Current Treatments for HCV

Current Treatments for HCV Mitchell L. Shiffman, MD, FACG Advisory Committee/Board Member: Achillion, Anadys, Boehringer-Ingelheim, BMS, Conatus, Genentech, Gen-Probe, Gilead, Globeimmune, GSK, Janssen, Merck, Novartis, Vertex Grant/Research Support: Abbott, Achillion, Anadys, Beckman-Colter, BMS, Boehringer-Ingelheim, Genentech, Gilead, Globeimmune, Idenix, Merck, Novartis Speakers Bureau: Genentech, Gilead, GSK, Merck, Vertex CURRENT TREATMENTS FOR HCV Mitchell L Shiffman, MD Director Liver Institute of Virginia Bon Secours Health System Richmond and Newport News, VA Copyright 213 American College of Gastroenterology 1

POTENTIAL CONFLICTS OF INTEREST 21-212 Abott: DSMB, G Anadys: DSMB, G Bayer: S Bristol-Myers-Squibb: A,G,S Conatus: A,G Exalenz: A Genentech/Roche: A,C,G,S Gilead: A,G,S Globeimmune: A,G Idenix: G Inhibitex: A,G Intercept: A,G Merck/Schering-Plough: A,G,S Novartis: A,G Pfizer: A Romark:C Salix: A,S Vertex: A,S Human Genome Sciences: C Zymogenetics: A,G A=Advisor, C=Consultant, G=Grants, S=Speaker CURRENT TREATMENT FOR HCV GENOTYPE 1 Peginterferon, ribavirin and an HCV protease inhibitor Telaprevir Boceprevir Protease inhibitors: Genotype specific Not generally effective against other HCV genotypes Must be utilized with Peginterferon and ribavirin Both protease inhibitors act at the same site Virologic failure cannot be overcome by the other agent Both protease inhibitors yield similar results Copyright 213 American College of Gastroenterology 2

TREATMENT NAÏVE TELAPREVIR 9 8 7 6 5 4 3 2 1 Naïve Caucasian AA TPV Placebo IM Jacobson et al. N Eng J Med 211; 364:245-2416. TREATMENT NAÏVE BOCEPREVIR 9 8 7 6 5 4 3 2 1 Naïve Caucasian AA BOC Placebo F Poordad et al. N Engl J Med 211; 364:1195-126. Copyright 213 American College of Gastroenterology 3

TREATMENT NAÏVE TELAPREVIR 9 8 7 6 5 4 3 2 1 Mild BF/Cx <8K >8K 1A 1B Fibrosis HCV RNA Genotype TPV Placebo IM Jacobson et al. N Eng J Med 211; 364:245-2416. TREATMENT NAÏVE TELAPREVIR 9 8 7 6 5 4 3 2 1 Mild BF/Cx <8K >8K 1A 1B Fibrosis HCV RNA Genotype TPV Placebo IM Jacobson et al. N Eng J Med 211; 364:245-2416. Copyright 213 American College of Gastroenterology 4

TREATMENT NAÏVE TELAPREVIR 9 8 7 6 5 4 3 2 1 Mild BF/Cx <8K >8K 1A 1B Fibrosis HCV RNA Genotype TPV Placebo IM Jacobson et al. N Eng J Med 211; 364:245-2416. TREATMENT OF CHRONIC HCV DIFFERENT PARADIGMS TELAPREVIR Start Telaprevir with Peginterferon and Ribavirin Continue with Peginterferon and Ribavirin Provide maximal viral suppression with triple therapy up front then stop the anti-viral agent and eradicate HCV with peginterferon and ribavirin BOCEPREVIR Start Peginterferon and Ribavirin as Lead-In Add Boceprevir to Peginterferon and Ribavirin Continue with Peginterferon and Ribavirin Suppress viral species that may be resistant to the anti-viral agent up front then eradicate HCV with triple therapy Copyright 213 American College of Gastroenterology 5

Log HCV RNA (IU/ml) EXTENDED RVR RESPONSE GUIDED THERAPY 7 Developed from observations 6 5 4 3 2 1 Telaprevir Boceprevir 4 8 12 16 2 24 WEEKS made from peginterferon/ribavirin Applied to the triple therapy paradigms Patients who achieve RVR Treated for a shorter duration Achieve maximum SVR Patients with delayed virologic response Become HCV RNA negative after week 4 Require 48 weeks of treatment to reduce relapse Have lower SVR rates TREATMENT NAÏVE - TELAPREVIR RAPID VIROLOGIC RESPONSE Patients (%) 1 8 8 TPV 7 Placebo 6 6 4 2 RVR SVR Log HCV RNA (IU/ml) 5 4 3 2 1 PEG-RBV TPV -4 4 8 12 16 2 24 28 WEEKS IM Jacobson et al. N Eng J Med 211; 364:245-2416. Copyright 213 American College of Gastroenterology 6

