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Doc Gumshoe Follows up on Alzheimer's, Biogen, Anavex... and on evidence and causality in general

By Michael Jorrin, "Doc Gumshoe", October 23, 2019

The many welcome comments to the Alzheimer’s piece that posted a couple of weeks ago prompt me to supply answers (if I am able to do that), but also set my mind to wandering on the fringes of a number of issues that may be of interest to the Gumshoe constituency.

Anavex 2-73

At the top the list, chronologically at least, was a question about Anavex Life Sciences (AVXL) and its leading candidate Anavex 2-73.   Doc Gumshoe discussed Anavex 2-73 in a previous piece about Alzheimer’s, entitled “Alzheimer’s Wrap-Up,” which posted nearly four years ago – December 21, 2015.   At that moment, Anavex had announced, to great fanfare, the results of a small uncontrolled clinical trial in which they gave about 50 subjects their drug, following which they evaluated their cognition, using the standard tests.   Most of these 50 subjects did a little better after being treated with Anavex 2-73, but only a little better.   I find myself in total agreement with what I said then, that there is no way of knowing if that slight improvement on those tests was due to the drug.   There was no control group as a basis of comparison, and it would hardly be surprising if these 50 subjects, pleased and excited to be in a clinical trial of a supposedly promising new drug, actually did do a bit better on those tests.   That could be considered a placebo effect.   The absence of a control group increased my skepticism by at least a factor of ten, and the ballyhoo surrounding the announcement of the test results by another factor of ten.

That was four years ago.   What has happened since?   A few months ago, Anavex Life Sciences announced a Phase 2 study, to be conducted in Spain, to evaluate Anavex 2-73 as a treatment for dementia in patients with Parkinson’s disease.   

What Anavex 2-73 does is target the sigma-1 receptor, which is located in the endoplasmic reticulum in the brain.   Activation of this receptor is said to stimulate the functioning of the cellular recycling system, which gets rid of old cells and permits the growth of new cells, preventing the accumulation of toxic protein clumps, including amyloid beta and tau protein.

Anavex cites experiments in mice and worms to support their claims that their drug may be effective in improving cognition in humans.   In mice, Anavex 2-73 restored the function of damaged nerve cells and improved motor function.   In worms, deposition of amyloid beta induced paralysis, which was reversed by Anavex 2-73.

It seems pretty clear that Anavex 2-73 is a long, long way from emerging as a useful drug in the treatment of Alzheimer’s disease.   Whether one of the Big Pharma moneybags sees promising signs in the doings of Anavex and swoops in with an offer too big to refuse is anybody’s guess.   My guess is that it’s Anavex’s big hope. 

Donepezil and Memantine

Both of these drugs are among the tiny few that are actually FDA approved for the treatment of Alzheimer’s disease.   Donepezil (Aricept), from Eisai/Pfizer, was originally marketed for Parkinsonism, and has demonstrated clear benefit in preventing falls, which commonly affect Parkinson’s patients and is one of the troubling symptoms of that disease.   The effect on cognition, both in Parkinson’s and Alzheimer’s, is small – at best it slows the decline.   

Donepezil is a cholesterinase inhibitor, cholesterinase being an enzyme that degrades acetylcholine, which in turn is a neurotransmitter essential for brain activity.   So the essential mechanism of donepezil is that it slows down the agent that degrades another agent that is essential for transmission of information in the brain.

Memantine (Namenda), from Forest Pharmaceuticals, an antagonist of N-methyl-D-aspartate (hence the name Namenda), is thought to work by preventing glutamate-induced damage of neurons in Alzheimer’s disease.   As with donepezil, the effect on cognition consists at best of slowing the decline.

Donepezil and memantine are frequently prescribed together in the hope that the dual mechanisms of action will slow the decline in cognition to a greater degree than could be achieved by either drug alone.

Enbrel and Alzheimer ’s disease

Amgen, the maker of Enbrel (etanercept) has been accused of prioritizing their profit margin over the possibility that their highly successful drug might be valuable in the treatment of Alzheimer’s.   

Enbrel, as perhaps you know, is one of a handful of drugs that is highly effective in the treatment of rheumatoid arthritis.   Enbrel’s mechanism of action is that it binds to a receptor on a cytokine called tumor necrosis factor alpha (TNFα), thus preventing TNFα molecules from using that same receptor as a way of binding to sites in the body, where it causes severe inflammation.   There is some evidence that TNFα exacerbates the harmful effects of amyloid beta and tau protein, as well as very early evidence that TNFα antagonists such as Enbrel may delay the progression of those harmful effects, and thus may be useful in the treatment of Alzheimer’s disease.  

