Durability of Response and Rate of Re-emergence of Wild Type at Boceprevir (BOC) Resistance-Associated Variant (RAV) Loci in Genotype 1a and 1b Patients: Interim Analysis of Long-Term Follow-Up of Patients Treated With Boceprevir + PegIntron +/- Ribavirin Richard J.O. Barnard, John Howe, Donald J. Graham, Robert A. Ogert, Jianmin A. Long, Navdeep Boparai, Patricia Mendez, Clifford Brass, Janice Albrecht, Robert Ralston

Summary of Boceprevir Boceprevir is a NS3 protease inhibitor that has completed phase 3 clinical trials o RESPOND-1; Phase 2 Dose finding-study in previous null responders + IFN +/- RBV o SPRINT-1; Phase 2 Safety/Efficacy Study in treatment naïve patients +IFN/RBV o SPRINT-2; Phase 3; Response-guided therapy vs 48-week therapy study + IFN/RBV in treatment naïve patients (800mg BOC TID) o RESPOND-2; Phase 3; Response-guided therapy vs 48-week therapy study + IFN/RBV in previously treated patients (800mg BOC TID) SVR rates were superior to control arms in RESPOND-2, (59-66% vs 21%) and SPRINT-2 (63-66% vs 38%) Resistant Associated amino acid Variants (RAVs) were detected in 53% of non-SVR patients in SPRINT-2/RESPOND-2 studies As HCV does not integrate into the human genome, the issue of the longevity of RAVs selected in non-SVR patients is unknown IFN = Pegylated Interferon, RBV = Ribavirin

In vitro Characterization of Boceprevir NS3 RAVs in Enzymatic Studies Position 170 is Isoleucine in genotype 1a and Valine in Genotype 1b V36M a T54A T54S V55A R155K a A156S I/V170A Fold Change Ki* Genotype 1a Genotype 1b Majority Variants Detected from Clinical Studies (Present in >25% of Patients) Genotype 1a; V36M, R155K Genotype 1b; T54A, T54S, A156S, V170A Variants also detected at Position V55, V158 and M175L

Long-Term Follow-Up Study These analyses were undertaken to characterize the rates of re-emergence of wild-type at boceprevir resistant loci in non-SVR patients with detectable RAVs Study Description o Patients are being monitored for at least 3.5 years post-therapy o Resistance variants were detected by population sequencing of the NS3 protease region (aa codons 1-181) Patients who received at least one dose of study medication in a previous Phase 1, 2, or 3 Boceprevir Clinical Study EOT a Study duration max 3.5 years after EOT Screenin g/ Baseline Mo 3 Mo 6 Mo 12 Year 1 Mo 18 Mo 24 Year 2Year 3 Mo 30 Mo 36 a patients may have rolled over at different times after enrollment in the previous treatment protocol.

Objectives and Criteria for the Interim Analysis of Resistance Initial aim was to characterize the presence of boceprevir RAVs over time by population sequencing (~20-25% Sensitivity) Patients in interim analysis had to have viruses with at least one of the majority RAVs (detected in 25% of non-SVR patients) V36M, T54A/S and/or R155K Patients had to have viruses that were wild-type at that position prior to receiving boceprevir Patients had to have at least two years of follow-up data (183 patients in this interim analysis); majority of patients from RESPOND-1

Baseline Demographic and Disease Characteristics Demographic and baseline characteristics of age, sex, race, ethnicity, weight, BMI and viral load are consistent with previously studies in HCV patients Patients enrolled in the long-term follow up study were typically white males; average age was 49 to 52 years The distribution of genotypes was similar among the patient groups The average length of time since probable exposure to HCV was 25 to 30 years

Return of Wild-Type at Individual RAV Loci by Population Sequencing Genotype 1b RAV not individual RAV Loci, % 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Time Since the End of Treatment (Yrs) T54A T54S *All RAVs Genotype 1a *Refers to any Boceprevir RAV (Includes V36, Q41, F43, T54, V55, R155, A156, V158, I/V170) RAV not individual RAV Loci, % 2 Time Since the End of Treatment (Yrs) % 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% V36M T54S R155K *All RAVs 0

Median Rates of Return of Wild-Type at Specific RAV Loci # Refers to any Boceprevir RAV (Includes V36, Q41, F43, T54, V55, R155, A156, V158, I/V170) *By population sequencing

Individual Viral Load Plots from Patients infected with Genotype 1b Virus BL WT Log 10 Viral Load (IU/mL) T54A/S & V170A T54S & V55A T54S WT Time (Weeks) Genotype 1b Patient 1 Time (Weeks) WT -16BL WT T54A V158I/M T54A Log 10 Viral Load (IU/mL) Genotype 1b Patient 2 WT = Wild Type BL = Baseline IFN/RBV Lead-In IFN/RBV + BOC Follow-up

Viral Load Plot from a Patient infected with Genotype 1a Virus V36M R155K Variant Frequency, % Quantification of Variants By 454-Sequencing Week 28 V36M R155K Week 100 LOQ= Limit of Quantification WT = Wild-Type IFN/RBV + BOC Follow-up Longitudinal Analysis Wk 28 Week Log 10 Viral Load (IU/mL) LOQ WT V36M/R155K

Conclusions Different RAVs are selected in genotype 1a and 1b viruses WT at each RAV loci re-emerged at different rates depending on the specific RAV selected o WT re-emerged most rapidly in genotype 1a or 1b viruses with V36M or T54A, as compared to viruses with either T54S or R155K Variation in the appearance of resistance and rates of re-emergence of WT at each loci reflects relative fitness of the specific RAVs in the specific genetic background In patients that fail with multiple RAVs, individual RAVs can decline at different rates o Studies are ongoing to analyze the linkage in viruses with multiple RAVs The majority of patients in this interim analysis are from phase 2 studies