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Alzheimer's Disease

More on BAN2401, Unfortunately

If you’re interested in Alzheimer’s clinical trials, and especially in the Biogen/Eisai antibody (BAN2401) that I last wrote about here, today has been a big day. But maybe not a good day.

That last post from from July, when the two companies had released data about the BAN2401 trials, and a lot of questions were raised. The 10mg dose showed apparent beneficial changes on cognitive scores, but the lower ones were worse than placebo. And the APOE4 status of the patients was a confounding variable. There ended up being far more APOE4+ patients in the placebo group, and that’s a known risk factor for Alzheimer’s – was this making the antibody treatment group look better than it should?

Today’s data were an attempt to put those fears to rest – it compares the high-dose APOE4+ patients in the antibody treatment group with those in the placebo group, and the companies conclude that things are fine, and that the two groups saw similar rates of decline due to Alzheimer’s. But as this article at STAT shows,  there’s a big problem with that analysis: because of the skew in the APOE4 patients (who were required to be removed from the treatment group because of possible side effects), this is a comparison of 113 people in the placebo group and only ten patients in the treatment group. If you want to draw conclusions from a subgroup that size in an Alzheimer’s trial, you are free to do so. But I sure don’t recommend it.

There’s more to the presentation, but it’s not good either. As @AndyBiotech pointed out on Twitter, the companies are not mentioning those bad lower-dose numbers for BAN2401 at all (and there’s certainly no breakout of their differences, if any, based on APOE4 status). Overall, this would seem to do nothing at all to put anyone’s mind at ease about the prospects for the drug. And when you look back to that early July hype about positive results, what we have now is pretty sad. If you bought Biogen stock back then on that news, you regret it. If you got your hopes up for a solid clinical trial result for Alzheimer’s disease, you regret it. Do Biogen and Eisai regret anything, you wonder?

19 comments on “More on BAN2401, Unfortunately”

  1. luysii says:

    Most readers of this blog are much younger, hence at less risk of symptoms from Alzheimer’s disease (although there is fairly good evidence that plaque formation has already started in you as well), so the following will give you an idea of what Biogen, Eisai and some of the rest of you are fighting (and why it is very worthwhile to do so).

    Back in the day (1956) most colleges were not coed, so a couple went to colleges as close to each other as possible (Princeton and Douglas) although she could have gone to Smith. Now she is mentally declining, probably from Alzheimer’s, while her husband of 55+ years is still sharp (PhD, worked at Los Alamos, etc. etc.) is attempting to care for her as her mental capacity diminishes gradually. It is very hard on him (and her as well as she realizes what is going on).

    1. Chrispy says:

      Alzheimer’s is horrible. It must be awful to just be aware enough to know that you will be a burden.

      1. The Iron Chemist says:

        From everything that I’ve heard and seen, the worst thing about AD is that the patients know that there’s something wrong and that they should recognize people they don’t recognize.

        Honestly, I think that there needs to be a Manhattan Project-style push to treat neurological disorders. Everyone needs to just lay their cards on the table and work together. If there’s a breakthrough, there will be enough profits to go around.

        1. loupgarous says:

          In the case of the Manhattan Project, the underlying science had mostly been done, and the engineering issues, while daunting (creating kilograms of an element that hadn’t existed until Glenn Seaborg’s team made it, and separating two isotopes of another actinide element only four AMU apart in mass, which meant learning how to work with fluorinated salts of that element and gargantuan magnets) were known technologies that had to be developed from laboratory to large industrial scales.

          All we needed was cash and uranium. The United States and its Commonwealth allies were convinced they were in a race with Hitler to develop nuclear weapons and found what they needed. The race turned out not to be even close. Prosecution of the wars it was already in was more than Germany could afford.

          The bill for the Manhattan Project in 2018 dollars was $22 trillion. Considering this had to be done in secret from most of Congress, it was a masterwork of financial sleight-of-hand.

          Project Apollo’s reported cost to Congress was $111.3 trillion in 2018 dollars, and couldn’t possibly have been hidden from Congress.

