Pfizer had clues that his star drug could prevent Alzheimer's disease. Why did not he inform the world?

A team of Pfizer researchers made a startling discovery in 2015: The treatment of rheumatoid arthritis Enbrel, a potent anti-inflammatory drug of society, appeared to reduce by 64% the risk of Alzheimer's disease.

The results come from an analysis of hundreds of thousands of insurance claims. Confirming that the drug would actually have this effect in humans would require an expensive clinical trial – and after several years of internal discussions, Pfizer chose not to conduct further investigations and chose not to disclose the data to the public, confirmed the company.

Researchers at the company's Division of Inflammation and Immunology have asked Pfizer to conduct a clinical trial on thousands of patients, which would cost $ 80 million, to determine whether the signal Content in the data was real, according to an internal company document obtained by The Washington Post.

"Enbrel could potentially prevent, treat and slow the progression of Alzheimer's disease safely," says the document, a PowerPoint slide show prepared for review by an internal Pfizer committee in February 2018.

The company told The Post that it had decided during its three years of internal reviews that Enbrel did not look promising for the prevention of Alzheimer's disease because the drug did not directly reach the brain tissue. He felt that the probability of success of a clinical trial was low. A summary of his statistical results prepared for an external publication, he said, did not conform to his "rigorous scientific standards".

Science was the only determining factor for moving forward, said company spokesman Ed Harnaga.

Similarly, Pfizer stated that it had chosen not to publish its data because of its doubts about the results. According to him, the publication of the information could have led outside scientists to take an invalid route.

Pfizer's deliberations, which have yet to be released, open a rare window into the frustrating search for Alzheimer's treatments at one of the world's largest pharmaceutical companies. Despite billions of dollars spent on research, Alzheimer's disease remains a stubbornly prevalent disease without effective prevention or treatment.

Some outside scientists do not agree with Pfizer's assessment that studying Enbrel's potential in the prevention of Alzheimer's disease is a scientific impasse. On the contrary, they say, this could be an important way to fight the disease and slow cognitive decline in its infancy.

Pfizer privately shared the data with at least one prominent scientist, but outside researchers contacted by The Post believe that Pfizer should also have at least published its data, which would allow researchers to have broad access to the results.

"Of course they should, why not?" Said Rudolph Tanzi, a leading researcher on Alzheimer's disease and a professor at Harvard Medical School and Massachusetts General Hospital.

"It would be in the interest of the scientific community to dispose of this data," said Keenan Walker, an assistant professor of medicine at Johns Hopkins, who studies how inflammation contributes to Alzheimer's disease. . "Whether it's positive or negative data, it gives us more information to make more informed decisions."

Internal discussions on potential new uses of drugs are common in pharmaceutical companies. In this case, Pfizer's deliberations show how the decisions made by industry leaders – who ultimately are accountable to shareholders – can impact far beyond the boardrooms of the board.

While Enbrel's deliberations ended early last year, Pfizer was pulling out of Alzheimer's research. She announced in January 2018 that she would close her division of neurology, where treatments for Alzheimer's disease were being explored, and dismissed 300 employees.

Meanwhile, Enbrel has reached the end of his patent life. Profit declines as generic competition emerges, decreasing financial incentives for further research on Enbrel and other drugs in its class.

"I'm really frustrated with all this," said Clive Holmes, a professor of biological psychiatry at the University of Southampton, in Britain, who had previously received Pfizer support for Enbrel research in Alzheimer's, a separate trial for 2015 conducted in 41 patients who were inconclusive.

He added that Pfizer and other companies did not want to invest heavily in research, but only for their markets to be undermined by generic competition.

"Someone may appear and say, 'Look, I have a drug that takes me too much here,'" said Holmes, referring to the advent of generic versions of Enbrel. "I think that's what it's all about." & # 39;

According to critics, the market forces that dissuaded Pfizer from investing in Alzheimer's clinical trials are rooted in Enbrel's "life cycle", the period of 20-year patent exclusivity when a brand manufacturer is reaping the monopolistic benefits of a drug. According to industry standards, Enbrel, a relatively old injectable biologic drug, was approved by the FDA for rheumatoid arthritis in 1998. It has also been approved for the treatment of psoriasis.

Pfizer obtained the right to market it internationally during the acquisition of drug maker Wyeth in 2009. But Enbrel, which reported $ 2.1 billion to Pfizer in 2018, is now facing competition from generics.

Pharmaceutical companies are often criticized for extending the life of a patent for a drug – and generating new benefits – by simply changing the molecule of a drug or by changing the method of the drug. 39, administration in the body. But it's a "heavy burden" for a company to obtain regulatory approval to use a drug against a completely different disease, said Robert Field, a professor of law and health care management. at Drexel University.

"Our patent laws do not provide the right incentives," Field said. Medication treatment of early Alzheimer's disease "would be a boon to American patients, so we should do everything we can as a country to encourage the development of treatments.It's frustrating that there may be a missed opportunity. "

As the Enbrel lifecycle comes to an end, Pfizer has launched a new drug against rheumatoid arthritis, Xeljanz, that works differently from Enbrel. Pfizer puts its marketing energy behind the new treatment. As Enbrel's revenues decrease, those of Xeljanz increase. Xeljanz's patent expires in 2025 in the United States and in 2028 in Europe, according to Pfizer's public revelations. The drug is expected to allow Pfizer to earn billions more every year for the foreseeable future.

Bet money on a clinical trial of Enbrel for a totally different illness, especially when Pfizer had doubts about the validity of its internal analysis and that it made little sense in terms of business, said a former Pfizer executive who was aware of the internal debate and is anonymous to discuss matters internal to Pfizer.

