Tratamiento de la Hepatitis C Rafael Esteban Hospital General Universitario Valle de Hebrón Barcelona

Tratamiento de la Hepatitis C Rafael Esteban Hospital General Universitario Valle de Hebrón Barcelona

rrent HCV Therapy 8% % sustained response 6% 4% 2% % 54-61% 41% 34% 25% 16% 6% IFN 24w IFN 48w Peg IFN-R 24w IFN-R 48w Peg-R

Standard de Tratamiento: Peginterferon α + ribavirina HCV Genotype Genotype 1 (4, 5, 6) Genotype 2/3 CV-RNA quantitative at week 12 2 2 log drop Peginterferon-α plus -12 mg ribavirin for 48 weeks Peginterferon-α plus 8 mg ribavirin for 24 weeks

ctors Related to Therapy Response Virus Genotype Viral load Treatment Adherence Early Virologic Response Ribavirin Dosage Interfering agents (e.g., alcohol) Patient Age Race Weight Cirrhosis Hepatic steatosis HIV co-infection Pre-treatment expression of IFN- response genes IL28b

act of Genotype on SVR Rates PegIFN alfa-2b 1.5 µg/kg/wk + RBV 8 mg/day for 48 wks PegIFN alfa-2a 18 µg/wk + weight-based RBV (1 or 12 mg/d) for 48 wks 1 8 82 8 76 6 4 54 42 6 4 56 46 2 2 n = 511 348 163 n = 453 Overall Overall Genotype 1 Genotype 2/3 298 14 Genotype 1 Genotype 2/3 M, et al. Lancet. 21;358:958-965. Fried MW, et al. N Engl J Med. 22;347:975-982.

tterns of Virologic Response PegIFN alfa and RBV 7 Null Response* 6 5 4 Partial Response* 3 2 Relapse 1 Undetectable RVR EVR ETR SVR -8-4 -2 4 8 12 16 2 24 32 4 48 52 6 72 Wks After Start of Therapy bset of Nonresponse

l Kinetics and Outcome Importance of Rapid logic Response Virologic Response (%) 1 8 6 4 2 RNA Status Wk 4 Wk 12 Wk 24 91 91 Neg Neg Neg 94 72 > 2 log Neg Neg 9 6 < 2 log Neg Neg 86 48 > 2 log > 2 log Neg 9 43 < 2 log > 2 log Neg PegIFN alfa-2a + RBV (N = 453) ETR SVR 13 2 Any Pos Pos ted from Journal of Hepatology, 43, Ferenci P, et al, Predicting sustained virological responses in chronic hepatitis C ts treated with peginterferon alfa-2a (4 KD)/ribavirin, 425-433, 25, with permission from Elsevier. ww.sciencedirect.com/science/journal/1688278

at are Genome wide association ns (GWAS)? Responders Non-responders SNP C or T Pharmacogenetic Analysis of the rs1297986 C allele

R by genotypes of rs1297986 on et al, AASLD 29, oral (LB5); Nature Sept. 29; 461: 399-41

Multivariate Analysis of Baseline Predictors of SVR (Genotype 1 HCV) ITT analysis of patients from IDEAL study who consented to genetic testing, regardless of adherence level dictor Adjusted Odds Ratio (95% CI) P Value 97986 CC 5.2 (4.1-6.7) <.1 RNA level 6, IU/mL 3.1 (2.3-4.1) <.1 te vs black 2.8 (2.-4.) <.1 anic vs black 2.1 (1.3-3.6).41 AVIR F-F2 2.7 (1.8-4.) <.1 ting blood sugar < 5.6 mmol/l 1.7 (1.3-2.2) <.1 pson AJ, et al. Gastroenterology. 21;139:12-129.

HCV RNA decline in relation to IL28b in Genotype 1 patients under treament Median HCV RNA Reduction (log 1 IU/mL) Weeks 2 4 6 8 1 12-1 -2-3 -4-5 -6-7 TT CT CC pson A et al. Gastroenterology 21

New Drugs for Hepatitis C Thompson A et al J of Hepatol 29

Types of drugs Type of drugs Genetic Barrier/ AV Efficacy Other Protease Inhibitor Low/ High Only Gen 1 lymerase Inhibitor Nucleoside Analog High / Low Few in develop All genotypes ymerase Inhibitor Non Nucleo Low/ Medium Genotype 1 Ciclofilin Inhibitor No/ Low Charlton et al AASLD 21.

oceprevir (BOC) is a linear peptidomimetic ketoamide serine NS3 protease inhibitor Effective against Genotype 1 Demonstrated activity in treatment naïve and experienced populations in phase 2 clinical trials

