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Alzheimer's Disease

They Don’t Know

Well, Biogen has released more data on its Alzheimer’s antibody, aducanumab. The people (like me) who were doubtful (or worse) that they had enough to make a case for FDA approval remain doubtful. And the people (there are some) who think that it’s approvable haven’t changed their minds, either, from what I can see. Frankly, if you wanted it approved after the very limited information we had before, you’re probably not a mind-changing sort of person to start with, but that might be another topic.

As you may recall, Biogen had two Phase III trials going, Engage and Emerge, and both were halted back in March. They now say that one of these generated positive data on a re-analysis, and yesterday the company made their case that the difference was due to more patients getting the higher dose of the drug in the Emerge trial. But I honestly have a hard time seeing how this works. There was a protocol change during the studies that resulted in more patients getting the high dose, true – but after that change, sure, the high-dose patients managed to scrape over the line into statistical significance, but even the low-dose patients also showed better responses. Which makes no sense. That looks like an artifact to me; I don’t see any reason to assume that it isn’t, and I think that the burden is on Biogen to explain why it isn’t. The only way I can see making that case with a straight face is to run another trial with that hypothesis in mind from the start.

If Biogen is right, that new trial design would generate solid data that no one could brush off – a major triumph for the company and a major advance in Alzheimer’s therapy. If, though, these results are just accidental byproducts of squeezing the data too hard in a couple of halted trials, then no such signal will appear. This is why we run trials. When Biogen people stand up and make the case for aducanumab, they are (whether they are trying to or not) making the case for running a confirmatory trial. Not for getting the FDA to approve it as is.

Why not? Why not give those Alzheimer’s patients and their families hope? If it doesn’t work for Alzheimer’s, though, then aducanumab will likely do real harm to some people (all drugs have side effects) and do good to no one. And I think that the odds are better – much better – that it indeed doesn’t work for Alzheimer’s. Giving “hope” under these circumstances is, in my opinion, more like cruelty dressed up. On top of that, there is harm in making everyone pay for an expensive placebo as well. I would expect the drug to rapidly become one of the largest prescription expenditures in the country, landing especially hard on the elderly population (Medicare, the VA system, etc.) and it would be helpful, to say the least, if we did not do that on the basis of maybe-sorta-squint-hard data. Which is what we have now. It’s in the Scottish-court category of “Not Proven”.

No, the burden of proof is still on Biogen, and the way to provide that proof is to immediately start enrolling patients in a confirmatory trial. That’s what others have done under these circumstances (think Eli Lilly and solanezumab, their own anti-amyloid antibody), and by golly the confirmatory trials confirmed that these drugs didn’t work. If Biogen thinks that they can beat that track record, they should step up and do it. The company said last month that it would start re-dosing patients: have they? How many? Why shouldn’t we wait to see what happens to them? And if it’s worth going back to the people in the trial like this, isn’t it worth starting with a fresh cohort dosed in what the company thinks is the right way from the start, the way that patients would be in the real world after an FDA approval? Why not, exactly?

Here’s where I blow my chances of ever being employed by Biogen. The kinds of statements that some people at the company have been making – that aducanumab is ready for approval now, that the FDA would be remiss in not granting it, all that stuff – are to my eyes just irresponsible. Saying that you have an Alzheimer’s drug when you don’t quite know if you have one or not is wrong. As for the FDA, approving a drug when you don’t quite know if it will help anyone is wrong. And counterproductive, and a bad precedent, and expensive and all that other stuff, but first off, it is wrong.

That’s all I have to say.

64 comments on “They Don’t Know”

  1. Isidore says:

    I don’t find anything in the above to disagree with, except for the statement that the Biogen people are saying that the company has an Alzheimer’s drug when they don’t quite know if they have one or not. Since we have no way of knowing what they truly believe I suggest that we need to take them at their word when they say that they have a drug which works [“I believe the drug works […] I’m very excited about the prospect of getting the drug approved.” – Al Sandrock, Biogen head of research]. Whether Dr. Sandrock’s belief that the drug work is justified from the clinical data is, of course, the big question here.

    1. Hap says:

      I don’t know that it matters what they believe – it’s what they can prove (what they have evidence for) that should matter. What they claim shouldn’t matters for approval, but but it should matter for whether people believe them later on.

