The FDA is up to more of its malarkey with the latest amyloid-targeting drug, a BMJ investigation finds.
Donanemab, the latest Great Amyloid-busting Hope for Alzheimer’s disease, seems to be following aducanumab and lecanemab into a mire of controversy over dubious results and conflicts of interest.
An investigation for the BMJ by journalists Jeanne Lenzer and Shannon Brownlee details problems with the drug’s efficacy, deaths and missing data in clinical trials and the FDA advisory committee members’ ties to drug makers in the Alzheimer’s space.
They kick off with this burn from George Perry, editor in chief of the Journal of Alzheimer’s Disease, who told them the new anti-amyloid drugs “all demonstrate an imperceptible slowing of dementia in the midst of serious adverse effects, including death”.
The amyloid theory of AD aetiology has been dominant for decades, possibly assisted by scientific fraud, with not one properly convincing drug to show for billions of dollars’ worth of research.
Eli Lilly’s donanemab, which the Back Page’s brain insists on reading as “doner kebab”, was approved by the FDA in July having been rejected in January last year because of extensive missing trial data and doubts about long-term safety.
The donanemab arm of Lilly’s trial had around twice the deaths and twice the rate of brain bleeds and swelling as the placebo group, and a higher rate of discontinuation, with withdrawals excluded from the final analysis and no record of whether they were still alive. Lilly engaged some third-party investigators to track down the patients lost to follow-up, which evened out the death rate slightly – but how much you want to trust this entirely opaque process is, well, up to you.
Lilly pulled an endpoint switcheroo, Lenzer and Brownlee report, from the widely used “clinical dementia rating scale – sum of boxes” (CDR-SB) test, which the FDA wanted it to use, to its own “integrated Alzheimer’s disease rating scale” (iADRS), a 144-point composite scale of cognition and activities of daily living.
Even on its own scale, Lilly could only show a clinically meaningless three-point difference between the disease progression in the two groups, which it spun into “slowing decline by 35%”.
To make matters almost comically worse, donanemab could be doing harm. All drugs in this monoclonal antibody class seem to cause brain atrophy, beyond that caused by Alzheimer’s, the BMJ reports. The FDA noted that levels of the neurofilament light protein, which increases with brain cell death, were higher in the donanemab arm than placebo, when they should have decreased if the drug was actually slowing neurodegeneration.
Then there’s the financially compromised advisors.
After an independent advisory committee came down almost unanimously against Biogen and Eisai’s aducanumab in 2020, with three members quitting in protest, the FDA approved it anyway and replaced the advisors.
When lecanemab, also from Eisai and Biogen, came up for approval last year, the committee had at least four members with ties to the makers. They approved it and so did the FDA.
When it was donanemab’s turn this year, Lenzer and Brownlee report, the committee consisted of eight members with a collective $US62,000 in consulting and speaker fees and $US10.5 million in research grants from companies involved in amyloid-targeting Alzheimer’s therapies.
The FDA gave the journalists a “no comment” on these extensive conflicts of interest.
The agency has given Lilly an extremely generous 13 years to complete its post-market registry-based review and final safety report. Yes, Alzheimer’s moves slowly, but that’s a lot of potential sales of an expensive drug that has shown unconvincing efficacy.
Even after covering this mab saga for years, this is a really disturbing read.
There’s an almost universal desperation for a drug that works against this disease, from patients, their families and carers, people who’ve watched it happen and don’t want it to happen to them, neurotic journalists who’ve written too many stories about it, and of course drug companies who can make a fortune out of all the above.
That puts an extra burden on regulators, not to grease the bureaucratic wheels for a faster new treatment but to make sure a lot of vulnerable people aren’t sold another very, very expensive lemon.
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