Should FDA Place Hold on Troubled Alzheimer’s Drug?
The journal Science and other FDA watchers are indirectly putting pressure on FDA to place a clinical hold on an ongoing Phase 3 clinical trial of Cassava Sciences’ invrestigational Alzheimer’s drug simufilam following a recent $40 million settlement with the U.S. Securities and Exchange Commission (SEC) related to misleading statements made about the results of a previous clinical trial. The SEC settlement is the company’s latest pitfall after Science published a report earlier this year (see story) on FDA’s concerns about the results of tests conducted in a City University of New York (CUNY) laboratory run by pharmacologist Hoau-Yan Wang on the Cassava drug. The article detailed findings from an FDA inspection that found Wang never calibrated his equipment or completed verification experiments to ensure his tests were accurate, sensitive, and conducted with appropriate precision. They also said he used improper statistical tests that resulted in inaccurate determinations of sample concentrations.
As part of the SEC action, the government charged Wang with manipulating clinical trial results. “Wang received information that unblinded him to some aspects of the Phase 2 clinical data, which he used to identify about a third of the patients enrolled in the trial,” it contended. “Using information that unblinded him to aspects of the trial data, Wang was able to manipulate the data to create the appearance that the drug had caused dramatic improvements in biomarkers associated with Alzheimer’s disease, such as total tau and phosphorylated tau, which are common indicators of neurodegeneration in Alzheimer’s patients. The order also finds that Wang knew Cassava would disclose the manipulated data when announcing the results of its Phase 2 clinical trial, and Cassava did, in fact, publicize the data in a press release and investor deck issued on 9/14/2020.”
The SEC further alleged that Cassava misled investors by announcing that the company’s therapy significantly improved patient cognition. “Among other things, Cassava claimed that the Phase 2 results showed significant improvement in episodic memory of the Alzheimer’s patients involved in the clinical trial,” it said. “In reporting the results, however, Cassava failed to disclose that the full set of patient data — as opposed to the subset of data hand-selected by Burns [former senior vice president of neuroscience Lindsay Burns] — showed no measurable cognitive improvement in the patients’ episodic memory.”
A 10/1 Science commentary is now questioning why the Phase 3 trial is still ongoing after all that has occurred with the simufilam clinical trials and associated reporting. “The publicly disclosed results were the impetus to move on to Phase 3 trials and the impetus to raise another $260 million from various investors,” it says. “But the numbers appear to have been cooked at every level. It appears that an honest, competent look at the data would have shown that the drug did not work at all… Should we be dosing Alzheimer’s patients with a compound that (at best) we have no confidence in and at worst could be an outright fraud? After all that's happened, what does it take to stop a trial?”
A 10/2 New York Times piece on Cassava’s predicament also questioned how simufilam remains in advanced clinical trials. “If the efficacy and the underlying data is being questioned, which it is, why would you continue the study?” George Perry, an Alzheimer’s researcher at the University of Texas at San Antonio, told the Times. It noted that while some data have been challenged, the company maintains there are still research and clinical results that suggest the drug may work.
FDA has the authority to pause or end clinical trials, and “may take appropriate action” to protect participants if it becomes aware of data falsification after a detailed review, an agency spokeswoman told the Times. For now, the agency is not showing its hand and remains steadfast that it does not comment on ongoing clinical trials or ongoing investigations, she added.
Despite the recent setbacks, the company told the Times that it was optimistic the Phase 3 trial would be a success. A spokesman for Cassava said that the SEC’s charges related to inadequate securities disclosures were not meant to make a judgment about simufilam’s full scientific evidence. “We won’t know the results of our first Phase 3 study until later this year, but we believe there are good reasons to believe our trial could be successful,” recently appointed CEO Rick Barry said in a statement provided to the Times.