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posted by Fnord666 on Monday November 28 2016, @02:32AM   Printer-friendly
from the now-where-did-I-put-my-keys dept.

The amyloid hypothesis is the theory that the accumulation of beta-amyloids in the brain leads to Alzheimer's Disease. These amyloids are "sticky" protein fragments, and the idea is that something in the body that normally regulates them fails and they accumulate in the brain. The idea was proposed in the early 1990s when it was observed that many Alzheimer's patients exhibited larger than normal amounts of amyloid plaques. This hypothesis has driven a very active area of research for drugs and treatments that address beta-amyloids.

In what some see as a fundamental blow to the hypothesis itself, it was recently announced that one of the leading drugs, solanezumab from Eli Lilly, has failed in a large trial of people with mild dementia. The clinical trial involved more than 2,100 people diagnosed with mild dementia due to Alzheimer’s disease, but the results showed only a small benefit of the drug. Eli Lilly has also been conducting prevention trials where the drug is given to people known genetically to be high-risk for the disease, and they said they will discuss with their clinical trial partners whether they will continue those studies.

Lilly’s result may say more about the characteristics of solanezumab than the accuracy of the underlying amyloid hypothesis, says Christian Haass, head of the Munich branch of the German Centre for Neurodegenerative Diseases. The antibody targets soluble forms of amyloid, he points out, so it “could be trapped in the blood without ever reaching the actual target in the brain in sufficient quantities”.

The appeal of the amyloid hypothesis is that it is a simple one. However, in the 25 years since it was proposed, it has led to essentially no progress in preventing or curing the disease. Criticism of the theory has grown with each failed result.

“We’re flogging a dead horse,” adds Peter Davies, an Alzheimer’s researcher at the Feinstein Institute for Medical Research in Manhasset, New York. “There’s no sign of anybody getting better, even for a short period, and that suggests to me that you have the wrong mechanism.”


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

Positive Result in Mice as Alzheimer's Drug Trials Fail and Regulatory Barriers Are Rolled Back 7 comments

Merck has ended a trial for the experimental Alzheimer's treatment verubecestat, a BACE1 inhibitor, after it was found to be ineffective. Biogen has increased the sample size of a trial for aducanumab, worrying some investors. The news comes after the failure of drugs such as solanezumab and intepirdine to treat Alzheimer's and dementia.

The FDA has proposed new guidelines that would make it easier to treat Alzheimer's by lowering the bar for clinical success:

In proposed new guidelines released on Thursday, the FDA appears open to trial goals that better match early patient populations, including people who have yet to display memory loss or functional impairment, such as the ability to wash or dress themselves or cook meals.

The draft guidelines suggest that improvement in biomarkers, such as amount of beta amyloid in the brain, a protein linked to the disease, may be an acceptable goal for deeming a drug successful in patients with no symptoms. FDA guidelines used in prior studies demanded that a drug demonstrate both cognitive and functional improvements.

A bipartisan group of Senators and Congressman have introduced the Concentrating on High-Value Alzheimer's Needs to Get to an End (CHANGE) Act, which would also reduce regulatory barriers faced by clinical trials. The annual cost of Alzheimer's and dementia care in the U.S. is projected to rise to $1.1 trillion by 2050.

Meanwhile, a group of researchers has found that targeting BACE1 enzymes could remove existing amyloid plaques (in mice):

Knocking back an enzyme swept mouse brains clean of protein globs that are a sign of Alzheimer's disease. Reducing the enzyme is known to keep these nerve-damaging plaques from forming. But the disappearance of existing plaques was unexpected [open, DOI: 10.1084/jem.20171831] [DX], researchers report online February 14 in the Journal of Experimental Medicine.

The brains of mice engineered to develop Alzheimer's disease were riddled with these plaques, clumps of amyloid-beta protein fragments, by the time the animals were 10 months old. But the brains of 10-month-old Alzheimer's mice that had a severely reduced amount of an enzyme called BACE1 were essentially clear of new and old plaques.

An Alzheimer's treatment, donepezil, has been used to treat alcohol-related brain damage in mice.

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  • (Score: 1, Flamebait) by MichaelDavidCrawford on Monday November 28 2016, @02:55AM

    by MichaelDavidCrawford (2339) Subscriber Badge <mdcrawford@gmail.com> on Monday November 28 2016, @02:55AM (#433885) Homepage Journal

    he says that like it's a bad thing.

