Alzheimer’s Disease and the FDA: Two Things To Watch

By Henry T. Greely

Image courtesy of the NIH on Flickr
SARS-CoV-2, Black Lives Matter, and American presidential politics may be the most important things happening—for reasons neuroethical and beyond—but they are not the only things happening that may prove important for neuroethics. Alzheimer’s disease, for example, has not gone away. The U.S. Food and Drug Administration (FDA) recently made one decision about Alzheimer’s disease and will soon make another, each of which may well have neuroethical implications.1

On May 28, 2020, the FDA approved a radiopharmaceutical called Tauvid, or flortaucipir F18, for diagnosing Alzheimer’s disease.2 This compound attaches to sites in the brain where the tau protein has formed clumps, the so-called “tangles” that are one of the two physical signs necessary, along with the presence of dementia, for a diagnosis of Alzheimer’s disease. But the compound not only attaches to tau tangles; it also contains a radioactive isotope of the element fluorine, Fluorine-18. Fluorine-18 quickly decays into oxygen-18 by (97 percent of the time) giving off two positrons.3 The effects of these rapidly annihilated positrons can be detected by Positron Emission Tomography: PET scans. That means that tau tangles inside a person’s brain can be “seen” on the computer-generated imagery of a PET scan.

You may recall that I said tau tangles were one of two necessary physical signs. The other sign is the build-up of “plaques” on the outside of the membranes of brain neurons of a peptide (essentially a small protein) called beta-amyloid 42. The FDA approved three different radioligands to allow PET scans to detect these amyloid plaques, in 2012, 2013, and 2014.4 With the addition of PET scanning for tau tangles, people can now be diagnosed with Alzheimer’s disease without the need to remove a piece of their brains, either at autopsy or through a living brain biopsy.

Plaque and tangles do not spring up overnight but grow over many years before symptoms appear. A person whose brain is clear of either amyloid plaque or tau tangles will not be diagnosed with Alzheimer’s disease anytime soon. How soon before the person shows symptoms? We don’t yet know but probably one or more decades, not one or two years. On the other hand, the presence of tau tangles and amyloid plaques does not mean that someone will be diagnosed with Alzheimer’s disease; it is not rare to find, on autopsy, that people without dementia have substantial amounts of tangles and plaque.5 The presence of tau and plaque, however, surely changes the odds of a diagnosis. We do not yet know by how much but, with the scanning now broadly available, we should before long. Although the FDA only approved Tauvid (and its amyloid predecessors) for diagnosis, under the off-label use doctrine, doctors can prescribe FDA-approved drugs (including radiopharmaceuticals) for any purpose they choose.

A PET scanner
Image courtesy of Wikimedia Commons
“That’s nice,” you think, “but what’s the neuroethical issue in better Alzheimer’s diagnosis?” The relevance is that these PET scans can be used not just to diagnose Alzheimer’s disease but to predict it, or, more accurately, to predict “not it.” And it is the ability to predict who will, might, or will not be diagnosed with Alzheimer’s disease in the relatively near future that raises neuroethics issues (as well as legal ones). Predicting future conditions, particularly diseases, lead to most of the ethical and legal issues in human genetics. Alzheimer’s disease may provide the first broad example of those issues from neuroimaging—and we will need to decide what to do about them. For example, we have GINA, the Genetic Information Non-Discrimination Act, for genetic discrimination (which provides some protection for people at known genetic risk for Alzheimer’s disease); will we need a NINA too, and, if so, with what terms?6

Right now, this is a “thing to watch.” When amyloid PET scans were approved for clinical use in 2012, I expected a surge of use for predictive purposes. It didn’t happen. Why not? PET scans aren’t cheap (around $3,000 or so) and are not covered by insurance. And the relevant professional groups and disease organizations opposed predictive use. But, also, an amyloid scan by itself was not that informative, especially as the build-up of tau tangles seems to correlate more strongly with the onset of the disease. Will Tauvid change things? My guess is that it will, at least partially, but we’ll see. (Or, I should say, we’ll see if we watch.)7

The second issue is even more tentative. One of the many frustrating things about Alzheimer’s disease is that despite decades of efforts and the expenditure of literally scores of billions of public and private dollars, we have no good interventions, preventive or therapeutic, for the disease. Much of that time and money has been spent chasing the so-called “Amyloid Hypothesis:” the extremely plausible idea that blocking the build-up of amyloid plaques could prevent or treat the disease.8 There are many good reasons to believe the amyloid hypothesis, from observational studies (no amyloid plaques, no Alzheimer’s disease), to genetic evidence, to the results of research on mice with (not very good) versions of Alzheimer’s disease. The problem has been that human trials of drugs that block or reverse amyloid plaque build-up in laboratory dishes or in mice keep failing in humans, over and over and over.