The most substantial evidence supporting the role of Enbrel in Alzheimer’s comes from an observational study based on insurance claim data.   The data from two cohorts, each of 127,000 individuals, were compared.   One cohort had been diagnosed with Alzheimer’s disease and the second cohort was free of Alzheimer’s.   In the second cohort, without Alzheimer’s disease, 302 individuals were being treated with Enbrel, while in the first cohort, with Alzheimer’s, 110 individuals were being treated with Enbrel.   Based on that somewhat doubtful evidence, it seemed to be a reasonable conclusion that Enbrel might be beneficial in preventing Alzheimer’s disease.

Why then did Amgen not go forward with a clinical trial to shed more light on this intriguing possibility?   Several commentators have suggested that Amgen turned its back on a research avenue that might possibly have led to a huge win in the battle against Alzheimer’s, and did so for a sordid motive: the patent life of Enbrel is drawing to a close, so it’s not worth their while to invest in more research on that drug.   

Putting it that way does indeed sound sordid and far from the reputation-enhancing posture that big pharma outfits like to adopt.   But considering the realities, it would be hard or Amgen to have come to a different conclusion.   For one, to get positive data on the effect of etanercept/Enbrel on the progression of Alzheimer’s disease, it would be necessary to conduct a very large trial – several thousand subjects – over a long period – several years.   The price tag would certainly be close to a billion dollars, or possibly even more.   And the study sponsor would obviously have to take into consideration the really long odds against such a trial being even a relative success; after all, the success rate for Alzheimer disease trials to date has been close to zero.   All in all, I don’t think Amgen’s failure to follow up on the distant possibility that Enbrel might be a useful treatment modality for Alzheimer’s is all that sordid.

Alpha blockers and dementia

A couple of readers commented on the possible relationship between tamsulosin (Flomax) and dementia.   Tamsulosin is a member of a class of drugs called alpha blockers, whose principal use is in the treatment of benign prostatic hyperplasia (BPH).   BPH is a fairly common condition that can affect that subset of the human race that has a prostate gland (namely, us males).   What happens is that the prostate enlarges and put a squeeze on the urethra, which passes right through the prostate.   This makes it difficult to urinate.   

Alpha blockers block the receptors for the alpha form of adrenaline, a hormone that has a range of effects, most notably the so-called “fight or flight” response.   In general, adrenaline tends to increase muscle tension, speed up the heart rate, increase respiratory function, constrict the arteries, and raise blood pressure.   Alpha blockers have a blood pressure-lowering effect, but their cousins, the beta blockers are more generally used as antihypertensives.   

Currently, the primary usefulness of alpha blockers is to alleviate BPH.   Several alpha blockers are used for that purpose, including tamsulosin, doxazosin, terazosin, alfuzosin, silodosin, and prazosin. 

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The link between alpha blockers and dementia was explored in a retrospective analysis using Medicare data.   This study concluded that tamsulosin could increase the risk of dementia in men with BPH who are between 65 and 74 years of age.   Oddly, in this study the increase in the risk of dementia in men over 75 years of age was lower than in younger patients.

The Medicare-based study was contradicted by a Korean study based on data from their National Health Insurance database, which included nearly 60,000 patients with BPH.   The alpha blockers used by patients in the study were tamsulosin, doxazosin, terazosin, and alfuzosin.   Of the four blockers, terazosin was associated with the highest risk of dementia; however, the risk of dementia was somewhat lower in all four cohorts using alpha blockers than in the cohort that was not using any alpha blocker. 

What can we conclude from this?   Not a whole lot.   We can’t say either that alpha blockers contribute to dementia or that they protect from dementia.   To the reader who said that the Korean study permitted him to breathe easier, Doc Gumshoe would add his own conclusion, that breathing easier might well be an excellent way to ward off dementia.  

How reliable is the evidence on health-care issues?

That is, of course, the central question when it comes to assertions about risks to our health and our lives.   The competing assertions about whether the drugs used to treat one disease or condition either exacerbate or alleviate another disease or condition are frequently supported by evidence of doubtful quality.   This is true also of the relation between many of our habits and activities and our health.   For example, there is ample evidence that inhaling the smoke that issues from burning tobacco is severely injurious to our health, resulting in several diseases and shortening the lifespan of smokers.   The evidence for this is robust.   We have very strong statistical evidence of the link, and we also have a very clear understanding of the mechanisms through which inhaled tobacco smoke causes this damage.

