O. Giouleme Assistant Professor of Gastroenterology Ippokration General Hospital of Thessaloniki

O. Giouleme Assistant Professor of Gastroenterology Ippokration General Hospital of Thessaloniki

Disclosures Advisory Board: Abbvie Pharmaceuticals Speaker: Gilead Sciences, Bristol-Myers Squibb Research grants: Gilead Sciences, Abbvie Pharmaceuticals Clinical Trials: Merck&Dohme The presentations may contain new scientific data, as these have been presented in international congresses or scientific journals that may contain data beyond the approved summary of Product Characteristics (SmPC) (EOF Circular 49392/07.7.2011). For full prescription information please refer to the SmPC before prescribing.

SVR* (%) -2011: Have We Reached Glass Ceiling for SVR with Standard of Care? 100 80 All Gt Gt 1 Gt 2/3 61-79 76-82 60 40 18-39 35-43 33-36 42-46 20 6-19 11-19 10-22 0 Duration (Wk) IFN Monotherapy 24 48 72 Peg-IFN IFN + RBV Peg-IFN + RBV *Range of values reported; lower bar represents lower value. RBV, ribavirin. Poynard T et al. Lancet. 1998;352:1426-32; McHutchison JG et al. N Engl J Med. 1998;339:1485-92; Reichard O et al. Lancet. 1998;351:83-7; Fried MW et al. N Engl J Med. 2002;347:975-82; Manns MP et al. Lancet. 2001;358:958-65.

HCV

p7 Multiple Classes of Direct-Acting Antiviral Agents 5 UTR Core E1 E2 NS2 NS3 NS4B NS5A NS5B 3 UTR Protease Polymerase Ribavirin NS3 Protease Inhibitors NS5A Replication Complex Inhibitors NS5B NUC Inhibitors NS5B Non-NUC Inhibitors Telaprevir Boceprevir Simeprevir Asunaprevir ABT-450 MK-5172 Faldaprevir Sovaprevir ACH-2684 Daclatasvir Ledipasvir Ombitasvir MK-8742 GS-5885 GS-5816 ACH-3102 PPI-668 GSK2336805 Samatasvir Sofosbuvir VX-135 IDX21437 ACH-3422 Dasabuvir BMS-791325 PPI-383 GS-9669 TMC647055 *Representative list; may not be fully inclusive.

First generation DAAs NS3/NS3-4A protease inhibitors (boceprevir, telaprevir) Approved 2011 Became SOC for HCV-1 patients in combination with PEG- IFN/RBV SVR ~ 70% Many limitations low genetic barrier many side effects complex medication regimen poor SVR rates in prior non-responders, cirrhosis only genotype 1

SVR rate (%) Evolution of HCV genotype 1 treatment: the future? 100 80 63 79% 90-100% 60 40 20 2 7% IFN 1 16 28% IFN + RBV 1 42 54% Peg-IFN + RBV 2 4 First wave DAA + Peg- IFN + RBV 5,6 Second wave DAA Future? 0 1990 2000 2010 2014 1. McHutchison JG, et al. N Engl J Med 1998;339:1485 92; 2. Fried M, et al. N Engl J Med 2002;347:975 82 3. Manns MP, et al. Lancet 2001;358:958 65; 4. Hadziyannis SJ, et al. Ann Intern Med 2004;140:346 55 5. Telaprevir EU SmPC; 6. Boceprevir EU SmPC

Sofosbuvir Nucleotide analog- inhibitor of the NS5B polymerase Acts as a chain terminator-inhibition of RNA synthesis Prodrug is converted intrahepatically to its active metabolite Advantages NS5B active site is well-conserved across HCV genotypes pangenotypic efficacy Mutations in the active site of NS5B result in the detrimental condition of the virus resistance was not observed

Sofosbuvir December 2013: FDA(Food & Drug Administration) approval January 2014: EMA(European Medicine Agency) approval for <pangenotyping HCV treatment either in combination with PEG-IFN/RBV, or in IFN free combination with RBV or other DAAs> Is of special interest due to: 1.pangenotypic efficacy 2.high potency 3.low side effects 4.high barrier to resistance 5.easy oral administration 6.all oral regimens

Sofosbuvir Phase 3 Study Designs IFN- LIMITING ALL ORAL THERAPY No response-guided therapy Week 0 12 16 24 36 Treatment-Naïve: NEUTRINO GT 1,4,5,6 SOF + PegIFN + RBV, n=327 SVR12 SVR24 GT 2,3 GT 2,3 GT 2,3 GT 2,3 TN GT 1 TN GT 2,3 TE Treatment-Naïve and Treatment-Experienced: VALENCE GT 2 GT 3 Historical Control: TVR or BOC + PegIFN + RBV SOF + RBV, n=73 SOF + RBV, n=250 Treatment-Naïve: FISSION SOF + RBV, n=256 PegIFN + RBV, n=243 PegIFN-Unable: POSITRON SOF + RBV, n=207 PBO, n=71 Treatment-Experienced: FUSION SOF 400 mg/d; PegIFN 180 μg/wk; RBV 1000-1200 mg/d for SOF+RBV arms and 800 mg/d for PegIFN+RBV arm SVR12 SVR12 SOF + RBV, n=103 PBO SVR12 SOF + RBV, n=98 Treatment-Naïve and Treatment-Experienced HCV/HIV: PHOTON-1 SOF + RBV, n=68 SOF + RBV, GT 1 n=114, GT 2,3 n=41 SVR12 SVR12 SVR12 SVR12 SVR12 SVR12

