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Alzheimer's Disease

Aducanumab at the FDA

So it’s finally time for Biogen to sit down with an FDA advisory committee to look at their proposed Alzheimer’s therapy, the anti-amyloid antibody aducanumab. I last wrote about it here, back in December, and you know what? I haven’t changed my mind a bit, because (1) no new data have emerged (none were expected) and (2) I have not had a change of heart about the existing numbers. You can read the post and the links in it for more, but to put it briefly: I do not think that Biogen has demonstrated efficacy. I think that they have enough of a hint to run a better confirmatory trial, should they so desire, but they do not. They desire to go to the FDA, get the drug approved, and begin printing money.

And I would be all for a drug company printing money if they had a drug that could really alter the course of Alzheimer’s disease, but (once again) Biogen has not, in my opinion, demonstrated that they have anything like that. And I am definitely not all for a drug company printing money for something that really doesn’t do anyone any good. Because everyone knows what’s going to happen if aducanumab is approved: the pent-up demand for something, anything to treat Alzheimer’s is immense. Has been immense forever. There are a lot of people who have a family member with the disease, and they will demand treatment with the new drug that the FDA has approved to fight the disease. Who could blame them?

The FDA has released its briefing documents for the advisory committee meeting, and they took a lot of people by surprise (I was one of them). A key document is here, and a key section of it starts around internally numbered page 147 of the PDF. That the FDA clinical reviewer’s commentary on the efficacy data in the trial, and let’s say that he’s a lot more convinced than I am. Here’s a writeup on it at Stat, from Damian Garde and Adam Feuerstein.

There are two studies under discussion: 301 and 302. Broadly speaking, 301 (also known as ENGAGE) was negative, and 302 (also known as EMERGE) was positive, and the problem has been which result to believe and to account for why they’re different. There’s also a problem in that the data are incomplete; Biogen itself stopped work in the clinic when a futility analysis suggested that the antibody was not working, but revived their hopes with a post hoc analysis. (Here’s my writeup on this at the time). But the FDA clinical reviewer is very persuaded by the positive results, and believes that the negative trial was skewed by a population of fast-deteriorating patients. As I recall, Biogen’s rationale was that the negative trial looked better if you went for the subset of patients who got sufficient exposure; I don’t think they had advanced the fast-deteriorating-cohort explanation at the time, although I’d be glad to be corrected about that. Those rapid progressors seem to have mostly been in the high-dose arm of 301, and to be fair, that is where the greatest problem with the results showed up. And I mean “problem” in the sense of “worse than placebo”. But with the new analysis, the clinical reviewer is unbothered by 301, adds its good parts into 302, and concludes that the data are “robust and exceptionally persuasive”.

This is what goosed Biogen’s stock price the other day, as well it might. But even at the time, people were starting to notice the comments of the FDA’s statistical reviewer, which start on internally numbered page 247 of the same PDF. “Inconsistency on many levels summarizes the final clinical efficacy data from these trials,” is how things start off there, and the review goes on to note (among other things) the missing data at week 78 (due to the trial halt, and the time point that had shown the most evidence of benefit). “It is not justifiable to search 301 for patients who are most similar to 302“, it goes on to say, “because that may have selection bias and gives the impression that 302 is right and 301 is wrong, for which there is no justification not relying on post-hoc analyses“. Statements like that, and there are many, give one the strong impression that this reviewer had read at least a draft of the clinical reviewer’s work. Biogen, the review goes on to note, is advancing that post-hoc “rapid progressor” theory, but the reviewer says that after the completion of the study is too late to try to address that – and besides, an effective drug would be unlikely to fail so completely just due to rapid progressors in what was considered a study in people early in the disease.

Overall, the statistical reviewer says that the negative 301 study “should not be discounted without some extremely compelling reason (which there is not)”. Overall, after working through a number of the issues in the trial, the conclusion is that “. . .the totality of the data does not seem to support the efficacy of the high dose. . .the reviewer believes that there is no compelling substantial evidence of treatment effect or disease slowing, and that another study is needed. . .” The figures that follow in the PDF are worth a look too, if you’re into this sort of thing. They get into a great deal more detail than I have time or space to here in this post, but they constitute a sustained attack on the hypothesis that that aducanumab has shown efficacy and the interpretability of the data presented for that case.

