Will This Drug Help Us Beat Alzheimer’s? Or Will It Doom Its Makers Instead?

Millions of people living with Alzheimer’s are waiting for better treatments. The most effective drugs on the market help people manage their symptoms—memory loss, difficulty organizing thoughts, shortened attention span—but don’t stop the progression of the disease.

For decades, scientists and clinicians developing novel treatments for Alzheimer’s have targeted plaques in the brain made of beta-amyloid proteins. Some believe these plaques are an underlying cause of the disease and lead to progressive cognitive impairment, dementia, and eventually death. Unfortunately, more than a hundred different experimental treatments designed to reduce plaque aggregation in the brain have failed to halt or prevent Alzheimer’s progression in clinical trials. Many experts have grown skeptical of this approach for treatment. And in the wake of the Theranos scandal, skepticism around highly touted medical innovations is at an all-time high.

“I think pursuit of the amyloid hypothesis has failed basically because there is little direct evidence that amyloid is itself a direct driver of Alzheimer's disease,” Karl Herrup, a neurobiologist at the University of Pittsburgh, told The Daily Beast. “From that assertion, it would follow logically that focusing on strategies to get rid of amyloid are not likely to be successful pathways to Alzheimer’s disease therapy.”

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But that has not deterred the pharmaceutical industry from charging forward anyway. Roche, Biogen and Eli Lilly are just a few of the pharma companies still focusing their efforts on developing and testing drugs that reduce beta-amyloid plaques. In June 2021, the Food and Drug Administration gave its stamp of approval for Aduhelm, developed by Biogen and Eisai—against the advice of its scientific advisory panels, which led to protest resignations. The drug’s safety and efficacy record continues to remain spotty.

Perhaps no Alzheimer’s drug has garnered more controversy in recent years than simufilam, developed by Texas-based pharma company Cassava Sciences. Simufilam is thought to bind a misfolded protein called filamin A to prevent the formation of beta-amyloid plaques. (Some studies first supporting this hypothesis have been retracted, while other experts have said the study used to illustrate the drug binding is flawed.)

September 2021 results from a Phase 2 trial showed that two-thirds of Alzheimer’s patients taking the simufilam for a year showed cognitive improvement without any safety issues—a result that surprised scientists and generated excitement among investors, some of whom refer to themselves as SAVAges (a reference to the company’s stock symbol, SAVA).

Yet other experts have cast doubts on the findings. Stanford neuroscientist and Nobel laureate Thomas Südhof told the New York Times the Phase 2 results “make no sense to me whatsoever,” and felt Cassava’s working theories for the drug were “implausible and contrived.” Others raised concerns over the study’s lack of a control group, and its small pool of only 50 participants.

Nonetheless, simufilam received the green light from the FDA in January 2021 to advance into the final clinical trial phases, which will test the drug’s safety and efficacy.

That’s in spite of the fact that Cassava is dealing with a flurry of accusations of data manipulation and fraud from competing parties who themselves are being called out for shady dealings and conflicting financial interests. Salvos are being lobbed back and forth through formal channels as well as social media, by people directly involved as well as outside observers attempting to make sense of the whole situation.

To understand the fallout behind simufilam and what could be next, it’s worth taking a look at how Cassava even got here in the first place with its once-promising new drug.

Cassava Sciences only recently pivoted toward Alzheimer’s treatments. It was known until 2019 as Pain Therapeutics, and its biggest project was around developing a form of oxycodone that could be applied as a gel. The FDA repeatedly turned down approval of the gel, and went on to reprimand the company in September 2016 for marketing the product before approval.

Pain Therapeutics’ fortunes would change quickly. Back in 2012, simufilam emerged as an exciting drug candidate for Alzheimer’s from research collaborations between Lindsay Burns, vice president of Pain Therapeutics since 2002, and Hoau-Yan Wang, an associate medical professor at the City University of New York (CUNY). The company began a Phase 1 clinical trial in 2017 and rebranded into Cassava in 2018. It’s worth noting Burns is married to Remi Barbier, the CEO of Cassava Sciences. Wang was listed as a scientific adviser for the company in 2018, despite the fact that he was directly doing research on behalf of the company.

