Misdirection on a field

Charles Piller’s July 21st article “BLOTS ON A FIELD?” tells the story of how a researcher, Dr. Schrag, came to conclude that papers on AB56 by Dr. Lesne et al. may contain falsified data. Mr. Piller without evidence claims the AB56 papers to be extremely important for Alzheimer’s Disease research and uses this narrative as a basis for the decades long failure of drugs that test the amyloid hypothesis.

In reality, the amyloid hypothesis gained widespread attention in the 1990s long before the AB56 research of Lesne (2006) and continues to this day with the idea of AB56 long discarded. The exaggerations of Mr. Piller motivated the Director of the National Institute of Aging to make the following announcement within days:

It is notable that the Aβ*56 oligomer was one of many being explored at the time, and no Alzheimer’s biomarker or experimental therapy based on Aβ*56 has since been developed. Instead, immunotherapies targeting Aβ monomers (a single “unit” of Aβ), other types of oligomers, and the longer amyloid fibrils have been the focus of studies on potential drugs to effectively treat dementia.

Piller’s article subtly conflates Simufilam with the entirely unrelated and long discarded idea of AB56. Simufilam targets the restoring of the shape of a protein (FilaminA). Misfolded FilaminA is claimed to cause toxic signalling that leads to a build up of AB42 and other biomarkers that lead to Alzheimers Disease. Open label trials of Simufilam, run in multiple FDA sites have shown significant reduction in disease progression in > 80% of patients. Randomized controlled trials are ongoing and results are expected middle of 2023 and 2024.

Piller’s article makes numerous other misleading claims as listed below.

Piller: “two prominent neuroscientists who are also short sellers who profit if the company’s stock falls—believed some research related to Simufilam may have been “fraudulent,” according to a petition later filed on their behalf with the U.S. Food and Drug Administration (FDA)”

Dr. Pitt isn’t “a prominent neuroscientist”. He isn’t even a neuroscientist. Rather, he is a cardiologist that happens to be a childhood friend of the co-author Dr. Bredt. Piller leaves out important context on Dr. Bredt, a former executive from J&J (Johnson & Johnson) who learned of Cassava Sciences research as part of exploring a potential partnership at the request of J&J. Dr. Bredt would later be involved in a startup funded by J&J with competitive interests in protein misfolding for neurodegenerative diseases.

Piller: “Schrag, …had already gained some notoriety by publicly criticizing the controversial FDA approval of the anti-Aβ drug Aduhelm. His own research also contradicted some of Cassava’s claims. He feared volunteers in ongoing Simufilam trials faced risks of side effects with no chance of benefit.”

Mr. Piller’s wording here subtly conflates two entirely unrelated things (i) Dr. Schrag’s work against Aduhelm and the amyloid hypothesis with (ii) Cassava and its completely different approach. By using specific language in the first sentence with respect to Aduhelm and vague language in the next sentence with respect to Simufilam, the reader is led to assume commonality. Its important to note that Dr. Schrag drafted both (i) the attack on the AB56 research and (ii) the rejected FDA petition attempting to convince the FDA to halt the clinical trials of Simufilam.

Piller: “[Dr. Schrag] identified apparently altered or duplicated images in dozens of journal articles… Cassava denies any misconduct”

Here again, Mr. Piller’s wording subtly misdirects his readers to believe Dr. Schrag has claimed misconduct with respect to dozens of journal articles published by Cassava or specific to Simufilam. He didn’t.

Piller: “Science asked two independent image analysts—Bik and Jana Christopher…”

Although referred to as an “independent” analyst, Dr. Bik has long been a star witness repeatedly showing up in coordinated short driven media efforts and has interacted with short attackers criticizing Cassava on social media. In spite of this history, Mr. Piller chooses to promote Dr. Bik to his readers as “independent” and additionally does not mention her controversial history as the Scientific and Editorial Director of the now defunct uBiome which is currently subject to DOJ criminal charges for fraud.

