The Next Theranos? An Alzheimer’s Drug and a CUNY Professor Face Questions Over Research Validity

Cassava Sciences touted the drug simuphilam as a cure to Alzheimer’s Disease. Now, the core science behind the drug that was partially pioneered by a CUNY professor is being questioned by scientists and regulators alike.

The scientific journal PLoS One retracted five studies co-authored by Dr. Hoau-Yan Wang, an associate medical professor at the CUNY School of Medicine and longtime Cassava board member, this past March. The news comes after two other journals cited “expressions of concern” over the research being done by Wang and Cassava’s chief scientist, Lindsay Burns.

Dr. Wang’s lab studies the molecular mechanisms of neurodegenerative diseases such as Alzheimer’s disease. Alzheimer’s is the most common form of dementia that affects over 5.8 million Americans as of 2020. It leads to cognitive decline in the form of memory loss and may eventually result in one not being able to respond to their environment. 

How Tau tangles affects neuronal function. Courtesy:

Experts have hypothesized that the tau protein may be responsible for the disease. Tau normally helps stabilize cells called neurons that communicate messages throughout the nervous system. In Alzheimer’s, however, they are thought to be hyperphosphorylated, which is when molecules have too many phosphate groups attached to them. The addition of these phosphate groups changes the morphology of the molecule and causes the Tau protein to tangle and hinder neuronal activity.

Cassava and Wang claim that Filamin A – the target molecule of simuphilam – is responsible for the hyperphosphorylation of Tau. Filamin A is a protein that helps connect the cell’s cytoskeleton together, giving a cell its shape and structure. Wang’s studies suggest that altered Filamin A promotes tau hyperphosphorylation

Dr. Wang’s proposed mechanism of filamin A in the hyperphosphorylation of tau. Courtesy: Burns, L. H., & Wang, H.Y. (2017). Altered filamin A enables amyloid beta-induced tau hyperphosphorylation and neuroinflammation in Alzheimer’s disease. Neuroimmunology and Neuroinflammation, 4(12), 263.

However, no other lab has confirmed that there is a connection between Filamin A and Alzheimer’s, nor have they discovered that simuphilam binds to Filamin A. Nobel Laureate and Neuroscientist Dr. Thomas Südhof told The New York Times that Cassava’s theories, “​​…are not in the mainstream of the field, and to me they seem implausible and contrived.”

Some have gone even further to suggest that Wang’s data may have been intentionally manipulated to back up his claims. After growing speculation on forums such as PubPeer, two scientists filed a citizen’s complaint to the Food and Drug Administration (FDA), citing irregularities in Wang and Cassava’s data in numerous studies. It is of note that both scientists had short-selling positions on Cassava’s stock prior to filing the report.

While the FDA denied the petition on grounds that it was, “…not the appropriate subject of a citizen petition,” it is investigating Cassava with the aid of other regulatory agencies, such as the Securities and Exchange Commission (SEC) and the National Institute of Health (NIH). Wang’s research was partially funded by NIH grants, totalling over $17 million dollars of taxpayer money over a seven-year period. CUNY has also launched its own internal investigation into the matter. 

Much of the data used to support Wang’s papers comes from Western blotting – a technique used to show the presence of a protein in a given sample. However, some Western blot images in Wang’s papers are alleged to have been either duplicated from other figures or Photoshopped.

In Western blots, samples are loaded onto wells, migrate on a gel based on size and then are stained with probes for a particular protein of interest. Each band in a particular lane represents the presence of a particular protein.

Dr. Elizabeth Bik, a microbiome and science integrity consultant, points out that many of the bands from one Western blot in Wang’s papers look very similar to bands on a completely different experiment, even though there should be slight variations in how the bands appear from experiment to experiment. Furthermore, bands seemed to be irregularly spaced, which is not common for Western blots running on the same gel. It suggests that these images were not from the same experiment but rather consist of different bands pieced together using image manipulation. 

While the differences may not seem significant at first glance, experts like David Vaux, the deputy director of science integrity and ethics at the Australian Walter and Eliza Hall Institute of Medical Research, say otherwise. 

“It is not conceivable that features in the images (such as apparent duplications) arose due to coincidence (chance) or accident, leaving the only plausible explanation being that the images were deliberately falsified or fabricated” said Vaux in an interview with RetractionWatch.

Cassava responded to the citizen’s petition with its own statement explaining the irregularities in their data. In regards to the Western blot data, they rebutted: “The Western blots bands shown in the allegation are control bands. Control bands are supposed to be highly similar.” They also provided explanations for their use of post-mortem tissue and other experiments that were another point of contention. Dr. Hoau-Yan Wang, on the other hand, did not respond to this issue.

Despite this, there is still skepticism over the validity of simuphilam’s clinical trial data. Cassava has administered the drug to 70 participants over two clinical trials, and despite the allegations, is currently looking to recruit 1,000 participants for a phase III clinical trial in the fall. In its statement, Cassava reported that patients experienced increases in cognition over a 12-month trial in Sept. 2021. Experts, however, have questioned whether the duration of the clinical trial was long enough to ascertain that the cognitive improvements experienced by those in the study were long-term effects. 

There was also no placebo group in the study. Placebo controls are fake treatments given to participants in a study to serve as a comparison with the experimental drug. Participants may report feeling better solely due to the placebo effect – a phenomenon where a participant elicits an outcome that is solely due to the psychological notion that they are getting treatment rather than the active effects of a drug. This can often skew studies to show that a certain treatment is having an effect even though it is purely psychological in nature.

But even barring the allegations of wrongdoing, the inconclusive data still raise ethical questions over how we should look at clinical trial results – especially when the disease in question is one that lacks any other options for treatment. 

Simuphilam is not the only drug that has had controversy over its data. The FDA approved Aduhelm, another Alzheimer’s drug, in June 2021, even as many studies were murky on its effects on participants. It was allowed through a process called “accelerated approval,” which grants more leniency in requirements for last-resort drugs of grave diseases.

“FDA approval should be based on sound scientific evidence except in certain unusual circumstances, such as absence of alternative treatments, severity of the disease, and a reasonable, scientifically based, belief that the drug has properties that may have a beneficial effect on disease progression” said Dr. Jeffrey Blustein, a professor of bioethics at the City College of New York. These unusual circumstances may apply to Alzheimer’s, where there is no alternative treatment aside from the two experimental drugs.

Aduhelm and simuphilam fall into a gray area where they are both first-time attempts at curing a degenerative disease, but also face criticism over how sound their data is. Regardless, many citizens have pushed for these experimental treatments as a last hope, including some protesting in favor of expanded access to Aduhelm outside of the Department of Health and Human Services. Dr. Blustein also notes that drug companies have often yielded to public pressure to make such drugs available to a wider scope of individuals even before full approval.

But how far would you go when the alternative is rapid, cognitive decline? Could you justify giving a drug with inconclusive data and unknown long-term effects to prevent a devastating disease?

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