Session Title: Parallel Session:
HEPATITIS C: DRUG DEVELOPMENT
Presentation Date: Apr 15, 2010
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
E. Gane1, R. Rouzier2, C. Stedman3, A. Wiercinska-Drapalo4, A. Horban4, L. Chang5, Y. Zhang5, P. Sampeur6, I. Najera7, N. Shulman7, P. Smith5, J. Tran5
1Auckland Clinical Studies, Auckland, New Zealand, 2Centre CAP, Montpellier, France, 3Christchurch Clinical Studies Trust, Christchurch, New Zealand, 4Department of Hepatology and Immunodeficiencies, Warsaw Medical University, 5Warsaw Medical University & Hospital of Infectious Diseases, Warsaw, Poland, 6Roche, South San Francisco, CA, 7Roche, Nutley, NJ, 8Roche, Palo Alto, CA, USA. *email@example.com
Background: Co-administration of low dose ritonavir resulted in larger increases in RG7227 trough concentration than area under the curve (AUC) and marginal increase in maximum concentration (Cmax), offering the opportunity to reduce the dose and/or dosing frequency of RG7227 in future Phase 2 studies. The present study evaluated the safety, tolerability, antiviral activity and pharmacokinetics (PK) of once-daily (QD) and twice-daily (BID) ritonavir boosted RG7227 (RG7227/r) in combination with standard of care (SOC) in treatment-naïve HCV genotype 1 patients.
Material & methods: In a double-blind, placebo-controlled, Phase 1b multiple-ascending dose (MAD) study, treatment-naïve HCV genotype 1 patients were randomized to receive RG7227/r or placebo/r plus SOC for 15 days. RG7227/r regimens were 100/100mg BID (Cohort 1), 200/100mg QD (Cohort 2), and 200/100mg BID (Cohort 3). Blood samples for HCV RNA, PK, and resistance monitoring were collected at baseline and throughout the study.
Results: Cohort 1 and 2 provided blinded data for this abstract. The following table summarizes virologic response of RG7227/r compared to un-boosted 900 mg BID, the highest dose evaluated in a previous MAD study (placebo/r data are not shown due to small N of 2):
[Summary of Virologic Response]
| || ||HCV RNA Log10 (IU/mL), Median ||Below Limit of Quantification* n (%) ||Undetectable** n (%) || |
|RG7227/r + SOC Regimen ||N ||Baseline ||Change from Baseline (Day 15) ||Day 9 ||Day 15 ||Day 9 ||Day 15 ||Viral Load Rebound n (%) |
|100/100mg BID ||9 ||6.51 ||-5.13 ||7 (78%) ||7 (78%) ||6 (67%) ||6 (67%) ||0 (0%) |
|200/100mg QD ||6 ||6.29 ||-4.80 ||3 (50%) ||4 (67%) ||2 (33%) ||3 (50%) ||0 (0%) |
|Un-boosted 900mg BID (historical) ||7 ||6.99 ||-5.29 ||2 (29%) ||4 (57%) ||1 (14%) ||1 (14%) ||0 (0%) |
|* < 40 IU/mL for this study, < 25 IU/mL for historical ** < 15 IU/mL for this study, < 9.3 IU/mL for historical |
RG7227/r AUC and Cmax were approximately 6- to 9-fold and 4- to 10-fold lower, respectively, than previously observed for 900 mg BID un-boosted. Inter-patient PK variability for RG7227/r was also lower than historical un-boosted RG7227. RG7227/r and placebo/r plus SOC were generally well tolerated. Complete data for all 3 cohorts will be presented.
Conclusion: Relative to un-boosted 900 mg BID, ritonavir boosting of low dose RG7227 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.