Hepatitis C virus RNA elimination and development of resistance in replicon cells treated with BMS-790052.
BMS-790052, a first-in-class hepatitis C virus (HCV) replication complex inhibitor, targeting nonstructural protein 5A (NS5A), displays picomolar to nanomolar potency against genotypes 1 to 5. This exceptional potency translated into robust anti-HCV activity in clinical studies with HCV genotype 1-infected subjects. To date, all BMS-790052-associated resistance mutations have mapped to the N-terminal region of NS5A. To further characterize the antiviral activity of BMS-790052, HCV replicon elimination and colony formation assays were performed. Replicon was cleared from genotype 1a and 1b replicon cells in a time- and dose-dependent manner. Elimination of the genotype 1a replicon required longer treatment durations and higher concentrations of BMS-790052 than those for the genotype1b replicon. Single amino acid substitutions that conferred relatively low levels of resistance were observed at early time points and at low doses. Higher doses and longer treatment durations yielded mutations that conferred greater levels of resistance, including linked amino acid substitutions. Replicon cells that survived inhibitor treatment remained fully sensitivity to pegylated alpha interferon (pegIFN-α) and other HCV inhibitors. Moreover, genotype 1a replicon elimination was markedly enhanced when pegIFN-α and BMS-790052 were combined. Resistant variants observed in this study were very similar to those observed in a multiple ascending dose (MAD) monotherapy trial of BMS-790052, validating replicon elimination studies as a model to predict clinical resistance. Insights gained from the in vitro anti-HCV activity and resistance profiles of BMS-790052 will be used to help guide the clinical development of this novel HCV inhibitor.
Department of Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
Chunfu
C
Wang
Haichang
H
Huang
Lourdes
L
Valera
Jin-Hua
JH
Sun
Donald R
DR
O'Boyle
Peter T
PT
Nower
Lingling
L
Jia
Dike
D
Qiu
Xin
X
Huang
Aneela
A
Altaf
Min
M
Gao
Robert A
RA
Fridell
D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics*; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D020128:Inhibitory Concentration 50; D016898:Interferon-alpha / Q000494:pharmacology; D010641:Phenotype; D011092:Polyethylene Glycols / Q000494:pharmacology; D011753:Pyrones / Q000008:administration & dosage*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012093:Replicon / Q000235:genetics*; D017384:Sequence Deletion; D014230:Triazoles / Q000008:administration & dosage*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics; D011743:Pyrimidines
D000998:Antiviral Agents; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D011753:Pyrones; D012324:RNA-Dependent RNA Polymerase; D011994:Recombinant Proteins; D014230:Triazoles; D017361:Viral Nonstructural Proteins; C550357:filibuvir; D011743:Pyrimidines; C087036:NS-5 protein, hepatitis C virus; C100416:peginterferon alfa-2a