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Cassava Sciences (symbol: SAVA) is a pharmaceutical company based in Austin, Texas, U.S. 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, after a citizen petition attempting to suspend the clinical trials was rejected by the Food and Drug Administration (FDA) in February. Cassava Sciences has denied any wrongdoing and raised concerns about the motivations behind the FDA petition. 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.

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. As of 2022, it is also developing SavaDx (originally PTI-125Dx), a blood test aimed at diagnosing Alzheimer's. The company had 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.

History

Founding

Cassava Sciences was founded by Remi Barbier in May 1998 as Pain Therapeutics. Barbier first heard of the research led by Stanley M. Crain at the Albert Einstein College of Medicine in New York City around 1993. Crain invited Barbier to his lab and explained the potential pharmaceutical and financial benefits. In 1998, Barbier started Pain Therapeutics in South San Francisco, CA, with an initial investment of one million dollars.

In 2019, the company changed its name to Cassava Sciences, Inc., with the stock ticker SAVA, stating in a press release that the name better reflected "the Company's strategic focus on drug development for neurodegenerative diseases".

Products

The company started with three drug candidates: Oxytrex, Remoxy and PTI-901 (modified naltrexone for irritable bowel syndrome). Oxytrex was a mixture of oxycodone, a generic opioid, combined with naltrexone that aimed to enhance analgesia while reducing opioid tolerance and withdrawal symptoms. Its Phase III trial was underpowered due to high dropout rates, causing the share value of the company to recede by 19% the next day. Remoxy was a twice-daily oxycodone. Clinical trials for Remoxy in 2006 were successful. The FDA declined to approve Remoxy, culminating in the final rejection in 2018 after an FDA advisory meeting raised concerns about its potential risk of abuse. Barbier accused the FDA of "math errors, material mistakes and misrepresentations", which the agency denied.

In August 2020, the World Health Organization, and the United States Adopted Names (USAN) assigned the chemical name simufilam to the company's experimental drug (previously called PTI-125). The company reported in 2020 that initial biomarker analysis of CSF samples from its Phase IIb clinical trials failed. According to a Cassava Sciences press release, the first Phase III trial would enroll about 750 participants, and the second 1,000. Stat stated that enrollment had slowed as of April 2022, as people were deterred from enlisting due to the prevailing controversies.

Cassava is developing SavaDx (originally PTI-125Dx), a blood test aimed at diagnosing Alzheimer's.

Leadership and performance

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

Cassava's senior vice president of neuroscience, Lindsay Burns, is a co-author on journal papers involving Cassava products and the wife of Barbier.

The Wall Street Journal (WSJ) stated in 2021 that 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, and along with Cassava's officers, can receive bonuses based on Cassava's market performance.

Patrick Keefe wrote in The New Yorker in January 2022 that Cassava had an "unusual compensation scheme" based on its stock market valuation. The cash bonuses were not based on producing successful drugs or gaining FDA approval, rather are tied to the price of the company's stock and "specific valuations for twenty consecutive days". The WSJ stated that, under this plan, Barbier could reap $108 million.

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

Staffing

As of November 2021, Cassava had 25 employees.

Financial

The company had no drug approved as of 2021, and no product revenues between 2013 and 2021.

Cassava and its collaborators were awarded NIH grants of $20 million between 2015 and 2021.

The Wall Street Journal 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, before falling to $42 after a petition was filed with the FDA in August 2021, questioning the company's research. It stated that the company produced no product revenues between 2013 and 2021.

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 the experimental drug. Two anonymous sources told Reuters that the investigation involved criminal charges over allegations that the company had "manipulated research results". A citizen petition attempting to suspend the clinical trials had been rejected by the Food and Drug Administration (FDA) in February 2022 as the request fell out of the purview of the citizen petition process.

Cassava Sciences has denied any wrongdoing, raised concerns about the motivations behind the FDA petition, and responded that it had already disclosed a request for information by government agencies in 2021. According to Reuters, Cassava "neither confirmed nor denied" the DOJ probe, but Kate Moss, attorney, replied via email that "Cassava Sciences vehemently denies any and all allegations of wrongdoing" and "has never been charged with a crime, and for good reason – Cassava Sciences has never engaged in criminal conduct."

The Wall Street Journal stated in 2021 that the SEC, the NIH, and CUNY were also investigating allegations of manipulated data.

