 |
|
|
| |
HCV-796, Polymerase Inhibitor
|
| |
| |
DDW, May 19-24, 2007 Washington DC
Pharmacodynamic Analysis of the Antiviral Activity of the Non-Nucleoside Polymerase Inhibitor, HCV-796, in Combination With Pegylated Interferon Alfa-2b in Treatment-Naive Patients With Chronic HCV
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 naive 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 mg/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.
Favorable Cross-Resistance Profile of HCV-796 and SCH-503034 and Enhanced Anti-Replicon Activity Mediated By Combination Treatment
R. Ralston1; A. Y. Howe2; R. Chase1; A. Skelton1; X. Tong1; M. Flint2; S. Mullen2; C. Broom3; E. Emini2
1. Virology, Schering-Plough Research Institute, Kenilworth, NJ, USA.
2. Wyeth Research, Collegeville, PA, USA.
3. ViroPharma Incorporated, Exton, PA, USA.
Background: Cell-culture replicon studies evaluated the combined antiviral effects of two novel inhibitors of hepatitis C virus (HCV): SCH-503034 (Schering-Plough), a NS3 protease inhibitor, and HCV-796 (Wyeth/ViroPharma), a non-nucleoside polymerase inhibitor. Each inhibitor demonstrated significant antiviral activity in early clinical studies. Replicon studies demonstrated that genetic variants exhibiting reduced susceptibility can be selected from each compound. Because SCH-503034 and HCV-796 target different viral enzymes, a potential exists for enhanced in vivo antiviral effect if the inhibitors are used in combination, as well as the potential for forestalling in vivo selection of clinically resistant HCV. The present replicon studies were performed to ascertain the likelihood of achieving these goals.
Methods: The combined antiviral effect of SCH-503034 and HCV-796 was evaluated using genotype 1b HCV replicon cells. Each compound was individually assessed for its ability to inhibit the activity of variant replicons exhibiting reduced susceptibility to the other inhibitor.
Results:
The combination of SCH-503034 and HCV-796 notably enhanced replicon inhibition in treated cells, in a dose-dependent manner, compared with the effect of each inhibitor used alone. The antiviral effect of the combination was at least additive. No cytotoxicity was observed. SCH-503034 exhibited equivalent inhibitory activity against the wild-type replicon and replicon variants expressing single polymerase amino acid substitutions that engender reduced susceptibility to HCV-796. The inhibitory effect of HCV-796 against replicon variants with protease amino acid substitutions mediating reduced susceptibility to the protease inhibitor was found to be identical to that observed against the wild-type replicon. The combination significantly reduced the frequency of emergence of resistant colonies compared to each inhibitor used alone.
Conclusions: The anti-replicon activity of the combination of SCH-503034 and HCV-796, as well as the activity of each compound against replicons with reduced susceptibility to the other compound, strongly support the combined use of these two inhibitors in clinical trials. The cell-culture replicon data suggest that the in vivo antiviral effects of the combination will be notably improved over the effects seen to date with monotherapy. Importantly, compared with monotherapy, the combination will likely impose a greater genetic barrier to the selection of clinically resistant viral variants.
|
| |
|
|
|
|
|
