Questions about the safety and effectiveness of a new Alzheimer's drug

The safety and effectiveness of donanemab – an Alzheimer’s drug recently approved by the U.S. Food & Drug Administration (FDA) – is being questioned in a study published by The BMJ.

Journalists Jeanne Lenzer and Shannon Brownlee examine not only concerns about the drug's effectiveness and the number of deaths among patients taking it, but also the financial ties of the “independent” advisory members who recommended its approval to drug manufacturers.

Developed by Eli Lilly, donanemab is the latest in a new class of anti-amyloid drugs that deliver antibodies against beta-amyloid, a protein thought to trigger Alzheimer's disease.

In January 2023, the FDA denied approval of donanemab, citing a “high rate” of missing data and questioning the drug's long-term safety. The agency found a higher rate of treatment discontinuations due to side effects (often brain bleeding and swelling) in patients receiving donanemab compared to placebo, as well as an “imbalance” in the overall number of deaths.

Lilly confirmed three deaths in patients receiving donanemab, and an outside company hired to obtain the missing data found two additional deaths in patients in the donanemab group and five deaths in the placebo group.

However, Steven Goodman, a clinical trial expert at Stanford University, says that without more details about the outside company's methods, it is impossible to assess the reliability of the new data.

“In addition, there was no information about the health status of these patients other than death or cause of death,” he says, adding that “the failure to formally follow up patients who discontinued treatment was a significant design flaw, especially when that discontinuation was partly due to side effects of the drug.”

The investigation also found that seven of the eight doctors hired by the FDA to review donanemab received direct payments from pharmaceutical companies.

Three of them had financial ties to Lilly, two had ties to Roche, Lilly's development partner in developing a new blood test for Alzheimer's disease, two others own patents on amyloid antibodies, and the eighth doctor received research funding from Janssen for another Alzheimer's drug.

Using the public OpenPayments database, members’ CVs, information in published articles and the Google patent ownership database, The BMJ found that individual consultants received up to $62,000 in consulting and speaking fees and up to $10.5 million in research grants from 2017 to 2023.

When asked about the extensive financial conflicts among medical consultants, The BMJThe agency stated: “FDA does not comment on matters concerning individual members of an advisory committee.”

Lenzer and Brownlee also describe how the main (primary) outcome of the donanemab trials was changed during the trial from the widely accepted Clinical Dementia Rating Scale – Sum of Boxes (CDR-SB) to Lilly's own Integrated Alzheimer's Disease Rating Scale (iADRS).

And although the results showed no clinically meaningful difference between patients on the drug and placebo, Lilly said donanemab slowed the progression of Alzheimer's disease by 22%. The company also promoted donanemab by saying it “slows decline by 35%.”

“That's a misleading statement,” says Alberto J. Espay, a neurologist and specialist in clinical epidemiology and health research at the University of Cincinnati. “It's a relative difference that turns a very small absolute difference into a number that seems impressive.”