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

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.

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

R

esistance

A

ssociated amino acid

V

ariants (RAVs) between G1a and G1b viruses among non-SVR patients enrolled in SPRINT-2 and RESPOND-2

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

SPRINT-2/RESPOND-2 Phase 3 Trials

– – – 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

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.

HCV Genotype 1 Subtype Analysis

Genotype 1a Trugene Genotype Assay G1a Sequence Failed Method 1 Genotype 1 or Genotype 1b Confirm Subtype by NS5B Sequence Method 2 NS3/4a Sequence Assay Phylogenetic Analysis Method 3

● 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

Patients Achieving SVR by HCV Genotype in SPRINT-2 and RESPOND-2

80

G1a G1b

SPRINT-2 (Treatment Naive) 59% 66% 62% 73% 60 40 35% 41% 80 60 RESPOND-2 (Previous PR non-responders)

G1a G1b

67% 64% 71% 53% 20 40 20 24% 18% 62/177 51/126 106/179 89/134 147/237 85/117 0 11/46 6/34 50/94 44/66 61/96 43/61 0 PR only BOC-RGT BOC-PR48 PR only BOC-RGT BOC-PR48

Treatment Arm Treatment Arm

● 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.

Detection of Resistance Associated Variants (RAVs) in Boceprevir Treated patients (SPRINT-2 and RESPOND-2) RAVs (% of all BOC treated patients) RAVs (% of all non-SVR Subjects treated with BOC) 80

G1a G1b

80

G1a G1b

60 60 58% 48% 48% 40 41% 40 20 0 19% 10% 87/468 24/232 SPRINT 2 16% 11% 31/188 14/127 RESPOND 2 20 0 87/151 24/50 SPRINT 2 31/65 13/41 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.

Frequency of RAVs in Non-SVR Patients by Genotype 1 subtype

55% † 47% †

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

Frequency Distribution of Boceprevir RAVs Detected Post Baseline Among Boceprevir Treated patients (SPRINT-2 and RESPOND-2)

100 90 80 70 60 61 68 G1a G1b 50 42 40 30 37 19 20 10 3 3 3 6 0 3 0 3 0 V 36 A V 36 M T5 4A T5 4C T5 4G T5 4S V 55 A 3 24 1 0 3 8 0 5 26 4 3 0 5 7 5 0 32 1 0 1 0 0 3 V 55 I R 15 5K R 15 5T A 15 6S A 15 6T A 15 6V V 15 8I V 17 0A I1 70 F I1 70 T V 17 0T M 17 5L 0 5

● V36M and R155K were the predominant (>25%) RAVs in HCV G1a ● T54A/S, A156S and V170A were the predominant RAVs (>25%) in HCV G1b

Genetic Variation Between Genotype 1a and 1b Partially Explains Different RAV Frequencies RAV Genotype WT Codon RAV Codon # changes

V36M R155K T54A G1a G1b G1a G1b G1a GTG GTT/C AGG CGG ACT A TG A T G A A G AA G G CT 1 2 1 2 1 T54S G1b G1a ACT ACT G CT T CT 1 1 A156S G1b G1a ACT GCC T CT T CC 1 1 V/I170A G1b G1a GCC/T ATC T CC or GC C T CT 1 2 G1b G/ATA/G G C A/G 1

►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

RAVs Detected in a higher % of Non-SVR Patients with a poor Interferon Response at TW4

<1 log ↓ in viral load 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.

Frequency and Distribution of RAVs Detected at Baseline vs. Post-Baseline RAVs Associated With Virologic Failure

Q41H V36L V36I V170M V55I V170T I170T I170F T54G T54C M175L A156V V36A A156T R155T V158I V170A V55A A156S T54A T54S V36M R155K 0 0 0 0 0 0 0 0 0 0 1 0 0 1 2 2 1 2 4 (Boceprevir Arm of SPRINT-2 and RESPOND-2) Baseline RAVs Post-Baseline RAVs 14 15 18 22 Not associated with Viral Failure Associated with Viral Failure Q41H V36L V36I V170M V55I V170T I170T I170F T54G T54C M175L A156V V36A A156T R155T V158I V170A V55A A156S T54A T54S V36M R155K 0 0 0 0 1 1 1 1 1 1 2 2 4 6 9 10 12 13 16 23 36 0 20 40 60 Patients, n All data based on population sequencing.

RAVs=resistance associated amino acid variants. 80 0 20 40 Patients, n 60 72 80 80

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

(SPRINT-2 and RESPOND-2) Total † Interferon Responders ‡ Patient n SVR (%) Poor Interferon Responders § Patients n SVR (%) † RAVs and 2 with baseline RAVs). ‡ Total with Week 4 vial load available (treatment week 4 data not available for 12 patients without baseline Patients with ≥1 log 10 decrease in viral load at treatment week 4.

§ Patients with <1 log 10 decrease in viral load at treatment week 4.

SVR=sustained virologic response; RAVs=resistance associated amino acid variants.

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

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