"It was probably a development of high-risk drugs, very expensive and very long-term, that was off strategy," said the former leader.

Another former executive, who also spoke under cover of anonymity to discuss Pfizer's operations, said Pfizer offered virtually no explanation internally for choosing not to continue the investigation early in 2018, at the end of the internal debate.

"I think the financial situation is that they are not going to profit from it," said the second former executive.

Pharmaceutical companies have often been pilloried for failing to fully disclose the negative side effects of their medications. What happens when the opposite is the case? What obligation does a company have to disseminate potentially beneficial information about a drug, especially when the benefits in question could improve the prospects of treating Alzheimer's disease, a disease that affects at least 500,000 new people? patients a year?

An expert in medical ethics argued that Pfizer was responsible for publishing positive results, even though it was not as powerful as the obligation to disclose negative results.

"To have acquired the knowledge, to refuse to divulge it to those who could follow it, hides a potential advantage, and thus damages and probably prejudices to people at risk of developing Alzheimer's disease by hindering research," said Bobbie Farsides, professor of clinical and biomedical ethics. in Brighton and Sussex Medical School in London.

Another specialist in health care ethics warned that the pharmaceutical companies' disclosure request should remain focused on the information collected during clinical trials.

"I think you have to draw boundaries and say that all the information in their records does not necessarily have to be disclosed to others," said Marc Rodwin, a law professor at Suffolk University Law School in Boston.

Pfizer markets Enbrel out of North America. Another pharmaceutical company, Amgen, which owns Enbrel's marketing rights in the United States and Canada, said it was aware of Pfizer's data and also decided that the results were not promising. Amgen said market factors had no role in his deliberations.

"Unfortunately, our exploratory work did not yield sufficiently solid results to warrant additional studies," Amgen said.

Sometimes doctors prescribe drugs for uses that are not approved by the Food and Drug Administration. But none of the experts surveyed as part of this story said that such an "unspecified" use of Enbrel would be appropriate for Alzheimer's disease, because of the very nature of Alzheimer's disease. limited data collected so far. They also do not think that such a prescription is going on. to a significant extent.

The role of brain inflammation in Alzheimer's disease is attracting more and more attention from academics after the failure of several experimental drugs that targeted the accumulation of plaques on the brain tissue. In 2016, researchers at Dartmouth and Harvard Universities published a study on insurance claims data, similar to Pfizer's internal findings, which showed a potential benefit from Enbrel. Enbrel "proves promising as a potential treatment" for Alzheimer's disease, the study revealed.

Pfizer's analysis of the potential benefits of Enbrel for the brain stems from the company's Immunology and Inflammation division, based in a large Pfizer office complex in Collegeville, Pennsylvania.

The 2015 statisticians analyzed real world data, hundreds of thousands of health insurance claims involving people with rheumatoid arthritis and other inflammatory diseases, according to the Pfizer PowerPoint obtained by The Post.

They divided these anonymous patients into two equal groups of 127,000 each, one of the patients with a diagnosis of Alzheimer's and the other of non-patients. Then they checked the treatment with Enbrel. There were more people, 302, treated with Enbrel in the no diagnosis group of Alzheimer's. In the Alzheimer's group, 110 had been treated at Enbrel.

The numbers may seem minimal, but they reflected in the same proportion when the researchers verified the claims information from another database. The Pfizer team also produced very similar numbers for Humira, a drug marketed by AbbVie that works like Enbrel. The positive results also appeared when it was checked for "memory loss" and "mild cognitive impairment", indicating that Enbrel could be beneficial for the treatment of early stages of Alzheimer's disease.

A clinical trial to prove the hypothesis would take four years and would involve 3,000 to 4,000 patients, according to the Pfizer document that recommends a trial. According to the document, Pfizer would gain a positive public relations "halo effect" by investigating a treatment for Alzheimer's disease.

Enbrel reduces inflammation by targeting a specific protein called TNF-a. Pfizer's claims data analysis adds to a growing body of evidence that general targeting of TNF-α in the body could prevent Alzheimer's disease, said Holmes, professor of biological psychiatry at the University of Southampton.

Holmes is one of the few researchers to have access to Pfizer data. he obtained permission from the company to use it in a grant application for a small clinical trial that he undertakes in England.

"If that's true in reality, if you did it in clinical trials, it's huge – it would be huge," Holmes said. "That's why it's so exciting."

One reason for caution: another class of anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), has shown no effect against mild to moderate Alzheimer's disease in several clinical trials conducted there a decade ago. Nevertheless, long-term follow-up of one of these trials showed a benefit if NSAID use started while the brain was still normal, suggesting that the timing of treatment might be critical.

Pfizer also stated that he was skeptical because Enbrel has only a limited effect on the brain. The Enbrel molecule is too big to pass through the "blood-brain barrier" and target TNF-a directly in brain tissue, the company said.

Yet, Alzheimer's researchers believe that inflammation outside the brain – called peripheral inflammation – influences inflammation in the brain.

"There is plenty of evidence to suggest that peripheral or systemic inflammation could be a factor in Alzheimer's disease," said Walker, a researcher at Johns Hopkins. It's a fair assumption that combating inflammation out of the brain with Enbrel will have a similar effect on the brain, he says.

"I do not believe that Enbrel would need to cross the blood-brain barrier to modulate the inflammatory / immune response in the brain," Walker said.

"It is increasingly evident that peripheral inflammation can affect the functioning of the brain," said rheumatologist Christopher Edwards, of Southampton University, UK.

"It's important that it's published and that it's in the public domain," Edward said of Pfizer's data. "He must be available."