New Alzheimer’s Drugs Are Bringing Back the Wrong Memories
I remember when, in 1999, the FDA approved Vioxx, a pain reliever that went on to kill an estimated 50,000 Americans. According to whistleblowers the FDA not only had the data to prevent the tragedy, they obstructed the investigation.
I also remember the inspiring story of Frances Kelsea, an FDA physician who in 1960 refused to approve thalidomide despite approval in dozens of other countries, and industry pressure. The drug caused over 10,000 birth defects worldwide, but just 17 in the US where it was never approved.
Now, in 2024, the FDA is on the verge of approving a third Alzheimer’s Disease drug. The first was Aduhelm in 2021, the second was Leqembi, in 2023. Donanemab, the third, is under review. The three are extremely similar. They’re all monoclonal antibodies, they all reduce amyloid plaques in the brain, and they all don’t work.
In the 1980s researchers discovered amyloid plaques were associated with Alzheimer’s, spawning the ‘amyloid hypothesis’. If the plaques cause cognitive decline, it was hoped, removing them may slow or even reverse Alzheimer’s.
Unfortunately, the theory has been dashed. First, studies show many with Alzheimer’s have no brain amyloid. Second, scientific reviews show at least 72 anti-amyloid agents have been researched, and none have worked. This includes nine monoclonal antibodies, a class that has failed so miserably and consistently a 2021 meta-analysis announced “the time has come to divert therapeutic efforts away from AAB [amyloid] immunotherapy.”
Abject failure is certainly the case for Aduhelm. Two FDA studies were halted early for futility, and an expert panel voted 9-1 against approval (the FDA approved it anyway). Meanwhile, Leqembi ‘slowed cognitive decline’ by just 0.45 points on an 18-point scale, less than half the 1-point minimum deemed meaningful. Finally, the donanemab trial used a 144-point scale and reported a 3-point edge, well below the 9-point minimum determined by the company's own research.
These failures highlight a crucial distinction: statistical versus clinical differences. Studies often find a ‘statistical’—meaning mathematically identifiable—difference between groups. But research is a human task and thus inherently biased, so trial results commonly lean toward the drug. Particularly in large trials (the Alzheimer’s trials enrolled thousands) this often leads to a ‘statistical’ difference.
But a clinical difference affects people’s lives. Which is why there are thousands of studies examining and meticulously defining the ‘minimal clinically important difference’ for scales like those in the Alzheimer’s trials. Those studies tell us the ‘differences’ in the antibody drug trials were so small that people with the disease, their families, and their doctors, would literally never notice them. In other words, they’re not real differences.
Another issue may also be confusing starry-eyed loyalists. The drugs removed amyloid plaques quite effectively—a finding that effectively closes the door on the amyloid hypothesis. Vanquishing amyloid plaques didn’t help people with Alzheimer’s.
The chicanery of parading differences well below the thresholds for true benefit is happening now for a reason: We’re heading into a perfect storm of potential profit for AD drugs. Nearly 7 million in the US have symptomatic Alzheimer’s, with an expected doubling by 2050. This will likely balloon with the use of new, flawed blood tests that severely over-diagnose Alzheimer’s. And the drug, given through IV infusions, costs nearly $30K per year (not including infusion costs, facility fees, and other charges).
A final tidbit: The drugs cause brain swelling, headaches, confusion, and occasionally death—in huge numbers. Donanemab, the latest, caused 24% of people’s brains to swell, while another 9% suffered infusion reactions. That’s 1 in 3 people seriously harmed by the drug, and zero helped. What’s worse, as noted in these pages, one can always expect the harms to be greater and the benefits smaller than reported in trials.
As the FDA wrestles with the amyloid drugs, it seems natural to remember the agency’s performance on harmful drugs of the past. But an effective Alzheimer’s treatment should bring back different memories.
great info