Talk:Simufilam

Mechanism

From the NYT article cited on this page: "[They claim] simufilam restores the normal shape and functioning of a protein called filamin A that becomes warped in the brains of people with Alzheimer’s disease, ... But Alzheimer’s experts said they knew of no independent studies that supported this hypothesis or would explain the results."

Not a WP:MEDRS but enough to make me wary about adding the mechanism with a primary source as ref. I'll add "better source needed" for the moment; it would be nice if someone came up with a better solution. --ἀνυπόδητος (talk) 08:32, 22 April 2022 (UTC)

The first sentence under Pharmacology needs an edit: "Burns and Wang reported in 2008 ... and in 2020 that by disrupting that simufilam reduces the ultra-tight binding of amyloid beta 42..." No idea what "that" is referring to. Does not make sense. The 2008 publication is not really relevant unless the fact that simufilam also binds this site on FLNA is spelled out explicitly. Here's a suggestion:

"In 2020, Burns and Wang demonstrated that by binding FLNA, simufilam reduces the ultra-tight binding of Abeta42 to the alpha 7 nicotinic receptor."

Also this sentence is not relevant here: "Two papers unrelated to Alzheimer's disease that reported FLNA binding by certain opioid antagonists and FLNA's role in opioid tolerance and dependence were retracted for "similarities in background pixels" in western blot images without evidence of data manipulation." This section is Pharmacology of Simufilam. SighSci (talk) 18:42, 12 September 2022 (UTC)

Simufilam vs. filamin A

@Chhandama: The new additions to article seem to mix up simufilam (the small-molecule drug) and filamin A (the protein). For example:

• "The existence of simufilam as an opioid antagonist ..." – shouldn't this be filamin A? Not sure.
• "In 2010, Burns and Wang identified the protein and named it PTI-609" – PTI-609: a novel analgesic that binds filamin A to control opioid signaling says that PTI-609 binds to the protein filamin A. But is this a WP:MEDRS?
• "In 2012, their research team redescribed it as PTI-125 and reported it as a novel compound" – now this isn't about filamin A any more but about simufilam.
• "The original discovery paper claimed it as a filamin A-binding peptide of 300-kDa size." – can't be right. Filamin A is a ~300 kDa-peptide, but simufilam (260 g/mol, not a peptide) binds to filamin A.
• and probably more.

Could you look into this? -- ἀνυπόδητος (talk) 10:50, 1 May 2022 (UTC)

Thank you for pointing out. Chhandama (talk) 07:36, 2 May 2022 (UTC)

Disputes

From an edit made by user:71.41.248.226 ["(edited for accuracy)"], there are some points that may not follow Wikipedia policies on neutrality, reliable source, original research and possibly conflict of interest:

1. "The link between FLNA and Alzheimer's disease is novel and will be ultimately determined by clinical data." Speculation and original idea.
2. "...alleged research misconduct, which focused primarily on Western blot images from mostly unrelated publications as old as 2005." "Mostly" is an overstatement, 2005 paper is used as reference of data manipulations in later papers. -- This 2005 paper was found by the journal editor to have "no evidence of data manipulation" and it is unrelated to simufilam or Alzheimer's disease.
3. "...retracted for "unresolved issues" relating to "similarities in background pixels" of Western blot images, but with no evidence of data manipulation" seems to hide the fact that PLOS One retracted the two papers for unreliable data.
4. Some statements are presenting research results: "change from baseline (mean pearson's r=0.06)", "simufilam reduces tau hyperphosphorylation by preventing or disrupting filamin A's linkage to the alpha7 nicotinic acetylcholine receptor and to toll-like receptor 4", "significantly reduced from baseline after 28-day treatment". Not encyclopedic.
5. Lindsay Burns is not Senior Vice President of "Neuroscience" but of Cassava Sciences.
6. Citation removal and damage. Chhandama (talk) 06:12, 6 May 2022 (UTC)

