In Vitro Antiviral Profile of Ruzasvir: A Potent and Pan-genotype Inhibitor of HCV NS5A [Antiviral Agents]

Inhibition of NS5A has emerged as an attractive strategy to intervene in HCV replication. Ruzasvir (formerly MK-8408) was developed as a novel NS5A inhibitor to improve upon the potency and barrier to resistance of early compounds. Ruzasvir inhibited HCV RNA replication with EC₅₀ values of 1-4 pM in Huh 7 or 7.5 cells bearing replicons for HCV genotypes 1-7. The antiviral activity was modestly (10-fold) reduced in the presence of 40% normal human serum. The picomolar potency in replicon cells extended to sequences of clinical isolates available in public databases that were synthesized and tested as replicons. In GT1a, ruzasvir inhibited common NS5A resistance-associated substitutions (RASs) with the exception of M28G. De novo resistance selection studies identified pathways with certain amino acid substitutions at residues 28, 30, 31 and 93 across genotypes. Substitutions at position 93 were more common in genotypes (GTs) 1-4 while changes at position 31 emerged frequently in GTs 5 and 6. With the exception of GT4, the reintroduction of selected RASs conferred a 100-fold or more potency reduction in the antiviral activity of ruzasvir. Common RASs from other classes of direct-acting antiviral agents (DAAs) did not confer cross-resistance to ruzasvir. The interaction of ruzasvir with NS3/4A protease inhibitor (grazoprevir) and NS5B polymerase (uprifosbuvir) pro-drug was additive to synergistic with no evidence of antagonism or cytotoxicity. The antiviral profile of ruzasvir supported its further evaluation in human trials in combination with grazoprevir and uprifosbuvir.

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