Regulatory FDA Advisory Committee Raises Concerns About Eli Lilly’s Alzheimer’s...

FDA Advisory Committee Raises Concerns About Eli Lilly’s Alzheimer’s Drug Donanemab


The FDA’s advisory committee has raised concerns about Eli Lilly’s Alzheimer’s drug donanemab, particularly regarding the risk of brain bleeds in trial patients taking antithrombotics. The committee has also flagged the use of tau PET imaging in the trial. Since patients are allowed to stop dosing once they reach a certain amyloid clearance threshold, concerns about the dosing regimen have also emerged.

The data submitted to the committee came from a 1,736-patient study called the Study AACI, or the phase 3 TRAILBLAZER-ALZ 2 trial. Participants were treated with donanemab to assess its impact on disease progression, measured by changes in the Alzheimer’s Disease Rating Scale (iADRS) at 76 weeks.

Currently, Biogen and Eisai’s Leqembi is the only other Alzheimer’s drug on the market. Like Leqembi, Lilly’s monoclonal antibody has raised safety concerns. Amyloid-related imaging abnormalities (ARIA) are a chief concern for monoclonal antibodies, which is why Leqembi carries a black box warning. ARIA refers to the risk of brain bleeds and swelling, which has led to several deaths in this class of drugs, including three in Lilly’s Study AACI. There are two types of ARIA: ARIA-E (edema) and ARIA-H (hemosiderin deposition).

Eli Lilly reported a 5% adverse event rate for donanemab, with 24% of patients experiencing ARIA-E, 15% ARIA-H superficial siderosis, and 25% ARIA-H microhemorrhage. The FDA is concerned because no conclusion can be drawn about the actual risk of these events due to limited exposure to non-aspirin antithrombotic medications in the trial.

The FDA expects more caution in determining symptoms caused by donanemab before prescribing anticoagulants, as ARIA-E can mimic stroke symptoms. Additionally, the use of PET imaging to select patients likely to progress during the study has raised concerns. Patients with tau presence in their PET scans were included and split into low/medium tau level populations. The exclusion of patients with no or very low tau levels from the controlled portion of the trial was also questioned by the FDA.

Once patients reached a certain amyloid clearance on their PET scans, they ceased donanemab treatment. The percentage of patients stopping treatment increased from 17% at 24 weeks to 60% at 76 weeks. This regimen, new to the Alzheimer’s field, meant that the dosing regimen could not be fully tested due to varying discontinuation points.

Most issues identified by the board were already known to Lilly, which provided swift justifications. A new meeting of the Peripheral and Central Nervous System Drugs Advisory Committee is scheduled to further discuss the drug’s merits and shortcomings, ensuring a thorough evaluation before a verdict on its approval.

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