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Why Pfizer did not report that rheumatoid arthritis medicine can prevent Alzheimer's




A research team inside Pfizer made a startling search in 2015: The company's blocked 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. Confirmation that the drug would actually have that effect in humans would require an expensive clinical trial – and after several years of internal discussion, Pfizer opted for further investigations 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 of thousands of patients, which they estimated would cost $ 80 million, to see if the signal in the data was genuine, according to an internal company document obtained by The Washington Post.

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

The company told The Post that it decided during his three years of internal assessment that Enbrel did not show promise of Alzheimer's prevention because the drug does not now brain tissue. It is believed the likelihood of a successful clinical trial being low. A summary of their statistical findings prepared for non-publication says they do not meet their "strict scientific standards."


Despite promising preliminary data in an internal analysis, Pfizer chose to conduct a clinical trial to see if the drug Enbrel can prevent Alzheimer's disease. (Spencer Platt / Getty Images)

Science was the only decisive factor in the future, said the company's spokesman Ed Harnaga.

Likewise, Pfizer said it chose to publish its data due to doubts about the results. It said that publishing the information could have led non-researchers down an invalid road.

Pfizer's deliberations, which have not previously been revealed, provide a rare window into the frustrating search for Alzheimer's treatments in one of the world's largest drug companies. Despite billions spent on research, Alzheimer's remains a stubbornly widespread disease without effective prevention or treatment.

Some outside researchers disagree on Pfizer's assessment of studying Enbrel's potential in Alzheimer's prevention is a scientific death. Rather, they say it can keep important clues to fighting the disease and reducing cognitive decline in the earliest stages.

Pfizer shared data privately with at least one prominent researcher, but outside researchers contacted by The Post believe that Pfizer should also have published their data in least, and make the findings widely available to researchers.

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

"It would be helpful for the scientific community to have the data out there, "said Keenan Walker, an assistant professor of medicine at Johns Hopkins who studies how inflammation contributes to Alzheimer's." If there were positive data or negative data, it gives us more information to get better informed decisions. "

Internal discussions on possible new use of drugs are common in pharmaceutical companies. In this case, Pfizer's considerations show how business leaders' decisions – ultimately responsible for the shareholders – can have far-reaching implications over the company's governments. [19659018] [This $ 1,650 pill will tell you if you took it. Is it the future of medicine?]

As the Enbrel consultation ended early last year, Pfi became zer out of Alzheimer's research. It announced in January 2018 that it would shut down its neurology division, where Alzheimer's treatments were explored, and add 300 employees.

Meanwhile, Enbrel has reached the end of his patent life. The results fall as generic competition arises, reducing financial incentives for further research into Enbrel and other drugs in its class.

"I'm really frustrated myself for the whole thing," said Clive Holmes, a professor of biological psychiatry at the University of Southampton, UK, who received previous support from the Pfizer for the Enbrel study in Alzheimer's, a separate 2015 trial of 41 patients. which proved unsafe.

He said that Pfizer and other companies will not invest heavily in further research to get their markets undermined by generic competition.

"Someone may come up and say," Look, I have a me-for-stuff here, "Holmes said, referring to the advent of generic versions of Enbrel." I think that's what this is about. & # 39; & # 39;

& # 39; An Unanswered Opportunity & # 39;

The broader market forces criticized by critics Pfizer from investing in Alzheimer's clinical studies are rooted in Enbrel's lifecycle, 20 years of patent exclusivity, when a brand manufacturer obtains monopoly gains from a drug. According to industry standards, Enbrel, an injectable biological drug, is relatively old, with FDA approval for rheumatoid arthritis in 1998. It has also been approved to treat psoriasis.

Pfizer got the right to market it internationally when it bought the drug user Wyeth in 2009. But Enbrel, who earned Pfizer $ 2.1 billion in 2018, is now facing generic competition.

The drug companies are often criticized for prolonging the lifelong life of a drug – and gaining new profits – by simply adjusting the molecule of a substance or changing the method of delivery in the body. But it's a "heavy boost" for a company to gain regulatory approval to use a drug for a completely different disease, says Robert I. Field, professor of law and health management at Drexel University.

"Our patent laws do not provide the necessary incentives," Field said. Drug therapy for early Alzheimer's "would be a gift for American patients, so we should do everything we can as a country to encourage the development of treatments. It is frustrating that it can be an unanswered opportunity."

As Enbrel's life cycle goes down, Pfizer has introduced a new rheumatoid arthritis drug, Xeljanz, which works differently from Enbrel, while Pfizer puts on its marketing muscles behind the new treatment, while the Enbrel revenue shrinks, Xeljanz's revenue grows. The patent expires in 2025 in the United States and 2028 in Europe, according to Pfizer's announcement. The drug is on track to make Pfizer billions more every year for the foreseeable future.

Bet on a clinical study of Enbrel for a completely different disease, especially When Pfizer had doubts about the validity of the internal analysis, little business sense made sense, said a former Pfizer director who was aware of the internal debate and spoke on condition of anonymity to discuss internal Pfizer cases.

"There was probably high risk, very expensive, very long-term drug development that was off-strategy

Another former leader, who also spoke on condition of anonymity to discuss Pfizer operations, said that Pfizer offered almost no explanation internally to select further investigations in early 2018, when the internal debate ended.

