More on the Aduhelm Backlash and Something Interesting ... to Nerds

****I've been working to figure MailChimp out, and make the blog post emails more readable.  This should be an improvement over yesterday's post.****

We said in yesterday's post that some insurance companies will likely balk at Biogen's high price for Aduhelm.  Last week, insurer Point32Health indicated that they were unlikely to cover Aduhelm, at least at the proposed pricing.  Point32Health was formed as a merger between Tufts Health Plan and Harvard Pilgrim Health care, and it serves 2.2 million members in New England.  Point32Health's president, Dr. Michael Sherman, told the Boston Globe that Biogen was favoring corporate profits over patient interests.  He believes the price should be a tenth of what Biogen is starting with.

As we discussed in Beating the Dementia Monster, Aduhelm is one of several treatments that can remove amyloid plaques from the brain.  The prevailing understanding of the disease for a long time was the idea that the principal characteristic of the disease was the accumulation of amyloid plaques on nerve cells.  An over-simplification: the plaques interfere with the functions of brain cells and interfere with communication between cells.  The plaques eventually kill the cells.  This was called the amyloid hypothesis.  Alternatively the tau hypothesis focuses tau protein pathology in the microtubules. 

At least in its original form, the Amyloid hypothesis did not account for the tau tangles that Alois Alzheimer saw with his microscope in the brain of a 55-year old German hausefrau, Auguste Deter.  (We discuss tau tangles in Beating the Dementia Monster.)  This was, of course, during her autopsy.  Nevertheless, an important theme of the search for an Alzheimer's drug has been that an effective drug must remove the amyloid plaques.  Ban2401 is one of several other treatments that can do this.  The expectation is that, if you remove the amyloid plaques, you both stop progress of the disease and improve cognition.  

But it hasn't worked out that way.  Ban2401 has not, at least immediately, improved cognition after removing the plaques.  Aduhelm removes plaques too, but there remains a question as to whether it is effectively improving cognition.  Not all researchers believe the Amyloid hypothesis explains Alzheimer's disease, and not all think that plaque removal is the path to a successful treatment.  Some believe that the FDA's approval of Aduhelm encourages us to take our eyes off the ball ... finding a fundamentally different approach to understanding the disease and its treatment.

In an odd way, the controversy over Aducanumab has contributed to the search for alternatives.  There has been some improvement in cognition from the treatments that remove plaques, but not nearly as much as predicted or hoped.  So perhaps the plaques play a more tangential role in the disease that we haven't anticipated.  We discussed this in Beating the Dementia Monster, but this idea is finding new strength in aducanumab research.

Dr. Bart De Strooper, who leads the U.K. Dementia Research Institute at University College London, speaks out against a simple cause-effect relationship between amyloid accumulation and cognitive decline.  Instead, it may be that amyloid accumulation triggers a series of disease processes.  This is called the amyloid cascade hypothesis, and it too has its detractors.

Professor Takeshi Iwatsubo of the University of Tokyo suggests that plaque removal treatments succeed when there is a corresponding reduction in tau tangles, which is not always the case.  He suggests, however, that in the case of the aducanumab trial that did marginally improve cognition, it may be that the load of tau tangles was also lowered during treatment.  Why?  Do we need to understand more about the relationship between the collapse of microtubules we see in the tau hypothesis and the role of beta amyloid in Alzheimer's disease?   

These researchers say "yes."  We still have work to do. 

The Aduhelm Controversy -- It's not calming down...

****This is our first blog post that uses MailChimp to manage email.  I was able to navigate the process of setting MailChimp up, transferring all subscribers over from Feedburner, and setting up a new subscription interface on the blog.  Hopefully everything is working OK.  At this point, the only thing I don't like about it is that I can't change the email font size.  For me the font is too small, but I can't make it bigger.****

There continues to be controversy and consternation around the FDA's approval of Aduhelm, the monoclonal antibody therapy generically known as aducanumab.  Not so much any more about the very odd way it was approved -- with questions about whether it even works or not -- but more about the $56,000/year cost.  Some are afraid that if Biogen can get Medicare/Medicaid and the insurance companies to go along with the cost, it will green-light significantly higher costs for other drugs.  Considering how many elderly people might want to receive Aduhelm and how expensive Biogen is making it, government insurance payments could simply blow up the already ticking time bomb of Medicare.

