By Liz Highleyman

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.

Based on these preliminary results, the investigators suggested that "R7128 1500 mg [twice-daily] combined with [pegylated interferon/ribavirin] in prior HCV genotype 2/3 non-responders provides a high rate of RVR (> 86%), similar to R7128 + [standard of care] in genotype 1 non-responders, with an acceptable side-effect profile."

"These high response rates in a difficult-to-treat patient population suggest that combination therapy featuring R7128 deserves further exploration in both treatment-naive and non-responsive genotype 2/3 patients with HCV," they concluded.

Race/ethnicity and Weight

In a related study, investigators performed a sub-analysis of 2 cohorts (n = 25 each) of genotype 1 patients in the same study, looking at differences in response according to race/ethnicity and weight. Cohort 1 received 500 mg twice-daily R7128 or placebo while Cohort 2 received 1500 mg twice-daily R7128 or placebo, all with plus pegylated interferon/ribavirin.

Among the 50 subjects randomized into these 2 cohorts, 48% were white, 24% were Latino, 16% were African-American, and 8% were classified as "other." 54% of whites, 33% of Latinos, 38% of African-Americans, and 75% of "other" patients weighed > 85 kg. Proportions with body mass index (BMI) > 30 were 15%, 42%, 25%, and 25%, respectively.

Results

• 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.

Based on these findings, the investigators concluded, "R7128 administered in combination with [pegylated interferon + ribavirin] for 28 days demonstrated clinically significant antiviral potency regardless of race/ethnicity, with a numerical improvement in RVR rates in Latino patients who received R7128 1500 mg [twice-daily]."

Auckland Clinical Studies Limited, Auckland, New Zealand; Fundacion de Investigacion d Diego, Santurce, Puerto Rico; University of Florida, Gainesville, FL; Weill Cornell Medical College, New York, NY; Duke Clinical Research Institute, Durham, NC; University of Miami, Miami, FL; Quest Clinical Research, San Francisco, CA; Orlando Immunology Center, Orlando, FL; University of Colorado, , Aurora, CO; University of Pennsylvania, Philadelphia, PA; Pharmasset, Inc., Princeton, NJ; Roche, Palo Alto, CA.

11/14/08

References

EJ Gane, M Rodriguez-Torres, DR Nelson, and others. Antiviral Activity of the HCV Nucleoside Polymerase Inhibitor R7128 In HCV Genotype 2 and 3 Prior Non-Responders: Interim Results of R7128 1500mg BID with PEG-IFN and Ribavirin For 28 Days. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract LB10.

M Rodriguez-Torres; J Lalezari, EJ Gane, and others. Potent Antiviral Response to the HCV Nucleoside Polymerase Inhibitor R7128 for 28 Days With Peg-IFN and Ribavirin: Subanalysis by Race/Ethnicity, Weight and HCV Genotype. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1899.