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Alzheimer's Disease

A Brief Note About Aducanumab

There’s a big FDA decision coming up in the next few days: whether or not to approve the Biogen antibody for Alzheimer’s (aducanumab). I’ve had several people ask me what I think about this, and I can only refer them to what I said in 2019 and what I said late last year as well. Given the current data, I do not think that aducanumab should be approved. I don’t believe that Biogen’s clinical trials have really demonstrated efficacy against the disease, and the FDA briefing documents show that there are many people in the agency who agree with that position (see that second link above). The agency is supposed to consider efficacy and safety, and on this basis alone I think aducanumab comes up short.

There’s another huge factor that is not officially under the purview of the FDA (not directly, anyway). And that’s the huge pent-up demand for something, anything, that can treat Alzheimer’s. That is a moral hazard, as I’ve said many times over the years, because it puts pressure on regulators to approve things just to show that they’ve approved something, and it puts pressure on companies to try to push marginal projects over that regulatory line in hopes of reaping a huge immediate windfall from millions of desperate families. I don’t mind using the word “tragedy” for that outcome. That’s what it would be: a massive waste of money based on false hopes. Neither expenses nor hopes are on the FDA’s official list of issues to consider, but believe me, they’re real.

As always, I do not envy the FDA’s job here. They will face incandescent rage no matter which way they come down on this issue. But since that’s the case, why not face it for the right reasons? Reject aducanumab. Tell Biogen to go back and run a better clinical trial if they think it really works – they could have been doing that already, you know. Because as it stands now, there is not a convincing case that it will help anyone with Alzheimer’s disease.

Update: more at Stat, and at BioCentury.

65 comments on “A Brief Note About Aducanumab”

  1. biotechtoreador says:

    Clinical studies cost money that BIIB needs to repurchase shares so it can prop up its share price: after all, that’s the point of a pharmaceutical company….

  2. Bion says:

    What’s your take on Annovis Bio?

  3. Lane Simonian says:

    Spot on!

  4. Bo says:

    I will be interested to see the results of the tau targeting treatments that will be investigated as part of the DIAN-TU in an upcoming worldwide clinical trial. This was announced earlier this year (link: https://medicine.wustl.edu/news/international-alzheimers-clinical-trial-to-test-tau-drugs/). One drug of interest is the antibody E2814 (Eisai) that targets the microtubule binding region of tau for potential reduction in tau tangles associated with AD.

    1. aairfccha says:

      Interesting, sure, but you probably shouldn’t hold your breath. AFAIK a methylene blue derivative (also aimed at tau proteins) didn’t do too well in trials.

      1. rtah100 says:

        TauRx has announced that the activity of methylene blue is highly concentration dependent (seemingly something to do with its charge distribution affecting mode of action) and they are running new trials at much lower doses.
        https://taurx.com/the-science/clinical-trials/phase-3

        There is some good general TauRx information on tau as a target here, including a nice poster.
        https://www.targetingtau.com/

    2. Not-an-epidemiologist says:

      I don’t know — personally, I feel anti-tau antibodies are even more of a shot in the dark than anti-β-amyloid antibodies at this stage. We don’t even know the mechanisms of tau propagation (or even, categorically, whether this occurs at all in AD). This treatment is assuming that (a) tau aggregates are transmitted between neurons in a form that can be recognised and bound by anitbodies, and (b) that even if this is so, that an antibody treatment would stop this sufficiently, and (c) that stopping tau propagation is sufficient to make a difference in disease progression in any case.

      Drugs that prevent tau aggregation intracellularly might be the best of a series of bad bets in my book. However, we don’t even know if tau pathology is more causative of AD neurodegeneration than β-amyloid pathology, or even how the two are related. Hell, there’s still arguments about which comes first in pre-clinical staging. And for a disease that we’ve known about for over a century, that is depressingly nuts.

      (and, you know, the fact that far too many researchers are on either Team-Aβ or Team-tau is even more depressing. Talk about false dichotomies …)

      1. Radioactive Man says:

        Has any clinical trial looked at dosing an anti-A-beta drug and and anti-tau drug simultaneously? Would that be a sensible thing to look at?

  5. Simon says:

    But if they approve it, they can bask in the new CDC
    levels of credibility…

  6. Jake says:

    Re: Alzheimers, has there been any movement on the Porphyromonas gingivalis hypothesis?

    1. JasonP says:

      “Germ” cause of ALZ is a hotly debated subject.
      https://www.alzforum.org/news/conference-coverage/more-data-herpes-and-alzheimers-disease

      Dr. Leslie Norins put $1MM of prize money for anyone who can prove it.