So on June 23, Senators Elizabeth Warren (D-MA) and Dr. Bill Cassidy (R-LA) sent a letter to the chair and ranking member of the Senate finance committee expressing concern about the approval of the drug and its cost.  The thrust of the letter was to outline the political and practical uncertainties that approval of the drug brings forward with a long list of concerns.  They note specifically the questions about its effectiveness, and they state that government compensation must be contingent on clinically-demonstrated efficacy.  They propose a value-based system that connects payment arrangements with demonstration of clinical effectiveness.  (This sound to me like compensation will require another phase 3 trial, perhaps something more rigorous than what the FDA is already requiring of Biogen going forward.)

It seems to me that the letter does a good job of outlining the challenges that approval of Aduhelm brings with it. 

A Change Coming to the Blog

I am extremely grateful to all who subscribe to this blog.  It's satisfying to me to know that there are people who find what I have to say interesting and helpful, and it encourages me to keep posting.

The blog is hosted by Blogger, which is part of Google.  I use Feedburner to manage subscriptions, notably email subscriptions.  Feedburner is also part of Google, except that Google is in the process of cutting back on what Feedburner actually does.  I don't know if they plan to discontinue the service completely, but for now they are dropping the email service.  So someday soon you will no longer receive email updates from the blog.

At least not from Feedburner.  If I can keep my wits about me during the process, I will transition from Feedburner to a service called Mailchimp.  So the blog mail will be coming from a different source, which may baffle your spam filter.  I'll notify readers before actually making the transition, so people can white-list the blog if emailed blog posts begin ending up in your junk mail folder.

Setting this up may not be trivial for me, so stay tuned...

Aricept actually treats Alzheimer's disease, not just symptoms?

In Beating the Dementia Monster we repeated the conventional wisdom around the cholinesterase inhibitors, that they may temporarily improve cognition among those with Alzheimer's disease, but you're still dead on the same day.  They treat the symptoms, not the disease.  But maybe that's not true.  The problem with that statement is that there was very little research in which people were followed for an extended period of time to see if the drugs might actually do more than address symptoms. 

There are three cholinesterase inhibitors, galantamine (Razadyne, etc.), donepezil (Aricept, etc.) and rivastigmine (Exelon, etc.).  They have been around since the 1990s and have been widely used.  I tried donepezil for a short time in 2015 when I was first diagnosed, but I found that it made me sick.  So I quit using it, going on to rely on lifestyle changes to treat my disease.  But maybe I should give it another shot.

There is excitement around a new Swedish study published in the journal Neurology, "Long-term Effects of Cholinesterase Inhibitors on Cognitive Decline and Mortality."  The study results were summarized in this press release.   The study investigated long-term effects of the three cholinesterase inhibitors on cognitive decline, development of severe dementia, and on mortality.  (Alzheimer's is a deadly disease.)  The study population was patients with Alzheimer’s dementia or mixed Alzheimer’s dementia.  The researchers used data from the Swedish Dementia Registry.  

The study included 11,652 cholinesterase inhibitor users and 5,826 non-users.  They had a mean age of 81.2, and 62% were female.  The researchers evaluated cognitive function using the Mini-Mental Status Examination (MMSE).  Scores lower than 10, on a scale from 0 to 30, indicates severe dementia, while scores between 21 and 24 indicate mild dementia. 

At the start of the study, the mean MMSE score was 21.2 for all patients, 22 for cholinesterase inhibitor users, and 21.9 for non-users.  During the average five-year follow-up period, cholinesterase inhibitor users were found to have better MMSE scores at any visit compared with non-users.  Those taking one of the drugs had some slowing of decline, but I didn't find the numbers impressive.  Of the three, galantamine (Razadyne) had the strongest effect on cognition.  Also, it was the only one that had the ability to decrease the risk of developing severe dementia.  

Thirty-five per cent of the patients died during the five-year follow up period, however mortality among users of cholinesterase inhibitors was 27% lower than the control.  Razadyne users had a 29% decrease in mortality, Aricept users had a 22% reduction in mortality, and Exelon users had only a 14% reduction.  I guess the takeaway is that, taken over a period of time, cholinesterase inhibitors substantially improve cognition and extend the lives of Alzheimer's patients.  And Razadyne seems to do both best. 

So this has me thinking that I need to look into this again.  I will be in Seattle for my annual cognitive tests in a week, and I will see my neurologist two weeks after that.  This will be on the agenda.

A Definitive Study on Exercise and Alzheimer's Disease? Finally?

