2.7 million infected with chronic hepatitis C (CHC) in the United States

1. Ribavirin DAA Interferons Drug(s) Exposure-vs.- Response Predictors of Response HCV Clinical Trial Simulation Virus Genotype Unified Platform Infected Hepatocyte Literature Database Host Genotype Semi-mechanistic model (Snoeck, et. al) Pegasys,180 µg, GTP 1/4 Inception of an HCV Platform Model for IL-28B Genotype Treatment Duration Optimization and Cure Rate Maximization Pegasys, 180 ug Phyllis Chan, PhD Route 206 & Province Line Road P.O. Box 5400, Princeton, N.J. 08543-5400 phyllis.chan@bms.com 1Hui Min Chan, PhD, 1Xiaodong Wang, PhD, 2Nelson Jumbe, PhD, 2Russell Wada, PhD, 1Alaa Ahmad, PhD, and 1Vikram Kansra, PhD 1Bristol-Myers Squibb, Princeton, NJ, USA 2Quantitative Solutions, Inc., Menlo Park, CA, USA METHODS (continued) RESULTS (continued) INTRODUCTION (CDC 2002) • 2.7 million infected with chronic hepatitis C (CHC) in the United States • Peginterferon α-2a (PEG-IFN; weekly subcutaneous injection) + ribavirin (RBV; twice daily oral) given for up to 52 weeks is the current standard-of-care treatment for CHC • Treatment success based on treatment duration, adverse events, host and viral genotypes • Effective therapy is sustained virologic response (SVR, undetectable HCV RNA at 24 weeks post treatment) and occurs in 40-50% viral genotypes 1 and 4, and 70-80% for genotypes 2 and 3 treated • Model assumptions: • Drug effects described by Emax model • ε = DosePEG-IFN/(ED50PEG-IFN+DosePEG-IFN) • ρ = DoseRBV/(ED50RBV+DoseRBV) • Dose reductions were not incorporated • CC genotype as 100% increase in infected cell death rate (Thompson 2010) • SVR not adjusted for other factors (baseline viral load, degree of fibrosis, race, gender, etc.) • Some GT 1&4 patients may require a longer duration to achieve SVR • 16 to 24 weeks of treatment appears to be the optimal duration for CC genotype • Longer duration appear to provide no better benefit • Shorter durations are anticipated to have much lower SVR • SVR predictions of the implemented model with dropout agrees with observed SVR from HCV clinical database • The Roche model may slightly underestimate SVR rates Figure 2: HCV Quantitative Framework Table 2: Roche VK model simulations of SVR with/without dropouts OBJECTIVE • The inception of an HCV disease-model platform based on a viral kinetic model for PEG-IFN+RBV, using individual data and bridging to new situations with published summary data to project SVR for different treatment scenarios. This approach provides a quantitative framework for HCV drug development thereby complementing the FDA AIMS initiative. METHODS • Implement the published Roche viral kinetic (VK) model: • By using VK and clinical outcomes from 5,500 CHC patients in a clinical database • 93% received 24 weeks of treatment or more • 61% received 48 weeks of treatment or more • 47% received PEG-IFN monotherapy • 53% received PEG-IFN+RBV combotherapy • Perform SVR outcome projections, using R, for different: • Treatment durations • Host genotypes (CC/non-CC), which represent SNPs variations on chromosome 19 • Virus genotypes (1&4/2&3) • Dropout rates • Compare SVR projections vs. literature values • Roche VK model assumes PEG-IFN dose-dependently inhibits the production of virions • VK model assumes RBV dose-dependently renders a fraction of newly produced virions non-infectious Figure 3: Range of SVR responses in the clinical database RESULTS • Dropout rates were linearly interpolated • Dropouts captured as no SVR irrespective of viral load Figure 1: VK model simulations of SVR without dropouts Figure 1: Integrated disease-model platform for HCV Table 3: Comparison of SVR from the Roche model with SVR from clinical database Each scenario utilizes 100 simulated trials, each trial with 100 subjects. Trials use model parameters sampled over parameter uncertainty. Band represent 5th to 95th percentile confidence interval. The center line represents the median prediction. EOT is end of treatment. Figure 2: Dropout rates from the literature database for various PEG-IFN treatment durations CONCLUSIONS • The model links PEG-IFN+RBV doses and viral kinetics and integrates clinical data and literature information across different PEG-IFN treatment durations and host/virus genotypes to provide an assessment of SVR24 projections and variability to support HCV drug development • This framework is being expanded to include directly acting antivirals and other anti-HCV agents in development. Table 1: Dropout model for PEG-IFN REFERENCES • Center for Disease Control. Medical Management of Chronic Hepatitis B and Chronic Hepatitis C. 2002. • Snoeck E, Chanu P, Lavielle M, Jacqumin P, Jonsson EN, Jorga K, Goggin T, Grippo J, Jumbe NL, Frey N. A comprehensive hepatitis C viral kinetic model explaining cure. Clin Pharm Ther. 2010 Jun;87(6):706-13. • Thompson AJ, Muir AN, Sulkowski MS, et al. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology. 2010 Jul;139(1):120-9. 10/05/2009 - N7