Cassava Sciences

Cassava Sciences (symbol: SAVA) is a pharmaceutical company based in Austin, Texas, USA. Established in 1998 as Pain Therapeutics, the new name was adopted to focus on drugs for neurodegenerative diseases like Alzheimer's disease.[1][2] Its founder, Chief Executive Officer and President, Remi Barbier, was inspired by research on the actions of opiate conducted at the Albert Einstein College of Medicine in the early 1990s.[3] The major initial works were on the painkiller Oxytrex (oxycodone combined with naltrexone), an antiabuse opioid Remoxy (modified oxycodone) and PTI-901 (modified naltrexone for irritable bowel syndrome).[4] None of the drugs were approved by the Food and Drug Administration. Remoxy, as the most promising prescription drug among them,[5] was turned down by FDA for the fourth time in 2018 due to high potential risks.[6]

Cassava Sciences, Inc.
FormerlyPain Therapeutics, Inc.
TypePrivate
IndustryPharmaceuticals
Founded1998 (1998) in Austin, Texas, US
FounderRemi Barbier
HeadquartersAustin, Texas, US
Key people
  • Lindsay Burns (Senior Vice President)
  • Nadav Friedmann (Chief Medical Officer)
  • James W. Kupiec (Chief Clinical Development Officer)
Products
Websitehttps://www.cassavasciences.com

SavaDx (originally known as PTI-125Dx), a blood-test kit, and simufilam (earlier called PTI-125 and sumifilam), an oral-tablet drug for Alzheimer's disease, are the two most important products. Simufilam has undergone Phase I clinical trials since 2018 with good results, and the final stages of Phase II and Phase III trials started in 2022.[7] The drug made the company the sixth-best performing US stock in 2021.[8]

Cassava Sciences has no laboratory of its own. The main research works are done by its Senior Vice President Lindsay Burns in collaboration with Hoau-Yan Wang, an Associate Medical Professor at the City University of New York, who serves as the company's scientific advisor.[9] While simufilam was being assessed by the FDA for approval, scientific controversies arose in 2021 on the research papers that described the discovery and development of the drug as there were evidently manipulated data.[10] The situation led to a steep fall in the stock price of the company.[11] Five papers related to Wang's research under Cassava Sciences published in PLOS One were retracted in 2022.[12]

History

The establishment of Cassava Sciences (as Pain Therapeutics) was originally inspired by the development of painkillers naloxone and naltrexone, which are opioid antagonists, as medications for alcohol or drug use disorders. Remi Barbier first heard of the research led by Stanley M. Crain at the Albert Einstein College of Medicine in New York City around 1993.[3] Since the 1980s, Crain's team had been investigating the effect of these drugs as a powerful painkiller for substance (such as morphine and cocaine) use disorders.[13][14][15] In 1995, Crain and Ke-Fei Shen found that an extremely low (picomolar) concentrations of naloxone and naltrexone showed better painkilling and reduced morphine dependence in experimental mice.[16] Crain invited Barbier to his lab and explained the potential pharmaceutical and financial benefits.[3] In 1998, Barbier started the Pain Therapeutics in Austin, Texas,[17] with an initial investment of one million dollars.[3]

The first drugs

The company started with three drug candidates: Oxytrex, Remoxy and PTI-901 (which is a modified naltrexone for irritable bowel syndrome).[4] Oxytrex is a mixture of oxycodone, a generic opioid medication, combined with ultra-low dose of naltrexone, aimed to reduce pain in substance withdrawal symptoms. An initial clinical trial gave a good overall result, to which Barbier remarked: "the drug really worked as intended."[17] But the Phase III trial failed, the results of which caused share value of the company down by 19% the next day.[18] Remoxy is a modified oxycodone meant to be long acting and prevent substance dependence. The clinical trials started in 2006.[17] The FDA declined to approve the drug for the fourth time in 2018 due to high potential risks. The company faced 36% loss in its shares.[6]

