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Alzheimer's Disease

The Return of Aducanumab

When last heard from, Biogen and Eisai’s aducanumab (another amyloid-targeting antibody for Alzheimer’s) had failed in Phase III and the whole effort was being terminated. Then came Tuesday. Biogen then startled everyone by announcing that a review of the clinical data had convinced them that the drug had actually worked – or at least worked enough to be worth an FDA submission, which they say is exactly what they’re going to do next. Here are their slides (start at about #11), where they make their case.

There were two Phase III trials, ENGAGE and EMERGE, which started at nearly the same time in the fall of 2015. By June of 2017, patients had been enrolled for the futility analysis (which would read out earlier), and by June of 2018, both studies reached full enrollment. In December 2018 the last data for the futility check were collected and began to be worked up, and in March of this year the results were completed. That, by golly, is when things came to a shuddering halt, because that analysis suggested that further dosing in the treatment groups had no chance of reaching a useful endpoint.

Comes now Biogen, noting that at the time of that futility analysis, EMERGE was “trending positive” while “ENGAGE” was not. The company does not have a solid explanation for the divergence. There were, though, amendments to the trial protocols along the way (some of which allowed for higher dosing later in the trials), and they hypothesize that these could have made a difference due to the enrollment schedules. The company says that now they they have access to more data than they had at the discontinuation, they believe that the new larger dataset’s results disagree with the results of the futility analysis. The company believes that the cohort of people in the ENGAGE study who had sufficiently large exposure were trending along with the (better-looking) EMERGE data, and it’s my impression that they want to use these together to make their case for efficacy. Differences in exposure to the high-dose aducanumab, they say, “largely explain” the differences between the futility analysis and this new interpretation, and that “following consultation with the FDA” they believe that they have sufficient data for a regulatory filing. (No doubt they do, but do they have enough data for a successful approval?)

This news spilled a lot of coffee in the pre-market. BIIB shares had closed Monday at about $223 (pretty much where they were after aducanumab hit the skids in March) and opened Tuesday at $310 (pretty close to the $323 it had been before the March crash), and trading down to $282 at the close. Clearly a lot of investors suddenly believe in the drug again and are willing to put money on that proposition. Are they right?

I’m going to ignore all the data on those slides about amyloid level in the brain via PET scans and suchlike. I honestly do not care; what’s important are the measures of dementia. And while the new larger EMERGE data do look like there’s a dose-responsive effect in the primary measurement (the CDR-SB scale) and three secondary dementia scores, the ENGAGE data actually show worse than placebo for CDR-SB at the higher dose (see slide 19 in Biogen’s presentation). They’re also worse than placebo in the MMSE scoring, but both the ADAS-Cog13 and the ADAS-ADL-MCI scales show apparent dose-responsive improvement. I have no idea why four different dementia rating systems should give such different results, and to a first approximation, no one else seems to have a good idea, either. So we’ve got the EMERGE/ENGAGE difference to explain (you’ve seen Biogen’s explanation, higher dosing later in the trial), and the variable results within the ENGAGE trial itself. And who are these high-dose patients in the ENGAGE study that Biogen says line up with the EMERGE trial? Ed Silverman at Stat quotes an analyst saying that it looks like fewer than 100 patients out of the whole set. That reminds me a bit of Biogen and Eisai’s tease of “We’re seeing positive data!” during the clinical trials, which also turned out to be based on a smaller number of patients than one would want when making a call on Alzheimer’s efficacy.

Admittedly, the EMERGE data look better, but Biogen’s explanation for the differences between the two is necessarily post hoc. It makes a good story, but the FDA would be well within their rights to ask the company to prove it with another Phase III, this time run under the conditions that are hypothesized to work the best. That, to me, seems like the most likely outcome of any regulatory submission, and this could happen at several points. It could come out of an advisory committee meeting that decided that it couldn’t make a clear call based on the package as it stands, or the agency could make that call on its own regardless of the Ad-Comm. You also have the nastier possibility of a Complete Response Letter even before a thorough review of the submission, but Biogen clearly thinks that they’ll get further than that, and they’re probably right (those “discussions with the FDA” they made sure to mention).

