An investigation has cast a shadow over the recent FDA approval of donanemab (Kisunla), an Alzheimer's drug developed by Eli Lilly, with concerns mounting over its safety, efficacy, and potential conflicts of interest among the advisory panel that recommended its approval. The drug, part of a new class targeting beta-amyloid, a protein believed to cause Alzheimer's, has been touted as a breakthrough, but faces increasing scrutiny.
Safety Concerns and Adverse Events
Originally denied approval by the FDA in January 2023 due to a "high rate" of missing data and insufficient long-term safety characterization, donanemab's clinical trials revealed worrying trends. Treatment discontinuation due to adverse events, including brain hemorrhage and swelling (amyloid-related imaging abnormalities or ARIA), was more frequent in the donanemab group (36.8%) compared to the placebo group (14.9%).
Lilly acknowledged three deaths linked to ARIA in patients taking donanemab. Interim data also showed an "imbalance" in overall deaths, with 17 (2.7%) in the donanemab group and 10 (1.4%) in the placebo group. To address the missing data, Lilly hired an outside company to search for mortality information, which narrowed the death imbalance to 19 in the donanemab arm and 15 in the placebo arm.
Steven Goodman, a physician and professor of epidemiology at Stanford University, questioned the reliability of the new mortality data due to a lack of details on the outside company's methods and the absence of information on health outcomes beyond death.
Conflicts of Interest
The investigation revealed financial ties between FDA advisory committee members and pharmaceutical companies, including Lilly and Roche (Lilly's partner in developing an Alzheimer's blood test). Individual advisors received up to $62,000 in consulting and speaking fees and up to $10.5 million in research grants from 2017 through 2023. The FDA's response to these concerns was a terse statement: "The FDA does not comment on matters related to individual members of an advisory committee."
Efficacy in Question
The primary endpoint of the donanemab studies was the integrated Alzheimer's disease rating scale (iADRS), a 144-point composite scale created by Lilly. The FDA had preferred the more widely accepted clinical dementia rating scale—sum of boxes (CDR-SB) test. In the phase 3 trial, patients in the donanemab arm worsened by 10.2 points on the iADRS, while those on placebo worsened by 13.1 points, an absolute difference of 2.9 points.
Lilly stated that donanemab slowed progression by 22%, a relative difference. Alberto J Espay, a neurologist and specialist in clinical epidemiology and healthcare research at the University of Cincinnati, called this a misleading statement, transforming a tiny absolute difference into an impressive-sounding number.
Post-Market Monitoring
Due to safety concerns, the FDA is requiring Lilly to conduct a post-market registry-based, prospective, observational study to track events, including deaths, brain hemorrhage, and oedema, with a final safety report due in 2037.
