 Design Randomisation* 2 : 1 Double blind *Randomisation was stratified on genotype (1a vs 1b) and ILB28 genotype (CC or non-CC) N = 134 N = 257 W24W48 QUEST-2 Study: SMV + PEG-IFN + RBV for genotype 1 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 or PEG-IFN  -2b 1.5  g/kg/week –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 Manns M. Lancet 2014;384: QUEST-2 > 18 years Chronic HCV infection Genotype 1 Treatment-naïve HCV RNA > 10,000 IU/ml No HBV or HIV co-infection

 Objectives –Difference in SVR 12 (HCV RNA 20%, by intention to treat –Sensitivity analysis : comparison of SVR 12 in both groups with a logistic regression model including baseline HCV RNA (log 10 IU/ml, included as a continuous variable) and the stratification factors (HCV genotype 1 subtype and IL28B genotype) –Secondary endpoints : SVR 24, % patients stopping treatment at W24 based on response-guided therapy, failure, safety  PEG-IFN Therapy –63% of patients in each arm were randomized to receive PEG-IFN alfa- 2a or PEG-IFN alfa-2b; the remainder was assigned PEG-IFN alfa-2a QUEST-2 Study: SMV + PEG-IFN + RBV for genotype 1 Manns M. Lancet 2014;384: QUEST-2

SMV N = 257 Placebo N = 134 Median age, years4647 Female46%43% White / Black92% / 6%92% / 7% HCV genotype : 1a / 1b41% / 58% Baseline Q80K mutation : genotype 1a / genotype 1b23% / < 1%41% / 0 Metavir score F3 / F417% / 12%26% / 0 IL28B genotype CC29%31% Discontinued study, n (%) Adverse event Withdrew consent Lost to follow-up Non-compliance Other 12 (5%) (13%) Baseline characteristics and patient disposition QUEST-2 Study: SMV + PEG-IFN + RBV for genotype 1 Manns M. Lancet 2014;384: QUEST-2

 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 225 (91%) patients who met RGT, 86% had SVR 12 –Of the 16 who did not, 31% had SVR 12 QUEST-2 Study: SMV + PEG-IFN + RBV for genotype 1 % All1a All1a Q80K+1b p < a Q80K- p < N Manns M. Lancet 2014;384: QUEST-2 SVR 12 (HCV RNA < 25 IU/ml) SMVPlacebo p = 0.25

SVR 12 (HCV RNA < 25 IU/ml) % CCCTTT F4F0-F2 F3 Metavir fibrosis score IL28B genotype  SVR 12 by baseline HCV RNA –≤ 800,000 IU/ml : 454/58 (93%) in SMV vs 81% in placebo ; p < –> 800,000 IU/ml : 155/199 (78%) in SMV vs 39% in placebo ; p < all p < p = QUEST-2 Study: SMV + PEG-IFN + RBV for genotype N Manns M. Lancet 2014;384: QUEST-2 SMVPlacebo

Virologic failure  Emergence of resistance among SMV-treated patients who failed to achieve SVR 12  Emergence of NS3 mutations in 41/42 (52%) –Genotype 1a (N = 16) : most common = R155K alone (N =13) or in combination (N = 2), or D168V (N = 1) ; 5/16 with Q80K at baseline –Genotype 1b (N = 25) : most common = D168V ; Q80R + D168E ; no Q80K at baseline  No impact of RBV dose reduction (24% of SMV and 31% of placebo) on outcome QUEST-2 Study: SMV + PEG-IFN + RBV for genotype 1 SMVPlacebo On-treatment failure18/257(7%)43/134 (32%) Met stopping rule (W12 or W24 or W36)4%28% Relapse 30/236 (13%) 25/30 within 12 weeks 21/88 (24%) Manns M. Lancet 2014;384: QUEST-2

SMV N = 257 Placebo N = 134 Discontinuation due to adverse event2 (< 1%)0 Grade 3 adverse event27%31% Grade 4 adverse event6%4% Headache39%37% Fatigue37%42% Pyrexia31%40% Pruritus26%27% Rash Grade 3-4 Leading to discontinuation 27% 2 (< 1%) 3 (1%) 20% 0 1 (< 1%) Photosensitivity Grade 3-4, leading to discontinuation 4% 0 < 1% 0 Neutropenia21%27% Anemia21%28% Adverse events QUEST-2 Study: SMV + PEG-IFN + RBV for genotype 1 Manns M. Lancet 2014;384: QUEST-2

QUEST-2 Study: SMV + PEG-IFN + RBV for genotype 1  Summary –A significantly higher percentage of treatment-naive patients with chronic HCV genotype 1 infection achieved SVR 12 (primary efficacy endpoint) with SMV in combination with PEG-IFN + RBV than with placebo in combination with PEG-IFN + RBV and has lower on-treatment failure and relapse rates This superiority of SMV was seen irrespective of the type of PEG-IFN-alfa used –91% of patients in the SMV group met criteria for response-guided therapy and were eligible to shorten treatment and stop at W24, and 86% of these subsequently achieved SVR 12 –IL28B non-CC genotype, cirrhosis, and high baseline HCV RNA were associated with lower SVR rates –in patients with HCV genotype 1a SVR 12 was similarly high in patients with or without the Q80K polymorphism at baseline However, SVR 12 was significantly lower in placebo group overall vs SMV group with Q80K polymorphism (p < 0.05) –Most patients treated with SMV who did not achieve SVR 12 had emergent mutations at the time of failure –Adverse events in the SMV group were clinically manageable, and most were grade 1 or 2. Discontinuation for adverse event was rare in both groups Manns M. Lancet 2014;384: QUEST-2