Cassava Sciences

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Cassava Sciences, Inc.
FormerlyPain Therapeutics, Inc.
Company typePublic
Nasdaq: SAVA
IndustryPharmaceuticals
Founded1998; 26 years ago (1998) in South San Francisco, California, U.S.
FounderRemi Barbier
HeadquartersAustin, Texas, U.S.
Websitewww.cassavasciences.com

Cassava Sciences is an American pharmaceutical company based in Austin, Texas. The company was founded in 1998 by chief executive officer and president Remi Barbier as Pain Therapeutics, Inc., changing its name in 2019.

Cassava is developing simufilam (previously known as PTI-125 and sumifilam), an oral-tablet drug candidate for the treatment of Alzheimer's disease; simufilam is in phase III clinical trials as of 2022. Reuters reported on July 27, 2022, that the United States Department of Justice (DOJ) is investigating Cassava Sciences over research results related to the experimental drug.[1] A citizen petition attempting to suspend the clinical trials was filed with the Food and Drug Administration (FDA), but the FDA said that the citizen petition "was not a proper avenue" to stop the trials in February 2022.[1] Cassava Sciences has denied any wrongdoing and raised concerns about the motivations behind the FDA petition.[2] The U.S. Securities and Exchange Commission (SEC), the U.S. National Institutes of Health (NIH), and City University of New York (CUNY) were also investigating allegations of manipulated data.[3]

Cassava (as Pain Therapeutics) initially worked on three drugs: the pain drugs Oxytrex and Remoxy, and PTI-901, which aimed to treat irritable bowel syndrome. The company had no drug approved as of 2021, and no product revenues between 2013 and 2021; with 25 employees, the company's stock was the sixth-best performing in 2021 before falling after the FDA petition.[3]

History

Founding

Cassava Sciences was founded by Remi Barbier in May 1998 as Pain Therapeutics,[4][5] focusing on opioids and chronic pain.[6] Barbier first heard of the research led by Stanley M. Crain at the Albert Einstein College of Medicine in New York City around 1993.[6] Crain invited Barbier to his lab and explained the potential pharmaceutical and financial benefits.[6] In 1998, Barbier started Pain Therapeutics, Inc. in South San Francisco, California,[7] with an initial investment of $1 million.[6]

Name change

Following the fourth FDA rejection of one of its experimental pain drugs, Remoxy, Cassava announced in August 2018 it would reorganize the company to focus on products for treating and diagnosing Alzheimer's.[8] In 2019, the company changed its name to Cassava Sciences.[9]

Corporate affairs

Leadership

Remi Barbier is Cassava's president, chief executive officer and chairman of the board.[3][10]

Other officers, as of December 2022, are James W. Kupiec, chief medical officer, and Eric Schoen, chief financial officer.[10][11] Senior vice presidents are: R. Christopher Cook (senior counsel), Michael Marsman (regulatory affairs), Michael Zamloot (tech operations), George Thornton (technology), and Lindsay Burns (neuroscience).[10] Burns is married to Barbier.[12][13][14]

Hoau-Yan Wang, a professor at City University of New York (CUNY) is a consultant who is on Cassava's advisory board. He is a co-author, with Burns, of many journal papers. The Wall Street Journal (WSJ) stated in 2021 that, along with Cassava's officers, he can receive bonuses based on Cassava's market performance.[3]

Patrick Keefe wrote in The New Yorker in January 2022 that Cassava's bonus plan provides for potential cash bonuses tied to "specific valuations [of the company's stock] for twenty consecutive days". He added that the "full incentive scheme could exceed two hundred million dollars, and it was not pegged to F.D.A. approval or to the success of the drug—just to the share price. This appeared to create an incentive for the company to pump its own stock."[12] The WSJ stated that, under this plan, Barbier's bonus could reach $108 million.[3]

According to Charles Piller, writing in Science, Barbier would not specify who were the company's 2022 scientific advisers.[15][a]

Financial

The company had no product revenues between 2013 and 2021.[3]

Cassava and its collaborators were awarded NIH grants totalling $20 million between 2015 and 2021.[3][b]

