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Pharmacodynamic Analysis of the Antiviral Activity of the Non-Nucleoside Polymerase Inhibitor, HCV-796, in Combination With Pegylated Interferon Alfa-2b in Treatment-Naïve Patients With Chronic HCV
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DDW, May 22, 2007, Wash DC
E. S. Maller1; D. Raible2; P. Chandra2; D. Harper2; J. Speth2; P. Shaw3; G. Bichier4; S. Villano5
1. Clinical Research & Development, Wyeth Research, Collegeville, PA, USA.
2. Clinical Pharmacology, Wyeth Research, Collegeville, PA, USA.
3. Northwest Kinetics, Tacoma, WA, USA.
4. Center for Clinical Trials Research, University of Florida, Gainesville, FL, USA.
5. ViroPharma Incorporated, Exton, PA, USA.
Background: HCV-796 is an inhibitor of hepatitis C virus (HCV) RNA-dependent RNA polymerase that has demonstrated antiviral activity across multiple HCV genotypes, both in vitro and in Phase 1 clinical studies.
Methods: In a randomized, double-blind study, adult patients with chronic HCV infection who were naïve to treatment were randomized to receive oral HCV-796 (100, 250, 500, or 1000 mg) or placebo every 12 hours for 14 days. All patients were to receive pegylated interferon alfa-2b (PEG, 1.5 _g/kg) on day -1 (one day before start of HCV-796/placebo) and day 7. Each cohort receiving HCV-796+PEG enrolled 9-12 patients. Virologic response was analyzed by individual pharmacokinetic (PK) parameters and various demographic/baseline characteristics. HCV RNA was assayed with a lower limit of detection of 50 IU/mL.
Results: Overall, the mean baseline HCV RNA level was 6.4 log10, and 66% of patients were infected with HCV genotype 1. At day 14, the mean reduction in HCV RNA ranged from 3.3-3.5 log10 in the combination therapy groups vs. 1.6 log10 in the PEG group. Activity differed by HCV genotype. Mean reductions at day 14 for genotype 1 ranged from 2.6-3.2 log10 in the combination therapy groups vs. 1.2 log10 for PEG. For genotype non-1 the respective reductions were 3.5-4.8 log10 vs. 2.6 log10. Based on individual HCV RNA plots over time, there was somewhat greater variability in virologic response in the HCV-796 100 mg q12h combination group compared with higher dose groups. However, analyses of individual virologic responses in the combination therapy groups did not reveal correlations with individual HCV-796 PK parameters (Cmax, AUC, or Cmin) across the range of doses tested. At HCV-796 doses of 250 mg q12h or higher, combination with PEG resulted in 33-67% of genotype 1 patients with reductions from baseline >3 log10 on day 14 (13-17% below 50 IU/mL). For genotype non-1, 67-100% had reductions >3 log10 on day 14 (50-75% below 50 IU/mL). There were no apparent differences in virologic response in the combination therapy groups when analyzed by patient age, race, sex, or baseline HCV RNA level.
Conclusions: The combination of HCV-796 and PEG provides antiviral activity across multiple HCV genotypes that is greater than either agent used alone. Pharmacodynamic analyses suggest similar short-term antiviral activity at HCV-796 doses of 250 mg q12h or higher when combined with PEG. Clinical studies of more long-term administration of combination therapy are in progress to determine if these effects are durable.
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