Formerly | Pain Therapeutics, Inc. |
---|---|
Company type | Public |
Nasdaq: SAVA | |
Industry | Pharmaceuticals |
Founded | 1998South San Francisco, California, U.S. | in
Founder | Remi Barbier |
Headquarters | Austin, Texas, U.S. |
Website | www |
Cassava Sciences is an American pharmaceutical company based in Austin, Texas. The company was founded in 1998 by 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. In June 2024, the United States Department of Justice charged an advisor to Cassava Sciences, Hoau-Yan Wang, with fraud over research results related to the experimental drug. Less than a month later, the president, chief executive officer and chairman of the board, Remi Barbier, resigned along with Lindsay Burns, his wife, [1] who was a Cassava senior vice president and Wang's co-author.
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 concerns over simufilam research. [2]
Cassava Sciences was founded by Remi Barbier in May 1998 as Pain Therapeutics, [3] [4] focusing on opioids and chronic pain. [5] Barbier first heard of the research led by Stanley M. Crain at the Albert Einstein College of Medicine in New York City around 1993. [5] Crain invited Barbier to his lab and explained the potential pharmaceutical and financial benefits. [5] In 1998, Barbier started Pain Therapeutics, Inc. in South San Francisco, California, [6] with an initial investment of $1 million. [5]
Following the fourth Food and Drug Administration (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. [7] In 2019, the company changed its name to Cassava Sciences. [8]
Remi Barbier was Cassava's president, chief executive officer and chairman of the board [2] [9] until his abrupt July 2024 resignation, when Richard J. (Rick) Barry was named executive chairman of the board. [10] [11]
Other officers, as of July 2024, are James W. Kupiec, chief medical officer, and Eric Schoen, chief financial officer. [9] [12] Senior vice presidents are: R. Christopher Cook (senior counsel), Michael Marsman (regulatory affairs), Michael Zamloot (tech operations), and George Thornton (technology). [9]
Lindsay Burns the senior vice president for neuroscience and Barbier's wife [13] [14] [15] [16] also resigned in 2024 following the indictment of her co-researcher Wang on charges of fraud. [10] [11]
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." [14] The WSJ stated that, under this plan, Barbier's bonus could reach $108 million. [2]
According to Charles Piller, writing in Science , Barbier would not specify in 2022 who were the company's 2022 scientific advisers. [17] [lower-alpha 1] Hoau-Yan Wang, a professor at City University of New York (CUNY) is a consultant who was on Cassava's advisory board. [21] 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 could receive bonuses based on Cassava's market performance; [2] he was indicted in June 2024 for falsifying data related to Cassava's Alzheimer's drug in development, simufilam. [21] [22] [23] [24]
The company had no product revenues between 2013 and 2021. [2]
Cassava and its collaborators were awarded National Institutes of Health (NIH) grants totalling $20 million between 2015 and 2021. [2] [lower-alpha 2]
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. [2] 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. [14] The share price fell to $42 after a petition was filed with the FDA in August 2021, questioning the company's research. [2] After Wang's June 2024 indictment, the stock fell by 46% to a new low of about $10 per share. [22] [25]
As of November 2021, Cassava had 25 employees. [2]
The company had no drug approved as of 2021. [2]
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. [2] [8] 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." [8] (Wang and Burns had earlier published together on FLNA's role in naloxone and opioid receptor signaling. [8] [26] [27] [28] [29] )
The company started with three drug candidates focused on opioid treatment: Oxytrex, Remoxy and PTI-901 (low-dose naltrexone for irritable bowel syndrome). [30]
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. [6] The phase III trials had high drop out rates and failed. [31]
Remoxy was a twice-daily gel form of oxycodone intended to be abuse-deterrent. [6] [8] It was repeatedly rejected by the FDA, [8] culminating in the final rejection in 2018 after an FDA advisory meeting raised concerns about its potential risk of abuse. [32] According to The New York Times, the FDA reprimanded Cassava Sciences for appearing to promote the unapproved drug. [8] Barbier accused the FDA of "math errors, material mistakes and misrepresentations", which the agency denied. [32]
In August 2020, the chemical name simufilam was assigned to the company's experimental drug, previously called PTI-125, [33] which Cassava Sciences says can restore misshaped FLNA in the brain. [8] Open-label studies had started in March 2020, [8] 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. [8] [14] [34] It was later revealed that the outside lab was Wang's CUNY lab. [14] [8] In October 2021, larger trials were initiated; [8] Cassava Sciences announced in December 2021 that the first phase III trial of simufilam would enroll about 750 participants, and the second 1,000. [8] [35] In the first quarter of 2022, 60 participants were enrolled; [8] Stat stated that enrollment had slowed as of April 2022, as people were deterred from enlisting due to the prevailing controversies. [15]
In June 2024, Wang was indicted by the United States Department of Justice (DOJ) [36] for fraud and charged with falsifying data on $16 million in grant applications to the NIH related to simufilam. [37] [38] [22] [23] [24] The DOJ and the U.S. Securities and Exchange Commission (SEC) were also investigating two senior Cassava employees. [39] Barbier and Burns abruptly resigned in July 2024. [10] [11]