    --
    Yes I Have No Bananas. [gofundme.com]
    • (Score: 4, Funny) by Hartree on Monday November 28 2016, @03:07AM

      by Hartree (195) on Monday November 28 2016, @03:07AM (#433891)

      Well, it's probably preferred by the horse that's still alive.

      • (Score: 0, Informative) by Anonymous Coward on Monday November 28 2016, @03:13AM

        by Anonymous Coward on Monday November 28 2016, @03:13AM (#433893)

        Fellating. Fellating a live horse.

        • (Score: 0) by Anonymous Coward on Monday November 28 2016, @09:18AM

          by Anonymous Coward on Monday November 28 2016, @09:18AM (#433958)

          Not a big deal for a horse, he can do it himself!

  • (Score: 0) by Anonymous Coward on Monday November 28 2016, @04:06AM

    by Anonymous Coward on Monday November 28 2016, @04:06AM (#433901)

    That's science. Sometimes, you hit a strike. Most of the times, though, you hit the gutter.

    I for one welcome our new editor.

    • (Score: 2, Interesting) by Francis on Monday November 28 2016, @06:02AM

      by Francis (5544) on Monday November 28 2016, @06:02AM (#433921)

      It's going to depend upon why this failed, if it's a matter of it just not getting into the brain, that's one thing.

      But, ultimately, if they've been working in this line for that long without much to show for it, that's probably not a good thing. Unfortunately, biotech can take a long time until you get a result, and if it doesn't work, then you're left starting over again, hopefully with some new insights about why it didn't work.

      • (Score: 0) by Anonymous Coward on Monday November 28 2016, @06:16AM

        by Anonymous Coward on Monday November 28 2016, @06:16AM (#433926)

        Unfortunately, biotech can take a long time until you get a result, and if it doesn't work, then you're left starting over again, hopefully with some new insights about why it didn't work.

        No you won't. Your funding will be gone. Someone else will start over, because you're fired. If you're lucky, you'll end up teaching high school biology. If you're unlucky, you'll never work again.

        • (Score: 0) by Anonymous Coward on Monday November 28 2016, @06:08PM

          by Anonymous Coward on Monday November 28 2016, @06:08PM (#434127)

          The best thing that can happen to most people who get involved (ie creative, inquisitive) is to get out of academic biomed research. It is all politics and gaming metrics at this point. Industry is better but moving the same direction since meeting FDA arbitrary metrics is more important than actually figuring out what is going on or whether some treatment "works".

          • (Score: 1) by Francis on Tuesday November 29 2016, @05:54AM

            by Francis (5544) on Tuesday November 29 2016, @05:54AM (#434361)

            That sounds an awful lot like picking your own poison.

            Ultimately, they both suck and if you don't deliver results you'll have issues with funding. Unfortunately, that means positive results, there's few corporations like Edison's back in the day where you can try thousands of times without success before giving up. Granted, the lightbulb is a rather extreme example and had an extremely obvious application, but I doubt you'd get away with even a fraction of that many tries these days.

  • (Score: 2, Interesting) by Anonymous Coward on Monday November 28 2016, @05:36AM

    by Anonymous Coward on Monday November 28 2016, @05:36AM (#433919)

    If amyloid plaques break connection networks in the brain, just removing the plaques isn't necessarily going to fix the connection networks -- the damage might have already been done. They could also be a symptom rather than the cause. In any case, getting negative results is more information than no information.

    • (Score: 2) by Fnord666 on Monday November 28 2016, @06:37AM

      by Fnord666 (652) on Monday November 28 2016, @06:37AM (#433932) Homepage

      If amyloid plaques break connection networks in the brain, just removing the plaques isn't necessarily going to fix the connection networks -- the damage might have already been done. They could also be a symptom rather than the cause. In any case, getting negative results is more information than no information.

      Several of the other studies are looking at people with a genetic predisposition to the condition. I think the hope was that they would be able to prevent any new plaques from forming.

      • (Score: 0) by Anonymous Coward on Monday November 28 2016, @07:43AM

        by Anonymous Coward on Monday November 28 2016, @07:43AM (#433939)

        The "diabetes type 3" theory seems more promising.

        https://soylentnews.org/article.pl?sid=16/10/16/1657238 [soylentnews.org]

        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3709085/ [nih.gov]

        The plaque stuff has never been convincing to me. It was like saying scar tissue is the problem. In some cases maybe but in most cases you should be looking for the real causes for the scar tissue.

