A common heartburn drug shows promise in treating Covid-19

The fast-growing list of possible treatments for the novel coronavirus includes an unlikely candidate: famotidine, the active compound in the over-the-counter heartburn drug Pepcid. On 7 April, the first COVID-19 patients at Northwell Health in the New York City area began to receive famotidine intravenously, at nine times the heartburn dose. Unlike other drugs the 23-hospital system is testing, including Regeneron’s sarilumab and Gilead Sciences’s remdesivir, Northwell kept the famotidine study under wraps to secure a research stockpile before other hospitals, or even the federal government, started to buy it. “If we talked about this to the wrong people or too soon, the drug supply would be gone,” says Kevin Tracey, a former neurosurgeon in charge of the hospital system’s research.

As of Saturday, 187 COVID-19 patients in critical status, including many on ventilators, have been enrolled in the trial, which aims for a total of 1174 people. Reports from China and molecular modeling results suggest the drug, which seems 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 touted by President Donald Trump and some physicians and scientists—has made Tracey wary of sparking premature enthusiasm. He is tight-lipped about famotidine’s prospects, at least until interim results from the first 391 patients are in. “If it does work, 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 is based at Massachusetts General Hospital and has extensive connections in the biodefense world, has spent time in disease hot zones around the world, including the 2003 outbreak of another coronavirus disease, SARS, in Hong Kong. In mid-January, he was in Nanjing, China, working on an avian flu project. As the COVID-19 epidemic began to explode in Wuhan, he followed his Chinese colleagues to the increasingly desperate city.

The virus was killing as many as one out of five patients older than 80. Patients of all ages with hypertension and chronic obstructive pulmonary disease were faring poorly. Callahan and his Chinese colleagues got curious about why many of the survivors tended to be poor. “Why are these elderly peasants not dying?” he asks.

In reviewing 6212 COVID-19 patient records, the doctors noticed that many survivors had been suffering from chronic heartburn and were on famotidine rather than more-expensive omeprazole (Prilosec), the medicine of choice both in the United States and among wealthier Chinese. Hospitalized COVID-19 patients on famotidine appeared to be dying at a rate of about 14% compared with 27% for those not on the drug, although the analysis was crude and the result was not statistically significant.

But that was enough for Callahan to pursue the issue back home. After returning from Wuhan, he briefed Robert Kadlec, assistant secretary for preparedness and response at the Department of Health and Human Services, then checked in with Robert Malone, chief medical officer of Florida-based Alchem Laboratories, a contract manufacturing organization. Malone is part of a classified project called DOMANE that uses computer simulations, artificial intelligence, and other methods to rapidly identify U.S. Food and Drug Administration (FDA)-approved drugs and other safe compounds that can be repurposed against threats such as new viruses.

Malone had his eyes on a viral enzyme called the papainlike protease, which helps the pathogen replicate. To see whether famotidine binds to the protein, he would ordinarily need the enzyme’s 3D structure, but that would not be available for months. So Malone recruited computational chemist Joshua Pottel, president of Montreal-based Molecular Forecaster, to predict it from two crystal structures of the protease from the 2003 SARS coronavirus, combined with the new coronavirus’ RNA sequence.

It was hardly plug-and-play. Among other things, they compared the gene sequences of the new and old proteases to rule out crucial differences in structure. Pottel then tested how 2600 different compounds interact with the new protease. The modeling yielded several dozen promising hits that pharmaceutical chemists and other experts narrowed to three. Famotidine was one. (The compound has not popped up in in vitro screens of existing drug libraries for antiviral activity, however.)