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.
Results
 |
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.
4/27/10
Reference
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.
