1. Futuros tratamientos de la hepatitis C Maria Buti Hospital Universitario Valle Hebron and Ciberehd del Instituto Carlos III Barcelona Spain IV Curso para Residentes “Diagnostico y Tratamiento de las Enfermedades Hepáticas”. Barcelona 2013

2. Future Treatment Aspirations: Overcoming the Barriers to Increase the Chance of Cure for More Current HCV Care 1 Future of HCV Care North CS, et al. Gen Hosp Psych. 2012. Epub ahead of print IFN Sparing Regimens Simpler, shorter duration Improved tolerability/ adherence Broadly Efficacious Burden of Advanced Disease Health-Care Costs Increase Screening

3. Preclinical Phase I Phase II Phase III Filed Boceprevir Telaprevir TMC-435 MK7009ITMN191/R7227 BI201335 BMS650032 GS9256 MK5172 (MSD) ABT450 (ABT) ACH2684 BMS 790052 AZD-7295 BMS 824393 PPI-1301 EDP-239 GSK IDX719 MSD IFN λ Alisporivir Nitazoxamide Silibinine Vitamine D R7128 GS- 7977 BI Japan Tobacco R0622 Medivir GLS9393 Biocryst BMS189 BMS791325 Filibuvir GS9190 ANA598 BI201127 Vx222 ABT333 ABT072 IDX 375 IDX 184 SCY-835 PPI-461 VBY-376 VX-985 VX-813 GS9451 RG7348 TMC 647055 A837093 VX-916 VX-759 Celgosivir Bavituximab Lots of DAAs in Development AVL-181 AVL-192 ACH-2928 GS-5885 Nucleoside NS5B Polymerase Inhibitors Nucleotide NS5B Polymerase Inhibitors Non Nuc NS5B Polymerase inhibitors NS3/4A Protease inhibitors NS5A inhibitors DAA combinations Others Cyclophilin IDX 077 IDX 079 ABT267 Adapted from Bourliere M, et al. Clin Res Hepatol Gastroenterol. 2011;35(suppl 2):S84-S95.

4. Farmacos combinados con PegIFN and Ribavirina Pendientes de Aprobacion en Octubre del 2013 ClaseFarmacoDosisActividad Analogo de los Nucleotidos Inhibidor de la SofosbuvirDiarioPangenotipic0 [1,2] Inhibidor Proteasa NS3A FaldaprevirDiarioGT 1, 4, 5, 6 [3] Inhibidor Proteasa NS3A SimeprevirDiarioGT 1, 2, 4, 5, 6 [4] 1. Gane EJ, et al. N Engl J Med. 2013;368:34-44. 2. Herbst DA. Expert Opin Investig Drugs. 2013;22:527-36. 3. White PW, et al. Antimicrob Agents Chemother. 2010;54:4611-4618. 4. Moreno C, et al. J Hepatol. 2012;56:1247-1253.

5. Simeprevir+PR en Genotipo 1 QUEST-2: SVR Manns M, et al. EASL 2013. Abstract 1413. Reproduced with permission. Brazo SMV Duracion TGR 91% of pts en el brazo de SMV con TGR n/N = SMV + P/R P/R Todos 24 sem48 sem 100 80 60 40 20 0 SVR12 (%) 81 50 86 32 209/25767/134202/2357/22

6. QUEST-1: SVR12 by Fibrosis Level, Subtype, and Baseline Resistance Jacobson I, et al. EASL 2013. Abstract 1425. Reproduced with permission. 18/31 n/N = 5/17188/22960/113 82 53 58 29 SMV + P/R P/R 100 80 60 40 20 0 SVR12 (%) No CirrhosisCirrhosis 105/11729/56105/14736/74 71 49 90 52 100 60 20 0 SVR12 (%) GT 1aGT 1b 80 40 Differences in SVR12 by Subgroup (95% CIs) GT 1a/other HCV - With baseline Q80K vs Pbo - Without baseline Q80K vs Pbo GT 1b HCV 28.2 (13.4-42.9) 4.7 (-14.6 to 24.1) 40.3 (25.8-54.8) 42.1 (26.5-57.6) 147 60 86 117 74 74 74 56 SMV (n) Pbo (n) Favors Placebo Favors SMV -100-50050100

