How greed and profit fueled one failed Alzheimer drug

On May 3, 2021, Matt Price drove his 73-year-old father Stephen from their New Jersey home to a medical strip mall on the Jersey Shore, for his first injection of an experimental drug called simufilam. Cassava Sciences, a Texas biopharma company, had developed simufilam to treat (and possibly cure) Alzheimer’s disease, the most common form of dementia that afflicts tens of millions of people worldwide. 

When Matt, 27, first heard about simufilam, “it sounded exciting,” writes Charles Piller in his new book, “Doctored: Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer’s” (Atria/One Signal Publishers), out now. Rather than simply calming symptoms, simufilam promised “to slow, stop, or reverse cognitive decline — or for people who have no symptoms, prevent them — by attacking Alzheimer’s biochemical cause,” writes Piller.

It was based on a long-debated notion called the “amyloid hypothesis,” which argued that Alzheimer’s is caused by the buildup of the protein amyloid in the brain. “If true, its removal would lead to a cure,” writes Piller. The discovery was shocking, especially given that it’d been introduced by a small biotech company that previously specialized in opioid painkillers and “had never taken a drug to market in its fifteen years of existence,” writes Piller. “Yet it claimed to have discovered a new molecule that stabbed the dark heart of the terrible illness.”

Even in the beginning, Matt Price, a Harvard-trained epidemiologist and global-health specialist, had his doubts. Cassava’s theory, which had not yet been validated by independent researchers, “seemed weird and a bit thin,” Matt told the author.

His concerns would soon be confirmed by a whistleblower, who produced “convincing evidence that lab studies at the heart of the dominant hypothesis for the cause of Alzheimer’s disease might have been based on bogus data,” writes Piller. The amyloid hypothesis wasn’t just wrong, but it took valuable resources away from other promising theories on how to treat Alzheimer’s. It was just the latest example, writes Piller, “of the exaggeration, hype, and sheer fakery and fraud that has characterized Alzheimer’s research for decades.”

And it’s not a problem confined to Alzheimer’s research alone. As of this month, at least 55,000 medical and scholarly studies have been retracted, according to the Retraction Watch database from the Center of Scientific Integrity. And it’s estimated that there may be as many as several hundred thousand fake studies still circulating and not yet identified. Even when they are exposed, journals are often slow to retract the bogus studies, if it happens at all. It’s not just an issue of wasted research dollars. “It makes people start to distrust the clinical research enterprise,” says Price.

Simufilam began as an experimental drug — code-named PTI-125 — developed by neuroscientists Lindsay Burns and Hoau-Yan Wang. It was designed to target filamin A, which becomes twisted into an abnormal shape and causes inflammation in the brain, promoting the formation of myloid-beta proteins. PTI-125, the researchers suggested, could reverse those terrible effects. 

The drug was renamed simufilam in August of 2020, and in preliminary studies, patients started showing improvement after just a month — “extraordinary for any Alzheimer’s trial,” writes Piller. Simufilam began to seem like the holy grail, “the dream drug that generations of researchers had searched for in vain,” the author writes. By late July 2021, the tiny biopharma company, whose sample size for their simufilam experiments was a minuscule fifty participants, suddenly had a market valuation of $5.4 billion.

The victory was short-lived. On Aug. 18, 2021, just weeks after the company’s stock reached record highs, two neuroscientists — Geoffrey Pitt of Weill Cornell Medical College and David Bredt, a former executive at drugmakers Eli Lilly and Johnson & Johnson — submitted a “citizen petition” to the FDA, asking them to take a closer look at simufilam. Their main concern was that the drug’s development “contained manipulated scientific images,” writes Piller. “In short, they asserted, the work looked like it had been doctored.”

To help prove their suspicions, they brought in Matthew Schrag, a neurologist and neuroscientist at Vanderbilt University, who would become “the most important whistleblower in the history of Alzheimer’s,” writes Piller. When they asked for Schrag’s help, “my response was, ‘You think I’m stupid enough to do that?’ ” Schrag told the author. “Apparently, I was.”

Using ImageJ and MIPAV, software developed and endorsed by the NIH, Schrag carefully studied the images used in the simufilam study. He had a “seasoned eye for detecting digital manipulation with common software programs,” writes Piller. Almost immediately, he spotted proof of manipulation. “Schrag saw micrographs — magnifications of microscopic features of brain tissue — that seemed obviously cloned,” writes Piller. “Yet they were presented as findings for different experimental conditions.”

Schrag worried that he wasn’t just uncovering evidence of research misconduct, but something much larger and more ominous. “How had those problems gone unnoticed for years or even decades?” Piller writes. “[Schrag] wondered nervously: What other Alzheimer’s research should be reconsidered with skeptical eyes?”