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In review of Lilly Alzheimer’s drug, FDA staff focus on safety, patient selection

Dive Brief:

  • Expert advisers to the Food and Drug Administration will need to weigh whether Eli Lilly’s experimental Alzheimer’s disease drug donanemab is widely effective or should be restricted only to people who have deposits in their brains of a toxic protein called tau, according to documents released Thursday ahead of a key regulatory meeting next week.
  • The FDA will also ask its advisers to provide guidance on whether and when it’s safe for people to stop taking donanemab based on reductions in another toxic protein called amyloid, as well as on the risks of mild brain swelling that can result from donanemab and other drugs of its type.
  • If approved, donanemab would be the third amyloid-targeted drug to launch. Biogen has withdrawn the first, called Aduhelm, after much controversy and few sales. Eisai, along with Biogen, more recently won approval of a second, called Leqembi, which brought in sales of $19 million in the first quarter.

Dive Insight:

When members of the Peripheral and Central Nervous System Drugs Advisory Committee convene Monday, it will have been 364 days since FDA reviewers received Lilly’s application for approval. Lilly had expected a decision by the end of March, but said the FDA decided it needed the committee’s input because of Lilly’s unique trial design.

The FDA appears to be proceeding more cautiously with reviews of Alzheimer’s drugs, particularly since the controversy over the approval of Aduhelm, which came over the negative views of many of the agency’s own staff, as well as members of the advisory committee because of muddy clinical data. The decision led to the resignation of three members of the advisory committee.

With donanemab, the issues before the committee center on Lilly’s decision to restrict enrollment to people with tau deposits in their brains alongside amyloid — the protein primarily blamed as a cause of Alzheimer’s.

Lilly’s TRAILBLAZER-ALZ 2 trial measured cognitive impairment in people with low or medium levels of tau and across the overall study population, which included those with high levels of the protein, after 76 weeks of treatment.

The trial found donanemab slowed progression by 35% for those with low and medium levels and 22% for the entire population, when compared to those on placebo. Trial researchers didn’t do a separate analysis for the high-tau group because not enough were enrolled to measure statistical significance.

The FDA has asked its advisers to vote on whether they believe donanemab is effective across the entire trial population, or more narrowly for a subset of Alzheimer’s patients. Leqembi has no restriction on its use based on presence or levels of tau.

TRAILBLAZER-ALZ 2 also allowed doctors to stop using donanemab when participants’ amyloid burden dropped below a certain level. By the end of the trial, 60% had met the stopping criteria. The FDA is asking its advisers to discuss if “there are scientific and/or clinical considerations that may factor into a decision to stop or continue dosing with donanemab if approved,” although agency reviewers have not asked for a vote on that question.

Advisers also will have to weigh the risk of a type of brain swelling called ARIA, for which Leqembi already has a black box warning, and any elevated risk that donanemab might represent. The briefing documents cite at least two, and possibly three, donanemab-related deaths from brain swelling that occurred in clinical studies.

Brian Skorney, an analyst at Baird, noted that the FDA found no imbalance in deaths in testing of Leqembi.“We think this provides support for the expectation that donanemab’s worse ARIA rate can translate into worsened outcomes,” Skorney wrote in a client note Thursday. “In our proprietary survey work, we have already noticed a slight physician preference for Leqembi’s safety profile over donanemab, but we think this ratio could now skew even further in favor of Leqembi.”

Stifel analyst Paul Matteis had a similar view, writing Leqembi’s “clear safety advantage is a huge deal for risk-averse neurologists, especially for a drug class where the magnitude of efficacy continues to be debated.”