Patients with HCV RNA <LLOQ (%) > 90% SVR 12 Across Treatment-Naïve Genotypes 1, 2, 3, 4, 5, 6 100 90% 97% 93% 100% 80 60 40 20 0 GT 1, 4 NEUTRINO GT 2 FISSION & VALENCE GT 3 VALENCE GT 5/6 NEUTRINO Lawitz E, et al. N Engl J Med. 2013 May 16 Lawitz E, et al. APASL 2013. Singapore. Oral #LB-02 Zeuzem S, et al. AASLD 2013. Washington, DC. #1085

Effect of Negative Predictors on SVR Rates Across SOF Studies Predictors of Relapse Multivariate Regression Analysis (Combined Dataset) Factor Odds Ratio p-value HCV RNA 800,000 IU/mL 4.7 <0.001 Cirrhosis 4.0 0.001 IL28B non-cc 3.4 <0.001 Weight 75 kg 2.5 0.01 Treatment experienced 2.3 0.001 Male 2.3 0.01 Sofosbuvir-based regimens were highly effective, even in patients with a combination of multiple negative factors SVR12 rates were comparatively lower in patients with 5 or 6 of the negative predictors Foster G, EASL, 2014, O66

SVR12 (%) Effect of Negative Predictors on SVR Rates Across SOF Studies SVR Rates of SOF-Based Regimens Across Genotypes and Among Patients with Multiple Negative Predictive Factors Retrospective multivariate analysis of Phase 2 and 3 SOF data identified 6 negative predictors associated with relapse: Prior treatment failure, cirrhosis, IL28B non-cc, HCV RNA 800,000 IU/mL, body weight 75kg, male gender GT1 subgenotype (GT1a vs GT1b) was not a significant predictor in the univariate analysis. (OR:1.8; P=0.14) 89% of patients in the Phase 3 program had up to 4 negative predictors SVR12 Rates by Number of Negative Predictors and Genotype GT 1 GT 2 GT 3 GT 1 n=339 GT 2 n=285 SOF + PegIFN + RBV 12 weeks ATOMIC, NEUTRINO SOF + RBV 12 weeks FISSION, POSITRON, FUSION, VALENCE 100 80 60 100 100 100 100 100 100 99 100 93 96 93 86 94 86 61 79 62 67 53 GT 3 n=247 SOF + RBV 24 weeks VALENCE 40 20 Foster G, EASL, 2014, O66 0 0 4/ 4 5/ 5 26/ 26 22/ 22 22/ 22 69/ 69 69/ 70 43/ 43 114/ 122 78/ 81 0 1 2 3 4 5 6 Number of Negative Predictors 55/ 59 89/ 104 65/ 69 57/ 66 11/ 18 26/ 33 23/ 37 N/A 4/ 6 8/ 15

Integrated Safety Analysis of SOF Phase 3 Studies Adverse Events Summary GT 2, 3 GT 1, 4-6 All-oral IFN-based Patients, % Placebo 12 wk n=71 SOF+RBV* 12 wk n=650 SOF+RBV 16 wk n=98 SOF+RBV 24 wk n=250 PegIFN+ 800mg RBV* 24 wk n=243 SOF + PegIFN+ WB RBV* 12 wk n=327 Any AE 78 87 88 91 96 95 Grade 3 AE 1 7 4 7 19 15 AE leading to DC 4 1 0 <1 11 2 Serious AE 3 3 3 4 1 1 2% discontinuations due to AEs in the SOF-containing arms No individual AE led to treatment discontinuation in more than 1 patient receiving SOF + RBV HCC, pyrexia, and cellulitis were the only SAEs occurring in >1 patient in any treatment arm Anemia was the only AE leading to treatment D/C in >1 patient receiving SOF+PegIFN+RBV (2/327) Both patients subsequently achieved SVR12 *RBV dose was 1000 1200 mg/day with SOF-containing regimens and 800 mg/day with PegIFN+RBV regimen. DC, discontinuation. Gordon S, EASL, 2014, P1171

1. sofosbuvir plus ledipasvir 2. sofosbuvir plus daclatasvir 3. sofosbuvir plus simeprevir

Ledipasvir/Sofosbuvir: A Single Tablet Regimen (STR) Ledipasvir Picomolar potency against HCV GT 1a and 1b 1 Effective against NS5B RAV S282T 2 Once-daily, oral, 90 mg LDV NS5A inhibitor Sofosbuvir Potent antiviral activity against HCV GT 1 6 Effective against NS5A RAVs 3 High barrier to resistance Once-daily, oral, 400-mg tablet SOF - NS5B nucleotide polymerase inhibitor Ledipasvir/Sofosbuvir STR Once-daily, oral fixed-dose (90/400 mg) combination tablet, RBV-free Minimal DDIs, no food effect >2000 patients treated LDV NS5A inhibitor SOF - NS5B nucleotide polymerase inhibitor EMA Granted LDV/SOF Accelerated Assessment (27 March, 2014) FDA Granted Priority Review and Breakthrough Status (PDUFA: 10 Oct, 2014) 1. Lawitz E, et al. EASL 2011, poster 1219; 2. Cheng G, et al. EASL 2012, poster 1172; 3. SOVALDI [PI]. Gilead Sciences, Inc. Foster City, CA December 2013

