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.
Chemiotics II 
Comments
What is your opinion on the role of infectious disease in the etiology of Alzheimers and other chronic neurological illnesses? For example, Kris Kristofferson was diagnosed with Alzheimers, but (according to his Wikipedia page, which gives a reference) he was found to have Lyme disease and was completely cured by a course of intravenous (I think) antibiotics.
Similarly, the patients in Oliver Sacks’s book “Awakenings” came down with what Sacks called “Parkinsonism”, which was apparently caused by the flu of 1918. He reserved the term “Parkinson’s disease” for the idiopathic condition. But what if much of the Parkinson’s that we see is actually caused by infectious disease?
For example, what if “the 5” were idiopathic cases and the other cases were due to infectious disease? Conversely, what if “the 5” had Alzheimer’s caused by infectious disease, but Simufilam has anti-viral or anti-bacterial properties?
Peter:
Sorry for the delay in responding, there has been a lot going on. The classic example of an infection producing dementia is tertiary syphilis, something so rare that I never saw a case. However the Lyme organism is a spirochete (like syphilis) so curable dementia is a certainly possible from it. Chronic Lyme disease is minefield, and death threats have been made against those who have said that most of it is psychological.
So, given those precedents, the idea that infection could produce neurologic disease has been quite popular. There have been a few successes along the way, namely the prion diseases, AIDs dementia (even though the retrovirus isn’t infecting neurons).
Literally thousands of papers were written about a possible infectious cause of MS, because of the elevated levels of immunoglobulin G in the cerebrospinal fluid — the only way we had after clinical presentation to diagnose the disease until MRI came along. None of them panned out, so I became cynical about the idea as applied to other neurodegenerations.
In 1918 Parkinsonism appeared in those who had ‘encephalitis lethargica’ which caused a huge epidemic 100 years ago and then disappeared.
All the possibilities you mention are plausible, but would take a lot of work to prove.
I am a regular reader of your blog and have also followed your comments on mathematica site. Please don’t take it the wrong way, but as a clinical neurologist, how could you not know or not inclined to find out about the difference between Adas-cog and MMSE. It was disappointing to see the lack of preparation for this particular article. I stopped reading it after you were wondering aloud about it 😦
Curtis Maury
ADAS-Cog and MMSE are used in research and drug development. They aren’t needed in clinical practice. Simple questions such how many grandchildren do you have? How old are they? What did you have for lunch? Etc. etc. tell you if a patient is demented or not.
Why do it this way? Rubbing an individual’s nose in their dementia is rather sadistic and can occasionally bring on a strong emotional reaction. The family/caregiver are usually pretty accurate as to whether the patient is getting worse from visit to visit.
I did find it disturbing that SAVA switched the way they were analyzing progression between 9 months and 1 year and will have to look at the correlation in the numeric valuations of the two dementia scores (like converting Fahrenheit and Centigrade).
I just heard from someone at SAVA about this point. The MMSE of 16 – 26 was used for initial entry into the study. The cognitive evaluation didn’t switch to MMSE, and ADAS-Cog in its various forms, 11, 12, 13 will be used in the double blind study.
Yet more reasons why I never got involved (e.g. learned about) with MMSE or ADAS-Cog –MMSE takes about 15 minutes whereas ADAS-Cog takes 45 and is therefore more accurate. Neither leaves much room in a 1 hour neurologic consultation. So they are basically research instruments and totally unsuited for clinical neurologic practicioners (which I was for decades)
Excellent article
Thank you !