      Alzheimer’s Germ Quest, Inc.
      https://alzgerm.org/

      No winner of that competition, but pizes awarded none-the-less.

      https://www.alzforum.org/news/community-news/alzgerm-challenge-no-winner-small-prizes-8-scientists

  7. edski says:

    I agree with your total statement. If approved, other companies holding trials much better than this in every other area will be compromised.

  8. anon the II says:

    I’m still trying to get my head around how an antibody, floating around on one side of the blood-brain barrier, manages to get rid of it’s target, floating around on the other side of the blood-brain barrier.
    I’m not buying the stuff about osmotic pressure or Le Chatelier’s principle.

    1. Anonymous says:

      It’s well demonstrated that it crosses the blood brain barrier and clears plaque. That is 100% demonstrated in all trials so far. What’s up in question is whether clearing the plaques themselves is actually useful in terms of clinical outcomes.

    2. johnnyboy says:

      I don’t think that aducanumab (or other antibodies without BBB-penetrating modifications) would cross the BBB to a significant extent in young, healthy people. In AD patients however, there is thought to be vascular dysfunction (vascular amyloid deposition, for one), which probably increase blood vessel permeability and allow the antibody to penetrate to an extent into the perivascular parenchyma. Evidence for such antibody penetration in humans is indirect (mainly from the evidence of plaque reduction), but in aged mice models of AD, penetration has been confirmed.

      1. DrOcto says:

        So you’re saying a symptom is required for the treatment to reach it’s target. And if it then starts to work? the treatment can no longer get in and symptoms return.

        1. Dr CNS says:

          No, you are not getting the BBB closed by the antibodies. Presumably, BBB deterioration gets worse.
          If the BBB gets weaker and the antibodies penetrate into the parenchyma, there’s all sort of blood-borne materials that can infiltrate the brain and cause further disease.
          How about closing the BBB as a way of treating AD or other neurodegenerative diseases?

  9. Sulphonamide says:

    I was told (by someone working on the Tau-targeting side) that people with AD have a more leaky BBB and this lets therapeutic antibodies through, albeit not desperately effectively. I don’t know enough to refute this assertion but would be interested to hear from experts. That the previous amyloid failures were caused by insufficient brain conc of the antibody, rather than the whole theory being bankrupt, seems to be a not unreasonable straw to cling to, though presumably one has to ignore the failure of small molecule secretase inhibitors for that not to sound decidedly fanciful.

    1. JasonP says:

      No that is part of the drug discovery process – figuring out the dosage to give that isn’t toxic and gets “enough” of the drug to the target to be effective. So getting stuff through the BBB to solve Alzheimer’s isn’t a 100% solved issue, but the things they are trying ARE getting through. I noted some time ago there was research on “carriers” or ways to fool the BBB to take up a drug by piggybacking it on something else the BBB recognizes as friendly.

      There is whole theory/side of this, suggesting leaky BBB causality. Best I can tell the champion of this theory is Berislav Zlokovic at USC.
      https://www.alzforum.org/news/research-news/even-without-amyloid-apoe4-weakens-blood-brain-barrier-cognition

      http://www.ncbi.nlm.nih.gov/pubmed/32376954
      http://www.ncbi.nlm.nih.gov/pubmed/32350425

      Now the experts can pick up where I have missed or left off.

  10. luysii says:

    Well, I’ve been there with drugs that don’t work (in a meaningful sense) for Alzheimer’s. Tragic is the right word. Cognex (tacrine) an anticholinesterase which presumably increases the supply of acetyl choline at the synapse was released to much positive press. I never saw it significantly improve anyone with Alzheimers disease, nor did any clinical neurologist of my acquaintance in a drawing area of over 1 million. The local academic institution used it as a marketing tool and said it was wonderful.

    So, of course, I’d give Cognex, hoping that this might be the single patient that it helped. But it never was, and I watched family after family change from hope to crushing disappointment.

    Hopefully another attack will work — https://luysii.wordpress.com/2021/03/25/the-science-behind-cassava-sciences-sava/

    Full disclosure — Lindsay Burns, a principal in the company is a longtime friend since her teenage years so I’m rooting for her and the drug. Unfortunately I think that even if it works, unexpected side effects will likely take it off the market.

    1. AQR says:

      In your experience, which are the best antidepressant/anxiolytic to use in Alzheimer’s patients? Is there any evidence that one mechanism might be superior to others?

      1. luysii says:

        AQR — I have been retired for some years, so my experience is out of date. My experience was that all the anxiolytics worsened the dementia in proportionally to their anxiolytic effects, ditto for the antidepressants. Hopefully better drugs are available presently.

        1. luysii says:

          What I said wasn’t clear enough. Worsen the dementia means that the individual becomes more confused when on the drug is present. When the drug washes out they go back to square one. The drug does NOT intensify the process causing the dementia.

