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

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 Epub ahead of print IFN Sparing Regimens Simpler, shorter duration Improved tolerability/ adherence Broadly Efficacious Burden of Advanced Disease Health-Care Costs Increase Screening

Preclinical Phase I Phase II Phase III Filed Boceprevir Telaprevir TMC-435 MK7009ITMN191/R7227 BI BMS GS9256 MK5172 (MSD) ABT450 (ABT) ACH2684 BMS AZD-7295 BMS PPI-1301 EDP-239 GSK IDX719 MSD IFN λ Alisporivir Nitazoxamide Silibinine Vitamine D R7128 GS BI Japan Tobacco R0622 Medivir GLS9393 Biocryst BMS189 BMS Filibuvir GS9190 ANA598 BI Vx222 ABT333 ABT072 IDX 375 IDX 184 SCY-835 PPI-461 VBY-376 VX-985 VX-813 GS9451 RG7348 TMC A 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.

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: Herbst DA. Expert Opin Investig Drugs. 2013;22: White PW, et al. Antimicrob Agents Chemother. 2010;54: Moreno C, et al. J Hepatol. 2012;56:

Simeprevir+PR en Genotipo 1 QUEST-2: SVR Manns M, et al. EASL Abstract 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 SVR12 (%) /25767/134202/2357/22

QUEST-1: SVR12 by Fibrosis Level, Subtype, and Baseline Resistance Jacobson I, et al. EASL Abstract Reproduced with permission. 18/31 n/N = 5/17188/22960/ SMV + P/R P/R SVR12 (%) No CirrhosisCirrhosis 105/11729/56105/14736/ SVR12 (%) GT 1aGT 1b 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 ( ) 4.7 (-14.6 to 24.1) 40.3 ( ) 42.1 ( ) SMV (n) Pbo (n) Favors Placebo Favors SMV

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 Abstract Reproduced with permission. 60/ 87 16/ / / / / 45 9/ 16 FDV 120 mg n/ N = 226/ / / / Patients (%) Achieved ETS SVR12 in ETS Pts SVR12 (%) GT 1aGT 1b FDV 240 mgPlacebo < 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.

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 Abstract Reproduced with permission. P/R: pegIFN alfa-2a 180 µg/wk + RBV mg/day HCV RNA < LLOQ (%) Wk 4EOTSVR12 321/325326/ /327 n/N =

NEUTRINO: SVR12 With Sofosbuvir + P/R According to Genotype and Fibrosis Level Lawitz E, et al. EASL Abstract Reproduced with permission. SVR12 (%) No Cirrhosis Cirrhosis 252/27343/54 SVR12 According to Fibrosis Level SVR12 (%) GT 1GT 4GT 5,6 261/29227/28 7/ 7 SVR12 According to Genotype n/N =

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 Abstract Nelson D, et al. EASL Abstract Nelson D, et al. EASL Abstract Jacobson I, et al. EASL Abstract Jacobson I, et al. EASL Abstract Manns M, et al. EASL Abstract Ferenci P, et al. EASL Abstract 1416.

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 Abstract Nelson D, et al. EASL Abstract Nelson D, et al. EASL Abstract Jacobson I, et al. EASL Abstract Jacobson I, et al. EASL Abstract Manns M, et al. EASL Abstract Ferenci P, et al. EASL Abstract 1416.

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

* 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 Regimen/Duration Null Responder ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-267 ABT-333 RBV SVR 12 % SVR 24 * % Breakthrough/Rel apse / / / / / / / / / 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, Abst. 3. N = 571

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, Abst. 3. Note: Value must also be more extreme than the baseline value 3 DAAs + RBV

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 ,

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:

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

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

ELECTRON Study: Sofosbuvir + Ledipasvir (NS5A )or GS (NonN NS5B) + RBV: 12 week Regimens in GT1 non cirrhotic SOF + RBVSOF + LDV + RBVSOF + GS 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, 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.

Genotype 2Genotype 3 E. Gane et al, Abstract 5. EASL, April 2013; Lawitz et al., N Engl J Med DOI: /NEJMoa FISSION study SOF+RBV 12 wks SVR12 results by Genotype and Fibrosis

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, Abst. 6. GT3= 62%, Relapse 75%

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, Abst. 61.

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