7. STARTVerso1: SVR12 According to ETS, Genotype, and Fibrosis Level 23% of pts with GT 1a HCV had Q80K at baseline; not predictive of SVR12 Ferenci P, et al. EASL 2013. Abstract 1416. Reproduced with permission. 60/ 87 16/ 45 143/ 171 52/ 86 172/ 212 30/ 45 9/ 16 FDV 120 mg n/ N = 226/ 259 233/ 261 194/ 226 208/ 233 100 80 60 40 20 0 Patients (%) Achieved ETS SVR12 in ETS Pts 87 89 86 89 100 80 60 40 20 0 SVR12 (%) GT 1aGT 1b 69 36 84 60 FDV 240 mgPlacebo 81 67 56 < F3≥ F3F4 ETS defined as HCV RNA < 25 IU/mL at Wk 4 and HCV RNA < 25 IU/mL, target not detected at Wk 8.

8. NEUTRINO: 12 Wks’ Sofosbuvir + P/R in Treatment-Naive GT 1/4/5/6 HCV Patients Open-label, single-arm study of sofosbuvir 400 mg QD + P/R for 12 wks in treatment-naive patients with GT 1/4/5/6 HCV – 17% had cirrhosis; 89% had GT 1, 9% had GT 4, < 1% had GT 5, 2% had GT 6 HCV Lawitz E, et al. EASL 2013. Abstract 1411. Reproduced with permission. P/R: pegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day HCV RNA < LLOQ (%) 99 90 100 80 60 40 20 0 Wk 4EOTSVR12 321/325326/327 295/327 n/N =

9. NEUTRINO: SVR12 With Sofosbuvir + P/R According to Genotype and Fibrosis Level Lawitz E, et al. EASL 2013. Abstract 1411. Reproduced with permission. SVR12 (%) 92 80 100 80 60 40 20 0 No Cirrhosis Cirrhosis 252/27343/54 SVR12 According to Fibrosis Level SVR12 (%) 89 96 100 80 60 40 20 0 GT 1GT 4GT 5,6 261/29227/28 7/ 7 SVR12 According to Genotype n/N =

10. Summary of Safety Findings From Phase III Trials Greatly improved Hb profile with simeprevir and faldaprevir vs boceprevir/telaprevir with no significant increase over pegIFN/RBV [5-7] Simeprevir [5,6] – Generally well tolerated; no added safety signals with triple therapy Faldaprevir [7] Generally well tolerated (clinically benign and transient bilirubin increases with 240 mg dose; higher incidence of gastrointestinal events and rash) Sofosbuvir [1-4] – Generally well tolerated; low rates of grade 3/4 AEs, serious AEs, and treatment discontinuation due to AEs; improved profile with SOF/RBV vs pegIFN/RBV 1. Lawitz E, et al. EASL 2013. Abstract 1411. 2. Nelson D, et al. EASL 2013. Abstract 6. 3. Nelson D, et al. EASL 2013. Abstract 6. 4. Jacobson I, et al. EASL 2013. Abstract 61. 5. Jacobson I, et al. EASL 2013. Abstract 1425. 6. Manns M, et al. EASL 2013. Abstract 1413. 7. Ferenci P, et al. EASL 2013. Abstract 1416.

