HCV-796, a non-nucleoside hepatitis C virus (HCV) polymerase inhibitor being co-developed by ViroPharma and Wyeth Pharmaceuticals, has demonstrated potent antiviral activity in vitro in preclinical studies.

This randomized, double-blind, placebo-controlled Phase 1b study was an ascending multiple-dose trial to assess the antiviral activity, pharmacokinetics, and safety of HCV-796 in patients with chronic hepatitis C.

Treatment-naive participants (72% with genotype 1 HCV) were enrolled in sequential, ascending dose cohorts of up to 16 patients (12 active, four placebo) per group. They received 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg, or 1500 mg HCV-796 monotherapy, or else placebo, twice daily for 14 days. At baseline, the mean HCV RNA was 6.6 log10; all participants had viral loads of at least 10,000 IU/mL.

Results

• HCV-796 reduced plasma HCV RNA levels by 0.3 to 1.4 log10 (50% to 97%) depending on dose; the maximal antiviral effect was seen at day 4.
• Antiviral potency increased with dose, producing peak response at 500 mg or higher.
• In the 1000 mg cohort, the mean reductions in HCV RNA were 1.4 log10 (96%) on day 4; 1.3 log10 (95%) on day 7; and 0.7 log10 (80%) on day 14.
• On day 4, 83% of patients in the 1000 mg group had greater than 1.0 log10 reduction in HCV RNA from baseline; 33% of these patients had reductions greater than 1.5 log10, and 25% had reductions greater than 2.0 log10.
• On day 14, 17% of patients in this cohort had reductions from baseline greater than 2.0 log10.
• Antiviral activity appeared similar among patients infected with genotype 1 compared with other genotypes.

The mean pharmacokinetic parameters for the 1000 mg dose cohort on day 14 were:

• Cmax = 2186 ng/mL (standard deviation ± 764 ng/mL);
• Tmax = 1.8 hr (SD ± 0.9)
• t1/2 = 53.7 hr (SD ± 28.7)
• area under the curve (AUC) = 20046 ng*hr/mL (SD ± 7633)
• CL/F = 58.0 L/hr (SD ± 25.5)
• V/F = 4163 L (SD ± 1960)
• accumulation ratio = 4.2 (SD ± 1.7)

Pharmacokinetic exposure was less than dose-proportional with increasing doses, and appeared to reach a plateau at the 1000 mg dose.
Reductions in alanine aminotransferase (ALT) level were observed during therapy at all dose levels, while the placebo group experienced a small ALT increase. HCV-796 was generally well tolerated with no dose-limiting toxicities or serious treatment-related adverse events. The most frequently reported side effects was mild to moderate headache. Small, transient increases in unconjugated bilirubin were observed. Three participants discontinued due to adverse events.
The researchers concluded that HCV-796 demonstrated antiviral activity and was generally safe and well tolerated when given for 14 days.

5/30/06

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