TY - JOUR
T1 - Evaluation of VCH-759 monotherapy in hepatitis C infection
AU - Cooper, Curtis
AU - Lawitz, Eric J.
AU - Ghali, Peter
AU - Rodriguez-Torres, Maribel
AU - Anderson, Frank H.
AU - Lee, Samuel S.
AU - Bédard, Jean
AU - Chauret, Nathalie
AU - Thibert, Roch
AU - Boivin, Isabel
AU - Nicolas, Olivier
AU - Proulx, Louise
N1 - Funding Information:
The authors have declared that this study was funded by ViroChem Pharma Inc. J.B., N.C., R.T., I.B., O.N., and L.P. are employees of ViroChem PharmaInc. The other authors have also declared a relationship with the manufacturers of the drugs involved.
PY - 2009/7
Y1 - 2009/7
N2 - Background/Aims: VCH-759 is a non-nucleoside inhibitor of HCV RNA-dependent polymerase with sub-micromolar IC50 values versus genotype 1a/1b replicons. Methods: The antiviral activity, pharmacokinetics and tolerability of VCH-759 administered as monotherapy for 10 days with a 14 day follow-up period were evaluated in 31 treatment-nai{dotless}̈ve genotype 1 participants. Three cohorts received: 400 mg thrice (t.i.d.), 800 mg twice (b.i.d.), 800 mg t.i.d or placebo. Results: VCH-759 was well tolerated with the most frequent adverse event being gastrointestinal upset in both the active and placebo groups attributable, in part, to the dosing vehicle. VCH-759 was rapidly absorbed and trough plasma levels were at or above the IC90 (non protein-adjusted) for all dosing regimens. The mean maximal decrease in HCV RNA log10 (IU/mL) was 1.97, 2.30 and 2.46 for 400 mg t.i.d., 800 mg b.i.d. and 800 mg t.i.d. doses. Viral polymerase genotypic sequencing revealed emergence of HCV variants in a majority of participants that coincided with on-treatment viral rebound. Conclusions: VCH-759 was well tolerated and achieved a ≥ 2 log10 decline in HCV RNA with 800 mg b.i.d. and t.i.d doses. In a subset of participants, viral rebound was observed and associated with resistant variants. This data supports further evaluation of VCH-759 in combination with interferon-ribavirin treatment.
AB - Background/Aims: VCH-759 is a non-nucleoside inhibitor of HCV RNA-dependent polymerase with sub-micromolar IC50 values versus genotype 1a/1b replicons. Methods: The antiviral activity, pharmacokinetics and tolerability of VCH-759 administered as monotherapy for 10 days with a 14 day follow-up period were evaluated in 31 treatment-nai{dotless}̈ve genotype 1 participants. Three cohorts received: 400 mg thrice (t.i.d.), 800 mg twice (b.i.d.), 800 mg t.i.d or placebo. Results: VCH-759 was well tolerated with the most frequent adverse event being gastrointestinal upset in both the active and placebo groups attributable, in part, to the dosing vehicle. VCH-759 was rapidly absorbed and trough plasma levels were at or above the IC90 (non protein-adjusted) for all dosing regimens. The mean maximal decrease in HCV RNA log10 (IU/mL) was 1.97, 2.30 and 2.46 for 400 mg t.i.d., 800 mg b.i.d. and 800 mg t.i.d. doses. Viral polymerase genotypic sequencing revealed emergence of HCV variants in a majority of participants that coincided with on-treatment viral rebound. Conclusions: VCH-759 was well tolerated and achieved a ≥ 2 log10 decline in HCV RNA with 800 mg b.i.d. and t.i.d doses. In a subset of participants, viral rebound was observed and associated with resistant variants. This data supports further evaluation of VCH-759 in combination with interferon-ribavirin treatment.
KW - Antiviral activity
KW - Non-nucleoside NS5b inhibitor
KW - Pharmacokinetics
KW - Proof-of-concept study
KW - Safety and tolerability
KW - Variant identification
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U2 - 10.1016/j.jhep.2009.03.015
DO - 10.1016/j.jhep.2009.03.015
M3 - Article
C2 - 19446909
AN - SCOPUS:67349148535
SN - 0168-8278
VL - 51
SP - 39
EP - 46
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 1
ER -