          1. AQR says:

            Thank you.

  11. anonnymous says:

    My reckon that FDA will approve it. The situation is similar to when the Duchenne Muscular Dystrophy advocates pressurized FDA to approve the drug that showed bare essential efficacy?

  12. John Wayne says:

    It would be pretty funny if the FDA approved it, but no insurance company agreed to pay for it because it doesn’t work.

    1. JT says:

      Not funny. As Derek right points out, families of patients with dementia are terrified, desperate and are ready to try anything that offers to slow or reverse the progression of this horrible disease.

      I can forsee families mortgaging their homes, taking out loans and otherwise ruining their own lives financially for this drug, which appears to be offering nothing but empty promises.

  13. biotechreader says:

    The FDA is in a tight spot and the data is ambigous. All politics aside I think the best course of action is for the FDA to request a new clinical trial using the higher dosage.

  14. BL says:

    These are great points, but isn’t there a double standard here, especially when it comes to FDA approvals for cancer biologics? Aside from the checkpoint inhibitors, there have been countless monoclonal antibodies that were approved for cancers which show only marginal benefit. Or worse yet, many were approved with dubious statistical significance or risks that would be unacceptable in any other disease. And these are still being approved today. The rationale is that something — even a modest increase in survival — is better than the standard of care especially for advanced cancers with bleak survival statistics. Why shouldn’t Alzheimer’s patients have access to drugs under the same standard?

    1. JasonP says:

      We already have Acetylcholinesterase inhibitors and NMDA-receptor antagonists that fit those criteria! Oops! 😉

    2. David says:

      BL: “double standard” — it’s OK for FDA to approve a marginally effective agent, based on valid trials, conducted and analyzed in accordance with pre-specified methods. It’s not OK when the pre-specified analysis shows futility and then the company goes back after the fact, adds in more subjects who completed the trial after the trial had been formally ended by an oversight board, and finds (using a new analysis method that was invented after the fact just for this trial) that the trial wasn’t really a failure after all, but miraculously now does show a marginal benefit, and by the way the cases of brain edema weren’t really all that bad. Apologies for the run-on sentence, but that’s the only way to capture all the screwy aspects of the aducanumab data.

      1. Simon says:

        Good point. Heres an article on that and FDA scientists shilling for it..
        https://www.thedailybeast.com/fda-weighs-new-alzheimers-drug-but-benefits-are-uncertain?ref=home

  15. Derek Freyberg says:

    I don’t know how many of you watched “60 Minutes” last Sunday, where they reprised and updated a story on the “90+ Study”, a study by UC Irvine of the very elderly (though I’m not sure that being 90 counts as very elderly anymore). One aspect of the study is cognitive change, and a number of the study participants have made donations of brain tissue. My takeaway from the story was that the presence of brain anomalies such as amyloid deposition did not seem to be at all well-correlated with the presence of cognitive decline in life – they had brain tissue that was loaded with anomalies but where the person had suffered no cognitive decline before death. This does not seem to bode well for the likely success of aducanumab as a treatment, leaving completely aside Biogen’s shenanigans in the clinical trials.

    1. rtah100 says:

      This is not discussed enough!

      There is the famous nun study where many nuns had significant amyloid deposits on post-mortem / life everlasting but had functioned perfectly well as nuns up to death. Which could be attributed to an ordered life in a close community or just to a low bar to success! There seems to be little correlation between amyloid alone and cognitive decline. Also, more fundamentally, the neuropathological definition of AS is presence of amyloid plaques and tau tangles. If they define the disease, why are we only treating one of them?

  16. Ron says:

    Kinda of OFF TOPIC. Perhaps if/when FDA approves this–They will approve the use of Ivermectin to treat Covid19! MUCH more favorable data.

    1. An Old Chemist says:

      @Ron: In India, Ivermectin is being extensively used as a prophylaxis to ward off covid-19

      Goa Recommends Ivermectin to All Above 18 After Scientists Say Its Use Can ‘End Covid-19 Pandemic’.

      https://australiannationalreview.com/health/goa-recommends-ivermectin-to-all-above-18-after-scientists-say-its-use-can-end-covid-19-pandemic/

      1. zero says:

        That’s the kind of headline that should trip your bullshit detector.

  17. Tim says:

    This isn’t a statement about the usefulness and safety (or lack thereof) of this specific drug. I’m not a chemist or doctor or medical researcher in any way even remotely a subject matter expert on the drug.

    But generally I’m not sure I would necessarily consider pressure to approve a severe moral hazard. The FDA has built in incentive to not approve. Approve a harmful drug, and have that harm take place, and it gets a lot more negative attention then if you fail to approve a drug that could have saved lives or otherwise produced better outcomes for people.