Outright approval at the end of the process is possible, too: none of those people who piled into BIIB stock yesterday were hoping for just another Phase III trial. I think that’s only an outside chance, though. Edit: there’s another possibility: conditional approval by the FDA, with a revisit-in-X-years provision, similar to what was done with Avastin in breast cancer. I can’t say I like that prospect much. Getting that pulled back was enough of a mess, in spite of clear evidence that the drug did no good, and this would be even worse.

There are a *lot* of factors at work here, and for better or worse not all of them are scientific. I wrote about some of them while Eli Lilly was thrashing around with their own anti-amyloid, solanuzemab; here’s the short version: there is nothing that really helps for Alzheimer’s. The first actual disease-modifying therapy will very quickly show revenues of over ten billion dollars a year and rising, probably to levels we have never seen before. There are huge numbers of desperate patients and their families who will immediately demand any such drug, and who could blame them? Meanwhile, there is what I can only describe as a moral hazard for drug developers in this area: if you could only get something approved, it would become the biggest drug in the world even if it doesn’t really help people all that much. I mean. . .

My point is, if you’re going to unleash something like this, it had better be good. An Alzheimer’s drug like this has the potential to alter the entire drug-expenditure landscape in the US – every private insurance company, employer contributions, state-sponsored programs, Medicare, the VA, ACA participants, the lot. You will want clear evidence of benefit before you do that. The FDA does not consider drug pricing in its decisions, but it does have an explicit mandate to consider efficacy (and efficacy versus safety). They could very well decide that they want a clearer read on that efficacy before we start dosing millions of Alzheimer’s patients with a drug that had already been killed off by its own developers. And before we start paying for such dosing.

There’s a moral hazard for the FDA, too. The pressure will be on to approve something, anything for Alzheimer’s. It looks like aducanumab will be the first time a big (potentially) disease-modifying therapy will get as far as an actual regulatory submission – everything else has blown up before that point. Now comes the hard part: dealing with the actual data. It would be so much easier with a clear clinical victory, but that’s not what we have here. The Biogen/Eisai data are internally contradictory and very much open to argument. Argue we shall.

61 comments on “The Return of Aducanumab”

  1. Barry says:

    If you miss the clinical endpoints you had set before the Phase III, you have failed the Phase III. If you want to go back and do another Phase III with new endpoints, it’s your money.

    1. John Wayne says:

      I agree, but this requires senior folks in the FDA to have a spine. I don’t like our chances.

    2. Ian Malone says:

      Ah, but CDR-SB was the pre-specified endpoint, and the high and low dose arms are pre-specified, https://www.clinicaltrials.gov/ct2/show/NCT02484547 So while Phase 2 amyloid antibody trials may have seen sub-group analyses that went nowhere, this isn’t the same thing and it’s harder to object to. It’s a confusing picture no doubt.

      Have been impatiently looking forward to Derek’s take on this since the result was announced 🙂 Another trial does seem likely. They’re also planning to offer a continuation study for previous participants who had treatment stopped, though that’s unlikely to produce much definitive data.

  2. Jim says:

    Another problem is that future trials may not be able to compare vs PBO because aducanumab may be required in the control arm. That would be a disaster

    1. Sally says:

      Isn’t that the exact next trial suggested yesterday? No placebo; everyone gets the drug?

      1. Ian Malone says:

        No, one of the things they are doing is essentially re-starting extensions studies for people who had discontinued when the trial was pulled. I’m not sure if that will be open-label only or there are any still in blinded arms. Open label extensions where everyone goes on treatment after the randomised phase finishes are relatively common in AD trials, in theory you can get some data by looking at changes in trajectories and also gather more long term efficacy information (though without a good control).
        However, the question about future trials having to have an aducanumab arm is tied ethical considerations in trial design. In situations where death or morbidity is involved, ethically, “it is generally inappropriate to use a placebo control.” (From EMA guidance on choice of control group in clinical trials, https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-10-choice-control-group-clinical-trials-step-5_en.pdf )
        “Whether a particular placebo controlled trial of a new agent will be acceptable to subjects and investigators when there is known effective therapy is a matter of investigator, patient, and institutional review board (IRB)/independent ethics committee (IEC) judgment, and acceptability may differ among ICH regions.”
        Likely the efficacy (if it is efficacious) of adu. will be a factor in that kind of decision.

    2. Emjeff says:

      No chance. You haven’t shown the drug is effective.

  3. The Godfather says:

    How is this drug different than earlier drugs in the same class that failed in clinical trials (thus far)?

    1. anon says:

      The Godfather is asking the right question. To put a finer point on it: Who else has used a similar MoA & found sufficiently compelling evidence to persevere with that same MoA? What was the degree of similarity in those MoA? What indicators do we have of the compellingness of the evidence motivating perseverance? And was the rationale similar to what Biogen is saying?

  4. Chris says:

    This would be precedent setting if the Neuro division approved a drug largely based on post-hoc analyses. I doubt they would want to open the flood gates for future submissions.

    Also would appear to go against FDA wording in their guidance doc for development of Alzheimer drugs as below:

    Given the panoply of available neuropsychological tests, a pattern of
    putatively beneficial effects demonstrated across multiple individual tests would increase the persuasiveness of the finding; conversely, a finding on a single test unsupported by consistent findings on other tests would be less persuasive.

  5. ScientistSailor says:

    We have a disease-modifying therapy, it’s called vigorous aerobic exercise.

    1. Esteban says:

      Now if you could just squeeze that into a capsule…

      1. John Wayne says:

        Exercise is hard to formulate

      2. Anonymous says:

        Salk Inst, May 2, 2017 (link in my handle)
        “Exercise-in-a-pill” boosts athletic endurance by 70 percent.
        “Salk Institute scientists, building on earlier work that identified a gene pathway triggered by running, have discovered how to fully activate that pathway in sedentary mice with a chemical compound,* mimicking the beneficial effects of exercise, including increased fat burning and stamina. The study, which appears in Cell Metabolism on May 2, 2017, not only deepens our understanding of aerobic endurance, but also offers people with heart conditions, pulmonary disease, type 2 diabetes or other health limitations the hope of achieving its benefits pharmacologically.”

        * = GW1516 = en.wikipedia.org/wiki/GW501516

        1. Stardust says:

          The Wikipedia article mentions GW501516 was shelved due to rapidly causing cancer in multiple organs during rat trials. I’ve heard a defense through the bodybuilder grapevine that the dosages were unrealistically high (5x) and long (2 years) [ see https://www.jpnm.org/gw501516-cardarine ], but that’s wishful thinking. Tox screens run at high dosages to flush out rare side effects – a sampler platter of cancers early in the animal stage is quite a red flag.

          Nevertheless, the drug has proceeded to human trials – albeit in the gym, rather than the clinic. Hopefully someone will reach out to the users and inquire about any unexpected growths, so we can have a follow-up paper… people are taking it anyway, might as well put them to use.

          1. Michael Langberg says:

            I believe that they’re called “gains” in the bodybuilding community. And who is to judge if your extra pectoral mass is 70% rhabdomyosarcoma?

          2. metaphysician says:

            You know, a drug that caused rapidly developing cancer probably *would* produce a variety of clinically meaningful improvements in Alzheimer’s Disease outcomes. After all, the recipients would be much less likely to show symptoms, show symptom progression, or die of AD.

            I can’t remember, didn’t someone seriously suggest tobacco as having a protective effects vs AD? *ahem*

    2. Matthew TKK says:

      Not if your evidentiary standards are rigorous – show me the study or meta-analysis which concludes that is therapeutic for AD.

  6. anon says:

    Should I draw any correlation between Ehlers departing and this announcement so quickly thereafter?

    1. anon says:

      Ehlers was never one to blush during his academic career about optimistic interpretation of data. If he saw something in this resurrection that concerned him, it must be pretty bad.

  7. Passerby says:

    Given the FDA’s recent track record in approving drugs showing tiny benefits in a tiny pool of patients, I sadly won’t be surprised if they approved this one.