LDV/SOF Clinical Development Program 1022 Cirrhotic Subjects Enrolled ELECTRON LONESTAR ELECTRON- 2 ION-2 ION-4 HCV/HIV Co-infection ERADICATE HCV/HIV Co-infection French ANRS HCV/HIV Co-infection Egypt GT 4 French GT 4,5 Russia GT 1,3 Korea/ Taiwan/ China GT 1 Australia TAP IVDU Japan GT 1 Nosocomial HCV SOLAR-1 SOLAR-2 ION-3 LONESTAR-3 SYNERGY Bleeding Disorders ION-1 SIRIUS Retreatment GT 1 GT 1, incl. PI failures GT 4 GT 1/4 GT 1/2/3/6 Immediate Post-liver Transplant GT 1/3 GT 4/5 Special populations Enrolling cirrhotics Post-renal Transplant Brain Imaging Study Sickle Cell Anaemia

LDV/SOF Phase 3 Program LDV/SOF Phase 3 Program (ION-1, ION-2, ION-3) Wk 0 Wk 8 Wk 12 Wk 24 LDV/SOF + RBV ION-1 ION-2 LDV/SOF LDV/SOF + RBV LDV/SOF ION-3 LDV/SOF + RBV LDV/SOF ION-1: treatment naïve,16% cirrhotic; N = 865 ION-2: treatment experienced, 20% cirrhotic; N = 440 ION-3: treatment naïve, non-cirrhotic; N = 647 N = 1952 total patients (11% cirrhotic [n=224]) Afdhal N, et al. N Engl J Med 2014; 370: 1889-98; Afdhal N, et al. N Engl J Med 2014; 370: 1483-93; Kowdley K, et al. N Engl J Med 2014; 370: 1879-88

SVR12 (%) ION Phase 3 Program (ION-1, ION-2, ION-3) Efficacy Summary LDV/SOF LDV/SOF+RBV 100 99 97 98 99 94 93 96 94 96 99 99 80 60 40 20 0 211/ 214 211/ 217 212/ 217 215/ 217 202/ 215 201/ 216 12 Weeks 24 Weeks 8 Weeks 12 Weeks 12 Weeks 24 Weeks ION-1 GT 1 treatment-naïve including cirrhotics ION-3 GT 1 treatment-naïve non-cirrhotic ION-2 GT 1 treatment-experienced including cirrhotics and PI failures 208/ 216 102/ 109 107/ 111 108/ 109 110/ 111 97% (1888/1952) overall SVR rate 3% (64/1952) did not achieve SVR 1.3% (26) LTFU 0.1% (2) virologic breakthrough (both due to non-adherence) 1.8% (36) relapsed Error bars represent 95% confidence intervals. Afdhal N, et al. N Engl J Med 2014; 370: 1889-98; Afdhal N, et al. N Engl J Med 2014; 370: 1483-93; Kowdley K, et al. N Engl J Med 2014; 370: 1879-88.

SVR12 (%) ION-2 (LDV/SOF±RBV x 12 or 24 weeks) SVR12: Absence of Cirrhosis vs. Cirrhosis Absence of Cirrhosis Cirrhosis 100 95 86 100 99 100 99 100 82 80 60 40 20 0 83/87 19/22 89/89 18/22 86/87 22/22 88/89 22/22 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV Error bars represent 95% confidence intervals Afdhal N, EASL, 2014, O109 Afdhal N, et al. N Engl J Med 2014; 370: 1483-93. 12 Weeks 24 Weeks

ION Phase 3 Program (ION-1, ION-2, ION-3) Pooled Safety n (%) LDV/SOF (N=1080) LDV/SOF+RBV (N=872) Total (N=1952) Adverse Event 800 ( 74%) 745 ( 85%) 1545 ( 79%) Treatment Related AEs 484 ( 45%) 617 ( 71%) 1101 ( 56%) Grade 3 AE 46 ( 4%) 45 ( 5%) 91 ( 5%) SAE 34 ( 3%) 17 ( 2%) 51 ( 3%) Treatment-Related SAE 4 ( <1%) 1 ( <1%) 5 ( <1%) AEs Leading to Study Drug Modification/Interruption 6 ( 1%) 118 ( 14%) 124 ( 6%) Treatment DC due to AE 6 ( 1%) 7 ( 1%) 13 ( 1%) Death 0 0 0 Data on File, Gilead Sciences, Inc.

LDV/SOF ± RBV: Compensated Cirrhosis An Integrated Safety and Efficacy Analysis of >500 Subjects with Compensated Cirrhosis Treated with LDV/SOF±RBV Wk 0 Wk 12 Wk 24 Wk 36 n=118 LDV/SOF SVR12 n=204 LDV/SOF + RBV SVR12 n=133 LDV/SOF SVR12 n=58 LDV/SOF + RBV SVR12 513 subjects with HCV GT 1, compensated cirrhosis Pooled data from Phase 2 and 3 LDV/SOF ± RBV studies LONESTAR, ELECTRON, ELECTRON-2, Japanese Phase 3 study, ION-1, ION-2, SIRIUS Primary efficacy endpoint: SVR12 Bourliere, AASLD, 2014, Oral #82

LDV/SOF ± RBV: Compensated Cirrhosis Demographics Treatment Naïve n=161 Treatment Experienced n=352 Total N=513 Mean age, y (range) 58 (35 77) 57 (23 77) 58 (23 77) Male, n (%) 101 (63) 241 (68) 342 (67) Black, n (%) 13 (8) 13 (4) 26 (5) Asian, n (%) 27 (17) 52 (15) 79 (15) Mean BMI, kg/m 2 (range) 27 (18 44) 28 (17 50) 28 (17 50) IL28B non-cc, n (%) 104 (65) 300 (85) 404 (79) GT 1a, n (%) 86 (53) 220 (63) 306 (60) Mean HCV RNA, log 10 IU/mL (range) 6.4 (4.5 7.6) 6.5 (3.9 7.7) 6.4 (3.9 7.7) Prior PI failure N/A 240 (68) 240 (47) Cirrhosis determination method, n (%) Liver biopsy 72 (45) 169 (48) 241 (47) FibroScan >12.5 kpa 65 (40) 160 (45) 225 (44) FibroTest >0.75 + APRI >2 24 (15) 23 (7) 47 (9) Bourliere, AASLD, 2014, Oral #82