      • (Score: 4, Interesting) by opinionated_science on Monday November 28 2016, @11:34AM

        by opinionated_science (4031) on Monday November 28 2016, @11:34AM (#433987)

        The Amyloid pre-cursor (AB) lives on Chr 21, for which Down's syndrome (21 trisomy) is the only one that lives to adulthood.

        All Downs patients, will get Alzhemiers by virtue of the fact they have 3 copies of A-Beta.

        There are variants from 36-43 amino acids long. The longer this peptide gets, the easier it aggregates.

        If you take the gene from Human and give it to a mouse (which don't get Alz), they get it everytime.

        It's definitely the gene. We simply don't know enough about the mechanism leading to the plaque aggregation and the damage that is done in the process (said elsewhere). So fixing this may not help the patient, as the damage is already done.

        Source: designed some drugs that worked fine in the computer, less fine in the lab...

    • (Score: 2) by Hyperturtle on Monday November 28 2016, @03:34PM

      by Hyperturtle (2824) on Monday November 28 2016, @03:34PM (#434065)

      Also note that removing a symptom does not mean the person is cured.

      I am hoping that the preventative trials, when the medication is given to people that are genetically predisposed to the disease are provided the drug, that it in some way helps prevent or slow down the eventual onset.

      In a way it may turn out to be like aspirin.

      Aspirin does nothing to clean out cholesterol. But it can help prevent heart attacks by thinning the blood. Giving aspirin after a heart attack can't prevent the years of cholesterol build up, and can't repair damage. It can, however, help improve the odds of survival. It is no cure to lifelong damage that surgery was required to patch up, and it is no replacement for other therapies -- like behavioral changes that can further reduce the odds of another heart attack.

      This drug solanezumab may prove to be similar in that an ounce of prevention is worth it because there is no cure. It isn't known if you can proberly exercise dementia away or keep it at bay. Probably, a healthy lifestyle will do you good in this regard as well.

      Since this drug treats a symptom, the plaque build-up, it may very well be that by reducing the amount of plaque over many years, it can help prevent damage that occurs as a result of the plaque build-up, and thus result in lessened or more managable symptoms. For all we know, it may turn into a chronic disease to manage as a result of having to need to regularly take solanezumab to prevent issues from getting worse--especially upon the on-set of middle-age.

      Like aspirin, better late than never -- but it may result in less spectacular results.

      If everything wasn't so profit driven, we may have more drugs that help with prevention... but it costs so much to get modest results, and often failures--at least failures as per the measurements they are taking (modest diminishment of symptoms or delayed onset is a failure compared to a miraculous cure that raises the stock price overnight).

      I hope that they put the drug on the market anyway. If people made homeopathy a multi-million dollar industry, then we have here a drug that very likely provides a real benefit -- even if minor. To throw it away... well. If it comes to that, maybe I can raise the funds to buy the rights to manufacture it and dilute it a million times and call it a treatment and recoup my investment?

    • (Score: 0) by Anonymous Coward on Monday November 28 2016, @04:40PM

      by Anonymous Coward on Monday November 28 2016, @04:40PM (#434089)

      all these stupid hacks ever do is try to treat the symptoms and use people as Guinea pigs so they can learn in general. your disease is just a way for them to get to hack on you. the researchers just want to learn. the drug makers and the government want control over mankind. reproduction, intelligence, life span, thoughts, everything. Chattle get sick and die from stupid shit anyways so you might as well experiment on them before they turn into compost.

      • (Score: 0) by Anonymous Coward on Wednesday November 30 2016, @03:32AM

        by Anonymous Coward on Wednesday November 30 2016, @03:32AM (#434794)

        Chattel + cattle?

  • (Score: 2) by DannyB on Monday November 28 2016, @03:25PM

    by DannyB (5839) Subscriber Badge on Monday November 28 2016, @03:25PM (#434064) Journal

    Strikes A Blow To The Theory? WTF? Who cares about theories and science. What this does is strike a blow to corporate profits for the drugs.

    Can't the FDA please just allow profitable drugs to market on the word of the manufacturer without the inconvenience of needing science behind the drug?

    Corporations say: Please help us Trump, you're my only hope!

    --
    When trying to solve a problem don't ask who suffers from the problem, ask who profits from the problem.