The WSJ wrote that, due to the promise of its experimental Alzheimer's drug, Cassava Sciences stock became the sixth-best stock of 2021, driving the company's value to over $US5 billion, with the stock price reaching $125 per share.[3] Keefe noted that part of the increase in share price was driven by discussion and hype in online forums, making it a so-called meme stock.[12] The share price fell to $42 after a petition was filed with the FDA in August 2021, questioning the company's research.[3]

Staffing

As of November 2021, Cassava had 25 employees.[3]

Research candidates

The company had no drug approved as of 2021.[3]

FLNA hypothesis

Filaman A (FLNA) is a protein that Cassava Sciences says becomes misshaped in people with Alzheimer's, leading to amyloid buildup in the brain contributing to the disease; Cassava journal papers, co-authored by Wang and Burns, suggest that the shape of FLNA in the brain can be restored.[3][9] A 2022 article in The New York Times stated that none of the Alzheimer's experts they spoke with knew of any support for the FLNA hypothesis; Lawrence Sterling Honig, professor of neurology at Columbia University Irving Medical Center, said: "But in fact, all the evidence seems to be from this [Wang's] lab."[9] (Wang and Burns had earlier published together on FLNA's role in naloxone and opioid receptor signaling.[9][19][20][21][22])

Oxytrex, Remoxy and PTI-901

The company started with three drug candidates focused on opioid treatment: Oxytrex, Remoxy and PTI-901 (low-dose naltrexone for irritable bowel syndrome).[23]

Oxytrex was a mixture of oxycodone, a generic opioid, combined with ultra-low-dose naltrexone that aimed to enhance analgesia while reducing opioid tolerance and withdrawal symptoms.[7] The phase III trials had high drop out rates and failed.[24]

Remoxy was a twice-daily gel form of oxycodone intended to be abuse-deterrent.[7][9] It was repeatedly rejected by the FDA,[9] culminating in the final rejection in 2018 after an FDA advisory meeting raised concerns about its potential risk of abuse.[25] According to The New York Times, the FDA reprimanded Cassava Sciences for appearing to promote the unapproved drug.[9] Barbier accused the FDA of "math errors, material mistakes and misrepresentations", which the agency denied.[25]

Alzheimer's disease

In August 2020, the chemical name simufilam was assigned to the company's experimental drug, previously called PTI-125,[26] which Cassava Sciences says can restore misshaped FLNA in the brain.[9] Open-label studies had started in March 2020,[9] and Cassava Sciences had reported in May 2020 that initial biomarker analysis of cerebrospinal fluid (CSF) samples from its phase IIb clinical trials of PTI-125 had failed, but reported in September 2020 that a new analysis by an "outside lab" showed improvements in biomarkers, adding that individuals with Alzheimer's also showed improvements in cognition with simufilam.[9][12][27] It was later revealed that the outside lab was Wang's CUNY lab.[12][9] In October 2021, larger trials were initiated;[9] Cassava Sciences announced in December 2021 that the first phase III trial of simufilam would enroll about 750 participants, and the second 1,000.[9][28] In the first quarter of 2022, 60 participants were enrolled;[9] Stat stated that enrollment had slowed as of April 2022, as people were deterred from enlisting due to the prevailing controversies.[13]

Allegations of research fraud

Reuters reported on July 27, 2022, that a criminal investigation of Cassava Sciences had been started by the United States Department of Justice (DOJ) over research results related to simufilam.[1] Two anonymous sources told Reuters that the investigation involved allegations that the company had "manipulated research results".[1] A citizen petition attempting to suspend the clinical trials was filed with the Food and Drug Administration (FDA), but the FDA said that the citizen petition "was not a proper avenue" to stop the trials in February 2022. The request that FDA conduct an investigation fell out of the purview of the citizen petition process.[1]

The Wall Street Journal stated in 2021 that the SEC, the NIH, and CUNY were also investigating allegations of manipulated data.[3] In October 2023, CUNY reported that they could obtain none of Wang's original data, which meant that they were unable to either prove or disprove allegations that the images were improperly manipulated;[29][30][31] they paused the investigation a few weeks later over concerns about confidentiality and integrity of the process.[32]