SVR12 (%) LDV/SOF ± RBV: Compensated Cirrhosis Results: SVR12 by Treatment Duration 100 95 LDV/SOF ± RBV, N=513 98 80 60 40 20 0 305/322 188/191 12 Weeks 24 Weeks SVR rates were similar with 12 or 24 weeks of LDV/SOF ± RBV Error bars represent 95% confidence intervals. Bourliere, AASLD, 2014, Oral #82

LDV/SOF ± RBV: Compensated Cirrhosis Results: SVR12 by Treatment Regimen Overall SVR12 12 12 wk wk Duration 24 wk Treatment Naïve 98% 97% 99% Treatment Experienced 95% 94% 98% Regimen LDV/SOF LDV/SOF + RBV 96% 99% 95% 96% LDV/SOF 12 wk 96% 90% Duration/± RBV LDV/SOF + RBV 12 wk LDV/SOF 24 wk 98% 97% 96% 98% LDV/SOF + RBV 24 wk 100% 100% Among TE cirrhotic subjects, 12 weeks of LDV/SOF + RBV resulted in similar SVR rates to 24 weeks of LDV/SOF alone Bourliere, AASLD, 2014, Oral #82 80 90 100 The combination of SOF/LDV with RBV is not approved for the treatment of HCV patients with compensated cirrhosis 80 90 100

LDV/SOF ± RBV: Compensated Cirrhosis Results: Safety Summary Subjects, n (%) LDV/SOF 12 and 24 Wk n=251 LDV/SOF + RBV 12 and 24 Wk n=262 TOTAL N=513 AEs 190 (76) 225 (86) 415 (81) Treatment-related AE 118 (47) 196 (75) 314 (61) Grade 3 AE 19 (8) 20 (8) 39 (8) Serious AE 15 (6) 9 (3) 24 (5) Treatment-related serious AE 1 (<1) 4 (2) 5 (1) AE leading to study drug modification/interruption 3 (1) 38 (15) 41 (8) Treatment D/C due to AE 0 1 (<1) 1 (<1) Death 0 1 (<1) 1 (<1) Grade 3 4 lab abnormality 39 (16) 35 (13) 74 (14) Hemoglobin < 10 g/dl 1 (<1) 26 (10) 27 (5) Hemoglobin < 8.5 g/dl 0 3 (1) 3 (<1) Bourliere, AASLD, 2014, Oral #82

Bourliere, AASLD, 2014, Oral #82 The combination of SOF/LDV with RBV is not approved for the treatment of HCV patients with compensated cirrhosis LDV/SOF ± RBV: Compensated Cirrhosis Conclusion 96% of this group of 513 subjects with compensated cirrhosis achieved an SVR High rates of SVR were observed in all subgroups Among treatment-experienced subjects, 12 weeks of LDV/SOF resulted in a 90% SVR rate Adding RBV or extending treatment duration increased this rate to 96% LDV/SOF was well tolerated in subjects with cirrhosis Use of RBV resulted in more frequent AEs and Hb declines

SVR Rate (%) High SVR Rates with LDV/SOF in HCV Genotype 1 Treatment-Naïve Patients 1986 1998 2001 2002 2011 2013 2014 * 100 90 94-99 80 68-75 80-81 60 54-56 40 34 42 39 20 6 16 0 IFN 6 mo IFN 12 mo IFN+RBV 6 mo IFN+RBV 12 mo *Year of data presentation at EASL 2014 and publication in NEJM PEG 12 mo PEG+RBV 12 mo PI+PEG +RBV 6-12 mo SMV+PEG +RBV 6-12 mo SOF+PEG +RBV 3 mo Adapted from Strader DB, et al. Hepatology 2004;39:1147-71. INCIVEK [PI]. Cambridge, MA: Vertex Pharmaceuticals; 2013. VICTRELIS [PI]. Whitehouse Station, NJ: Merck & Co; 2014. Jacobson I, et al. EASL 2013. Amsterdam. The Netherlands. Poster #1425. Manns M, et al. EASL 2013. Amsterdam. The Netherlands. Oral #1413. Lawitz E, et al. APASL 2013. Singapore. Oral #LB-02; Afdhal N, et al. N Engl J Med 2014; 370: 1889-98; Kowdley K, et al. N Engl J Med 2014; 370: 1879-88. LDV/SOF 2-3 mo