In 2015 I began reading that exercise might help with stalling the progress of my Alzheimer's disease, and my subsequent experience proved those claims to be correct.  But the authoritative annual Alzheimer's Association Facts and Figures Report continues to be circumspect on the subject, saying more research is needed before anything definitive can be said.  As we explain in Beating the Dementia Monster, I've read a lot of research on exercise, and I'm not sure what more they still need.

In my recent post on Posiphen research, I mentioned a sponsor, the Alzheimer's Disease Cooperative Study, and I linked to their web site.  There, they mention another intriguing study, the Exert Study.  The objective of the study is to see what happens when people with MCI due to Alzheimer's disease and who have been sedentary begin getting aerobic exercise and persevere for 18 months.  The study is now well underway, and they expect to finish in November of this year.  

But ... I don't know how covid has affected execution of the Exert study.  It has required participants to go to the gym with a personal trainer four times/week for the whole 18 months.  Well, gyms were closed for a long time, and I don't know how they managed the social distancing with the trainers.  So I don't know how this will work out.

As I describe in Beating the Dementia Monster, I began getting some exercise by walking the mile to work every day in October 2015, and then I joined the gym in December.  It was probably April when I began to sense a change, and it was later that year when testing for the insulin study began to provide objective evidence of improvement.  I don't know if everyone's cognition will respond as mine did, but I think that six months of good data should show something positive. 

Another promising drug trial

Now that Aduhelm is on its way, we should remember that there are other therapeutics under evaluation.  One of those is a drug candidate known as ANVS401 (or Posiphen).  Rather than an infusion, this drug would be a conventional pill, and, after a covid-induced hiccup, it is late in its phase 2a trial.  Preliminary results have been very encouraging.

ANVS401 is being developed by Annovis Bio, a small pharmaceutical company in Berwyn, PA that specializes in a specific approach to neurodegenerative diseases.  They have a portfolio of three drug candidates that focus particularly on Alzheimer's and Parkinson's diseases.  While Aduhelm and several other Alzheimer's interventions remove accumulated amyloid and other plaques, ANVS401 attempts to prevent their generation in the first place.  

Annovis is conducting the current trial along with the Alzheimer’s Disease Cooperative Study (ADCS).  It's called The Discover Study.  It is a one-month trial studying several cohorts of subjects.  In the first cohort to finish the trial, results with 14 early stage Alzheimer's patients and 14 early stage Parkinson's patients were very promising.  Before completion of the phase 2a trial, the researchers plan to involve 68 subjects.  They hope to have results for us in July or August, so stay tuned.

The trial is measuring levels of neurotoxic proteins, neurotransmitters, neurotrophic factors, inflammation, and nerve cell death, as well as cognitive improvement.  The study is being conducted in six sites in the U.S., including the University of California San Diego, Johns Hopkins, Indiana University, Washington University, Cleveland Clinic, and Columbia University.  All subjects are not receiving the drug simultaneously.

This is a phase 2a study.  Earlier, Annovis conducted three phase 1 studies with smaller populations of test subjects.  Unlike aducanumab (now Aduhelm), there was no brain swelling and there were no micro-hemorrages.  The drug was "well tolerated." 

Annovis claims that their results with ANVS401 have been much better than the results for aducanumab at the end of aducanumab's phase 3 trial (a low bar).  This is only after one month of treatment with ANVS401.

If this trial goes as anticipated, the phase 3 trial will follow.  A phase 3 trial uses many more test subjects, and the results from these trials don't always fulfill the promises of successful phase 1 and 2 trials.

It's getting ugly out there..

The FDA's conditional approval of Aducanumab has not gone over well.  As we noted before, the approval was over the objection of the FDA's independent advisory panel, and now three of the 11 members have quit in anger over the decision.   

And that anger is spreading.  Some activists are calling for the resignation of Janet Woodcock, the FDA's acting Commissioner.  Who knows where that will end up.

Biogen's stock price has held on to its dramatic gains that followed the FDA's approval.  But I notice some analysts have begun to call it "overvalued."  We'll see what happens with all of this.

As seen on TV

Late this morning I got a call saying that the local TV station wanted my take on the FDA's approval of Aduhelm.  This is the same TV station that interviewed me back in 2019.  A little after noon, the reporter came to our house and set up her gear.  After a brief discussion, she fired up her camera and did the interview.  Here is the result.

Welcome Aduhelm ... for better or worse

The big news today is that the FDA has acted on aducanumab, approving it for use as a treatment for Alzheimer's disease.  (It will be marketed as "Aduhelm.")  The approval comes by way of the FDA's "accelerated approval pathway," which allows a drug to be approved even if it has not been shown to be effective.  

