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
The new additions to article seem to mix up simufilam (the small-molecule drug) and filamin A (the protein). For example: Could you look into this? -- ἀνυπόδητος (talk) 10:50, 1 May 2022 (UTC)
 * "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.


 * 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 . Sandy Georgia  (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: 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). Sandy Georgia (Talk)  18:36, 1 September 2022 (UTC)
 * Talk:Cassava Sciences/Primary sources

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. Sandy Georgia (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.   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 ?? Sandy Georgia  (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 :) Sandy Georgia (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. Sandy Georgia (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)


 * The cited NY Times article indicates that they're related, We can't overrule the judgment of the sources. MrOllie (talk) 23:01, 12 October 2022 (UTC)

They are related to the company but not to the drug Simufilam. You guys are conflating the two development processes into one just like the NY times article did. Put those on the Remoxy page not on here. I think all the "controversial" topics about the drug should be organized in the allegations of research irregularities. Why does it have to be told throughout. There are great sources that have followed their journey over the years that show the development timeline of the drug that are WAY more credible than the new york times in medical research. Here is one that has done a good job covering the actual story:

https://alzheimersnewstoday.com/pti-125/

I think the page should be similar to that, then put the allegations in their own section.

Mnachtrab (talk) 01:04, 13 October 2022 (UTC)


 * just like the NY times article did Yes, that is what we are supposed to do. We follow the reliable sources, we do not overrule them because we personally think we know better. then put the allegations in their own section. No, that is not going to happen. See WP:STRUCTURE. - MrOllie (talk) 01:12, 13 October 2022 (UTC)

CP discussion
The CP discussion in the main cassava wiki page changed the wording away from the wording in the simufilam article. This Simufilam page says:

"The US Food and Drug Administration received a citizen petition in August 2021 to stop the clinical trials. Other scientists have also questioned the preclinical results, citing the small sample size, alleged methodological flaws in an in vitro technique, alleged manipulations of western blot images and potential conflict of interest. After the FDA declined to act on the citizen petition as investigation is not within their purview..."

Declined to act is not what they did. The CP was rejected by the FDA... Please review the references to the CP in the cassava page and change the language to reflect what  SandyGeorgia edited there after reviewing that language... or just reference the CP with NEUTRAL language and point readers to the other page.

A citizen petition attempting to suspend the clinical trials was rejected by the Food and Drug Administration (FDA) in February 2022. Cassava Sciences has denied any wrongdoing and raised concerns about the motivations behind the FDA petition. Mnachtrab (talk) 11:19, 18 October 2022 (UTC)


 * You have been told numerous times about how to format edit requests yet are still failing to follow the instructions. I have tweaked the text slightly to match the Reuters source more closely, but there is nothing in there about the petition being rejected or declined. SmartSE (talk) 12:52, 18 October 2022 (UTC)

What is wrong with the format of request? Can you please be more respectful?

-Matt Mnachtrab (talk) 15:54, 19 October 2022 (UTC)

To be clear, I am saying the cassava wiki page. It is phrasing what happened with the CP different than the simufilam page. I am suggesting the simufilam page use the same language or just refer to the Cassava wiki page. Mnachtrab (talk) 00:27, 20 October 2022 (UTC)


 * They don't need to match exactly. But supposing they did, why would we not make Cassava Sciences match this one rather than the other way round? MrOllie (talk) 00:31, 20 October 2022 (UTC)
 * In fact, I've gone ahead and moved Cassava Sciences closer to the wording of the source as well. MrOllie (talk) 00:37, 20 October 2022 (UTC)

Build out the Clinical Trial Phases of Simufilam
IN PROGESS - SAVING WHILE I BUILD - FEEL FREE TO DO REPLIES AND LET ME KNOW WHAT YOU THINK OF THE PROJECT

To interested parties: Simufilam (PTI-125) have a long history of development that has gone through many stages from clinical to phase 3. I know other editors have called out that i have a point of view or COI, but I did some work to gather information for the whole history sighting actual sources (journal article, clinicaltrials.gov and company filings) secondary sources if it has been written about. I propose we use a format/layout that is like this page: https://en.m.wikipedia.org/wiki/Phases_of_clinical_research

This is a pretty large suggested change to the page, so I welcome feedback on how to implement it. I don't mind doing the work and formatting to get it in final form on the main page then removing my edit rights after it's done. Or if there is a good way to do a large edit somewhere else i can do it there then insert after we agree on content. This is all fact based non-controversial. Just the history of the drug.