Simufilam and new name

In 2008, Lindsay Burns (later Senior Vice President and wife of Barbier[2]), working with Hoau-Yan Wang and his student Maya Frankfurt of the City University of New York, found that there was a small molecule (a 300-kDa protein) which they identified as filamin A (FLNA) that binds naloxone and its analogue, naltrexone. The research was funded by Pain Therapeutics and the findings were published in PLOS One. They claimed that the discovery of FLNA binding could "create an opportunity to formulate a new generation of pain therapeutics that may provide long-lasting analgesia with minimal tolerance, dependence and addictive properties."[19] The next year, Burns and Wang reported a possible signalling mechanism of the molecular binding in the same journal.[20] In 2010, the two reported an identification of a chemical compound PTI-609 (PTI for Pain Therapeutics, Inc.) as "a novel analgesic" that also binds to the opioid antagonist-binding site on FLNA. They made an explicit statement: "PTI-609 was designed after discovering filamin A as the high-affinity target of naltrexone or naloxone."[21]

In 2012, Burns and Wang's team introduced PTI-125 as "a novel compound" (possibly an analogue of PTI-609[21]) in The Journal of Neuroscience, in which they showed the molecule as binding to FLNA.[22] FLNA is a key protein that maintains normal cell shape and division and as such has important implication in neurological disorder like Alzheimer's disease in which the protein is distorted, as their investigations revealed.[23][22] In 2017, they reported in Neurobiology of Aging that PTI-125 could reverse abnormal FLNA and restore brain damage symptoms in Alzheimer mice.[24][25]

Several drugs have been investigated for Alzheimer's disease, but most of them failed or even did not make it to clinical trials as they are often toxic to normal cells.[26] In 2018, having a new drug candidate, Pain Therapeutics received research grants ($260,585) from the National Institutes of Health for the clinical trials of PTI-125 as an Alzheimer drug.[27][28] With this new focus, the company changed its name to Cassava Sciences, Inc., with the symbol SAVA, in 2019.[29] In August 2020, following and advice from the World Health Organization,[30] the United States Adopted Names (USAN) assigned the chemical name as simufilam, of which Barbier remarked it as "an absolutely new type of drug therapy for Alzheimer’s disease."[31] The company reported in 2020 that the initial clinical trials failed[2] upon which its shares declined by 75%.[8] However, subsequent trials showed good results,[32] and Barbier claimed it as "the first drug—to our knowledge—that can restore cognition."[2] By then Wang had become science advisor to the company.[12] Announcing the Phase II results and future Phase III in February 2021, Barbier contended: "I believe the rest of the year may be equally exciting."[33]

Simufilam and issues of research misconducts

In August 2021, the Food and Drug Administration received a citizen petition expressing concerns of unreliable research and misuse of scientific data on Cassava Sciences research.[2] Submitted by Jordan A. Thomas of the law firm Labaton Sucharow in New York City, the letter requests for halting the clinical trials and resolving important issue,[9] such as:

  1. Claims that filamin A is associated with Alzheimer's disease and that simufilam binds to filamin A are not supported by any independent research;
  2. Images of western blots in Burns and Wang's papers that described simufilam' activities showed anomalies and data manipulations;
  3. The biomarker data in clinical trials also indicate possible data manipulations; and
  4. "Remarkable" molecular experiments that looked suspicious.[34]

Cassava Sciences publicly responded that each claim was "false and misleading." It maintained that the research data were genuine, as Barbier announced, "As a science company, we champion facts that can be evaluated and verified."[9] It initially claimed that some data in clinical trials were produced by their partner Quanterix Corporation, to which the latter made an open statement saying: "Quanterix or its employees did not interpret the test results or prepare the data charts presented by Cassava."[35][36]

In November 2021, The Wall Street Journal revealed the lead scientific whistleblower as David Bredt,[8] a neuroscientists at Johnson & Johnson.[37] Bredt had noticed Cassava Sciences when its stock share increased in the early 2021 as simufilam became a promising drug. He was immediately concerned with the experimental method in the clinical trials that did not use placebos. After examining all the related research papers, he remarked, "They were making statements that were incompatible with biology and with pharmacology," and said that the research was worth to "win five Nobel Prizes." He decided to team up with Geoffrey Pitt, a cardiologist and a professor at Weill Cornell Medical College, and approached Thomas.[2] Bredt and Pitt holds Cassava Sciences shares and they were concerned that scientific rationale of simufilam clinical trials "is unsound."[8]

In February 2022, Patrizia Cavazzoni, Director of the Center for Drug Evaluation and Research, responded and rejected the petition on the ground that the requested actions will need public disclosure of research materials which FDA is obligated to keep confidentiality on. The letter concludes:

