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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/
______________

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

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http://www.theneuroethicsblog.com/2020/08/alzheimers-disease-and-fda-two-things.html

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