Citizen petition to the FDA

In August 2021, the FDA received a citizen petition alleging concerns about unreliable research and potential data manipulation in Cassava Science's preclinical research for simufilam. Submitted by Jordan A. Thomas of the law firm Labaton Sucharow in New York City, the letter requested that the FDA halt the clinical trials until the issues could be resolved. Cassava Sciences maintained that the claims about the research data were "fictional" and said the FDA's process had been used abusively.

In November 2021, the whistleblowers who filed the FDA petition (and could benefit financially as whistleblowers) were identified as neuroscientist David S. Bredt, and his childhood friend, cardiologist Geoffrey Pitt, a professor at Weill Cornell Medical College. Bredt had noticed Cassava Sciences when its stock price increased in 2021 following early positive trial results for simufilam. 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". According to The New York Times, Cassava had initially reported that a reanalysis of simufilam's effectiveness was done by "an outside lab," which was later revealed to be the lab of Wang. Among other methodological concerns, Bredt and Pitt suspected irregularities in Western blot images in papers by Wang and Burns, and were concerned that the 2020 "reanalysis" of findings had been done by Wang's lab, which was not an "outside lab"—a fact that should have been revealed to investors and disclosed in Cassava's filings. Barbier responded that Wang was not an employee, so he considered his lab separate.

Bredt and Pitt shorted shares of Cassava Sciences, expecting the price of its stock to drop once problems with the research were revealed. After the stock's precipitous drop caused by the FDA petition, it was revealed that they were short sellers. Bloomberg News reported that the August selloff of Cassava shares earned short sellers $100 million.

Piller identified Vanderbilt University neuroscientist Matthew Schrag as the whistleblower who examined images from the papers and reported irregularities to the NIH; he received $18,000 for his analysis of the images. In February 2022, the FDA rejected the petition stating: "Please note that your Petitions are being denied solely on the grounds that your requests are not the appropriate subject of a citizen petition. 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."

Other concerns raised

The New York Times wrote 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"; Lawrence Sterling Honig, professor of neurology at Columbia University Irving Medical Center, noted: "But in fact, all the evidence seems to be from this lab." Robert Howard, professor of psychiatry at the University College London, remarked on the lack of placebo and small sample size that making such research conclusion "at the very least is implausible". Elisabeth Bik, image-manipulation consultant, agreed to the citizen petition and alleged data errors and inconsistencies in the publications, identifying many irregularities consistent with instances of copy and paste across different experiments. 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... are not in the mainstream of the field, and to me they seem implausible and contrived."

Journal investigations

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

Following the public controversies, The Journal of Neuroscience reassessed the 2012 paper that described simufilam binding to FLNA. 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". 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".

PLOS One re-examined all the Burns and Wang's research papers in March 2020 and found "similarities in background pixels" in the Western blot data. Five of Wang's papers were retracted, two of which were co-authored with Burns that include the original papers on the discovery of FLNA binding as it relates to opioid receptor signaling. Three papers are on prenatal cocaine. The FLNA retraction notices both mention image irregularities, "vertical irregularities suggestive of splice lines". Retraction notices stated: "The data and comments provided did not resolve the concerns about the integrity and reliability of data presented in this article. In light of these issues, the PLOS ONE Editors retract this article."

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

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.
2. See Reporter.nih.gov Advanced search for NIH grants totaling over $20 million for Cassava Sciences.

