HCV Polymerase Inhibitor R7128 Demonstrates Good Antiviral Activity in Genotype 2 or 3 Prior Non-responders and Relapsers

Given the suboptimal efficacy, side effects, and cost of interferon-based therapy for chronic hepatitis C virus (HCV) infection, investigators have explored several novel drugs that directly target various stages of the viral lifecycle -- an approach called "STAT-C."

In a late-breaker presentation at the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) last week in San Francisco, researchers reported the data on one such agent, Roche and Pharmasset's HCV polymerase inhibitor R7128, in prior non-responders with HCV genotypes 2 or 3. This represents one cohort in a larger study that also included genotype 1 patients.

While individuals with genotype 2 or 3 respond more favorably to therapy than those with genotype 1, patients who fail to respond to a prior course of interferon-based therapy have poor response rates when re-treated with the current standard of care, pegylated interferon plus ribavirin. Investigational STAT-C agents have often been tested in non-responders, but usually those with genotype 1.

Preclinical studies showed that R7128 (a prodrug of PSI-6130) demonstrated activity against genotype 2/3 HCV in vitro, the investigators noted as background. When administered at doses of 1000 to 1500 mg twice-daily in combination with standard of care for 28 days in treatment-naive genotype 1 patients, 85%-88% achieved rapid virological response (RVR), or undetectable HCV RNA at week 4 of therapy.

The present study included 25 non-cirrhotic patients with HCV genotype 2 (n = 10) or 3 (n = 15) who failed to achieve sustained virological response (SVR) after previous interferon-based therapy lasting at least 12 weeks; half were primary non-responders and half were relapsers. Most (60%) were men, 40% were white, 40% were Hispanic, and the mean age was 53 years. The median baseline HCV RNA level was about 6 log10 IU/mL.

Participants were randomly assigned to receive 1500 mg twice-daily R7128 (n = 20) or placebo (n = 5), administered with 180 mcg/week pegylated interferon + 1000-1200 mg/day weight-adjusted ribavirin for 28 days, followed by pegylated interferon + ribavirin alone for a minimum of 20 weeks.

Results

• At week 4, 90% of patients receiving R7128 achieved RVR (HCV RNA < 15 IU/mL), compared with 60% of those receiving placebo.

• The mean decrease in HCV RNA was 5.0 log10 IU/mL in the R7128 arm compared with 3.7 log10 IU/mL in the placebo arm.

• Responses were similar for patients with genotype 2 and genotype 3.

• R7128 was well tolerated overall.

• No serious adverse events (AEs) were reported and there were no discontinuations due to AEs.

• AEs were similar in prevalence and severity to those previously reported with pegylated interferon + ribavirin alone.

• Laboratory safety assessments revealed no grade 3-4 changes in hematocrit, hemoglobin, absolute neutrophil count, or platelets, nor clinically significant changes in other laboratory parameters, vital signs, or ECGs

• Among participants receiving placebo + standard of care, only 1 white patient (10%) achieved RVR.

• Among patients in Cohort 1 receiving 500 mg R7128, RVR rates were 45% for whites, 25% for Latinos, 0% (0 of 3) for African-Americans, and 0% for "other."

• Among patients in Cohort 2 receiving 1500 mg R7128, the corresponding RVR rates were 90%, 86%, 50% (1 of 2), and 100% (1 or 1), respectively.

• Patient sex, weight, and BMI were not significant predictors of antiviral response.

• No serious adverse events (AEs) were reported, and no differences in AEs were noted according to race/ethnicity.