"I think the economic case is that they will not make money from it," said second executive director.

& # 39; Drug companys have often been pilloried not to completely disclose negative side effects of their drugs. What happens when the opposite is true? What commitment does a company have to spread potentially beneficial information about a drug, especially when the benefits in question can improve the outlook for treatment of Alzheimer's, a disease affecting at least 500,000 new patients a year?

A medical ethics expert claimed that Pfizer has a responsibility to publish positive findings, though not as strong as a necessity to reveal negative findings.

"Having acquired the knowledge, refusing to disclose it to those who can act on it, hiding a potential benefit, and thus wrong, and probably damaging those at risk of developing Alzheimer's by preventing research," says Bobbie Farsides , Professor of Clinical and Biomedical Ethics at Brighton and Sussex Medical School in London.

Another health care professional warned that the demand for drug company information should remain focused on information gathered during clinical trials.

"I think you have to draw some boundaries, and say that not all the information they have in their files must be disclosed to others, says Marc A. Rodwin, a lawyer at Suffolk University Law School in Boston.

Pfizer markets Enbrel outside North America. Another drug company, Amgen, who has the rights to market Enbrel in the US and Canada, says it knew about the Pfizer data and likewise determined the findings little law. Amgen said that market factors did not play a role in their consideration.

"Unfortunately, our exploratory work has not yielded strong enough to guarantee further studies," Amgen said.

Analyzing Insurance Liability

Sometimes, drugs prescribe drugs for uses not approved by the Food and Drug Administration. But none of the experts interviewed for this story said that such use of Enbrel would be appropriate for Alzheimer's because of the very limited nature of the data to date. They also did not say that they believe that such a regulation is to any significant degree.

The role of cerebral infarction in Alzheimer's has recently become more accentuated by academics after several experimental medications had not been susceptible to the buildup of plaque on the brain tissue. In 2016, researchers from Dartmouth and Harvard universities published a study of insurance claims data – like Pfizer's internal findings – that showed a potential benefit to Enbrel. Enbrel "shows laws as a potential treatment" for Alzheimer's, the study found.

Pfizer's analysis of potential Enbrel benefits in the brain leapt from the company's division of immunology and inflammation, based in a large Pfizer office complex in Collegeville, Pa

In 2015, statisticians analyzed real-world data analyzes, hundreds of thousands of medical insurance claims. which involved people with rheumatoid arthritis and other inflammatory diseases, according to Pfizer PowerPoint retrieved from the post.

They shared the anonymous patients in two equal groups of 127,000 each, one of the patients with an Alzheimer's diagnosis and one of the patients without. Then they checked for Enbrel treatment. There were several people, 302, treated with Enbrel in the group without Alzheimer's diagnosis. In the Alzheimer's group, 110 had been treated with Enbrel.

The figures may seem small, but they were mirrored in the same proportion when the researchers checked insurance claims information from another database. The Pfizer team also produced similar figures for Humira, a substance marketed by AbbVie which acts as Enbrel. The positive results also appeared when they were checked for "memory loss" and "mild cognitive impairment", indicating that Enbrel may benefit from treating the early stages of Alzheimer's.

A clinical trial to prove that the hypothesis would take four years and involve 3,000 to 4,000 patients, according to the Pfizer document that recommended a trial. The document said that Pfizer would get a positive "relative halo effect" by examining Alzheimer's treatment.

Enbrel reduces inflammation by targeting a particular protein called TNF-α. The Pfizer analysis of requirement data added to a growing body of evidence that targets mostly TNF-α in the body has the potential to prevent Alzheimer's, says Holmes, a professor of biological psychiatry at the University of Southampton.

Holmes is among the few researchers who have access to Pfizer data; He won the company's permission to use it in a grant application for a small clinical trial he is pursuing in England.

"If it's true, if you did it in a clinical trial setting, it's huge – it would be great, says Holmes. One reason for caution: Another class of anti-inflammatory therapies, called non-steroidal anti-inflammatory drugs (NSAIDS), showed no effect on mild to moderate Alzheimer's in several clinical studies, a decade ago, yet long-term follow-up of one of these trials indicated an advantage if NSAID use began when the brain was still common, suggesting The treatment time could be the key.

Pfizer said it was also skeptical because Enbrel only has a limited effect on the brain, the Enbrel molecule being too large to pass through the "blood-brain barrier" and targeting TNF-α in brain tissue.

Nevertheless, Alzheimer's researchers believe that inflammation outside the brain – called peripheral inflammation – affects inflammation of the brain.

"There is much evidence that peripheral e. More systemic inflammation can be a driver for Alzheimer's disease, "said Walker, John's Hopkins researcher. It is a good hypothesis that combating inflammation outside the brain with Enbrel will have a similar effect in the brain, he said.

"I don't think Enbrel would need to cross the blood brain barrier to modulate the inflammatory / immune response in the brain," Walker said.

"There is growing evidence that peripheral inflammation can affect brain function," said rheumatologist Christopher Edwards of the University of Southampton, UK.

"It is important that it is published and in the public domain," added Edward of the Pfizer data. "It must be out there. & # 39; & # 39;



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