SPRINT 2: Study Design l 3 Week 4 Week 28 Week 48 Week 72 PR lead-in PR + Placebo Follow-up PR lead-in PR + Boceprevir TW 8-24 HCV-RNA Undetectable Follow-up TW 8-24 HCV-RNA Detectable PR + Placebo Follow-up PR lead-in PR + Boceprevir Follow-up eron (P) administered subcutaneously at 1.5 µg/kg once weekly, plus ribavirin (R) using weight based 6-14 mg/day in a divided daily dose ir dose of 8 mg thrice daily

Baseline Characteristics Cohort 1 (Non-black) Cohort 2 (Black) Arm 1: 48 P/R N = 311 Arm 2: BOC RGT N = 316 Arm 3: BOC/ PR48 N = 311 Arm 1: 48 P/R N = 52 Arm 2: BOC RGT N = 52 Arm 3: BOC/ PR48 N = 55 n age (years) 48 49 49 51 52 51 (%) 55 63 6 67 56 6 on (%) rth America 65 72 7 98 98 95 rope 32 25 27 2 2 5 mean (SD) 27 (5) 28 (5) 27 (5) 28 (4) 29 (5) 31 (6) subtype (%)* 6 62 63 79 75 73 36 35 33 17 25 24 RNA level, IU/mL (%) 92 91 93 1 94 96 AVIR F3/F4 (%) 7 8 12 2 15 11 ing performed by NS5B sequencing (Virco, Mechelen, Belgium)

RINT 2: SVR and Relapse Rates (ITT) 4 125 311 p <.1 p <.1 23 37 162 67 68 211 316 213 311 9 8 21/232 18/23 48 P/R BOC RGT BOC/PR48 Non-Black Patients SVR* Relapse Rate % Patients 1 8 6 4 2 p =.44 23 12 52 p =.4 42 22 14 52 12 2/14 3/25 53 17 48 P/R BOC RGT BOC/PR48 Black Patients 29 55 6 35 efined as undetectable HCV RNA at the end of the follow-up period. The 12-week post-treatment HCV RNA level was used if the 24-week postvel was missing (as specified in the protocol). A sensitivity analysis was performed counting only patients with undetectable HCV RNA d at 24 weeks post-treatment and the SVR rates for Arms 1, 2 and 3 in Cohort 1 were 39% (122/311), 66% (27/316) and 68% (21/311), and in Cohort 2 were 21% (11/52), 42% (22/52) and 51% (28/55), respectively.

SVR Based on Week 4 PR Lead-In in Non-Black Patients 1 log 1 HCV RNA decline from baseline <1 log 1 HCV RNA decline from baseline 52 121 234 5 82 82 187 228 29 21 73 178 218 39 31 79 Boceprevir Resistance-associated Variants*: 1 log 1 decline: BOC RGT: 4% (9/232) BOC/PR48: 4% (9/231) < 1 log 1 decline: BOC RGT: 47% (45/95) BOC/PR48: 35% (33/94) 3/62 48 P/R BOC RGT BOC/PR48 previr resistance-associated variants determined with population sequencing

Rationale for Lead-in Phase 4 weeks of PegIFN alfa-2b and ribavirin Achievement of steady-state drug levels Alpha interferon-mediated immune system activation Lower HCV burden May reduce the emergence of viral resistance by decreasing the pool of pre-existing viral quasi-species

oceprevir: Adverse Events and Discontinuations Anemia and dysgeusia reported more frequently in BOC arms vs control in SPRINT-2 [1-2] come erse event, % 4-Wk PR + Response- Guided BOC/PR (n = 368) 4-Wk PR + 44-Wk BOC/PR (n = 366) 48-Wk PR (n = 363) emia [1] 49 49 29 EPO use 41 46 21 sgeusia [2] 37 43 18 ontinuations due to 12 16 16 erse events, % [1] emia [1] 2 2 1 1. Poordad F, et al. AASLD 21.

TELAPREVIR - ADVANCE PR48 (Control) Peg-IFN + RBV T12/PR24 (or 48) Telaprevir + Peg-IFN + RBV Peg-IFN + RBV ervr Yes No No further treatment Peg-IFN/RBV 24 additional weeks T8/PR24 (or 48) Telaprevir + Peg-IFN + RBV Peg-IFN + RBV 4* 12 24 36 48 Weeks * Stopping rule time point for Telaprevir ervr = extended RVR, undetectable at W4 and 12

Efficacy Results from ADVANCE SVR Results (Intent to Treat Analysis) Patients with SVR (%) The SVR rates observed in the two telaprevir-based treatment arms were statistically significant when compared to the control arm (p<.1) AASLD 21

ADVANCE: SVR Rates in Patients Who Qualified For 24 Weeks of Therapy 57% and 58% of patients qualified for 24 weeks of therapy (assessment at Week 4) in 8-wk and 12-wk TVR arms, respectively 1 89 83 8 SVR (%) 6 4 2 n/n = 171/27 189/212 8-wk TVR/PR + 16/4-wk PR 12-wk TVR/PR + 12/36-wk PR

