More Than Just Heartburn: Does Famotidine Effectively Treat Patients with COVID-19?

Abstract

Famotidine is an exquisitely specific inverse agonist of the human histamine H2 receptor. This agent is primarily administered as a treatment for gastroesophageal reflux disease (GERD) and related foregut disorders attributable to acid hypersecretion. Early in the COVID-19 outbreak, multiple research groups employing computational docking algorithms (computer programs that predict the interactions between small molecules and proteins at the atomic level) identified famotidine as a potential competitive inhibitor of both principal proteases expressed by the novel human coronavirus SARS-CoV-2. These groups posited that this remarkably safe, inexpensive, off-patent (generic) drug might directly inhibit replication of SARS-CoV-2, providing clinical benefit for COVID-19 patients. Subsequent non-clinical bench research has clearly demonstrated that famotidine does not bind to either protease to a significant extent and does not inhibit SARS-CoV-2 replication (see [1] for summary). Many of the unique clinical symptoms observed during the early phase of COVID–19 are consistent with known effects of histamine release. Most likely, if famotidine reduces the severity for COVID-19, it acts via its antagonism or inverse agonism of histamine signaling and arrestin-biased activation [1]. Multiple retrospective studies, case series, or reports have since been performed seeking to clarify whether famotidine treatment improves clinical outcomes in outpatient or in newly admitted inpatient cohorts suffering from COVID-19 disease. In some retrospective analyses, significant benefit has been reported, while others conclude no benefit. In this issue of Digestive Diseases and Sciences, Drs. Sun, Chen, and colleagues report the first rigorous metaanalysis of data abstracted from peer-reviewed and published retrospective studies available up to the time of analysis (October 2020) [2]. Their findings clearly establish that famotidine administration at the standard GERD treatment doses (20–40 mg/day) does not provide a significant benefit in reducing the risk of serious illness, death, and intubation for hospitalized COVID-19 patients. Although not available to Sun, Chen et al. at the time of their analysis, an independent retrospective study by the Janssen/Johnson & Johnson team of Drs. Shoaibi, Fortin et al. [3] has further confirmed and extended these findings. Retrospective analyses of clinical datasets are one of the most powerful tools available to rapidly test whether drug repurposing “hits” have clinical merit. The retrospective analysis approach is straightforward, and the logic is compelling: If a repurposed candidate can be identified, and the pharmaceutical is prescribed at sufficient frequency (for another indication such as GERD) in patients suffering from a disease (such as COVID-19), then a retrospective analysis may be useful. As clinical patient data accumulate, sufficient cases exposed to both the repurposed drug candidate and the disease may support analysis of potential association. Nevertheless, this approach presumes that the dosing regimen (timing, route, and level) for the common indication (GERD) is within the therapeutic window required for the hypothesized new clinical indication (COVID-19). To illustrate, it is unrealistic and naïve to assume that the dosing regimen for an over-the-counter indication would be the same as for a life-threatening hyper-inflammatory response to a novel infectious pathogen since the dosing, pharmacokinetics, and pharmacodistribution recommended for the licensed indication may not align with that required for the repurposed clinical indication. To avoid artifacts, retrospective propensity score analysis requires sufficient knowledge of confounding variables in order to support statistical correction and adjustment. For example, in the case of COVID-19 and patients with GERD, one might assume that patients receiving first-line therapy with proton pump inhibitors (PPI) and also suffering from COVID-19 might serve as a valid control population for patients receiving second-line GERD therapy (famotidine). * Robert W. Malone [email protected]