References

1. ^ Schoen, Eric (March 27, 2019). "Pain Therapeutics Announces Name Change to Cassava Sciences, Inc". GlobeNewswire (Press release). Cassava Sciences, Inc. Retrieved April 28, 2022.
2. ^ 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.
3. ^ Keown, Alex (February 11, 2022). "The Show Will Go On for Cassava after FDA Denies Citizen Petition". BioSpace.com. Retrieved August 19, 2022.
4. ^ 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.
5. ^ "Science podcast 220722 with Charles Piller and Sarah Crespi" (PDF). Science. July 22, 2022. Retrieved August 19, 2022. See Piller 2022.
6. ^ 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.
7. ^ Jacobs, Tom (2005). "No pain, no gain?". Nature Biotechnology. 23 (8): 934. doi:10.1038/nbt0805-934. PMID 16082357. S2CID 20266178.
8. "Pain Therapeutics, Inc. – Cruelty Free Investing". crueltyfreeinvesting.org. Retrieved May 7, 2022.
9. "SAVA – Cassava Sciences Inc Company Profile". CNN Business. Retrieved May 7, 2022.
10. ^ 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.
11. ^ Sturgeon, Christopher (June 15, 2006). "Pain Therapeutics Takes Different Path". Genetic Engineering and Biotechnology News. Retrieved April 29, 2022.
12. "Pain Therapeutics slumps as Oxytrex fails Phase III trial". PharmaTimes. November 23, 2005. Retrieved April 29, 2022.
13. ^ "A 'disoriented' Pain Therapeutics flips out after FDA rejects appeal on Remoxy". Endpoints News. Retrieved June 15, 2022.
14. "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.
15. "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.
16. ^ Feuerstein, Adam (April 5, 2022). "Troubles mount for Cassava Sciences, as patient enrollment lags for Alzheimer's drug studies". Stat. Retrieved April 30, 2022.
17. "SavaDx". Cassava Sciences. Retrieved August 20, 2022.
18. ^ "Management". Cassava Sciences. Retrieved August 19, 2022.
19. "Lindsay Burns Barbier '87". www.harvardvarsityclub.org. Retrieved May 2, 2022.
20. ^ 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.
21. "United States Securities and Exchange Commission Form 10-K, Cassava Sciences, Inc". Cassava Sciences, Inc. March 23, 2021. Retrieved July 31, 2022.
22. "United States Securities and Exchange Commission Form 10-K, Cassava Sciences, Inc". Cassava Sciences, Inc. February 28, 2022. Retrieved July 31, 2022.
23. "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)
24. "Cassava Sciences Responds to Media Reports" (Press release). Cassava Sciences. July 27, 2022. Retrieved August 16, 2022.
25. "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" (Document). regulations.gov. {{cite document}}: Unknown parameter |access-date= ignored (help); Unknown parameter |url= ignored (help) As referenced by Piller 2022.
26. ^ McKenzie, Heather (August 27, 2021). "UPDATED: Cassava Sciences Responds to Allegations that Data is Manipulated and "Defies Logic"". BioSpace. Retrieved April 28, 2022.
27. ^ 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.
28. Jaeger, Jaclyn (March 2, 2022). "The Cassava Sciences saga: Short sellers, 'gaming' the FDA, and the damaging ripple effects". Compliance Week. Retrieved July 31, 2022.
29. Flanagan, Cristin (August 31, 2021). "Cassava Short Sellers Reap $100 Million in August Stock Rout". Bloomberg News. Retrieved August 20, 2022.
30. Cavazzoni, P. (February 9, 2022). "Response Letter from FDA CDER to Labaton Sucharow" (Document). regulations.gov. {{cite document}}: Unknown parameter |access-date= ignored (help); Unknown parameter |url= ignored (help)
31. "Two expressions of concern arrive for papers linked to beleaguered biotech Cassava". Retraction Watch. December 20, 2021. Retrieved August 20, 2022.
32. "Journal mulls expression of concern for Cassava Sciences paper". Retraction Watch. November 22, 2021. Retrieved August 20, 2022.
33. "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.
34. "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.
35. Akst, Jef (March 31, 2022). "PLOS ONE Pulls Five Papers Tied to Alzheimer's Drug Controversy". The Scientist. Retrieved April 28, 2022.
36. "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. March 30, 2022. doi:10.1371/journal.pone.0266629. PMC 8967007. PMID 35353864.
37. "Retraction: High-Affinity Naloxone Binding to Filamin A Prevents Mu Opioid Receptor–Gs Coupling Underlying Opioid Tolerance and Dependence". PLOS ONE. 17 (3): e0266627. March 30, 2022. doi:10.1371/journal.pone.0266627. PMC 8967022. PMID 35353861.
38. 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.
39. 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.
40. Wang, Hoau-Yan; Lee, Kuo-Chieh; Pei, Zhe; Khan, Amber; Bakshi, Kalindi; Burns, Lindsay H. (2017). "PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis". Neurobiology of Aging. 55: 99–114. doi:10.1016/j.neurobiolaging.2017.03.016. PMID 28438486. S2CID 207163555.
41. "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.

External links

• Company website

• 1998 establishments in Texas
• Pharmaceutical companies of the United States
• Companies based in Austin, Texas
• Alzheimer's disease research
• Medical scandals