      1. Isidore says:

        The point, which I think is an important one, is that it makes a difference whether they are convinced based on their reading of the clinical data that they have a drug that’s effective or whether they are not sure that they have an effective drug but are pushing for approval anyway. If after a new clinical trial or after it’s been approved and used widely aducanumab turns out not to be effective, the former would have been an error based on overinterpreting or misinterpreting the clinical data, whereas the latter could be viewed as an attempt at deception. Unless there is clear evidence to the contrary, why attribute to deception what can be explained by error.

        1. Hap says:

          The problem is that the data is ambiguous at a point when it really shouldn’t be (at least for one to believe that one has an effective anti-Alzheimer’s drug). The effect is kind of capped, by the research results and it doesn’t seem very big.

          If the drug were someone else’s, would they being saying that this was an effective anti-Alzheimer’s drug?

          1. Isidore says:

            Obviously none of us has the answer to this question. Again, I have no idea what the Biogen people are really thinking, so I am taking them at their word that they believe their interpretation of the data, even though many others have serious doubts.

        2. Nameless says:

          But they cancelled the trial early because results were bad. This is not being “convinced based on their reading of the clinical data that they have a drug that’s effective”. It exactly the opposite.

  2. Hap says:

    If you don’t know (can’t know) that it’s an effective anti-Alzheimer’s agent but want to act as if you did know, then you’re being pretty dishonest.

    If it’s approved (with monitoring) then Biogen would be getting the federal government, insurance companies, and individuals to pay for its new P3 trial. Which would be great if they could get it, but seems bogus for everyone else (that “you shouldn’t have to pay to get into legitimate trials” thing).

    This (approving aducanumab with current data) seems like a very bad idea.

    1. loupgarous says:

      If Biogen gets NDA based on the same data which halted the EMERGE trial for futility, it not only makes marketing the new, extended Phase III trial, but with pharmacovigilance that FDA itself says only picks up ten percent of adverse events.

      We’d be depending on people who aren’t paid or required to document effects of a new drug to the extent required by a clinical research form to do so. With the fluoroquinolones, discovery of significant adverse effects (from tendon tears to aortic dissections) only occurred after approval in countries which had computerized patient records to sort for such adverse events after or during fluoroquinolone treatment (those were Taiwan and Canada).

      It’s one more argument for nationwide, standard-format searchable patient records everywhere (especially here in the US). We’d pick up more AEs, sooner, than we do now. We might even, after that, find out which drugs really work for which conditions – and learn that we have potential new therapies for existing diseases which are already on the pharmacy shelves that deserve clinical trials. For which Congress should consider paying CROs directly, instead of the current situation where “grandfathered” drugs get safety and efficacy trials in exchange for exorbitant pricing afterwards.

      1. Klaus Witte says:

        Just one addition on fluoroquinolone toxicity: The first reports on tendon ruptures appeared as early as 1991 in several publications from French authors, and the first review was published in 1996. https://www.ncbi.nlm.nih.gov/pubmed/8953819
        Reports from Taiwan and Canada appeared a decade later.

  3. anon says:

    The burden of dividends must be heavier than the burden of proof.

    1. John Wayne says:

      lol

  4. ScientistSailor says:

    Wow, Looking at that STAT piece, Sandrock’s quotes sound a lot like Republican’s blind loyalty to Trump…

    also:
    “Ehlers knew about the aducanumab results, “and I can tell you he was excited about it,” said Sandrock on Thursday. Ehlers’s decision to leave Biogen to join a venture capital firm was more about wanting to be “close to the science,” he added.”

    That’s funny, joining a VC firm to get closer to the science?

    I

    1. HFM says:

      “It is difficult to get a man to understand something when his salary depends upon his not understanding it.” – Upton Sinclair

      1. Churlish says:

        Exactly this.

      2. kidsneedbraces says:

        It’s difficult to get scientist to call BS on a ridiculous project when their paycheck depends on it too.

        1. AM says:

          Or (I think more commonly the case) their ego.

          (Ego issues: also one of the main reasons someone would post a superfluous political comment in a scientific discussion.)

    2. loupgarous says:

      I was about to say “that’s like joining a monastery to get laid”, but today that’s not such a great analogy.

  5. dearieme says:

    ‘even the low-dose patients also showed better responses.’

    And to think that some sceptical souls say that the Hawthorne Effect was bogus.

