A few months ago, the FDA approved a new drug, aducamumab, to treat Alzheimer’s disease. This was the first time in 20 years that the FDA approved a drug for Alzheimer’s, and while that may sound hopeful, many experts have already pointed out that it was a colossal mistake, and a looming tragedy for Alzheimer’s patients. Here are 4 reasons why the approval of aducamumab (also called Aduhelm) is such a disaster.
1. The new drug just doesn’t work. The biggest problem is that Aduhelm doesn’t slow down or reverse the progress of Alzheimer’s. More than a year ago, I wrote about the failure of two trials of aducamumab. The two trials, designed to be identical to one another, were halted in March 2019 by the drugmaker, Biogen, due to a “futility analysis” that showed it just wasn’t working.
In other words, there was no point in continuing the trials. So Biogen halted them.
But then Biogen tried to rescue the drug. In what can only be described as torturing the data to try to find a result that they really, really wanted, they went back and looked at a subset of patients in one of the two trials, called EMERGE, and claimed that the higher-dose patients actually did get a benefit.
But the patients didn’t benefit. All that Biogen could argue was that some patients had lower levels of amyloid plaques in their brains. An independent group of scientists also looked again at Biogen’s data, and published a report saying that their analysis still didn’t support any benefit for patients.
It’s true that plaques do indeed accumulate in the brains of Alzheimer’s patients, and aducamumab does seem to reduce plaques. However, despite 30 years of research, no one has been able to show that reducing these plaques has any effect on the progress of the disease.
More to the point, the two trials run by Biogen, which measured clinical signs of disease, found that aducamumab didn’t affect the patient’s illnesses. It didn’t slow down or reverse the inevitable course of Alzheimer’s disease.
The FDA’s own outside panel of experts evaluated the evidence and strongly rejected aducamumab. (10 of 11 voted to reject it, and one panelist was uncertain.) The panel found that not only was there no clinical benefit, there was also a significant risk of harm, including dangerous swelling in the brain. About one-third of patients experienced these risks, and 10% of patients had to stop treatment because of adverse side effects.
And yet in July of 2021, in a nearly unprecedented action, the FDA approved the new drug. Three of the committee members resigned in protest.
Somehow, Biogen convinced the FDA to approve aducamumab based on the drug’s effect on a surrogate endpoint: the level of amyloid plaque in the brain. One could argue that this is similar to approving statins based on their effect on cholesterol levels: by reducing cholesterol, we can reduce the risk of heart disease. The analogy might be apt, but there’s a huge difference: we have data showing that lowering cholesterol does indeed reduce the risk of heart disease. In contrast, despite decades of study, we still don’t have any data showing that reducing the levels of amyloid plaques slows down or reverses Alzheimer’s.
2. A failed hypothesis. This leads to the second reason why the FDA’s action is such a disaster. For 30 years now, the Alzheimer’s community has pursued the “amyloid hypothesis,” which asserts that the buildup of amyloid plaques in the brain is the primary cause of Alzheimer’s. This was considered a huge breakthrough when John Hardy first proposed it back in 1991, and hundreds (perhaps thousands) of papers have been published since that time, exploring this hypothesis.
Over 100 drugs have been developed and tested for their ability to reduce plaques, and some of them (like aducamumab) do indeed reduce plaque levels. Unfortunately, none of them slowed down the course of the disease, so they never obtained FDA approval.
After 30 years of effort, it’s clearly time to recognize that the amyloid hypothesis is a failure. And yet the Alzheimer’s research community continues to cling to it, despite all the evidence that targeting plaques simply doesn’t work to treat the disease.
The FDA’s approval, over the objection of its own experts and a big outcry from the biomedical research community, will only breathe new life into this failed hypothesis. Even more unfortunate is that, by approving a treatment based on a surrogate endpoint, the FDA is now encouraging drugmakers to keep focusing on plaques, which will starve any efforts to find other causes–and other potential treatments–for this devastating disease.
This leads me to the third reason why the FDA’s approval of aducamumab is a disaster.
3. Greed wins. Why did Biogen work so hard to find some shred of evidence that they could use to convince the FDA to approve their new drug? The answer can be found in the price that Biogen set for the drug: $56,000 per year. As the editors of JAMA Internal Medicine have pointed out, if even one-sixth of Alzheimer’s patients in the U.S. alone were to take this drug, the annual cost would be $57 billion, which is far greater than the cost of all Medicare part B drugs combined in 2018.
In other words, aducamumab’s costs could bankrupt Medicare. Or to put it another way, Biogen doesn’t seem to care if Medicare goes bankrupt, as long as they can grab some massive profits.
What is still mysterious is why the FDA decided to overrule its own advisors. The FDA’s defense seems to be that they will require Biogen to continue collecting data “to verify the drug’s clinical benefit.” But they are giving Biogen 8 years to collect this data. That’s 8 years during which Biogen will reap massive profits, Medicare might collapse under the strain, and Alzheimer’s patients will continue to suffer.
In October, the FDA announced an investigation of its own approval process for Aduhelm. This seems rather bizarre: if the FDA suspects there was “improper contact” between Biogen and its own internal staff, then it should simply withdraw approval for the drug until the investigation is complete.
4. This whole affair is taking cruel advantage of a vulnerable, desperate group of patients. Finally, perhaps the worst aspect of this whole fiasco is how cruel it is to Alzheimer’s patients. As Dr. Jason Karlawish explained in JAMA Neurology, even though he disagrees with the FDA’s decision to approve this drug:
“I must preserve and protect each patients’ autonomy. One way I do this is by being teacher to patients and their caregivers so they can make choices about how to live well with this disease. I cannot deny them the choices the health care system gives them. Aducanumab is now a choice.”
Karlawish goes on to write that he will explain to patients that the benefits are uncertain, and the risks of brain swelling and other bad side effects are very real. But if the patients choose to try it, he will reluctantly prescribe Aduhelm.
We don’t have any effective treatment for Alzheimer’s, and it is a devastating illness. Patients and their families are likely to be desperate, and the mere fact of FDA approval will give them hope. I’ve no doubt that many will want to try Aduhelm, despite the risks. Giving them false hope is simply cruel.
And don’t forget that Biogen halted its own trials of Aduhelm due to “futility.”
The FDA made a huge mistake in overruling its expert panel and approving an Alzheimer’s drug that just doesn’t seem to work, that is outrageously costly, and that might cause serious harm to some patients. Let’s hope that this decision can be reversed. The world needs a safe and effective treatment for Alzheimer’s, and for now, we simply don’t have one.
