1. OBV/PTV/r + DSV + RBV OBV/PTV/r + DSV + placebo Randomisation* Partial blind 18-70 years Chronic HCV infection Genotype 1 Treatment-naïve HCV RNA > 10,000 IU/ml No cirrhosis No HBV or HIV co-infection * Randomisation 1:2 if genotype 1a (PEARL-IV) ; 1:1 if genotype 1b (PEARL-III), stratified on IL-28B (CC or non-CC) W12W24W60 SVR 12 PEARL III & IV Ferenci P. NEJM 2014;370:1983-92  Design  Treatment regimens –Co-formulated ombitasvir (OBV)/paritaprevir (PTV)/rironavir (r) : 25/150/100 mg qd = 2 tablets –Dasabuvir (DSV) : 250 mg bid –RBV : 1000 or 1200 mg/day (bid dosing) according to body weight (< or ≥ 75 kg) PEARL-III and IV Studies: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV genotype 1

2.  Efficacy endpoints –Sustained virologic response (HCV RNA < 25 IU/mL) 12 weeks after end of treatment, with two-sided 95% CI, modified ITT analysis –Non-inferiority of SVR assessed vs estimated rate of SVR 24 with a telaprevir- based regimen –for genotype 1a : 72%, 95% CI: 68 to 75 –for genotype 1b : 80%, 95% CI: 75 to 84 –Non-inferiority (primary end-point) established if lower bound of the 95% CI for the SVR greater than the upper bound of the 95% CI for SVR of telaprevir-based therapy minus 10.5%, i.e. 65% in PEARL-IV and 73% in PEARL-III ; power 95% –Superiority in PEARL-IV (genotype 1a) if lower margin of the 95% CI for the SVR 12 > 75% ; in PEARL-III (genotype 1b) if lower margin of the 95% CI for the SVR 12 > 84% ; power 90% –Non inferiority of RBV vs placebo in both studies : SVR 12 rate, with lower margin of the 95% CI for the difference = -10.5% ; power 95%  Trial conduct –Hemoglobin and hematocrit results blinded to investigators, unless criteria for virologic failure or relevant predefined toxicity were met PEARL III & IV Ferenci P. NEJM 2014;370:1983-92 PEARL-III and IV Studies: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV genotype 1

3.  HCV RNA : COBAS TaqMan real-time RT–PCR assay, v 2.0 (Roche)  Virologic failure : –2 consecutive HCV RNA > 1 log 10 IU/ml above the nadir at any time during treatment, –HCV RNA ≥ 25 UI/ml at all assessments during treatment among patients who received at least 6 weeks of treatment, –confirmed HCV RNA ≥ 25 IU/ml after a level < 25 IU/ml during treatment  Virologic relapse : confirmed HCV RNA ≥ 25 IU/ml between the end of treatment and 12 weeks after the last dose of study drug among patients who completed treatment and had an HCV RNA < 25 IU/ml at the final visit during the treatment period  Exploratory analysis : stepwise logistic-regression model to assess the association between the rate of SVR 12 and continuous and categorical subgroup variables PEARL III & IV Ferenci P. NEJM 2014;370:1983-92 PEARL-III and IV Studies: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV genotype 1

4. 3D + RBV N = 100 3D + placebo N = 205 Mean age, years51.651.4 Female30%37.1% Race : white/black86.0% / 10.0%83.4% / 12.7% Body mass index, mean (SD) 26.9 ± 4.026.7 ± 4.3 Metavir fibrosis score : F0-F1 / F2 / F363% / 21% / 16%64% / 17% / 19% IL28B CC genotype31.0%30.7% HCV RNA log 10 IU/ml, mean (SD) 6.64 ± 0.506.53 ± 0.68 Discontinued treatment, N011 For adverse event / for virologic failure-2 / 6 PEARL III & IV Ferenci P. NEJM 2014;370:1983-92 Baseline characteristics and patient disposition PEARL-IV Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV genotype 1a

5. 3D + RBV N = 210 3D + placebo N = 209 Mean age, years48.449.2 Female49.5%58.9% Race : white/black94.3% / 4.8%94.2% / 4.8% Body mass index, mean (SD) 25.8 ± 3.826.1 ± 4.2 Metavir fibrosis score : F0-F1 / F2 / F371% / 18% / 11%68% / 23% / 10% IL28B CC genotype21.0%21.1% HCV RNA log 10 IU/ml, mean (SD) 6.29 ± 0.776.33 ± 0.67 Discontinued treatment, N11 Withdrew consent11 PEARL III & IV Ferenci P. NEJM 2014;370:1983-92 Baseline characteristics and patient disposition PEARL-III Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV genotype 1b