Here’s an instance of an assertion that had mostly gone uncontested, but has recently been questioned based on the strength, or lack of it, of the evidence supporting that assertion.   About three weeks ago, on October 1st,  Annals of Internal Medicine  published a paper entitled “Effect of Lower Versus Higher Red Meat Intake on Cardiometabolic and Cancer Outcomes: A Systematic Review of Randomized Trials.”   It was in their “Clinical Guidelines” section, from the American College of Physicians.   

The conclusions of this paper essentially contradicted the advice of nutritionists going back at least a couple of generations, that eating red meat, whether fresh or processed, was bad for our health, particularly with regard to cardiovascular diseases.   The authors of the study reviewed 12 eligible clinical trials that attempted to evaluate the effects of red meat in our diets.   The trial that provided the most reliable evidence enrolled 48,835 women and attempted to evaluate the relationship between dietary red meat and all-cause mortality, cardiovascular mortality, and cardiovascular disease.   In all three of those cases, the evidence suggested that these diets have little or no effect on those three outcomes.   In each of those three case, the calculated hazard ratio was 0 .99, with the confidence interval narrowly spanning 1.00.   Similarly, red meat was found to have little or no effect on total cancer mortality, the incidence of cancer, and breast cancer.   The evidence supporting those conclusions was evaluated as being of low to very low certainty.   

The conclusion stated in the study was this:  “Low- to very-low-certainty evidence suggests that diets restricted in red meat may have little or no effect on major cardiometabolic outcomes and cancer mortality and incidence.”

This contradicts the guidelines from most major national and international health organizations, including WHO’s International Agency for Research on Cancer, which four years ago proclaimed that people should avoid processed meats if they want to avoid certain types of cancer.   The American Heart Association and various US government agencies have also suggested cutting back on meat eating for the sake of better health.  

The authors of the Annals study have said that people could go right on eating meat if they want to.   However, various commentators of the study have pointed out that there are other issues linked to meat consumption, including animal welfare issues, and the environmental costs of raising animals for food.

And it has also been pointed out that it matters a great deal what people consume instead of red meat and processed meats.  Making up for the protein in meat requires adding nutrient-rich vegetables, dairy, nuts, olive oil, and such, but avoiding junk food.   It’s certainly possible that some of the red meat avoiders did eat a lot of junk food, which is why any healthful effects of meat avoidance might have been negated by the unhealthful effects of what they ate instead.   Short of a large, rigidly controlled, lengthy trial, it’s impossible to be precise.

What else might be affecting those conclusions?

Particularly in retrospective or observational studies, where multiple factors are taken into consideration before arriving at a conclusion, the results of the study may be due to factors that are ignored.   For example, a study of that type a few years ago was conducted in New York City on a population of patients in the city hospital system.   The aim of the study was to validate the assumption that people could derive measurable benefits by avoiding sugary soft drinks.   The basis of the assumption was the observation that consumption of sugary soft drinks was a contributing factor to the development of type 2 diabetes.   But one of the findings of the study was that individuals who regularly consumed artificially sweetened soft drinks had a higher mortality rate than the general population.   Why would this be?

The study was not powered to evaluate any other life-style habits of the individuals in the study, beyond recording their ages and what kind of beverages these individuals regularly consumed.   A possible explanation for the difference in mortality might be that the artificial sweeteners in the diet drinks had some toxic qualities, even though there has been no real evidence.   But another explanation is that people who choose the diet soft drinks use that as a pretext to indulge in other unhealthy foods, and it was the other parts of their diets that caused the disparity in mortality rate.   In other words, what else were they eating or drinking?

A similar situation emerged in one of the earliest studies of hormone replacement therapy (HRT), the Nurses Study, published in 1976.   One of the conclusions of that study was that HRT led to a number of specific health benefits.   Many of these were flatly contradicted by the Women’s Health Initiative, which got going in 1993.   Again, how could this be?   Both studies were large and scrupulously well conducted.   However, a factor that was not considered in the Nurses Study was that those nurses who were using HRT might have been generally more particular about a healthy life style, and that it was differences in life style and not HRT itself that contributed to those health benefits.

