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Alzheimer's Disease

Alzheimer’s and the Rare Disease Model

Politico is a good source for national political stories, but I don’t usually look to them for coverage of drug development. But they’ve done a good job with their recent “Pharma Issue”. One of the stories (by David Freedman) is on the difficulties of Alzheimer’s drug discovery, which are legendary. The contrast between a therapeutic area like that one and the more recent trend towards rare disease drugs is not lost on them:

But as America looks squarely at the biggest health challenges of the future, there’s reason to worry that the system we’ve built may not be adequate to what’s in front of us. When it comes to the two diseases likely to become our biggest killers— Alzheimer’s and diabetes—death rates are relentlessly ticking up, with few solutions on the horizon. Even more alarming, to many experts who look at America’s long-term health future, is that incentives appear to be leading toward more drugs like Kalydeco, pricey treatments for small groups of patients, rather than toward drugs to tackle major new chronic killers. And if they ever do succeed against these diseases, the costs could be high enough to threaten the solvency of the whole U.S. health care system.

. . .the puzzles of Alzheimer’s and diabetes begin to look as much like a policy challenge as a scientific one. With today’s incentives, the pharma industry has built an attractive business model on narrowly targeted drugs like Kalydeco. Bigger, murkier and more complex diseases like diabetes and Alzheimer’s require a much larger investment with little confidence that it will result in correspondingly lucrative products—or even any products at all.

As the article does mention, that hasn’t stopped a number of companies from trying – Lilly’s massive investment in Alzheimer’s is noted, for example, but the fact that it hasn’t paid off at all so far is perhaps an illustration of just that point made above. One possibility is that we’re kidding ourselves when we think of Alzheimer’s as just one disease, subject to one therapy. Perhaps the rare-disease model can apply there as well:

Some are already talking about Alzheimer’s as a bundle of diseases rather than a single distinct problem. “Alzheimer’s is a mix of pathologies,” says Serge Gauthier, who directs Alzheimer’s research at the Centre for Studies in Aging at McGill University in Montreal. “We need to try treating it not with a single drug, but with different drugs that target the specific disease activities in the patient’s brain.” Trials that will test Alzheimer’s drug candidates on the 10 percent of patients who have a particular pair of genes that seem linked to a particular variation of the disease are already in the planning stage, Gauthier says. If such narrower patient-population tests produce encouraging results, he adds, drug companies are likely to take a fresh look at some of the previously tested candidates who failed in bigger groups of patients, and consider a new trial on more carefully filtered groups of individuals.

The tricky part of that, as the piece also mentions (to its credit) is that the underpinnings of Alzheimer’s are currently so obscure that even getting such trials underway is difficult. Part of the whole rare-disease mindset is that you have such a clear, solid link to human pathology that your chances of success in the clinic are increased dramatically, but “clear, solid link” is a hard thing to come by in Alzheimer’s, where even the most broadly considered hypotheses are constantly under attack (and with reason). Alzheimer’s is about as far from a classic monogenic disease as you can get, and it’s worth remembering that even those are still no stroll through the peony beds, either. Rare disease drug discovery only looks appealing in contrast to the rest of the drug industry.

The article does bring up a worry that I’ve expressed myself, that the system as it exists now is set up for a company to make huge profits from (say) a new Alzheimer’s drug that shows statistically significant results, enough to get FDA approval, but not enough to make much (if any) real-world difference. No one’s even been able to get that far, but scientifically the likelihood is that if anyone does find something that it’ll be in that category, unfortunately.

There’s also the clinical readout to consider. If you’ve got that solid mechanistic hypothesis (restore function of Protein X), then you can generally expect a reasonably fast, reasonably strong clinical effect. But Alzheimer’s trials are a fearsome grind because the disease is so slow-moving and difficult to quantify, and it’s hard to see what’s going to change that part. To that end, though, the article ends up with a call for better biomarkers to speed up trials and make them less expensive, but that’s hardly controversial. Everyone’s realized for decades that we need such things, but here we are, and not for lack of trying. On the other hand, the good news is that even expensive Alzheimer’s therapies, if they really do some good, will almost surely save more health care costs overall because of the horrible burden of chronic care. But first we have to get something to work. . .

