Mercidita T. Navarro

DAUPHINE: a randomized phase II study of danoprevir/ritonavir plus peginterferon alpha‐2a/ribavirin in HCV genotypes 1 or 4

Danoprevir is a hepatitis C virus (HCV) protease inhibitor with activity against genotypes (G)1/G4, which is maintained at lower doses by ritonavir‐boosting. We report results of a large, randomized, active‐controlled phase IIb study of ritonavir‐boosted danoprevir (danoprevir/r) plus peginterferon alpha‐2a/ribavirin (P/R) in treatment‐naive patients with HCV G1/4 infection.

Randomized controlled trial of danoprevir plus peginterferon alfa-2a and ribavirin in treatment-naïve patients with hepatitis C virus genotype 1 infection.

BACKGROUND & AIMS The combination of a hepatitis C virus (HCV) protease inhibitor, peginterferon, and ribavirin is the standard of care for patients with HCV genotype 1 infection. We report the efficacy and safety of response-guided therapy with danoprevir (a potent second-generation protease inhibitor), peginterferon alfa-2a (40 KD), and ribavirin in these patients. METHODS Treatment-naïve patients (N = 237) were randomly assigned to groups given 12 weeks of danoprevir (300 mg every 8 hours; 600 mg every 12 hours, and 900 mg every 12 hours) or placebo plus peginterferon alfa-2a and ribavirin, followed by peginterferon alfa-2a and ribavirin. Patients given danoprevir who had an extended rapid virologic response (eRVR4-20: HCV RNA <15 IU/mL during weeks 4-20) stopped therapy at week 24; those without an eRVR4-20 continued therapy to 48 weeks. Patients who were given placebo received 48 weeks of peginterferon alfa-2a and ribavirin. The primary efficacy end point was sustained virologic response (SVR: HCV RNA <15 IU/mL after 24 weeks without treatment). RESULTS Rates of SVR were higher among patients given danoprevir 300 mg (68%), 600 mg (85%), and 900 mg (76%) than placebo (42%) (95% confidence interval: 26%-59%). Seventy-nine percent of patients given danoprevir 600 mg had an eRVR4-20; among these, 96% had an SVR. Serious adverse events were reported in 7% to 8% of patients given danoprevir and 19% given placebo. Four patients given danoprevir (1 patient in the 600-mg group and 3 in the 900-mg group) had reversible, grade 4 increases in alanine aminotransferase, which led to early discontinuation of the 900-mg arm of the study. CONCLUSIONS The combination of danoprevir, peginterferon alfa-2a, and ribavirin leads to high rates of SVR in patients with HCV genotype 1 infection, but high doses of danoprevir can lead to grade 4 increases in alanine aminotransferase. Studies of lower doses of danoprevir with ritonavir, to reduce overall danoprevir exposure while maintaining potent antiviral activity, are underway; Clinicaltrials.gov number, NCT00963885.

1177 RAPID AND SUSTAINED ACHIEVEMENT OF UNDETECTABLE HCV RNA DURING TREATMENT WITH RITONAVIR-BOOSTED DANOPREVIR/PEG-IFNa-2A/RBV IN HCV GENOTYPE 1 OR 4 PATIENTS: DAUPHINE WEEK 12 INTERIM ANALYSIS

with some preliminary data indicating that at least one of the mutations in NS4B confers partial Legalon-SIL resistance in cell culture. Conclusion: Mutations selected during Legalon-SIL treatment in vivo and in cell culture primarily map to viral membrane attachment regions in NS3 and NS4B, arguing for a primary mode of action targeting RNA replication independent of inhibition of the viral polymerase. Further phenotypic analysis of the mutants will help to elucidate the mechanism of action of Silibinin.

Effect of meal and antisecretory agents on the pharmacokinetics of danoprevir/ritonavir in healthy volunteers.

To evaluate the effect of a low‐ and high‐fat meal and co‐administration of ranitidine or omeprazole on the pharmacokinetics of ritonavir‐boosted danoprevir (DNVr).

Two-way interaction study between ritonavir boosted danoprevir, a potent HCV protease inhibitor, and ketoconazole in healthy subjects.

BACKGROUND Danoprevir is a potent, highly selective, macrocyclic, orally bioavailable inhibitor of the hepatitis C virus protease, and a substrate of cytochrome P450 (CYP) 3A. It is co-administered with low-dose ritonavir, a potent CYP3A inhibitor, to enhance danoprevir pharmacokinetics. Ketoconazole is a substrate for and potent selective inhibitor of CYP3A. METHODS In this open-label, 3-period study, the 2-way interaction potential between ritonavir-boosted danoprevir (danoprevir/r) and ketoconazole was investigated in 18 healthy subjects. Subjects initially received ketoconazole 200 mg q24h for 4 days (Period 1) followed by a 7-day washout period. Danoprevir/r 100/100 mg q12h was then given for 10 days (Period 2) followed by a further 4 days of danoprevir/r 100/100 mg q12h plus ketoconazole 200 mg q24h (Period 3). Serial blood samples were collected for the determination of danoprevir, ritonavir and/or ketoconazole plasma concentrations, and calculation of pharmacokinetic parameters. Safety and tolerability were monitored throughout the study. RESULTS Co-administration of ketoconazole with danoprevir/r modestly increased the danoprevir AUCτ by 1.44-fold, with no effect on danoprevir Cmax. Co-administration of danoprevir/r with ketoconazole substantially increased ketoconazole AUCτ and Cmax by 3.71-fold and 1.73-fold, respectively. Danoprevir/r was well tolerated when administered alone or with ketoconazole. CONCLUSIONS These results indicate that the effect of potent CYP3A inhibitors, such as ketoconazole, on danoprevir/r pharmacokinetics is not likely to be clinically relevant.

Effect of Ritonavir‐Boosted Danoprevir, a Potent Hepatitis C Virus Protease Inhibitor, on the Pharmacokinetics of Methadone in Healthy Subjects Undergoing Methadone Maintenance Therapy

To investigate the steady‐state pharmacokinetics of methadone when coadministered with ritonavir‐boosted danoprevir (DNVr).

1192 HIGH SUSTAINED VIROLOGICAL RESPONSE RATES WITH RESPONSE-GUIDED DANOPREVIR PLUS PEGINTERFERON ALFA-2A (40KD) AND RIBAVIRIN IN TREATMENT-NAIVE, HCV GENOTYPE 1 PATIENTS: ATLAS STUDY FINAL RESULTS

1191 LOW RATE OF ON-TREATMENT RESISTANCE TO DANOPREVIR BOOSTED BY RITONAVIR (DNVR) COMBINED WITH PEG-IFNa-2A/RIBAVIRIN: 12 WEEK INTERIM ANALYSIS FROM DAUPHINE STUDY S. Le Pogam, M. Navarro, L. Bu, A. Voulgari, M. Illnicka, J.M. Yan, K. Klumpp, I. Najera. Virology Discovery, Hoffmann-La Roche, Nutley, NJ, Biostatistics, Genentech, South San Francisco, CA, USA; Biostatistics, Roche Pharma Development in Asia Pacific, Shanghai, China; Clinical Development, Roche Products Ltd, Welwyn, UK; Discovery Technologies, Hoffmann-La Roche, Nutley, NJ, USA E-mail: sophie.le_pogam@roche.com