a controversial drug that sputtered commercially after Medicare declined to broadly reimburse for it. The FDA had approved Aduhelm despite an advisory committee rejection of the drug.

“The FDA was burned pretty badly with Aduhelm,” said Brian Balin, a professor at the Philadelphia College of Osteopathic Medicine who studies Alzheimer’s disease. Donanemab’s side effects could put patients with mild cognitive impairment at risk, he said, adding of the FDA’s action Friday, “I think it’s a wise decision.”

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Jason Karlawish, associate director of the Alzheimer’s Disease Research Center at the University of Pennsylvania’s Perelman School of Medicine, said Eli Lilly’s clinical trials were well designed. “This is not Aduhelm part two,” Karlawish said. “It’s fair to say that this decision is a surprise, but it’s not a cause for worry. The data shows [donanemab] is effective.”

The FDA does not comment on drugs that are pending approval. The agency forms advisory committees of independent experts to offer scientific counsel on drugs and medical devices before making a decision on whether to approve them. The committees, which meet in public hearings, vote to recommend approval of a drug or device, although the agency is not bound by the vote. The committee on donanemab is expected to meet later this year.

Donanemab is designed to attack a sticky substance in the brain known as amyloid beta, which has been linked to Alzheimer’s. Clinical trials have shown that donanemab slows cognitive decline of people in the early stages of the disease. But the promise of amyloid-targeting drugs remains divisive within the field.

Those drugs don’t reverse the effects of the disease, said Marwan Sabbagh, a behavioral neurologist at the Barrow Neurological Institute who served on the advisory committee for Leqembi.

“The reality is these patients are less worse,” Sabbagh said of those taking amyloid-targeting drugs. “They do not actually get better on these drugs, but we slow the rate of decline.”

Matthew Schrag, a neurologist at Vanderbilt University Medical Center, continues to be skeptical of the focus on amyloid to treat Alzheimer’s. “The absolute magnitude of the benefit is very small,” he said. “I think it is entirely appropriate that the FDA thoroughly vets donanemab and avoids the perception that the approval process is rushed.”

Donanemab, which is administered once a month by infusion, showed in clinical trials that it slowed the mental decline of participants by 35 percent, as measured by cognitive tests and activities such as driving and managing finances. But it also aroused safety concerns, with trial investigators attributing the deaths of two participants to a complication from the drug. That complication, known as ARIA, usually involves swelling or bleeding in the brain, and has dogged Aduhelm and Leqembi as well.

In a clinical trial for donanemab, 24 percent of patients experienced a form of ARIA, with 6 percent having symptoms of it. Those rates of ARIA are higher for Lilly’s donanemab than Leqembi, according to Myles Minter, an analyst at William Blair. “Although we believe donanemab will ultimately be approved, the increased ARIA risk remains a concern,” he wrote in a research note Friday.

This isn’t the first signal that the FDA is taking a cautious approach in its review of donanemab. The agency denied Lilly’s application for accelerated approval in January 2023, focusing in on the trial’s unique design that allowed participants to stop taking the experimental drug after scans showed a certain level of amyloid had been cleared from the brain. Many patients in the trial discontinued the drug as early as six months; the FDA requested data on at least 100 patients who had received 12 months of continuous treatment.

“While the decision is a surprise at this stage in the review process, the safety and appropriate administration of treatments is paramount,” the Alzheimer’s Association said in a statement. “On behalf of everyone who could benefit from this treatment, we strongly urge the FDA to move swiftly in this next stage of its review.”

Because donanemab is administered intravenously, only certain medical centers can perform the procedure. Given logistical constraints, Lilly has said that it expects the initial launch of the drug to reach a limited number of patients and contribute only modestly to its earnings once approved.

Lilly’s stock price fell 2.3 percent Friday.

In a sign of the headwinds that donanemab may face if approved, the rollout of Leqembi has gone more slowly than its makers had envisioned. There were about 2,000 patients receiving the drug as of January, a far cry from the 10,000 that Eisai had once forecast by the end of this month. Its partner Biogen reported collecting just $10 million for the drug last year.

“Most clinicians are pleased to have Leqembi for patients,” Jay Olson, an Oppenheimer analyst, wrote in a note to clients in February, adding that “some doctors remain skeptical.”

Drugmakers are also looking beyond therapies that seek to remove amyloid beta and exploring other potential causes of Alzheimer’s disease. Biogen and Johnson and Johnson are also developing drugs that target tau, a protein that looks like tangles in the brain and is linked to the disease. In January, Biogen chief executive Christopher Viehbacher called the company’s tau candidate a “crown jewel” in its pipeline of experimental drugs.

Novo Nordisk is investigating the potential benefits that semaglutide — the active ingredient in the blockbuster diabetes drug Ozempic — has on people with early Alzheimer’s, with results from a late-stage trial expected in late 2025.

The FDA’s advisory committee for donanemab could offer clues that shape the prospects of other Alzheimer’s therapies, including a next-generation, amyloid-targeting drug also made by Eli Lilly, according to David Risinger, a senior analyst at Leerink Partners.

“It remains to be seen what FDA is most concerned about,” he said.

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