35 comments on “Alzheimer’s and the Rare Disease Model”

  1. Kent G. Budge says:

    The longer we live, the more we will suffer from diseases that are hard to cure. Alzheimer’s and diabetes, as well as cancer and heart disease, are what’s left when you stop dying of stuff that’s relatively easy to fix.

    1. Emjeff says:

      This is absolutely true. I remember a professor of healthcare econ I had years ago who spoke of the “illusion of health” – the idea that we are just on the cusp of “curing everything” is nonsense, because as we age, new diseases will move in to fill the gap.
      Prior to the 1940s, we died of infectious diseases like dysentery and pneumonia. In the 19040s-1990s, we died of heart disease and cancer. Now us health-obsessed baby boomers are about to die in nursing homes with our brains turned into pudding. It’s a hell of a situation.

  2. Uncle Al says:

    Dump some Congo Red in there, look, then go combinatorial on Alzheimer’s booty. Contrast with intrathecal and brain ventricles administered poly(1-vinylpyrrolidone) solution. But…that’s crazy talk! DOI:10.1016/j.bpj.2012.07.008 WWII used polyVP solution as a blood plasma substitute. What fraction of treated soldiers got Alzheimer’s versus their untreated cohort? The US (in theory) tracks veterans’ health.

    Congo Red quantitates grafted monolayers of pVP on Plexiglas – strong interaction! Who has some ALZET osmotic pumps?

  3. Pfired says:

    Pfizer exiting neuroscience completely

    1. Anonymous says:

      Lost in the Comments thread in an AD topic, is the brief Reply by ‘Pfired’ that Pfizer has exited Neuroscience. This is significant! My understanding is that all NS R&D will cease and job losses total several hundred. Is that accurate?

      1. Ian read says:


  4. arcya says:

    “the system as it exists now is set up for a company to make huge profits from (say) a new Alzheimer’s drug that shows statistically significant results, enough to get FDA approval, but not enough to make much (if any) real-world difference”

    You can just say Mementine my guy we all know what you mean

    1. Derek Lowe says:

      Aricept, too, as far as I’m concerned. But I was particularly worried about this with Lilly’s antibody, because they kept beating on it so desperately.

      1. arcya says:

        ah man that’s the WORST part about all the amyloid beta antibodies – like they are pretty clearly are not effective, and the only good thing that has come out of that repeated failure is that maybe we can begin to move on from the amyloid beta hypothesis? But AD trials are so expensive that companies frantically trying to recoup their losses are digging harder and harder into their post-hoc analyses and at some point *might actually get some amyloid beta blocker approved*. THEN we’d be back to square one, with nothing that works and everyone and their brother running amyloid beta trials again.

        1. Barry says:

          Alas, no. The true believers in the beta-amyloid hypothesis argue that Lilly’s antibody didn’t get where it needed to act.

          1. Kelvin says:

            To be honest, I think that’s a fair hypothesis in light of all the evidence.

            But then why on earth did they (and many others) doggedly pursue the same strategy/MoA with the same kind of molecule, knowing already that antibodies haven’t gotten where they needed to act???

            Insanity is doing the same thing over and over, and expecting a different result!

          2. arcya says:

            So we’re supposed to believe that Lily didn’t do proper pharmacokinetics studies before they hit phase III? Forget mice, no one did path on pts that died during phase I to confirm their antibody localization and efficacy?

            Lily wants us to think that after solanezumab (and all the other amyloid beta antibodies) failed, that the real problem is that they actually did not design their studies properly and maybe their drug still works, which is the most annoying kind of post-hoc justification.

            I don’t doubt that amyloid beta oligomerization / aggregation plays an important role in AD development, but the evidence has not suggested that it is an appropriate target to stop AD progression.

  5. In Vivo Veritas says:

    I wish the author didn’t draw such strong parallels between AD and diabetes. He argues that both diseases are hard to drug, and sites the rise in new diabetes cases as evidence. That’s a huge problem with diabetes, but that’s not evidence of a lack of efficacious treatment options – there are plenty, as opposed to AD where there are exactly none. The issue with diabetes is preventing the onset of the disease. It’s not clear to me that this will come in pill form ……. and, as far as I know, nobody is working on such a pill……..

    1. Derek Lowe says:

      That’s one reason I didn’t emphasize the diabetes angle in the blog post – I found the fit awkward for just the reason you describe. Diabetes has not only many drugs, but a choice of several completely different mechanisms! (And for what it’s worth, it can also be partially fixed, if the patient is but willing, by diet and exercise – try that with Alzheimer’s. . .)