Cassava Sciences has denied any wrongdoing.[2] Kate Moss, attorney, stated via email to Reuters that "Cassava Sciences ... has never been charged with a crime, and for good reason – Cassava Sciences has never engaged in criminal conduct."[1] Piller summarized an email from Barbier as saying Cassava had "hired investigators to review its work, provided 'nearly 100,000 pages of documents to an alphabet soup of outside investigative agencies,' and asked CUNY to investigate ... 'there is no evidence of research misconduct'."[15] On November 3, 2022, Cassava Sciences filed a defamation lawsuit in the U.S. District Court of the Southern District of New York against defendants Quintessential Capital Management LLC, Drs. David Bredt and Geoffrey Pitt and other short sellers. According to Bloomberg, the lawsuit alleges that defendants “orchestrated a smear campaign against Cassava that included more than 1,000 false and defamatory statements.”[33] On March 28, 2024, the judge dismissed Cassava's lawsuit, finding "that the majority of the defendants' statements were protected under the First Amendment as statements of opinion or scientific debate, and that the fraction of statements that were adequately alleged to be defamatory were not published with actual malice".[34]

Citizen petition to the FDA

In August 2021, the FDA received a citizen petition–filed on behalf of two whistleblowers—alleging concerns about unreliable research and potential data manipulation in Cassava Science's preclinical research for the experimental drug.[12][15][35] The petition was submitted by Jordan A. Thomas, who was then with the law firm Labaton Sucharow in New York City, and requested that the FDA halt the clinical trials until the issues could be resolved.[36] According to Compliance Week, Thomas certified that the petition included "information known to the petitioner which are unfavorable to the petition".[36] Cassava Sciences maintained that the claims about the research data were "outlandish" and said the FDA's process had been used abusively.[3] Cassava's stock value dropped 55% after the petition was filed.[37]

The petitioners who filed the FDA complaint were identified months later, in November 2021, as neuroscientist David S. Bredt,[3] and cardiologist Geoffrey Pitt, a professor at Weill Cornell Medical College.[3][12] When the petition was filed, Bredt was an executive partner at a firm that raised investment capital for another biotechnology company working on Alzheimer's treatment.[36][38] He had noticed Cassava Sciences when its stock price increased in 2021 following early positive trial results for simufilam.[12] After examining the preclinical research papers, Bredt remarked that "they were making statements that were incompatible with biology and with pharmacology", and said that if the research was in fact legitimate, it should "win five Nobel Prizes".[12] According to The Wall Street Journal, Cassava's initial report that the reanalysis of simufilam's effectiveness was done by "an outside lab"—later revealed to be the CUNY lab of Wang, "a longtime paid consultant to the company"—was not revealed to investors; the news had led to a doubling of the company's stock price.[3] Bredt and Pitt suspected the re-analysis had been done by Wang, which was later confirmed by Barbier. Barbier responded that Wang was not an employee, so he considered his lab separate.[3] Among other methodological concerns, the petitioners suspected irregularities in Western blot images in papers by Wang and Burns, and were concerned that the 2020 "reanalysis" of findings by Wang had not been disclosed in Cassava's filings and that individuals enrolled in trials would be taking a drug that might not be safe.[3][12] They shorted shares of Cassava Sciences, expecting the price of its stock to drop once problems with the research were revealed.[3] After the stock's precipitous drop caused by the FDA petition, it was revealed that they were short sellers; Compliance Week stated that Thomas had not revealed this information when he certified the citizen petition.[36] Bloomberg News reported that the August selloff of Cassava shares earned short sellers $100 million,[39] and Compliance Week stated that Bredt and Pitt "potentially ... made millions".[36]

In July 2022, Piller identified Vanderbilt University neuroscientist Matthew Schrag as another whistleblower who examined images. Schrag reported to the NIH irregularities in 34 papers with authors linked to Cassava Sciences or its work, including Wang, Burns and Cassava advisor Steven Arnold, a Harvard University neurologist. Schrag was paid $18,000 by the petitioners' attorney for his hundreds of hours of analysis of the images.[15] Piller contacted other experts who he said "generally agree" with Schrag's conclusions.[15]

