1265. AT-527, an Oral Purine Nucleotide Prodrug Exhibiting Potent In Vitro Antiviral Activity Against Human Coronaviruses, Including SARS-CoV-2

Abstract

BackgroundCoronaviruses (CoVs) are the causative pathogens of several human diseases, including seasonal respiratory infections (HCoV-229E and HCoV-OC43), Middle East respiratory syndrome (MERS-CoV), severe acute respiratory syndrome (SARS-CoV-1) and the novel CoV recently identified as the virus responsible for the current COVID-19 pandemic, SARS-CoV-2. AT-527 is currently in Phase 2 clinical trials and has demonstrated potent activity and a well-tolerated safety profile in HCV-infected subjects. Here we report the in vitro activity of AT-511, the free base form of AT-527, against SARS-CoV-2 and other CoVs.MethodsBHK-21, Huh-7, RD and differentiated normal human bronchial epithelial (dNHBE) cell cultures were exposed to virus and serial dilutions of test compounds. Independent assessments of antiviral activity were obtained by determining effective concentrations of test compounds required to 1) prevent half-maximal (EC50) virus-induced cytopathic effect (CPE) using MTT or neutral red staining and 2) produce virus yield reductions (VYR) by 90% (EC90) using standard endpoint dilution CCID50 assays in Vero 76 cells. Half maximal cytotoxicity of test compounds was determined by dye (MTT or neutral red) staining in the absence of added virus or by microscopic inspection (dNHBE cells only).ResultsTable 1 presents the in vitro activities of AT-511 against several coronaviruses. Also included in these assays are the antiviral activities of potential COVID-19 oral treatments, including chloroquine, hydroxychloroquine and N4-hydroxycytidine.Table 1. In Vitro Activity of AT-511 Against Various Human Coronaviruses ConclusionThe data demonstrate the potent in vitro activity of AT-511 against several CoVs, with individual EC90 values ranging from 0.34 to 1.2 µM against HCoV-229E, HCoV-OC43, SARS-CoV-1 and SARS-CoV-2 and less activity against MERS-CoV (average EC90 = 36 µM). The potent in vitro antiviral activity of AT-511 against SARS-CoV-2 (EC90 = 0.55 µM), associated with the AT-527 safety profile in treated HCV patients, support the ongoing clinical evaluation of the safety and efficacy of AT-527 in COVID-19 patients.DisclosuresSteven S. Good, MS, Atea Pharmaceuticals, Inc. (Employee) Adel Moussa, PhD, Atea Pharmaceuticals, Inc. (Employee) Xiao-Jian Zhou, PhD, Atea Pharmaceuticals, Inc. (Employee) Keith Pietropaolo, B.A., Atea Pharmaceuticals, Inc. (Employee) Jean-Pierre Sommadossi, PhD, Atea Pharmaceuticals, Inc. (Board Member)