Once again, it might be factors that are not included in the study that account, at least in part, for the findings.       

The same reservations apply to many other cause and effect links

Several readers – not just of the Doc Gumshoe tract about Alzheimer’s, but of a number of others – cast serious doubt on the efficacy of pharmaceuticals in general, making statements such as:

“Like cancer and heart disease, there won’t be an artificial drug cure for Alzheimer’s either. For all three, it isn’t even fully understood how they develop.   The best cure for any disease is the one thing that Big Pharma hates beyond all the world…prevention. ” 

Those doubts – or should I say, convictions – are frequently accompanied by assertions that pharmaceutical companies are engaged in a plot to suppress information about “natural” treatments for disease in order to protect their own ineffective but expensive “artificial drugs.”   I suspect that at least a part of that mindset comes from mistrust of the evidence that pharmaceutical companies and the medical profession in general present in support of specific drug treatments for a disease or condition.    

And by the way, Big Pharma certainly does not hate prevention.   Several of the most widely used pharmaceuticals are used expressly for prevention.   Of course, advocates of “natural” treatments will point out that those drugs are mostly used in persons who have conditions that might have been prevented in the first place – i.e., if you had been on the right diet or taking the right supplements for most of your life, you wouldn’t have developed hypertension or elevated cholesterol.  I wonder.

Given the complexity of the process of drug development and the experiments that are conducted, at huge expense and involving sometimes thousands of people, it is almost inevitable that doubts should arise as to the strength of their evidence.   What is being investigated is a possible cause and effect relationship: does drug A cure disease B?   As has been pointed out, cause and effect relationships are almost impossible to observe directly.   We see the bat hitting the ball, and we see the ball flying out to the center field fence, but we cannot actually see the transfer of energy from the bat to the ball.   We can only infer it.   

This is true also of the effect of a drug, whether artificial or natural, on our physiology or on whatever is causing the disease that affects us.   We can only infer that the disease has a cause, and that if the disease goes away or lessens in intensity, it is that drug that brought about that change.   In some cases, this can be quite difficult. 

When it comes to issues like the treatment of infectious diseases, we can be pretty certain whether a particular treatment “cures” a specific infection.   You notice I put  the word “cures” in quotes.   With regard to infectious diseases in particular, there are two sorts of “cures.”   “Clinical cure” means that the particular symptoms of the infection go away.   “Bacteriologic cure” means that the presence of the pathogen that causes the infection has been reduced at least to nearly undetectable levels.  Both kinds of cures are necessary to establish good evidence that the drug or treatment works.   And even then, the possibility exists that our own immune system attacked the pathogen, reduced the population of the pathogen, and eliminated the symptoms.   The observation of the specifics of what happens when a drug is used to treat an infection is made in the light of extensive clinical background experience, e.g., it generally takes about ten to fourteen days for that particular infection to run its course, so if the symptoms go away in three days, it’s probably the drug.   That’s a clinical cure.   A bacteriologic cure is declared when the number of pathogens per milliliter drops below the number needed for that particular pathogen to multiply.   What are being measured are called “colony-forming units,” or CFUs – a quantity that is known for most pathogens.   Thus, the evidence supporting the effectiveness of most drugs used to treat infections is considered to be quite strong.   

But that degree of certainty is much more difficult to attain in most other diseases.   The word “cure” is often linked with “cancer” and other diseases, more often than not in an optimistic way, or perhaps as an advertising come-on.   In serious discussions of cancer treatment, the kinds of phrases that are perhaps equivalent to “cure” are phrases such as “progression-free survival” or “undetectable” levels of a cancer marker.   Those can certainly be measured, but not until quite a long time after the initial onset of the particular cancer.   To develop statistically significant and clinically meaningful evidence about a treatment for a specific form of cancer takes much longer, and in many cases is much more ambiguous.  

And when it comes to drugs whose purpose is not to treat a specific disease, but to prevent it, or at least to lower the risk of developing that disease, the strength of the evidence runs from very strong to flimsy or non-existent.   For example, it’s pretty clear that antihypertensive drugs diminish the risk of heart disease.   We understand the ways in which high blood pressure contributes to the risk of heart disease, we understand the mechanisms through which antihypertensives lower blood pressure, and we have excellent statistical data, going back several decades, demonstrating that in large populations, subjects taking high blood pressure medications have fewer heart disease events.  

