A team of researchers inside Pfizer made a startling find in 2015: The company’s blockbuster rheumatoid arthritis therapy Enbrel, a powerful anti-inflammatory drug, appeared to reduce the risk of Alzheimer’s disease by 64 percent.
The results were from an analysis of hundreds of thousands of insurance claims. Verifying that the drug would actually have that effect in people would require a costly clinical trial — and after several years of internal discussion, Pfizer opted against further investigation and chose not to make the data public, the company confirmed.
Researchers in the company’s division of inflammation and immunology urged Pfizer to conduct a clinical trial, which they estimated would cost $80 million, to see whether the signal contained in the data was real, according to an internal company document obtained by the Washington Post.
“Enbrel could potentially safely prevent, treat and slow progression of Alzheimer’s disease,” said the document prepared for review by a Pfizer committee in February 2018.
The company said it decided during its three years of internal reviews that Enbrel did not show promise for Alzheimer’s prevention because the drug does not directly reach brain tissue. A synopsis of its statistical findings prepared for outside publication, it said, did not meet its “rigorous scientific standards.” It said publishing the information might have led outside scientists down an invalid pathway. Science was the sole determining factor against moving forward, spokesman Ed Harnaga said.
Pfizer’s deliberations, which previously have not been disclosed, offer a rare window into the frustrating search for Alzheimer’s treatments inside one of the world’s largest drug companies. Despite billions spent on research, Alzheimer’s has no effective prevention or treatment.
Some outside scientists disagree with Pfizer’s assessment that studying Enbrel’s potential in Alzheimer’s prevention is a scientific dead end. Rather, they say, it could hold important clues to combating the disease and slowing cognitive decline in its earliest stages.
Pfizer did share the data privately with at least one prominent scientist, but some researchers said Pfizer also should have published its data, making the findings available to researchers.
“Of course they should. Why not?” said Rudolph Tanzi, a leading Alzheimer’s researcher and professor at Harvard Medical School and Massachusetts General Hospital.
“It would benefit the scientific community to have that data out there,” said Keenan Walker, an assistant professor of medicine at Johns Hopkins. “Whether it was positive data or negative data, it gives us more information to make better informed decisions.”
Internal discussions about possible new uses of drugs are common in pharmaceutical companies. In this case, Pfizer’s deliberations show how decisions made by executives — who are accountable to shareholders — can have an impact well beyond boardrooms.
As its Enbrel deliberations ended early last year, Pfizer was getting out of Alzheimer’s research. It announced in January 2018 that it would be shutting down its neurology division, where Alzheimer’s treatments were explored, and laying off 300 employees.
Enbrel has reached the end of its patent life. Profits are dwindling as generic competition emerges, diminishing financial incentives for research into Enbrel and other drugs in its class.
As Enbrel’s life cycle winds down, Pfizer has introduced a new rheumatoid arthritis drug, Xeljanz. Pfizer is putting its marketing muscle behind the new drug, which is on track to make Pfizer billions each year.
Wagering money on a clinical trial of Enbrel for an entirely different disease, made little business sense, said a former Pfizer executive who was aware of the internal debate and spoke on the condition of anonymity. “It probably was high risk, very costly, very long term drug development that was off-strategy,” the executive said.
Drug companies frequently have been pilloried for not fully disclosing negative side effects of their drugs. But what obligation does a company have to spread potentially beneficial information about a drug?
A medical ethics expert argued that Pfizer has a responsibility to publicize positive findings, although it is not as strong as an imperative to disclose negative findings.
“I do think you have to draw some limits, and say that not every piece of information they have in their files has to be disclosed with others,” said Marc Rodwin, a professor at Suffolk University Law School.
Pfizer markets Enbrel outside North America. Amgen, which holds Enbrel rights in the U.S. and Canada, said it knew of the Pfizer data and similarly decided the findings held little promise. “Our exploratory work did not yield results strong enough to warrant further studies,” Amgen said.
Enbrel reduces inflammation by targeting a protein called TNF-a. The Pfizer data added to a growing body of evidence that broadly targeting TNF-a has the potential to prevent Alzheimer’s, said Clive Holmes, an Alzheimer's researcher and professor at the University of Southampton.
Holmes is among the few researchers who has gained access to the Pfizer data.; he won the company’s permission to use it in a grant application for a small clinical trial.
“If it’s true in reality, if you did it in a clinical trial setting, it’s massive — it would be huge,” Holmes said. “That’s why it’s so exciting.”
One reason for caution: another class of anti-inflammatory therapies, called nonsteroidal anti-inflammatory drugs (NSAIDS), showed no effect against mild-to-moderate Alzheimer’s in clinical trials a decade ago. Still, a long-term follow-up of one of those trials indicated a benefit if NSAID use began when the brain was still normal, suggesting that timing could be key.
Pfizer said it also was skeptical because the Enbrel molecule is too large to pass through the “blood-brain barrier” and directly target TNF-a in brain tissue. Yet researchers believe inflammation outside the brain influences inflammation within the brain.
“There is a lot of evidence suggesting that peripheral or systemic inflammation may be a driver of Alzheimer’s disease,” Walker said. It is a fair hypothesis that fighting inflammation outside the brain with Enbrel will have a similar effect inside the brain, he said.
“There is increasing evidence that peripheral inflammation can influence brain function,” said rheumatologist Christopher Edwards, of the University of Southampton. “It’s important that [the Pfizer data is] published, and in the public domain. It needs to be out there.”