A September 2022 FDA report [40] was obtained under the US Freedom of Information Act; in March 2024, Science journal's Piller called the report "damning", saying the FDA found a "litany of problems" that raise "questions about the credibility of claims by Wang and Cassava about simufilam". [41]
Reuters reported in July 2022 that a criminal investigation of Cassava Sciences had been started by the DOJ. [42] 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. [42]
The Wall Street Journal stated in 2021 that the SEC, the NIH, and CUNY were investigating allegations of manipulated data. [2] 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; [43] [44] [45] they paused the investigation a few weeks later over concerns about confidentiality and integrity of the process. [46]
Cassava Sciences has denied any wrongdoing. [47] Following Wang's June 2024 indictment, Cassava Sciences issued a press release stating that, "Wang's work under these grants was related to the early development phases of the Company's drug candidate ... [he] had no involvement in the Company’s Phase 3 clinical trials of simufilam." [21] [22] Kate Moss, attorney, stated via email to Reuters in July 2022 that "Cassava Sciences ... has never been charged with a crime, and for good reason – Cassava Sciences has never engaged in criminal conduct." [42] 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 ... " [17]
In August 2021, the Food and Drug Administration (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. [14] [17] [48] 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. [49] According to Compliance Week, Thomas certified that the petition included "information known to the petitioner which are unfavorable to the petition". [49] Cassava Sciences maintained that the claims about the research data were "outlandish" and said the FDA's process had been used abusively. [2] Cassava's stock value dropped 55% after the petition was filed. [50]
The petitioners who filed the FDA complaint were identified months later, in November 2021, as neuroscientist David S. Bredt, [2] and cardiologist Geoffrey Pitt, a professor at Weill Cornell Medical College. [2] [14] 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. [49] [51] He had noticed Cassava Sciences when its stock price increased in 2021 following early positive trial results for simufilam. [14] 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". [14] 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. [2] 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. [2] 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. [2] [14] They shorted shares of Cassava Sciences, expecting the price of its stock to drop once problems with the research were revealed. [2] 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. [49] Bloomberg News reported that the August selloff of Cassava shares earned short sellers $100 million, [52] and Compliance Week stated that Bredt and Pitt "potentially ... made millions". [49]
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. [17] Piller contacted other experts who he said "generally agree" with Schrag's conclusions. [17]
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”. [8] [53]
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.” [54] 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". [55]
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". [8] 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. [8] 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. [2] 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." [8]
Several journal papers involving Cassava work and collaborators have been re-examined by their publishers. [56] [57]
Following the public controversies, The Journal of Neuroscience reassessed the 2012 paper that described simufilam binding to FLNA. [2] 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". [2] [58] 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". [59]
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, [60] saying they identified multiple errors. The journal issued a correction and indicated that its final decision awaited conclusions from the CUNY investigation. [2] [8] [61]
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". [50]
PLOS One re-examined Wang's research papers in March 2020 and found problems with data integrity that were not resolved. [62] Five of Wang's papers were retracted, two of which were co-authored with Burns [8] 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". [27] [28] The notices state: "The data and comments provided did not resolve the concerns about the integrity and reliability of data presented in this article." [63] [64]
A 2005 Neuroscience journal article on opioid tolerance was co-authored by Burns, Wang and others. [65] 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. [17]
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. [17] [66] 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. [17] 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. [17] 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. [50]
Oxycodone, sold under various brand names such as Roxicodone and OxyContin, is a semi-synthetic opioid used medically for treatment of moderate to severe pain. It is highly addictive and is a commonly abused drug. It is usually taken by mouth, and is available in immediate-release and controlled-release formulations. Onset of pain relief typically begins within fifteen minutes and lasts for up to six hours with the immediate-release formulation. In the United Kingdom, it is available by injection. Combination products are also available with paracetamol (acetaminophen), ibuprofen, naloxone, naltrexone, and aspirin.
