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Famotidine heartburn remedy can deactivate a key enzyme that the new coronavirus uses to make copies (gold) of itself.
NIH
By Brendan Borrell
COVID-19 Science reports are supported by the Pulitzer Center.
The rapidly growing list of possible treatments for the new coronavirus includes an unlikely candidate: famotidine, the active compound in the over-the-counter heartburn medication Pepcid. On April 7, the first COVID-19 patients at Northwell Health in the New York City area began receiving famotidine intravenously, at nine times the dose of heartburn. Unlike other drugs that the 23-hospital system is testing, including Regeneron’s sarilumab and Gilead Science’s remdesivir, Northwell kept the famotidine study under wraps to secure an arsenal of research before other hospitals, or even the federal government, they will start buying it. “If we were to discuss this with the wrong people or too soon, the supply of drugs would disappear,” says Kevin Tracey, a former neurosurgeon in charge of the hospital system investigation.
As of Saturday, 187 critically ill patients with COVID-19, including many with ventilators, had enrolled in the trial, which targets a total of 1,174 people. Reports from China and the results of molecular models suggest that the drug, which appears to bind to a key enzyme in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), could make a difference. But the hype surrounding hydroxychloroquine and chloroquine, the unproven antimalarial drugs promoted by President Donald Trump and some doctors and scientists, has left Tracey wary of sparking premature enthusiasm. He is pursing his lips over the prospects of famotidine, at least until the provisional results of the first 391 patients arrive. “If it works, we’ll know in a few weeks,” he says.
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A globe-trotting infectious disease doctor named Michael Callahan was the first to call attention to the drug in the United States. Callahan, who resides at Massachusetts General Hospital in Boston and has extensive connections in the world of biodefense, has spent time in hot disease areas around the world, including the 2003 outbreak of another coronavirus disease, SARS, in Hong Kong. In mid-January, I was in Nanjing, China, working on an avian flu project. When the COVID-19 epidemic began to explode in Wuhan, he followed his Chinese colleagues to the increasingly desperate city.
The virus was killing one in five patients over the age of 80. Patients of all ages with hypertension and chronic obstructive pulmonary disease did poorly. Callahan and her Chinese colleagues were curious as to why many of the survivors tended to be poor. “Why don’t these elderly peasants die? he asks.
By reviewing 6212 COVID-19 patient records, doctors noted that many survivors had suffered from chronic heartburn and were taking famotidine instead of omeprazole (Prilosec), the drug of choice both in the United States and among the wealthiest Chinese. Hospitalized patients with famididine COVID-19 appeared to be dying at a rate of about 14% compared to 27% for those not taking the drug, although the analysis was crude and the result was not statistically significant.
But that was enough for Callahan to continue the problem at home. After returning from Wuhan, he reported to Robert Kadlec, assistant secretary of Readiness and Response for the Department of Health and Human Services, then registered with Robert Malone, medical director of Alchem Laboratories, a Florida-based contract manufacturing organization . Malone is part of a classified project called DOMANE that uses computer simulations, artificial intelligence, and other methods to quickly identify drugs approved by the US Food and Drug Administration. USA And other safe compounds that can be reused against threats like new viruses.
Malone had his eyes on a viral enzyme called papain-like protease, which aids in pathogen replication. To see if famotidine binds to protein, you’d normally need the enzyme’s 3D structure, but that wouldn’t be available for months. Malone then recruited computational chemist Joshua Pottel, president of the Montreal-based Molecular Forecaster, to predict it from two crystalline structures of the 2003 SARS coronavirus protease, combined with the RNA sequence of the new coronavirus.
It was hardly plug-and-play. Among other things, they compared the gene sequences of new and old proteases to rule out crucial differences in structure. Pottel then tested how 2,600 different compounds interact with the new protease. The modeling yielded several dozen promising successes that pharmaceutical chemists and other experts reduced to three. Famotidine was one. (However, the compound has not appeared on the in vitro screens of existing drug libraries for antiviral activity.)
“If it works, we’ll know in a few weeks,” says Kevin Tracey of Northwell Health, who leads the famotidine study.
Northwell Health
With tantalizing Chinese data and the model pointing to famotidine, a low-cost and generally safe drug, Callahan contacted Tracey to conduct a double-blind randomized study. COVID-19 patients with decreased kidney function would be excluded because high doses of famotidine can cause heart problems in them.
After obtaining approval from the Food and Drug Administration, Northwell used his own funds to launch the effort. Only taking half of the required famotidine in sterile vials took weeks, because the injectable version is not widely used. On April 14, the US Advanced Biomedical Research and Development Authority. USA (BARDA), which operates under Kadlec, awarded Alchem a $ 20.7 million contract for the test, most of which paid Northwell’s costs.
The study’s draft protocol was only intended to assess the efficacy of famotidine, but Trump’s “game-changing” antimalarial drug was rapidly becoming the standard of care for inpatients with COVID-19. That meant that the researchers could only recruit enough subjects for a trial that evaluated a combination of famotidine and hydroxychloroquine. Those patients would be compared to a hydroxychloroquine arm alone and a historical control arm made up of hundreds of patients previously treated in the outbreak. “Is it good science? No, “says Tracey.” It’s the real world. “
Michael Callahan during a medical evacuation of COVID-19 patients from a cruise ship.
Michael Callahan
Anecdotal evidence has encouraged the Northwell researchers. After talking to Tracey, David Tuveson, director of the Cold Spring Harbor Laboratory Cancer Center, recommended famotidine to his 44-year-old sister, an engineer at New York City hospitals. She had tested positive for COVID-19 and developed a fever. Her lips turned dark blue from hypoxia. She took her first oral famotidine megadose on March 28. The next morning, his fever broke and his oxygen saturation returned to a normal range. Five sick coworkers, including three with confirmed COVID-19, also showed dramatic improvements in taking over-the-counter versions of the drug, according to a case history spreadsheet Tuveson shared with Science. Many patients with COVID-19 recover with simple medications to relieve symptoms, but Tuveson credits the medication for heartburn. “I would say it was an effect of penicillin,” he says.
After a chain of emails about Tuveson’s experience spread widely among doctors, Timothy Wang, chief of gastroenterology at Columbia University Medical Center, saw further evidence of the famotidine promise in his own retrospective review of the records of 1620 patients hospitalized with COVID-19. Last week, he shared the results with Tracey and Callahan, adding them as co-authors in an article that is now being reviewed in Annals of Internal Medicine. However, all three researchers emphasize that the actual test is the test that is being conducted. “We still don’t know if it will work or not,” says Tracey.
Callahan has been busy since his return from China. Kadlec deployed him on medical evacuation missions for Americans on two heavily infected cruise ships. Now back to rounds of patients in Boston, he says famotidine lead underscores the importance of science diplomacy in dealing with an infectious disease that knows no borders. When it comes to the COVID-19 experience, he says, “There are not a lot of smart people in the [National Institutes of Health] or Harvard or Stanford can beat an average doctor in Wuhan. “