The FDA rejected the petition in February 2022 because the requests were "not the appropriate subject of a citizen petition", saying also that the rejection was not “a decision by the agency to take or refrain from taking any action”.[9][40]

Other concerns raised

A New York Times article stated in April 2022 that "many scientists have been deeply skeptical of the company's claims, asserting that Cassava's studies were flawed, its methods opaque and its results improbable".[9] Robert Howard, professor of psychiatry at the University College London, remarked that the lack of placebo and small sample size meant research conclusions were "implausible" at the least.[9] Elisabeth Bik, image-manipulation consultant, agreed to the citizen petition and alleged data errors and inconsistencies in the publications, identifying potential irregularities consistent with instances of copy and paste across different experiments.[3] Thomas C. Südhof, Nobel laureate neuroscientist at Stanford University, also commented: "The overall conclusions with regard to Alzheimer's disease make no sense to me whatsoever... [The findings of Cassava Sciences] are not in the mainstream of the field, and to me they seem implausible and contrived."[9]

Journal investigations

Several journal papers involving Cassava work and collaborators have been re-examined by their publishers.[41][42]

Following the public controversies, The Journal of Neuroscience reassessed the 2012 paper that described simufilam binding to FLNA.[3] The journal published a correction along with the original images in December 2021 remarking that the "error does not affect the conclusions of the article".[3][43] After further data concerns were brought to the attention of the journal, it issued an expression of concern stating that the issue was under investigation by CUNY, and that the journal would "await the outcome of that investigation before taking further action".[44]

The journal Neurobiology of Aging found "no compelling evidence of data manipulation intended to misrepresent the results", but issued an expression of concern on a 2017 paper,[45] saying they identified multiple errors. The journal issued a correction and indicated that its final decision awaited conclusions from the CUNY investigation.[3][9][46]

The Journal of Prevention of Alzheimer’s Disease investigated a 2020 simufilam-related, also co-authored by Wang, and decided to take no action. Its editor reported finding "no convincing evidence of manipulation of data or intent to mislead".[37]

PLOS One re-examined Wang's research papers in March 2020 and found problems with data integrity that were not resolved.[47] Five of Wang's papers were retracted, two of which were co-authored with Burns[9] that include the original papers on the discovery of FLNA binding as it relates to opioid receptor signaling. The FLNA retraction notices mention "vertical irregularities suggestive of splice lines" and that the "pixel patterns in background areas of blot images ... appear more similar than would be expected".[20][21] The notices state: "The data and comments provided did not resolve the concerns about the integrity and reliability of data presented in this article."[48][49]

A 2005 Neuroscience journal article on opioid tolerance was co-authored by Burns, Wang and others.[50] According to Piller, Cassava has stated that the journal found no manipulation of images, but said the journal would respond to any new concerns based on the CUNY investigation.[15]

Cassava advisors Wang and Arnold were co-authors on a highly-cited 2012 paper in the Journal of Clinical Investigation (JCI); Piller states that it forms a key part of Cassava's position that simufilam reduces resistance to insulin.[15][51] He writes that the paper relied on a method of analyzing how brain tissue "purportedly generates chemical signals"; Schrag found no indication the work, which he says "contradicts basic neurobiology", had been replicated.[15] He sent two groups of images to JCI; the editor responded that they did not investigate further after examination of one of the groups did not corroborate Schrag's analysis.[15] A group of four whistle-blowers also submitted concerns about the paper starting in August 2021. The four whistleblowers were independent of the two that filed the FDA petition, but they were also holding short positions on Cassava. JCI's investigation did not corroborate their concerns about the paper.[37]

Notes

  1. ^ The company's SEC Form 10-K filings from 2021 state that Scientific Advisory Board members included Jeffrey Cummings, Steven Arnold, Barbara Sahakian, Trevor Robbins, and Hoau-Yan Wang.[16][17][18]
  2. ^ See Reporter.nih.gov Advanced search for NIH grants totaling over $20 million for Cassava Sciences.