Fentanyl is a highly potent synthetic piperidine opioid primarily used as an analgesic. It is 20 to 40 times more potent than heroin and 100 times more potent than morphine; its primary clinical utility is in pain management for cancer patients and those recovering from painful surgeries. Fentanyl is also used as a sedative. Depending on the method of delivery, fentanyl can be very fast acting and ingesting a relatively small quantity can cause overdose. Fentanyl works by activating μ-opioid receptors. Fentanyl is sold under the brand names Actiq, Duragesic and Sublimaze, among others.
Naloxone, the active ingredient in Narcan, is an opioid antagonist: a medication used to reverse or reduce the effects of opioids. Naloxone is commonly used to restore breathing after an opioid overdose. Effects begin within two minutes when given intravenously, five minutes when injected into a muscle, and ten minutes as a nasal spray. Naloxone blocks the effects of opioids for 30 to 90 minutes.
Oxycodone/paracetamol, sold under the brand name Percocet among others, is a fixed-dose combination of the opioid oxycodone with paracetamol (acetaminophen), used to treat moderate to severe pain.
Buprenorphine, sold under the brand name Subutex among others, is an opioid used to treat opioid use disorder, acute pain, and chronic pain. It can be used under the tongue (sublingual), in the cheek (buccal), by injection, as a skin patch (transdermal), or as an implant. For opioid use disorder, the patient must have moderate opioid withdrawal symptoms before buprenorphine can be administered under direct observation of a health-care provider.
Mitragyna speciosa is a tropical evergreen tree in the coffee family native to Southeast Asia. It is indigenous to Cambodia, Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea, where it has been used in herbal medicine since at least the 19th century. It has also historically been consumed via chewing, smoking, and as a tea. Kratom has opioid-like properties and some stimulant-like effects.
Oxymorphone is a highly potent opioid analgesic indicated for treatment of severe pain. Pain relief after injection begins after about 5–10 minutes, after oral administration it begins after about 30 minutes, and lasts about 3–4 hours for immediate-release tablets and 12 hours for extended-release tablets. The elimination half-life of oxymorphone is much faster intravenously, and as such, the drug is most commonly used orally. Like oxycodone, which metabolizes to oxymorphone, oxymorphone has a high potential to be abused.
Naltrexone, sold under the brand name Revia among others, is a medication primarily used to manage alcohol use or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been found effective in the treatment of other addictions and may be used for them off-label. An opioid-dependent person should not receive naltrexone before detoxification. It is taken by mouth or by injection into a muscle. Effects begin within 30 minutes, though a decreased desire for opioids may take a few weeks to occur. Side effects may include trouble sleeping, anxiety, nausea, and headaches. In those still on opioids, opioid withdrawal may occur. Use is not recommended in people with liver failure. It is unclear if use is safe during pregnancy. Naltrexone is an opioid antagonist and works by blocking the effects of opioids, including both opioid drugs as well as opioids naturally produced in the brain.
Mefenamic acid is a member of the anthranilic acid derivatives class of nonsteroidal anti-inflammatory drugs (NSAIDs), and is used to treat mild to moderate pain.