Backed by the early Phase 2 data, Cassava Science’s stock hit highs of $135.30 at the end of July 2021. On Aug. 18, an FDA citizen petition was filed by the law firm Labaton Sucharow on behalf of two scientists, David Bredt and Geoffrey Pitt, expressing “grave concerns about the quality and integrity of the laboratory-based studies surrounding this drug candidate and supporting the claims for its efficacy.” The petition asked the FDA to pause simufilam’s clinical trials until data was audited and reviewed.

After the petition became public, CUNY started investigating Wang for scientific misconduct—an investigation that is still ongoing. Biotech investor Adrian Heilbut (who is short-trading Cassava stock) has accused CUNY of dragging their feet on investigating Wang's misconduct properly and thoroughly—perhaps willfully. A CUNY spokesperson told The Daily Beast "the allegation of research misconduct is under investigation” but declined to comment further.

Eight days later after the petition’s filing, Labaton Sucharow revealed Bredt and Pitt held short positions in the stock, a disclosure that was absent in the initial filing.

By Sept. 1, the stock price had dropped to under $52. Several more law firms filed suit against Cassava Sciences on behalf of other investors.

Jordan Thomas, the attorney who filed the petition, convinced Bredt and Pitt to speak to the Wall Street Journal about their concerns. That led to a November 2021 story that suggested the Securities and Exchanges Commission was investigating Cassava Sciences over data manipulation. When reached by The Daily Beast, an SEC spokesperson did not confirm or deny the existence of an investigation.

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The same day the Wall Street Journal story was published, MPM Capital issued a press release stating it has raised $51 million for Protego Biopharma, which is developing solutions for diseases involving protein misfolding. Bredt had joined MPM Capital as an executive partner in April 2021, though was no longer listed as part of the company by October. Still, Barbier would later say that Bredt had “strange entanglements” due to his connections to his former employer.

The FDA rejected the citizen petition in February of this year, saying the requests to halt trials were not appropriate for a citizen petition. FDA officials have previously noted that these petitions are abused by drug companies to slow down the work of competitors.

“We said from the outset that the allegations are false,” Barbier said in a February statement. “FDA’s citizen petition privilege is not to be trifled with by stock market participants.”

Barbier, as well as many investors, argued the FDA petition was filed to drive down the price of the stock and allow people who had bet against the company to make money in the market. In addition, many scientists who pointed out concerns, as well as journalists, were accused of being paid to drop the price of the stock.

Cassava hasn’t sat quietly during these happenings. The Wikipedia pages for simufilam and for Burns have recently been edited by an IP address originating from Cassava Sciences’ headquarters. These changes included removing mentions of Burns being married to Barbier; dismissing alleged research misconduct because the papers in question were published in 2005 and “mostly unrelated”; and an addition that suggested the citizen’s petition was filed after the price of Cassava Sciences’ stock soared. Wikipedia editors flagged the changes for policy violations and added that the user must disclose any conflicts of interest.

Some investors who spoke to The Daily Beast on the condition of anonymity felt there were issues with preclinical data in the simufilam trials. But they did not think those issues were grounds for halting the clinical trial, especially since there were no safety issues and the Phase 2 cognitive data which the company had released—showing that simufilam led to cognitive improvements in two-thirds of Alzheimer’s patients—seemed strong.

James Heathers, chief scientific officer at Cipher Skin and a metascientist with expertise in scientific integrity, looked at the preliminary cognitive data for The Daily Beast. (Heathers has no conflict of financial interest with Cassava Sciences.)

“If I was reviewing this for a journal or a conference, and they sent me this, the list of things I don’t like about it would be longer than the actual document,” he said, specifically highlighting the lack of a control group given a placebo. In a clinical trial without a placebo control, it is very difficult to tell whether changes in a participant’s condition are the result of the drug being studied, or another variable.

