954

Abstract

Introduction: Therapeutic options for RSV, a leading cause of lower respiratory infection in children and adults, are suboptimal. Ribavirin has antiviral effect but its controversial mild clinical therapeutic benefit and environmental contamination issues preclude its routine use. MDT-637 is a novel RSV fusion inhibitor not yet evaluated for therapeutic effect in man. The extent to which the achievable human concentration of an antiviral exceeds its invitro viral inhibitory concentration, can predict its clinical efficacy. Methods: RSV A-long (MOI=0.001) was co-incubated in duplicate with ascending concentrations of ribavirin or MDT-637, added to HEp-2 cells and incubated x 72 hrs. Viral concentrations were then assessed by quantitative PCR (qPCR). 50% Inhibitory Concentrations (IC50) were measured and compared to achievable human MDT-637 and ribavirin peak and trough concentrations. For calculations, measured MDT-637 concentrations in human respiratory secretions were extrapolated based on known solubility in simulated lung fluid. Achievable human ribavirin concentrations were from the literature. Genotypic diversity was based on RSV G-protein. Results: The IC50 for MDT-637 and ribavirin (against RSV A-long) was 2.1 and 16,973ng/ml respectively representing >7,000x greater potency of MDT-637. Using RSV A-long, the ratio of achievable peak respiratory secretion concentration to IC50 was 86,000x for MDT- 637 and 25x for ribavirin. The ratio of trough concentration to IC50 was 18,000x for MDT-637 and 1.6x for ribavirin. MDT-637 IC50s were also measured vs. 3 lab strains [RSV-ALong (ATCC-VR26, clade NH/A1), RSV-A2 (VR-1540), RSV-B (VR-955)] and 7 clinical strains [clades NH/A2, NH/A4, NH/B2, NH/B3, BE/GB2]. The IC50s ranged from 0.50-7.37ng/ml. Conclusions: MDT-637 is several thousand times more potent invitro compared to ribavirin. Achievable human MDT-637 concentrations in respiratory secretions exceed the IC50s by factors thousands of times greater than does ribavirin. Furthermore, MDT-637 has broad invitro antiviral activity on clinical strains of different RSV genotypes and clades. Together, this data implies that MDT-637 may produce a superior clinical effect compared to ribavirin on natural RSV infections.