In March 2019 the biotech company Biogen announced yet another failure, saying it and its Japanese partner, Eisai, were stopping two large Phase 3 clinical trials of their amyloid plaque blocker, which they named Aducanumab. But then, in October—to everyone’s surprise—Biogen changed its mind and said a new analysis of the failed trials showed that the drug did work. They announced they would use these “failed” trials to seek FDA approval for Aducanumab. After a few delays, on July 8, 2020, it did. That gives FDA 60 days to decide whether to accept the filing or to reject it, summarily. If it does accept it, it will then go into the normal, multi-month (sometimes stretching into years) FDA review process.9

Amyloid plaque and tau tangles
Image courtesy of Wikimedia Commons
A possible FDA-approved drug to treat Alzheimer’s disease? That sounds great; how can there be neuroethics issues? Well, in the last few years, FDA has surprised many by approving drugs with poor evidence that they worked, especially when they were offered to treat serious diseases with no good treatments.10 In a sense, it is a regulatory approval parallel to “Right to Try” initiatives: if nothing is proven to work, why not let people choose to try something that might work? Alzheimer’s disease certainly qualifies as a serious disease with no good treatments, one that can leave patients (and patients’ families) with no hope.

Would approving Aducanumab be bad? Certainly not if you are a company seeking to sell it. But even the most optimistic view of the Aducanumab findings is that, at best, it may slow the decline, and, at worst, it may do more harm from side effects than any benefits. Alzheimer’s researcher Jason Karlawish has written about some of the issues around the drug, concluding that even if it works as well as Biogen urges, as the title of his article states “Aducanumab Isn’t the Simple Solution to the Complicated Alzheimer’s Crisis.”11

Are there neuroethics issue in an (undoubtedly) expensive but largely-to-wholly ineffective FDA-approved drug for desperate patients and families? Or in an arguably increasingly politicized FDA awarding a blockbuster drug to a firm and giving hope, baseless or not, to millions of Americans? Seems so to me.

At a time when our understanding of the brain is increasing at a high and accelerating rate, new science and new regulatory decisions will raise new issues, in neuroethics and other areas. This blog post looked at two that particularly interest me, and I hope will interest some of you. But I want its real lesson to be the value for neuroethics of always scanning the horizon, always looking ahead to see what challenges we may soon need to confront.


