Why most criticisms of Cassava Sciences are irrelevant, and two which are not

Most criticisms of Cassava Sciences are irrelevant (see later), but there are two which could doom the company.  Here they are.

Both criticisms involve the results of the 1 year open label trial of Simufilam. You will recall that patients improved on average.  The study was criticized for cherry picking patients and data.  However a closer reading of the results found that 5/50 patients improved their ADAS-Cog Score by 50% after a year on the drug — for details please see https://luysii.wordpress.com/2021/08/25/cassava-sciences-9-month-data-is-probably-better-than-they-realize/.

These results are spectacular and absolutely nothing like this has been seen in untreated (or even treated) Alzheimer patients.

So what are the criticisms? Forget cherry picking of the data, as Cassava didn’t do it, and even if they did these results are so spectacular that cherry picking is irrelevant.

Doom criticism #1 — the data are false and made up by Cassava.  In Montana this was a practice in the gold mining days, when a few nuggets were sprinkled in an otherwise worthless mine to delude the unwary.  This was called salting the mine.

This is unlikely as the data were reported from sites producing the data, not Cassava.  Further Lindsay Burns told me that the 5 spectacular results came from 5 different sites administering the drug.  I was worried that one site was screwing up and measuring ADAS-Cog incorrectly.

Doom criticism #2 — People are paid to enter these studies.  How much isn’t clear.  Could the 5 have faked the dementia and then gotten better on subsequent testing?  Cassava tests to make sure  subjects are actually taking the drug.   This is a possibility but remote.

Now for the irrelevant criticisms.

#1 The mechanism of action of simufilam makes no sense.  It certainly is quite radical — for details see — https://luysii.wordpress.com/2021/03/25/the-science-behind-cassava-sciences-sava/.

Why is it radical?  The nicotinic cholinergic receptor is an ion channel.  Binding of another protein to it is not postulated to open the channel, but to alter its binding to another protein (filaminA) inside the cell. This is a totally new mechanism for drug action on ion channels — binding to the channel so its binding to something inside the cell changes.  Simufilam is held to change the conformation of filamin A.

Well that’s pretty damning.  Why can it be ignored?

Because 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.

So criticizing Cassava’s theory of why Simufilam appears to do what it does is like a med school classmate (he went to the University of Chicago) who was always saying — “That’s how it works in practice, but how does it work in theory?”

#2 There are problems with the electrophoresis data of years ago, and with the biomarkers of Alzheimer’s disease. Possibly true, but people don’t visit doctors because of abnormal biomarkers.  Such criticisms are irrelevant to the therapeutic results Cassava has reported.

So it’s time to proceed with the studies currently entering patients.  It is important to note that the FDA has approved the study and the way it will be done, Cassava will stand or fall on the placebo controlled study.  They won’t be asked to do a new one.

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Comments

  • Peter Shenkin  On November 28, 2021 at 8:57 pm

    Let’s not dismiss the possibility that mutations in the aBeta protein affect the action of the protein prior to the formation of plaque, and that these changes are responsible for susceptibility to Alzheimers. The plaque could thus be a benign side-effect of the mutations, rather than a cause of the disease. This has been proposed in the past, but I do not have a reference.

    • luysii  On November 28, 2021 at 10:01 pm

      Peter:

      If you can get your hands on Cell vol. 184 pp. 4857 – 4873 ’21
      do so. The pictures are fabulous, particularly that of abeta. You’ll see exactly why the mutations are where they are and what they are. There is a known aBeta mutation which is protective against Alzheimer’s, as I recall but I can’t find it.

  • Peter Shenkin  On November 28, 2021 at 10:42 pm

    I’ll try to see if I can get it somehow. David Eisenberg did a post-doc with Walter Kauzmann (later my Ph.D. advisor) and they wrote a book together on water.

  • Aang  On December 11, 2021 at 4:43 pm

    Dr. Lewis if you are willing can you reach out to the ad-science blog at adscienceblog21@gmail.com. We hope to collaborate with you on some scientific topics related to Cassava Sciences. Cheers!

    • luysii  On December 12, 2021 at 12:30 pm

      Aang: Thanks for the offer, but I’ll pass. Remi has said he may call on me to talk to Wall Street types about the science behind Cassava, and I’d like to confine my knowledge of it to what I’ve read in published journals and my clinical experience

      • Aang  On December 17, 2021 at 12:39 pm

        thank you for the response and for agreeing to share your expertise. Hopefully we can touch base another time.

  • Charlie  On January 28, 2022 at 12:32 pm

    Isn’t doom criticism number 2 also irrelevant?… as clinical sites give lumbar punctures to test if their CSF contains ptau

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