Seniors Housing & Healthcare Trends

LOS ANGELES: Just over a month ago, an academic journal published an investigation that detonated at the heart of the multibillion-dollar race to develop a breakthrough treatment for Alzheimer’s and dementia. The report’s central claim was that a foundational research paper might, in fact, be an “elaborate mirage”, in which the lead researcher doctored lab images to prove that a newly discovered group of proteins caused cognitive impairment.

In a field desperate for breakthroughs, the 2006 paper appeared to have uncovered, finally, a smoking gun. The alleged discovery gave the field a much-needed boost and helped to unleash a deluge of funding to start-ups and researchers. The revelation last month that it may have been a fabrication has left scientists, investors and companies wrestling with uncomfortable questions. Did the original paper – one of the most cited in the field – send an entire industry off on a wild goose chase? Have a decade-and-a-half, and billions of dollars in private and public research funding, been wasted?

Bart de Strooper, director of the Dementia Research Institute of the UK, said: “The fraud is very bad for morale and is damaging the reputation of the field.”

A debate is raging over how damaging the alleged fraud is. Some claim that the fallout does not undermine what is one of the field’s central hypotheses – that so-called amyloid beta proteins that build up in the brain are a key driver of memory loss. Indeed, venture capitalists, Wall Street investors and public funding bodies have poured billions of dollars into companies targeting amyloid beta. Alzheon, a biotech working on a pill to combat Amyloid beta build-up, raised $US50 million ($73 million) this year after a pair of failed stock market floats. Rival Acumen Pharmaceuticals raised $US125 million ($182 million) in a float last month.

Some researchers claim that the allegedly faked results have derailed the field, helping to funnel billions of dollars toward a dead end while starving potentially more impactful areas of study. Grace Stutzmann, chairwoman of neuroscience at the Rosalind Franklin University, said that companies had carried out roughly 20 “phase 3” human clinical trials targeting amyloid beta proteins. All but one, Biogen’s controversial Aduhelm drug, have failed at that last hurdle. The amyloid hypothesis, she said, had become “too big to fail”.

Aduhelm was the one exception. When the Food and Drug Administration (FDA) approved it last year in the US, it became the first drug targeting amyloid beta to make it to market. It has been a huge disappointment. Weak efficacy data led the US government to limit its willingness to pay for it. The company pulled its application for approval in Europe this year after the regulator expressed similar misgivings. Biogen’s chief executive resigned a month later.

Matthew Schrag was the Vanderbilt University neuroscientist who uncovered the alleged manipulation in the original paper. His work formed the basis of the Science investigation and was corroborated by several scientists. He said: “I do think this a moment to reevaluate the foundations of this hypothesis.”

So how did we get here? Last summer Schrag was hired by two investors to look into the research underlying the star Alzheimer’s drug candidate of a biotech company called Cassava Sciences. The investors, who were neuroscientists, were sceptical of Cassava’s work and bought short positions in the shares that would pay out if the stock fell. Schrag uncovered “serious concerns of research misconduct”, including the potential manipulation of western blots, a lab technique to isolate and identify proteins. Cassava’s drug candidate focuses on amyloid beta, bits of proteins that lock together like Lego and build up in the brains of people hit by dementia.

Based on Schrag’s findings, the investors filed a petition to the FDA to halt clinical trials. The regulator denied the request but did not address the allegations, claiming the fund’s “citizen petition” was not the right route to force such an action. Cassava, a $US1 billion ($1.455 billion) company listed on the Nasdaq exchange in New York, has strenuously denied the allegations and said last Thursday that another journal that had published Cassava research found, after review, “no convincing evidence” of misconduct. Remi Barbier, Cassava’s chief executive, added: “I’m hopeful that written pronouncements from neutral and independent science experts will help close the chapter of baseless attacks against our science.”

Schrag’s Cassava work led him to analyse other amyloid beta research, including the 2006 paper by a French scientist at the University of Minnesota called Sylvain Lesne. It claimed to have uncovered a new protein grouping, called amyloid beta star 56. When Lesne isolated it and injected it in the brains of young rats, his paper said, it dramatically reduced their cognitive abilities, implying they were a potential cause of dementia. Lesne’s paper has been cited more than 2000 times. Like with his Cassava findings, however, Shrag thought Lesne’s western blot images were forged. He filed a whistleblower report, and several scientists have corroborated his work.