Delayed Dosing of S-033188, a Novel Inhibitor of Influenza Virus Cap-dependent Endonuclease, Exhibited Significant Reduction of Viral Titer and Mortality in Mice Infected with Influenza A Virus

Abstract

BackgroundBoth epidemic and pandemic influenza are major public health concerns, but current standard treatment limits its usage by 48 hours from onsets. Furthermore, no antiviral drug has been shown to definitively reduce serious complications, hospitalization, or mortality in a randomized clinical trial. S-033188 is an orally available small molecule inhibitor of cap-dependent endonuclease that is essential for transcription and replication of influenza A and B virus. In this study, we evaluated the efficacy of delayed dosing of S-033188, either as single agent or in combination with oseltamivir, in mice infected with lethal doses of influenza A virus.MethodsBALB/c mice were intranasally inoculated with A/PR/8/34 strain at 8.0 × 102 tissue culture infectious dose 50 (TCID50)/mouse. Mice were orally treated with S-033188 (0.5, 1.5, 15 or 50 mg/kg), oseltamivir phosphate (10 or 50 mg/kg), S-033188 (0.5 or 1.5 mg/kg) in combination with oseltamivir phosphate (10 or 50 mg/kg), or vehicle BID for 5 days, beginning at 96 hours after virus infection. Survival and body weight were then monitored through a 28-day period after infection. In addition, viral titer in the lung was determined during the treatment. Mice were euthanized and regarded as dead if their body weights were lower than 70% of the initial body weights according to humane endpoints.ResultsS-033188 monotherapy (15 or 50 mg/kg, BID for 5 days) completely eliminated mortality in mice, whereas oseltamivir monotherapy (10 or 50 mg/kg, BID for 5 days) exhibited only 10% or 40% survival (Figure1), respectively. S-033188 monotherapy also significantly reduced viral titer and prevented body weight loss, consistent with the prolonged survival. Furthermore, S-033188 (0.5 or 1.5 mg/kg) in combination with oseltamivir phosphate (10 or 50 mg/kg) exhibited significant improvement of mortality as compared with each oseltamivir phosphate monotherapy.ConclusionDelayed dosing of S-033188 exhibited significant efficacy in mice infected with lethal doses of influenza A virus compared with clinically equivalent or supratheraputic dosing of oseltamivir phosphate. Furthermore, delayed dosing of S-033188 in combination with oseltamivir phosphate exhibited significant improvement of mortality as compared with each oseltamivir phosphate monotherapy.Disclosures All authors: No reported disclosures.