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Doctors and scientists are studying many existing drugs with the hope of finding therapies they can repurpose to fight COVID-19. Some of these, like Gilead Sciences’ remdesivir, directly go after the virus SARS-CoV-2, which causes the disease. Others, like Incyte’s ruxolitinib, aim to dampen the overactive immune response that characterizes later stages of disease in COVID-19.
And then there are the oddballs. Take famotidine, the active ingredient in the over-the-counter heartburn drug Pepcid. The histamine-H2-receptor antagonist works by preventing stomach acid production. That it would have any activity in an infectious disease is a bit of a head-scratcher.
Doctors first became interested in famotidine after hearing reports that people in China who took the drug for heartburn were surviving COVID-19, while other people who essentially had the same risk factors but were taking different heartburn drugs like cimetidine or omeprazole (sold in the US as Tagamet and Prilosec, respectively) were dying from the disease. Perhaps famotidine was somehow bolstering these patients and improving their chances for survival.
In early April, doctors began a clinical trial at New York’s Northwell hospitals to test that theory. They reasoned that even if evidence for famotidine’s effectiveness was largely anecdotal, the drug has been around since the 1980s and has a good safety profile. If it worked, it would be a fast and cheap way to ease the symptoms of COVID-19.
They decided to use high doses of intravenous famotidine. Their goal was to enroll 1,200 people with moderate to severe COVID-19 and see if those that got famotidine were less likely to die or require a ventilator. Then, in late April, the first news report about the trial appeared in Science. Boxes of Pepcid began to fly off of pharmacy shelves as people sought out any potential remedy during the pandemic.
Shortly afterward, on May 8, a team, led by Columbia University doctors Daniel Freedberg and Julian Abrams, posted a study on the preprint server medRxiv that compared the outcomes of people with COVID-19 who were prescribed famotidine within 24 hours of being admitted to the hospital to those who didn’t get the heartburn drug. They looked at the records of more than 1,600 patients at Columbia University Irving Medical Center between late February and mid-April. Of those, 84 patients received 10–40 mg of intravenous famotidine daily over the course of about 6 days.
The patients who got famotidine fared better. According to the study, they were far less likely to die or require a ventilator—a twofold decrease in risk—than those not receiving the drug. The results were published in the peer-reviewed journal Gastroenterology later in May (2020, DOI: 10.1053/j.gastro.2020.05.053).
“This is merely an association, and these findings should not be interpreted to mean that famotidine improves outcomes in patients hospitalized with COVID-19,” the team says in a statement. “It is also not clear why those patients who received famotidine had improved outcomes.”
For clarity on famotidine’s effectiveness, the team recommends awaiting the outcome of the trial going on at Northwell hospitals. “Hopefully the results from this trial will determine whether famotidine is efficacious for the treatment of COVID-19,” the team says in its statement.
Meanwhile, in early June, the journal Gut published a small case series of 10 people who developed COVID-19 and reported taking famotidine during their illness (2020, DOI: 10.1136/gutjnl-2020-321852). These people were not sick enough to go to the hospital, but their symptoms, such as cough and shortness of breath, improved within a day or two of taking the heartburn drug. It’s a small study, and the researchers acknowledge that it’s not enough to establish there’s any real benefit from taking famotidine for people who have COVID-19. Those authors recommend a clinical trial with famotidine be carried out with patients with milder disease in addition to the trial going on at Northwell hospitals.
But the Northwell trial has slowed for two reasons, says Joseph Conigliaro, the physician who is leading it. Cases of COVID-19 in New York have declined, making it challenging to reach the enrollment requirements for the study.
And shifting treatment approaches have further complicated efforts. When the trial began, COVID-19 patients in New York were getting the antimalarial hydroxychloroquine as part of their treatment regimen. So the study was designed to compare patients receiving hydroxychloroquine and famotidine with patients receiving hydroxychloroquine and a placebo. But that standard treatment regimen has changed, and hydroxychloroquine is no longer given routinely. As a consequence, the researchers are looking to modify the study’s protocol, Conigliaro says.
Until the results of the study are in, Conigliaro can’t say whether famotidine works. “As a physician, I can’t tell people ‘go out and buy famotidine, and if you start getting an inkling of anything start taking it,’ ” he says. Even though the drug has long been considered safe, it’s unclear how to guide people to take it in terms of dose and disease stage. “We need to wait for the results of our trial,” he says.