          Since the bill for development of new drugs runs in low billion-dollar ranges for newer compounds, despite new chemistry, biology, biochemistry and molecular biology having to be developed, it might be argued that Big Pharma is already doing something harder than the Manhattan Project much more economically.

          Likewise, placing men on the Moon was comparatively simple physics. Implementing the physical solution to the problem required massive, costly engineering effort, but no conceptual science that hadn’t been worked out by Wernher von Braun, Konstantin Tsiolkovsky, Robert Goddard, and the British Interplanetary Society (notably, Arthur C. Clarke).

          Since Big Pharma doesn’t appropriate all the money required for a task ahead of time (as Congress does) Parkinson’s Law seems to be the reason why, despite most drug development projects dying in their later stages, we don’t see Manhattan or Apollo project-sized price tags for drug development.

          Throwing money at problems in advance without a clear idea of the work needed creates opportunities for waste and overspending. Arguably, Project Apollo was so much more expensive than the Manhattan Project because it was politically needful to share the jobs and money available during the Project around the country, and that magnified the cost considerably.

          1. roger says:

            Apollo’s cost was $25.4 billion as reported to congress, about $144 billion in 2017 dollars, nothing like over $100 trillion.

          2. Scadriel says:

            And the Manhattan prokect cost 22 billion, with a b. Do a sanity check on your numbers, the entire US gdp in 2017 was only 19 trillion.

          3. loupgarous says:

            Good catch. I offer no excuse, my math was broken. As close as I can figure, I did the chained dollars calculations twice.

            And yet, when you sum up all the drug development work so far on Alzheimer’s you get a figure not far off the correct numbers (in 2018 dollars). It’s highly doubtful that just writing a $22 billion check (in the range for modern “do something” projects at the Federal level, except for aerospace and defense) would necessarily yield new insights into the actual mechanisms of Alzheimer’s Disease, much less how to treat it effectively.

            Big Data looking at everyone’s medical charts could discover relationships we don’t see yet, not just for Alzheimer’s but a host of diseases we should be looking at more critically.

            Associated privacy issues deserve consideration, but I doubt a Big Data collection of the nation’s patient charts would breach privacy to a greater degree than Big Health Insurance and CMS have already breached them. It could suggest, for example, whether (as has been suggested in this article’s comment space) a link between herpes simplex infection and increased Alzheimer’s Disease incidence is worth investigating.

            Big Data examination of the nation’s medical charts could screen for many more potential links between infections and what we think are unrelated issues, find severe adverse events after NDAs are granted for drugs (now, only 10% of severe AEs are reported to FDA), and as knowledge of the human genome increases, suggest new targets for biologic therapy.

            That would be worth a $22 billion dollar outlay, assuming Congress doesn’t find rat holes for half of it before work even begins.

    2. loupgarous says:

      A very good friend of the family lost her husband to Alzheimer’s when he was very young even for onset (his late forties). Progress to death was rapid and merciless. Our friend is now energetically raising funds for and awareness of Alzheimer’s Disease.

  2. metaphysician says:

    Any comments on the alleged connection between Alzheimer’s risk and herpes simplex virus? Is there any reason to be more hopeful about this being accurate than any prior Alzheimer’s “breakthrough”?

    ( I can’t find a proper scientific article on the topic, so here’s at least a link:
    https://www.independent.co.uk/voices/alzheimers-disease-cause-study-brain-evidence-herpes-cold-sore-virus-a8601041.html )

  3. Old Timer says:

    What I really don’t understand is how B/E can be touting these results as “positive” in light of a) statistics, b) the field, c) the SEC, d) common sense… Can some MBA explain to me how these press releases make any sense??

    1. Scott says:

      I’m only a BBA, not an MBA, but what you’re smelling is marketing. And if you think that marketing smells an awful lot like a cattle feed-lot, you are correct!

  4. Eka-Si says:

    Presumably it’s this one? https://clinicaltrials.gov/ct2/show/NCT01767311

    Primary outcome is pretty clear, and there absolutely should be a pre-specificed analysis plan.

  5. loupgarous says:

    A ten patient treatment arm is not unheard of for side issues, but efficacy? That would be troubling, and I doubt the FDA would be impressed.

