The safety and effectiveness of donanemab – an Alzheimer’s drug recently approved by the US Food & Drug Administration (FDA) – is being questioned in a study published by The BMJ Today.
Journalists Jeanne Lenzer and Shannon Brownlee explore concerns not only about its effectiveness and the number of deaths among patients taking the drug, but also about its financial ties to drug makers among the “independent” advisory panelists who recommended approval.
Donanemab, developed by Eli Lilly, is the latest in a new class of anti-amyloid drugs that release antibodies against beta-amyloid, a protein believed to cause Alzheimer’s disease.
In January 2023, the FDA denied approval of donanemab, citing a “high rate” of missing data and doubts about the drug’s long-term safety. The agency noted a higher rate of treatment discontinuation due to side effects (often brain bleeding and swelling) in patients taking donanemab compared to placebo, and an “imbalance” in the overall number of deaths.
Lilly acknowledged three deaths among patients taking donanemab, and an outside company it hired to obtain the missing data discovered two additional deaths among patients in the donanemab arm and five deaths in the placebo arm.
But Steven Goodman, an expert in clinical trial design at Stanford University, says it is not possible to assess the reliability of the new data without more details about the third-party company’s methods.
“There was also no information on health outcomes in those patients other than death, nor on the causes of the deaths,” he says, adding that the “inability to formally track patients who stopped treatment was a significant design flaw, especially when that shutdown was implemented.” partly due to drug side effects.”
The study also found that seven of the eight physicians assigned by the FDA to review donanemab received direct payments from pharmaceutical companies.
Three had financial ties to Lilly, two had ties to Roche, Lilly’s development partner in creating a new blood test for Alzheimer’s disease, and two others have patents on amyloid antibodies, and the eighth doctor received research funding from Janssen for another Alzheimer’s disease medicine.
Using the OpenPayments public database, members’ CVs, disclosures in published articles and Google’s patent ownership database, the BMJ found that individual advisers received up to $62,000 (£47,000; €56,000) for consultancy and speaking fees and up to $62,000 ( £47,000; €56,000) $10.5 million in research grants from 2017 to 2023.
Asked about the extensive financial conflicts among the physician advisors found by the BMJ, the agency said, “The FDA does not comment on matters related to individual members of an advisory committee.”
Lenzer and Brownlee also describe how the key (primary) outcome of the donanemab studies was changed during the trial from the widely accepted ‘Clinical Rating Scale for Dementia – The Sum of Boxes’ (CDR-SB) to Lilly’s own Integrated Disease Rating Scale of Alzheimer’s. iADRS).
And despite the results showing no clinically meaningful difference between patients taking the drug and placebo, Lilly stated that donanemab slowed the progression of Alzheimer’s disease by 22%. The company has also promoted donanemab as “slowing the decline by 35%.”
“That is a misleading statement.” says Alberto J Espay, a neurologist and specialist in clinical epidemiology and healthcare research at the University of Cincinnati. “That’s a relative difference that turns a very small absolute difference into a number that seems impressive.”
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Magazine reference:
Lenzer, J., and Brownlee, S. (2024). Donanemab: Conflict of interest found in FDA committee that approved new Alzheimer’s drug. BMJ. doi.org/10.1136/bmj.q2010.