Scientists are meanwhile trying to figure out why a heartburn medicine might also fight COVID-19. Using computational methods, a group in China used SARS-CoV-2 genes to predict the structures of viral proteins. The group then computationally screened existing drugs to see which could potentially act on those protein targets. Their study suggests that famotidine could inhibit the virus’s 3-chymotrypsin-like protease, which plays a role when the coronavirus makes copies of itself while inside the host (Acta Pharm. Sin. B 2020, DOI: 10.1016/j.apsb.2020.02.008).
Similarly, computational chemists at the scientific software company Molecular Forecaster virtually docked a library of 2,700 existing drugs and nutraceuticals to see which fit into a model of the papain-like protease, another key protein in SARS-CoV-2 replication. They were collaborating with scientists working for a US Department of Defense project called DOMANE. Famotidine was one of a few drugs that appeared to interact with the protease in the computational studies, says Robert Malone, a physician and consultant who is on the DOMANE team.
But other evidence derails those computational studies. Matthew D. Hall, acting director of biology and group leader, Early Translation Branch, at the National Center for Advancing Translational Sciences (NCATS), part of the US National Institutes of Health, points out that his group did studies in cells that show famotidine doesn’t have any ability to fight SARS-CoV-2. “In a direct antiviral assay, we don’t see any activity for any of the compounds in this class,” he says.
As a drug-repurposing candidate, Hall says, famotidine is attractive because it’s safe, affordable, and accessible. But making further conclusions about its usefulness in COVID-19 will require clinical trial data. If those trials show promise, Hall says, “I think there’s going to be some intriguing science trying to draw a connection between [clinical] activity and how it’s actually working in the context of SARS-CoV-2 infection. Understanding the primary mechanism may also drive long-term development of new therapeutics that are more potent.”
Malone has been working with a team of scientists to get a better understanding of just how famotidine might be working. Results of his team’s study, which have not yet been peer reviewed, appeared on a preprint server on May 23 (Research Square 2020, DOI: 10.21203/rs.3.rs-30934/v1).
Like the NCATS work, the team’s tests showed that famotidine has no effect on SARS-CoV-2’s papain-like protease, nor does it kill the virus. Instead, Malone and colleagues think the drug is working through its usual target—histamine H2 receptors. Famotidine treats heartburn by blocking H2 receptors, which when activated by histamine stimulate cells in the stomach to secrete acid.
But H2 receptors aren’t just in the stomach—they’re all over the body. Malone and colleagues argue that COVID-19 is disrupting mast cells, which release histamine and other signaling molecules in response to an inflammatory or allergic reaction. These cells can be found at the boundary between tissue and an external environment. They’re on the skin and line the gut and lungs. Malone reasons that mast cells could be responsible for the overactive immune response, often described as the cytokine storm, which does damage to patients with severe cases of COVID-19. By blocking the histamine that mast cells release, famotidine can dampen some of that response.
If famotidine is effective in COVID-19, why isn’t the other commonly used H2 blocker, cimetidine? The answer, Malone claims, comes down to pharmacokinetics: famotidine makes it into the bloodstream more readily than cimetidine.
Adrian M. Piliponsky, an immunologist at Seattle Children’s Research Institute who studies mast cells, says that it’s possible mast cells are playing a role in the inflammatory response to COVID-19. He notes that mast cells play a role in infections with other viruses. He thinks the idea proposed by Malone and colleagues merits further study, and he’s interested in seeing the results of the clinical trial.
Malone also would like to see a comprehensive trial of famotidine in people who are in the early stages of COVID-19. But he doesn’t think the drug alone will resolve the world’s COVID-19 pandemic. “We’re committed to trying to create an outpatient cocktail of drugs that will significantly reduce morbidity and mortality for COVID-19 and have it ready for deployment in the fall,” he says.
In the meantime, doctors are urging caution for people who might see these early results and rush out to stock up on Pepcid. Carl J. Lavie, medical director of cardiac rehabilitation and prevention at the John Ochsner Heart and Vascular Institute, recently cowrote a letter to the editor of Mayo Clinic Proceedings encouraging doctors to wait for the clinical trial results.
He tells C&EN that it’s premature to recommend famotidine just for COVID-19, but he adds, “I also think that it is benign, so it would seem very reasonable to use for upper GI symptoms now” before giving other heartburn drugs like omeprazole.
This story was updated on June 16, 2020, to correctly characterize famotidine as a histamine-H2-receptor antagonist, not an agonist.
This story was updated on June 22, 2020, to correctly identify the group that did a virtual docking study. It was chemists at Molecular Forecaster, not DOMANE.