What Underlies the Benefit of Famotidine Formulations Used During COVID-19?

Dear Editors:

This letter is in reference to the study by Freedberg et al¹ recently published in Gastroenterology. This retrospective analysis of an inpatient cohort admitted to 2 hospitals in New York found that patients with coronavirus disease 2019 (COVID-19) who were treated with famotidine exhibited a lower risk of death or mechanical ventilation as composite outcomes over a 30-day period. The study was based on computational modelling, which proposed famotidine might inhibit viral replication through direct interaction with the 3-chymotrypsin-like protease,² and was also preceded by a small, short-term follow-up, outpatient study suggesting that famotidine use was associated with symptomatic improvement.³ However, the current study published in Gastroenterology provides additional value because the previous cohort was much smaller in number, included patients without a proven COVID-19 diagnosis, and lacked a control group.

The current study by Freedberg et al¹ brings a few questions to mind, which we hope the authors can answer. In the conclusions, the authors stated, “The study was premised on the assumption that use of famotidine represented a continuation of home use.” In the Results section, they also say, “Home use of famotidine was documented on admission medication reconciliation in 15% of those who used famotidine while hospitalized.” These points bring up a few questions.

• 1.Does this indicate that the remaining 85% patients given famotidine during hospitalization were using over the counter formulations at home which were not prescribed by a physician?
• 2.Were these formulations continued in-patient?
• 3.What were the formulations of famotidine used by the hospital pharmacies?
• 4.Did some included patients receive concomitant treatment with antacids, particularly calcium-containing compounds?
• 5.It is also mentioned that 28% hospitalized COVID-19 patients received famotidine intravenously. Was there a difference in outcomes between the intravenously treated group and the orally treated group?

We ask since popular over the counter famotidine formulations such as Pepcid Complete commonly contain 800 mg calcium carbonate per 10 mg famotidine. The answers to these questions are pathophysiologically relevant as we have recently published a report in your journal,⁴ suggesting that the hypocalcemia commonly seen in severe COVID-19 disease is prognostically and mechanistically relevant to disease outcomes. We proposed that calcium supplementation early in the disease can, by interacting with fatty acids, decrease the lipotoxicity, which may exacerbate the disease and result in organ failure.

Using in silico molecular docking screens, famotidine has been characterized as potentially being able to bind papain-like protease (PLpro) and 3 chymotrypsin-like protease (Mpro) of SARS-CoV-2.^{2 , 5} To explore this notion further, we downloaded crystal structures of PLpro and Mpro from RCSB.org (PDB IDs 6WX4 and 6LU7, respectively) and imported these to Schrodinger Maestro. The structures were prepared for docking, and famotidine was docked to both proteases using the XP docking protocol. Famotidine was found to dock to PLpro with a GlideScore of –6.86 kcal/mol and to Mpro with a GlideScore of –4.05 kcal/mol. This finding represents a weak, nonspecific binding of famotidine to both PLpro and Mpro, and is in contradiction to previous molecular docking studies. Recently, in vitro experiments have shown that famotidine does not inhibit PLpro or Mpro, and it does not directly inhibit SARS-CoV-2 infection,^{6 , 7} supporting our molecular docking data that famotidine does not bind to either protease. It has been hypothesized that famotidine could indirectly treat COVID-19 through antagonism or inverse agonism of histamine signaling as a result of binding to the H2 receptor,⁶ but this hypothesis has yet to be rigorously tested.

Although the results of the randomized clinical trial on the benefits of intravenous famotidine in treating COVID-19 (NCT04370262) are excitedly awaited; the clues gained by the studies published in both Gastroenterology ^{1 , 4} and Gut,³ give hope that COVID-19 could be combated by delving deeper into, and understanding the mechanistic basis of what was observed.