When I learned of the Food and Drug Administration’s approval of aducanumab (Aduhelm) for Alzheimer’s disease, I was struck by the parallels with the agency’s approval of tacrine (Cognex) in 1993, the first drug approved for Alzheimer’s which was later removed from the market.
As a young scientist at the National Institutes of Health studying Alzheimer’s disease in the late 1980s, I — and many of my colleagues — focused on a substance called acetylcholine. It is a neurotransmitter that is important for attention and memory. Scientists had found that a large hub of nerve cells that make acetylcholine showed severe damage in people with Alzheimer’s disease. The hope was that increasing acetylcholine in the brain could ease Alzheimer’s symptoms, at least for some time, much as dopamine replacement helps people with Parkinson’s disease.
Pharmaceutical companies built on this work to develop drugs generally called cholinesterase inhibitors that increased acetylcholine in the brain by inhibiting the enzyme that breaks it down, allowing more of the neurotransmitter to stay around to stimulate nerve cells.
The FDA’s approval of tacrine in 1993 surprised me, given what I knew about the drug. The FDA had not found evidence of effectiveness in two rounds of review. The drug’s sponsor, Warner-Lambert, and the NIH funded another drug trial and, with new tests and statistical maneuverings, its results were deemed “positive.” An analogy could be made to “teaching to the test” for students, or giving a kid who can’t read a passing grade so the school can have another “positive” — a higher pass rate.
The FDA approved a related drug, donepezil (Aricept) in 1996, which supplanted tacrine, as it was safer and its once-daily dosing was more convenient than the four daily doses recommended for tacrine. (Tacrine was discontinued in 2013, as it was shown to damage the liver.) Despite donepezil’s questionable effectiveness, it became a blockbuster, bringing in revenues of more than $1 billion annually. This peaked in 2010 with more than $3 billion in sales.
Just as the focus in the 1980s and 1990s was on drugs that targeted acetylcholine, the Alzheimer’s-industrial complex, as I came think of it, then coalesced around the brain protein known as amyloid as the next target for drugs. Corporations, nonprofits, and governments invested billions of dollars toward developing drugs and tests, something the late Sharon Begley called the Alzheimer’s “cabal” in STAT.
Political pressure to approve tacrine was massive, just as it was with Aduhelm. And as with Aduhelm, the Alzheimer’s Association — aligned with its corporate donors — pushed for approval. And that’s what the FDA did, the third time around, despite questions about whether it actually helped people with Alzheimer’s disease or just slightly bumped up some numbers statistically on tests.
In the late 1990s, when I worked at the FDA, a colleague mentioned “approval by the Wall Street Journal.” I looked up editorials in the paper showing a yearslong drumbeat with op-eds entitled “Requiem for Alzheimer’s Patients” and the like after the FDA initially found the evidence for tacrine wanting.
In April 2021, before the aducanumab approval, the Wall Street Journal’s editorial board wrote a piece with the headline “The Battle Over an Alzheimer’s Treatment: Biogen’s promising drug is caught in the FDA’s political and bureaucratic limbo.” More telling is the Journal’s headline on its story about aducanumab’s approval on June 7, “Biogen’s Alzheimer’s Drug Is a Wall Street Winner, Controversy or Not.”
The academic wrangling on how much of a real difference donepezil and subsequent copycats made in the lives of people with Alzheimer’s continued for years. One could often predict a doctor’s or researcher’s answer if one knew whether or not they were getting paid by the corporation making the drug, although it was often difficult to know, as this was not always disclosed, including at the NIH.
Several years after the approval of donepezil and related cholinesterase inhibitors, the American Geriatrics Society made this treatment recommendation: “Although some randomized control trials suggest that cholinesterase inhibitors may improve cognitive testing results, it is unclear whether these changes are clinically meaningful. It is uncertain whether these medicines delay institutionalization, improve quality of life or lessen caregiver burden.”
In Alzheimer’s disease (and any illness), what’s needed are treatments that make a difference in people’s lives, not just “statistically significant” changes in numbers on a test. It makes sense that donepezil and related drugs, which have mild stimulant effects, might help focus attention during a memory test, but this isn’t going to make a difference in how well individuals can help care for themselves. An article published recently in The Lancet Psychiatry makes a similar point on “the need to show minimum clinically important differences in Alzheimer’s disease trials.”
The authors note that by neglecting to define such minimum differences, drug company sponsors “are motivated to power trials to detect statistical significance for only small and potentially inconsequential effects …”
With the statistical resurrection of an Aduhelm trial and the subsequent change in what would constitute a passing grade, the FDA made a decision to approve the drug, perhaps with an additional 21st century twist: the billions of dollars invested in the amyloid juggernaut may have made it too big to fail.
Susan Molchan is a psychiatrist currently practicing psychiatry in Bethesda, Md., and a former program director at the National Institute on Aging for clinical trials, biomarkers, and neuroimaging in Alzheimer’s disease.