Our thoughts on the Aducanumab Debacle

Sometimes it takes a slap in the face to wake up to how bad a situation really is, and when it comes to healthcare, one need look no further than this article from the Atlantic. In it, two law professors discuss the implications of the recent approval of Aduhelm (aducanumab) for Alzheimer’s disease, concluding, among other far-reaching effects, that its gargantuan costs may actually require states to cut their education budgets (Can you imagine your child coming home and saying, “Mommy, in school today the teacher said we could only learn our times tables to 3 because of the Aduhelm cuts. But we did learn to multiply by 56,000 since that’s the annual drug cost …”), and that Medicare’s bill for this single drug may exceed the total cost of all other drugs combined. These are truly jaw-dropping implications, and all for something that has never worked, which was panned 10-0 by the advisory panel, and whose approval incited three resignations from the advisory panel itself. Sadly, here was a classic example in which the goals of healthcare and the goals of healthcare business diverged, and business won out over health.

But what has been missed in all of the many opinion pieces on Aduhelm — and what was indeed missed by the FDA itself — is that the approach taken with Aduhelm is based on a misconception: in the past, it was believed that Alzheimer’s disease was caused by the buildup of amyloid in the brain, and so removing the amyloid should remove the Alzheimer’s, right? Unfortunately, that turned out to be wrong, and the various amyloid-removing drugs — from aducanumab to solanezumab to bapineuzumab to others — actually proved the misconception. Thus, whereas these drugs were touted as “disease-modifying agents,” they turned out to be “amyloid-modifying agents”— the amyloid was reduced, but the Alzheimer’s was not improved. This was the lesson, over and over again, with each drug.

Therefore, the FDA’s explanation of its approval could not have been more counterfactual: it explained that it was approving aducanumab because there is evidence that it reduces amyloid, and the amyloid removal is “reasonably expected” to lead to clinical benefit. But that is exactly what the trials disproved! In fact, removing the amyloid leads to brain hemorrhage, brain swelling, and other nasty side effects in about 40% of patients (and 50% in the ApoE4+ group, the very group that is at high risk for Alzheimer’s, and thus especially needy of an effective therapy), but the one thing it does not do is improve cognition — the only true requirement of an Alzheimer’s therapy! This is like approving a new drug because everyone who received it died, so no one who received it is complaining that it didn’t work — it indicates a misunderstanding that is so fundamental that it would be laughable were it not so malignant.

I think we can all agree that we want the same thing — better outcomes for patients with Alzheimer’s disease, and a reduction in the global burden of dementia. That will require an outcomes-first approach rather than a business-first approach. As the brilliant physicist Richard Feynman said, “For a successful technology, reality must take precedence over public relations, for Nature cannot be fooled.” In the aducanumab trials, Nature was not fooled. Sadly, the FDA was, and we shall all be paying for this — in taxation, in Medicare, in state budgets, in drug prices, in family bankruptcies, in brain hemorrhages, and in innumerable other ways — for many years to come.

We can do better, we are doing better — let’s keep addressing the actual causes of Alzheimer’s disease, and keep improving the outcomes for the many patients in need.