Current and Future Treatment of Chronic Hepatitis C

1. Current and Future Treatment of Chronic Hepatitis C John Scott, MD, MSc University of Washington

2. Case • 43 yo Asian woman w/ chronic Hep C, GT 1, HCV RNA level of 2 million IU/ml • ALT 53, INR 1.0, Albumin 4.1 • Liver biopsy: grade 2 inflammation, stage 2 fibrosis • HTN • What to do next? • Treat now or wait?

3. Outline • Epidemiology • Natural History • Current Therapy -Efficacy -Side effects -Mechanism of action -Kinetics • Future Therapy

4. Epidemiology • 3.9-4.1 million Americans are HCV Ab+ • May be as high as 7 million • 2.7-3.2 million are chronically infected • Highest prevalence in 30-54 yo • Highest prevalence in African Americans and Hispanics CDC. MMWR 1998 47(RR-19):1-38 Alter M. NEJM 1999 341:546-52 Armstrong GL. Ann Intern Med 2006 144:705-14

5. Risk Factors for HCV • Injection drug use (60%) • Blood transfusion before 1992 • Multiple sex partners • Iatrogenic (hemodialysis, re-use of vials, etc) • Intranasal cocaine • Piercing, tattooing, scarification • Unknown (10%)

7. Evolution of therapy for HCV ~1990’s mid-90’s ~2000-01

8. What is Pegylation? • Covalent attachment of polyethelene glycol to peptide • Increases hydrodynamic size • Prolonged circulation, delayed renal clearance • PegIntron (12kd, Schering), Pegasys (40kd, Roche) • Enzon pharmaceutical • Adenosine deaminase • Others: Neulasta (GCSF), doxorubicin

9. Side Effects of PegIFN/Ribavirin • Depression ranging from mild to suicidality • Irritability, aggressive behavior • Worsening of mania • Fatigue • Insomnia • Myalgias, fever, flu-like symptoms • Hair loss • Cytopenias “Interferon Man” Slide courtesy Chia Wang

11. The importance of viral kinetics Scott J and Gretch DR. JAMA 2007.

12. Kinetics and SVRGT 1 (Pegasys + RVN) Ferenci P. J Hepatol 2005; 43:425-33

13. Mechanism of Action: Interferon HCV HCV virions Interferon alfa Assembly IFN receptors JAK OAS: activates antiviral RNAses PKR: inactivates viral ptn translation ADA: edits viral RNA HCV replicative complex Viral RNA PKR ADA IRF9 OAS STAT STAT1 ISG mRNA ISGF3 ISRE Adapted from Hoofnagle J. NEJM 2006

14. Effect of IFN-/Ribavirin Average HCV RNA level reduction (log IU/ml) +0.5 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 -3.0 -3.5 Group A: untreated Group C: IFN-3 MU tiw -4.0 Group D: IFN-3 MU tiw + ribavirin 1.0-1.2 g qd -4.5 -5.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Days (Pawlotsky et al., Gastroenterology 2004;126:703-14) slide courtesy of JM Pawlotsky

15. Ribavirin Prevention of Relapse Treatment Follow-up 5 0 * * Continue ribavirin > wk 24 4 0 Stop ribavirin at wk 24 * % relapse (HCV RNA +) 3 0 * p<0.05 2 0 * * 1 0 0 24 30 36 48 52 60 72 Weeks of treatment (Bronowicki et al., Gastroenterology 2006;131:1040-8) slide courtesy of JM Pawlotsky

16. Ribavirin’s Antiviral Mechanisms • Direct inhibition of HCV RNA-dependent RNA polymerase ? • Depletion of intracellular GTP pools via IMPDH inhibition ? • RNA mutagenesis leading to "error catastrophe" ?