  6. loupgarous says:

    Tell me if I’m wrong here, but isn’t “worse than placebo” generally indicative of toxicity? Perhaps not when confounding variables like the APOE4 status issue exist, but it’s not comforting.

  7. Anon says:

    Time to call the SEC, because what these guys are trying to pull is fraud.

  8. An Old Chemist says:

    REVIEW ARTICLE
    Front. Aging Neurosci., 19 October 2018 | https://doi.org/10.3389/fnagi.2018.00324
    Corroboration of a Major Role for Herpes Simplex Virus Type 1 in Alzheimer’s Disease
    Ruth F. Itzhaki*

    https://www.frontiersin.org/articles/10.3389/fnagi.2018.00324/full

    1. loupgarous says:

      Worth noting from the paper:

      “Three very significant publications have appeared in the current year, all providing data on the health and illnesses of a population over several years—information which is not available in the UK1 nor, probably, in most other countries. In Taiwan, there are records of over 99% of the population and it seems that the data are being exhaustively mined by Taiwanese epidemiologists for links between, for example, various viruses, and certain chronic disorders, including senile dementia (SD). These are yielding important results. All three articles describe data on herpes virus infections—a family of viruses that affects the vast majority of people worldwide, at least by the age of 60 or so. These viruses, once in the body, are harbored there for life, usually in a latent state but can be reactivated to an active, replicative state. Only a certain proportion of those infected actually show overt symptoms; the remainder are asymptomatic (as is the case for many or perhaps all microbial diseases). In the Taiwan publications, the word “infection” is used to denote people who showed overt signs of the disease such as shingles or recurrent cold sores or genital sores, rather than for all those who carry the virus asymptomatically in either a latent or an active, productive state. Also, the term “SD” is used rather than AD because in some cases the diagnosis was uncertain…. “

      Not only does this paper show evidence of an AD- HSV-APOE4 causative link, but it’s also proof data mining of patient charts is a powerful tool for developing information on such links.

      1. loupgarous says:

        It’s also worth noting that the first extensive studies of tendinopathy, cardioarrhythmias, retinal detachment and other opthalmic structural disorders, and other disorders as related to use of fluoroquinolone antibiotics were retrospective studies of selected patient populations (elderly) in Taiwan and Ontario, Canada. Data mining of patient records was key in the Taiwanese studies and probably a large factor in the Toronto/Ontario studies.

        A “Manhattan Project” is indicated to attack the problems of Alzheimer’s disease and other intractable, deadly, debilitating illnesses. That project ought to be data mining of patient records on the national scale, here in the United States, and in other populous areas with high medical utilization rates, to detemine actual risk factors for these diseases and population subgroups in which susceptibility to them is high. Then we can study common factors among the patient subgroups to determine why they are more at risk of AD and other severe illnesses which are resistant to treatment.

        Recovery of the investment in such data mining could occur in faster identification of new treatments for Alzheimer’s Disease and, possibly, several cancers and other illnesses, associated reductions in costs of management of these diseases and assistive care for these patients, longer patient life and greater quality of life for these patients.

        The Taiwanese medical data mining effort should be studied extensively, as a guide to how a successful medical data mining effort was assembled, and how it works. Emphatically, other nations shouldn’t try to replicate this success without seeing how it was accomplished in the first nation to make two major achievements in the epidemiology of previously unstudied adverse drug effects and in Alzheimer’s Disease (where epidemiological factors hadn’t been identified with notable success before).

        It’s likely additional dividends can be reaped in faster identification of post-marketing patient injuries and severe adverse events in drugs after they’ve been approved for sale, development of better guidelines for use of those drugs (to improve effectiveness, patient outcomes, and reduce incidence of patient injury and adverse events in general), and lower medical treatment costs by learning how to intervene in illnesses more quickly and economically.

        Epidemiology in general can be improved, not just from better pharmacovigilance, but overall – reporting of new outbreaks of infectious illness could be improved and made much quicker.

  9. Dave says:

    The atom bomb project was *not* just engineering. You don’t put von Neumann, Fermi, Bohr, Feynman, Ulam, etc.. to work on an engineering project. There was a whole *heck* of a lot of invention that went on.

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