We take the issues you raise seriously. 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.[38]

The link between filamin A and Alzheimer's disease is still doubtful and is not supported by other research, as Lawrence Sterling Honig, professor of neurology at Columbia University Irving Medical Center, noted: "But in fact, all the evidence seems to be from this [Wang's] lab."[10] The placebo effect, a beneficial non-drug treatment, is important in clinical trials as it can have beneficial influence on the treated patients as the drugs, particularly in brain research.[39][40] The clinical trial results announced in September 2021 showed 50 Alzheimer participants in the study and no use of placebos.[41] 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."[10] Elisabeth Bik, image-manipulation consultant, agreed to the citizen petition that there were data errors in the publications, and also found several additional inconsistencies.[8] She asserted that there were many 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... [The findings of Cassava Sciences] are not in the mainstream of the field, and to me they seem implausible and contrived."[10] Quintessential Capital Management, a hedge fund, issued a comprehensive report of the "in-depth study" of the company in November 2021.[42][43] The report asserted that the research and the clinical trials were "tainted by deception and misconduct." Two of the company's official had criminal records as fraudsters, simufilam was based on unsubstantiated claims and forged data, and research subjects in clinical trials were chosen to make impressive results.[44] It also meantioned about the misconduct of Evelyn Lopez-Brignoni, the lead scientists in the clinical trials, to which the FDA had given an open warning in September 2021.[45][46] In the warning letter, FDA accused Lopez-Brignoni that she "did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of clinical investigations [Title 21 of the Code of Federal Regulations]."[47] The report concluded:

Cassava Sciences could be a scheme orchestrated by management to enrich itself at the expense of shareholders, patients, and the US Federal Government... In our opinion, Simufilam is a worthless compound, and any touted benefit is the [sic] likely the result of a combination of forgery, "cherry picking" of patients and statistical manipulation of data, of which we have plenty of disturbing evidence.[44]

Cassava Sciences had announced in May 2020 that Phase II first stage trial was a failure.[48] Three month later, it announced a reanalyzed result claiming that simufilam was safe and effective in improving cognitive performance in Alzheimer people.[49] Barbier reported that the reanalysis was done by "an outside lab," which was later revealed to be that of Wang's.[10] Wang's role in the company as a paid advisor was not disclosed publicly.[8] The company announced the start of Phase III trials in December 2021. The first stage would require 750 participants, and the second, 1000.[50] It is not clear if the study will be completed as people seem to be reluctant for participating due to the prevailing controversies. As of April 2022, only 60 people were enrolled in the study.[51]

Reactions from the journals

Following the public controversies, The Journal of Neuroscience reassessed the 2012 paper that described simufilam binding to FLNA.[22] Marina R. Picciotto, the editor-in-chief, declared in November 2021 that there were no evidence of data manipulation after the original data from the authors were examined; however, she noted that some images were duplicated in the same paper.[8] The authors published the correction along with the original images in December 2021 remarking that the "error does not affect the conclusions of the article."[52] However, the original images created further inconsistency on the overall data, and the journal issued an expression of concern on 19 January 2022:

The editors have been made aware of concerns about Western blots in this study, including those published with the article's erratum (Wang et al., 2021[53]). These and other concerns are currently under investigation by the academic authorities at the City University of New York (CUNY). JNeurosci will await the outcome of that investigation before taking further action.[54]

PLOS One re-examined all the Burns and Wang's research papers in March 2020 and found manipulations in the western blot data. Five of Wang's papers published under the support of Cassava Sciences were retracted, out of which two were co-authored with Burns[12] that include the original papers on the discovery of FLNA binding, the retraction notes of which reads:

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.[55][56] HYW [Hoau-Yan Wang] and LB [Lindsay Burns] did not agree with the retraction. MF [Maya Frankfurt] either did not respond directly or could not be reached. HYW stands by the article’s findings.[56]

Neurobiology of Aging also issued an expression of concern on the 2017 paper,[24] saying that although there were no "compelling evidence of data manipulation intended to misrepresent the results," they found at least eight errors in different parts of the result. The journal concludes:

The authors have requested a corrigendum to correct these issues. However, Neurobiology of Aging is aware of an ongoing inquiry of these and other concerns by the sponsoring institution, the City University of New York (CUNY), and will make a final decision as to appropriate corrective action once that inquiry has been concluded.[57]

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