Summary of Simufilam Phases of Clinical Research
Cassava Science performed preclicial work with Hoau-Yan Wang at CUNY. After preclinical research, they created a clinical trial strategy utilizing small early studies on a broad panel of biomarkers to detect if Simifulam could impact any biomarkers associated with Alzheimer’s disease pathology. The small phase 2 studies were used to inform a larger open label prior to a large and expensive phase 3 trial.

Preclinical simufilam (formally PTI-125) Research 1 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6621293/; Novel Drug Knocks Aβ Off Synapses, Reduces Toxicity | ALZFORUM

2 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4541970/

3 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6621293/

4 https://www.alzforum.org/news/research-news/novel-drug-knocks-av-synapses-reduces-toxicity

5 PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis - PubMed (nih.gov)

6 LuoISSX19-PTI-1125.pdf (labcorp.com)

PTI-125 Phase 1 Study
Description: This is a Phase 1 study to evaluate the safety profile of PTI-125 in healthy volunteers. Single center, randomized, double-blind, placebo controlled, SAD study of three escalating doses of PTI-125. A total of 24 healthy subjects enrolled in one of three dose cohorts. Each cohort will contain 8 subjects; six receive PTI-125 and two receive placebo. Three SAD does of PTI-125 oral solution (50, 100 or 200 mg) or placebo solution will be administered [5 ].

Results: The drug showed to be safe and well tolerated and the absence of dose-limiting effects did not show evidence increases in treatment dose causes problems. Additionally, the drug showed potential effectiveness because it was absorbed by the patients bodies rapidly [4 ].

PTI-125 Phase 2a Study
Description: This is a Phase 2a, multi-center, open-label study of PTI-125 in mild-to-moderate AD patients, 50-85 years of age. A total of twelve (12) patients will be enrolled into the study. Patients will receive 100 mg b.i.d. of PTI-125. The objectives of this study are to investigate the safety, pharmacokinetics and effect on biomarkers of PTI-125 following 28-day repeat-dose oral administration [2 ].

Results: The drug had no drug-related adverse events in the study. As published in The Journal of Prevention of Alzheimer's Disease, the study results showed Total tau, neurogranin, and neurofilament light chain decreased by 20%, 32% and 22%, respectively [3 ].

PTI-125 Phase 2b Study
Description: Randomized, placebo-controlled clinical trial that enrolled 64 people with mild to moderate Alzheimer’s. Participants were randomly assigned to receive either 50 mg or 100 mg oral tablets of simufilam, or a placebo, twice a day. The objective was to assess if the treatment lowered levels of Alzheimer’s-related biomarkers in participants’ cerebrospinal fluid in 28 days [7 ]

Results: The drug was safe and well tolerated. Initial results indicated there were not significant differences between the treatment and placebo group [6 ], but upon review the researchers found there was significant variation in biomarker reading in the placebo group so the samples were reanalyzed [8 ]. Upon reanalysis of Simufilam (formerly PTI-125) phase 2b results, it was found to improve many Alzheimer Disease biomarkers. The drug showed evidence of disease-modifying effects with statistical significant improvement in total-tau, P-tau, amyloid beta-42, Proinflammatory IL-6, and many other biomarkers associated with Alzheimer’s disease pathology [9 ].

Phase 2 Open Label Safety Study
Description: In progress work

Results: In progress work

Phase III (RETHINK-ALZ)
Description: A 52-week safety and efficacy study of simufilam (PTI-125) given twice daily to participants with mild-to-moderate Alzheimer's disease (AD) for 52 weeks. Approximately 750 participants will be randomized (1:1) to receive either placebo or 100 mg tablets of simufilam, twice daily, for 52 weeks. Clinic visits will occur 4 weeks after the baseline visit, and then every 12 weeks until the end of the study. The safety of simufilam, and its efficacy in enhancing cognition and slowing cognitive and functional decline will be evaluated [10]

Phase III (REFOCUS-ALZ)
Description: A 76-week safety and efficacy study of simufilam (PTI-125) given twice daily to participants with mild-to-moderate Alzheimer's disease (AD) for 76 weeks. Approximately 1083 participants will be randomized (1:1:1) to receive either placebo, 50 mg tablets of simufilam, or 100 mg tablets of simufilam, twice daily, for 76 weeks. Clinic visits will occur 4 weeks after the baseline visit, and then every 12 weeks until the end of the study. The safety of simufilam, and its efficacy in enhancing cognition and slowing cognitive and functional decline will be evaluated.[11]