With regard to cholesterol-lowering drugs, the evidence for their effectiveness in reducing cardiac risk is pretty good, but not iron clad.   We have strong data showing that in individuals who are already at an elevated risk for cardiac incidents, lowering cholesterol reduces that risk.   The data on risk reduction in the general population not at elevated risk for cardiac events is reasonably good, but not as strong as for at-risk persons.   We generally know about the way deposits of cholesterol-carrying low-density lipoprotein particles in our arteries are the causative entities in heart attacks and strokes, but we aren’t a thousand percent sure about what causes those particles to behave in that way.   We think perhaps inflammation has a role.   We know how statins reduce the levels of those low-density lipoprotein particles in our circulation, but we’re also aware of some limitations to their usefulness.   

That the evidence in favor of using statins and other cholesterol-lowering agents is not iron-clad in no way means that we should throw them in the trash.   It seems to me that many advocates of abandoning statins are mostly at the same time also advocating alternative treatments with absolutely zero evidence in their favor.   (Note: I am not talking about PCSK9 inhibitors!)   It’s possible that some of these treatments may turn out to be as efficacious, or even more, than the current standards.   But that would have to be established in a thorough, painstaking, and entirely open way.   This has not happened so far.   

Dementia in women may be underdiagnosed for a counterintuitive reason

You may have noticed in the previous Doc Gumshoe piece about Alzheimer’s that about two-thirds of the 5.7 million people in the US currently diagnosed with Alzheimer’s are women.   The main reason for that huge discrepancy is that women, on average, live about five years longer than men, and it’s in those last five years of life that Alzheimer’s typically manifests.

But now a news item emerges that suggests that dementia, and by implication Alzheimer’s disease, is underdiagnosed in women.   That’s because women generally score better on tests of amnestic mild cognitive impairment than men.   Amnestic mild cognitive impairment – a mouthful! – basically means that the manifestation of that particular form of dementia is forgetting words.   But tests of this early form of dementia (aMCI for short) are used, among several others, as an aid in detecting the earliest forms of Alzheimer’s.   Because women in general have an edge on this test, their scores may stay above the level that constitutes an early warning sign of AD, which can have negative implications for the chance to manage the disease, or at least cope with some of its manifestations.   In other words, women with early signs of Alzheimer’s or of dementia may be missed.

In a study done at the Albert Einstein School of Medicine in New York City, researchers looked at Rey Auditory Verbal Learning Test (RAVLT) scores in a cohort from the Mayo Clinic Study of Aging.    The RAVLT involves learning a list of 15 unrelated words and recalling as many words as possible over five immediate-recall trials, and then learning another list and recalling these words after a 30-minute delay.   Women significantly outperformed men in RAVLT scores – 42.3 vs. 35.6 on the immediate recall test, whose scores can range from 0 to 75,  and 6.2 vs. 4.5 on the delayed recall test on a range of 0 – 15.   This difference does not necessarily mean that the cohort of men in the test were experiencing more severe dementia than the women; forgetting names and words is far from a definitive indication of dementia.   But tests such as the RAVLT are often used in assessing the relative cognition of patients in whom dementia is suspected.   That difference, by the way, was detected in a population in which the women on average were nearly five years older than the men.

When a diagnosis of aMCI was made based on the combined scores for both sexes, this diagnosis was made much more frequently in men ( P < 0.001) than in women, but when the scores were evaluated on a sex-specific basis, this difference was eliminated (P = 0.62).

The frequencies of a diagnosis of aMCI using sex-specific diagnostic criteria compared with conventional criteria increased from 26% to 36% in women and decreased from 45% to 35% in men.   Further examination of cerebrospinal fluid and depositions of tau protein and amyloid beta, as well as frequency of the APOEε4 gene, which is strongly associated with AD, supported the hypothesis that sex-specific diagnostic criteria significantly improved accuracy. 

You may well ask why this matters, if there are no treatment options that have been shown to delay the onset of Alzheimer’s once the disease has taken root?   Well, that dismissive statement is not totally accurate.   The above-mentioned drugs that are mostly used in Parkinsonism – donepezil and memantine – do seem to slow down the progression of AD, and a number of non-drug therapies that keep the mind and body healthy, busy and stimulated, also seem to help.   Best to get as early an indication of creeping cognitive loss as possible and adopt whatever at that moment appears to be most helpful.