References 
  1. I have a long article on the ethical and legal implications of predicting Alzheimer’s disease. Greely, H. T. (forthcoming, fall 2020). Predicting Alzheimer’s Disease. The Elder Law Journal.   It goes into the issues in this blog post, and many more, in (too?) great detail. 
  2. FDA. (2020, May 28). FDA Approves First Drug to Image Tau Pathology in Patients Being Evaluated for Alzheimer’s Disease. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-image-tau-pathology-patients-being-evaluated-alzheimers-disease
  3. Wikipedia. Fluorine-18. https://en.wikipedia.org/wiki/Fluorine-18.  van der Born, D., Pees, A., Poot, A. J., Orru, R. V. A., Windhorst, A. D., & Vugts, D. J. (2017). Fluorine-18 Labeled Building Blocks for PET Tracer Synthesis. Chem Soc. Rev. 46, 4709-4773, 4711. https://doi.org/10.1039/C6CS00492J
  4. Zakaib, G. D. (2012, Apr. 9). FDA Approves Amyvid for Clinical Use. Alzforum. https://www.alzforum.org/news/research-news/fda-approves-amyvid-clinical-use.  Zakaib, G. D. (2013, Nov. 21). FDA Approves a Second Amyloid Imaging Agent. Alzforum. https://www.alzforum.org/news/research-news/fda-approves-second-amyloid-imaging-agent.   Jeffrey, S. (2014, Mar. 21). FDA Approves Third Amyloid PET Tracer for Alzheimer’s. Medscape. https://www.medscape.com/viewarticle/822370 
  5. Begley, S. (2016, Nov. 14). Their Brains Had the Telltale Signs of Alzheimer’s. So Why Did They Still have Nimble Minds? https://www.statnews.com/2016/11/14/alzheimers-brain-amyloid-plaque/
  6. See Kostiuk, S. A. (2012). After GINA, NINA? Neuroscience-Based Discrimination in the Workplace. Vand. L. Rev. 65, 933.
  7. The day before I submitted this post, news broke of research showing analysis of the amount of a particular form of the tau protein in a blood serum seems very accurate at diagnosing Alzheimer’s disease, and potentially at predicting it.  Belluck, P. (2020, July 29). “Amazing, Isn’t It?” Long Sought Blood Test for Alzheimer’s in Reach. N.Y. Times. Available at https://www.nytimes.com/2020/07/28/health/alzheimers-blood-test.html.  Blood draws, even with protein analysis, would be much cheaper and easier than PET scans. We’ll see if this holds up, but, in any event, it is at least several years from an FDA application, let alone approval.  
  8. See Begley, S. (2019, June 25). The Maddening Saga of How an Alzheimer’s ‘Cabal’ Thwarted Progress Toward a Cure for Decades. STAT. https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarted-progress-toward-cure/ (reviewing the history of amyloid hypothesis research and arguing that it stifled research in other treatments).
  9. On August 7, two days after I submitted the “final” version of this blog post, the FDA announced that it had accepted Aducanumab for review and that it had given it priority review status. This accelerated the date by which the FDA is supposed to make a decision on the drug to March 7, 2021. This is certainly not a final decision by the FDA to approve the drug but Biogen, and its investors, are surely encouraged.  Carroll, J. (2020, Aug. 7). Biogen Scores a Priority Review for its Alzheimer's Drug Aducanumab, Moving One Giant Leap Forward in its Controversial Quest. Endpoints News. https://endpts.com/biogen-scores-a-priority-review-for-its-alzheimers-drug-aducanumab-moving-one-giant-leap-forward-in-its-controversial-quest/.
  10. See Chen, C. (2018, Jun 26). FDA Increasingly Approves Drugs Without Conclusive Proof They Work. PBS.org. https://www.pbs.org/newshour/health/fda-increasingly-approves-drugs-without-conclusive-proof-they-work (explaining FDA has recently approved more experimental treatments despite limited evidence);  Brennan, Z. Sarepta Wins Controversial FDA Approval for First DMD Drug. Reg. Focus. https://www.raps.org/regulatory-focus%E2%84%A2/news-articles/2016/9/sarepta-wins-controversial-fda-approval-for-first-dmd-drug (noting FDA approved Sarepta even though outside experts said evidence of the drug’s efficacy was lacking).  
  11. Karlawish, J. (2019, Dec. 20). Aducanumab Isn’t the Simple Solution to the Complicated Alzheimer’s Crisis. STAT. https://www.statnews.com/2019/12/20/aducanumab-isnt-simple-solution-complicated-alzheimers-crisis/
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Henry T. (Hank) Greely is the Deane F. and Kate Edelman Johnson Professor of Law at Stanford University, where he directs its Center for Law and the Biosciences as well as the Stanford Center for Neuroscience an
d Society. He began serving a two-year term as president of the International Neuroethics Society in November 2017. He chairs the California Advisory Committee on Human Stem Cell Research; and serves on the Neuroscience Forum of the National Academy of Medicine; the Committee on Science, Technology, and Law of the National Academy of Sciences; and the NIH BRAIN Initiative’s Multi-Council Working Group, whose Neuroethics Division he co-chairs. And he likes playing (doubles) tennis even though he is, to be charitable, not very good.

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Greely, H. T. (2020). Alzheimer’s Disease and the FDA: Two Things To Watch . The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2020/08/alzheimers-disease-and-fda-two-things.html

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