Protease Inhibitor Danoprevir (RG7227/ITMN-191) Shows Antiviral
Activity at Lower Doses When Boosted with Ritonavir
Roche and InterMune's investigational hepatitis C virus
(HCV) NS3/4A protease inhibitor danoprevir
(formerly known as RG7227 and ITMN-191) was effective
at lower doses when boosted with ritonavir (Norvir),
according to research presented last week at the 45th
Annual Meeting of the European Association for the Study
of the Liver (EASL 2010)
in Vienna. Danoprevir/ritonavir was generally well-tolerated
and demonstrated favorable antiviral activity in combination
with pegylated interferon plus ribavirin.
Gane from the University of Auckland in New Zealand and colleagues
evaluated the safety, tolerability, antiviral activity, and pharmacokinetics
of once-daily and twice-daily ritonavir-boosted danoprevir in
combination with pegylated interferon plus ribavirin for previously
untreated patients with genotype 1 chronic hepatitis C.
as an HIV protease inhibitor, is a strong inhibitor of the CYP3A
enzyme, which metabolizes many drugs in the liver. Adding a small
amount of ritonavir slows processing of other these drugs, allowing
them to reach higher concentrations in the body.
Laboratory studies and a small Phase 1 clinical trial in healthy
HCV negative volunteers showed that adding a low dose of ritonavir
resulted in increases in danoprevir trough concentration (lowest
level between doses), while only minimally raising area under
the curve (AUC; total concentration over time between one dose
and the next) and maximum concentration (Cmax).
The present study was a double-blind, placebo-controlled, Phase
1b multiple-ascending dose trail that included 30 treatment-naive
patients with HCV genotype 1.
Participants were randomly assigned to receive danoprevir/ritonavir
or placebo/ritonavir in combination with a standard-of-care pegylated
interferon alfa-2a (Pegasys) plus ribavirin regimen for 15
days. Danoprevir/ritonavir was tested at doses of 100/100 mg twice-daily,
200/100 mg once-daily, and 200/100 mg twice-daily. Outcomes were
compared with those from a previous study that tested a maximum
dose of 900 mg twice-daily unboosted danoprevir.
patients using boosted danoprevir achieved undetectable HCV
viral load (< 15 IU/mL) at day 15 compared with those in
the placebo arm and those who previously used high-dose unboosted
100/100 mg twice-daily: 67% (6 of 9);
200/100 mg once-daily: 50% (4 of 8);
200/100 mg twice-daily: 100% (8 of 8);
danoprevir 900 mg twice-daily: 14% (1 of 7);
20% (1 of 5). 20% (1 of 5).
decreases in HCV viral load were similar in all danoprevir-containing
arms (-5.1, -4.8, -4.6, and -5.3 log IU/mL, respectively),
but larger compared with the placebo arm (-2.7 log IU/mL).
participants in any arm experienced viral load rebound during
was generally safe and well-tolerated, and no participants
discontinued due to adverse events.
rates of side effects were similar in patients taking danoprevir/ritonavir
and the standard-of-care regimen alone.
event rates varied considerably across the different danoprevir/ritonavir
arms without a clear dose effect.
rash and eye pain appeared to be reported more often in the
danoprevir/ritonavir arms than in the placebo arm.
danoprevir AUC was 4- to 16-fold lower than previously observed
for 900 mg twice-daily unboosted danoprevir, and Cmax was
7- to 23-fold lower.
Based on these findings, the investigators concluded, "Relative
to unboosted 900 mg [twice-daily], ritonavir boosting of low dose
RG7227 [danoprevir] provides robust and sustained virologic response
at significantly lower AUC and Cmax, parameters which are often
correlated with safety."
results indicate that further exploration of ritonavir boosting
on the safety and efficacy of RG7227 is warranted," they
Given these promising findings, developers added 2 additional
cohorts of prior complete non-responders to pegylated interferon/ribavirin
who will be re-treated with danoprevir/ritonavir plus the standard-of-care
regimen for 12 weeks; the first patient in the amended protocol
enrolled in late March.
"The results from this study indicate that robust viral kinetics
in treatment-naive patients can be achieved by ritonavir boosting
of very low doses of danoprevir," Dr. Gane said in a press
release issued by InterMune. "We look forward to the results
of the two 12-week cohorts in prior [standard-of-care] null responders
recently added to this study which will provide further insights
into the antiviral efficacy and safety profile of low doses of
Auckland Clinical Studies, Auckland, New Zealand; Centre CAP,
Montpellier, France; Christchurch Clinical Studies Trust, Christchurch,
New Zealand; Department of Hepatology and Immunodeficiencies,
Warsaw Medical University, Warsaw, Poland; Warsaw Medical University
& Hospital of Infectious Diseases, Warsaw, Poland; Roche,
South San Francisco, CA; Roche, Nutley, NJ; Roche, Palo Alto,
E Gane, R Rouzier, C Stedman, and others. Ritonavir boosting of
low dose RG7227/ITMN-191, HCV NS3/4A protease inhibitor, results
in robust reduction in HCV RNA at lower exposures than provided
by unboosted regimens. 45th Annual Meeting of the European Association
for the Study of the Liver (EASL 2010). Vienna, Austria. April
14-18, 2010. Abstract
Haznedar, J Fretland, G Leong, and others. Impact of low dose
ritonavir boosting on the pharmacokinetics of RG7227 (ITMN-191),
a highly potent and selective inhibitor of the HCV NS3/4A protease.
45th Annual Meeting of the European Association for the Study
of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010.
Inc. InterMune Reports Virologic Response of Ritonavir-Boosted
Danoprevir (RG7227/ITMN-191) in Patients with Chronic Hepatitis
release. April 15, 2010.