TREATMENT NAÏVE - BOCEPREVIR RAPID VIROLOGIC RESPONSE Patients (%) 1 8 8 BOC 7 Placebo 6 6 4 2 RVR SVR Log HCV RNA (IU/ml) 5 4 3 2 1 PEG-RBV BOC -4 4 8 12 16 2 24 28 WEEKS IM Jacobson et al. N Eng J Med 211; 364:245-2416. FDA RECOMMENDED ALGORITHM TELAPREVIR TREATMENT NAIVE TPV+ If ervr: If NO ervr: Measure HCV RNA 4 12 24 36 48 HCV RNA Hard Stop Rules <1 <1 UD Copyright 213 American College of Gastroenterology 7

FDA RECOMMENDED ALGORITHM BOCEPREVIR TREATMENT NAIVE If ervr: BOC+ If NO ervr: BOC+ PEG + RBV Measure HCV RNA 4 8 12 24 28 36 48 HCV RNA Hard Stop Rules <1 UD TREATMENT OF CHRONIC HCV SVR AND TIME TO RESPOND 1 % of Patients 8 6 4 2 Boceprevir Telaprevir RVR Delayed Response TIME OF VIROLOGIC RESPONSE ML Shiffman and R Estaban Liver Intl 212; 32 (suppl 1):54-6. Copyright 213 American College of Gastroenterology 8

TELAPREVIR PHASE 3 ADVANCE SUDY NAÏVE: 8 vs 12 WEEKS Telaprevir PEGIFN-2a Ribavirin Telaprevir PEGIFN-2a Ribavirin If ervr: PEGINF + Ribavirin If NO ervr: PEGINF + Ribavirin Weeks of TPV Overall SVR 8 12 83% 89% 5% 54% 69% 75% PEGINF-2a + Ribavirin 44% 4 8 IM Jacobson et al. N Eng J Med 211; 364:245-2416. 12 24 48 Weeks RETREATMENT OF CHRONIC HCV VIROLOGIC RESPONSE PATTERNS Log HCV RNA (IU/ml) 8 7 6 5 4 3 2 1 Peginterferon/Ribavirin 2-log decline Limit of detection -6 6 12 18 24 3 36 42 48 54 6 66 72 78 WEEKS A Sethi and ML Shifman Clin Liver Dis 25; 9:453-471. Copyright 213 American College of Gastroenterology 9

RETREAT PEGINF/RIBAVIRIN FAILURES TELAPREVIR 9 8 7 6 5 4 3 2 1 Relapse Partial Null PRIOR TREATMENT RESPONSE TPV Placebo S Zeuzem et al. N Eng J Med 211; 364:2417-2428. RETREAT PEGINF/RIBAVIRIN FAILURES BOCEPREVIR 9 8 7 6 5 4 3 2 1 Relapse Partial Unresponsive PRIOR TREATMENT During Lead-In B Bacon et al. N Engl J Med 211; 364:127-1217. BOC Placebo Copyright 213 American College of Gastroenterology 1

FDA RECOMMENDED ALGORITHM TELAPREVIR Treatment naïve and Prior Relapse TPV+ If ervr: If NO ervr: Measure HCV RNA 4 12 24 36 48 HCV RNA Hard Stop Rules <1 <1 UD FDA RECOMMENDED ALGORITHM TELAPREVIR Treatment naïve and Prior Relapse TPV+ If ervr: If NO ervr: Prior Non-Response and Cirrhosis TPV+ 4 12 24 36 48 HCV RNA Hard Stop Rules <1 <1 UD Copyright 213 American College of Gastroenterology 11

FDA RECOMMENDED ALGORITHM BOCEPREVIR Prior Relapse Partial Response If ervr: BOC+ If NO ervr: BOC+ PEG + RBV Measure HCV RNA 4 8 12 24 28 36 48 HCV RNA Hard Stop Rules <1 UD FDA RECOMMENDED ALGORITHM BOCEPREVIR Prior Relapse Partial Response If ervr: BOC+ If NO ervr: BOC+ PEG + RBV Prior Null Response INF Insensitive Cirrhosis BOC + 4 8 12 24 28 36 48 HCV RNA Hard Stop Rules <1 UD Copyright 213 American College of Gastroenterology 12