  8. Andre Brandli says:

    Derek, many thanks for your thorough analysis of the available Biogen data on aducanumab. I have had a look at the slides and I have to admit that the data for the primary and secondary endpoints for the EMERGE study looks convincing for both the ITT and OTC populations. There is a dose-response correlation with all endpoints analysed! By contrast, things look very different for the patient populations in the ENGAGE trial. Here, only patients treated with the low dose of adecanumab show consistent improvements over placebo. This is probably the reason for Biogen labelling this study as supportive. At higher doses, things become complicated. There is no improvement over placebo for the two first endpoints (CDR-SB, MMSE). In fact, the adecanumab-treated patients do worse than placebo treated ones. In other words, if BIOGEN had only done the ENGAGE trial everybody would be very impressed with the data…. Notably, 35% of patients experience problems of ARIA-edema. It is unclear whether this is similar in both studies. Overall, my prediction is that the FDA will approve aducanumab given that this is the only drug for which there is evidence for efficacy in the the treatment for AD. Ultimately, one would need an oral drug for AD prevention.

  9. AC says:

    Under your March 2019 blog post about aducanumab, this gem of a comment appeared:

    “Biogen’s stock is down 27% in premarket trading, which suggests that a significant number of investors expected this drug to work. Which makes me wonder, who are these investors, and what were they smoking?”

    I guess those same people are back under the influence judging by that 34% premarket jump.

    1. anon says:

      Hindsight is always 20/20.

    2. loupgarous says:

      In 1996, the then-Federal Reserve Board chairman Alan Greenspan gave us a descriptive term for what happens when pharma stock prices jump on equivocal clinical evidence like this, coupled with trust that FDA will keep approving medications based on cherry-picked clinical study results, not clear evidence of clinical safety and efficacy – “irrational exuberance”.

      Plus ça change, plus c’est la même chose.

  10. mallam says:

    If approved, the resulting criticism of high cost by patients, caregivers and insurance companies (if they cover it at all) will be well deserved. But this will be on the FDA as much as on Biogen.

    1. anon says:

      So Dennis Selkoe likes the amyloid hypothesis…

  11. Anon says:

    Why would Ehlers abandon his opportunity to be the first R&D chief in 40 years to bring a new AD therapeutic to patients? Because he doesn’t believe it.

  12. NorthernBioSkeptic says:

    Can we discuss the puny, puny effect size? A 23% reduction in the rate of decline in their best trial group? Seriously? And the treatment is not exactly cheap, easy and side-effect free either. With a big enough trial you can get statistical significance out of all sorts of things – but what about clinical significance? Is this going to actually improve the lives of patients and caregivers, even if we heroically assume that the 23% number holds up?

    1. Derek Lowe says:

      It’s true: the data look real (well, for that trial), but is that really going to do anything for patients? That’s why I express the worries in the last paragraphs. . .

    2. Stephen says:

      exactly. All the patients declined from a score of say around 180 to around 80 which is a devastating loss in function in just over a year. However the best difference in final scores between placebo and treated arm is only 74 to 87 – e.g. the patients were declining like a rocket in both cases and would be fully demented in no time but you will have to look after demented Aunt Martha for a few months more on Aducanumab .

      1. Stephen says:

        whoops read the wrong numbers above but the overall idea is right

        1. Ian Malone says:

          Those numbers are likely the number of participants in group at each visit. The graph to look at is probably CDR-SB change from baseline pg 22, 1 point versus 2 points over 18 months. This is not a very fast rate of decline, if you can slow by 23%. CDR ratings don’t directly correspond to sum-of-boxes, but CDR 0.5 very mild to CDR 1.0 mild is at about 4, CDR 1.0 to CDR 2.0 (moderate) is around 8-9. So if it’s 3 years to change from mild to moderate, then 23% rate reduction takes that to 4 years. The ADCS-ADL-MCI is intended a measure of ability to cope with everyday tasks, so you are potentially talking about real extra time of independent or lightly supported life. (As an imager I’ll have to concede this is an advantage of functional outcomes…)

  13. William Gerber says:

    Much written about groupthink in alz research and alternative theories being squashed by powerful KOLs and journals (the amyloid “cabal”). Instead of moving on, will Biogen’s actions stall progress with alternatives? I’m sure those who were immersed in amyloid groupthink are more than open to being vindicated. Let’s waste another couple of decades.

