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posted by charon on Thursday February 16 2017, @10:52AM   Printer-friendly
from the senility-creeps-unabated dept.

Dr. Derek Lowe, from In the Pipeline, writes about another disappointing failure to treat Alzheimer's Disease:

Merck announced last night that the first Phase III trial of their beta-secretase (BACE) inhibitor verubecestat was stopped because of futility. The monitoring committee, after looking over the data so far (the trial's been running since 2012) concluded that there was no real chance of seeing efficacy.

[...] The list of Alzheimer's clinical failures is impressive, but the list of failures to clinically validate the amyloid hypothesis is even more so.

[...] Beta-secretase inhibitors have failed in the clinic. Gamma-secretase inhibitors have failed in the clinic. Anti-amyloid antibodies have failed in the clinic. Everything has failed in the clinic. You can make excuses and find reasons – wrong patients, wrong compound, wrong pharmacokinetics, wrong dose, but after a while, you wonder if perhaps there might not be something a bit off with our understanding of the disease. Remember, every time one of these therapies comes around, it builds on the failures before it. Better and better attempts are made – I mean, verubecestat seems to be a pretty good compound, from the preclinical drug discovery perspective. It's surely the best swing anyone's taken at beta-secretase (and there have been many). But it just flat out did not work.

The good news about this study is that it adds to the evidence that the amyloid hypothesis of Alzheimer's Disease is a blind alley and that the presence of amyloid plaques is simply correlative and not causative. As more data comes in from the study, I hope that the evidence will be conclusive enough that more effort will be spent on pursuing other therapeutic targets.

See also: https://en.wikipedia.org/wiki/Alzheimer's_disease#Amyloid_hypothesis


Original Submission

Related Stories

The FDA Saved Taxpayers from Paying Billions for Ineffective Alzheimer's Therapy 57 comments

Dr. Lowe, from In the Pipeline, writes of how the efficacy requirements of the FDA save US taxpayers money:

Remember solanezumab? That was the amyloid-targeting antibody that Eli Lilly kept on investigating in trial after trial, looking for some effect on Alzheimer’s. Last November, the final, final word finally came down that it really, truly, does not work. To recap, mouse model results with a similar antibody were published in 2001. Phase I results of solanezumab itself were published in 2010, and Phase II results were published in 2012.

The authors of the NEJM [New England Journal of Medicine] paper would like to point out that under the current system, the cost of investigating all this was largely borne by the drug’s developers, not the patients and not the taxpayers

[...] Under a system designed to speed up drug approvals, people might have started taking it back in 2010-2012, when the Phase I and II results showed no adverse effects.

[...] We have a very tightly regulated and opaque market indeed in this country for prescription drugs and every other form of health care, and it’s not a very good place to discover prices or utilities. You could imagine a system where these things could be done better than we’re doing them, but such a system would be pretty far from what we have going now.

[...] The NEJM paper estimates, pretty conservatively, that had solanezumab been given conditional approval back in 2012 or so, that we – meaning Medicare, for the most part, which is to say all taxpayers, but also insurance companies and patients – would have spent at least ten billion dollars injecting Alzheimer’s patients with an expensive placebo. No one would have gotten the tiniest bit better. False hope all around, with no benefit, and billions of dollars down the tubes.

Note: Bold added by submitter.

http://blogs.sciencemag.org/pipeline/archives/2017/05/09/there-are-failures-you-know
http://www.nejm.org/doi/full/10.1056/NEJMp1701047
https://en.wikipedia.org/wiki/Solanezumab
https://en.wikipedia.org/wiki/Alzheimer%27s_disease
https://soylentnews.org/article.pl?sid=16/11/27/0147228
https://soylentnews.org/article.pl?sid=17/02/16/0116248


Original Submission

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  • (Score: 3, Informative) by opinionated_science on Thursday February 16 2017, @12:05PM

    by opinionated_science (4031) on Thursday February 16 2017, @12:05PM (#467758)

    It has been shown that the amyloids are responsible - we don't know if they are the *only* factor.

    One proof is really quite simple - give the amyloid gene of different lengths (up to 42) to mice, and they develop symptoms in 10 months which mice normally don't (10 months is ancient for a mouse).
    Trisomy 21(Downs) carriers in humans get Alzheimers very quickly (before 40), as the ABgene is on chr 21 a bad dosage gets amplified.

    The length of the ABeta product matters - aggregation of the fibrils into plaques occurs more aggressively, and is harder to break up.

    There are many compounds we can get to break up ABeta. There are fewer we can get into the body. There are a few (like this) that looked to down regulate AB production.

    There is a strong correlation between diabetes and Alzheimers - yet another reason to stay slimmer than is easy...