ADVANCE: Response Rates According to Race/Cirrhosis 1 8 8-wk TVR/PR + 16/4-wk PR 12-wk TVR/PR + 12/36-wk PR 48-wk PR 58 62 25 SVR (%) 6 4 2 53 62 33 n/n = 23/4 16/26 7/28 n/n = 45/85 45/73 24/73 Blacks Bridging fibrosis/cirrhosis

laprevir: Discontinuations Discontinuations due to adverse events in Phase III ADVANCE: come, % 8-Wk TVR/PR + 16/4-Wk PR (n = 364) ontinuation of TVR/placebo due to 12-Wk TVR/PR + 12/36-Wk PR (n = 363) 48-Wk PR (n = 361) 7 11 1 ontinuation of all drugs due to AEs 8 7 4 emia 3.3.8.6 son IM, et al. AASLD 21. Abstract 211.

egifn alfa2 and Ribavirin in treatment of hronic Hepatitis C 1 Proportion of Non Response 8 6 58% 54% 4 2 α2b α2a 18% α2b 24% α2a Genotype 1 Genotype 2 and 3 Manns et al. Lancet 21 Fried et al N Eng J Med

dy 17: TVR/PR Retreatment of Pts With PR lure in PROVE 1/2/3 Trials 1 97 8 75 SVR (%) 6 4 59 37 55 2 N = 177 n = 51 n = 29 n = 8 n = 29 Total Prior Null Response Prior Partial Response Prior Breakthrough Prior Relapse T, et al. EASL 21. Abstract 4. Graphic reproduced with permission.

Study Arms and Dosing Regimen ol R Week 4 Week 36 Week 48 Week 72 PR lead-in PR + Placebo Follow-up Week 12 futility TW 8 HCV-RNA Undetectable Follow-up C T 62 PR lead-in PR + Boceprevir TW 8 HCV-RNA Detectable/ TW 12 Undetectable PR + placebo Follow-up / 8 1 PR lead-in PR + Boceprevir Follow-up -RNA measured by the Cobas TaqMan assay (Roche). Patients with detectable HCV-RNA (LLD=9.3 L) at week 12 were considered treatment failures. interferon (P) administered subcutaneously at 1.5 µg/kg once weekly, plus Ribavirin (R) g weight based dosing of 6-14 mg/day in a divided daily dose previr dose of 8 mg thrice daily

POND-2 SVR and Relapse Rates tion to treat population % of Patients 1 8 6 4 2 p <.1 p <.1 59 32 21 66 15 12 SVR Relapse Rate 17 8 8 25 95 162 17 111 17 161 14 121 PR 48 BOC RGT BOC/PR48 SVR rates in BOC RGT and BOC/PR48 arm not statistically different (OR, 1.4; 95% CI [.9, 2.2]) ek HCV RNA level used if 24-week post-treatment level was missing. A sensitivity analysis where g data was considered as non-responder, SVR rates for Arms 1, 2 and 3 were 21% (17/8), 58% 2) and 66% (16/161), respectively.

by Week 8 HCV RNA Response Intention to Treat lation SVR (%) 1 8 6 4 2 1 12 Undetectable HCV RNA at Week 8 Detectable HCV RNA at Week 8 86 88 4 43 46% of patients in BOC RGT arm were eligible for shorter therapy ~6 times as many patients on BOC regimens (46-52%) achieved undetectable HCV RNA at week 8 compared to control (9%) 7 7 8 65 64 74 29 72 74 84 3 7 PR 48 BOC BOC/PR48 RGT

R by Week 4 PR Lead-In Response 1 8 73 79 6 33 34 4 25 2 12 15 46 15 44 17 67 8 11 9 114 PR 48 BOC RGT BOC/PR48 Poorly Responsive to IFN <1 log 1 viral load decline at treatment week 4 PR 48 BOC RGT BOC/PR48 Responsive to IFN 1 log 1 viral load decline at treatment week 4

SPOND-2: Adverse Events Over tire Treatment Course Adverse events more common in BOC arms vs control Anemia and dysgeusia ome 4-Wk PR + Response- Guided BOC + PR (n = 162) 4-Wk PR + 44-Wk BOC + PR (n = 161) 48-Wk PR (n = 114) rse event, % [1] emia 43 46 2 sgeusia 43 45 11

In Vitro resistance to Protease (A) and Polymerase (B) Inhibitors

Combination of two oral drugs in HCV G-1Patients ucleoside Polymerase (R7128) and Protease (R7227) Inhibitor e EJ et al. EASL 29

Summary Combination of Protease Inhibitors with PEG-IFN and RBV will increase SVR in genotype 1 patients from 4% to 6-7% Relapse rate decline to 5-1% Treatment duration may be shorten for a proportion of patients Discontinuation rates may increase due to AEs A new era in HCV therapy starts