Cassava Sciences: What happened and what they should do next

The results of 9 months treatment with Sumafilam reported 29 July were exactly what I had hoped for;  namely continued improvement over baseline and over the 3 and 6 month interim results.  Yet the stock tanked that day, and has come back about 50% from the low.  It’s the old sick joke, the operation was a success but the patient was a failure.

I had a few guesses as to what happened in a post I wrote 30 July

” 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?”

 

My guesses were totally wrong.  What actually happened was a very well timed and very well coordinated bear attack on the price of the stock.

 

As Lindsay Burns was presenting positive data the morning of July 29th, an article run by a guy with a political science degree attacked her data, using 3 neurologists, all developing other drugs for Alzheimer’s disease. At the same time some 200 Million  dollars worth of sell orders were placed (likely by several hedge funds).  The stock tanked.

 

Reality has subsequently intruded, as SAVA’s stock has rebounded 50% from the attack.

 

So what should Cassava do at this point?  Assume, as time passes, that patients continue improve or remain stable (as they already have for 9 months).  Within the next 3 months, and possibly sooner, SAVA will have  1 year results.  If patient cognition continues to show improvement (over 9 months, over baseline), game over.  No one taking care of an Alzheimer patient has ever seen them better off cognitively after a year has passed. .

 

The bears should not be forewarned as they have been. The 12 month results should released without warning, early in the week, so the bears don’t have the weekend to respond.  It would be an interesting short squeeze.

What Cassava Sciences should do now

Apparently someone important didn’t like the way Cassava Sciences analyzed their data and their stock tanked again today..  Unfortunately all of this seems to be behind a paywall, and the someone important isn’t named.  I’d love a link if any reader knows of one — just put it in as a  comment below.

I’m not important, but I thought Cassava’s results were quite impressive.  They had enough cases and enough time for the results to be statistically significant

For one thing,  Cassava dealt with severely impaired people (see below) who would be expected to show greater neuronal dropout, senile plaques and neurofibrillary tangles, than recently diagnosed patients.   Neuronal loss is not reversible in man, despite hoards of papers showing the opposite in animals.

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.

So an increase of 3 points in this group is about a16% improvement.

Here’s what Cassava should do now.  Their data should be re-examined as follows.  Split the ADAS-CoG scores into 3 groups: highest middle and lowest. Quartiles are usually used, but I don’t think 50 patients is enough to do this.  Then examine the median improvement in each of the three.  I’d use median rather than average as with small numbers in each group, a single outlier can seriously distort things — think of the survival of Stephen Hawking in a group of 12 ALS patients.

If the patients with the highest ADAS-CoG scores have the highest median improvement, there is no reason mildly impaired individuals should have a less than 16% improvement in their scores.  This means that a person with ADAS-CoG of 60 should achieve a perfect score of 70,  e.g. return to normal.

This would be incredibly useful for early Alzheimer’s disease.

There is a precedent for this.  Again it’s Parkinson’s disease.

As I mentioned in an earlier post, I was one of the first neurologists in the USA to use L-DOPA for Parkinsonism.  All patients improved, and I actually saw one or two wheelchair bound Parkinsonians walk again (without going to Lourdes).  They were far from normal, but ever so much better.

However,  treated mildly impaired Parkinsonians became indistinguishable from normal, to the extent that I wondered if I’d misdiagnosed them. These results were typical.   For a time, in the early 70s neurologists thought that we’d actually cured the disease.  It was a very heady time.  We were masters of the neurologic universe — schizophrenia was too much dopamine, Parkinsonism not enough. Bring on the next neurotransmitter, bring on the next disease.

We hadn’t cured anything of course, and the underlying loss of dopamine neurons in the substantia nigra continued.  Reality intruded for me with one such extremely normal appearing individual I’d diagnosed with Parkinsonism a few years earlier. He needed surgery, meaning that he couldn’t take anything by mouth for a while.  L-DOPA could only be given orally, and he looked quite Parkinsonian in a day or two.

If reanalysis of the existing data shows what I hope, Cassava Sciences should start another study in Alzheimer patients with ADAS-CoG scores of over 50.  If I’m right the results should be spectacular (and lead to immediate approval of the drug).

A little blue sky.  Sumafilam will then come to be known as intellectual Viagra, as all sorts of oldsters (such as yrs trly) will try to get it Alzheimer’s or no Alzheimer’s.

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

 https://finance.yahoo.com/news/cassava-sciences-seat-top-charts-142318201.html

“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.

The science behind Cassava Sciences (SAVA)

I certainly hope Cassava Sciences new drug Simufilam for Alzheimer’s disease works for several reasons

l. It represents a new approach to Alzheimer’s not involving getting rid of the plaque which has failed miserably

2. The disease is terrible and I’ve watched it destroy patients, family members and friends

3. I’ve known one of the principals (Lindsay Burns) of Cassava since she was a teenager and success couldn’t happen to a nicer person. For details please see https://luysii.wordpress.com/2021/02/02/montana-girl-does-good-real-good/.

Unfortunately even if Sumifilam works I doubt that it will be widely used because of the side effects (unknown at present) it is very likely to cause.  I certainly hope I’m wrong.

