Pfizer had clues to prevent Alzheimer's disease. Why didn't it tell the world?

A team of researchers inside Pfizer made a startling search in 2015: The company's blocking 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 ̵[ads1]1; and after several years of internal discussion, Pfizer proceeded to 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 of thousands of patients, whom 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 reported the record that it decided During its three years of internal review, Enbrel did not show promise of Alzheimer's prevention because the drug did not reach directly into biological tissues. It is believed the likelihood of a successful clinical trial being low. A summary of their statistical findings prepared for release outside states that they do not meet their "strict scientific standards."

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 because of its doubts about the results. It said that publishing the information could have led non-researchers down an invalid road.

Pfizer's deliberations, previously unpublished, provide a rare window into frustrating search for Alzheimer's treatments in one of the world's largest drug companies.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 scientists disagree on Pfizer's assessment studying Enbrel's potential in Alzheimer's prevention is a scientifically dead end. Rather, they say it can hold important clues to fighting disea and slowing down cognitive decline in its earliest stages.

Pfizer privately shared the data with at least one prominent researcher, but outside researchers contacted by The Post believe that Pfizer should also have at least published its data, making the findings widely 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 community to get the data out there, "said Keenan Walker, an assistant professor of medicine at Johns Hopkins studying how inflammation contributes to Alzheimer's." Whether it was positive data or negative data, it provides us with more information to make 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 a far-reaching impact over the company's governments. [19659002] When the Enbrel deliberations ended early last year, Pfizer came out of Alzheimer's research, announcing in January 2018 that it would be down rheology subjects 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 show 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;

The broader market forces criticized by critics Pfizer from investing in Alzheimer's clinical studies are rooted in Enbrel's "life cycle", the 20-year patent exclusivity period when a brand manufacturer piles 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 received Pfizer $ 2.1 billion in 2018, is now facing generic competition.

Drug companies are often criticized for prolonging a patent's patent life – and gaining new profits – by simply adjusting a molecule of a drug or changing the method of delivery in the body. But it is a "heavy boost" for a company to win regulatory approval to use a drug for a completely different disease, says Robert Field, law 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 there may be a missed opportunity. & # 39; & # 39

As Enbrel's lifecycle Pfizer has introduced a new rheumatoid arthritis drug, Xeljanz, which works differently from Enbrel, Pfizer puts its marketing muscle behind the new treatment, while the Enbrel revenue shrinks, Xeljanz's revenue grows. In the US and 2028 in Europe, according to Pfizer's publication, the drug is about to make Pfizer billions more every year for the foreseeable future.

Wagering funds a clinical study of Enbrel for a completely different disease, especially when Pfizer had doubts The validity of their internal analysis, made little business sense, said a former Pfizer leader who was aware of the internal debate and talked about the state of anonymity to discuss in pfizer cases.

"It was probably high risk, very expensive, very long-term drug development that was off-strategy," said the former director.

Another former executive, who also talked about the condition of anonymity to discuss Pfizer operations, said Pfizer offered virtually no explanation internally to select further investigation at the beginning of 2018 when the internal debate ended.

"I think the economy is that they will not make money from it," said the other former director.

Drug companies have often been pilloried not to completely reveal negative side effects of their drugs. What happens when the opposite is the case? What commitment does a company have to spread potentially beneficial information about a drug, especially when the benefits in question can improve the prospects of treating Alzheimer's, a disease affecting at least 500,000 new patients a year?

medical ethics expert claimed that Pfizer is responsible for publishing positive findings, although it is not as strong as a necessity to disclose negative findings.

"Having acquired the knowledge, refused to disclose it to those who can act on it , hides a potential benefit, and thus flaws and probably damages those who are prone to developing Alzheimer's by preventing research, says Bobbie Farsides, professor of clinical and biomedia k 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 revealed to others," says Marc Rodwin, a legal professor at Suffolk University Law School in Boston.

Pfizer markets Enbrel outside North America, another drug company, Amgen, which 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 market factors did not play any

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

Sometimes, drugs prescribe drugs for use not approved by the Food and Drug Administration But none of the experts interviewed for this story said that "off-label" use of Enbrel would be appropriate for Alzheimer's because of the very limited nature of the data to date. Nor do they believe that such a regulation is to any significant degree.

The role of brain infarction in Alzheimer's has recently received closer attention among academics after several experimental medications had not been able to correct the buildup of plaques on 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 promise as a potential treatment" for Alzheimer's, the study found.

Pfizer's analysis on 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, Pennsylvania.

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

They shared the anonymous patients in two equal groups of 127,000 each, one of the patients with 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 researchers check ed 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 specific protein called TNF-α. Pfizer claims data analysis added a growing evidence that Broad-targeted TNF-a 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's data, he won the company's permission to use it in a grant application for a small clinical trial he runs in England.

"If it's true in reality, if you did it in a clinical trial setting, it's massive – it would be great," Holmes said. "That's why it's so exciting."

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 trials ten years ago. Nevertheless, a long-term follow-up of one of these trials indicated an advantage if NSAID use began when the brain was still normal, suggesting that 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 is too large to pass through the "blood-brain barrier" and targeted at TNF-α in brain tissue, the company said.

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

"There is a lot of evidence that peripheral or systemic inflammation may be a driver for Alzheimer's disease," said Walker, John's Hopkins researcher. is a fair hypothesis that fights 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 in the UK.

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