  6. Arteminsinin says:

    Often times it is not your gut (microbiome) determines your brain as the GV-971 team suggested. It is your butt determines your brain – where you sit decide what you want or try to believe.

  7. anon says:

    When you do not have that slam dunk evidence (granted that AD, Psychological diseases etc. where reading the clinical out come can be challenging!) and then you brood over your data, then it is no good. Biogen need to move on and call the shots for what it is and not s(h)it on it!

  8. “Drug” is a legal category, determined in the US by the FDA. If an investigational material does not yet have that approval, it is not a drug.

    1. loupgarous says:

      Title 21, Code of Federal Regulations, Part 312 – “Investigational New Drug Application” uses the term “drug” repeatedly to refer to what the FDA calls “investigational new drugs”. So FDA AND Congress (whose laws FDA enforces) use the word “drug” to refer to investigational new drugs frequently.

      The appeal to authority works better if you use our good friend Google before typing.

  9. Wavefunction says:

    Why does this sound like the classic case of torturing the data to get it to confess to anything you want?

    1. Nameless says:

      I heard no screams. Anyways, trials have to be approved by ethic committies.

      1. loupgarous says:

        Wavefunction’s right. What Biogen’s doing (on very shaky scientific ground) is saying that the same data that called for early discontinuation of a Phase III study for futility now indicate efficacy. It’s very close to rewriting the study analysis to fit the data. If FDA greenlights aducanumab now, every other pharma firm will want that kind of favorable treatment, and we get more drugs approved on shaky data. That’s not what we want, especially after CDER overruled an ADCOM to approve eteplirsen.

  10. Harrison says:

    The occurrence of ARIA-E in apoE4 carriers is over 40% at the high dose. While that’s better than I thought it would be, still… yikes. They don’t breakdown the ARIA-H by genotype, but that could push the overall ARIA rate in apoE4+ patients well over 50%. Just can’t see how this can be approved without some kind of black-box warning and/or requirement for genotyping.

  11. Churlish says:

    Have there been other examples of Ph3 clinical trials that were stopped for futility by the IDMC that were then used as the key clinical evidence in an FDA filing? If so, how did those filings go? That aspect alone is very surprising to me, beyond the posthoc analyses of these data.

    It seems pretty clear what Biogen’s regulatory strategy is: they intend to follow the path of Sarepta’s eteplirsen and gather political pressure to get this approved despite the available evidence.

  12. 10 Fingers says:

    “Saying that you have an Alzheimer’s drug when you don’t quite know if you have one or not is wrong. As for the FDA, approving a drug when you don’t quite know if it will help anyone is wrong. And counterproductive, and a bad precedent, and expensive and all that other stuff, but first off, it is wrong.”

    I could not agree more. And, if you all will forgive a sentimental, unabashed bit of echoing in agreement, I offer the following quote, the sense of which I also could not agree with more:

    “This is America…and here, right matters.”

    1. Hap says:

      I wish I believed that more than I do right now.

  13. Zee Bendelstein says:

    As we saw with eteplirsen, to name a high-profile instance, the FDA is not beyond approving expensive drugs with marginal/questionable/potentially non-existent benefit when there is enough pressure from select groups.

    1. Derek Lowe says:

      True, and I hated that one. But are they willing to more or less break the prescription drug health care system on the same kind of basis?

      1. Zee Bendelstein says:

        Could it be the straw that breaks the camel’s back?
        As you said the budget impact is large enough to cause strain across the system. May be the catalyst that has has wide-ranging impact on pricing control hurting real innovation more broadly.

  14. KazooChemist says:

    Interesting article today from Bloomberg on the recent fast pace of approvals at FDA.

    https://www.msn.com/en-us/news/money/fda-is-green-lighting-drugs-at-breakneck-speed-and-raising-alarm/ar-BBXRMmR

    1. loupgarous says:

      Good article. I was ready for campaign literature, now that Mike Bloomberg’s thrown his hat into the ring, but this was good, objective coverage. Thanks for sharing it.

    2. Dr meatloaf says:

      the people think they’re being denied access to “breakthrough” drugs because the FDA is being to careful so they say, ok fine, have atter, go ahead, we’ll have a few years of everyone getting fu##ed up on bad drugs and then there will be an uproar over the FDA not being careful enough.

      1. loupgarous says:

        Activism isn’t accountable. Activists (of whatever stripe or political polarization) get away with talking endless trash about Big Pharma, FDA, the “medical establishment”, whatever, but rarely are held accountable for the bad things that happen when they influence policy.

