HCV Polymerase Inhibitor RG7128 plus Protease Inhibitor
RG7227 (ITMN-191) Suppresses HCV Viral Load without Interferon
Combination hepatitis C treatment using the nucleoside
analog hepatitis C virus (HCV) polymerase inhibitor
(formerly R7128) plus the HCV NS3/4A protease
(formerly R7227, also known as ITMN-191) produced
potent antiviral activity in a 2 week study, researchers
reported this month at the 60th Annual Meeting
of the American Association for the Study of Liver
Diseases (AASLD 2009) in Boston. If confirmed
in larger studies, these findings from the INFORM-1
trial -- the first to test an all-oral combination
anti-HCV regimen -- suggest that effective treatment
may be possible without interferon or ribavirin.
therapy consisting of pegylated
interferon plus ribavirin is the current standard of
care for chronic hepatitis
C, but there is a need for treatments that are more
effective, easier to administer (oral rather than injected),
and have fewer side effects.
INFORM-1 trial -- conducted by Roche in collaborations with
InterMune and Pharmasset -- tested a combination regimen
consisting of 2 directly targeted oral anti-HCV agents without
interferon or ribavirin. As with antiretroviral therapy
for HIV, combining agents targeting multiple steps of the
viral lifecycle may offer greater potency and reduce the
emergence of drug resistance.
this Phase 1 double-blind, ascending-dose trial, 64 adults
with genotype 1 chronic hepatitis C were randomly assigned
(8 per cohort) to receive various combinations of RG7128
and RG7227 (or placebo) for up to 14 days. Some participants
were treatment-naive and others were treatment experienced,
including some who had a null response to previous interferon-based
therapy (HCV RNA decrease <1 log10 in 4 weeks or <2
log10 in 12 weeks).
first 2 study cohorts received low-dose monotherapy with
either 500 mg RG7128 twice-daily or 100 mg RG7227 3-times-daily
on days 1-3. Both cohorts then received a combination of
both drugs on days 4-7. Next, additional cohorts received
escalating doses of RG7128 (500 or 1000 mg twice-daily)
plus RG7227 (600 or 900 mg twice-daily, or 100 or 200 mg
3-times-dialy) for 14 days.
of the participants took pegylated interferon or ribavirin
during RG7128/RG7227 dosing, but did received standard of
care therapy using pegylated
interferon alfa-2a (Pegasys) plus ribavirin after the
initial 2-week dosing period.
results presented at the AASLD meeting focused on the final
3 cohorts, consisting of patients who received the higher-dose
twice-daily regimens. Data from the initial lower-dose cohorts
reported at the European Association for the Study of
the Liver (EASL) meeting this past April.
patients receiving twice-daily RG7128/RG7227 regimens
experienced a continual decline in HCV RNA during the
study period, with viral decline showing a biphasic
highest response rate at day 13 -- 88% with viral load
below the lower limit of quantification (LLOQ, <43
IU/mL) and 63% below the lower limit of detection (LLOD,
<15 IU/mL) -- was seen in treatment-naive patients
receiving 1000 mg RG7128 plus 900 mg RG7227 twice-daily.
previous null responders receiving the same doses, the
corresponding response rates were 50% below LLOQ and
25% below LLOD.
the 1000/900 mg dose cohorts, HCV RNA fell by a median
-5.1 log10 IU/mL for treatment-naive participants and
-4.9 log10 for prior null responders.
who received the lower 600 mg dose of RG7227 plus 1000
mg RG7128 had lower response rates, 50% below LLOQ and
13% below LLOD.
there were also no significant differences between twice-daily
and 3-times-daily dosing.
with HCV genotype 1a and 1b also responded similarly.
patient who received a lower dose (500/200 mg) of RG7128/RG7227
experienced viral rebound, but had no identified resistance
mutations and went on to achieve undetectable viral
load on standard-of-care therapy.
RG7128/RG7227 combination was generally well-tolerated.
treatment-related serious adverse events, dose modifications,
or drug discontinuations were reported.
most commonly reported adverse events were headache,
nausea, and diarrhea, which occurred with a frequency
similar to that seen in the lower-dose cohorts.
emergent resistance to RG7128 or RG7227 was observed
during the study period.
on these findings, the researchers concluded that the combination
of RG7128 and RG7227 for up to 14 days "provided significant
antiviral potency in treatment-naive and experienced patients,
sustained viral reductions, and appears safe and well-tolerated
as a twice-daily oral regimen."
results from this study of the RG7227/RG7128 combination
raise hopes that we can deliver an interferon-free regimen
for our patients in the future," said lead investigator
Edward Gane, MD, in a press release issued by InterMune.
"Current HCV therapy includes up to 12 months of weekly
interferon injections which can be associated with significant
side effects. In addition, not all patients can take interferon
due to intolerance or contraindications. We look forward
to the results of additional studies with these potent compounds."
collaborating companies announced that Roche will initiate
a Phase 2 trial program in the first quarter of 2010. INFORM-2
will assess rapid virological response (undetectable HCV
RNA after 4 weeks of therapy) in prior non-responder genotype
1 patients receiving twice-daily RG7128/RG7227 alone and
in combination with pegylated interferon alfa-2a, ribavirin,
or both. Longer-term studies evaluating sustained virological
response (undetectable HCV RNA 24 weeks after completing
therapy) are anticipated for the first half of 2010.
Palo Alto, CA; Intermune, Brisbane, CA; Pharmasset, Princeton,
NJ; Auckland Clinical Studies, Auckland, New Zealand; The
Alfred, Melbourne, Victoria, Australia; Christchurch Clinical
Studies, Christchurch, New Zealand; Austin Hospital, Heidelberg,
Victoria, Australia; Royal Adelaide Hospital, Adelaide,
EJ Gane, SK Roberts, CA Stedman, and others. Combination
Therapy with a Nucleoside Polymerase (R7128) and Protease
(R7227/ITMN-191) Inhibitor in HCV: Safety, Pharmacokinetics,
and Virologic Results from INFORM-1. 60th Annual Meeting
of the American Association for the Study of Liver Diseases
(AASLD 2009). Boston. October 30-November 1, 2009. Abstract
Le Pogam, M Chhabra, S Ali, and others. Combination Therapy
with Nucleoside Polymerase R7128 and Protease R7227/ITMN-191
Inhibitors in Genotype 1 HCV Infected Patients: Interim
Resistance Analysis of INFORM-1 Cohorts A-D. 60th Annual
Meeting of the American Association for the Study of Liver
Diseases (AASLD 2009). Boston. October 30-November 1, 2009.
Morcos, R Kulkarni, D Ipe, and others. Pharmacokinetics/Pharmacodynamics
(PK/PD) of Combination R7227 and R7128 Therapy from INFORM-1
Demonstrates Similar Early HCV Viral Dynamics when R7227
is Combined with either PEG-IFN/Ribavirin (SOC) or R7128.
60th Annual Meeting of the American Association for the
Study of Liver Diseases (AASLD 2009). Boston. October 30-November
1, 2009. Abstract 1594.
Results: Robust Antiviral Suppression Achieved with Combination
of Nucleoside Analog Polymerase Inhibitor RG7128 and Protease
Inhibitor RG7227. Press release. November 3, 2009.
Study: HCV Protease R7227+HCV Nucleoside R7128; Twice Daily
Oral Medication Shows Promise in Treating Patients with
Hepatitis C. Press release. November 2, 2009.