SVR Rate (%) High SVR Rates with LDV/SOF in HCV GT 1 TN or TE Patients with Bridging Fibrosis-Cirrhosis 1986 1998 2001 2002 2011 2013 * 2014 * 100 86-94 90 80 70 40-71 58-65 80-81 60 40-56 50 40 30 20 10-13 17-29 7-41 21 4-47 41-42 10 5 0 IFN 6 mo IFN 12 mo IFN+RBV 6 mo IFN+RBV 12 mo PEG 12 mo PEG+RBV 12 mo BOC+ PEG+RBV 6-12 mo TVR+ PEG+RBV 6-12 mo SMV+ PEG+RBV 6-12 mo FDV+ PEG+RBV 6-12 mo SOF+ PEG+RBV 3 mo LDV/SOF 3 mo *Year of presentation/publication of SMV-, FDV-, and SOF-based regimens in HCV GT 1-3 patients with bridging fibrosis-cirrhosis Adapted from Strader DB, et al. Hepatology 2004;39:1147-71. INCIVEK [PI]. Cambridge, MA: Vertex Pharmaceuticals; 2013. VICTRELIS [PI]. Whitehouse Station, NJ: Merck & Co; 2014. McHutchison J, et al. NEJM 1998; 339: 1485-92; Poynard T, et al. Lancet 1998: 352: 1426-32; Manns M, et al. Lancet 2001; 358: 958-65; Fried M, et al. NEJM 2002; 347: 975-82; Hadziyannis S, et al. Ann Intern Med 2004; 140: 346-55; McHutchison J, et al. NEJM 2009; 361: 580-93. PEGASYS [PI]. Hoffmann-La Roche Inc; 2013. PEGINTRON [PI]. Whitehouse Station, NJ: Merck & Co; 2013. Jacobson I, et al. EASL 2013; Manns M, et al. EASL 2013; Ferenci P, et al. EASL 2013; Fontaine H, et al. EASL 2013. Amsterdam, The Netherlands. #60; Lawitz E, et al. EASL 2013. Amsterdam, The Netherlands. Oral #1411; Lawitz E, et al. N Engl J Med. 2013 May 16; ; Afdhal N, et al. N Engl J Med 2014; 370: 1889-98; Afdhal N, et al. N Engl J Med 2014; 370: 1483-93; Kowdley K, et al. N Engl J Med 2014; 370: 1879-88.

SVR12, % Cross-Study Comparison: VALENCE, LONESTAR-2, PROTON/ELECTRON, and ELECTRON-2 SOF-Based Regimens for HCV GT 3 100 80 60 SOF+RBV x 24 weeks (VALENCE) LDV/SOF+RBV x 12 weeks (ELECTRON-2) SOF+PegIFN+RBV x 12 weeks (TN: PROTON/ELECTRON; TE: LONESTAR-2) 100 94 97 87 89 83 83 73 62 40 20 0 Treatment Naïve Treatment Experienced Non-Cirrhotic Treatment Experienced Cirrhotic SOF-based regimens resulted in similar SVR12 rates in TN and TE HCV GT 3 Zeuzem S, et al. NEJM. 2014. Gane, EASL, 2014, Oral #6 Gane E et al. NEJM 2013;368:34 44. Lawitz E et al. Lancet Infect Dis 2013;13:401 408. Gane, AASLD, 2014, Poster #LB-11 99/105 26/26 38/39 85/98 25/28 10/12 29/47 16/22 10/12 The approved treatment duration of the combination of SOF/LDV with RBV for GT3 is 24 weeks

SVR12, % NIAID SYNERGY All-Oral Treatment for GT 4 with LDV/SOF Interim results from a single center, open-label, Phase 2a trial of LDV/SOF in HCV GT 4 Wk 0 Wk 12 Wk 24 N=21 LDV/SOF SVR12 Demographics Age 55 ± 10 Male, n (%) 14 (67) Black, n (%) 9 (43) Country of Origin Egypt, n (%) 6 (29) United States, n (%) 5 (24) Ethiopia, n (%) 4 (19) Cameroon, n (%) 3 (14) HCV RNA > 800,000 IU/mL, n (%) 13 (62) Treatment Experienced, n (%) 8 (38) Cirrhotic, n (%) 7 (33) 100 80 60 40 20 0 95 19/20 * *One subject has not reached SVR12 timepoint yet Kapoor, AASLD, 2014, Oral #240 95% SVR12 with LDV/SOF for GT 4 HCV No subject discontinued due to an AE

SVR12, % ELECTRON-2: LDV/SOF in GT 6 LDV/SOF for 12 Weeks for HCV GT 6 Two-center, open label study of LDV/SOF for 12 weeks in TN/TE subjects with HCV GT 6 Wk 0 Wk 12 Wk 24 N=25 LDV/SOF SVR12 Demographics Mean age, y (range) 51 (26 76) Male, n (%) 16 (64) White, n (%) 4 (16) Asian, n (%) 22 (88) Mean BMI, kg/m 2 (range) 23.6 (18.5 30.7) IL28B non-cc, n (%) 5 (20) Cirrhosis, n (%) 2 (8) Mean HCV RNA, log 10 IU/mL (range) 6.7 (4.4 7.7) TN, n (%) 23 (92) 100 80 60 40 20 0 96 24/25 No subjects discontinued due to an AE Gane, AASLD, 2014, Poster #LB-11 HCV genotype 6 is not included in the approved indications of SOF/LDV.

AI444-040 study: objective and design Objective: Phase 2 study to evaluate DCV + sofosbuvir (SOF), ± ribavirin (RBV), in treatment-naive, genotype (GT)-1-3 infected patients, and in GT1-infected patients who failed telaprevir (TVR) or boceprevir (BOC) treatment Primary endpoint: SVR 12 following 12 or 24 weeks of treatment Week 24 SVR 12 n=15 7dLI A: 7 d Lead-in SOF, then DCV+SOF Follow-up Chronic HCV GT1a/1b naive (n = 126) n=14 C: DCV+SOF Follow-up n=15 E: DCV+SOF+RBV Follow-up n=41 G: DCV + SOF Follow-up n=41 H: DCV+SOF+RBV Follow-up Chronic HCV GT2/3 naive (n = 44) Chronic HCV GT 1, TVR or BOC failure (n = 41) n=16 n=14 n=14 n=21 n=20 Week 12 SVR 12 7dLI B: 7 d Lead-in Follow-up SOF, then DCV+SOF Follow-up D: DCV+SOF Follow-up F: DCV+SOF+RBV Follow-up Week 24 SVR 12 I: DCV+SOF Follow-up J: DCV+SOF+RBV Follow-up RBV: 1000-1200 mg/day, weight-based (GT 1); 800 mg/day (GT 2/3). GT, genotype, DCV, daclatasvir, SOF, sofosbuvir (GS-7977), RBV, ribavirin, TVR, telaprevir, BOC, boceprevir, SVR, sustained virologic response Sulkowski et al. N Engl J Med 2014;370:211 21.