        The orphan drug lobby helped get us exorbitant prices on old drugs. Now, one wing of that lobby has created two tiers of new drug approval – the science-based approach, and the approach that leans on bad science, political maneuvering and skillful publicity. This is a problem with the FDA that nationalizing the drug industry will only make worse, because it places politicians and their nepots in greater power over new drug approval.

  15. loupgarous says:

    Biogen haven’t demonstrated a dose-response relationship that makes sense to an objective observer, but they’re telling FDA they have, anyway.

    At best, they’ve shown (possibly) the longer you’re onaducanumab, the better you do. It’s odd they’re pushing dose-response as a reason for their interpretation of the EMERGE study, when that’s not the obvious take-away. Derek’s right in that we could be seeing an odd artifact in those results. Occam’s Razor would cause an objective observer to look for that, first.

    Biogen needs new studies which control for possibly confounding variables, not retrospective analyses of study results tuned to make the data look better.

    1. loupgarous says:

      pardon the typo on aducanumab. Maybe my subconscious tried to wedge odanacatib in there, too.

  16. MattF says:

    ‘Observing a pattern in data’ is not inconsistent with ‘random’. In fact, one seat-of-the-pants criterion for randomness is that you will (eventually) see -every- possible pattern in a random data set. A pattern that looks significant can happen to come up early, and then disappear.

    1. loupgarous says:

      Especially troubling is seeing a pattern in data which originally caused the study to end for futility. It’s perilously close to rewriting the study hypothesis to fit the data.

      If Biogen sees things going on in that old data they didn’t before, new studies are the best way to prove it.

  17. Invisible man says:

    Just to put things in context, does anyone know what the NNT is for this treatment?
    (number needed to treat).

    1. Jeff Brender says:

      Not sure what the NNT would be, but the measured effect size (0.5) at 78 weeks for the primary endpoint CDR-SB test around 50% of neurologists would consider it clinically significant for the EMERGE trial. The effect doesn’t seem to be diminishing with time so if the EMERGE results are to be believed it would be definitely distinct somewhere within the second year.
      Part of the problem seems to be the recognized insensitivity of the Alzheimer’s impairment tests to distinguish between shades of mild cognitive impairment in the early stages of the disease
      https://www.alzheimersanddementia.com/article/S1552-5260(17)32112-X/fulltext

  18. Lane Simonian says:

    The bluster and the reality:

    Will the FDA approve aducanumab?

    Sandrock didn’t offer a prediction, but if the FDA rejects the drug now or asks Biogen to conduct another large clinical trial to collect additional data, it would mean “lots more people” would get Alzheimer’s without a drug to help them.

    “It’s in their hands now,” said Sandrock.

    “Expect a lot of statistical arguments from every side, but we think at the end of the day a marginal benefit, potentially impactful safety effects, numerous conflicting data points and an overall statistical mish-mash is unlikely to lead to regulatory validation,” wrote Brian Skorney, an equity analyst at Baird, in a note to investors in October.”

    Anti-amyloid drugs appear to have almost no benefit for non-APOE4 carriers and limited benefits for APOE4 carriers who are aleady declining more rapidly during the early stages of Alzheimer’s disease to begin with.

    https://www.alzforum.org/news/conference-coverage/second-look-ban2401-data-still-positive-despite-snafu

    https://www.ncbi.nlm.nih.gov/pubmed/29182706

    Back to self-post regulation.

    1. loupgarous says:

      “Sandrock didn’t offer a prediction, but if the FDA rejects the drug now or asks Biogen to conduct another large clinical trial to collect additional data, it would mean “lots more people” would get Alzheimer’s without a drug to help them.”

      Going from these data, if they get aducanumab, Alzheimer’s Disease patients will still be without a drug to help them. If they carry the APOE4 gene, they get a drug that has significant toxicity in that population and won’t help them very much. The risk/benefit ratio (as other posters have mentioned) for APOE4 carriers should require a black box warning in the only patient population that shows even weak efficacy for the drug. Primum non nocere.

      1. Lane Simonian says:

        Exactly right. Aducanumab may slow the rate of decline in APOE4 carriers to a rate similar to non-APOE4 carriers but with greater risks of serious side effects even with titration.

