|
|
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.
|