    1. anon says:

      Hindsight is always 20/20. Fund your own alternative research then. I’ll give you a couple of decades.

  14. Anon says:

    A “statistically significant” p-value of 0.05 implies a 1 in 20 chance that a drug which is completely useless will give a “positive” result. Now how many amyloid antibody trials have we run as an industry? Multiple hypothesis testing anyone?

    1. anon3 says:

      Does the FDA take that into account? By the 100th antibody hitting this same mechanism, surely a handful will show a significant effect….

    2. loupgarous says:

      One reason why, at least in biomedical work, the threshhold for “statistical significance” has moved toward p=0.005 and more careful selection of significance tests in clinical work.

      1. Norrie Russell says:

        Agreed. The use of phrases such as “trending positive” or “approaching significance” is shamelessly used too often by company presenters or company sponsored academics.

    3. Ted says:

      Yes, and at this point the aggregated results point to failure by pAb therapy…

      -t

  15. An Old Chemist says:

    ‘Trick or Treat?’ Analysts react to Biogen’s aducanumab surprise:

    https://www.fiercebiotech.com/biotech/trick-or-treat-analysts-react-to-biogen-s-aducanumab-surprise

  16. luysii says:

    How many times have I heard “Well he died in (electrolyte) balance”, showing the hazards of treating a marker rather than the disease.

    A 23% slower rate of decline is clinically irrelevant.

    1. metaphysician says:

      That depends on the baseline rate. If a disease is expected to kill the patient in a week, a 23% slower progression just means they die in 9 days. That isn’t enough for anybody to care about, unless its *really* cheap and easy. If a disease is expected to kill a patient in 10 years, a 23% slower progression means they last almost 13 years. Three extra years of life is not something to sneer at, by contrast. Assuming, natch, that all else is equal: 2 extra days of being relatively healthy and energetic and in full faculties is probably worth more than 3 years of being personality-dead and nearly comatose in a bed.

      Which is why it really depends on the benchmarks they looked at. People care about delaying onset of detectable symptoms, or onset of incapacitating symptoms. They don’t care, by and large, about preserving a dead brain in a shambling body.

      1. luysii says:

        Metaphysician — what you say is quite true “They don’t care, by and large, about preserving a dead brain in a shambling body.” But unfortunately that’s at least half of the course, based on clinical experience. Well, maybe not brain dead, but severely diminished. One of cruelest things about Alzheimer’s is that many of them look the picture of physical health.

        This prolongation without improvement is exactly what I saw with Riluzole for ALS. There was never a reversal and none is claimed for the Aducanumab.

        If we really had a good drug for Alzheimer’s it would be screamingly obvious as the demented began to function again.

        1. metaphysician says:

          Sadly, I am skeptical this can ever happen ( at least not without Clarketech medicine centuries in the future ). Meaningfully reversing late stage Alzheimers is very likely equivalent to meaningfully reversing combustion: you can’t do it, because the damage is already done. A good AD drug, IMO, would be a highly effective preventative, arresting disease progression. Actual improvement should only be expected to the same extent as one might expect improvement from serious brain damage.

          I suppose its *possible* that AD is a disease that damages the “hardware” of the brain, while leaving the “software” of memory still mostly-intact but inaccessible and unusable. I would not bet on this being so, sadly.

  17. Scott says:

    Sunk Cost fallacy strikes again!!!

  18. johnnyboy says:

    Lilly designed a whole new Ph3 trial (Expedition) based on promising subgroup results for mild AD patients in a previous failed trial for Sola. That subgroup data looked convincing, and that subgroup was larger than the 100 or so patients in Biogen’s, and their rate of slowing of cognitive decline was greater than aducanumab’s. I think we all know where that Expedition went. Biogen is grasping at straws, this is not going to end well.