        I hesitate to add this since I am not good at math, but there seems to be a discrepancy in Biogen’s math (-0.40 difference in decline versus placebo, 23% slower rate of decline versus placebo in high dose group in Emerge trial).

        Aducanumab Placebo
        2.51 (mean CDR-SB scores at baseline) 2.47
        1.34 (decline from baseline) 1.74
        3.85 (total decline) 4.21
        53% (rate of decline) 70%

        A 23% slower rate of decline is barely significant, but a 17% slower rate of decline is probably not.

        Aducanumab likely does not slow down the rate of decline in non-APOE4 carriers, and likely minimally slows down the rate of decline in APOE4 carriers with the risk of severe adverse effects. If this is true, the FDA should not approve this drug or at the very least should require another trial.

        1. M says:

          The rate of decline changed by .4, from 1.74 to 1.34. So the rate slowed by 0.4 / 1.74 = 23%.

          1. Lane Simonian says:

            It appears that they did know.

            This is a mixture of extrapolation and actual numbers but what this anaylsis seems to show is that aducanumab has nearly no effect of non-ApoE4 carriers, but results in about a 25% slower decline in early Alzheimer’s disease in ApoE4 carriers.

            Decline in non-ApoE4 carriers at 78 weeks in early Alzheimer’s disease: 1 point
            Decline in ApoE4 carriers at 78 weeks in early Alzheimer’s disease: 2 points
            Percentage of ApoE4 carriers in placebo group: 70% (about)
            Percentage of non-ApoE4 carriers in placebo group: 30% (about)

            1 x .3= .3
            2 x .7=1.4
            Average rate of decline 1.7

            Decline in non-ApoE4 carriers on aducanaumab at 78 weeks: 1 point
            Decline in ApoE4 carriers on aducanumab at 78 weeks: 1.5 points (25% percent less decline from 2 points)
            Percentage of ApoE4 carriers in drug group: 70% (about)
            Percentage of non-ApoE4 carriers in drug group: 30% (about)

            1 x .3= .3
            2 x .25= .5
            2 – .5 = 1.5 x .7 = 1.05
            Average rate of decline: 1.05 + .3 = 1.35

            Most likely aducanumab has almost no effect on non-ApoE4 carriers and only slighlty slows down the sharper decline in ApoE4 carriers with potentially severe side effects. If these calculations and assumptions are correct, I don’t know how the FDA can approve aducanumab for Alzheimer’s disease.

  19. JasonP says:

    I just don’t get this idea that there is one ‘silver bullet’ out there that is going to be the sole ‘cure!’

    Seems like the solution is going to involve several aspects:
    * Clear out the trash (both AB & Tau)
    * Cease new production
    * Control / reduce inflammation
    * Create new connections or neurogenesis

    So the incessant search for one drug that fixes everything is unfathomable. That said, this drug DOES appear to solve one leg of the puzzle – taking out the trash. And for that biological result, we should celebrate.

  20. JasonP says:

    I just don’t get this idea that there is one ‘silver bullet’ out there that is going to be the sole ‘cure!’

    Seems like the solution is going to involve several aspects:
    * Clear out the trash (both AB & Tau)
    * Cease or at least slow new production
    * Control / reduce inflammation
    * Create new connections or neurogenesis

    So the incessant search for one drug that fixes this disease is unfathomable. That said, this drug DOES appear to solve one leg of the puzzle – taking out the trash. And for that biological result, we should celebrate.

    Now can we get on with combination therapies? Please!

    1. loupgarous says:

      @JasonP:

      “So the incessant search for one drug that fixes this disease is unfathomable. That said, this drug DOES appear to solve one leg of the puzzle – taking out the trash. And for that biological result, we should celebrate. Now can we get on with combination therapies? Please!”

      In Alzheimer’s Disease, amyloid formation has already done its work by the time a patient is diagnosed. The clinical studies (done by outfits like Lilly with half a billion dollars of skin in the game – motivated to find efficacy if it’s there to see) all show it’s futile to treat for amyloid formation – any improvement in patients’ health is hard or impossible to see. That includes the clinical data Biogen now says shows efficacy, but originally halted the EMERGE study for futility.

      A combination therapy including a amyloid antibody won’t work if the idea is to treat as many patients as possible with therapy most likely to help them. It just adds an expensive and potentially toxic drug to the treatment regimen for no reason.