Phase III (Open-label Extension for Phase 3 Clinical Trials of Simufilam)
Description: This is a multi-national, multi-center, fixed-dose, 52-week, open-label extension study. After completing participation in either RETHINK-ALZ (PTI-125-06) or REFOCUS-ALZ (PTI-125-07), subjects will have the option to participate in this study. After the subject provides consent and the Investigator confirms the subject satisfies both inclusion and exclusion criteria, the study drug will be administered at the research site on Study Day 1 and subsequent visits will be scheduled.

We anticipate up to 1600 subjects may enroll in this study. Approximately up to 150 clinical sites in the USA, Canada, South Korea, and Australia will have the option to participate in this collaborative research effort.

For subjects electing to participate, the clinical and laboratory assessments from the Week 76 (REFOCUS-ALZ) or Week 52 (RETHINK-ALZ) End-of-Treatment visit will serve as Baseline Visit assessments for the open-label study on Study Day 1. All subjects will return in 4 weeks and every 12 weeks thereafter for safety assessments. At all post-baseline visits, subjects will report any adverse events since their last visit. In addition to adverse event monitoring, safety will be evaluated at every visit by vital signs, brief examinations, clinical laboratory tests (biochemistry, hematology, and urinalysis) and the Columbia Suicide Severity Rating Scale (C-SSRS). Study drug use since the last visit will be assessed and a new bottle of study drug will be dispensed.

The emerging subject safety assessments will be monitored throughout the study by an independent Data Safety Monitoring Board (DSMB).[12]

Mnachtrab (talk) 13:47, 18 October 2022 (UTC)


 * This level of detail is far, far too much for a Wikipedia article. That seems to be an artefact of overuse of primary sources and other stuff that doesn't meet WP:MEDRS such as these alzheimer's news sites. I would oppose any inclusion like this. - MrOllie (talk) 14:04, 18 October 2022 (UTC)


 * Yes I agree. SmartSE (talk) 14:09, 18 October 2022 (UTC)

Stat news
I have the full text from Stat, which says no more effective than placebo. Sandy Georgia (Talk)  16:37, 28 January 2023 (UTC)
 * https://www.statnews.com/2023/01/24/new-results-show-cassavas-alzheimers-drug-has-placebo-like-efficacy/


 * SG, how usable do you think the source is for a statement about drug effectiveness? It looks like a reputably published blog/column. Good enough for wikivoice? With attribution? Judging just by the preview. Firefangledfeathers (talk / contribs) 17:49, 28 January 2023 (UTC)
 * While the author goes into good detail comparing early results to later, he also expresses strong opinions on the topic, so although the Stat (website) meets reliability in spades, it is filed under "Adam's take", so I would err on the side of caution and attribute the statement, rather than use Wikivoice. Let me know if I should email you a copy. Sandy Georgia (Talk)  18:07, 28 January 2023 (UTC)
 * Agree. Adam's statement directly conflicts with the statement of the lead consulting statistician who analyzed the data. Here's her quote: “The data for simufilam are noteworthy,” said Suzanne Hendrix, PhD. “The improvement in ADAS-Cog over 1 year in mild patients taking simufilam is well outside the expected range of historic placebo decline rates from numerous other studies.” Adam F. has a history of biased reporting on this company, even calling the CEO one of the top 10 worst CEOs for engaging on Reddit, when this CEO has never had a social media account of any kind. That is false and defamatory, just like this "placebo-like efficacy" headine. Note he did not comment on the 205% slowing of decline in mild patients in the randomized withdrawal study, which is unprecedented Phase 2 data. Subicculum (talk) 17:29, 7 August 2023 (UTC)
 * That you personally dislike the source or think the author is biased is immaterial. We are not going to substitute your opinion or your interpretation of a primary source for the judgment of a secondary source. MrOllie (talk) 18:04, 7 August 2023 (UTC)

Stat directly contradicts the quote of the statistician
Stat claimed that "well outside the historical range for placebo responses from numerous other studies" means placebo-like. That statement clearly shows a conflict. And Stat did not comment on the July article, which was placebo-controlled. Subicculum (talk) 16:51, 2 August 2023 (UTC)