  18. Cassandra says:

    Is this commentary a bit of a double standard from Mr Lowe? Not enough efficacy evidence for Aducanumab to “start printing money” but the same goose is walking around having participated in a phase 3 trial for an experimental vaccine with no medium to long term efficacy or safety data! Laughable.

    1. Kevin H says:

      Come back when aducanumab has unambiguously strong safety and efficacy data over any term – short or long – and costs $50 per patient for a full course of treatment.

      Otherwise, you’re being very silly.

    2. Dolph says:

      Moron.

  19. Albert says:

    It should either work or not, no matter how desperate people are. But it’s clear that nowadays too many outside factors can affect science and scientists, especially those who are working in the regulatory agencies, so I will not be surprised if it’s approved.

  20. Jin says:

    If this gets approved by the FDA, they might as well as approve Praying as a valid cure for all diseases

    1. metaphysician says:

      Given the aforementioned “nun study”, praying probably has better evidence for efficacy against Alzheimers than aducanumab. . .

  21. formerBiogenEmployee says:

    Approved!

    1. KS says:

      What dah fuh. Evidence matters no more.

  22. Old Snake Eyes says:

    RIP Evidence Based Medicine

  23. Oligodendrocyte expert says:

    How do you spell boondoggle? Is it FDA or is B-i-o-g-e-n??

  24. Oligodendrocyte expert says:

    Oops….or is it B-i-o-g-e-n. Poor QC when I’m pissed off, I guess.

  25. Lambchops says:

    Since there was some comment upthread about what payers may think I’ll direct those people to ICER’s draft assessment report for some initial thoughts: https://icer.org/news-insights/press-releases/icer-releases-draft-evidence-report-on-aducanumab-for-alzheimers-disease/

    Somehow can’t see Biogen slapping on a $2500 per patient per year price tag . . .

  26. Thoryke says:

    I think we still have swag somewhere from the Reminyl launch; as far as I know, the actual impact on AZ progression was not nearly as durable…

  27. anonnymous says:

    Lifting false hope for some, and hype for others. Efficacy no longer matters! Pretense and rumor that it is good, is great enough for FDA to approve it. And, I spent 30y of career in med. chemistry!!!!!

  28. BernYeeBankAccounts says:

    Its a sad day for medicine, for the FDA and their credibility and a sad day for the patients and their families who will not receive any benefits while having their bank accounts drained.

    And if the antibody is crossing the BBB because its “leaky” guess what?, so are the microbial pathogens- whatever they are.

  29. Daren Austin says:

    Open season on pharmacology-based approvals on central acting mAbs now? Aducanumab is a great mAb. Potent, reaches target (even with 300x dilution) and engages appropriately. But pharmacology does not equal efficacy. Will they use the same criteria for alpha synuclein – the protein was removed in Parkinson’s and UPDRS may or may not have moved? Asking for errr Biogen?

  30. myma says:

    I called up my father this afternoon to very specifically tell him not to bother with this one for my mother. I told him about how they did the advanced math on the clinical trial results, the price tag, and the company’s own stock value.

  31. Mandark says:

    I just hope the EMA will not follow suit.

    1. sgcox says:

      Also wait for NICE: – yeah, twenty pee sounds about right.
      Stock up popcorn and enjoy Daily Something hysteria.

  32. Isidore says:

    How nice this FDA approval, coming as it did on the 25th anniversary of the approval of Biogen’s Avonex.

  33. Albert says:

    I thought the purpose of the clinical trial is to evaluate whether targeting b-amyloid will treat AD, but it turns out that it’s to see whether targeting b-amyloid could treat b-amyloid, no matter if it treats AD.

    1. Argyreia says:

      At this point it seems like basically cosmetics for brain scans and little else.

  34. Dolph says:

    It really happened. The FDA had its Trump-moment…

  35. Lothar Lindemann says:

    The decision should have been deferred until a new trial either confirms or refutes an efficacy signal – not before. We will see if the FDA will be able to take it off the market again in case the post-approval committed trial turns out negative.

    There should be a detailed review on sponsors, lobbying groups etc. who were involved in pressuring the FDA. The scientific advisors to the FDA recommended 10:0 (with one abstinence) against approval.

    And the price tag in the US is supposedly 56 k USD / year.

  36. dearieme says:

    “But since that’s the case, why not face [incandescent rage] for the right reasons?”

    Well put. I must say that Science , capital S, is flourishing while sciences, small s, are languishing. It makes me want to spit.

  37. William M says:

    I have not been able to find out is how often this treatment is supposed to be used? Is it every 6 months for life? I know the trials were for a short period but I suspect this is a long term therapy. At 57K/yr for life this would possibly bankrupt Medicare.

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