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Evaluation of VCH-759 monotherapy in hepatitis C infection

2009; Elsevier BV; Volume: 51; Issue: 1 Linguagem: Inglês

10.1016/j.jhep.2009.03.015

1600-0641

Curtis Cooper, Eric Lawitz, Peter Ghali, M. Rodríguez‐Torres, Frank Anderson, Samuel S. Lee, Jean Bédard, Nathalie Chauret, Roch Thibert, Isabel Boivin, Olivier Nicolas, L. Proulx,

Hepatitis B Virus Studies

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-naı¨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. VCH-759 is a non-nucleoside inhibitor of HCV RNA-dependent polymerase with sub-micromolar IC50 values versus genotype 1a/1b replicons. 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-naı¨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. 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. 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.