SUMMARY: 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.

By Liz Highleyman

Edward 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.

Ritonavir, developed 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.

Results

	More 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 danoprevir:
	Danoprevir/ritonavir 100/100 mg twice-daily: 67% (6 of 9); Danoprevir/ritonavir 200/100 mg once-daily: 50% (4 of 8); Danoprevir/ritonavir 200/100 mg twice-daily: 100% (8 of 8); Unboosted danoprevir 900 mg twice-daily: 14% (1 of 7); Placebo/ritonavir: 20% (1 of 5). 20% (1 of 5).
	Mean 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).
	No participants in any arm experienced viral load rebound during treatment.
	Danoprevir/ritonavir was generally safe and well-tolerated, and no participants discontinued due to adverse events.
	Overall rates of side effects were similar in patients taking danoprevir/ritonavir and the standard-of-care regimen alone.
	Adverse event rates varied considerably across the different danoprevir/ritonavir arms without a clear dose effect.
	Skin rash and eye pain appeared to be reported more often in the danoprevir/ritonavir arms than in the placebo arm.
	Boosted 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."

"These results indicate that further exploration of ritonavir boosting on the safety and efficacy of RG7227 is warranted," they continued.

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 ritonavir-boosted danoprevir."

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, CA.

4/20/10

Reference

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 38.

JO 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. Abstract 753.

Other Sources

InterMune, Inc. InterMune Reports Virologic Response of Ritonavir-Boosted Danoprevir (RG7227/ITMN-191) in Patients with Chronic Hepatitis C. Press release. April 15, 2010.