References

  1. ^ a b c d e f Taylor, Marisa; Spector, Mike (July 27, 2022). "Exclusive: Cassava Sciences faces U.S. criminal probe tied to Alzheimer's drug, sources say". Reuters. Retrieved July 31, 2022.
  2. ^ a b "Science podcast 220722 with Charles Piller and Sarah Crespi" (PDF). Science. July 22, 2022. doi:10.1126/science.ade0384. Retrieved August 19, 2022. See Piller 2022.
  3. ^ a b c d e f g h i j k l m n o p q r s t u v w x Michaels, Dave; Walker, Joseph (November 17, 2021). "SEC Investigating Cassava Sciences, Developer of Experimental Alzheimer's Drug". Wall Street Journal. ISSN 0099-9660. Retrieved April 29, 2022.
  4. ^ "Pain Therapeutics, Inc. – Cruelty Free Investing". crueltyfreeinvesting.org. Retrieved May 7, 2022.
  5. ^ "SAVA – Cassava Sciences Inc Company Profile". CNN Business. Retrieved May 7, 2022.
  6. ^ a b c d Wolfson, Wendy (2005). "Janus-Faced Drugs: The Double-Edged Synthetic Opiate Trade". Chemistry & Biology. 12 (10): 1055–1056. doi:10.1016/j.chembiol.2005.10.003. PMID 16242645.
  7. ^ a b c Sturgeon, Christopher (June 15, 2006). "Pain Therapeutics Takes Different Path". Genetic Engineering and Biotechnology News. Retrieved April 29, 2022.[permanent dead link]
  8. ^ Mishra, Manas; Shyam, Ashwin (August 6, 2018). "FDA declines to approve Pain Therapeutics' opioid drug, shares plunge". Reuters. Retrieved September 2, 2022.
  9. ^ a b c d e f g h i j k l m n o p q r s t Mandavilli, Apoorva (April 18, 2022). "Scientists Question Data Behind an Experimental Alzheimer's Drug". The New York Times. ISSN 0362-4331. Retrieved April 28, 2022.
  10. ^ a b c "Management". Cassava Sciences. Retrieved October 23, 2023.
  11. ^ "Cassava Sciences Mourns the Death of Board Member and Officer Nadav Friedmann, PhD, MD". BioSpace. Retrieved October 23, 2023.
  12. ^ a b c d e f g h i j Keefe, Patrick Radden (January 15, 2022). "Jordan Thomas's Army of Whistle-Blowers". The New Yorker. Archived from the original on July 22, 2022. Retrieved April 29, 2022.
  13. ^ a b Feuerstein, Adam (April 5, 2022). "Troubles mount for Cassava Sciences, as patient enrollment lags for Alzheimer's drug studies". Stat. Retrieved April 30, 2022.
  14. ^ "Lindsay Burns Barbier '87". www.harvardvarsityclub.org. Retrieved May 2, 2022.
  15. ^ a b c d e f g h i Piller, Charles (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 August 28, 2022.
  16. ^ "United States Securities and Exchange Commission Form 10-K, Cassava Sciences, Inc". Cassava Sciences, Inc. March 23, 2021. Retrieved July 31, 2022.
  17. ^ "United States Securities and Exchange Commission Form 10-K, Cassava Sciences, Inc". Cassava Sciences, Inc. February 28, 2022. Retrieved July 31, 2022.
  18. ^ "Scientific Advisory Board". Cassava Sciences. March 5, 2021. Archived from the original on March 5, 2021. Retrieved July 31, 2022.{{cite web}}: CS1 maint: bot: original URL status unknown (link)
  19. ^ "Five studies linked to Cassava Sciences retracted". Retraction Watch. March 30, 2022. Retrieved September 1, 2022.
  20. ^ a b PLOS ONE Editors (March 30, 2022). "Retraction: Naloxone's Pentapeptide Binding Site on Filamin A Blocks Mu Opioid Receptor–Gs Coupling and CREB Activation of Acute Morphine". PLOS ONE. 17 (3): e0266629. doi:10.1371/journal.pone.0266629. PMC 8967007. PMID 35353864.