CX717 is an ampakine compound created by Christopher Marrs and Gary Rogers in 1996 at Cortex Pharmaceuticals. It affects the neurotransmitter glutamate, with trials showing the drug improves cognitive functioning and memory.
Hydrocodone/paracetamol is the combination of the pain medications hydrocodone and paracetamol (acetaminophen). It is used to treat moderate to severe pain. It is taken by mouth. Recreational use is common in the United States.
Trevena, Inc. is a clinical stage biopharmaceutical company, headquartered in Chesterbrook, Pennsylvania, USA, and is involved in the discovery and development of G-protein coupled receptors (GPCR) biased ligands. Trevena was founded in 2007 with technology licensed from Duke University, which originated in the labs of company founders Robert Lefkowitz winner of the 2012 Nobel Prize in Chemistry and Howard Rockman. Trevena's approach to drug discovery is based on utilizing ligand bias, or functional selectivity, at GPCR targets to produce drugs with improved efficacy and reduced side effect profiles. Trevena was named one of the top 15 US startups of 2008 by Business Week.
Filamins are a class of proteins that hold two actin filaments at large angles. Filamin protein in mammals is made up of an actin-binding domain at its N-terminus that is followed by 24 immunoglobulin-like repeat modules of roughly 95 amino acids. There are two hinge regions; between repeats 15-16 and 23-24. Filamin gets cleaved at these hinge regions to generate smaller fragments of the protein. Filamin has two actin-binding sites with a V-linkage between them, so that it cross-links actin filaments into a network with the filaments orientated almost at right angles to one another.
Lindsay H. Burns is an American neuroscientist and rower who won a silver medal at the 1996 Summer Olympics. She was a senior vice president of the pharmaceutical company Cassava Sciences until July 2024 and married to its CEO Remi Barbier.
Oliceridine, sold under the brand name Olinvyk, is an opioid medication that is used for the treatment of moderate to severe acute pain in adults. It is given by intravenous (IV) injection.
Aducanumab, sold under the brand name Aduhelm, is a monoclonal antibody designed to treat Alzheimer's disease. It is a monoclonal antibody that targets aggregated forms (plaque) of amyloid beta (Aβ) found in the brains of people with Alzheimer's disease to reduce its buildup. It was developed by Biogen and Eisai. Aducanumab is given via intravenous infusion.
David S. Bredt is an American molecular neuroscientist.
There is an ongoing opioid epidemic in the United States, originating out of both medical prescriptions and illegal sources. The epidemic began in the United States in the late 1990s, according to the Centers for Disease Control and Prevention (CDC), when opioids were increasingly prescribed for pain management, resulting in a rise in overall opioid use throughout subsequent years.
Mitragynine is an indole-based alkaloid and the most abundant active alkaloid in the Southeast Asian plant Mitragyna speciosa, commonly known as kratom. The total alkaloid concentration in dried leaves ranges from 0.5 to 1.5%. In Thai varieties, mitragynine is the most abundant component while 7-hydroxymitragynine is a minor constituent. In Malaysian kratom varieties, mitragynine is present at lower concentration. Such preparations are orally consumed and typically involve dried kratom leaves which are brewed into tea or ground and placed into capsules. Mitragynine consumption for medicinal and recreation purposes dates back centuries, although early use was primarily limited to Southeast Asian countries such as Indonesia and Thailand where the plant grows indigenously. Recently, mitragynine use has spread throughout Europe and the Americas as both a recreational and medicinal drug. While research into the effects of kratom have begun to emerge, investigations on the active compound mitragynine are less common.
Simufilam (PTI-125) is an experimental medication for the treatment of Alzheimer's disease. It is being developed by the American pharmaceutical firm Cassava Sciences. The drug is in phase III clinical trials as of October 2023. There are two phase III clinical studies: RETHINK-ALZ, a 52-week trial, is set to complete in 2024, and REFOCUS-ALZ, spanning 76 weeks, is projected to finish in 2025.
{{cite web}}
: CS1 maint: bot: original URL status unknown (link)