Abstract

Antiviral Activity of EP-NI266, a Potent Nucleotide HCV Polymerase Inhibitor
Speaker: Christopher Owens
Author: C.M. Owens1*, M.H.J. Rhodin1, A. Polemeropoulos1, I.J. Kim2, Y.-L. Qiu2, G. Wang2, L.J. Jiang1, Y.S. Or2
Affiliation: 1Pharmacology, 2Chemistry, Enanta Pharmaceuticals, Inc., Watertown, MA, USA. *cowens@enanta.com
Background: Chronic infection with the hepatitis C virus (HCV) is becoming a major global health burden. Current therapies have sub-optimal response rates, are associated with significant side effects or can select for resistance. The design of nucleotide inhibitors (NI) such as EP-NI266 was undertaken in response to this unmet medical need.
Results: The single agent antiviral activity of EP-NI266 was first determined in cells expressing an HCV subgenomic replicon. EC50 values were obtained for EP-NI266 in genotypes (gt) 1a and 1b at 129 nM and 77 nM compared with 297 nM and 211 nM for PSI-7977. Transient replicon mutant studies demonstrated an absence of cross-resistance between reported direct acting antiviral (DAA)-resistant mutants and EP-NI266. The acute combination effects for EP-NI266 in combination with other DAA compounds, a cyclophilin (CyP) inhibitor or Interferon (IFN) were studied. The combinations were found to be additive to synergistic in reference to Bliss Independence and combination index (CI) additivity models at the concentrations tested. EP-NI266, in combination with an NS5A or CyP inhibitor, suppresses the emergence of HCV resistance when replicon cells are grown in the presence of G418 and combinations of test compounds. In addition, a long-term viral reduction assay was conducted with a fixed dose of compound over 6 passages of gt1a replicon cells in the absence of G418 selection. In this assay, gt1a replicon RNA was undetectable by passage 2 in cells treated with EP-NI266 alone, and by passage 1 for EP-NI266 in combination with an NS5A inhibitor.
Conclusions: EP-NI266 is a highly potent nucleotide inhibitor of HCV replication. It possesses an excellent cross-resistance profile and is additive to synergistic with other HCV inhibitors. In addition, these data suggest that our NI, when used in combination with an NS5A or CyP inhibitor, has great potential for suppressing the emergence of HCV resistance in patients.