FDA Staff Emphasize Safety and Patient Selection in Lilly Alzheimer’s Drug Review

The upcoming advisory committee meeting for the Food and Drug Administration (FDA) will focus on the evaluation of Eli Lilly’s experimental Alzheimer’s drug, donanemab. The key issues at hand include determining the drug’s effectiveness and safety profile, especially regarding its impact on individuals with varying levels of the toxic protein tau in their brains. The advisers will also consider whether patients can safely discontinue the drug based on reductions in another protein, amyloid, and assess the risks of mild brain swelling associated with donanemab.

Donanemab, if approved, would be the third drug targeting amyloid proteins to be introduced to the market. Biogen initially launched the first such drug, Aduhelm, but withdrew it due to controversy and poor sales. Later, Eisai and Biogen’s Leqembi, the second drug, received approval and generated $19 million in sales during its first quarter.

The Peripheral and Central Nervous System Drugs Advisory Committee, which will review donanemab, marks nearly a year since the FDA received Eli Lilly’s application for approval. While Lilly anticipated a decision by March’s end, the FDA opted to involve the advisory committee due to the unique design of Lilly’s clinical trials.

The FDA has adopted a cautious stance on Alzheimer’s drug reviews following the contentious approval of Aduhelm. The approval of Aduhelm went against the recommendations of several FDA staff members and advisory committee participants, causing several to resign. The controversy stemmed from unclear clinical data, leading to heightened scrutiny for subsequent Alzheimer’s drugs.

A central topic for the advisory committee is Lilly’s decision to limit study participants to those with tau deposits in their brains in addition to amyloid. The TRAILBLAZER-ALZ 2 trial by Lilly evaluated cognitive impairment in individuals with low to medium levels of tau, as well as the broader study group, including those with high tau levels, over 76 weeks of treatment. The results showed that donanemab slowed disease progression by 35% in those with low and medium tau levels and by 22% across the entire population, compared to placebo. However, there was no separate analysis for high-tau individuals due to insufficient enrollment.

The FDA has requested the advisory committee to vote on whether donanemab is effective for the entire trial population or only a specific subset of patients with Alzheimer’s. Unlike donanemab, Leqembi is not restricted based on tau presence or levels.

In the TRAILBLAZER-ALZ 2 trial, physicians were permitted to discontinue donanemab when participants’ amyloid burden fell below a specific threshold. At the trial’s conclusion, 60% of participants met the stopping criteria. The FDA seeks the advisory committee’s input on the scientific and clinical factors that might influence the decision to stop or continue donanemab treatment if it gains approval. However, a vote on this question has not been requested.

Additionally, the committee will need to consider the risk of brain swelling, known as ARIA, which already has a black box warning for Leqembi. Clinical studies have linked at least two, possibly three, deaths from brain swelling to donanemab.

Brian Skorney, an analyst at Baird, highlighted that FDA testing of Leqembi did not reveal an imbalance in deaths, suggesting donanemab’s higher ARIA rate might lead to worse outcomes. According to proprietary survey data, physicians show a slight preference for Leqembi's safety profile over donanemab, a trend that might intensify.

Stifel analyst Paul Matteis echoed this sentiment, noting that Leqembi’s clear safety advantage is significant for risk-averse neurologists, especially given the ongoing debate over the efficacy of such drugs.

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