HCV RNA <LLOQ Patients, % HCV RNA <LLOQ Patients, % AI444-040 study: SVR 12 primary endpoint (mitt) for treatment-naive patients GT1 GT2 GT3 a 100% 100% 100% 100% 95% 100 100 a 92% 89% 80 60 40 80 60 40 20 0 15 15 A LI b SOF, DCV + SOF 14 14 C DCV + SOF 15 15 E DCV + SOF + RBV 41 41 G DCV + SOF 39 41 H DCV + SOF + RBV 20 0 24 26 DCV + SOF ± RBV 16 18 DCV + SOF ± RBV 24 weeks 12 weeks 24 weeks SVR 12 rates were 98% in GT1a and 100% in GT1b SVR 24 rates ranged from 93 100% in GT1, and 88 100% in GT2/3 c LI, lead in; LLOQ = lower limit of quantitation (25 IU/mL), mitt, modified intent to treat a One patient had missing data at post treatment week 12 but achieved SVR24, and one who was lost to follow-up after achieving SVR4 b LI (lead in) with SOF was not included in subsequent trials c 93% and 88% were the percentage for the lead in arm. Sulkowski et al. N Engl J Med 2014;370:211 21. HCV genotype 2 is not included in the approved indications of Daclatasvir in combination with sofosbuvir.

SMV + SOF ± RBV: COSMOS study design Cohort 1: Prior null responders (METAVIR F0 F2), n=80 Cohort 2: Treatment-naïve and prior null responders (METAVIR F3 F4), n=87 Arm 1 SMV + SOF + RBV Follow up Randomised 2:1:2:1 Arm 2 Arm 3 SMV + SOF + RBV SMV + SOF Follow up Follow up Arm 4 SMV + SOF Follow up Stratification Week Cohort 1: HCV geno/subtype and IL28B 0 4 12 24 36 48 Cohort 2: HCV geno/subtype and population (naïve/null) SMV 150 mg QD + SOF 400 mg QD ± RBV 1000/1200 mg/day Jacobson I, et al. AASLD 2013. Abstract LB-3

SVR12, % COSMOS (SMV+SOF±RBV) Results SMV+SOF 12 weeks (N=14) SMV+SOF 24 weeks (N=15) SMV+SOF+RBV 12 weeks (N=27) SMV+SOF+RBV 24 weeks (N=24) 100 90 80 70 60 50 40 30 20 10 0 93 13/ 14 96 26/ 27 No viral breakthrough 93 14/ 15 5 non-virologic failures 79 83 89 100 100 100 100 100 100 100 100 100 89 Overall Q80K No Q80K GT1b GT1a 4 early treatment D/C 19/ 24 1 patient achieved SVR4 but died before SVR12 5/ 6 8/ 9 3/ 3 Relapse occurred in 3 patients (all GT 1a patients with Q80K polymorphism) SMV+SOF±RBV for 12 or 24 weeks led to SVR rates 90% in Metavir F0 2 null responders with HCV GT 1 Subgroup analyses are modified ITT Sulkowski M, EASL, 2014, O7 8/ 9 4/ 4 12/ 12 7/ 7 7/ 7 4/ 4 6/ 6 3/ 3 4/ 4

SVR12, % COSMOS (SMV+SOF±RBV) Results SMV+SOF 12 weeks (N=14) SMV+SOF 24 weeks (N=16) SMV+SOF+RBV 12 weeks (N=27) SMV+SOF+RBV 24 weeks (N=30) 100 90 80 70 60 50 40 30 20 10 0 93 13/ 14 93 25/ 27 100 100 100 100 100 100 100 100 100 100 93 91 88 86 16/ 16 28/ 30 3/ 3 7/ 8 4/ 4 11/ 11 Overall GT1a Q80K GT1b Metavir F4 No viral breakthrough Relapse occurred in 3 GT1a-infected patients (1 with Q80K, 2 without Q80K; all had NS3 mutations) Most common AEs: fatigue 37.9%, headache 19.5% Four serious AEs reported One patient D/C treatment due to AE 3/ 3 5/ 5 4/ 4 6/ 6 6/ 7 10/ 11 9/ 9 12/ 12 Subgroup analyses are modified ITT Lawitz E EASL, 2014, O165

HCV-TARGET Effectiveness and Safety of SOF-Containing Regimens for HCV Started Therapy HCV-TARGET 2.0 N=2063 SOF/P/R N=384 SOF/RBV N=667 SOF/SMV N=784 SOF/SMV/RBV N=228 SOF/SMV/RBV 14.9% SOF/PegIFN/RBV 23.1% SOF/RBV 8.8% SOF SM V SOF/PegIFN/RBV 0.9% SOF/PegIFN/RBV 8.5% SOF/SMV 53.1% SOF/RBV 99.1% SOF/RBV 91.5% Genotype 1 Jensen, AASLD, 2014, Oral #45 Genotype 2 Genotype 3 Real-world observational study of 2,063 patients treated with DAAs at academic (n=38) and community medical centers (n=15) in North America and Europe Post liver transplant HCV recurrence is not included in the approved indications of simeprevir and sorosbuvir

