ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients Randomised* Double-blind W12 W24 W48 Design 18-70 years Chronic HCV infection Genotype 1 HCV RNA > 10,000 IU/ml Failure (but not intolerant) to ≥ 12 weeks prior PEG-IFN + RBV Compensated cirrhosis allowed No HBV or HIV-co-infection N = 66 SMV 100 mg + PEG-IFN + RBV Placebo + PEG-IFN + RBV N = 66 SMV 150 mg + PEG-IFN + RBV Placebo + PEG-IFN + RBV N = 65 SMV 100 mg + PEG-IFN + RBV Placebo + PEG-IFN + RBV N = 68 SMV 150 mg + PEG-IFN + RBV Placebo + PEG-IFN + RBV N = 66 SMV 100 mg + PEG-IFN + RBV SMV : 100 (1 capsule) or 150 mg (2 x 75 mg capsules) QD PEG-IFN a-2a : 180 mg/week RBV (in 2 divided doses) : 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg N = 65 SMV 150 mg + PEG-IFN + RBV N = 66 Placebo + PEG-IFN + RBV * Randomisation was stratified on genotype (1a or 1b or other) and prior response to PEG-IFN + RBV (null response or partial response or relapse) ASPIRE Zeuzem S. Gastroenterology 2014;146:430-41

ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients W12 W24 W48 Design Randomised* Double-blind 18-70 years Chronic HCV infection Genotype 1 HCV RNA > 10,000 IU/ml Failure (but not intolerant) to ≥ 12 weeks prior PEG-IFN + RBV Compensated cirrhosis allowed No HBV or HIV-co-infection N = 66 SMV 100 mg + PEG-IFN + RBV Placebo + PEG-IFN + RBV N = 66 SMV 150 mg + PEG-IFN + RBV Placebo + PEG-IFN + RBV N = 65 SMV 100 mg + PEG-IFN + RBV Placebo + PEG-IFN + RBV N = 68 SMV 150 mg + PEG-IFN + RBV Placebo + PEG-IFN + RBV N = 66 SMV 100 mg + PEG-IFN + RBV N = 65 SMV 150 mg + PEG-IFN + RBV N = 66 Placebo + PEG-IFN + RBV Objective : SVR24 (HCV RNA < 25 IU/ml) by intention to treat. Significant difference in the overall population at 5% overall significance level, power 89%. Comparison SMV100 vs placebo, SMV150 vs placebo, then each SMV group vs placebo ASPIRE Zeuzem S. Gastroenterology 2014;146:430-41

ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients ARV-trial.com ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients Baseline characteristics SMV 100 mg SMV 150 mg 12W N = 66 24W N = 65 48W N = 68 Placebo Median age, years 52 50 48 51 Female 33% 32% 37% 26% 36% White 89% 92% 94% 90% 97% HCV RNA log10 IU/ml, median 6.5 6.7 6.6 HCV RNA > 800,000 IU/ml 88% 91% 86% 85% 83% Genotype 1a Genotype 1b 39% 59% 44% 54% 39% 60% 45% 55% 45% 52% 64% 41% 59% Metavir F3 / F4 (%) 22 / 11 25 / 21 21 / 21 17 / 20 16 / 19 11 / 20 20 / 16 IL28B CC 16% 17% 12% 18% 20% 22% Response to prior PEG-IFN + RBV Null response Partial response Relapse 24% 35% 25% 35% 40% 27% 33% 39% 35% 25% 40% 34% 40% 24% ASPIRE Zeuzem S. Gastroenterology 2014;146:430-41 3

ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients Protocol-defined virologic stopping rules Patients with an insufficient response to treatment, ie, not achieving 1 log10 reduction from baseline in HCV RNA at W4, 2 log10 reduction from baseline in HCV RNA at W12, or HCV RNA ≥ 25 IU/ml detectable at W24 or W36, discontinued all study medication (SMV/placebo and PEG- IFN/RBV) Study medication was also discontinued if viral breakthrough (confirmed, on treatment increase in HCV RNA of > 1 log10 IU/ml from the lowest level reached, or confirmed HCV RNA > 100 IU/ml in patients with HCV RNA previously < lower limit of quantification of 25 IU/ml or undetectable) at any time point during treatment Premature discontinuation N = 39 (8,4%) : withdrawal of consent, N = 21, lost to follow-up, N = 12, adverse event, N = 1, other, N = 5 Discontinuation of study medication SMV/placebo + PEG-IFN + RBV, N = 134 (29%) SMV/placebo only, N = 7 (1,5%) ASPIRE Zeuzem S. Gastroenterology 2014;146:430-41

ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients ARV-trial.com ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients SVR24 (HCV RNA < 25 IU/ml) 25 50 100 75 69.7 % 72.1 N 66 66.2 12W 80 22.7 66.7 65 68 60.6 24W 48W SMV 100 mg SMV 150 mg Placebo SVR24 : 60.6% to 80% for SMV arms versus 22.7% for placebo (p < 0.001) ; 65.5% for SMV 100mg and 72.9% for SMV 150 mg (p < 0.001 for both groups versus placebo); 68.2% for SMV 12W versus 69.2% for SMV 24W versus 70.2% for SMV 48W ASPIRE Zeuzem S. Gastroenterology 2014;146:430-41 5

ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients ARV-trial.com ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients SVR24 (HCV RNA < 25 IU/ml) according to prior response to PEG-IFN + RBV 25 50 75 37 % 57 N 27 85 19 9 68 16 23 67 78 Placebo SMV 100 mg SMV 150 mg 46 51 49 100 Relapse Partial response Null response SVR24 : 60.6% to 80% for SMV arms versus 22.7% for placebo (p < 0.001) ; 65.5% for SMV 100mg and 72.9% for SMV 150 mg (p < 0.001 for both groups versus placebo); 68.2% for SMV 12W versus 69.2% for SMV 24W versus 70.2% for SMV 48W ASPIRE Zeuzem S. Gastroenterology 2014;146:430-41 6

ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients ARV-trial.com ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients SVR24 (HCV RNA < 25 IU/ml) by genotype, according to prior response to PEG-IFN + RBV 25 50 100 75 33 39 N 12 82 56 13 7 8 23 34 85 42 24 26 1a 1b 15 44 45 43 9 40 68 89 88 84 58 Placebo SMV 100 mg SMV 150 mg % Relapse Partial response Null response SVR24 for SMV 150 mg : 63.1% for genotype 1a (60.9% if Q80K+ and 66.1% if Q80K-) versus 80.4% for genotype 1b ASPIRE Zeuzem S. Gastroenterology 2014;146:430-41 7

ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients SVR24 in SMV 150 mg group according to other characteristics and prior response to PEG-IFN + RBV Metavir F4 Relapse : 73% Prior partial response : 82% Prior null response : 31% IL28B genotype CC : 88% CT : 74% TT : 61% ASPIRE Zeuzem S. Gastroenterology 2014;146:430-41

ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients Treatment failure SMV 100 mg SMV 150 mg Placebo Viral breakthrough* 24 (12.2%) 18 (9%) 1 (1.5%) Relapse 21 (10.7%) 17 (8.5%) 12 (44.4%) Meeting virologic stopping rule 18 (4.5%) 34 (52%) * Generally before or at W12 NS3 emerging mutations Viral breakthrough : 41/42 Relapse : 34/35 Mostly R155K or D168V alone or a combination of Q80K or Q80R, R155K, and/or D168E mutations Genotype 1a : mainly R155K ; genotype 1b : mainly D168V ASPIRE Zeuzem S. Gastroenterology 2014;146:430-41

ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients ARV-trial.com ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients Adverse events, N (%) SMV 100 mg SMV 150 mg 12W N = 66 24W N = 65 48W N = 68 Placebo Adverse event leading to discontinuation SMV/placebo SMV/placebo + PR 10.6% 9.1% 9.1% 6.2% 4.6% 7.6% 6.1% 3.0% 4.5% 10.3% 2.9% 10.8% 9.2% 7.2% Grade 3-4 adverse event 32% 20% 36% 35% 39% 26% Serious adverse event 7.7% 10.6% 7.4% 12.3% Most frequent adverse event Fatigue Headache Pruritus Influenza-like illness Neutropenia 46% 27% 29% 24% 43% 40% 37% 23% 52% 44% 30% 24% 27% 41% 38% 27% 27% 22% 31% 17% Other AE of clinical interest Hepatobiliary Rash (any type) Anemia 8% 20% 23% 3% 22% 17% 5% 18% 5% 26% 15% 9% 39% 5% 18% 20% ASPIRE Zeuzem S. Gastroenterology 2014;146:430-41 10

ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients Summary Simeprevir once daily in combination with PEG-IFN + RBV achieved significantly improved SVR rates compared with placebo plus PEG-IFN + RBV in patients infected with HCV genotype 1 who failed to respond to previous PEG- IFN + RBV therapy Higher SVR24 rates were seen in patients with a prior partial or null response treated with SMV150 mg compared with SMV 100 mg. This trend was also observed across most subgroups No consistent beneficial trend for treatment duration > 12W with SMV SVR24 with SMV 150 mg was higher in genotype 1b than 1a among patients with a prior null or partial response SVR24 in patients with cirrhosis in the SMV150 mg group were substantially higher than in the placebo group (62% versus 0%, respectively) Viral breakthrough and relapse tended to be less common with SMV 150 mg versus 100 mg. Almost all failures had emerging NS3 resistance mutations No difference in incidence or severity of adverse events with SMV vs placebo No increase in anemia. Rash and neutropenia were more common with SMV Transient mild hyperbilirubinemia with SMV (inhibition of OATP1B1) ASPIRE Zeuzem S. Gastroenterology 2014;146:430-41