      1. David Freedman says:

        It’s true that diabetes makes for an at least slightly awkward pairing with Alzheimer’s, but it’s not entirely off base. If the claim is that there are several effective drugs for diabetes, we need to take a closer look at “effective.” Those drugs are effective in terms of better control of blood sugar levels, which is essentially how diabetes is defined. But almost all of those drugs fail to clearly demonstrate what we really want out of a diabetes drug (or any drug), namely good long-term outcomes. Only more recently do we have Jardiance, which has been shown to improve heart disease outcomes–but that’s really a first for diabetes drugs, and it leaves mostly unaddressed the many other problems that the disease eventually brings on. That may not clearly put it in the same boat as Alzheimer’s, but when you look at the diabetes numbers and trends, it’s hard to argue that it’s not a massive challenge roughly in a league with the challenge of Alzheimer’s–we need new drugs for both to head off growing long-term disease catastrophes.

        1. In Vivo Veritas says:

          I’d argue that there are better and better diabetes drugs that can & will help slow the typical relentless progression of the disease. GLP-1s will demonstrate durable CV benefit. GLP-1/Gulcagon/GIP may be better still. Other diabetes treatments may even be life extending independent of disease progression (see the pharma/aging post in that same Politico & Nir Barzali’s work with metformin). All of that simply increases the number of people living with T2D. The incidence of T2D is increasing for other (societal, social, epigenetic, political, public health, etc….) reasons, none of which are best addressed via pharma.

        2. NJBiologist says:

          “Those drugs are effective in terms of better control of blood sugar levels, which is essentially how diabetes is defined. But almost all of those drugs fail to clearly demonstrate what we really want out of a diabetes drug (or any drug), namely good long-term outcomes.”

          This is true now, and has been for a while, but it says something about how far diabetes care has come. The conversation used to be about managing (maybe preventing) diabetic ketoacidosis and hyperglycemic hyperosmolar state, two frequently lethal acute complications of diabetes. It’s good to push the standard of care forward, but it’s also good to remember that it used to be worse.

  6. screezus says:

    I tuned into Fresh Air yesterday and caught the end of an interview with British neuroscientist Joseph Jebelli on Alzheimer’s disease (and his new book about it). It’s an interesting discussion on the perils of the illness and where he sees possible treatments coming from.

  7. MTK says:

    The entire Politico series of articles on pharma and health is very interesting. One of the main themes is how part of the problem is not just scientific, but also based on public policy and how that policy shapes and influences research within the industry, i.e. orphan drug indications.

    Of course, if specific subtypes of AD or other chronic conditions can be described than they’ll be subject to the same incentives as many current cancer indications. Just as cancer is being increasingly appreciated by the lay public as a vast array of diseases with a common pathology, unchecked proliferation, it’s very possible that AD and other neurogenerative conditions such as ALS will be thought of in the same way. A slew of different diseases of different origin exhibiting a common phenotype.

  8. MoMo says:

    Treating a multifactorial disease with mono-dimensional drugs (relatively) sure has left many corpses and those are just those of biotechnologists and Pharma execs.

    As I’ve said here before- the sooner we all grow up and accept one drug, or maybe even 6, cant treat such a complex disease alone, the better off we as a Drug Purchasing Society will be.

    Instead we shill false-hope with overpriced Dime-Store candy to the masses desperate for help- and they still die young anyway.

  9. Harrison says:

    Somebody should write a book about the history of Alzheimer’s disease research, and why we are in the trouble we are in today. Multi-causal “senile dementia” became Alzheimer’s disease in the 1980s when NIA sought to align a dizzying array of diagnostic practices into a cohesive whole. This was all well and good for finding drugs like the cholinesterase inhibitors. In the early 1990s the amyloid cascade hypothesis was born on the backs of early-onset genes like APP and PS1. Those certainly look like monogenic rare diseases, where if you have the mutation you get the disease. Unfortunately common, late-onset dementia may only have face validity with the early-onset genetically linked disease. The vast majority of cases are “mixed pathology” dementias, but nonetheless classified as Alzheimer’s disease because of a 1980’s policy need. The late-onset cases even have their own genetic risk factor, apoE4, which has been essentially ignored as a research area for 20 years. The field turned to tau-mediated neurofibrillary tangles as a therapeutic approach out of desperation after ignoring them for years during the height of the amyloid research bonanza. Layer all those political aspects on top of something that is inherently difficult to study for the reasons Derek laid out, and you have a problem. One can only hope that the success of patient stratification in oncology will inspire a similar approach in Alzheimer’s.