11. Summary of Resistance Findings From Phase III Trials Sofosbuvir [1-4] – No S282T mutations identified; other NS5B genetic variants not associated with change in phenotypic susceptibility Simeprevir [5,6] – Baseline Q80K polymorphism present in 41% of patients with GT 1a HCV and associated with lower SVR12 rate in QUEST-1 [5] – Emergent NS3 protease mutations in > 90% of patients without SVR (GT 1a: R155K alone, with mutations at positions 80 and/or 168; GT 1b: most common mutation D168V, Q80R + D168E) [5,6] Faldaprevir [7] – Baseline Q80K present in 23% of patients with GT 1a HCV but not associated with SVR12 rate 1. Lawitz E, et al. EASL 2013. Abstract 1411. 2. Nelson D, et al. EASL 2013. Abstract 6. 3. Nelson D, et al. EASL 2013. Abstract 6. 4. Jacobson I, et al. EASL 2013. Abstract 61. 5. Jacobson I, et al. EASL 2013. Abstract 1425. 6. Manns M, et al. EASL 2013. Abstract 1413. 7. Ferenci P, et al. EASL 2013. Abstract 1416.

12. E1CE2p7NS2NS3NS4ANS4BNS5ANS5B Viral targets Host targets HCV Drugs in Development in All Oral Regimens * *On clinical hold, Idenix press release; **On clinical hold, Novartis press release NS3NS5ANS5BCyclophilin A PHASE III ABT-450/rABT-267 Non-nucleoside analogue ABT-333

13. * 8 patients with SVR12 have not returned for >24 weeks and are counted as virologic failures for SVR24; 3 patients relapsed between SVR12 and SVR24. Treatment-naïve ABT-450 ABT-333 RBV ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-267 ABT-333 ABT-450 ABT-267 RBV N ABT-450 ABT-267 ABT-333 RBV Wk 0 Wk 8 Wk 12Wk 24 80 79 80 41 Regimen/Duration Null Responder ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 RBV 45 43 ABT-450 ABT-267 ABT-333 RBV SVR 12 % SVR 24 * % Breakthrough/Rel apse 89880 / 10 85831 / 4 91891 / 8 90871 / 5 99960 / 1 93900 / 2 89 0 / 5 93 3 / 0 98951 / 0 AVIATOR Study: ABT-450/r, ABT-267, ABT-333 +/- RBV in Non- Cirrhotic, Naïve and Null Responders Kowdley K, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 3. N = 571

14. AVIATOR: Safety Grade 3 event, n Pooled (N =247) Treatment-Naïve (N =159) Null Responders (N = 88) ALT >5x – 20x ULN110 AST >5x – 20x ULN000 Alkaline Phosphatase >3x – 20x ULN000 Total bilirubin > 3x – 10xULN642 Hemoglobin < 8.0 – 6.5 g/dL000 Grade 4 event, n ALT > 20x ULN000 AST > 20x ULN000 Alkaline Phosphatase > 20x ULN000 Total bilirubin > 10x ULN000 Hemoglobin < 6.5 g/dL000 Kowdley K, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 3. Note: Value must also be more extreme than the baseline value 3 DAAs + RBV

15. E1CE2p7NS2NS3NS4ANS4BNS5ANS5B Viral targets Host targets HCV Drugs in Development in All Oral Regimens * *On clinical hold, Idenix press release; **On clinical hold, Novartis press release NS3NS5ANS5BCyclophilin A Faldaprevir non-nucleoside analogue BI-207127,

16. SOUND-C2: SVR12 by HCV GT-1 subtype and IL28B genotype Zeuzem et al., J Hepatol 2012;56(Suppl.2):S45 (Abstract 101) 1a non-CC1a CC1b non-CC1b CC 6/87/2210/1131/37 SVR12 (%) Faldaprevir 120 mg QD, deleobuvir 600 mg BID and RBV for 28 weeks:

