This week, under significant controversy, the FDA approved aducanumab, a medication to slow the progression of Alzheimer’s disease. If this were a straightforward drug approval, I would be among the first to celebrate. Alzheimer’s is a horrible illness and we desperately need better therapies to address its symptoms, slow its progression, and, ideally, cure or prevent it. Unfortunately, aducanumab has not really been proven to do any of these things, which leads us to our current situation. My summary of the situation is, in the words of Shakespeare, “much ado about nothing.”
At every level, the facts are underwhelming—from the rationale for the benefits of this medication, to the clinical evidence behind it, to the FDA’s approval. The approval belies a desire on the part of pharmaceuticals and other stakeholders to just do something, anything that might give the appearance of progress and to bolster hope, even if false. Here is a quick breakdown of what I see as wrong with the picture that aducanumab represents a substantial breakthrough:
- The Science: Amyloid is a protein the accumulates in the brains of people with Alzheimer’s. While amyloid is certainly related to Alzheimer’s, its exact role is still far from clear.1 On the one hand, genes that increase amyloid are associated with genetic forms of Alzheimer’s and amyloid is toxic to neurons in animal models. On the other hand, amyloid deposits in humans are not great predictors of clinical symptoms and some people with high levels of brain amyloid have no symptoms of Alzheimer’s. Moreover, dozens of large clinical trials of anti-amyloid therapies in people have consistently failed to show any perceptible benefit.
- The Trial: The clinical trials that led to the FDA decision were not positive trials. One showed no benefit, and the other showed a positive trend but did not meet its primary outcome and was stopped prematurely. In fact, it was only in subgroup analyses, and when looking at imaging markers of amyloid rather than clinical benefit, that aducanumab showed signs of benefit.2 Moreover, it is unclear if the very small changes in patient-reported outcomes represented any true clinical benefit. In technical terms, and particularly in very large trials like the ones for aducanumab (1500 people), one can find statistical significance for very small differences in the absence of clinical significance. In other words, with over 500 people in each group, the trial had the ability to detect differences in their scales at a group level that were smaller than what an individual would notice.
- The FDA Decision: Given the very weak evidence behind this drug, it was surprising that Biogen went to the FDA and I think it was even more surprising to many in the field that such an expensive drug ($56,000 per year) for such a common condition would be approved on such underwhelming evidence. But even here there is a catch. The FDA approved aducanumab under their accelerated pathway based on the surrogate endpoint of an imaging marker (PET scan) of amyloid, an endpoint the FDA says is “fairly likely” to predict clinical benefit. (This is a very tenuous proposition – PET has not been proven to predict the benefit of therapeutis and amyloid may not be the best marker as per #1 above.) However, per the FDA:
This pathway requires the company to verify clinical benefit in a post-approval trial. If the sponsor cannot verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug.
Thus it seems, that even the FDA is hedging its bets on this medication. Why they wouldn’t ensure the safety and efficacy of this drug before it is approved is beyond me. and Iit would not surprise me if the drug is eventually withdrawn for lack of efficacy or emerging safety issues or never practically sees the light of day because of insurance companies and Medicare not paying for it.
At the end of the day, we desperately need treatments, progress and real hope for Alzheimer’s disease. I understand the desperation of the many stakeholder groups that pushed aducanumab forward, but I question the purity of the motives of the pharmaceuticals, scientists and even the Alzheimer’s societies that pushed forward this product. At the end of the day, I can’t help but feel that for people living with Alzheimer’s and their families that the false hope and unwarranted hype will lead to greater disappointment than encouragement.
1. Drachman DA. The amyloid hypothesis, time to move on: Amyloid is the downstream result, not cause, of Alzheimer’s disease. Alzheimers Dement 2014;10:372-380.
2. Knopman DS, Jones DT, Greicius MD. Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019. Alzheimers Dement 2021;17:696-701.