Please quote the FDA docket precisely
"not a proper avenue" means the petitions did not bring any evidence but asked for the shut down to follow an FDA investigation to find any facts that could not be provided. This is indeed a proper avenue if there had been evidence. The actual quote is that the "petitions do no purport to set forth all factual information. Rather, you call on FDA to initiate an investigation and fact-finding process." Why was this more accurate and precise quote removed? Subicculum (talk) 17:04, 2 August 2023 (UTC)


 * This quote is from Reuters. It is preferable to quote a secondary source such as this rather the primary source of the FDA letter. The journalist has read the primary source and interpreted it for us. SmartSE (talk) 17:51, 2 August 2023 (UTC)
 * Yet it is misleading and intentionally vague to fit the storyline of the Reuters article. Why not clarify? Subicculum (talk) 21:55, 2 August 2023 (UTC)
 * We don't use primary sources to undercut the conclusions of reliable secondary sources in that way. That is why we would not 'clarify' MrOllie (talk) 17:26, 4 August 2023 (UTC)
 * Ok, although "not an appropriate avenue" with implication of "to stop a trial" is wrong and misleading. What the FDA said was that the petition was not an appropriate avenue to ask for an investigation by FDA. Most importantly, the FDA docket stated that the denial of the petition was based on lack of evidence to support their allegations. Reuters misconstrued this, so in this case is not a "reliable" representation or interpretation of the primary source. Subicculum (talk) 17:34, 7 August 2023 (UTC)
 * We're not going to substitute your judgment for that of Reuters - they are a reliable source and you are a person on a Wikipedia talk page. MrOllie (talk) 18:01, 7 August 2023 (UTC)
 * There is a misrepresentation here that we should correct. Per Reuters, the "not an appropriate avenue" comment refers to the request that the FDA launch an investigation. Our article language incorrectly ties it to the request that the FDA stop the trials. I think we should change was not a proper avenue" to stop the trials' to was not a proper avenue" to request an investigation. There's another issue as this content is in the lead but not the body. Firefangledfeathers (talk / contribs) 18:10, 7 August 2023 (UTC)
 * Edit conflicted :) Sandy Georgia (Talk)  18:11, 7 August 2023 (UTC)
 * Subicculum, the more effective way for you to use this page is to put side-by-side what the current content is, and what your suggested replacement is. Noting that your suggested edit is likely to be rejected if a primary source is used to refute a secondary source.  It is up to you to carefully craft proposed content that does not deny or contradict what the the (highly reliable) secondary source says, while also working in whatever it is you want to reflect from the primary source in a way that is not WP:UNDUE, WP:SYNTH or refuting a secondary source. As an example of how to work more collaboratively on Wikipedia to generate such a proposal, I suggest you spend some time reviewing how same is done in this discussion at J. K. Rowling. With the past rants the talk pages on this suite of articles have endured, a more effective way of proposing change that reflects the consensus model and collaboration required on Wikipedia will go a long ways. Sandy Georgia  (Talk)  18:10, 7 August 2023 (UTC)

Controversy about this article: request for comment

 * See previous discussions at COIN 1, COIN 2, COIN 3, Talk:Cassava Sciences/Archive 1 and Help desk,