Breaking news: BACE inhibitor aducanumab is not dead in the water

In the Doc Gumshoe 2019 refresher on Alzheimer’s disease, I reported that Biogen/Eisai had announced that they would end the Phase III trials of aducanumab in early AD and suspend further investigation of that once-promising drug.   Yesterday that decision was reversed, based on further analysis of those two trials.   Those two trials were stopped in March of this year, based on a futility analysis that relied on early data from 1,748 subjects who had completed the 18 months study period.   However, since then, further data from the full study, which had 3,285 subjects, became available.   Based on a new analysis of the larger dataset, a different outcome emerged.   In one of the two trials, the subjects being treated with aducanumab demonstrated 23% less clinical decline from baseline on the Clinical Dementia Rating – Sum of Boxes scores than did the placebo group, which was determined to be clinically significant (P = 0.01).   Based on these data, Biogen/Esai will apply to the FDA for approval of aducanumab in the treatment of patients with early AD.   

This looks at least like a glimmer of good news.

* * * * * * *

One of the Planet Gumshoe denizens upbraided me for saying something about “an old geezer losing his marbles.”   In my defense, I used that perhaps offensive phrase when I was attempting to explain why people might not be too eager to go through the process of being diagnosed for Alzheimer’s.   If the answer was that the person in question was indeed in the early stages of AD, that was certainly not good news, because he or she could not be offered a ready and effective treatment.   But if the answer was that it was not Alzheimer’s, then the answer was also not good news, since it likely meant age-related dementia – i.e., the offensive phrase quoted above.   

Thanks for the many interesting comments and my very best to all, Michael Jorrin (aka Doc Gumshoe)       

[Ed note: Michael Jorrin, who I dubbed “Doc Gumshoe” many years ago, writes about health and medicine topics for us a couple times a month.  He has been a medical writer for a long time (I didn’t say “geezer”), but is not a doctor.  He does not generally comment on investment topics, but has agreed to our disclosure and trading rules]

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vivian lewis
October 23, 2019 11:04 am

the reversal in the Biogen-Eisai phase 3 trials is an extraordinary event. The 2 companies early this year decided that their drug did not warrant further expenses for trials but the US Food & Drug Admistration called for a closer look at longer-term treatment results. And then it turned out that the people treated the longest with aducanumab did show better outcomes. I hope the FDA gets a royalty but meanwhile our stock ESALY is looking good too. The focus has been on the US but in fact Japan, with a much older population, is more in need of an Alzheimer’s drug.

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docdill
docdill
October 23, 2019 11:06 am

Thank you for the excellent discussion

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Eigard
Irregular
Eigard
October 23, 2019 11:55 am
Reply to  docdill

Xlnt indeed!

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Tom M
Member
Tom M
October 23, 2019 11:37 am

Thanks for the update. I am extremely skeptical of evidence based standard medicine since the review and trial process is highly flawed and tilted in favor of success. There is far too much vested interest and conflicts of interest for me to ever accepted most drug data. And the majority of it never sees anything but the shredder or is keep under lock and key. If I ever have a major problem or ailment, I will use every natural process I can find to heal it. I have no desire to just manage a disease with standard drugs and accept the side effects as natural. Almost every ailment has a non-drug cure but because they do not add to the profits of the medical community, they are ignored. I do not agree that Big Pharma is in the prevention business other than to have patients taking endless drugs for many decades for which they have no clue as to the long term consequences…or if they do, that truth will never see the light of day.

Paul Johnson
Paul Johnson
October 23, 2019 7:06 pm
Reply to  Tom M

Why do you think that the various “natural” remedies touted by the (highly profitable) non-FDA regulated vendors of natural products on scant to zero scientific evidence are any more likely to be effective ?

J Thomas
Guest
J Thomas
October 28, 2019 12:47 pm
Reply to  Paul Johnson

I am constantly amazed at the number of apparently legitimate studies that show that people who consume the most of a particular item have the lowest incidence of certain ailments — vitamins D, A, B-complex for example, and/or nuts and seeds etc. etc.
The evidence is out there to be found, seems to me.

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Yep
Yep
October 23, 2019 12:17 pm

As someone with diagnosed severely clogged arteries recommended 2 1/2 years ago for quadruple bypass surgery I can attest to the benefits of a plant based diet, exercise, and stress reduction. It’s a fact that saturated fat clogs arteries. It is highly likely that inflammation is what causes the plaque to rupture and cause a heart attack. For anyone to suggest that red meat and it’s saturated fat is not implicated in heart disease is to be a fool. BTW, I never had the surgery and am doing great on a plant based diet.

