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HIV and Coverage of the
45th Annual Meeting of the European
Association for the Study of the Liver (EASL 2010)

April 14 - 18, 2010, Vienna, Austria
Experimental HCV Polymerase Inhibitor RG7128 Is Effective with Standard Therapy in Genotype 2/3 Patients

SUMMARY: The investigational nucleoside analog hepatitis C virus (HCV) polymerase inhibitor RG7128, used in combination with pegylated interferon plus ribavirin, increased sustained virological response (SVR) rates among genotype 2 and 3 chronic hepatitis C patients who did not respond to a prior course of standard therapy, according to a small study presented at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010) this month in Vienna.

By Liz Highleyman

RG7128, being developed jointly by Roche and Pharmasset, has previously demonstrated favorable safety and efficacy in people with hard-to-treat HCV genotype 1, both in combination with standard therapy and as part of an all-oral regimen with the experimental HCV protease inhibitor RG7227.

Ed Gane from the University of Auckland in New Zealand and colleagues evaluated the performance of RG7128 in people with HCV genotypes 2 or 3, who make up about 25% of individuals with chronic hepatitis C in the U.S., about 30% in Europe, and more than 45% in Australia-Asia.

These genotypes typically respond better to an initial course of interferon-based therapy than genotype 1 (i.e., SVR rates as high as 80% for genotype 2 and 70% for genotype 3). But non-responders have a low rate of response to retreatment with pegylated interferon/ribavirin (20%-35% in prior studies) and may benefit from adding directly-targeted anti-HCV agents.

The study included 10 participants (40%) with HCV genotype 2 and 15 (60%) with genotype 3 who did not achieve SVR with at least 1 prior course of interferon-based therapy; 10 were prior non-responders -- including 2 with documented null response -- and 10 were relapsers. About 70% were men, the median age was about 50 years, about 60% were white, and about one-quarter were Hispanic. At baseline, 80% had liver fibrosis stage 3 or lower; people with cirrhosis were excluded.

A total of 20 patients were randomly assigned to receive 1500 mg RG7128 twice-daily plus pegylated interferon alfa-2a (Pegasys) and ribavirin for 28 days, followed by pegylated interferon/ribavirin alone for an additional 20-44 weeks (duration based on type of prior response and rapid response at week 4 of retreatment), while the remainder received placebo plus standard therapy; by chance, all 5 participants assigned to the placebo group were relapsers.


The average decrease in HCV RNA at week 4 was 5 log in the RG7128/standard-of-care arm compared with 3.7 log in the placebo/standard-of-care arm.
19 of 20 participants (95%) receiving RG7128 achieved rapid virological response (RVR), or undetectable HCV viral load (< 15 IU/mL) after 4 weeks of therapy, compared with 60% in the placebo arm.
13 participants (65%) receiving RG7128 achieved SVR, or continued undetectable HCV RNA 24 weeks after completion of treatment, compared with 60% in the placebo arm.
RVR was a strong predictor of SVR: 68% of patients in the RG7128 arm who achieved RVR -- but none of those without RVR -- went on to achieve sustained response.
90% of patients who took RG7128 with pegylated interferon/ribavirin for 48 weeks achieved SVR, compared with 67% of those treated for 24 weeks (the standard duration of therapy for genotypes 2/3) and none who discontinued therapy before 24 weeks.
63% of patients with HCV genotype 2 and 67% with genotype 3 achieved SVR with RG7128, not a significant difference.
60% of prior non-responders and 70% of relapsers in the RG7128 arm achieved SVR, again not a significant difference.
No treatment-emergent genotypic mutations conferring resistance to RG7128 were identified during the study.

"These results suggest that the nucleoside RG7128/standard-of-care is effective in retreatment of HCV genotype 2/3 relapsers/non-responders," the investigators concluded.

"This triple combination therapy may provide an attractive option for retreatment of genotype 2/3 patients with prior non-response to standard-of-care," they added. "Larger studies are required to confirm these findings, determine optimal duration, and evaluate utility in treatment-naive genotype 2/3 patients."

They further indicated that "RG7128 has preserved potency across viral genotypes due to the consistent mechanism of action of chain-terminating nucleoside analogs," unlike agents that specifically interfere with HCV enzymes such as protease, which can vary across genotypes.

University of Auckland, Auckland, New Zealand; Fundacion de Investigacion de Diego Santurce, Puerto Rico; Ponce School of Medicine, Santurce, Puerto Rico; University of Florida, Gainesville, FL; Weill Cornell Medical College, New York, NY; Duke Clinical Research Institute, Duke University, Durham, NC; Pharmasset Inc, Princeton, NJ; Roche Palo Alto LLC, Palo Alto, CA.


E Gane, M Rodriguez-Torres, DE Nelson, and others. Sustained virologic response (SVR) following RG7128 1500mg BID/peg-IFN/RBV for 28 days in HCV genotype 2/3 prior non-responders. 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010. (Abstract 37).

Other Source
Pharmasset, Inc. Pharmasset to Present New Data on RG7128 and PSI-7977 at the EASL Conference. Press release. April 13, 2010.