December 11th, 2019
Alzheimer’s Disease (AD), a type of dementia that results in memory loss and cognitive decline, is one of the most feared diseases in the U.S. Substantial time and resources have been expended to try and reverse or treat dementia and AD, (146 clinical trials from 1998 to 2017), but so far, these efforts have not proved successful. Until now?
Dementia researchers and patients were disappointed in March of 2019 when Biogen stopped two trials of its AD drug aducanumab because it seemed the drug had failed. However, in early December, Biogen presented a new analysis of one of these trials, showing that people taking a high dose of the drug experienced less cognitive decline compared to those in a placebo group. Some doctors have hailed this as a game-changer, the “the beginning of the end of Alzheimer’s disease.” Biogen’s head of research said he unequivocally believes the drug works, and practically dared the FDA not to approve it.
But there are many caveats that researchers have noted about this new analysis. First of all, the new results were not gathered according to the original trial protocol, and only came about because they added trial participants to receive high doses of the drug after the trial had “ended” in March. It is suspicious to keep enrolling people in a trial until you get the results that you want and then yelling “Eureka!” That’s what researchers call p-hacking, or “squeezing the data too hard.”
As Dr. Lon Schneider, researcher at the Alzheimer Disease Research Center, wrote about the results in The Lancet, “the findings turned favorable with added participants after the futility analyses, but they might have regressed to the mean if the sample had increase to its planned numbers…The effects seen in EMERGE could be random.” Even more dubious is that fact that the placebo group in the trial got worse, rather than stayed the same or improved. Schneider identified other potential biases of the results, including “increased dropouts, more missed doses and lower compliance, and a substantial amount of unblinding of the high-dose aducanumab treatment.”
Second, the actual results were underwhelming. Participants taking a high-dose of aducanumab experienced 23% less cognitive decline than those taking a placebo, which sounds good. But not so impressive is the absolute difference–only 0.4 points on a 3 point scale.
However, some researchers and advocates claim that any improvement, no matter how small, should be a reason to approve a new Alzheimer’s drug, because the need for a cure is so great. Maria Carrillo, chief science officer at the Alzheimer’s Association, said that the results warrant FDA review because taking this drug could be make patients “remember their loved ones a little longer.” Biogen officials too claimed that not approving the drug would be “depriving” patients of a potential cure.
These arguments make no sense given the dearth of evidence behind aducanumab. The lack of a cure is no reason to approve an ineffective drug; the drug will not help people remember their loved ones if it doesn’t work. As Stanford Univeristy researcher Dr. John Ioannidis pointed out, approving a drug based on patient need rather than evidence sets a dangerous precedent. “If we go down that path, we’re likely to introduce a lot of ineffective treatments for diseases that are really common,” he said. “It would be a complete mess.”
And the potential harms of exposing patients with mild cognitive decline to high doses of this drug (brain swelling, headache, dizziness, visual disturbances, nausea, and vomiting) are significant. Researcher Derek Lowe wrote in Science Translational Medicine, “If it doesn’t work for Alzheimer’s, then aducanumab will likely do real harm to some people and do good to no one. Giving ‘hope’ under these circumstances is, in my opinion, more like cruelty dressed up.”
When it comes to dementia and Alzheimer’s Disease, it appears that anxiety about cognitive decline is driving treatment decisions, rather than evidence. A recent survey found that half of middle-aged Americans believe they are likely to get dementia, and nearly 40% take vitamins or supplements to try and prevent dementia, even though these medications have not been shown to reduce cognitive decline. The rise in labeling people with elevated amyloid levels as having “preclinical Alzheimer’s Disease” may further drive the fear of dementia and use of unproven medications to treat it.
So far, using fear to push unproven dementia drugs is working. Let’s hope the FDA does not fall for this tactic; approving aducanumab without another trial would be a grievous error.