    There are no compounds we know that currently work sufficiently to arrest the conditions.

    Drug Design is Hard (TM).

    • (Score: 0) by Anonymous Coward on Thursday February 16 2017, @02:22PM

      by Anonymous Coward on Thursday February 16 2017, @02:22PM (#467785)

      Both the drug mentioned in TFA and the anti-amyloid antibodies from Lilly reduced amyloid in patient CSF (we'll have to wait to see their brains) and they had great results in animal models. If these therapies reduce amyloids, but do not affect disease in any measurable way (despite Lilly running many PIII trials) then at what point do you stop trying to reduce amyloids (at least directly)?

      The animal models were specifically designed to have an amyloid-driven disease and trisomy is not really great genetic evidence. There is better amyloid hypothesis-supporting genetic evidence in some early onset patients but there are also the ApoE4 carrying Nigerians that complicate things by not having the expected phenotype.

      Targeting amyloids seem to be a blind therapeutic alley. Amyloids may still be bad or they may be a biomarker for something bad, but the therapeutic targets that need to be pursued are probably upstream amyloid production or downstream (caspase activation or the immune system).

  • (Score: 0) by Anonymous Coward on Thursday February 16 2017, @12:05PM

    by Anonymous Coward on Thursday February 16 2017, @12:05PM (#467759)

    Too bad biomed programs are driving away all the competent people with their pointless and endless statistical significance hunts. The more money you give them, the more BS they will produce. Amyloids are the most thermodynamically stable state of peptides in general, it is so obvious this idea has cause and effect reversed.

    • (Score: 0) by Anonymous Coward on Thursday February 16 2017, @02:31PM

      by Anonymous Coward on Thursday February 16 2017, @02:31PM (#467792)

      If everything is so fucking obvious to you, then why don't you cure Alzheimer's?

      There is plenty of evidence that plaque formation can be pathological. Prion diseases such as Mad Cow, CJD, and CWD show very direct evidence of transmissible disease.

      Alzheimer's is complicated and there doesn't seem to be anything that is obvious about the causal mechanisms.

      • (Score: 0) by Anonymous Coward on Thursday February 16 2017, @02:38PM

        by Anonymous Coward on Thursday February 16 2017, @02:38PM (#467795)

        If everything is so fucking obvious to you, then why don't you cure Alzheimer's?

        First, knowing something is the wrong approach doesn't mean you know the right approach. You can just tell when people are wasting time/money. Second, I can't stand the culture of the biomedical community. Really, I was so angry and depressed all the time when I had to work with those people.

        • (Score: 0) by Anonymous Coward on Thursday February 16 2017, @03:33PM

          by Anonymous Coward on Thursday February 16 2017, @03:33PM (#467825)

          knowing something is the wrong approach

          You apparently know the amyloid hypothesis is wrong because it is obvious to you. How is all the genetic evidence so obviously wrong?

          I've been skeptical of the amyloid hypothesis for a while and new evidence keeps adding doubt to it being a complete explanation of the causal mechanism of disease, but it is certainly not obvious that it is entirely wrong.

          • (Score: 0) by Anonymous Coward on Thursday February 16 2017, @04:03PM

            by Anonymous Coward on Thursday February 16 2017, @04:03PM (#467839)

            As mentioned, all peptides can form amyloids, they are a generic structure. Beta-sheet aggregates are the lowest energy state for peptides, so there is no mystery they start forming when things get messed up.

            • (Score: 0) by Anonymous Coward on Thursday February 16 2017, @04:56PM

              by Anonymous Coward on Thursday February 16 2017, @04:56PM (#467864)

              Prions also form amyloids and their formation directly induces disease. How is it obvious that the amyloids in Alzheimer's are benign?

              Populations with genetic determinants that specifically predispose them to producing amyloid beta in the brain develop early onset Alzheimer's at a much higher rate than non-carriers. How is it obvious that all these cases are simply a coincidence?

              Populations with genetic determinants that predispose them to have inefficient clearance of amyloid beta in the brain have increased Alzheimer's risk than non-carriers. How is it obvious that these cases are a coincidence?

    • (Score: 0) by Anonymous Coward on Friday February 17 2017, @08:27AM

      by Anonymous Coward on Friday February 17 2017, @08:27AM (#468135)

      Would you mind jotting down the answer in the margin so we may study your works in the future?

  • (Score: 1, Funny) by Anonymous Coward on Friday February 17 2017, @01:31AM

    by Anonymous Coward on Friday February 17 2017, @01:31AM (#468035)

    The obvious rebuttal is that the FDA is holding these companies back.
    If they didn't have to actually prove that these drugs work, the drugs would already be on the market.
    I demand we let the free market decide!! That's the only sane way to operate anyway.