      1. Barry says:

        Oh, Lily’s no less than $3billion into this game, I think

        1. loupgarous says:

          With sunk costs that high, if β-amyloid inhibition was provably an effective therapy, I’m sure Lilly wouldn’t have been shy about saying so. But the statisticians at Lilly were honest. The only thing I saw there I had doubts on was a flirtation with Bayesian analysis, which I’ve since changed my mind on – it was probably entirely appropriate to consider a Bayesian approach with the data we had.

          I wonder if Biogen isn’t justifying their backwards shuffle on interpretation of the EMERGE data with something like a Bayesian analysis – in which tweaking the study criteria post hoc is one of the hazards.

  21. Biogone says:

    I suspect that 95% of Biogen’s staff is thinking the same way, that this does not work and should not be submitted for approval, but Biogen’s management is ignoring them and pushing through regardless.

    Which also says something about Biogen’s culture, and whether anyone would want to work there.

    Think hard before you apply.

    1. anon says:

      If they offered more money than my current position, I’d still work there.

  22. Oligodendrocyte expert says:

    Al Sandrock’s comment that Michael Ehlers was excited about the data would be laughable if it were not so nefarious. It is pretty clear Mike Ehlers left Biogen because he was against this insidious attempt to approve something that will not help anyone, and will cause actual harm to many.

  23. DrOcto says:

    Why pay for another expensive clinical trial, when you can test the treatment in the general public at their expense (state + insurance companies yes, but who pays for those….), and furthermore actually profit at the same time.

    Poor ethics, smart management.

  24. dipthroat says:

    the highest 10-milligram-per-kilogram dose

    Apparently, nobody noticed that’s an insanely high dose for a chronic therapeutic treatment. And if you consider the price of Humira “fair”, then a aducanumab dose should cost 10-15 times more. And that, not even taking into consideration potential both acute and chronic side effects of such large doses of exogenous antibody injected

    Biogen is basically adopting the same successful tactic employed by Sarepta to force the approval ox Exondys 51 by the FDA.
    FDA, on the other hand, seems ever more keen to approve drugs with limited or no therapeutic effect at all (like brexanolone, vascepa, AR101 etc.)

  25. cynical1 says:

    Maybe if aducanumab gets approved Quincy Bioscience can get Prevagen approved and then we can do combination trials that will completely cure the disease.

  26. Ian Malone says:

    Thank you for saying this:

    “Why not? Why not give those Alzheimer’s patients and their families hope? If it doesn’t work for Alzheimer’s, though, then aducanumab will likely do real harm to some people (all drugs have side effects) and do good to no one. And I think that the odds are better – much better – that it indeed doesn’t work for Alzheimer’s. Giving “hope” under these circumstances is, in my opinion, more like cruelty dressed up.”

    I’ve seen a worrying amount of the “it’s cruel to patients to point out the flaws in this work” argument and it’s simply wrong. If you want to give people hope this way (and I’m not sure you should), tell them broccoli cures AD. It wont, but it might at least do them some good cardiovascularly (and start a healthy diet early enough in life and you might reduce your risk).

  27. Lane Simonian says:

    Lon Schneider, an Alzheimer’s researcher, provides one of the best analysis of aducanumab results prior to the CTAD conference.

    https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(19)30480-6/fulltext

    Here are some of his many important points:

    “Finally, the 23% relative difference on the CDR-SB is smaller than it might seem, corresponding to an absolute difference of about 0·4 CDR-SB points (based on their figure), which is of uncertain clinical relevance, especially in light of the lack of effect in the ENGAGE trial.”

    “Although Biogen claims that the positive results of the EMERGE trial were driven by greater exposure to a higher dose in the larger dataset, the effect could just as likely been due to greater worsening in the placebo group.”

    The placebo decline in the ENGAGE trial was 1.55 and in the EMERGE trial it was 1.74.

    Aducanumab may be of no benefit to one group (non-APOE4 carriers) and of minimum benefit with substantial risk to another group (APOE4 carriers).

  28. KH says:

    It’s election day here in the UK, and against that background aducanumab frightens me almost as much as British politics …

    We have an election that – at least in part – is pitting the interests of the young against those of the old. And a (believed) treatment for AD is something that very much would be in the interests of older voters …

    And then we have the leading British newspaper, with an appalling track record of medical reporting and wrong-headed lobbying. Pitching approval for aducanumab would be par for the course for the Daily Mail …

    I can see aducanumab becoming a political issue in the UK in the next few years, and unfortunately I could also see a Tory government going along with this, as it would play perfectly to their base.