Here is the science behind the drug.  We’ll start with the protein the drug is supposed to affect — filamin A, a very large protein (2,603 amino acids to be exact).  I’ve known about it for years because it crosslinks actin in muscle, and I read everything I could about it, starting back in the day when I ran a muscular dystrophy clinic in Montana.  

Filamin binds actin by its amino terminal domain.  It forms a dimerization domain at its carboxy terminal end.  In between are 23 repeats of 96 amino acids which resemble immunoglobulin — forming a rod 800 Angstroms long.  The dimer forms a V with the actin binding domain at the two tips of the V, making it clear how it could link actin filaments together. 

Immunoglobulins are good at binding things and Lindsay knows of 90 different proteins filamin A binds to.  This is an enormous potential source of trouble.  

As one might imagine, filamin A could have a lot of conformations in addition to the V, and the pictures shown in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2099194/.

One such altered (from the V) conformation binds to the alpha7 nicotinic cholinergic receptor on the surface of neurons and Toll-Like Receptor 4 (TLR4) inside the cell.

Abeta42, the toxic peptide, has been known for years to bind tightly to the alpha7 nicotinic receptor — they say in the femtoMolar (10^-15 Molar) range, although I have my doubts as to whether such tiny concentration values are meaningful.  Let’s just say the binding is tight. 

The altered conformation of filamin A makes the binding of Abeta to alpha7even tighter. 

In some way, the tight binding causes signaling inside the cell (mechanism unspecified) to hyperphosphorylate the tau protein, which is more directly correlated with dementia in Alzheimer’s disease than the number of senile plaques. 

So what does Sumifilam actually do — it changes the ‘altered’ conformation of filamin A back to normal, decreasing Abeta signaling inside the cell.  

How do they know the conformation of filamin A has changed?  They haven’t done cryoEM or Xray crystallography on the protein.  The only evidence for a change in conformation, is a change in the electrophoretic mobility (which is pretty good evidence, but I’d like to know what conformation is changed to what).

Notice just how radical this proposed mechanism of action actually is.  The nicotinic cholinergic receptor is an ion channel, yet somehow the effect of Sumifilam is on how the channel binds to another protein, rather than how it conducts ions. 

However they have obtained some decent results with the drug in a very carefully done (though small — 13 patients) study in J. Prev Alz. Dis. 2020 (http://dx.doi.org/10.14283/ipad2020.6) and the FDA this year has given the company the go ahead for a larger phase III trial.

Addendum 26 March: The above link didn’t work.  This one should — it’s from Lindsay herself

https://link.springer.com/article/10.14283/jpad.2020.6

Why, despite rooting for the company and Lindsay am I doubtful that the drug will find wide use.  We are altering the conformation of a protein which interacts with at least 90 other proteins (Lindsay Burns, Personal Communication).  It seems inconceivable that there won’t be other effects in the neuron (or elsewhere in the body) due to changes in the interaction with the other 89 proteins filaminA interacts with.  Some of them are likely to be toxic. 

Montana girl does good, real good !

Montana is flyover country. Nobody smart lives there. We all know that.

But when I got there in 1972 an issue of Science contained an article by State Legislator about a modification of general relativity — https://en.wikipedia.org/wiki/Kenneth_Nordtvedt.  MIT grad, Harvard Junior Fellow etc. etc. 

Then there was the son of a doc I practiced with in Billings.   Honors physics at Billings Senior high school placed him in 2nd year physics at Harvard, from which he graduated in 4 years obtaining a masters in physics as well. 

Then there was a local boy, the Thiokol engineer who predicted the Challenger disaster and was over-ruled. 

The great thing about Montana was that no one ever bragged about this sort of thing.  There were so few people, that no one felt compelled to tell you about themselves, you’d find out about them soon enough.  The classic example was an excellent surgeon and friend I practiced with for 15 years.  Only on reading his obituary last year did I find out that he had a Fulbright after college.

Which brings me to Lindsay, a girl I first met when she was a high school student.  The family were ranchers with a beautiful spread on the east face of the Crazy mountains north of Big Timber.  I’m not sure how we first met — I don’t think I saw any of them as a patient.  But we all became friends and the galactic premiere of a cello sonata I wrote with a 19 year old secretary in a lumberyard was in their living room. 

The two least important things about Lindsay are that she was a centerfold and an olympic silver medalist in woman’s two person crew.  Don’t get excited about the centerfold bit, she was fully clothed, but for some reason the Harvard Alumni magazine had a 2 page picture on a field of daisys of her back in the 80’s when she was there. 

Lindsay went on to get a PhD from Cambridge and her work and that of her husband may have come up with something useful for Alzheimer’s disease.  I’ll talk about the science behind it in a future post.  But when the news broke today, the stock of her company hit 70  (it was around 7 at the beginning of the year).  For details please see — https://finance.yahoo.com/m/49fa6153-4235-3866-bff2-5a35470e54da/why-cassava-sciences-stock.html.

Couldn’t happen to a nicer girl.  Of course it didn’t just happen.  Decades of hard work went into it.  So as you fly across the country, look down.  Some people down there might be even smarter than you are.