Ask the Doctor: September 2021
Q. What does the new Alzheimer’s disease drug do, who is it for, and why is it so controversial?
A. Aducanumab (Aduhelm) is the first new U.S. Food and Drug Administration (FDA)- approved drug to treat Alzheimer’s in almost two decades. The controversy for the approval has been widespread, with good reason. First, we still do not know what actually causes Alzheimer’s disease. It’s known that there is an abnormal accumulation of beta-amyloid protein in the brain in people with Alzheimer’s. These sticky protein fragments can disrupt communications between brain cells. But does this cause the cognitive decline? Or does the decline cause the buildup? That and more about beta-amyloid is not fully understood, which is why it’s called “the amyloid hypothesis.” I have long been in the camp that does not believe that amyloid is the causative agent in Alzheimer’s. I have seen many brain samples from older adults with a great deal of amyloid but no history of memory problems. That observation alone suggests that there is more to the mechanism than amyloid. Moreover, multiple drugs have been shown to clear up beta amyloid on MRI scans, but getting rid of the toxic proteins did not lead to any cognitive benefits. As has been publicized, this drug approval went against the recommendation of the FDA’s Advisory Committee experts—none of them thought it should be approved. But the FDA does not have to follow the advice of this committee. After two years of trying to convince Americans to trust the scientific process and review, the FDA is now telling us that scientific review is optional or can be completely disregarded. This mixed message is not going to do anyone any good and may damage the FDA’s reputation beyond this one drug.
Among the many issues raised by experts is the lack of consensus on the meaning of “minimum clinically important difference (MCID)” in Alzheimer’s disease trials. MCID is the least amount of improvement that is needed to justify that the treatment has a benefit. Two Phase 3 clinical trials evaluating aducanumab were halted because the drug maker, Biogen, said the drugs would not likely meet the study’s objectives. Researchers scoured the data and subsequently reported that higher doses of the drug cleared beta amyloid. That led to the FDA fast-track approval. But again, there was no clinical evidence showing meaningful change in people’s cognition. On a 0-18-point scale, people in the trial with mild cognitive impairment (MCI) who took the higher doses of the drug had a mere 0.39-point advantage. People on lower doses fared no differently than those taking a placebo. There are also side effects to consider. In two clinical trials, about 40% of trial participants who took the drug experienced painful brain swelling, with symptoms that included headache, dizziness, visual problems, and vomiting. Some experienced brain microhemorrhages. Fall risk is certainly increased. The FDA’s go-ahead was conditional, requiring the company to conduct Phase 4 follow-up studies to monitor for serious reported side effects, including brain swelling and bleeding. In July the FDA tightened its prescribing guidelines, narrowing who should receive the treatment to people with early-stage Alzheimer’s disease with mild cognitive impairment. Aducanumab is an antibody that requires monthly intravenous infusions and regular MRI scans, which require lying motionless in a confined, noisy space. Such procedures are difficult for people with dementia who also often have anxiety.
Decisions about medications require consideration of risks and benefits. Some side effects could be tolerated, depending on benefits. This drug has no known benefits, so any side effects are not worth risking. Yet the FDA approved a drug that will cost $56,000 per year. Though costs will vary, people can expect to pay out-of-pocket costs in excess of $10,000 per year, which according to the Kaiser Foundation is out of reach for many retirees. It is troubling to me that taxpayer money may go towards a treatment with no clear benefit. Additionally, it will only be available to very wealthy individuals, which only adds to the inequality in our country.
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