  21. ^ a b PLOS ONE Editors (March 30, 2022). "Retraction: High-Affinity Naloxone Binding to Filamin A Prevents Mu Opioid Receptor–Gs Coupling Underlying Opioid Tolerance and Dependence". PLOS ONE. 17 (3): e0266627. doi:10.1371/journal.pone.0266627. PMC 8967022. PMID 35353861.
  22. ^ Burns LH, Wang HY (November 2010). "PTI-609: a novel analgesic that binds filamin A to control opioid signaling". Recent Pat CNS Drug Discov. 5 (3): 210–220. doi:10.2174/157488910793362386. PMID 20726836.
  23. ^ Jacobs, Tom (2005). "No pain, no gain?". Nature Biotechnology. 23 (8): 934. doi:10.1038/nbt0805-934. PMID 16082357. S2CID 20266178.
  24. ^ "Pain Therapeutics slumps as Oxytrex fails Phase III trial". PharmaTimes. November 23, 2005. Retrieved April 29, 2022.
  25. ^ a b "A 'disoriented' Pain Therapeutics flips out after FDA rejects appeal on Remoxy". Endpoints News. Retrieved June 15, 2022.
  26. ^ "USAN Modifies Lead Drug Candidate's Chemical Name to 'simufilam'". GlobeNewswire News Room (Press release). Cassava Sciences, Inc. November 27, 2020. Retrieved May 3, 2022.
  27. ^ "Cassava Sciences Announces Final Results of a Phase 2b Clinical Study of Sumifilam in Patients with Alzheimer's Disease" (Press release). Cassava Sciences. September 14, 2020. Retrieved August 31, 2022.
  28. ^ "Cassava Sciences Launches Clinical Website to Support Phase 3 Studies of Oral Simufilam in Alzheimer's Disease". GlobeNewswire News Room (Press release). Cassava Sciences, Inc. December 23, 2021. Retrieved April 30, 2022.
  29. ^ Piller, Charles (October 12, 2023). Co-developer of Cassava’s potential Alzheimer’s drug cited for ‘egregious misconduct’ (Report). Science. doi:10.1126/science.adl3444.
  30. ^ Subbaraman N, Walker J (October 13, 2023). "Cassava Sciences Adviser Found to Have Committed 'Egregious Misconduct'; Scientist, who is a City University of New York professor, didn't provide school investigators with data or records supporting his research". Wall Street Journal. ProQuest 2876611078.
  31. ^ Apoorva Mandavilli (October 14, 2023). "Scientists Investigating Alzheimer's Drug Faulted in Leaked Report". New York Times. Retrieved October 17, 2023.
  32. ^ Mandavilli, Apoorva (October 28, 2023). "CUNY Halts Investigation of Alzheimer's Researcher". The New York Times. Retrieved October 29, 2023.
  33. ^ Benny-Morrison, Ava (November 3, 2022). "Meme Stock Cassava Sues Short Sellers Alleging a Smear Campaign". Bloomberg.
  34. ^ Volokh, Eugene (March 29, 2024). "Drug Company's Libel Lawsuit Against Scientists Dismissed". Reason.com. Retrieved March 31, 2024.
  35. ^ "Requests that the FDA halt the current clinical studies of Simufilam PTI-125 sponsored by Cassava Sciences NCT04388254 and NCT04994483, pending audits of 1 the publications relied on by Cassava in support of its scientific claims concerning Simufilam; 2 the IND application for Simulifam's use in Alzheimer's Disease; and 3 all clinical biomarker studies of Simufilam in Alzheimer's Disease". regulations.gov. Retrieved August 19, 2022. As referenced by Piller 2022.
  36. ^ a b c d e Jaeger, Jaclyn (March 2, 2022). "The Cassava Sciences saga: Short sellers, 'gaming' the FDA, and the damaging ripple effects". Compliance Week. Archived from the original on August 1, 2022. Retrieved September 2, 2022.