These provisional approvals are for cases where a treatment has been shown to be effective against a surrogate endpoint in way indicating that it likely also hits the true endpoint.  In this case, the true endpoint is slowing the loss of cognition, while the surrogate endpoint is removal of amyloid plaques in the brain.  What trials have so far failed to prove to the satisfaction of some key players is that removing the amyloid plaques this way leads to at least slowing the decline of cognition.  Under this approval system, people with Alzheimer's can receive treatment with Aduhelm/aducanumab, but Biogen must continue work to prove that it is effective against the primary endpoint.  If they are unable to do so, the FDA may withdraw approval and take everyone off the treatment.

Aduhelm has some enthusiastic supporters.  OK, but there are some things to keep in mind when considering prospects that the treatment provides dramatic changes in the course of the disease.  It has been noted that the monoclonal antibody can slow progress of the disease in a limited population, but it has not been shown to either stop decline or improve cognition.  It can also cause micro-hemorrhages in the brain, necessitating periodic MRIs during treatment.  It is not a pill, but rather a monthly infusion requiring a medical visit each time. 

The limited population on which it has been tested includes those -- like me -- with MCI as well as some with early dementia.  Those who read Beating the Dementia Monster understand the progress of Alzheimer's disease from MCI to dementia. 

Not surprisingly, Biogen's stock price jumped sharply on the announcement.  It had been pretty flat over the past year.  But what does the future hold?

The hope is that, while this is not a cure, it opens a pathway for future research that will lead to increasingly more effective treatments.  It assumes the amyloid hypothesis is correct (which we discussed in Beating the Dementia Monster), although some researchers doubt the credibility of the amyloid hypothesis.  So, it could turn out to be a dead end that distracts from pursuing more effective approaches.

In all probability, some families will want to begin the treatment for their loved ones as soon as it is available.  Hopefully, they will have accepted the both the risks and uncertainty associated with it.

Another supplement

Carl is a fellow traveler dealing with MCI whom I've come to know through this blog.  He also has experienced improvement in his condition by attacking it through multiple domains.  In fact, he has written a history of his experience that I found very interesting.  One thing he believes has helped him a lot is taking the supplement Theracurmin twice per day.

Theracurmin is is a formulation of curcurmin, a chemical found in turmeric, that increases its "bioavailability."  You may have turmeric in your spice cabinet, and, if you (like me) love Indian food, you have tasted it in curry dishes many times.  Curcurmin makes curry yellow.  It has a reputation for fighting both inflammation and oxidation -- important weapons in the battle with Alzheimer's disease.  But it also has a reputation for having properties that cause poor bioavailability.  In other words, it may not be absorbed well in the digestive system.  Or, if it gets into the blood stream, it may not be able to penetrate the blood-brain barrier.

Several strategies have been employed to increase its bioavailability.  Most include grinding it into extremely fine particles.  Then other substances, like finely ground pepper, can be formulated with it to help move the particles into places they would not otherwise go.  Theracurmin is a water-dispersable colloid of curcurmin that the manufacturer claims significantly increases its bioavailability.    

As we've noted before, strategies to reduce inflammation in the brain by ingesting different products has failed to improve cognition in people with MCI.  Most notable is that clinical trials applying non-steroidal anti-inflammatory medications, such as namenda, have failed to affect cognition.  Will curcurmin, notably via Theracurmin, produce different results?

While there have been mixed results, several studies have been quite promising.  

In March 2018, the American Journal of Geriatric Psychiatry published the results of an 18-month, placebo-controlled study that found significant memory and attention benefits from daily use of Theracurmin.  Also, pre- and post-treatment cognitive benefits correlated with changes in amyloid plaque and tau tangle accumulation as measured with PET scans.  The first author of the study was Dr. Gary Small, who is director of the UCLA Longevity Center.  

This is very good news, but the results need to be replicated in further studies.        

Aside from the price tag, all indication is that Theracurmin has no troubling side effects.  Following Carl's lead, I have been taking it now twice daily for several months.  

Has it helped me?  Who knows.  I continue to get daily aerobic exercise, pursue the MIND diet, and do all of the other things we discuss in Beating the Dementia Monster.  My subjective sense it that my cognition has fluctuated since April 2019 with no clear trend.  I'm only able to correlate the fluctuations with my ability (or inability) to control my insomnia.  This, of course, is very subjective.  I'm just one test subject, so there is no control group.  My cognition will be tested again in July, and maybe that will yield some insight.