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Denoise Duve
Guest
Denoise Duve
October 23, 2019 12:51 pm

Thank you for your ongoing contributions to this subject. Having lost my mother in law to this heinous disease my wife now worries it is hereditary as it seems to run in her family.
Your periodic review of the state of advancement in this area are helpful in our understanding of where we can look for help.
Again thank you for your efforts.

Atil
Guest
Atil
November 5, 2019 8:15 pm
Reply to  Denoise Duve

Vascepa by Amarin is touted to reduce the risks of CAD/CVD.

Mike
Member
Mike
October 23, 2019 1:13 pm

Micheal – Thank-you for your follow-up but I feel you have shortchanged us again on Anavex. They have a placebo controlled phase 2b/3 trial. They also have good work on Parkinsons and Statistically significant trial result in Rhetts syndrom. Patients are switching from placebo to Anavex 2-73 on request and staying on trial so they can continue to receive the drug. I don’t think you actually looked again.

For your readers. The ATTENTION-AD study (Open Label Extension Study for Patients with Early Alzheimer’s Disease (AD) Enrolled in Study ANAVEX2-73-AD-004), which is an extension of the Phase 2b/3 ANAVEX®2-73-AD-004 clinical study currently underway, will give AD patients an opportunity to continue their treatment. This study is expected to last two years for patients included in the ANAVEX®2-73-AD-004 study, once they have completed the placebo-controlled 48-week Phase 2b/3 trial.

ATTENTION-AD will be conducted in parallel with the Phase 2b/3 ANAVEX®2-73-AD-004 study.

All patients who participate in the Phase 2b/3 ANAVEX®2-73-AD-004 study will be eligible to participate also in the ATTENTION-AD study under a voluntary open label extension protocol.

“This is an important development as the patients who have completed the main study, ANAVEX2-73-AD-004, are consistently expressing the wish to gain ongoing access to this investigational therapy” says A/Professor Stephen Macfarlane, FRANZCP, Head of Clinical Services at the Dementia Centre, HammondCare and Principal Investigator for both studies.

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Mike
Member
Mike
October 24, 2019 9:32 pm

Thank-you !

Gene_S
Gene_S
October 23, 2019 1:18 pm

https://www.drperlmutter.com/the-failure-of-alzheimers-drugs/
There is a FULL SERIES replay all weekend long
from 12:00 noon Friday, October 25th – October 27th at 11:59 PM

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OSUfball
Irregular
October 23, 2019 2:16 pm

A little off topic, but has anyone joined KSS’s new service once he stopped writing here? It seems pricey and am wondering if its worth it. Thanks.

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Dave R
Dave R
October 23, 2019 9:26 pm
Reply to  OSUfball

I lost a lot of money on his previous service.

Dave R
Dave R
October 23, 2019 9:27 pm
Reply to  OSUfball

I lost a lot of money on his last service.

catherine
catherine
October 23, 2019 10:26 pm
Reply to  OSUfball

The short answer is yes, and I’ve seen names from here on the new site. If you hope to be contacted, I’d suggest you offer your email address, as you are correct about it being off topic.

elg_66
October 23, 2019 5:56 pm

Excellent follow up, Michael.

Is there any evidence in the literature that you are aware of about increased incidence of early Alzheimer’s due to prolonged reduced oxygen tension such as in flight crews? Both my brother and a close friend, both career commercial airline pilots began to develop Alzheimer’s symptoms around age 65. I had heard a rumor that this may be a problem for all such flight crew members including cabin attendants, but I haven’t found anything yet on a Google search. The military probably hasn’t studied this since their career pilots aren’t exposed this way. – they either use oxygen (fighter pilots) or don’t fly near the hours at 10K foot pressurization in similar transport aircraft that commercial airline flight crews do. The commercial crews are up and down all day long for long days for several weeks each month. Any thoughts?

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Atil
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Atil
November 5, 2019 8:37 pm

There could be an underlying problem causing the Alzheimer-like symptoms in these pilots. Given their age, the symptoms could be traced to a weakened heart condition possibly from undiagnosed or inappropriately treated hypertension, which ultimately compromises the heart’s ability to pump sufficient blood and oxygen supply to the major organs of the body, including the brain, which has to shut off to protect itself, in the case of a failing heart. Other contributing lifestyle factors like faulty diet, stressful home life, work environment, lack of, or excessive exercise, fatigue, and genetics. Often the development of amyloid plaques in the brain causes it too.

