Cassava Sciences has faced a barrage of regulator scrutiny over alleged clinical impropriety in studies of an experimental Alzheimer’s candidate. Most recently, Cassava shelled out millions to fend off corporate misconduct allegations from the U.S. Securities and Exchange Commission.
Now, some experts want Cassava to get more heat from the FDA and have its clinical programs ground to a halt.
Last week, the beleaguered biotech announced it will pay $40 million to resolve the SEC investigation into whether it misled investors with doctored data.
The accusations stem from a phase 2 trial testing the company’s lead asset, simufilam, which targets the protein filamin-A. According to SEC charges, Dr. Hoau-Yan Wang — the drug’s co-developer, an associate medical professor at the City University of New York’s Medical School (CUNY) and a Cassava consultant — “received information that unblinded him” to some of the mid-stage data. Wang then manipulated the data “to create the appearance that the drug had caused dramatic improvements in biomarkers associated with Alzheimer’s … such as total tau,” the SEC stated.
“There is a moral obligation not to experiment on patients in this context.”
Dr. Matthew Schrag
Vascular neurologist, assistant professor of neurology, Vanderbilt University
Cassava published these results — but not the full set of patient data — and didn’t disclose Wang’s financial stake in the trial’s success, the SEC alleges.
The SEC charged Wang separately and reached settlements with Cassava’s former CEO and senior vice president of neuroscience for their roles in publishing the data.
None of the parties investigated by the SEC admitted guilt in their settlements, and the company’s new CEO, Richard Barry, who took the reins last month, has signaled his eagerness to move on.
“Cassava is pleased to put this matter behind us,” Barry said in a statement. “We can now focus all of our attention on completion of the ongoing phase 3 trials of simufilam.”
But calls for trials to be stopped have lingered for years.
A troubled past
Dr. Matthew Schrag was thrust into the Cassava controversy in 2021. Because of his position as a vascular neurologist and assistant professor of neurology at Vanderbilt University along with his image analysis skills, a colleague who needed to find an expert in Alzheimer’s trial results gave him a call.
In particular, Schrag was asked to help a lawyer who had filed a petition for two clients alleging Cassava presented results for simufilam with “anomalies” in images using Western blots, which display proteins in tissue samples, suggesting the data was rigged. The clients — Dr. Geoffrey Pitt and Dr. David Bredt — called on the FDA in their petition to stop Cassava’s clinical program.
Schrag’s analysis of Cassava’s preclinical and early-stage work confirmed those suspicions.
“The degree to which the drug bound to the target was extraordinarily high,” Schrag, whose investigative work is independent of his role at Vanderbilt, explained. “And then there was evidence of image tampering that made it look like samples were moved around and reused.”
Pitt and Bredt later admitted they had also shorted the company’s stock, which Cassava’s then-CEO said allowed them to profit from the public scrutiny. The FDA ultimately denied the petition.
“The Cassava Sciences case has further heightened the urgency of addressing scientific integrity in our field."
Joanne Pike
CEO, president, Alzheimer's Association
Still, suspicions mounted around Cassava’s work.
In 2022, an FDA investigation into a CUNY lab used by Wang revealed improper equipment maintenance and a lack of data security.
Last year, CUNY launched its own investigation into Wang. Although the inquiry was later halted, documents obtained by the journal Science revealed Wang failed to supply raw data to investigators who found “long-standing and egregious misconduct” in Wang’s “data management and record keeping.”
Wang was also indicted by the DOJ in June for “defrauding” the NIH out of $16 million in grant funding. After the DOJ announcement, Cassava issued a statement noting that Wang is no longer involved in the company’s clinical trials.
None of this pressure, however, has stopped Cassava’s clinical team from marching on.
Cassava’s ongoing trials
In late September, Cassava released interim results of its two phase 3 trials for simufilam from a safety review board that recommended the studies proceed as planned.
Schrag called simufilam a “hodge-podge” mix of the beta-amyloid hypothesis — the approach tied to clearing amyloid plaques from the brain — and an idea that emerged in the 90s suggesting that restoring levels of the neurotransmitter acetylcholine could improve Alzheimer’s outcomes.
“I think there’s virtually no supportive evidence for this approach outside of Cassava,” Schrag argued.
Cassava reported positive top line mid-stage data in 2023 suggesting simufilam “slowed cognitive decline” by 38% compared to a placebo in mild to moderate Alzheimer’s.
But Schrag’s evaluation of Cassava’s clinical results along with the SEC’s claims of misconduct mean the phase 3 program was built on “tampered” data, he said. Because of these allegations, Schrag argued there’s “no rationale” to continue phase 3 trials, pointing out that even with a positive outcome from a pivotal study, there would be no way the FDA could render a “responsible” approval — and that doctors aren’t likely to prescribe it.
“I don’t think any data coming out of Cassava can possibly be trusted,” Schrag said, expressing dismay that the FDA hasn’t stopped the trials already.
“These trials [should] have never been permitted to start, so I’m astonished by the direction this has gone,” he said. “There is a moral obligation not to experiment on patients in this context.”
Cassava’s phase 3 trials are fully enrolled with 1,900 participants.
The FDA declined to comment on the matter, saying it is generally “unable to discuss existing or potential applications” in an email statement, adding that it involves “confidential commercial information.”
In an emailed statement received after the original publication of this article, a Cassava spokesperson defended the scientific rationale of the company’s clinical program, arguing that “the hypothesized mechanism of action for simufilam is supported by extensive research conducted by laboratories independent of Cassava and CUNY ... [including] laboratories that have tested the drug using assays and animal models in both Alzheimer’s disease and other diseases.”
“There is no reason to terminate Cassava’s phase 3 trials,” the spokesperson said.
And while patient advocacy groups are often supportive of swiftly bringing new treatments to market, Alzheimer’s Association CEO and president Joanne Pike wouldn’t weigh in on whether the Cassava trials should continue, noting that the organization doesn’t have “all the data and information the FDA uses to make their decisions about accepting or rejecting a clinical trial.”
However, Pike pointed out that Cassava’s phase 3 participants should be “fully informed.”
“The Alzheimer’s Association strongly encourages a participant-centered approach to research, and responsible communications with trial participants,” Pike said in an email.
And despite the very high unmet need in Alzheimer’s, Pike emphasized that “putting profits ahead of people” and “scientific misconduct” are generally unacceptable.
“The Cassava Sciences case has further heightened the urgency of addressing scientific integrity in our field, and we commend the SEC’s investigation,” Pike said. “Federal agencies must aggressively pursue all credible allegations of misconduct.”
Cassava expects top line data from a phase 3 study by the end of this year, along with more results from the 76-week trial mark by mid-2025.