  37. ^ a b c Else H (January 2023). "Alzheimer's drug saga prompts journal to scrutinize whistle-blowers". Nature (News). doi:10.1038/d41586-023-00050-z. PMID 36639445. S2CID 255801597.
  38. ^ "Corrections: April 20, 2022". The New York Times. April 19, 2022. Retrieved September 4, 2022.
  39. ^ Flanagan, Cristin (August 31, 2021). "Cassava Short Sellers Reap $100 Million in August Stock Rout". Bloomberg News. Retrieved August 20, 2022.
  40. ^ Cavazzoni, P. (February 9, 2022). "Response Letter from FDA CDER to Labaton Sucharow". regulations.gov. Retrieved April 29, 2022.
  41. ^ "Two expressions of concern arrive for papers linked to beleaguered biotech Cassava". Retraction Watch. December 20, 2021. Retrieved August 20, 2022.
  42. ^ "Journal mulls expression of concern for Cassava Sciences paper". Retraction Watch. November 22, 2021. Retrieved August 20, 2022.
  43. ^ "Erratum: Wang et al., "Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A"". The Journal of Neuroscience. 41 (50): 10405. December 15, 2021. doi:10.1523/JNEUROSCI.2154-21.2021. ISSN 0270-6474. PMC 8672690. PMID 34759033.
  44. ^ "Expression of Concern: Wang et al., "Reducing Amyloid-Related Alzheimer's Disease Pathogenesis by a Small Molecule Targeting Filamin A"". Journal of Neuroscience. 42 (3): 529. January 19, 2022. doi:10.1523/JNEUROSCI.2306-21.2021. ISSN 0270-6474. PMC 8802929. PMID 34921050.
  45. ^ Wang HY, Lee KC, Pei Z, Khan A, Bakshi K, Burns LH (July 2017). "PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis". Neurobiol Aging. 55: 99–114. doi:10.1016/j.neurobiolaging.2017.03.016. PMID 28438486. S2CID 207163555.
  46. ^ "Expression of Concern: Wang et al., (2017) PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis. Neurobiol. Aging, 55:99–114". Neurobiology of Aging. 113: 152. 2022. doi:10.1016/j.neurobiolaging.2022.03.012. S2CID 247586479.
  47. ^ Akst, Jef (March 31, 2022). "PLOS ONE Pulls Five Papers Tied to Alzheimer's Drug Controversy". The Scientist. Retrieved April 28, 2022.
  48. ^ PLOS ONE Editorial Board (March 30, 2022). "Retraction: High-Affinity Naloxone Binding to Filamin A Prevents Mu Opioid Receptor–Gs Coupling Underlying Opioid Tolerance and Dependence". PLOS ONE. 17 (3): e0266627. doi:10.1371/journal.pone.0266627. ISSN 1932-6203. PMC 8967022. PMID 35353861.
  49. ^ PLOS ONE Editorial Board (March 30, 2022). "Retraction: Naloxone's Pentapeptide Binding Site on Filamin A Blocks Mu Opioid Receptor–Gs Coupling and CREB Activation of Acute Morphine". PLOS ONE. 17 (3): e0266629. doi:10.1371/journal.pone.0266629. ISSN 1932-6203. PMC 8967007. PMID 35353864.
  50. ^ Wang HY, Friedman E, Olmstead MC, Burns LH (2005). "Ultra-low-dose naloxone suppresses opioid tolerance, dependence and associated changes in mu opioid receptor-G protein coupling and Gbetagamma signaling". Neuroscience. 135 (1): 247–61. doi:10.1016/j.neuroscience.2005.06.003. PMID 16084657. S2CID 42012168.
  51. ^ Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, Fuino RL, Kawaguchi KR, Samoyedny AJ, Wilson RS, Arvanitakis Z, Schneider JA, Wolf BA, Bennett DA, Trojanowski JQ, Arnold SE (April 2012). "Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline". J Clin Invest. 122 (4): 1316–38. doi:10.1172/JCI59903. PMC 3314463. PMID 22476197.

External links

Retrieved from "https://mdwiki.org/wiki/Cassava_Sciences"