    1. Blind man hindsight says:

      Maybe Lilly will reconsider and file an NDA for their drug…
      Welcome to Pharma 2020… who would’ve thought…

  19. Crni says:

    So what would be a best guess on the time frame of when the FDA comes back on this? Just asking for a friend who is worried about the time value of put options.

  20. drOcto says:

    I’m less concerned about what the FDA think and more interested in what the SEC have to say. This looks like a Biogen pump and dump, plain and simple.

    But share investing is an exercise in mass psychology, so those that responded quickly to the news and have already re-sold can take their well earned 20%. And to those just entering now…. well…..prepare to be disappointed.

    1. loupgarous says:

      While Biogen’s announcement is the kind of “nuanced” forward-looking statement which has triggered ill-advised buys (those holding the stock before this presser of theirs are the only folks who came out well, assuming they jumped out of Biogen while they could get their money back), SEC either has a case backlog on pump and dump schemes which has led them to seemingly ignore some exceptional violators, or they’re just blase about the whole issue. Either way, Biogen’s probably safe from the SEC just now.

  21. Lambchops says:

    Also for anyone interested in futility analysis here’s a paper looking at a trial that was potentially stopped early in error due to the way the futility analysis was designed. It’s essentially trying to put a positive spin on a negative result but raises some good points around conditional power, the timing of analysis etc: https://academic.oup.com/annonc/article/28/7/1419/2981953

    I think there are some lessons to be learned from these trials too, clearly the pooling of the trial for the futility analysis combined with protocol amendments were not a good idea – suggests that if you are entering a trial uncertain of optimum dosing then think carefully about the design of the futility analyses – perhaps pre-specifying a longer time period after any amendments to the dose before carrying out futility analysis (though then this could potentially be used as a cheat to carry on trials that should be stopped, so may not be ethically sound?). Certain;y there are some trial design issues here, regardless of whether the results are positive/negative.

    As for the results of the larger data sets, I’m definitely in the “unconvinced, run another trial if you think it really works” camp at the moment – though that said there are probably approvals that have been given to oncology drugs with worse data so I can see why some people may advocate for conditional approval given the unmet need etc. However, given the results from other drugs in the field and the divergent results from the two studies seems like too big an ask.

  22. Me says:

    Well this is why the FDA asks fr replicate studies in these cases: having both of them reach stat. sig. is a higher bar than a single, larger study.

    I’ve seen these sort of things shot down (e.g. GSK’s Nucala in COPD had replicate studies with one successful and one not, and it was rejected almost unanimously at an Ad. Comm.). From that perspective, you’d expect a follow-up study to be required, but given the extreme need in AD you never know….

  23. An Old Chemist says:

    More Details Emerge on Biogen’s Alzheimer’s Comeback:

    https://www.biospace.com/article/inside-biogen-s-alzheimer-s-comeback-attempt/

  24. Vader says:

    Speaking as a non-biological scientist: My take away is “Don’t buy stock in Biogen.”

    Not because there may not be money to be made there; the market is funny that way. Because I don’t want to invest in junk science.

  25. Spingos Konstantinos says:

    Since brain network functionality is not a dose-response phenomenon, there is nothing to be cleared by dose-response trials. Efficacy will emerge at a probably unimagined dose level.

  26. Greg says:

    But if this Antibody based Drug is in the end a ‘disease-modifying’ drug, then as per one of the criteria that would demonstrate this disease modification (in accordance with the criteria laid out by the AD medical expert Jeffrey Cummings; DOI: 10.14283/jpad.2017.12), then would one expect the effects to persist upon drug withdrawal? One has to wonder whether Biogen can/have or are acquiring this data?

    1. Lambchops says:

      https://www.statnews.com/2019/10/25/alzheimers-patient-biogen-clinical-trial-aducanumab/

      In the above article about trial participant experience one person in the trial states that “They did actually follow up four months after cancellation to do testing to see if there was any impact of cancellation on neuro-psych testing. We don’t really know the results of that, but that seemed like a good thing.”

      Based on that there are some data but they are likely to be rather limited. Having read the criteria does it sound like these data would help?

    1. Greg says:

      How appropriate that Jeffrey Cummings has been asked to comments on this Ph3 Clinical trial.

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