Cassava’s Cognition Maintenance Study may prove Simufilam works

The FDA will approve less than perfect therapies if there is nothing useful for a serious condition.  Consider the following from Proc. Natl. Acad. Sci. vol. 119 e2120512119 ’22

“KRAS is the most frequently mutated oncogene in human cancer, with mutations detected across many lineages, particularly in the pancreas, colon, and lungs. Among the most commonly activating KRAS mutations at codons 12, 13, and 61, G12C occurs in ∼13% of lung and 3% of colorectal carcinomas and at lower frequencies in other tumors.

“In locally advanced or metastatic non–small-cell lung cancer (NSCLC) patients with KRASG12C mutations who have received at least one prior systemic therapy”  treatment with sotorasib resulted in the following “objective response  in 37.1% of the patients, with a median duration of response was 11.1 months.”   This is hardly a cure, but nonetheless “This promising anticancer activity has resulted in accelerated approval from the US Food & Drug Administration”

Which brings me to the current CMS study from Cassava Sciences.  I’ll let them speak for themselves. https://finance.yahoo.com/news/cassava-sciences-reports-first-quarter-130000375.html

Cognition Maintenance Study (CMS) – on-going
In May 2021, we initiated a Cognition Maintenance Study (CMS). This is a double-blind, randomized, placebo-controlled study of simufilam in patients with mild-to-moderate Alzheimer’s disease. Study participants are randomized (1:1) to simufilam or placebo for six months. To enroll in the CMS, patients must have previously completed 12 months or more of open-label treatment with simufilam. The CMS is designed to evaluate simufilam’s effects on cognition and health outcomes in Alzheimer’s patients who continue with drug treatment versus patients who discontinue drug treatment. The target enrollment for the CMS is approximately 100 subjects. Over 75 subjects have been enrolled in the CMS and 35 have completed the study.”

Even though the open label study was not randomized, this one will be.

Only someone who has actually taken care of  patients would know the following.  People who are getting no benefit from a drug will soon stop taking it.  This was particularly true for my experience with Cognex for Alzheimer’s disease.

Which is exactly why the fact that 75 patients who’ve been on Simufilam have decided to continue on in the CMS study.  Presumably they feel they are getting some benefit.

There are two possible hookers to this

l. The patients are being paid to enter CMS

2. The original cohort was 200, not all of whom have finished the 1 year.  So we don’t know how many could have been in CMS but chose not to.

As I discussed in an earlier post, the most impressive thing (to me at least) was that at 9 months 5/50 had significant improvement in their cognition — here’s a link — https://luysii.wordpress.com/2021/08/25/cassava-sciences-9-month-data-is-probably-better-than-they-realize/.

The CMS study should give us an idea of how they fared at 1 year and  at 18 months.

If:

l. gains in cognition were maintained on Simufilam

2. gains in cognition were lost off Simufilam

FDA approval should follow quickly.

Results on the 75 will be available this year.   Also available this year will be 1 year results on all 200 entering the open label study.

There are two other double blind studies in progress which will provide  more definitive answers, but they are far from full and will take much longer to complete.  So stay tuned.

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Comments

  • Richard Hunter  On May 31, 2022 at 2:10 pm

    Luysii, You obviously have deep understanding of neurochemistry and a passion for Alzheimer’s. Have you ever looked at the science behind Cognition Therapeutics’s CT1812? It seeks to mimic the effect of the Icelandic A673T mutation by preventing ABeta from binding and actually seems to cause it to be diplaced with the binding sites having a stronger affinity for the drug. I refer you to Izzo in Alzheimer’s and Dementia 2021;17:1365-1382 and other references in this https://ir.cogrx.com/static-files/c342afad-21ed-4a35-b91a-41f1e6a5b10e presentation. I would love to hear your thoughts.

    • luysii  On June 19, 2022 at 9:47 pm

      Richard — sorry for the delay in responding — apologies ! ! I’ll have a look and get to you. In the meantime have a look at the response to Dr. Lipman below.

      • Richard Hunter  On June 20, 2022 at 1:23 pm

        Luysii,

        Thank you beforehand for looking at CT1812. Though the NIH is not supposed to “talk” to the FDA, you’d think the $169M in grants Cognition has received to date would be of some benefit if it comes down to a “compassionate” approval. I find Dr. Lipman’s comments encouraging and if I recall correctly, none of the early cytokine cancer drugs had significant results. “Do no harm” is the rule, after that, all bets are off. Fortunately CT1812 seems to be safe as mother’s milk and on the encouraging side, there was a significant drug response with an increase in Abeta in the CNF in an under-powered phase I trial. If only we could be sure a marker based result would be acceptable as an indication of efficacy (as a proxy for a cognitive benefit)…CGTX has a market cap of $37.5M (really) and cash available of $153M…so there is a disconnect somewhere.
        I follow the Simufilam saga with interest.

