1. SOF/VEL 400/100 mg qd N = 500 N = 100 W12 Placebo > 18 years Chronic HCV infection Genotype 1, 2, 4, 5 or 6 Naïve or pre-treatment with IFN-based regimen Compensated cirrhosis allowed** No HBV or HIV co-infection Randomisation* 5 : 1 Double blind * Randomisation was stratified on genotype (1, 2, 4, 6 or indeterminate) and cirrhosis (yes or no) Genotype 5 were all included in the active arm SVR 12 ** Metavir F4 or Ishak 5-6 or Fibroscan > 12.5 kPa or Fibrotest > 0.75 and APRI > 2 ASTRAL-1  Design  Objective –SVR 12 (HCV RNA 5% to a prespecified rate of 85% (2-sided significance level of 5%, 90% power) ASTRAL-1 study: SOF/VEL in genotype 1, 2, 4, 5 or 6 FELD JJ. N Engl J Med. 2015 ; 373:2599-607

2. SOF/VEL N = 624 Placebo N = 116 Age, years, mean5453 Female40%41% White 79%78% Genotype 1a 1b 2 4 5 6 34% 19% 17% 19% 6% 7% 40% 16% 18% 19% 0 7% HCV RNA, log 10 IU/ml, mean6.3 + 0.666.3 + 0.58 IL28B CC30%31% Cirrhosis19%18% Treatment experienced PI + PEG-IFN + RBV PEG-IFN + RBV IFN + RBV 9% 20% 4% 5% 21% 3% Discontinuation, N Adverse event / lost to follow-up / investigator decision 2 1 / 1 / 0 3 2 / 0 / 1 Baseline characteristics and patient disposition ASTRAL-1 ASTRAL-1 study: SOF/VEL in genotype 1, 2, 4, 5 or 6 FELD JJ. N Engl J Med. 2015 ; 373:2599-607

3. * Superiority to 85% (p < 0.001) ASTRAL-1 SVR 12 overall and by genotype, % (95 % CI)  SVR 12 according to baseline NS5A RAVs –Absent, N = 359, SVR 12 = 100% ; Present, N = 257, SVR 12 = 99.2% 0 20 40 60 80 100 99 * (97.9- 99.6) 624 Total 210 98.1 (95.2-99.5) 1a 118 99.2 (95.4-100) 1b 104 100 (96.5-100) 2 116 100 (96.9-100) 4 41 100 (91.4-100) 6 Genotype 35 5 97.1 (85.1-99.9) 1 relapse 2 lost to follow-up 1 withdrew consent 1 relapse 1 death ASTRAL-1 study: SOF/VEL in genotype 1, 2, 4, 5 or 6 % FELD JJ. N Engl J Med. 2015 ; 373:2599-607

4. ASTRAL-1 SVR 12 by cirrhosis or prior treatment, % (95% CI) ASTRAL-1 study: SOF/VEL in genotype 1, 2, 4, 5 or 6 618 624 496 501 120 121 418 423 200 201 0 20 40 60 80 100 99 (97.7-99.7) 99.5 (97.3-100) 99.2 (95.5-100) 98.8 (97.3-99.6) NoYesNaïveExperiencedTotal CirrhosisTreatment History 1 relapse 1 death 1 withdrew consent 2 lost to follow-up 1 relapse 1 death 1 withdrew consent 2 lost to follow-up 1 relapse 624501121423201 % FELD JJ. N Engl J Med. 2015 ; 373:2599-607

5. ASTRAL-1 Characteristics of patients with virologic relapse AgeSexRaceGTCirrhosisIL28B HCV RNA Timing of virologic failure HCV treatment history Resistance-associated variants NS5ANS5B BLFUBLFU 56MWhite1aNoCT6.5FU W4NaïveQ30R (2.6%)Y93N (> 99%)None 58MBlack1bYesTT6.8FU W4PEG-IFN + RBV Q30L (1.1%) Q30R (98.7%) L31M (> 99%) Q30R (> 99%) L31I (2.8%) L31M (88.4%) L31V (8.6%) Y93H (72.3%) None HCV RNA in log 10 IU/ml; BL, baseline; FU, follow-up ASTRAL-1 study: SOF/VEL in genotype 1, 2, 4, 5 or 6 FELD JJ. N Engl J Med. 2015 ; 373:2599-607

6. SOF/VEL N = 624 Placebo N = 116 At least one adverse event78%77% Serious adverse events15 (2%)0 Grade 3-4 adverse events18 (3%)1 (< 1%) Discontinuation due to adverse event 1 (< 1%) Anxiety attack 2 (2%) Death1 (<1%)0 (0%) Adverse events in > 10% of patients Headache29%28% Fatigue20% Nasopharyngitis13%10% Nausea12%11% Hematologic abnormalities7%12% Hemoglobin < 10 g/dl2 (< 1%)0 Lymphocyte count 350-500/mm 3 3 (< 1%)0 Neutrophil count 500-750/mm 3 4 (1%)0 Platelet count 25,000-50,000/mm 3 1 (< 1%)0 Adverse events and hematologic abnormalities, N (%) ASTRAL-1 ASTRAL-1 study: SOF/VEL in genotype 1, 2, 4, 5 or 6 FELD JJ. N Engl J Med. 2015 ; 373:2599-607

7. ASTRAL-1  Summary –In this international, randomized, double-blind, placebo-controlled phase III study, treatment with sofosbuvir–velpatasvir for 12 weeks resulted in high rates of SVR 12 (99%) in patients with HCV genotype 1, 2, 4, 5, or 6, including those with cirrhosis and those who had received previous treatment and those who had not been treated –Virologic failure was rare in patients infected with HCV genotype 1, and there were no virologic failures among those with HCV genotype 2, 4, 5 –Presence of baseline NS5A RAVs did not impact SVR 12 Although the 2 patients who had a relapse had RAVs at baseline and at the time of virologic failure, 99% of the patients with baseline NS5A RAVs had a SVR 12, which suggests that pretreatment testing for RAVs is probably of little clinical value with SOF/VEL –Treatment with SOF/VEL for 12 weeks was well tolerated, with a safety profile similar to that of placebo treatment –SOF/VEL for 12 weeks provides a simple, safe, and highly effective treatment for patients with HCV GT 1, 2, 4, 5, or 6 infection, including those with compensated cirrhosis ASTRAL-1 study: SOF/VEL in genotype 1, 2, 4, 5 or 6 FELD JJ. N Engl J Med. 2015 ; 373:2599-607