Turning to the sidebar focused on Cassava, the article includes factual inaccuracies, glaring omissions, and/or confusing misdirection. Consider the following examples:

Piller: “[n February, FDA refused to pause the trials, calling the petition the wrong way to intervene, but said it might eventually take action.”

This wording spins the FDA’s categorical denial of Dr. Schrag’s failed petition to halt the Simufilam trials as if it was a mere temporary procedural hurdle. The petition denial is unequivocal: “your Petitions do not purport to set forth all relevant factual information. Rather, you call on FDA to initiate an investigation and fact finding.” In simpler terms, the FDA effectively said “you made a bunch of unsubstantiated allegations, of course I won’t stop the trials for this.” Contrary to Mr. Piller’s assertion, the FDA did not state it may eventually take action on the petition but instead merely included boilerplate at the end of denial: “This response does not represent a decision by the Agency to take or refrain from taking any action relating to the subject matter of your Petitions.”

Piller: “Independent image analysts and Alzheimer’s experts who reviewed Schrag’s findings at Science’s request generally agree with him.”

This sentence is vague and would be heavily criticized in the most basic of Journalism instructional classes. Mr. Pillar’s wording leaves unanswered questions like (i) which “independent” analysts (Dr. Bik?), (ii) which Alzheimer’s experts, and (iii) which Schrag findings were agreed with (the publications wholly irrelevant to Simufilam?)?

Piller: “Last year, Schrag reached out to most of the journals that published questioned papers. Seven were retracted—including five by PLOS ONE in April.”

Mr. Piller misdirects his readers here to assume these five PLOS retractions are specific to Simufilam/Cassava (they are not) by noting the retractions in the sidebar titled “Research backing experimental Alzheimer’s drug was first target of suspicion.” These PLOS retractions have been repeatedly and deceptively linked to Simufilam and Cassava and have even spurred corrections issued (quietly) in previous articles with remarkably similar messaging and tone to Mr. Piller’s article. Mr. Piller also leaves out critical context of how authors have reproduced the same findings as Dr. Wang.

Piller: “The most influential Cassava-related paper appeared in The Journal of Clinical Investigation in 2012. The authors—including Wang; Arnold; David Bennett, who leads a brain-tissue bank at Rush University; and his Rush colleague, neuroscientist Zoe Arvanitakis— linked insulin resistance to Alzheimer’s and the formation of amyloid plaques. Cassava scientists say Simufilam lessens insulin resistance. They relied on a method in which dead brain tissue, frozen for a decade and then partially thawed and chopped, purportedly generates chemical signals.”

The claim that the above discussed paper is the “most influential Cassava-related paper” is unfounded and bizarre. None of Simufilam, it’s mechanism of action, or Cassava are the subject of this paper. Nor does the paper even mention these topics or refer to Cassava. Mr. Piller brings up this paper to conflate it with Simufilam, criticize it, and thereby give the appearance of substantively criticizing Simufilam. In reality, it is irrelevant to Simufilam and there is no point in delving into the many reasons Dr. Schrag’s criticisms of a well-established research technique with collected brain tissue illuminates his substantial lack of competence in this area outside his focus – a lack of competence significant enough to require Mr. Piller to issue a correction (dubbed a “clarification”) to his article once readers likely explained the characterization of measuring transmitted nerve impulses was fundamentally a misunderstanding of the technique he is criticizing.

Piller: “Schrag and others say it contradicts basic neurobiology. Schrag adds that he could find no evidence that other investigators have replicated that result. (None of the authors agreed to be interviewed for this article.). That paper supported the science behind Simufilam, Schrag says, “and spawned an entire field of research in Alzheimer’s, ‘diabetes of the brain.’” It has been cited more than 1500 times.”

Again, this paper is wholly irrelevant to Simufilam and its mechanism of action.

1 Comment

  1. dalewayne2015 says:

    Thank you for all your time and effort.


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