The fact that Biogen stock jumped on the release of this document tells you most of what you need to know about the stock market (and about investing in biotech stocks in particular). You wonder how many people even got as far as the statistical review section before hitting the big green Buy button. Now, I have no idea of the internal politics of this FDA review – and since the place is staffed by humans, it will have politics. But this looks like a deeply divided briefing document – frankly, I can’t recall seeing one that was more at odds with itself. I don’t know what the advisory committee will make of all this, either, although it has to be noted that one of the AdComm members, David Knopman of the Mayo Clinic, has been recused by the FDA and will not sit. He was involved in the Biogen trials, which is indeed a conflict of interest – but he emerged from the experience as a critic of the drug who thinks that another trial is the only way to answer the questions about it.

I’ve been worried about this sort of situation in Alzheimer’s for years, and I’m not the only one. I really wish that we weren’t fighting out a big approval decision under such conditions, but here we are. I have no idea of what’s going to happen in the advisory committee, although the loss of Dr. Knopman increases the chance of a favorable vote. And beyond that, I have even less of an idea of what’s going to happen with the eventual approval decision. I don’t think that the FDA should approve aducanumab as it stands, in the same way that I don’t think that they should approve any drug for which the evidence is this equivocal. But the agency approved Exondys, so who knows what they’re capable of? We’ll find out. Lucky us.

And if they do, we’ll find out how many physicians will prescribe it, and how many insurance companies will pay for it. It would be something to see both of these groups hold the line, but I fear that the pressures will be just too great. Biogen is counting on just that, and I’m not happy about it.

22 comments on “Aducanumab at the FDA”

  1. Barry says:

    There are familial “experiments of nature” that implicate beta amyloid in AD. But it may be that–although they share symptoms–these are not the same disease at all.

    1. Ian Malone says:

      This certainly remains an open question: how different familial (dominantly inherited autosomal) and sporadic Alzheimer’s disease are. However if this was the only reason for amyloid targetting drugs to have a hard time in sporadic AD then we might expect them to fare better in familial AD, and so far they haven’t; solanezumab came out negative in its DIAN-TU arm this year. (There are actually a number of genetic angles; the dominantly inherited forms where the gene guarantees a carrier will develop AD if they live long enough, the APOE-e4 allele which increases the risk of AD but doesn’t guarantee it—in a normal lifespan at least—and a mix of other genetic factors with lower risk contribution that people are still unpicking, the first two both involve beta amyloid in some way.)

  2. Lambchops says:

    Intrigued to see what the decision is here.

    From a UK perspective I can’t help but be worried by this one should there be an FDA approval. It’s entirely conceivable that the EMA reaches a different decision on aducanumab (like the Exondys example mentioned by Derek), but in the post-Brexit world in theory the MHRA may be able to make their own decision on UK approval. The pressure to do so will likely be intense (we all know what the Daily Mail is like when it comes to Alzheimer’s, and the UK government will be desperate to dole out some good news to distract us from coronavirus). Really doesn’t seem like the best environment and test case for post-Brexit regulatory structures.

    1. A Nonny Mouse says:

      Worried? We won’t have the money to pay for it and NICE would never approve it on the basis of QALY calculations anyway, so it would be several years haggling, by which time they will have determined that it’s of no benefit anyway.

  3. Nesprin says:

    I would pay nearly any amount of money for an effective Alzheimer’s therapy, but the statements in the writeup are even more desperately hopeful than I can manage.
    My favorite:
    [Study 301] “may be understood well enough… to not represent evidence that the drug is ineffective.”
    and “Study 301 does not contribute to
    the evidence of effectiveness. The results of exploratory analyses, however, contribute to the overall understanding of Study 301 and together do not meaningfully detract from the persuasiveness of Study 302.”

