Controversy has swirled around aducanumab, an experimental drug developed by Biogen, long before the FDA approved it on Monday to treat early-stage Alzheimer’s disease. The agency now finds itself under scrutiny in a situation with no good outcome.
There were defensible arguments for approval, one of which is that until now there has been no disease-altering therapy to offer to individuals with Alzheimer’s or their families.
But that is not a problem the FDA can solve. Its decision should have been based solely on the drug’s safety and efficacy. But it wasn’t. Public comments from a broad spectrum of scientists and physicians over the past few weeks and months, including the FDA’s own panel of experts, have made it clear that the data needed to back up approval were simply not there.
Aducanumab is marginally effective at best. Only one of the trial groups outperformed the controls, and then only barely. Aducanumab also comes with possibly risky side effects due to brain swelling. Perhaps most important of all, however, aducanumab can never be made widely available. It is far too expensive: the company set a wholesale price of $56,000 per year. Yet, given the fear of Alzheimer’s disease, millions of U.S. residents over age 65 will surely want it. This will only serve to emphasize the disparities in care accessibility that our system is already struggling with. Were Medicare to begin coverage, the projected costs of treating all eligible recipients would quickly overwhelm the resources of the system.
How did we get here? Aducanumab can clear the brain deposits known as amyloid plaques, but there is strong evidence that amyloid plaques do not themselves cause Alzheimer’s disease. For evidence, look no further than the poor performance of virtually every anti-amyloid drug investigated to date. Why are we investing hundreds of millions of dollars each in dozens of human trials based on the same basic idea?
Drug development is expensive and fewer than one in ten drugs that start Phase 1 clinical trials end up with FDA approval. One would think that the savvy business managers at large pharmaceutical companies would have stopped the process of aducanumab development before they ramped up for parallel Phase 3 trials, but they did not. Why? The answer to this question does not lie in public health; it lies in stock price.
Biogen realized that if it admitted failure in Phase 3, it would pay a steep price on Wall Street. For evidence, consider its share price from December 2018 to December 2019. During the first six months of 2019, Biogen stock lost over 22% of its value. By the end of the year, however, much of that loss had been recouped. These downward and upward swings did not happen gradually over weeks or months; they happened over the course of just a few days.
The sharp downturn came on the heels of the announcement that the trials of aducanumab were being halted because the trial oversight board had determined that continuing would be futile. The upturn came over a few days in late October 2020 when, to the surprise of many in the field, the company announced that it had reexamined the trial data and decided to file for FDA approval. On Monday, after the FDA announced its approval for aducanumab, the company’s share price rose almost 40%.
The message is simple: Wall Street wants to keep the good news coming; don’t ever let them smell your fear.
Biogen and other pharmaceutical companies are an indispensable part of the search for a cure for Alzheimer’s disease, but their reasons for joining the effort differ from ours as health care consumers. The legally mandated mission of any publicly traded pharmaceutical company is not to cure disease, or even to help people feel better. Their mission is to make money.
Classical economists would argue that this is just the market being efficient — extracting products for the treatment of Alzheimer’s disease in the most cost-effective ways. Unfortunately, since these companies no longer perform their own basic research, they build their drug-development houses on shaky foundations. No matter how avidly they read the literature, they are missing a vital perspective on the drug development process. Financial markets, after all, care little for the slow, costly grind of basic research.
Biogen was forced to paper over weak science with intense lobbying. With the help of advocacy groups that they financially support, such as the Alzheimer’s Association, the FDA was pressured to go against the advice of its own analysts. In future writings, we will have more to say about how to respond to this FDA-industrial complex, but any likely solution lies in speaking in the only language a publicly traded company understands: money. Biogen saves billions of R&D dollars each year by piggybacking on the NIH-funded university laboratories for their basic research. Convincing the industry to do more basic research is hard, but it’s important to be clear-eyed about the fact that the folks in the front offices of many biopharma companies really don’t care if we ever find a cure for Alzheimer’s disease as long as they make money.
The public is starting to lose patience with the biomedical establishment. In approving aducanumab, the FDA was likely responding to this pressure. Sadly, as the cost and relatively poor performance of the drug become evident, trust in the FDA — and government in general — will erode. As hard as it would have been, disapproval was the correct decision. The FDA needed to send a clear and unambiguous message to the industry that it needs to give up its love affair with anti-amyloid approaches to Alzheimer’s disease. Such a message would have a been a bitter pill for the pill makers to swallow. But it would have been a major step in the long journey towards a cure of Alzheimer’s disease.
Karl Herrup is a professor of neurobiology and an investigator in the Alzheimer’s Disease Research Center at the University of Pittsburgh School of Medicine and author of “How Not to Study a Disease: The Story of Alzheimer’s” (MIT Press, October 2021). Jonathan Goulazian is a senior at the University of Pittsburgh majoring in neuroscience and economics. The opinions expressed here are theirs and do not necessarily reflect those of their employers or institutions.