Tag Archives: Cassava Biosciences

Amyloid Structure At Last ! 4 Polymorphs

Henry J. Heinz claimed to have 57 varieties of pickles in 1896, but Cell [ vol. 184 pp. 4857 – 4873 ’21  ] Page 4862 claims that 24 amyloid polymorphs of alpha-synuclein have been found and structurally characterized.

What does this actually mean in English? The previous 3 articles in this series have discussed the structure of amyloid — the most relevant being https://luysii.wordpress.com/2021/10/11/amyloid-structure-at-last/

Basically, in amyloid some of the protein backbone flattens out so it lies in a single plane, and thousands of the planes stack on top of each other producing the amyloid fiber.  In the case of alpha-synuclein some 56 of the 144 amino acids comprising the protein flatten out.   Just as throwing a chain with 56 links on the floor will give different conformations of the chain,  the conformation of alpha-synuclein is different in each of the polymorphs.

So what?

Well, different polymorphs of another protein, the tau protein which forms the neurofibrillary tangle in Alzheimer’s give rise to at least 25 clinically distinct neurological diseases called tauopathies (3 more are chronic traumatic encephalopathy, corticobasal degeneration, and Pick’s disease).  In each of the these four diseases, a different conformation of tau is seen.

Then Nature [ vol. 598,  pp. 359 – 363 ’21] blows the field wide open, finding 19 different conformations of tau in clinically distinct diseases. Each clinical disease appears to be associated with a distinct polymorphism.  This is also true for the polymorphisms of alpha-synuclein, with distinct conformations being seen in each of Parkinsonism, multiple system atrophy and Lewy body dementia.

In none of the above diseases is there a mutation (change in amino acid sequence) in the protein

Back to alpha-synuclein.  How did they get the 24 different conformations?  They incubated the protein under different conditions (e.g. different salt concentrations, different alpha-synuclein concentrations, different salts).

Why is this incredibly good news? 

Because it moves us past amyloid itself, to the conditions which cause amyloid to form.  Certainly, removing amyloid or attacking it hasn’t resulted in any clinical benefit for the Alzheimer patient despite billions being spent by Big Pharma to do so.

We will start to study the ‘root causes’ of amyloid formation.   The amino acid sequence of each protein is identical despite the different conformations of the chain in the amyloid. Clearly the causes must be different for each of the different polymorphs of the protein.  This just has to be true.

Some cynic said that people who talk about the root causes of crime never get their hands dirty.  Hopefully neuroscience is about to take off its gloves.

This is why alternative approaches to Alzheimer’s disease, such as Cassava Biosciences manipulation of filamin A, might bear fruit.   For details please see — https://luysii.wordpress.com/2021/03/25/the-science-behind-cassava-sciences-sava/

Just got this back from one of the authors of the Nature paper

“Yes, studying the conditions that lead to all these different structures
is certainly high on our to-do list now.”

 

If you decided to buy Cassava Sciences yesterday everything went perfectly (except the price)

Yesterday I laid out the pros and cons of buying Cassava Sciences that day.  The post is reproduced below the ***

Everything I hoped for came true.  The 50 patients on Sumafilam were followed for 9 months and their ADAS-CoG score improved by 3 points.  This is unprecedented for any Alzheimer’s drug.  Historical controls show that Alzheimer patients lost 5 points a year on ADAS-CoG.  So this is a potential net gain with therapy vs. no therapyof  6 – 7 ADAS-CoG points.  Recall that a perfect ADAS-CoG score is 70.  I’ve been unable to find what the average score of 50 patients was on entry.  The paper isn’t published, but is public record results having been presented at conferences (such as today).  Recall that historical controls must be used as the study was open label (e.g. no concurrent controls).

Addendum 30 July:  Since everything turns on ADAS-CoG, here is a link to a complete description along with some discussion — https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929311/

On a slide from Cassava’s presentation yesterday the ADAS-CoG average of the 50 patients on entry 9 months ago was 16.6.  With a perfect score of 70, it’s clear that these people were significantly impaired (please look at the test items to see how simple the tasks in ADAS-CoG actually are).    So an improvement of 3 points at 9 months is significant, particularly since a drop of 5 points is expected each year — yes I’ve seen plenty of Alzheimer patients with ADAS-CoG scores of zero or close to it. 

However using historical controls is a no no particularly in neurology and cardiology.

Why?

From an old post “MDs gradually woke up to the fallacy of using historical rather than concurrent controls particularly in studies of therapies to prevent heart attack and stroke, as the rates of both dropped significantly in the past 50 years, and survival from individual heart attacks and strokes also improved.

 

However, I think using ADAS-CoG is OK in Alzheimer’s as we’re  talking about a disorder with no useful therapy.

 

I’m pleased that I saw the possibility of continued improvement in cognition in yesterday’s post.

 

So all my hopes for the drug came true, yet the stock tanked, closing at 103 down 32 points (down 24%) !

 

Why?  Well, in the past few months, all companies with drugs for Alzheimer’s disease have been fluctuating in price together, and one of them (to remain nameless to protect the innocent) had the temerity to release a 25 day study today on their drug based on 14 patients.  The stock was down 60%.

 

So Cassava got tarred with this brush.

 

Another likely reason is that the rise in Cassava was fueled by very small investors.  If you watched the transactions on a day SAVA was soaring, the purchases were rarely over 200.  So many of them were likely buying because others were.  So they sold when others were.  Lemmings anyone?