The drug simufilam is highly controversial. Some people think the company is engaged in criminal behavior and the drug is a scam. Others think that stock short sellers are profiting off of deliberately tanking the stock. I would like to see this controversy represented more evenly, with a neutral point of view. I am not saying which side is right--just that the article is unbalanced and some people seem to be enforcing a one-sided view. Disclosure: I know Lindsay Burns personally. Asbruckman (talk) — Preceding undated comment added 21:47, 2 August 2023‎ (UTC)
 * Asbruckman, my experience with RfCs tells me this one is unlikely to be productive. There hasn't been a thorough discussion of the issues here, as required by WP:RFCBEFORE, and the RfC question itself is too broad to result in actionable consensus. I recommend removing the RfC tag and proceeding with local discussion. Firefangledfeathers (talk / contribs) 22:11, 2 August 2023 (UTC)
 * Discussion here (two COI editors blocked, the connection to Lindsay Burns if of interest, as other friends have weighed in re her article, lots of marginal press release churnalism used as sourcing in past versions). The faulty "RFC" gives no new sources. So what exactly are we RFCing about ? Sandy Georgia  (Talk)  22:32, 2 August 2023 (UTC)
 * The issue of balance is about three pages: this one, Cassava Sciences company, and Lindsay's own page. I have absolutely no opinion on who is right. I just think the pages take a strong opinion in one direction, violating NPOV.
 * I am an acquaintance of Lindsay's, not a friend. We've talked for about five minutes twice in the last 40 years. I'm not sure if I am allowed to make any edits here or not. I would prefer to stay out of it, but I'd like to see the pages more balanced. We will all know the truth when their clinical trials are further along, and until then it would be nice to be more circumspect about it?
 * Do people agree that this isn't a rock-solid one-sided situation? I think we need to address that question before we can move forwards.
 * Asbruckman (talk) 00:01, 3 August 2023 (UTC)
 * Discussions like this are usually based on sources or concrete proposals; you've given none. And there's no clear point to the RFC. Also, I noticed that the last time you requested help for your friend was during the same time frame when the last spate of SPAs and socks showed up at all three articles.  That suddenly editors are showing up again with the same claims raises a question of coordinated editing. The ongoing tendentious and disruptive editing probably have a lot to do with why the suite of articles hasn't risen above C-class.  Re a discussion of sources that might be included, I've had a google alert since the Fall 2022 disruption at these articles (almost a year ago), and I've seen only two new bits of reliably-sourced information come through-- neither of them favorable to Cassava, and neither included in the articles, so in terms of bias, unfavorable info to Cassava has been left out. You start the RFC with "Some people think" and "others think".   The article now cites The New York Times, Reuters, The New Yorker, and The Wall Street Journal, with investigations by the SEC, DOJ (criminal), NIH, and CUNY ... along with a string of primary sources and press releases from Cassava, in a matter otherwise covered by churnalistic sources.  What "some people think" is not how we determine balance.  Sandy Georgia  (Talk)  05:30, 3 August 2023 (UTC)
 * I will not be making any edits to these articles.
 * If I find any relevant primary sources, I will post them here on the talk page for consideration.
 * I am hoping other editors will take an interest in adding more balance to the discussion.
 * Asbruckman (talk) 13:19, 3 August 2023 (UTC)
 * I've removed the RfC tag; if you believe there is an issue with the neutrality of the article the best way to get more eyes on it is WP:NPOVN - RfC's are most useful when there is a clear question to be answered. BilledMammal (talk) 13:54, 3 August 2023 (UTC)
 * That's helpful--thanks. Asbruckman (talk) 16:38, 3 August 2023 (UTC)

Timing of FDA petition and SEC/DOJ investigations is inaccurate
The company released in November 2021 via 10-Q the existence of confidential requests for information by "certain government agencies." Plural. Also in November 2022, the SEC investigation was leaked to WSJ by the "whistleblowers" (who made their allegations based fully on public information with no inside information). There has been no corroboration of these claims by these investigations or by people with inside knowledge. Instead, they are supported only by the petitioners friends' statements such as the science is "not mainstream" etc. We know the FDA petition was filed in August 2021. It appears therefore that SEC and DOJ were also notified at the same time as the FDA (likely by the same "whistleblowers" who are now being sued for defamation). The confidential DOJ investigation was leaked to Reuters in July 2022, but that does not mean it was "started" then, and no where in the Reuters article does it say the investigation was just started. The current statements imply that FDA could not stop the trials and "after" that, DOJ initiated an investigation. This is clearly false. FDA response says the petitioners did not provide any evidence of their allegations, not that the petition was an improper avenue to stop a trial. It was an improper avenue to ask for an investigation. Please correct these two sentences that imply a false causality/timing and cite the true quote of FDA docket -- not the quote of the Reuters article falsely ascribed to the FDA. Subicculum (talk) 16:58, 4 August 2023 (UTC)


 * This reads like original research, and is hard to follow. Please make your requests more clear, as in:
 * Exact quote in the article now.
 * Exact proposed change (that is, new text)
 * Exact secondary reliable source backing the new proposed text. Sandy Georgia  (Talk)  17:05, 4 August 2023 (UTC)
 * PS, it would be helpful to understand that "regular Wikipedians" do not and have not followed this case as closely as the SPAs editing the topic have, so it would be very helpful if the requests here would be more clear and more clearly based on secondary reliable sources, so that source-to-text integrity can be evaluated by those of us not the familiar with the daily goings on. Sandy Georgia (Talk)  17:07, 4 August 2023 (UTC)
 * FDA response says the petitioners did not provide any evidence of their allegations, not that the petition was an improper avenue to stop a trial. We had a couple of now blocked paid accounts who tried out this argument as well. It didn't work then (and won't now) because it directly contradicts the plain wording of the cited source. MrOllie (talk) 17:21, 4 August 2023 (UTC)