  10. Anonymous says:

    Several families have been IDed with early onset AD. One large family in Columbia has a presenilin related AD. As of many months ago (when I saw it on 60 Minutes), this family was going to participate in a preventive study using antibodies to amyloid. There is another large family in the same region that has a different form of early onset AD.

    In some (many?) cases, APOE4 is implicated in AD. I wonder if the people at Arvinas are looking to use PROTAC ( to clear APOE4?

    1. Harrison says:

      A number of people are looking at decreasing or sequestering apoE. The problem with PROTAC is you have to degrade apoE in the the brain, and getting those into the brain is easier said than done.

  11. Chris Phoenix says:

    If you want to significantly reduce diabetes in the U.S. today, and SAVE money in the process…

    Quit subsidizing corn.

    1. Chris Phoenix says:

      I should clarify: Not because corn is bad in itself, but so much gets turned into HFCS and added to everything.

  12. Emjeff says:

    Chris Phoenix – I largely agree with you, although I put a little more responsibility on consumers, who surely should know better than to fill their stomachs relentlessly with pre-packaged garbage. However, I am all for decreasing corn subsidies for a whole host of reasons.

    On another topic, who wants to bet that Alzheimer’s ends up being infectious in nature; either viral or bacterial? I say this because all the other hypotheses have been shown to be nonsense. Perhaps dementia is a long-term response to a slow-growing pathogen, or a response to multiple bacterial/viral insults. If so, then one would predict that such a disease would be very hard to treat indeed, as the damage is done by the time symptoms show up. Testing this will be expensive and take a long time, but is probably not impossible.

    1. Some idiot says:

      I had a similar thought whilst pondering the juxtaposition of this blog entry and that previous… Would a search for microbial/viral DNA/RNA in affected tissue (vs healthy, or more healthy tissue) show anything? And then the thought came to me: surely someone has already done something similar. But I haven’t checked to find out…

  13. Stu West says:

    I had difficulty following the part of the article where various people discuss the idea that a drug for a big disease but priced like Kalydeco could break the reimbursement system. Surely the reason for Kalydeco’s high price is precisely because of the small patient population? Can someone fill in the blank on this for me?

    1. Barry says:

      E.g. Sovaldi costs $84,000.00/ treatment. An estimated 2.7-3.9 million people in the United States have chronic hepatitis C. They’re not going to get better untreated. Some, I suppose will die of something else before Hep C gets them. That’s still $20,000,000,000.00 in potential insurance claims at current pricing.

      1. Mister B. says:

        Sovaldi … What a delicious case study, isn’t it ?

        If I’m correct, the drug itself is a breakthrough, having higher cure rates, less side effects, than previous treatment. But pricing was subject to many discussions…

        Derek did an article about this example ( ) and comments were excellent ! 😉

        @Stu, you will get many of your answers in this article’s comment.

      2. Anonymous says:

        $20 B is a familiar number. Amgen sold over $20 B of Epogen and J&J sold twice as much Procrit and Aranesp from 1989 to 2011. However, …. “Amgen and J&J earned billions on the trio of anemia drugs Epogen, Procrit and Aranesp since their introduction in 1989. But over time, an understanding of their risks has grown, as have doubts about their effectiveness.”

        (Low RBC and Hep C are drastically different conditions. To reach those sales numbers, the epo drugs were extensively over-prescribed and overdosed to patients that did not need epo. There are other ways to treat low RBC but no other ways to treat Hep C.)

  14. me says:

    Maybe we can get clues from big data mining exercises. For example, do people who chronically take antivirals, or statins or metformin or who smoke tobacco have higher or lower incidences of AD? How about those who have had anti-CD20 drugs or been treated for RA?Someone must be looking at this.

    1. Kan says:

      Good Idea, I find it hard to believe that no on has looked at this already though..

    2. Barry says:

      It was the observation of fewer colon polyps in long-time NSAID users that moved Merck to launch a clinical study of Vioxx for cancer. Instead of a whole new patent life, they got a disaster.

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