Cassava Sciences — the clinical reality underneath the stock gyrations.

The stock of Cassava Sciences (symbol SAVA) has undergone some wild gyrations this year.  On 14 September it traded at 41.70, today just two weeks later it is trading in the upper 60s.

The important thing to keep in mind, is that 1 year out on treatment with SAVA’s drug Simufilam 50 patients with mild Alzheimer disease were (as a group) slightly improved.  This is absolutely unprecedented.  The best that previous therapy could accomplish was a slightly slower rate of decline — see arshttps://science.sciencemag.org/content/sci/373/6555/624.full.pdf — for a recent review of other therapy attempts.  So Cassava’s results are unprecedented.   While Alzheimer (and other dementia) patients fluctuate from day to day (like the tides from minute to minute) at the end of a year they are all worse.

These results have not been attacked, unlike their data on the effect of Simufilam on biomarkers which has been criticized by a person of standing — Elizabeth Bik — https://scienceintegritydigest.com/2021/08/27/cassava-sciences-of-stocks-and-blots/#more-2692.

But that’s irrelevant and guilt by association at best.  As a clinical neurologist, no one was ever brought to see me because of their biomarkers.

They have released part of their 1 year results — https://www.cassavasciences.com/news-releases/news-release-details/cassava-sciences-announces-top-line-results-12-month-interim.  There is a lot more that I’d like to know, but a press release is not a detailed scientific paper.

What follows is a lot of commentary and speculation about the 1 year data which we haven’t seen yet.

The results concern the first 50 patients to complete one year on the drug.  The dropout rate is stated to be under 10%.  Presumably this includes death, in a cohort (presently at around 200) with a significant mortality.  It would be interesting to know how many patients on entry made it to one year.

As a clinical neurologist I was particularly impressed with part of their data at 9 months.  Here’s a link — keep it handy — https://www.cassavasciences.com/static-files/13794384-53b3-452c-ae6c-7a09828ad389.

They measured cognitive changes by something called ADAS-Cog — a full description can be found in the following post — https://luysii.wordpress.com/2021/08/25/cassava-sciences-9-month-data-is-probably-better-than-they-realize/

ADAS-Cog score counts errors, so a perfect score would be 0, and a terrible score would be 70.  The range of deficit on entry was 16 – 26 (but possibly on something else called the MMSE) — this is what the 1 year results used.  The 9 month results used ADAS-Cog.  Perhaps they are actually the same thing — I don’t know.

On the link — https://www.cassavasciences.com/static-files/13794384-53b3-452c-ae6c-7a09828ad389 — look at the diagram titled “Individual Patient Changes in ADAS-Cog (N = 50).

There were 5 patients out of 50 at 9 months with improvements of 11 – 14, which would mean that they were pretty close to normal if their entry score was 16 and 50% improved if their score was 26.  From here out I’m just calling them ‘the 5’.

The 9 month report doesn’t discuss this, and only a clinician would know, but this is the way neurologic patients respond to treatment.  Some do extremely well while others have no effect.  Why?  It’s probably because not really understanding causation, we classify patients clinically (it’s all docs have after all).

I ran a Muscular Dystrophy Clinic for 15 years back in the day.  The Muscular Dystrophy Association was founded by parents of weak kids.  They didn’t know that some weakness was due to the muscle itself (what we’re now calling muscular dystrophy), some was due to disease affected the nerves from the spinal cord to the muscle (what we call a neuropathy now) and others were due to disease of the cells in the spinal cord giving rise to the nerves to the muscle (motor neuron disease).  That all came later.

It is quite presumptuous to say that Alzheimer’s disease is just one thing.  Perhaps the 5 patients doing so very well had it from a different (as yet unknown) cause than the other 45.  Even so such a treatment would be worth having.

So here are a few questions for the folks at Cassava about their data

l. Some 16 different sites were involved in the open label study.  Were all of ‘the 5’  from the same site (doubtful — but if true, perhaps they tested ADAS-Cog differently, casting doubt on these results).

2. What were the ADAS-Cog scores initially on ‘the 5’.

3. What happened to ‘the 5’ in the past 3 months (did they maintain improvement, slide back, or improve further?)

4. We must have lots more people passing the 3, 6, 9 month markers.  Have their results paralleled that of the first 50 reaching the mileposts?   It would be very useful to know if there are now more than 5 with improvements over 10 in ADAS-Cog at 9 months.

The slightly slowing of improvement at 1 year relative to 9 months is typical of neurologic disease.  When L-DOPA was first available in the USA in 1970, some patients because so normal that you couldn’t tell they had Parkinson’s disease, and for a few years, neurologists (myself included) thought we were actually curing the disease.  Of course we weren’t and the underlying pathology of Parkinsonism (death of neurons using dopamine) continued unabated.  The L-DOPA just helped the surviving neurons function more efficiently.  Something similar may be going on with Simufilam and Alzheimer’s.

Now for some blue sky about Simufilam. Just as the gray hair on the head of an 80 year old looks the same under the microscope as one from a prematurely gray 30 year old, the brain changes of Alzheimer’s disease (the senile plaque)  are the same regardless of the age of onset.  Assuming that the senile plaque is in someway related to dementia (despite the lack of effect of therapies trying to remove it) and given that we all accumulate a few as we age, could Simufilam improve cognition in the elderly?   Would it then be intellectual viagra and the blockbuster drug of all blockbuster drugs.

 

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.