Science article about fabrication

6-month investigation by Science provided strong support for Schrag’s suspicions and raised questions about Lesné’s research.JuanTamad (talk) 09:25, 31 July 2022 (UTC)

The Sylvain Lesné issue has no connection to this article, other than the article in Science that discussed both scandals:

• Science podcast July 22, 2022, with Charles Piller, author of Piller C (July 21, 2022). "Blots on a field?". Science. 377 (6604): 358–363. doi:10.1126/science.add9993. PMID 35862524. S2CID 250953611. Archived from the original on July 21, 2022.. SandyGeorgia (Talk) 16:23, 6 August 2022 (UTC)

Sorting primary sources

With two COI editors now blocked from this suite of articles, my attempt to sort the primary sources is at:

• Talk:Cassava Sciences/Primary sources

Perhaps some progress can be made towards cleanup. I'm not sure the chart is yet complete; still working (for example, I still have to review The New Yorker and others). SandyGeorgia (Talk) 18:36, 1 September 2022 (UTC)

Allegations of research irregularities section

This page is about simufilam. All three simufilam publications have been cleared of the allegations of data manipulation: Journal of Neuroscience, Neurobiology of Aging and Journal of Prevention of Alzheimer's Disease. The first two maintain expressions of concern to acknowledge the CUNY investigation that is still ongoing. The third is cleared with no expression of concern, but this clearance and quote can only be cited by a Cassava (August 18) press release. These other papers discussed here (those retracted) do NOT discuss simufilam or Alzheimer's disease and should be removed. SighSci (talk) 18:48, 12 September 2022 (UTC)

Those papers are part of the history of the FLNA hypothesis. SandyGeorgia (Talk) 20:33, 12 September 2022 (UTC)

They are NOT part of the history of "the FLNA hypothesis" unless you mean that FLNA is involved in opioid receptor signaling, which was also a new finding then, corroborated by one other researcher. FLNA being critical to AD pathology and the target of simufilam is NOT in those papers. Proteins are involved in many different functions, so are you going to claim that all papers about mTOR in cancer are foundational to mTOR in AD? Oh, sorry, strawman. Those two papers identified FLNA as important in opioid receptor signaling only. SEPARATELY and LATER, Dr. Wang realized that a very large protein was present when amyloid signals via alpha 7. There are not many proteins of this size, so he used some antibodies to figure out what it was. When he identified it as FLNA, Dr. Wang and Dr. Burns decided to try the FLNA-binding compounds being developed for analgesia TO SEE if they could disrupt FLNA's linkage to alpha 7. All of that is in the JNS paper that is the first and only foundational paper for simufilam. Not the JCI paper on insulin resistance as claimed by Piller, not the PLOS papers on opioid receptor signaling. I see through your intentions. Hiding that ALL three simufilam papers have been cleared, yet highlighting that these unrelated papers have been retracted -- controversially I might add. Anyone reasonable here? You should remove this entire section since NO papers on SIMUFILAM have had "irregularities" found by editors. SighSci (talk) 19:04, 20 September 2022 (UTC)

Just saw your formatting message. Therefore:

Current text: Two papers were retracted by journals and expressions of concern were issued for other papers.

Proposed text: There are three papers that discuss simufilam. No journal editor has found evidence of data manipulation, although two maintain expressions of concern to acknowledge the ongoing CUNY investigation. Editors of the third paper issued a statement released publicly by Cassava Sciences: "We do not find convincing evidence of manipulation of data or intent to mislead, and therefore take no action regarding the published paper." https://www.cassavasciences.com/news-releases/news-release-details/no-evidence-data-manipulation-science-publication-simufilam. SighSci (talk) 19:14, 20 September 2022 (UTC)

You are literally asking me to add "There are three papers that discuss simufilam. No journal editor has found evidence of data manipulation, although two maintain expressions of concern to acknowledge the ongoing CUNY investigation" ???? What secondary source supports this original research? This is very frustrating. Firefangledfeathers these requests need a new set of eyes because I am unable to decipher what SighSci wants or how to comply. Perhaps you can cut through it ?? SandyGeorgia (Talk) 19:20, 20 September 2022 (UTC)