  • Ken Lipman, MD  On June 18, 2022 at 1:34 pm

    Luysii, As a retired psychia

    • Ken Lipman, MD  On June 18, 2022 at 2:51 pm

      Luysii, As a retired psychiatrist, I have to think the Cassava CMS study may quickly be less blinded by the emergence of behavioral symptoms that may require additional medical treatment in the group not receiving simufilam. I would suspect that would become evident in the first few months off the medication and could facilitate the accelerated approval by the FDA. The reports for the open label studies were very impressive for the reduction of behavioral symptoms as the simufilam took effect.
      In addition, you should be aware that a recent study by a Japanese group demonstrated that filamin-A is implicated in tau aggregation in another tauopathy progressive supranuclear palsy. The authors actually cited several of the articles from the Cassava scientists in the bibliography. You can view that at: https://www.science.org/doi/10.1126/sciadv.abm5029.
      To be clear on my connection to this controversial topic, I have been a sometimes Cassava Sciences investor. I have also been following an intense public discussion occurring on the Yahoo Finance website on the webpage for the Cassava stock (sava) in the “conversations” section. The article above has been mentioned at least 3 times there by members of the public. Oddly, within 24 hrs the entries from the public citing this article have been removed from the visible discussion and can’t be found. It appears there is someone who does not want this article publicized.

  • luysii  On June 19, 2022 at 9:45 pm

    Ken — sorry for the delay in responding. Interesting point about clinically obvious effects of discontinuance. The time line for the effects to appear isn’t clear. It’s only a few days for L-DOPA, sometimes quite a bit longer for someone discontinuing anticonvulsants. You’d be more likely to know how long it is for antipsychotics.

    Your other point about possible mechanism of action of simufilam is true, but such arguments can be ignored. Here is probably more detail than anyone wants about the beautiful evidence that aBeta causes Alzheimer’s. Although the mechanism leads to an obvious therapy, none of them have worked.

    The mechanism of the aBeta peptide being the cause of Alzheimer’s has a huge amount of beautiful chemistry behind it — for details see — https://luysii.wordpress.com/2021/10/21/amyloid-structure-at-last-3-the-alzheimer-mutations/

    Here’s a quote from the post — skip this if you don’t have the necessary biochemical background, but to anyone with knowledge of protein chemistry it is beautiful and essentially confirms the amyloid hypothesis of Alzheimer’s disease

    “In 2007 there were 7 mutations associated with familial Alzheimer’s disease (10 years later there were 11). Here are 5 of them.

    Glutamic Acid at 22 to Glycine (Arctic)

    Glutamic Acid at 22 to Glutamine (Dutch)

    Glutamic Acid at 22 to Lysine (Italian)

    Aspartic Acid at 23 to Asparagine (Iowa)

    Alanine at 21 to Glycine (Flemish)

    All of them lower the energy of the amyloid fiber.

    Here’s why

    Glutamic Acid at 22 to Glycine (Arctic) — glycine is the smallest amino acid (side chain hydrogen) so this relieves crowding. It also removes a negatively charged amino acid next to the aspartic acid. Both lower the energy

    Glutamic Acid at 22 to Glutamine (Dutch) — really no change in crowding, but it removes a negative charge next to the negatively charged Aspartic acid

    Glutamic Acid at 22 to Lysine (Italian)– no change in crowding, but the lysine is positively charged at physiologic pH, so we have a positive charge next to the negatively charged Aspartic acid, lowering the energy

    Aspartic Acid at 23 to Asparagine (Iowa) –really no change in crowding, but it removes a negative charge next to the negatively charged Glutamic acid next door

    Alanine at 21 to Glycine (Flemish) — no change in charge, but a reduction in crowding as alanine has a methyl group and glycine a hydrogen.

    As a chemist, I find this immensely satisfying. The structure explains why the mutations in the 42 amino acid aBeta peptide are where they are, and the chemistry explains why the mutations are what they are. ”

    Evidence just doesn’t get any better than this.

    So we have beautiful convincing evidence that amyloid from the aBeta protein causes Alzheimer’s disease. EXCEPT that— innumerable trials of getting rid of the amyloid in the Alzheimer brain have not helped and often made things worse.

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