icon-folder.gif   Conference Reports for NATAP  
  59th Annual Meeting of the American Association
for the Study of Liver Diseases
Oct 31-Nov 1 2008
San Francisco, CA
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Antiviral Activity Of The HCV Nucleoside Polymerase Inhibitor R7128 In HCV Genotype 2 and 3 Prior Non-Responders: Results Of R7128 1500mg BID With PEG-IFN And Ribavirin For 28 Days
  Reported by Jules Levin
AASLD Nov 3 San Francisco, CA
Gane, Edward J1; Rodriguez-Torres, Maribel2; Nelson, David R3; Jacobson, Ira M4; McHutchison, John G5; Jeffers, Lennox6;
Beard, Amanda7; Walker, Sue7; Shulman, Nancy8; Symonds, William7; Albanis, Efsevia7; Berrey, M. Michelle7
1. Auckland Clinical Studies Limited, Auckland, New Zealand, 2. Fundacion de Investigacion de Diego, Santurce, PR, USA., 3. University of Florida, Gainesville, FL, USA., 4. Weill Cornell Medical College, New York, NY, USA., 5. Duke Clinical Research Institute, Durham, NC, USA., 6. University of Miami, Miami, FL, USA., 7. Pharmasset, Inc., Princeton, NJ, USA., 8. Roche, Palo Alto, CA, USA.
A mean 5.0 log10 decline in plasma HCV RNA was demonstrated following 28 days of combination therapy with R7128+SOC in HCV Genotype 2 or 3 infected subjects
Compared to prior treatment responses, R7128 provided additional antiviral activity in these subjects
R7128 was generally well-tolerated and demonstrated no evidence of acute target organ toxicity
Serum ALT levels normalized during R7128 therapy in 54% of subjects with elevated ALT at baseline
Pharmacokinetic data demonstrate that the 'new' formulation results in slightly higher plasma exposures compared to the previous formulation
R7128 has provided positive proof-of-concept that a direct acting antiviral can deliver additional antiviral potency in an HCV genotype 2 or 3 treatment failure population with an RVR of 90%. Longer term data is needed to determine adequate length of treatment in this population
As predicted by in vitro data, R7128 demonstrated similar potency against HCV GT 2 or 3 compared to a previous study of R7128 against GT1 HCV
The absence of virologic breakthrough reinforces the implications from monotherapy studies that nucleoside polymerase inhibitors have a high genetic barrier to resistance
The safety and efficacy of this combination study support further development of R7128 in combination with the standard of care (pegylated interferon and ribavirin) in this difficult to treat, HCV genotype 2/3 non-responder population and provides appropriate potency and safety to progress to Phase 2b studies to explore optimal treatment duration in HCV genotype 2 or 3 treatment-naïve patients
Background: Historically, HCV genotype (GT) 2 and 3 prior non-responders have demonstrated poor response rates to re-treatment with PEG-IFN/RBV (SOC). No direct-acting antiviral agent in development has shown significant activity in individuals infected with HCV GT 2/3. R7128 is a potent nucleoside analog inhibitor of HCV polymerase, with activity against HCV GT 2/3 in vitro. When administered at doses of 1000-1500mg BID in combination with SOC for 28 days in treatment-naïve, HCV+ GT 1 patients, R7128 delivered an 85-88% rapid virologic response (RVR). This study was designed to evaluate R7128 with 180µg PEG-IFN and 1000-1200mg RBV for 28 days in patients with HCV GT 2 or 3.
Methods: 25 patients (20 active/5 placebo) with genotype 2 (n=10) or genotype 3 (n=15) who had not previously achieved a sustained virologic response (SVR) with interferon-based therapy were enrolled. Patients received R7128 1500mg BID or placebo along with PEG-IFN/RBV for 28 days, followed by PEG-IFN/RBV alone for a minimum of 20 weeks. All patients were non-cirrhotic and all had been previously treated with at least 12 weeks of interferon-based therapy.
Results: Preliminary data are available for all 25 patients through Day 56. Plasma HCV RNA in patients receiving R7128 1500mg BID decreased 5.0 log10 IU/mL from baseline at Week 4 compared to 4.3 log10 IU/mL from baseline in the placebo with PEG-IFN/RBV group. An RVR was achieved in 90% of the R7128 treated group compared to 60% in the placebo+SOC group. Responses were similar for HCV GT 2 and 3. Specific prior treatment response data are available for all 25 subjects: 10 patients were non-responders and 15 were relapsers. No serious adverse events have been reported in this cohort. AEs were similar in prevalence and severity to those previously reported with SOC. Safety laboratory assessments revealed no trends in grade 3-4 changes in hematocrit/hemoglobin, absolute neutrophil count, or platelets, nor clinically significant changes in other safety laboratory parameters or vital signs.
Conclusions: These preliminary results suggest that R7128 1500mg BID combined with PEG-IFN/RBV in prior HCV genotype 2/3 non-responders provides a high rate of RVR (90%), similar to R7128+SOC in GT 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-naïve and non-responsive genotype 2/3 patients with
Study Design
R7128 1500mg BID was administered in combination with PEG-IFN/RBV (Pegasys® & Copegus®, SOC) for 28 days to 20 subjects infected with HCV genotype (GT) 2 or 3
5 subjects received a matching R7128 placebo + SOC
Subjects had previously failed an interferon-containing regimen with ribavirin due to nonresponse or relapse.
R7128 was administered as a new formulation, which was expected to yield slightly higher plasma drug exposures compared to the previous formulation
Safety Assessments
Physical exam, vital signs, clinical laboratory tests, electrocardiograms (ECGs), and adverse event (AE) assessments were performed throughout the study
Due to the limited number of placebo subjects in this cohort of HCV GT 2-3, a placebo group with subjects from all 4 cohorts of this study is included for comparison of AEs
Pharmacokinetic and Pharmacodynamic Assessments
Full PK profiles were obtained on Day 1 and Day 28
Samples for plasma HCV RNA analysis by Roche Cobas TaqMan (limit of detection <15 IU/mL) and resistance monitoring samples were collected throughout the study


Demographics and Clinical Safety
Demographics were similar across the groups as summarized in Table 2
No serious adverse events were reported in this cohort. One subject discontinued R7128 due to protocol specified stopping criteria (not treatment-emergent) and SOC due to ECG changes
The most commonly reported AEs are summarized in Table 3; a majority were mild in grade
No trends in laboratory abnormalities were noted.
Of those receiving R7128 or placebo with abnormal ALT at baseline, 54% and 80% normalized by Day 28
There were no clinically significant changes noted in the vital sign parameters across the treatment groups
With the exception noted above, no other clinically significant changes were reported for serial ECGs, including QTc prolongation beyond 500ms



Antiviral Activity
90% RVR was demonstrated in this cohort of treatment failure HCV GT 2 or 3 patients with R7128+SOC (Figures 1 and 2)
Prior treatment response had no impact upon R7128+SOC response, RVR was 60% in SOC prior relapsers
The antiviral activity observed with R7128+SOC was maintained across genotype 2 and 3; and consistent with in vitro data (Table 1)
Compared to prior therapy, the addition of R7128 resulted in a more rapid decline in plasma HCV RNA, based upon those subjects with available prior treatment histories (Figures 3-6)
HCV RNA values in the SOC alone group declined with a -3.7 log10 change from baseline compared to -5.0 in the R7128 cohort