Heathers also looked through cognitive data collected at three months, released via a Freedom of Information Act (FOIA) request made by Heilbut and Jesse Brodkin (another short-trader of Cassava Sciences stock), which was excluded from the final press releases of the data. Some values presented in tables showing three-month data released via the FOIA request did not make mathematical sense, according to Heathers.

Many, including Barbier and some investors, have accused Cassava’s critics of receiving financial or professional benefits. Among those critics is Elisabeth Bik, a Dutch microbiologist and world-renowned expert in scientific fraud who has noted evidence of image manipulation in several of simufilam’s preclinical studies, among other data. Bik has been harassed by supporters of Cassava Sciences’ stock across Twitter, Reddit, and Discord.

“Some accounts on Twitter appeared to have been set up specifically to engage with or harass me,” Bik told The Daily Beast over email. Market analyst Joe Springer began a YouTube channel which mostly focused on Cassava Sciences and has made YouTube videos attacking Bik’s credibility, such as one labeled “Bik - Editor for Fraud then Attacking Life-Saving Treatments.” He also operates a newsletter on Substack where he purports to offer stock tips for a $799-per-year subscription. He declined to respond to The Daily Beast for comment without final review of the story.

Bik added that she did not have any financial or professional conflicts of interest with Cassava Sciences. To the best of her knowledge, her Patreon has not received support from people holding a financial interest in Cassava Sciences.

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“Science is about finding the truth, and scientific publications are an important tool by which scientists communicate with each other,” Bik said. “Science should be self-correcting, and I try to be part of that.”

Another curiosity surrounding Cassava Sciences is the story around its scientific advisory board—something research and tech companies often organize to garner strategic advice from objective external perspectives. Despite its members being listed as advisers in a 2020 filing to the SEC, it’s not clear that Cassava was really listening to its board throughout simufilam’s development and testing.

One member Barbara Sahakian, a professor at the University of Cambridge in the U.K., wrote on Twitter last October: “I have not worked with Cassava for years and I never had shares in this company.”

Another adviser, Steven A. Arnold, a neuropsychologist at Harvard Medical School, told The Daily Beast over email: “There was only one formal advisory board meeting a few years ago,” in 2018, before Pain Therapeutics changed its name to Cassava Sciences, and that he received financial compensation for it. Arnold is listed as an author on seven published studies alongside Wang. In response to allegations of fraud, he said: “I don’t really know the truth of the allegations, I don’t think I have much to say.”

As previously mentioned, despite actively conducting research for Cassava Sciences, Wang was also listed as a scientific adviser. Jeffrey Cummings, professor of neurology at the University of Nevada, Las Vegas, was also listed as an adviser but he did not respond for comment. Barbier did not respond for comment on the matter.

In November, Twitter users noticed that Cassava Sciences had deleted a link on its website to the scientific advisory board. The page has been deleted as well.

Meanwhile, seven studies produced from Wang’s lab have been retracted by scientific journals. Five of these studies were linked to Cassava Sciences, due to concerns over image and data manipulation. Emails later released Brodkin and Heilbut’s FOIA request raised questions over whether the studies were properly blinded and whether some vials were properly labeled with patient’s initials.

As of May 5, Cassava Sciences has recruited 120 out of 1750 total patients for their Phase 3 clinical trials on simufilam. Two 76-week-long studies are scheduled to finish in October 2023 and June 2024. Cassava Sciences recently received approval from South Korean regulators to run part of their clinical trial in the country.

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While some of Cassava’s investors are active and vocal, a few investors told The Daily Beast they feared that they might experience professional consequences from supporting Cassava Sciences, and harassment from critics shorting the stock.

Scientists and investors are patiently awaiting results of the CUNY investigation and Phase 3 trials. Should the results pan out well and hold up to scrutiny, simufilam would be welcomed by the Alzheimer’s community and clinicians around the world. And such an outcome might also be the only way Cassava finds itself able to rid itself of its shaky reputation.

Read more at The Daily Beast.

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