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.
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.
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
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
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
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.
participants (65%) receiving RG7128 achieved SVR, or continued
undetectable HCV RNA 24 weeks after completion of treatment,
compared with 60% in the placebo arm.
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.
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.
of patients with HCV genotype 2 and 67% with genotype 3
achieved SVR with RG7128, not a significant difference.
of prior non-responders and 70% of relapsers in the RG7128
arm achieved SVR, again not a significant difference.
treatment-emergent genotypic mutations conferring resistance
to RG7128 were identified during the study.
results suggest that the nucleoside RG7128/standard-of-care
is effective in retreatment of HCV genotype 2/3 relapsers/non-responders,"
the investigators concluded.
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."
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
Pharmasset, Inc. Pharmasset to Present New Data on RG7128 and
PSI-7977 at the EASL Conference. Press release. April 13, 2010.