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HCV-796 Plus PegIntron Shows Greater Antiviral Activity Across All HCV Genotypes Than Either Agent Used Alone

HCV-796 is an experimental non-nucleoside hepatitis C virus (HCV) polymerase inhibitor that has shown antiviral activity across multiple HCV genotypes, both in laboratory testing and in Phase I clinical studies. The drug is in development by Wyeth Pharmaceuticals and ViroPharma.

At the 42nd annual meeting of the European Association for the Study of the Liver (EASL) in Barcelona, Spain (May 11-15, 2007), researchers presented results of a randomized, double-blind study in treatment-naive HCV patients who were randomized to receive oral HCV-796 (100, 250, 500, or 1000 mg) or else placebo every 12 hours for 14 days.

All patients received pegylated interferon alfa-2b (PegIntron) (1.5 mcg/kg) on day -1 (one day before start of HCV-796 or placebo) and day 7. No patients received ribavirin. Each cohort receiving HCV-796 plus PegIntron enrolled 9-12 patients. Overall, the mean baseline HCV RNA level was 6.4 log10, and 66% of patients were infected with HCV genotype 1.

Results

At day 14, the mean reduction in HCV RNA ranged from 3.3-3.5 log10 in the combination therapy groups compared with 1.6 log10 in the PegIntron monotherapy 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 with PegIntron monotherapy.

For patients with non-1 genotypes, 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 virological response in the HCV-796 100 mg combination group compared with higher-dose groups.

However, analyses of individual virological response in the combination therapy groups did not reveal correlations with individual HCV-796 pharmacokinetic parameters (Cmax, AUC, or Cmin) across the range of doses tested.

At HCV-796 doses of 250 mg or higher, combination with PegIntron resulted in 33%-67% of genotype 1 patients with reductions from baseline > 3 log10 on day 14 (13%-17% below 50 IU/mL).

Among patients with non-1 genotypes, 67%-100% had reductions > 3 log10 on day 14 (50%-75% below 50 IU/mL).

There were no apparent differences in virological response in the combination therapy groups when analyzed by patient age, race, sex, or baseline HCV RNA level.

Conclusion

In conclusion, the authors wrote, “The combination of HCV-796 and [PegIntron] 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 [every 12 hours] or higher when combined with [PegIntron]. Clinical studies of more long-term administration of combination therapy are in progress to determine if these effects are durable.”

05/22/07