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

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

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 ( 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

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. 

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  • Christophe L Verlinde  On March 25, 2021 at 9:35 pm

    Dear Luysii the DOI you listed cannot be found in the DOI System.


  • Christophe L Verlinde  On March 25, 2021 at 9:52 pm

    The following link goes directly to the article:


  • Christophe L Verlinde  On March 25, 2021 at 10:23 pm

    The paper referred to (J Prev Alz Dis) is from the phase 2a trial. I have not seen an official publication of phase 2b results, but comments in Alzhemimers News Today are not positive. See:'s%20investigational%20therapy,a%20Phase%202b%20clinical%20trial.

  • luysii  On March 26, 2021 at 3:17 pm

    The information from Alzheimer’s news today is from May of 2020. More recent information is available which led the FDA to grant permission for a phase III trial earlier this year

  • MITGrad (@MITGrad3)  On June 16, 2021 at 10:17 am

    Typo: Simufilam (not Sumifilam)
    Just curious about your safety concerns. Are they founded from your speculation or do you have a prior experience where you have evidence of protein-protein interactions causing safety issues? If there is any, the biggest positive lead on Simufilam is their safety. So far the data (which I believe is compelling up to 9 months and a few patients up to 12 months). Sure, there may be aspects of the drug mechanism not yet fully known, but the big drop in your article “big” makes me wonder if that was a passing word or really thought about one.
    Or is the concern relative to others.

  • Serge  On February 2, 2022 at 4:22 am

    Hi, thank you for shedding more lights into the science behind Simufilam and also rooting for Cassava. In this article, you mentioned last year that you believed that the treatment could be toxic because of its MOA on filaminA and the complex interactions not only in the brain. Yet, fast forward 1 year, there have been no serious (long lasting) side effects reported. Why is this the case in your opinion? I saw an article mentioning that given it aims to address altered FilaminA, if it is not altered then the drug will have no effect. Could it be that simple? (For the disclaimer, I have been invested in Cassava for more than 12 months)

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