In defense of Lindsay Burns
Today was not a good day to be Lindsay Burns. Both the New York Times (Business) and today’s Science magazine (4 October p. 15) had articles about Cassava Sciences’ settlement with the SEC, agreeing that Lindsay had misled investors subjecting her to an $85,000 and a ban from being an officer and a director. One of the most damaging claims was that Burns had cherry picked data (about which much more later).
The company has been under concerted short attack since August of 2021 and there is far more to the story than this.
Disclaimer #1: I do not own any stock or options in Cassava Sciences, have received no money from them or Lindsay at any time and don’t expect to in the future.
Disclaimer #2: Lindsay and her family are personal friends. Her parents were sheep ranchers out of Big Timber and I got to know them when I practiced neurology in Montana from ’72 to ’87. Lindsay was just a teenager back then and we really didn’t interact seriously until she began working on Simufilam as a treatment for Alzheimer’s disease years later.
Pedigrees are important to some reading this, so let’s get that out of the way.
Lindsay graduated Harvard in 1987 and got a PhD from Cambridge University
I graduated Princeton in 1960, Phi Beta Kappa, Sigma Xi, blah, blah, blah
I have a masters in chemistry from Harvard in 1962 working under R. B. Woodward — https://en.wikipedia.org/wiki/Robert_Burns_Woodward
I graduated Penn Med in 1966 and was board certified neurologist (and an occasional board examiner) practicing clinical neurology from 1968 to 2000 when I retired.
So my clinical experience with dementia and Alzheimer’s disease is quite extensive, and I’d guess that I saw a least one demented patient a week during those years.
I first became excited about Cassava’s drug Simufilam in 2021 when Lindsay released preliminary data in an open label trial of 50 patients followed for 9 months on Simufilam. 5/50 had a nearly 50% improvement in a cognitive measure. I never saw anything like this in decades of clinical practice. You can read about this in probably more detail than you want here https://luysii.wordpress.com/2024/09/27/cassava-sciences-9-month-data-is-probably-better-than-they-realize-2/.
Even if you assume that Lindsay ‘cherry picked’ the data, no one has data showing improvement in a subset of patients at nine months like this. The best the monoclonal antibody treatments of Alzheimer’s can offer is a slight lessening of the rate decline on average. Similar unprecedented improvement in a subset of cancer patients (not everyone) has led to an explosion of research on immune checkpoint blockade.
Cries that the study should be stopped because of an ‘inadequate research foundation’ are laughable. What follows is a detour into some exquisite neurochemistry that I couldn’t resist. You can skip to the *** for the rest of the post.
There can be no better research foundation (shown below) for monoclonal antibody treatment to remove aBeta peptide as a treatment for Alzheimer’s disease (lecanemab, aducanumab). Yet, the results have produced significant side effects (brain bleeds aka ARIA) and trivial decreases in the rate of mental decline. None have produced clinical improvement even in a small subset of patients.
The structure of the amyloid fibril formed by the aBeta42 peptide exactly shows why certain mutations are associated with hereditary Alzheimer’s disease. Here is a picture
https://www.alzforum.org/news/research-news/danger-s-bends-new-structure-av42-fibrils-comes-view
Scroll down to the picture above “Bonds that Tie”
If you need some refreshing on the general structure of amyloid, have a look at the first post in the series — https://luysii.wordpress.com/2021/10/11/amyloid-structure-at-last/
Recall that in amyloid fibrils the peptide backbone is flat as a flounder (well in a box 4.8 Angstroms high) with the amino acid side chains confined to this plane. The backbone winds around in this plane like a snake. The area in the leftmost loop is particularly crowded with bulky side chains of glutamic acid (single letter E) at position 22 and aspartic acid (single letter D) at position 23 crowding each other. If that wasn’t enough, at the physiologic pH of 7 both acids are ionized, hence negatively charged. Putting two negative charges next to each other costs energy and makes the sheet making up the fibril less stable.
The marvelous paper (the source for much of this) Cell vol. 184 pp. 4857 – 4873 ’21 notes that there are 3 types of amyloid — pathological, artificial, and functional, and that the pathological amyloids are the most stable. The most stable amyloids are the pathological ones. Why this should be so will be the subject of a future post, but accept it as fact for now
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.
****
Sorry couldn’t resist putting that in.
Cassava’s two studies in progress are double blind and placebo controlled. As of 24 September 2024, an Independent Data and Safety Monitoring Board (DSMB) evaluated the interim patient safety database for Oral Simufilam in ongoing phase 3 trials, and recommended that both trials continue as planned without modification.
Only if Cassava (or Lindsay) has actually falsified the data is anything wrong. The data from the two ongoing studies are managed by an outside company, and Cassava doesn’t get their hands on it until it’s released.
I find it incredible that a clinical neurologist or neuroscientist would want to stop Cassava’s 2 studies given our current lousy treatment of Alzheimer’s disease. There are certainly darker and more paranoid explanations of the behavior of those shorting and denigrating Lindsay and Cassava, which I won’t go into here as there is no solid evidence for them.