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Bourbon
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Bourbon
October 23, 2019 7:12 pm

This is a rather incomplete analysis of Anavex 273. It omits the follow-up studies of the p2 alzheimers group which are now in their fourth year with patients showing stable to improved performance. It omits the Rett Syndrome test, which showed remarkable improvement by using Anavex 273 in just 7 weeks. While the PDD study in Spain is mentioned, there is no mention of this study being extended to Australia also. The Rett test has also been expanded from the USA to Australia. The fact that the Australia govt is sponsoring all the Australian tests shows that they see something worth investing in.

In addition the article omits that Anavex has done genomic analysis of test patients to determine the genotypes that will most benefit from 273. Plus the mechanism of 273’s action has been described in recent independent research.

So the conclusion that Anavex is a long, long way from a marketable durg is simply wrong. It is likely that Australia and maybe the EU will approve it in 2020.

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Bourbon
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Bourbon
October 23, 2019 7:29 pm

Doc, I found this comment very interesting:

“Memantine (Namenda), from Forest Pharmaceuticals, an antagonist of N-methyl-D-aspartate (hence the name Namenda), is thought to work by preventing glutamate-induced damage of neurons in Alzheimer’s disease. ”

It is interesting that the strong statistically significant result in the Anavex 273 Rett test was tied to its ability to lower GLUTAMATE levels significantly. So it should work with alzheimers patients also.

Please take another look at Anavex. A successful alz drug is worth $20 billion as shown by BIIB’s market movements. If Anavex has an alz winner, with its market cap of $150 million, AVXL could be the investment of a lifetime!

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Mike
Member
Mike
October 23, 2019 7:46 pm
Reply to  Bourbon

I completely agree = as I made similar comments above. I can’t for the life of me figure out why people are ignoring (Doc included) there excellent results. I feel like it is a big Pharma thing ???? oh well – good for us I guess lol

clarkf
clarkf
October 23, 2019 8:54 pm

Great research! Kind of reminds me of the old radio program by Paul Harvey…And Now You Know the Rest of the Story.

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RampageKy
Member
October 24, 2019 12:10 am

I bought some Biogen earlier this year because I figured the upside/downside risk was worthwhile for a long-term investment. Reading these biotech stock reviews from Doc Gumshoe is about the extent of my medical education. So I might be missing something, but the Alzheimer’s study being reinstated sounds all kinds of fishy. Is a 23% reduction in clinical decline that significant? It sounds like the disease would be expected to progress at a slower pace, but it’s still growing. That might even be a worse outcome than letting nature take its course.

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Bourbon
Guest
Bourbon
October 24, 2019 3:22 pm
Reply to  RampageKy

Check the timing of BIIB Mgt’s bonus, stock options
The cynic in me says they needed to hit a target level to cash in their bonuses and options, and the earlier failure left them getting nothing. So shortly before year-end, they float this out there to pump up the stock price.
They even get Cramer to pump it.
Mgt gets their bonuses and cashes in their stock options at year-end, then the FDA pulls the plug next spring or summer. Mgt says they tried their hardest but all the fingerprints are the mean old FDA’s.
All for the cost of a few PRs and some paperwork.
The perfect heist, makes Ocean’s 11 seem like amateurs.

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Ljjdcm
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Ljjdcm
October 25, 2019 2:28 pm

A glimmer of good news? A drug that totally failed being brought back for FDA approval that doesn’t even freaking work? A probiotic study showed more benefit than this garbage. The Amyloid theory as causal is BS – the plaque is defensive -the only way this drug can have any palliative effect is to lower inflammation via immune suppression. Still, there’s lots of money to be made even on drugs that don’t work and when they find out that it’s actually causes other health issues – the lawsuit payouts will amount to nothing more than just the cost of doing business.

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Ralph
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Ralph
November 19, 2019 12:53 pm

“Breaking news: BACE inhibitor aducanumab is not dead in the water” Aducanumab is not a BACE inhibitor.

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sigmull
sigmull
December 18, 2021 8:29 pm

just came across this very late. We would appreciate bringing us up to date on Casava Sciences who are the furthest along in a Phase 2/3 study of Alzheimer’s.
They were derailed by a short seller accusations a couple of months ago.

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