HCV-TARGET Demographics n (%) SOF+PegIFN +RBV n=384 SOF+RBV n=667 SOF+SMV n=784 SOF+SMV +RBV n=228 Total n=2063 Male 253 (66.2) 422 (63.6) 478 (62.0) 147 (65.3) 1300 (63.7) Mean age, y (range) 53.9 (23-79) 56.9 (21-82) 59.5 (20-83) 58.8 (29-80) 57.6 (20-83) Caucasian 270 (70.3) 539 (80.8) 584 (74.5) 177 (77.6) 1570 (76.1) Black 68 (17.8) 37 (5.6) 96 (12.5) 33 (14.7) 234 (11.5) Treatment Status Naive 211 (54.9) 371 (55.6) 318 (40.6) 82 (36.0) 982 (47.6) Experienced 172 (44.8) 296 (44.4) 465 (59.3) 144 (63.2) 1077 (52.2) PI Failure 47 (27.3) 25 (8.4) 76 (24.8) 45 (31.3) 193 (17.9) Cirrhosis 120 (31.3) 302 (45.3) 440 (56.1) 137 (60.1) 999 (48.4) Hx Decompensation 12 (11.4) 136 (49.5) 167 (44.8) 60 (50.8) 375 (43.1) MELD >10 18 (17.1) 120 (43.6) 122 (32.7) 34 (28.8) 294 (33.8) Liver Cancer 25 (6.5) 66 (9.9) 88 (11.2) 32 (14.0) 211 (10.2) Liver Transplant 27 (7.0) 57 (8.5) 111 (14.2) 32 (14.0) 227 (11.0) HIV 14 (3.6) 18 (2.7) 8 (1.0) 7 (3.1) 47 (2.3) 78% (253/323) of GT 1, non-cirrhotic, naïve had a baseline HCV RNA <6 million IU/mL Jensen, AASLD, 2014, Oral #45 Post liver transplant HCV recurrence is not included in the approved indications of simeprevir and sorosbuvir

SVR4, % HCV-TARGET Effectiveness and Safety of SOF-Containing Regimens 100 90 80 70 60 50 40 30 20 10 0 12 Wk Regimens 85 SOF+PegIFN +RBV 89 SOF+SMV ±RBV SOF+PegIFN+ SOF+SMV SOF+SMV SOF+RBV Total RBV ±RBV n=784 n=667 n=2063 n (%) n=384 n=228 Completed treatment 332 (86.5) 189 (82.9) 663 (84.6) 429 (64.3) 1613 (78.2) Ongoing treatment 41 (10.7) 32 (14.0) 101 (12.9) 205 (30.7) 379 (18.4) D/C Prematurely* 11 (2.9) 7 (3.1) 20 (2.6) 33 (4.9) 71 (3.4) AE 6 (1.6) 5 (2.2) 16 (2.0) 17 (2.5) 44 (2.1) Death 1 (0.3) 2 (0.9) 6 (0.8) 3 (0.4) 12 (0.6) 81 140/164 269/303 44/54 168/187 *Not all premature D/C are summarised. Full list available in final slides. GT 1 GT 2 SOF+SMV±RBV Prior PI Failures SVR4/SVR12 Concordance: 94.4 98.2% PPV 90 SOF+RBV Jensen, AASLD, 2014, Oral #45

HCV-TARGET Post Transplant Effectiveness and Safety of Post-Transplant Patients Treated with SOF-Containing Regimens for HCV Started Therapy N=227 SOF/P/R N=27 SOF/RBV N=57 SOF/SMV N=111 SOF/SMV/RBV N=32 SOF/SMV/RBV 17.9% SOF/Peg/RBV 13.4% SOF/RBV 7.3% SOF/Peg/RBV 5.3% SOF/SMV 61.8% SOF/RBV 100% SOF/RBV 94.7% Genotype 1 N=5 will not start treatment; N=3 Data transfer pending Brown, AASLD, 2014, Oral #LB-4 Genotype 2 Genotype 3 Real-world observational study of 2,063 patients treated with DAAs at academic (n=38) and community medical centers (n=15) in North America and Europe

HCV-TARGET Post Transplant Demographics Post-Transplant Patients n(%) *Total, patients who started therapy SOF+PegIFN+ RBV N=27 SOF+RBV N=57 SOF+SMV N=111 SOF+SMV+ RBV N=32 Total* N=227 MALE 21 (77.8) 42 (73.7) 77 (69.4) 27 (84.4) 167 (73.6) MEAN Age, y (range) 60 (53-67) 59 (31-78) 61 (49-78) 59 (46-71) 60 (31-78) Age 65+ 3 (11.1) 13 (22.8) 25 (22.5) 4 (12.5) 45 (19.8) CAUCASIAN 22 (81.5) 47 (82.5) 81 (73.0) 27 (84.4) 177 (78.0) BLACK 3 (11.1) 3 (5.3) 10 (9.0) 3 (9.4) 19 (8.4) TREATMENT STATUS NAIVE 8 (29.6) 28 (49.1) 51 (45.9) 10 (31.3) 97 (42.7) EXPERIENCED 19 (70.4) 29 (50.9) 60 (54.1) 22 (68.8) 130 (57.3) PI FAILURE 4 (21) 0 (0.0) 7 (11.7) 4 (18.2) 15 (11.5) CIRRHOSIS 15 (55.6) 27 (47.4) 67 (60.4) 19 (59.4) 128 (56.4) MELD 10 6 (40.0) 14 (51.9) 14 (20.9) 6 (31.6) 40 (31.3) BASELINE IMMUNOSUPPRESSION TAC 21 (77.8) 41 (71.9) 90 (81.1) 22 (68.8) 174 (76.7) CSA 4 (14.8) 9 (15.8) 13 (11.7) 2 (6.3) 28 (12.3) EVEROLIMUS/SIROLIMUS 3 (11.1) 10 (17.5) 13 (11.7) 10 (31.3) 36 (15.9) MMF/MPA 11 (40.7) 17 (29.8) 48 (43.2) 20 (62.5) 96 (42.3) Brown, AASLD, 2014, Oral #LB-4