17. Adverse Events and discontinuations Number (%) of patients TID16W (n=81) TID28W (n=80) TID40W (n=77) BID28W (n=78) TID28W, no RBV (n=46) D/C due to AEs4 ( 4.9)10 ( 12.5)19 ( 24.7)6 ( 7.7)5 ( 10.9) Photosensitivity AEs Moderate4 (5)3 (4)6 (8)00 Severe01 (1)2 (3)00 Jaundice AEs Moderate2 (3)6 (8)3 (4)2 (3)0 Severe00000 Rash AEs Moderate2 (3) 04 (9) Severe1 (1)0 00 Vomiting AEs Moderate4 (5)10 (13)3 (4) 2 (4) ALT/GPT Grade 31 (1)002 (3)0 Bilirubin Grade 333 (41)15 (19)20 (26) 6 (13) Grade 44 (5)10 (13)5 (6)10 (13)0

18. E1CE2p7NS2NS3NS4ANS4BNS5ANS5B Viral targets Host targets HCV Drugs in Development in All Oral Regimens * *On clinical hold, Idenix press release; **On clinical hold, Novartis press release NS3NS5ANS5BCyclophilin A Ledipasvir (GS-5885) Nucleos(t)ide Analogue Sofosbuvir Non-Nucs GS-9669

19. ELECTRON Study: Sofosbuvir + Ledipasvir (NS5A )or GS- 9669 (NonN NS5B) + RBV: 12 week Regimens in GT1 non cirrhotic SOF + RBVSOF + LDV + RBVSOF + GS-9669 + RBV Naïve (n=25) Null (n=10) Naïve (n=25) Null (n=9) Naïve (n=25) Null (n=10) Week 18/25 (32)1/10 (10)11/25 (44)0/9 (0)3/25 (12)0/10 (0) Week 217/25 (68)7/10 (70)22/25 (88)4/9 (44)15/25 (60)2/10 (20) Week 425/25 (100)10/10 (100)25/25 (100)8/9 (89)23/25 (92)10/10 (100) EOT25/25 (100)10/10 (100)25/25 (100)9/9 (100)25/25 (100)10/10 (100) SVR422/25 (88)1/10 (10)25/25 (100)9/9 (100)23/25 (92)10/10 (100) SVR1221/25 (84)1/10 (10)25/25 (100) † 9/9 (100)23/25 (92)3/3 Patients with HCV RNA <LOD* over time, n/N (%) Gane E, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 14. * Analyzed by TaqMan® HCV Test 2.0 with limit of detection (LOD) of 15 IU/mL. † Includes 1 patient who stopped all treatment due to a serious adverse event (AE) at Week 8; this patient subsequently achieved SVR12. EOT, end of treatment; SVR4, sustained virologic response 4 weeks after EOT.

20. 58 59 44 54 10 11 8 13 89 145 99 139 13 38 11 37 Genotype 2Genotype 3 E. Gane et al, Abstract 5. EASL, April 2013; Lawitz et al., N Engl J Med 2013. DOI: 10.1056/NEJMoa1214853 FISSION study SOF+RBV 12 wks SVR12 results by Genotype and Fibrosis

21. 6/105/26 FUSION Study: Treatment-experienced, Genotype 2 or 3 Patients SVR12 by HCV Genotype/Cirrhosis SVR12 (Percentage) 25/267/923/2314/3814/2325/40 No cirrhosis SOF + RBV 12 weeks SOF + RBV 16 weeks No cirrhosisCirrhosis GT 2GT 3 Nelson D, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 6. GT3= 62%, Relapse 75%

22. POSITRON Study: Interferon Ineligible/Intolerant Genotype 2 or 3 Patients SVR12 by Cirrhosis Status GT 2GT 3 SVR12 (Percentage) 85/9216/1757/843/14 No cirrhosisCirrhosis Jacobson I, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 61.

24. Futuro Tratamiento hepatitis C Tratamiento oral Actividad antiviral en todos los genotipos Duracion más corta Problablemente sin ribavirina Seguridad y Eficacia excelente No Resistencias Amplia Aplicabilidad: Coinfeccion, Cirrosis descompensada Trasplantados, Enfermedad renal terminal