TREATMENT OF HCV INTERFERON RESPONSIVENESS Even with a protease inhibitor achieving SVR is still dependent upon the ability to respond to interferon Can be assessed by prior treatment response Relapse highly responsive Null response poorly responsive Interferon responsiveness is genetically mediated IL28B genotype CC highly responsive IL28B genotype TT poorly responsive Can be assessed by a lead-in response INTERFERON RESPNSIVENESS PRIOR TREATMENT RESPONSE 9 8 7 6 5 4 3 2 1 TPV BOC Relapse Partial Null PRIOR TREATMENT RESPONSE S Zeuzem et al. N Eng J Med 211; 364:2417-2428. B Bacon et al. N Engl J Med 211; 364:127-1217 Copyright 213 American College of Gastroenterology 13

INTERFERON RESPONSIVENESS IL28B GENOTYPE 1 8 6 4 2 TPV BOC PEGINF/R CC CT TT IL28B GENOTYPE IM Jacobson et al. EASL 211 F Poordad et al. EASL 211 INTERFERON RESPONSIVENESS RESPONSE TO LEAD-IN 1 8 Yes No 7 8 6 6 4 2 Naïve Retreatment Log HCV RNA (IU/ml) 5 4 3 2 1 PEG-RBV BOC >1 log decline in HCV RNA -4 4 8 12 16 2 24 28 WEEKS F Poordad et al. N Engl J Med 211; 364:1195-126. B Bacon et al. N Engl J Med 211; 364:127-1217. Copyright 213 American College of Gastroenterology 14

RESISTANCE TO PROTEASE INHIBITORS QUASISPECIES Single or multiple changes to the genetic sequence of HCV New quasispecies form all the time A-T-A-T-A-T-A-T-A-T-A-T-A-T- A-T-A-T-C-T-C-T-A-T-A-T-A-T- A-T-A-T-G-T-G-T-A-T-A-T-A-T- A-T-G-T-A-T-A-T-T-T-A-T-A-T- May lead to resistance against anti-viral agents Every patient infected with 1s of different quasispecies CHRONIC HCV POOL OF VIRAL SPECIES.A-T-A-G-C-T..A-T-A-G-C-T..A-T-A-G-C-T..A-T-A-G-C-T..A-T-C*-G-C-T..A-T-A-G-C-T..A-A*-A-G-C-T..A-T-C*-G-C-T..A-T-A-G-C-T..A-T-A-G-C-T..A-T-A-G-C-T..A-T-A-G-C-T. Copyright 213 American College of Gastroenterology 15

CHRONIC HCV IMPACT OF VIRAL MUTATIONS Wild type viral protein Anti-viral agent enters the binding site Viral protein inhibited Sensitive mutant viral protein Anti-viral agent still able to enter binding site Viral protein inhibited Resistant mutant viral protein Anti-viral agent unable to enter binding site Viral protein not inhibited HEPATITIS C VIRUS A POOL OF VIRUS Sensitive mutant Wild type Sensitive mutant Sensitive mutant Resistant mutants Copyright 213 American College of Gastroenterology 16

TREATMENT OF CHRONIC HCV EMERGENCE OF RESISTANCE rus (IU/ml) Vi "Wild Type" Sensitive mutant Resistant mutant ML Shiffman Clin Liver Dis 211; 15:665-675. Time MEASURING HCV RNA STOP RULES Log HCV RNA (IU/ml )7 6 5 4 3 2 1 Telaprevir 4 8 12 24 TREATMENT WEEK Log HCV RNA (IU/ml )7 6 5 4 3 2 1 Boceprevir 4 8 12 24 TREATMENT WEEK Copyright 213 American College of Gastroenterology 17

GENOTYPES 2 AND 3 IMPACT OF NOT ACHIEVING RVR 1 1 8 8 Patients without RVR 6 4 6 4 2 2 Yes RVR No 24 48 Weeks of Treatment ML Shiffman et al. N Eng J Med 27; 357:124-134. B Willems, et al. EASL 27. HCV GENOTYPES 2 AND 3 RESPONSE GUIDED THERAPY RCT comparing 24 vs 48 Weeks of treatment in patients without RVR STOP 1 6 4 Measure HCV RNA 2 8 4 12 24 48 RVR Randomize if HCV RNA (-) ML Shiffman et al. J Hepatology 213; (submitted) 24 48 Wks of Treatment Copyright 213 American College of Gastroenterology 18

CURRENT TREATMENT FOR HCV SUMMARY Either telaprevir or boceprevir combined with peginterferon and ribavirin is the current standard of care for patients with HCV genotype 1 Superior results in all patient groups compared to peginterferon and ribavirin Paradigms for the 2 drugs are different but yield similar results About 6% of patients will achieve a sustained virologic response and can be treated for only 24-28 weeks The ability to be cured of HCV is dependent upon interferon responsiveness Must adhere to strict stopping rules to avoid the emergence of resistant mutations Response guided therapy should be utilized for patients with genotypes 2, 3 and 4 Copyright 213 American College of Gastroenterology 19