Randomisation* 2 : 1 Double blind *Randomisation was stratified on genotype (1a or 1b or other) and IL28B genotype (CC, CT or TT) N = 133 N = 260 W24W48 Placebo + PEG-IFN + RBV SMV + PEG-IFN + RBV PEG-IFN + RBV W12 –SMV 150 mg : 1 pill QD ; PEG-IFN  -2a 180  g SC once weekly –RBV : 1000 or 1200 mg/day (BID dosing) according to body weight (< or ≥ 75 kg)  Response-guided therapy : in SMV group, patients with HCV RNA < 25 IU/ml at W4 and < 15 IU/ml at W12 stopped treatment at W24, otherwise they continued until W48  Virological stopping rules : SMV or placebo discontinued if HCV RNA > 1000 IU/ml at W4, with continuation of PEG-IFN + RBV. PEG-IFN + RBV discontinued if RNA reduction < 2 log 10 IU/ml at W12, or if HCV RNA confirmed ≥ 25 IU/ml at W24 or W36 open-label PROMISE > 18 years Chronic HCV infection Genotype 1 IFN-experienced ≥ 24 weeks with relapse HCV RNA > 10,000 IU/ml Compensated cirrhosis allowed No HBV or HIV co-infection Forns X. Gastroenterology 2014;146:  Design PROMISE Study: SMV + PEG-IFN + RBV for genotype 1 and relapse to prior IFN therapy

 Objectives –Primary endpoint : difference in SVR 12 (HCV RNA < 25 IU/ml) between the 2 groups : estimation of 20% in the placebo group, power of 90% to detect a significant difference with a 5% 2-sided significance level, by ITT –Secondary endpoints Virologic response in different patient subgroups (including METAVIR score, HCV 1 subtype, and IL28B genotype) Proportion of SMV-treated patients meeting RGT criteria to complete treatment at W24 Incidence of viral breakthrough (HCV-RNA increase of >1 log 10 IU/ml from the lowest level observed or HCV RNA > 100 IU/ml when previously < 25 IU/ml), on-treatment failure (confirmed detectable HCV RNA at end of treatment), or viral relapse (detectable HCV RNA during follow-up or at the time of SVR assessments after achieving undetectable levels at end of treatment) Incidence of adverse events and laboratory abnormalities Quality-of-life measures PROMISE Forns X. Gastroenterology 2014;146: PROMISE Study: SMV + PEG-IFN + RBV for genotype 1 and relapse to prior IFN therapy

SMV N = 260 Placebo N = 133 Median age, years52 Female31%41% White / Black94% / 3%96% / 3% HCV genotype : 1a / 1b42% / 57%41% / 59% Metavir score : F3 / F418% / 16%11% / 14% HCV RNA log 10 IU/ml, median IL28B genotype CC24%26% Time since end of prior (PEG)-IFN therapy, median months31 (4-141)31 (5-115) Discontinued study, N (%) Adverse event Withdrew consent Lost to follow-up Other 10 (3.8%) (10.5%) PROMISE Forns X. Gastroenterology 2014;146: Baseline characteristics and patient disposition

 Response guided therapy (RGT) : in SMV group, patients with HCV RNA < 25 IU/ml at W4 (undetectable or detectable) and < 15 IU/ml at W12 (undetectable) stopped treatment after W24 –Of the 241 (93%) patients who met RGT, 83% had SVR 12 –Of the 15 who did not, 40% had SVR 12 SMVPlacebo % All1a All1a Q80K+1b p < a Q80K- p < N PROMISE Forns X. Gastroenterology 2014;146: PROMISE Study: SMV + PEG-IFN + RBV for genotype 1 and relapse to prior IFN therapy SVR 12 (HCV RNA < 25 IU/ml)

PROMISE Forns X. Gastroenterology 2014;146: PROMISE Study: SMV + PEG-IFN + RBV for genotype 1 and relapse to prior IFN therapy SVR 12 (HCV RNA < 25 IU/ml) SMVPlacebo % CCCTTTF4F0-F2F3 Metavir fibrosis scoreIL28B genotype N all p < 0.01

 Emergence of resistance among SMV-treated patients who failed to achieve SVR 12 (sequencing data available in 52/59) – Emergence of NS3 mutations in 47/52 (90%) Genotype 1a (N = 30/32) : most common = R155K alone (N =15) or in combination (N = 4), or D168V/A/E/H (N = 10) ; 14/32 with Q80K at baseline Genotype 1b (N = 17/20) : most common = D168V or D168A/E/T SMVPlacebo Met W4 virologic stopping rule (continuation of PR)5 (1.9%)93 (69.9%) On-treatment failure8/260 (3.1%)36/133 (27.1%) Met stopping rule (W12 or W24 or W36)5 (1.9%)15 (11.3%) Relapse 46/249 (18.5%) GT 1a : 28% ; GT 1b : 12% 45/93(48.4%) PROMISE Forns X. Gastroenterology 2014;146: PROMISE Study: SMV + PEG-IFN + RBV for genotype 1 and relapse to prior IFN therapy Virologic failure

PROMISE Study: SMV + PEG-IFN + RBV for genotype 1 and relapse to prior IFN therapy SMV, N = 260Placebo, N = 133 First 12WEntire phaseFirst 12WEntire phase Discontinuation due to adverse event1.2%2.3%1.5%5.3% Grade 3 adverse event18.1%24.2%18%25.6% Grade 4 adverse event1.9%3.5%3%4.5% Serious adverse event1.2%5.4%2.3%7.5% Most common adverse events Fatigue32% 42%44% Headache32%33%36% Influenza-like illness30% 20% Adverse events of clinical interest Rash19%23%14%23% Pruritus24%28%17%28% Neutropenia15%18%17%22% Photosensitivity (Grade 3, N)4% (1)4% 0 Anemia11%17%6%20% PROMISE Forns X. Gastroenterology 2014;146: Adverse events

PROMISE Study: SMV + PEG-IFN + RBV for genotype 1 and relapse to prior IFN therapy  Summary –Oral, once-daily SMV150 mg for 12 weeks in combination with PEG-IFN + RBV followed by 12–36 weeks of PEG-IFN + RBV led to a significant improvement in SVR 12 compared with that seen in the placebo group, in patients with chronic HCV genotype 1 infection who had relapsed after previous IFN-based therapy –Overall, 79.2% of SMV-treated patients achieved SVR 12 compared with 36.1% of those who received PEG-IFN + RBV alone This superiority of SMV was seen across the different baseline characteristics (Gender, HCV RNA, Metavir score, IL28B genotype, HCV 1 subtype) –Almost all SMV-treated patients (92.7%) met RGT criteria and were eligible to stop PEG-IFN + RBV at W24. The SVR 12 rate in these patients was 83% –The SVR 12 rate with SMV was lower in HCV genotype 1a patients who had the Q80K polymorphism at baseline –Relapse rate was higher in genotype 1a –Most patients treated with SMV who did not achieve SVR 12 had emergent mutations at the time of failure –The safety and tolerability profile of SMV + PEG-IFN + RBV was generally similar to that of PEG-IFN + RBV alone, with no additional treatment-related adverse events. Discontinuation for adverse event was rare in both groups PROMISE Forns X. Gastroenterology 2014;146: