1. SPRINT-2/RESPOND-2 Boceprevir Plus Standard of Care Phase 3 Clinical Trials Analysis of Resistance Associated Variants by HCV Genotype 1 subtypes 1a and 1b

2. Background ► Nearly 170 million people worldwide are chronically infected with Hepatitis C virus (HCV) – HCV genotype 1 is the most common and least responsive to peginterferon alfa and ribavirin with geographic differences in HCV genotype 1 subtypes: Genotype 1a is predominant in Northern Europe and North America Genotype 1b is predominant in Southern and Eastern Europe and Japan – Leading indication for liver transplantation in Europe and United States and is major etiologic factor in hepatocellular carcinoma ► Boceprevir - binds to the active site of the HCV NS3 protease – Victrelis TM (Boceprevir) approved by FDA for treatment use in combination with peginterferon alfa and ribavirin in adult patients (≥18 years of age) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.

3. Objectives ► To compare the rate of sustained virologic response (SVR) of Boceprevir (BOC) dosed in combination with Peg- interferon alfa-2b (P) plus ribavirin (R) standard of care therapy in patients with Genotype 1a (G1a) and Genotype 1b (G1b) in the SPRINT-2 and RESPOND-2 clinical trials. ► To compare the frequency of Resistance Associated amino acid Variants (RAVs) between G1a and G1b viruses among non-SVR patients enrolled in SPRINT-2 and RESPOND-2

4. SPRINT-2/RESPOND-2 Phase 3 Trials ► SPRINT-2 - 1,097 previously untreated patients (two cohorts enrolled and analyzed separately) Cohort 1: 938 (86%) non-Black patients Cohort 2: 159 (14%) Black patients ► RESPOND-2 – 403 prior treatment failures to P/R (patients failing to attain sustained virologic response after an adequate course of therapy) ► Patient characteristics common to both studies – Patients mono-infected with chronic hepatitis C genotype 1 – Co-infection with HIV or HBV excluded – Adult (≥18 years) patients – Compensated liver disease with all degrees of fibrosis – Studies conducted primarily in North America and Western Europe

5. – Double-blind for BOC – 3 treatment arms ( all patients received a 4 week lead-in of P/R prior to having BOC or placebo added to their regimen) Arm 1: PR48 (Control) –4 weeks P/R then 44 weeks P/R + BOC placebo Arm 2: BOC RGT –4 weeks P/R then P/R + BOC using response guided therapy (RGT) Arm 3: BOC/PR48 –4 weeks P/R then 44 weeks P/R + BOC – Primary endpoint: SVR in each experimental arm compared to control arm COBAS TaqMan 2.0 (Roche) HCV Test Limit of Detection (LOD): 9.3 IU/ml Limit of Quantitation: 25 IU/ml All decisions based on LOD SPRINT-2/RESPOND-2 Phase 3 Trials

6. Methods ► Plasma samples were collected for resistance testing from patients at baseline and at or near the time of virologic failure in patients that did not achieve SVR. ► Viral genotype was determined at screening using the TruGene assay. Subsequently, genotyping was determined by a combination of NS5b sequencing and/or inferred from positive amplification using subtype-specific primers (Virco BVM, Belgium) ► Population sequencing of the NS3 region was performed by Virco. ► Sequences from G1a and G1b viruses were aligned to the H77S and Con 1 reference strains, respectively. Major RAVs identified based on changes at specified loci compared with reference strain sequences.

7. HCV Genotype 1 Subtype Analysis ● Many patients genotyped as 1a using the Trugene assay were inconsistent with methods 2 and 3 (low concordance) ● High concordance was observed between method 2 (used for final data analysis) and phylogenetic analysis of NS3/4a sequences

8. Patients Achieving SVR by HCV Genotype in SPRINT-2 and RESPOND-2 ● There was a consistent but small numerical advantage for patients Infected with G1b compared to G1a to achieve SVR in both Boceprevir arms of each study.

9. Detection of Resistance Associated Variants (RAVs) in Boceprevir Treated patients (SPRINT-2 and RESPOND-2) ●There was a consistently higher % of patients with RAVs detected in patients infected with HCV G1a compared to G1b in both BOC arms of each trial.

10. Frequency of RAVs in Non-SVR Patients by Genotype 1 subtype Patients infected with HCV Genotype 1b had lower % RAVs detected compared to Genotype 1a Infected patients † Expressed as a percentage of patients with sequence data available. RAVs=Resistance Associated Amino Acid Variants

11. G1a G1b Frequency Distribution of Boceprevir RAVs Detected Post Baseline Among Boceprevir Treated patients (SPRINT-2 and RESPOND-2) ● V36M and R155K were the predominant (>25%) RAVs in HCV G1a ● T54A/S, A156S and V170A were the predominant RAVs (>25%) in HCV G1b

12. RAVGenotypeWT CodonRAV Codon# changes V36MG1a G1b GTG GTT/C ATG 1212 R155KG1a G1b AGG CGG AAG 1212 T54AG1a G1b ACT GCT 1111 T54SG1a G1b ACT TCT 1111 A156SG1a G1b GCC GCC/T TCC TCC or TCT 1111 V/I170AG1a G1b ATC G/ATA/G GCC GCA/G 2121 Genetic Variation Between Genotype 1a and 1b Partially Explains Different RAV Frequencies ►V36M, R155K in G1b and V170A in G1a require 2 nucleotide changes and likely accounts for the different frequency observed between HCV G1a and G1b

13. RAVs Detected in a higher % of Non-SVR Patients with a poor Interferon Response at TW4 8 Patients missing TW4 viral load data and 42 with no sequence data are not included. RAV=resistance associated amino acid variant; SVR=sustained virologic response; TW=treatment week.

14. Frequency and Distribution of RAVs Detected at Baseline vs. Post-Baseline RAVs Associated With Virologic Failure (Boceprevir Arm of SPRINT-2 and RESPOND-2) All data based on population sequencing. RAVs=resistance associated amino acid variants. Baseline RAVsPost-Baseline RAVs Not associated with Viral Failure Associated with Viral Failure

15. SVR Rates By Treatment Week 4 Response in Patients With or Without Baseline RAVs

16. Summary Boceprevir, in combination with P/R significantly improved SVR rates compared with P/R alone in both treatment naïve and previously treated patients SVR rates among patients with G1b virus were consistently higher compared with G1a patients in both SPRINT-2 and RESPOND-2 phase 3 trials Detection of resistance variants was more common among G1a vs G1b viruses in both pivotal trials when analyzed by all boceprevir treated and subset not achieving SVR ►predominant RAVs for G1a : V36M and R155K ►predominant RAVs for G1b : T54A/S, A156S, V170A

17. Conclusions ► Genetic variation between G1a and G1b viruses likely contributes to the higher rate of SVR and lower rate of major RAV detection (in non-SVR patients) in HCV G1b patients treated with Boceprevir combination therapy ► non-SVR patients with a good Interferon response had fewer RAVs detected ► Majority of poorly interferon responsive non-SVR patients had RAVs detected at failure primarily due to the fact most patients failed during the BOC dosing period