This is an easy no from me. I need to be able to float—as if on a lazy river—on the warm water of reliable, secondary sources all the way to your preferred destination. Firefangledfeathers (talk / contribs) 19:36, 20 September 2022 (UTC)

Smile ... such a nice thought :) SandyGeorgia (Talk) 19:39, 20 September 2022 (UTC)

Why can you not cite the actual scientific papers themselves and for the two that have them, the expressions of concern that state they did not find clear evidence of data manipulation? Why are you so adverse to this? They need to be publicly discussed in the media to be mentioned? SighSci (talk) 20:42, 20 September 2022 (UTC)

I'm not adverse/averse to the change at all, but I am firmly apathetic. Help me care. You mention the expressions of concern. This would be a good time to link them, and quote the material in them that supports your recommended change. Firefangledfeathers (talk / contribs) 21:08, 20 September 2022 (UTC)

Well you should care because this section is very misleading as is. These EoCs were cited before and conveniently removed. I suspect SandyGeorgia may have her own COIs or connections to people involved in the FDA petition or trying to stop these clinical trials. She has demonstrated knowledge of another person posting on these talk pages that could only come from reading his posts on Twitter. I.e., once he disclosed his COI as a shareholder, she asked "how many shares?" How is that relevant? It's personal, but she apparently knew he was a major shareholder. She also apparently knew of his personal interest in AD, which should not itself be a COI. He follows all AD drug candidates, not just simufilam.

Two of the three journals provided statements to Cassava that were released in press releases. One did not issue any sort of editorial note. I cite both the EoCs and public statements below.

Proposed text: There are three published papers on simufilam. https://pubmed.ncbi.nlm.nih.gov/22815492/, https://pubmed.ncbi.nlm.nih.gov/28438486/, https://pubmed.ncbi.nlm.nih.gov/32920628/. No journal editor found evidence of data manipulation. The Journal of Neuroscience stated "No evidence of data manipulation was found for Western blot data." https://www.cassavasciences.com/news-releases/news-release-details/no-evidence-data-manipulation-science-publication-simufilam, but issued an erratum https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672690/ and an expression of concern pending results of the CUNY investigation. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8802929/ Neurobiology of Aging stated, "Overall, the editors did not find compelling evidence of data manipulation intended to misrepresent the results" but is also maintaining an expression of concern until the CUNY investigation concludes. https://www.sciencedirect.com/science/article/pii/S0197458022000562?via%3Dihub. Editors of the third paper issued a statement released publicly by Cassava Sciences: "We do not find convincing evidence of manipulation of data or intent to mislead, and therefore take no action regarding the published paper." https://www.cassavasciences.com/news-releases/news-release-details/no-evidence-data-manipulation-science-publication-simufilam SighSci (talk) 18:07, 22 September 2022 (UTC)

That's enough for me; with these bad faith allegations, you should be blocked, and I'm done trying to help out here ... unwatching the lot, good luck trying to find someone to help, please don't ping me back to this suite of articles, as I've had enough abuse. SandyGeorgia (Talk) 19:05, 22 September 2022 (UTC)

Retractions unrelated to Simufilam should be removed

These papers are unrelated to Simufilam and this sentence should be removed.

Two papers unrelated to Alzheimer's disease that reported FLNA binding by certain opioid antagonists and FLNA's role in opioid tolerance and dependence were retracted for "similarities in background pixels" in western blot images without evidence of data manipulation.

The expressions of concerns are also redundantly mentioned in the Allegations of research irregularities section. Same point the Opiod papers are unrelated to Simufilam so the retraction mention should be removed.

Two papers were retracted by journals and expressions of concern were issued for other papers.[27]

Mnachtrab (talk) 10:59, 11 October 2022 (UTC)