6. SVR 12 (HCV RNA < 25 IU/ml) 3D + RBV 3D + placebo PEARL-IV (GT 1a) 3D + RBV 3D + placebo PEARL-III (GT 1b) 3D + RBV 3D + placebo PEARL-IV, N320 On-treatment virologic failure 16 Relapse1/9810/194 Early discontinuation03 Missing data11 3D + RBV 3D + placebo PEARL-III, N12 On-treatment virologic failure 10 Relapse00 Early discontinuation00 Missing data02 Outcomes for patients without SVR 12 25 50 100 75 97 90.2 % 99.599.0 N100205210209 SVR 12 ≠ - 6.8% (95% CI: -12.0 to -1.5) ≠ - 0.5% (95% CI: -2.1 to 1.1) superiority, andnon-inferiority thresholds (vs TVR) PEARL III & IV Ferenci P. NEJM 2014;370:1983-92 0 PEARL-III and IV Studies: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV genotype 1

7. PEARL III & IV Ferenci P. NEJM 2014;370:1983-92  Multivariate analysis of factors associated with increased SVR –IL28B CC genotype (p = 0.03)  Resistance testing (population sequencing) –18 virologic failures (on-treatment or relapse) –Resistance, N = 18/18 Most frequent variants : –D168V (NS3), –M28T and Q30R (NS5A), –S556G (NS5B) PEARL-IV Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV genotype 1a

8. 3D + RBV3D + placebop Any adverse event92.0%82.4%0.03 AE leading to treatment discontinuation02 Serious AE3 (3.0%)1 (0.5% AE occurring in > 10% in either group Headache25.0%28.3% Fatigue46.0%35.1% Pruritus10.0%5.9% Nausea21.0%13.7% Insomnia17.0%7.8% 0.02 Diarrhea14.0%16.1% Laboratory abnormalities Hemoglobin < LLN42.0%3.9%< 0.001 Hemoglobin ≤ 10 g/dl4.0%00.01 Total biliubin > 3 x ULN3.0%0.5% ALT > 5 x ULN1.0%0.5% AST > 5 x ULN00 Adverse events and laboratory abnormalities, n (%) PEARL III & IV Ferenci P. NEJM 2014;370:1983-92 PEARL-IV Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV genotype 1a

9. 3D + RBV3D + placebop Any adverse event80.0%67.0% 0.003 AE leading to treatment discontinuation00 Serious AE4 (1.9%) AE occurring in > 10% in either group Headache24.3%23.4% Fatigue21.4%23.0% Pruritus11.9%5.3%0.02 Nausea11.0%4.3%0.02 Insomnia9.0%3.3%0.02 Diarrhea4.3%6.2% Laboratory abnormalities12.8% Hemoglobin < LLN51.2%3.4%< 0.001 Hemoglobin ≤ 10 g/dl9.0%0< 0.001 Total biliubin > 3 x ULN5.7%0.5%0.003 ALT > 5 x ULN1.0%0 AST > 5 x ULN00 PEARL III & IV Ferenci P. NEJM 2014;370:1983-92 Adverse events and laboratory abnormalities, n (%) PEARL-III Study: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV genotype 1b

10.  Summary –After 12 weeks of treatment with ombitasvir/paritaprevir/ritonavir and dasabuvir with or without RBV, 90.2% to 99.5% of previously untreated patients with HCV genotype 1 infection and no cirrhosis had a SVR 12 –Response rates in all treatment groups were superior to the historical response rate with a PEG-IFN-containing telaprevir- based regimen In genotype 1b, SVR 12 was > 99% with or without RBV A total of 18 patients with genotype 1a had virologic failure, and only 2/18 received RBV. The use of RBV in genotype 1a confers an additional benefit –Regardless of whether the antiviral regimen included RBV, the rate of discontinuation of the study drugs owing to adverse events was low (<1%) PEARL III & IV Ferenci P. NEJM 2014;370:1983-92 PEARL-III and IV Studies: ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin for HCV genotype 1