Tag Archives: Lindsay Burns

Nightmare on Wall Street

I’ve written several posts about Cassava Biosciences (symbol SAVA) and their potential drug for Alzheimer’s (see the end). The recent approval of Biogen’s ineffective (but highly lucrative) therapy Aducanumab for the disease brings forth the following nightmare. At a cost of > $50,000/year and millions of desperate famililes, Biogen will soon be rolling in money. The Cassava drug is orally available and should cost a fraction of that. Even better — it may actually work, although I think serious side effects are likely. Given the sketchy data getting Aducanumab through the FDA, Cassava’s drug represents a real threat to Biogen.

It will be perfectly legal for Biogen to outright buy Cassava and stop development. They will have the money. They won’t be able to do it on the sly, as any position of one company (or individual) in another greater than 5% of the value of the company must be reported to the SEC where it becomes public knowledge.

This from a cousin who is a stock market guru. His wife wasn’t available when I called being next door taking care of a woman with early Alzheimer’s, whose husband had to leave as his father suddenly passed away. She can’t be left alone. Such is the market for Aducanumab.

So will my friend Lindsay and her husband have the moral strength to resist Biogen?

Back in the day when I was in the service in Denver, a very wealthy stockbroker (who had brought the waterPik public) bought up many of beautiful old mansions on the west side of Cheeseman park. He then sold them to people he trusted (such as ourselves), so they wouldn’t be broken up into apartments (which was quite lucrative). I asked why the other people living on Humboldt street didn’t do the same. He said they had so much money they didn’t need character. The folks at Cassava don’t have a hell of a lot of money but hopefully they do have character.

Other posts on Cassava should you be interested are

The science behind Cassava Sciences (SAVA)

The science behind Cassava Sciences (SAVA)

I certainly hope Cassava Sciences new drug Sumifilam 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 https://luysii.wordpress.com/2021/02/02/montana-girl-does-good-real-good/.

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 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2099194/.

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 (http://dx.doi.org/10.14283/ipad2020.6) 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

https://link.springer.com/article/10.14283/jpad.2020.6

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.