Alzheimer’s drug donanemab developed by Eli Lilly will be discussed by the Peripheral and Central Nervous System Drugs Advisory Committee of the US Food and Drug Administration (FDA) on June 10 regarding its biologics license application for the treatment of early symptomatic Alzheimer’s disease (AD). This meeting follows the FDA’s decision in March to delay its ruling on the anti-amyloid agent, opting instead for a comprehensive review of the phase 3 TRAILBLAZER-ALZ 2 trial results by an external panel of experts.
Donanemab is an investigational immunoglobulin G1 monoclonal antibody targeting an insoluble, modified, N-terminal, truncated form of beta-amyloid. The TRAILBLAZER-ALZ 2 trial evaluated the safety and efficacy of donanemab compared to a placebo in 1,736 patients with early symptomatic Alzheimer’s disease, characterized by mild cognitive impairment or mild dementia, and evidence of amyloid and tau pathology on PET scans.
Patients in the trial received donanemab at an initial dose of 700 mg for the first three doses, followed by 1400 mg thereafter, administered once monthly for up to 72 weeks. Participants were stratified based on tau levels, a biomarker for Alzheimer’s disease progression, into a low/medium tau group and a combined tau group (low/medium and high tau).
Alzheimer’s Disease Drug Donanemab Shows Promise in Reducing Amyloid Plaque and Cognitive Decline
The results demonstrated that donanemab significantly reduced brain amyloid plaque burden and slowed cognitive and functional decline compared to placebo. The primary endpoint was the change from baseline to 76 weeks on the integrated Alzheimer’s Disease Rating Scale (iADRS), which measures cognition and activities of daily living. The least-squares mean change in the integrated Alzheimer’s Disease Rating Scale score at 76 weeks was -6.02 in the donanemab group -9.27 in the placebo group for the low/medium tau population, and -10.19 in the donanemab group and -13.11 in the placebo group for the combined population. Both results were statistically significant (P < .001).
However, the trial also reported amyloid-related imaging abnormalities of edema or effusion in 205 participants (24%) in the donanemab group, with 52 showing symptoms, compared to 18 (2%) in the placebo group, with no symptoms. Infusion-related reactions occurred in 74 participants (8.7%) receiving donanemab and four participants (0.5%) receiving placebo. There were three deaths in the donanemab group and one in the placebo group, all considered treatment-related.
The FDA’s decision to convene an advisory committee meeting, despite initial expectations of a first-quarter 2024 decision without such a meeting, was unexpected. Anne White, Executive Vice President of Eli Lilly and Company and President of Lilly Neuroscience, indicated that the FDA wanted to further examine safety and efficacy data, including safety results in donanemab-treated patients and the unique trial design of the TRAILBLAZER-ALZ 2 study.
FDA to Review Efficacy of Donanemab’s Limited-Duration Dosing for Alzheimer’s Disease
The FDA aims to discuss the efficacy implications of the trial’s limited-duration dosing regimen, which allowed patients to complete treatment based on amyloid plaque assessments and tau levels. Howard Fillit, MD, co-founder and Chief Science Officer of the Alzheimer’s Drug Discovery Foundation, emphasized that this additional step is part of the regulatory due diligence process and not a setback. The advisory committee will likely explore differences in the trial design between TRAILBLAZER-ALZ 2 and other studies, such as the CLARITY-AD study of lecanemab (Leqembi; Eisai Inc). Fillit believes that while the efficacy and safety profiles of donanemab and lecanemab are similar, the differences in dosing schedules, stopping rules, and tau imaging will be focal points of discussion.
Despite these discussions, Fillit and others in the field remain optimistic about the Alzheimer’s disease drug donanemab’s approval. Fillit sees the meeting as largely informational and expects that donanemab will receive FDA approval in the near future. J.K. Wall, Senior Director of Neuroscience Communications at Lilly, expressed full confidence in donanemab’s results and looks forward to further discussions with the FDA and other stakeholders.
Once approved, donanemab will join aducanumab and lecanemab as the third anti-amyloid monoclonal antibody available in the US. The presence of two available anti-amyloid agents, following Biogen’s discontinuation of aducanumab, is viewed positively by experts, as it reinforces the mechanism of action and offers competition in the field, ultimately benefiting patients. In conclusion, the upcoming FDA advisory committee meeting on June 10 is a critical step in the approval process for donanemab. With promising trial results and expert optimism, the Alzheimer’s disease drug is expected to gain FDA approval, providing a new treatment option for patients with early symptomatic Alzheimer’s disease.
Resource: Medscape, June 04, 2024
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