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."
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.
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.
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.
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
"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.
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
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.
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.
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]."
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.
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.
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.