    1. ST says:

      The Scott Emerson quote is a famous Leo Rosten story. Here is a quote from a textbook in physics.
      There is a Leo Rosten story about a rabbi who had a perfect parable for any subject. When asked how this happened to be, the rabbi tells a parable about a recruiter of the Tsar’s army.
      Riding through a village, this recruiter sees that there are many chalked targets on a barn, each with a bullseye bullet hole in the center. When the recruiter goes looking to rope in this “sharpshooter, ´´ a villager tells him, “Oh, that’s Shepsel. He is the shoemaker’s son. He is a little peculiar.´´ The recruiter is not discouraged until he is told, “You see, Shepsel shoots first, and then draws the circle.´´ The rabbi then said with a smile, “I only introduce subjects for which I have parables.´´

  4. Wilhelm Cody says:

    It will be interesting to compare the FDA response to this approval versus their very cautious approach to restarting the AstraZenica trial. As I recall, they decided it was worth examining auto immune responses in previous RNA vaccine trials just to be sure there wasn’t some overriding mechanism. Before I understood this, I was mildly critical but the concern was worth exploring.

    An historical example is the caution in approval of Cetus’s recombinant IL2 for treating melanoma. Basically go back and see whether there is an actual subset of patients who would really benefit from treatment. https://www.nytimes.com/1990/07/31/business/cetus-drug-is-blocked-by-fda.html

  5. FoodScientist says:

    I’m not surprised Biogen chose this course of action. They’re built to make money. Another study will likely make it harder to approve and cost.

  6. David says:

    “But this looks like a deeply divided briefing document – frankly, I can’t recall seeing one that was more at odds with itself.”

    Sarepta, 2016.

  7. Marko says:

    Thread about the FDA panel vote :

    https://twitter.com/megtirrell/status/1324808502670434305

    FDA panel vote on whether Biogen’s Study 302 (its positive study) provides strong evidence supporting the effectiveness of aducanumab for the treatment of Alzheimer’s disease:

    Yes: 1
    No: 8
    Uncertain: 2

    More votes in thread.

    1. tnr says:

      In decades past, this re-analysis would never have made it to an FDA Advisory Committee. I think its pretty clear that in the past few years, FDA has bent over backwards to allow more new drug approvals / emergency use authorizations. I have no clue whether this is politically motivated but it is certainly suspicious. Assuming that Biden is the President in March 2021 when the FDA must issue a decision, I think an approval is unlikely.

      1. Hopeful Layman says:

        Well, he will be, of course. But Trump will still be in office as a “lame duck” until then; if a vaccine maker applies for an EUA during that time (which is likely), will you distrust it for the reasons you’re suggesting here? We’ve been assured multiple times by a lot of people (incl. Fauci) that the process will be purely scientific and not political. I think (“assume”?) that the general consensus here is that that would be the case. Do you disagree?

        1. tnr says:

          Based on the data that Lilly has presented on its monoclonal antibody (not a vaccine) and more recent NIH trial data, I do not believe it is efficacious. So, if the FDA issued an EUA, to Lilly, yes, I would be distrustful. That is true no matter who is the President. I also do not believe in the efficacy of the Biogen anti-Alzheimer’s drug based on the data presented at the Advisory Committee.

    2. Daren Austin says:

      Did they decide to halt the ad com for futility and run a post-hoc analysis of the voting patterns?

  8. Simon AuclairtheGreatandTerrible says:

    Hey it can join all the worthless treatments for covid. We can just use placebos for everything.

  9. Bin says:

    If Aducanumab cannot be approved, what will be the next anti-amyloid targeting drug? Solanezumab or Gantenerumab? It seems that neither of them is even close to Aducanumab’s package. BAN2401? Will AD patients get any new drug within 5 years?

  10. Magrinho says:

    Another HPLC peak on BIIB’s stock chart.

  11. aairfccha says:

    “the loss of Dr. Knopman increases the chance of a favorable vote.”

    In the unfortunately likely case that Aducanumab is approved but turns out not to be an effective treatment, I have at least a faint hope for this motivating a cutback of cargo cult compliance.

  12. Anonymous Chemist says:

    Maybe they can market it as a supplement with a modified FDA disclaimer:

    “these claims HAVE been evaluated by the Food and Drug Administration, who were not really that impressed, but didn’t hate them either”.

  13. flem says:

    There are about a total of 2 million cancer patients in the US. and we know have big $ that market is. There are apparently 5-6 million Alzheimer’s patients in the US. Image the cost of PET scans to ID candidates for the drug. I don’t even want to think about the cost of therapy.
    Does anyone know what the dosage would be and how long patients would remain on therapy? There goes medicare for all!

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