SMV + PEG-IFN-2a + RBV for HCV Genotype 4 Treatment: Restore Study Overview

RESTORE Study: SMV + PEG-IFN -2a + RBV for HCV genotype 4 Design Open-label W24* or W48* 18-70 years Chronic HCV infection Genotype 4 Treatment-na ve or experienced with relapse or partial or null response to PEG-IFN + RBV HCV RNA 10,000 IU/ml No HBV or HIV co-infection W12 N = 107 SMV + PEG-IFN + RBV PEG-IFN + RBV * Treatment-na ve and relapsers stopped therapy at W24 if HCV RNA < 25 IU/ml at W4 and HCV RNA undetectable at W12 ; All other patients continued therapy until W48 SMV : 150 mg qd ; PEG-IFN -2a : 180 g SC once weekly RBV weight based (bid dosing) : 1000 mg/day if < 75 kg or 1200 mg/day if 75 kg Objective SVR12(HCV RNA < 25 IU/ml) with 95% two-sided CI, by ITT, descriptive analysis RESTORE Moreno C. J Hepatol 2015;62:1047-55

RESTORE Study: SMV + PEG-IFN -2a + RBV for HCV genotype 4 Baseline characteristics and patient disposition Prior partial Response N = 10 Prior relapse N = 22 Prior null response N = 40 Na ve N = 35 Median age, years 47 52 51 51 Female 26% 14% 0 28% HCV genotype 4a / 4d / other 35% / 24% / 41% 50% / 18% / 32% 30% / 30% / 40% 48% / 25% / 28% IL28B CC genotype 21% 5% 0 0 14% / 36% / 9% / 41% 20% / 30% / 0 / 50% 57% / 17% / 20% / 6% 24% /22% / 16% / 38% Metavir F0-F1 / F2 / F3 / F4 HCV RNA log10IU/ml, median 6.19 5.86 5.84 6.40 Discontinued treatment, N Lost to follow-up Withdrew 2 2 0 0 0 2 1 1 RESTORE Moreno C. J Hepatol 2015;62:1047-55

RESTORE Study: SMV + PEG-IFN -2a + RBV for HCV genotype 4 SVR12(HCV RNA < 25 IU/ml), % (95% CI) % 86.4 100 82.9 ( 70-95) ( 72-100) SVR12in patients with HCV RNA < 25 IU/ml at W4 and undetectable at W12 (RGT) 75 60 (30-90) Prior relapse 40 Na ve (25-55) 50 Met RGT criteria 31/35 20/22 W4 : HCV RNA undetectable 27/28 (96.4%) 17/18 (94.4%) 25 W4 : HCV RNA detectable 2/3 1/1 N 35 22 Prior relapse 10 Prior partial response 40 Prior null response 0 Na ve On-treatment failure, N 3 2 2 18 Virologic breakthrough, N 4 1 2 13 Relapse, N 3 1 2 6 RESTORE Moreno C. J Hepatol 2015;62:1047-55

RESTORE Study: SMV + PEG-IFN -2a + RBV for HCV genotype 4 Resistance testing (NS3) in treatment failure Available in 32/37 28/32 with emergence of NS3 mutations at positions 80, 122, 155, 156 and/or 168 Most frequent profile : D168V alone or D168E mutations at position 80 RESTORE Moreno C. J Hepatol 2015;62:1047-55

RESTORE Study: SMV + PEG-IFN -2a + RBV for HCV genotype 4 Adverse events during the SMV + PEG-IFN + RBV phase, N (%) N = 107 5 (4.7%) 0 1 (0.9%) 6 (5.6%) 1 (0.9%) Serious adverse event Possibly related to SMV AE leading to discontinuation of SMV (valium overdose) Grade 3 adverse events Grade 4 adverse events Most common adverse events Influenza-like illness Asthenia Fatigue Adverse events of clinical interest Anemia Dyspnea Neutropenia Photosensitivity (all grade 1) Pruritus (no grade 3-4) Rash (no grade 3-4) 46% 42% 35% 10% 11% 5% 2% 21% 14% RESTORE Moreno C. J Hepatol 2015;62:1047-55

RESTORE Study: SMV + PEG-IFN -2a + RBV for HCV genotype 4 Summary In this open-label study of genotype 4 infection, 12 weeks of SMV + 24-48 weeks of PEG-IFN + RBV achieved an overall SVR12 of 65% in treatment-na ve and prior relapsers SVR12was 83% and 86%, respectively, which is in line with SVR12rates observed in phase III studies of SMV + PEG-IFN + RBV in patients with genotype 1 Most of na ve and prior relapsers could stop PEG-IFN + RBV at W24 SVR12rates were similar across the different HCV genotype 4 subtypes, with slightly lower rates observed among patients with genotype 4d Adverse events were mainly grade 1 or 2, with few serious adverse events and no deaths Limitations No control arm RESTORE Moreno C. J Hepatol 2015;62:1047-55