SVR24 % HCV-TARGET Post Transplant HCV RNA Outcomes for SOF+SMV±RBV: Genotype 1 100% 94% 95% 90% 90% 86% 83% 80% 70% 60% 50% 40% 30% 20% 10% 0% 61/68 29/31 32/37 30/36 18/19 Overall No Cirrhosis Cirrhosis G1a G1b Cohort of patients with known treatment start date Excludes prior PI failures Brown, AASLD, 2014, Oral #LB-4 Post liver transplant HCV recurrence is not included in the approved indications of simeprevir and sorosbuvir

Please refer to the Summaries of Product Characteristics of individual products for the approved indications and treatment durations AASLD/EASL RECOMMENDATIONS 2014 GENOTYPE 1 AASLD LDV/SOF 12 or 24 weeks SOF+ SIM 12 or 24 weeks EASL SOF+PEG-IFN+RBV 12 weeks SOF+RIB 24weeks SOF+SIM± RBV 12 weeks SOF+DCV± RBV 12 or 24weeks GENOTYPE 2 SOF+RBV 12 or 16 weeks SOF+RBV 12or 16 weeks SOF+RBV+PEG-IFN 12 weeks GENOTYPE 3 GENOTYPE 4 SOF+RBV 24 weeks SOF+RBV+PEG-IFN 12 weeks LDV/SOF 12 weeks SOF+RBV 24 weeks SOF+PEG-IFN+RBV 12 weeks SOF+SIM± RBV 12 weeks SOF+PEG-IFN+RBV 12 weeks SOF+RBV 24 weeks SOF+DCV± RBV 12 or 24weeks SOF+PEG-IFN+RBV 12 weeks SOF+RBV 24 weeks SOF+SIM± RBV 12 weeks SOF+DCV± RBV 12 or 24weeks GENOTYPE 5 SOF+PEG-IFN+RBV 12 weeks SOF+PEG-IFN+RBV 12 weeks SOF+RBV 24 weeks GENOTYPE 6 LDV/SOF 12 weeks SOF+PEG-IFN+RBV 12 weeks SOF+PEG-IFN+RBV 12 weeks SOF+RBV 24 weeks

HCV Guidelines Greece (December 2014) Genotype 1 Genotype 2 Genotype 3 Genotype 4 Genotype 5 or 6 Peg-IFNα+RBV (PR) x24 or 48 wks x12-16 or 24 wks x16 or 24 wks x24 or 48 wks x24 or 48 wks (in naïve patients with mild moderate fibrosis, (in naïve pts without severe (in naïve pts without severe (in naïve patients with mild moderate (in naïve patients with mild moderate low viraemia, IL28B CC, check for RVR) fibrosis or cirrhosis) fibrosis or cirrhosis) fibrosis, IL28B CC, check for RVR) fibrosis, IL28B CC, check for RVR) SOF+PR x12 wks x12 wks x12 wks x12 wks SMV+PR / PR* x12 / 12 or 36 wks x12 / 12 or 36 wks (alternative) DCV+PR / PR (alternative) PR / BOC+PR /PR* (only if SOF or SMV not available) TPV+PR / PR* (only if SOF or SMV not available) SOF+RBV (not in 1a with Q80K) x4 / 24 or 44 / 0 or 20 or 0 wks x12 / 12 or 36 wks x24 wks (only if IFN contraindicated and other IFN free regimen not available) x12 or 24 / 12 or 0 wks x12 wks x24 wks x24 wks x24 wks SOF+SMV* x12 wks x12 wks SOF+DCV x12 or 24 wks x12 wks (non cirrhotics) (alternative) x12 or 24 wks (alternative) SOF/LDV SOF/LDV+RBV PRV/r/OBV+DSV+RBV* x12 wks (x8 wks for treatment naïve non-cirrhotics) x12 wks (for treatment experienced cirrhotics) x12 wks for 1a or 24 wks. (cirrhotics) x12 wks x12 wks (alternative) PRV/r/OBV+DSV* PRV/r/OBV±RBV x12 wks for 1b (alternative) *Not in patients with previous BOC/TPV failure. Peg-IFNα: pegylated interferon -α, RBV: ribavirin, SOF: sofosbuvir, SMV: simeprevir, DCV: daclatasvir, ΒΟC: boceprevir, TPV: telaprevir, LDV: ledipasvir, PRV/r: paritaprevir with ritonavir, OBV: ombitasvir, DSV: dasabuvir Please refer to the Summaries of Product Characteristics of individual products for the approved indications and treatment durations www.keelpno.gr x12 wks

Reflections-dilemmas in 2015 According to recent phase II,III studies, HCV treatment is moving to interferon-free regimens as SOC These regimens increase the possibility of cure HCV in all CHC patients Sofosbuvir represents an almost ideal backbone in HCV treatment especially in difficult to treat patients BUT High cost of new DAAs raises public health debates Their optimal and cost-effective use differ among different countries Treatment options depends on the health care and financial resources available