 

Nonetheless, SAVA’s data is much better than Biogen’s awful (and expensive) Aduhelm, so that Sumafilam is almost certain to be approved (1) if the data continue to be good (2) if a controlled trial controlled underway produces the same result.

 

So I think, in the long run, that the stock has a bright future, but as John Keynes said “In the long run we are all dead”

 

*** Yesterday’s post

 

Should you buy Cassava Sciences today?

Tomorrow Cassava Sciences will announce the interim results of an open label trial of its Alzheimer drug Sumafilam in 50 patients receiving the drug for 9 months. Should you buy the stock today?

The stock (symbol SAVA) has had a huge run this year starting at 7 and closing yesterday 27 July ’21 at 127.50.

I’ve been interested in the stock for several reasons

l. As a neurologist, I’ve watched patients, family members and friends deteriorate and die, being totally unable to help them.

2. I’ve known one of the principals in the company since she was a teenager in Montana — Lindsay Burns https://luysii.wordpress.com/2021/02/02/montana-girl-does-good-real-good/

3. Sumafilam is thought to work by a completely different mechanism of action than previous approaches (all of which have failed to produce a useful drug)– https://luysii.wordpress.com/2021/03/25/the-science-behind-cassava-sciences-sava/

In fact some of these therapies have actually made Alzheimer’s worse [ Nature Reviews Drug Discovery vol. 18 p. 327 ’19 ]

Tomorrow’s results should move the stock significantly.  If there is no improvement in cognition the stock will plummet.  If there is improvement the stock should soar, at least double again.  Why? Because we have no useful therapy.  Forget Biogen’s drug Aduhelm — the FDA advisory committee resigned in protest after the drug was approved, as the evidence for help was minimal at best.

Of course I’m rooting for the drug as a clinician and as a friend of Lindsay.

There is some evidence that the results tomorrow will show that the drug helps

A prior analysis after six months showed patients taking Cassava’s medication had a 10% improvement on cognition and 29% improvement on an inventory of dementia-related behavior, like delusions and anxiety.

 

The author of the article didn’t realize just how unprecedented these results are.  The numbers of patients (50) and the time (6 months) are long enough to make statistical fluke unlikely.

 

It is even possible that the patients will continue to improve — from the 6 month results, in which case the stock will go bananas.

 

Here’s why.
This isn’t in the books, but there is a precedent for continued improvement on Sumafilam based on my clinical experience with Parkinson’s disease.

 

I was one of the first docs able to prescribe L-DOPA for Parkinsonism in 9/70.  L-DOPA was released in the USA that month, after unconsciounable delay by the FDA.  I’d just left the Air Force and was starting to finish up my neurology residency at the University of Colorado.  The chief (James Austin) called me in and tasked me with setting up the brand new L-DOPA clinic.

 

 
We didn’t know what the drug would do, so we proceeded very cautiously.  Giving a little, watching, waiting, giving a little more, watching, waiting.  Wash rinse repeat.  The results were dramatic, as (like current therapy for Alzheimer’s disease), previous therapy was lousy. 

 

What became apparent to me, was that patients continued to improve ON THE SAME DOSE.   One of the mistakes GPs would make in subsequent years was increasing the dose quickly, since improvement was continuing (on the theory that if a little is good more would be better).  This pushed patients into toxicity (reversible fortunately). 

 

Something similar happens with all the antidepressants we have (except the ketamine derivatives).  You almost never see improvement in the first week or two. 

 

Do I know what tomorrow’s results will be?  Do I have inside information?  No.  Both my wife’s parents had decades long careers at the Securities and Exchange Commission (SEC), and I well know how they regard trading on inside information.

 

So these thoughts are just educated guesses.  If you are trying to decide whether or not to buy the stock, I hope they will be helpful to you.  Full disclosure: I do have a small position in the stock and am anxiously awaiting tomorrow’s results.

Nightmare on Wall Street

I’ve written several posts about Cassava Biosciences (symbol SAVA) and their potential drug for Alzheimer’s (see the end). The recent approval of Biogen’s ineffective (but highly lucrative) therapy Aducanumab for the disease brings forth the following nightmare. At a cost of > $50,000/year and millions of desperate famililes, Biogen will soon be rolling in money. The Cassava drug is orally available and should cost a fraction of that. Even better — it may actually work, although I think serious side effects are likely. Given the sketchy data getting Aducanumab through the FDA, Cassava’s drug represents a real threat to Biogen.

It will be perfectly legal for Biogen to outright buy Cassava and stop development. They will have the money. They won’t be able to do it on the sly, as any position of one company (or individual) in another greater than 5% of the value of the company must be reported to the SEC where it becomes public knowledge.

This from a cousin who is a stock market guru. His wife wasn’t available when I called being next door taking care of a woman with early Alzheimer’s, whose husband had to leave as his father suddenly passed away. She can’t be left alone. Such is the market for Aducanumab.

So will my friend Lindsay and her husband have the moral strength to resist Biogen?

Back in the day when I was in the service in Denver, a very wealthy stockbroker (who had brought the waterPik public) bought up many of beautiful old mansions on the west side of Cheeseman park. He then sold them to people he trusted (such as ourselves), so they wouldn’t be broken up into apartments (which was quite lucrative). I asked why the other people living on Humboldt street didn’t do the same. He said they had so much money they didn’t need character. The folks at Cassava don’t have a hell of a lot of money but hopefully they do have character.

Other posts on Cassava should you be interested are

The science behind Cassava Sciences (SAVA)