Knee-jerk reversing corrections to error and adding research in Pharmacology section
The edits correct a factually erroneous statement and add an update to the research under discussion by an additional group. The changes were explained and justified but nevertheless reversed twice without any consideration for the justification and under the excuse of attacking the messenger. This is not appropriate or neutral editing. The previous justification:

I. The statement "no other researchers have examined simufilam binding to FLNA" is not correct and is not supported by the citation. Subsequent research cited in this article contradicts this claim (though the burden of proof is on the one adding a claim). 2. The wording regarding the mouse study clarifies that the mice had overexpressed FLNA (which is relevant to much talk/debate). 3. This adds additional research of Simufilam modulation of aberrant FLNA activity.

As there has been no disagreement with the justification whatsoever, I will correct the paragraph and add the research again. If someone wishes to discuss this please reply here rather than kneejerk reversal. CFRCitation (talk) 18:38, 4 August 2023 (UTC)


 * See your talk page. Sandy Georgia (Talk)  22:21, 4 August 2023 (UTC)
 * The talk on the edits should be here for folks to read, not hidden away on my talk page (where there is an incorrect statement that you removed original research I added - you seem to be confusing my edits with those of another).
 * The latest edits you made simply removed the false statement I tried to address and did not remove key other information.
 * I am glad there is some progress here in provided a meaningful section on pharmacology. Thank you. 75.227.24.197 (talk) 22:36, 4 August 2023 (UTC)
 * And that's why you should discuss rather than edit war (you added to the original research). Sandy Georgia (Talk)  22:39, 4 August 2023 (UTC)
 * An original edit was placed with a detailed justification. This original edit was then reversed by someone ignoring the justification and without touching the talk page and therein lies the problem here.
 * There are community standards and we should all follow them. CFRCitation (talk) 22:47, 4 August 2023 (UTC)
 * So I don't really want to get involved in this, but I will point out the Marra et al 2023 reference added isn't a journal article. It appears to be a conference abstract, which means it is an unpublished study (i.e. hasn't been through peer review and it isn't clear if it is completed or on going). I don't known wikipedia's guidelines well enough to know the rules about citing conference abstracts, so I am going to stay out of this, but I thought it was important to point out. Maybe someone with more experience can comment on whether it is ok to cite? ZICgene (talk) 23:24, 4 August 2023 (UTC)
 * Thanks, ZICgene, i removed it, after I had already tagged it, noticing that it was wasn't PUBMED-indexed. That would explain it.  Presenting something at a conference is not the same as a peer-reviewed published study (and there's too much original research in here based on primary studies already). Sandy Georgia  (Talk)  23:48, 4 August 2023 (UTC)

Revert of 2023 study
MrOllie, I'm reinstating the information you reverted in accordance with WP:MEDRS. Please detail your specific reasoning here. Referencing WP:VAGUEWAVE as the guideline is not appropriate. KXAN-TV provides earned media coverage about a study; it's not offering medical advice. It simply states the study's results and is not a press release.

ALZForum is another source that you reverted. It's a reputable source. Could you point to a discussion where it's been established that this source is generally unreliable? I look forward to your response so we can work towards a consensus Lurweig (talk) 19:16, 26 September 2023 (UTC)


 * I referenced WP:MEDRS, which is directly on point. That is not a 'vague wave'. Wikipedia has very stringent sourcing requirements for biomedical claims, and given the company and this article's history you are going to have to closely adhere to those requirements. MrOllie (talk) 15:19, 1 October 2023 (UTC)

CUNY investigation
Charles Piller, Science report here, and also covered by The Wall Street Journal. This needs to be worked in here and at Cassava Sciences and Lindsay Burns, who is also implicated by the sources. FYI. Sandy Georgia (Talk)  16:06, 14 October 2023 (UTC)

March 2024 status
https://www.science.org/content/article/damning-fda-inspection-report-undermines-positive-trial-results-possible-alzheimer-s

Sandy Georgia (Talk)  16:13, 12 March 2024 (UTC)

Update on lawsuit
https://reason.com/volokh/2024/03/29/drug-companys-libel-lawsuit-against-scientists-dismissed/

Sandy Georgia (Talk)  03:10, 31 March 2024 (UTC)