    Worse yet, I could see such a government spotting a “clever” wheeze to partly address the costs of aducanumab by appropriating funds that are already going to Biogen for their other drugs, namely MS DMDs. Whilst clinically it would be obscene to trade a genuine gain in quality years for MS patients for at best a few months benefits in AD sufferers, it’s also clear that elderly voters fearing AD are a much larger and more reliable voting block and more politically valuable that young mothers actually suffering from MS.

    God I hate that the world has come to a state that such thoughts are possible …

  29. JasonP says:

    I must be horribly out of step, or thinking so far outside of the box that I’m in Lala-land?

    Why isn’t clearing out Amlyoid-Beta a useful goal and a clear target when it comes to Alzheimer’s? Sure appears as though, if the AB theory is correct, then it seems like mopping up this mess is a useful biologic function? What appears concerning is the thinking that ONE drug is going to fix the whole complex disease. I realize drug companys’ objectives are just that and it is hard to get away from the Block Buster driver.

    I suspect that curbing Tau is going to be key in reversing cognitive degeneration. But if the AB theory is correct, and AB triggers Tauopathy, why isn’t AB clearance useful target? Fix Tau and the AB driver/trigger still persists, then what?

    But further analysis of a VERY small sub-study with aducanumab suggests cleaning out AB might have positive effects on Tau and thus cognition.

    [i]The biomarker data elicited more positive reactions. Budd Haeberlein reiterated amyloid PET findings, reporting consistent plaque removal that correlated with dose. At 6 mg/kg aducanumab, SUVR dropped by 0.17 in both studies. At 10 mg/kg, SUVR dropped by 0.24 in ENGAGE and 0.27 in EMERGE, with group sizes ranging from 74 to 203 people. As previously reported, CSF p-tau and t-tau dropped dose-dependently in EMERGE, though group sizes here were tiny, ranging from 14 to 29 people in a trial that enrolled 1,638 participants total. In ENGAGE, p-tau and t-tau reduction were not dose-dependent, with group sizes ranging from 16 to 21.

    New in San Diego were tau PET data, using the second-generation tracer MK6240. Examining a medial temporal composite made up of hippocampus, parahippocampus, entorhinal cortex, and other anterior medial and lateral temporal lobe regions, the researchers found that the SUVR increased among people on placebo by about 0.09 over 14 months. For those on drug, the SUVR dropped by about 0.05 (see image above). The PET sub-study comprised 11 participants on placebo, 14 people on 6 mg/kg, and 11 on 10 mg/kg. The change in tracer uptake correlated inversely with dose.[/i]

    https://www.alzforum.org/news/conference-coverage/exposure-exposure-exposure-ctad-aducanumab-scientists-make-case

    But maybe, just maybe, once AB is cleaned out the innate immune system better responds to Tau?

    [i]In trials of aducanumab, as well as other anti-amyloid antibodies like BAN2401 and solanezumab, [b]the cognitive benefit seems to lag behind amyloid removal, hinting it could be due to a downstream effect.[/b] Defining the lag time between amyloid removal and a cognitive benefit is a priority for future anti-amyloid trials, researchers agreed. Stephen Salloway of Brown University, Providence, Rhode Island, who was the lead site investigator for the aducanumab trials, noted that although the cognitive benefit seen in the aducanumab trials was small, the data overall suggest an effect on disease progression. “We’re looking for a biological foothold we can build on,” he said.[/i]

    What? A biologic foothold? Not a Silver Bullet “cure?” This drug clearly doesn’t work, no demonstrative evidence seen yet. How long does it take for a drug to be designated “a cure?” If it is ineffective in 6-months? 12-months? 18-months? Then what, scrap it? It takes 20+ years to build up AB and trigger Tauopathy along the way, is it right to assume the cognitive benefits would only come immediately after dosing for period X?

    Once worked for an old chemist who taught me that even ‘bad” data had a story to tell and was useful in its own right.

    I get critical thinking and the scientific approach all as methods for preventing the sale of snake oil to the masses. It certainly has its place and is requisite, just hope the critical thinking doesn’t become so entrenched or habituated as to inhibit a look further into the data and what directions that may suggest

    I think this aducanumab data is such.

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