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Christopher Rowland
A business reporter focused on the effects of the health care economy on patient health, costs, and privacy
In 2015, a team of Pfizer researchers made a surprising discovery: Enbrel, its powerful anti-inflammatory, its anti-inflammatory rheumatoid arthritis seems to reduce the risk of Alzheimer's disease by 64%.
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 slideshow prepared for review by an internal Pfizer committee in February 2018.
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The company told The Post that it had decided during its three years of internal evaluations that Enbrel did not look promising for the prevention of Alzheimer's 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 meet his "rigorous scientific standards".
Despite promising preliminary data in an internal analysis, Pfizer chose not to conduct a clinical trial to determine if its drug Enbrel could prevent Alzheimer's disease. (Spencer Platt / Getty Images)
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 treatment 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 with no effective prevention or treatment.
Some outside scientists do not share Pfizer's view 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.
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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 E. 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 decisions made by industry leaders – which are accountable to shareholders – can have an impact far beyond corporate boardrooms.
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While Enbrel's deliberations ended early last year, Pfizer was pulling out of Alzheimer's research. He announced in January 2018 that he would close his neurology division, 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 Great Britain, who had already received Pfizer support for research on Enbrel in Alzheimer's & # 39. ; s. patients who have been 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. which it is. "
"A missed opportunity"
According to critics, the market forces that dissuaded Pfizer from investing in Alzheimer's clinical trials are rooted in the "Enbrel Life Cycle," the 20-year period of patent exclusivity when it comes to patenting. a brand manufacturer is reaping the monopolistic benefits of a drug. According to industry standards, Enbrel, an injectable biologic drug, is relatively old and was approved by the FDA for rheumatoid arthritis in 1998. It has also been approved for the treatment of psoriasis.
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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 for gaining new benefits – simply by changing the molecule of a drug or by changing the method of administration in the drug. body. But it's a "heavy burden" for a company to gain regulatory approval to use a drug to treat a completely different disease, said Robert I. Field, professor of law and health care management at the University of Toronto. Drexel University.
"Our patent laws do not provide the right incentives," Field said. Drug treatment for the onset of Alzheimer's disease "would be a boon to American patients. We should therefore do everything we can as a country to encourage the development of treatments. It's frustrating that there is a missed opportunity. "
As Enbrel's life cycle comes to an end, Pfizer has launched a new rheumatoid arthritis drug, Xeljanz, that works differently than Enbrel. Pfizer puts its marketing energy behind the new treatment. As Enbrel's revenues decrease, those of Xeljanz increase. Xeljanz's patent will expire 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.
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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 high-risk, very expensive and very long-term drug development 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 aspect is that they will not win anything," said the second former leader.
& # 39; Hinder the search & # 39;
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 for treating Alzheimer's disease, a disease that affects at least 500,000 new 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 therefore wrongs, and probably harms those who are at risk of developing Alzheimer's disease by hindering the 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 have to be disclosed with others," said Marc A. 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 has not produced sufficiently solid results to warrant additional studies," said Amgen.
Analysis of insurance claims
Sometimes doctors prescribe drugs for uses that are not approved by the Food and Drug Administration. But none of the experts interviewed for this article said that such an "unspecified" use of Enbrel would be appropriate for Alzheimer's, because of the very limited nature of the data so far. They also do not believe that such a prescription occurs significantly.
The role of brain inflammation in Alzheimer's disease is gaining more and more attention from academics after the failure of multiple experimental drugs to build plaque on brain tissue. In 2016, researchers at Dartmouth University and Harvard University published a study of insurance claims data, similar to Pfizer's internal findings, which showed a potential Enbrel advantage. Enbrel "proves promising as a potential treatment" for Alzheimer's, according to the study.
Pfizer's analysis of the potential benefits of Enbrel in 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 whom was diagnosed with Alzheimer's disease and the other of whom had not been diagnosed. Then they checked the treatment with Enbrel. There were more people, 302, treated in Enbrel in the group without Alzheimer's diagnosis. 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. Positive results also appeared when "memory loss" and "mild cognitive impairment" were verified, indicating that Enbrel could be beneficial for the treatment of the earliest 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 benefit from a positive "halo effect" in public relations by seeking 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 targeting TNF-a widely in the body could help prevent Alzheimer's disease, Holmes said. 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 it's true in reality, if you did it in clinical trials, it's huge – it would be huge," said Holmes. "That's why it's so exciting."
One reason for caution: Another class of anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), showed no effect against mild-to-moderate Alzheimer's disease in several clinical trials conducted ten years 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 may be a factor in Alzheimer's disease," said Walker, a Johns Hopkins researcher. It's a fair assumption that fighting inflammation outside the brain with Enbrel will have a similar effect to the inside of the brain, he said.
"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 becoming increasingly clear that peripheral inflammation can affect brain function," said rheumatologist Christopher Edwards of the University of Southampton in Britain.
"It's important that this is published, and in the public domain," Edward added, referring to Pfizer's data. "He must be there."
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