17. O N H N 2 N N H O O 2’5’OAS PKR Mx ADAR1 ISG20 ISG54 ISG56 … H O O H Ribavirin Antiviral Mechanisms ? ? ? Slide courtesy JM Pawlotsky

18. Future Therapies • Coming soon! (2011?) • Potent • Rapid antiviral resistance if used by itself • More side effects

19. HCV Life Cycle: Key Features • Multiple proteins mediate HCV entry: • CD81, Scavenger Receptor B1, Claudin 1, Occludin, Very Low Density Lipoprotein Receptor • Input HCV RNA is translated, a polyprotein is formed, and individual viral proteins are released from polyprotein by cellular and viral proteases • HCV proteins associate with endoplasmic reticulum membranes, the site of HCV replication • Virion assembly occurs at lipid droplets • HCV leaves the cell by hitching a ride on the apolipoprotein B secretion pathway • HCV life cycle is intimately tied with lipid metabolism Slide courtesy S Polyak

20. HCV Variability • RNA virus, RDRP lacks proof-reading function • Mutations arise during replication are not corrected • Genotypes • genetically divergent HCV isolates that can be grouped phylogenetically • Quasispecies • Highly related yet genetically distinct viruses Slide courtesy S Polyak

21. Drug Development is NOT Easy • one for every 1,000 drugs makes it into humans • One in 5 receive FDA approval Slide courtesy S Polyak

22. HCV Drug Development Phase of Development Preclinical I II III IV Viral entry inhibitorsHepatitis C immunoglobulin HCIg)HCV-Ab 68 and Ab 65 (monoclonal Ab) HCV RNA translation inhibitorsISIS 14803 (antisense) AVI – 4065 (antisense) Heptazyme (ribozyme)VGX-410C (small molecule IRES inhibitor)TT 033 (siRNA) Posttranslational processing inhibitors NS3-4A serine proteinase inhibitors BILN 2061 ITMN 191 VX-950 SCH 503034 ACH-806/GS-9132 HCV replication inhibitors NS5B polymerase inhibitors MK-0608 HCV-796 R1626 JTK-003 NM-283 XTL 2125 Cyclophilin B inhibitors DEBIO-025 NIM 811 NS5A inhibitors A-831, A-689 Helicase inhibitors QU663 Recombinant Ab fragments Virus assembly and release inhibitors UT-231B (iminosugar-glucosidase inhibitor) Celgosivir (glucosidase inhibitor) * * * * * * * (Pawlotsky JM, Chevaliez S, McHutchison JG, Gastroenterology 2007;132:1979-98)

23. HCV Lifecycle

24. HCV Lifecycle

25. NS3 Protease Targets Serine proteinase catalytic site (Pawlotsky JM, Chevaliez S, McHutchison JG, Gastroenterology 2007;132:1979-98)

26. NS3 Protease Inhibitors Having Reached Clinical Development • Peptidomimetic inhibitors • BILN 2061 (Boehringer-Ingelheim) • Telaprevir (VX950, Vertex & Tibotec) • Boceprevir (SCH503034, Schering-Plough) • TMC 435350 (Tibotec) • ITMN-191 (InterMune) • MK-7009 (Merck) • BI 201335 (Boehringer-Ingelheim

27. 1 0 -1 -2 -3 -4 -5 -6 VX-950 Alone or in Combination with Pegasys: Mean Viral Response Baseline Pegasys + placebo HCV RNA Change from Baseline (Log10 IU/mL) VX-950 VX-950 + Peg-IFN 1 2 3 8 9 4 5 6 7 B 10 11 12 13 14 Study Time (In Days) Reesink H et al. EASL. April 26-30, 2006. Vienna, Austria. Abstract 737. Slide courtesy Roche Medical Affairs

28. Phenotypic Characterization of Telaprevir-Resistant Variants • Highly sensitive clonal method • Detect 5% frequency of variants • Performed at days 4, 8, 12, 14 • 80 sequences/patient/time point Wild type T54A V36A/M R155K/T 36/155 A156V/T Low resistance High resistance Adapted from Kieffer T, et al. 2006 AASLD, Boston, #92

29. Telaprevir Peginterferon + Ribavirin 8 6 4 2 Log(10) HCV RNA IU/ml LOD = 10 IU/ml 14 Days 100

30. Telaprevir + Peg/RVN Peginterferon + Ribavirin 8 6 4 2 Log(10) HCV RNA IU/ml 14 100 Days Adapted from Kieffer T, et al. 2006 AASLD, Boston, #92

36. IFN sparing regimens? • Roche: protease + polymerase inhibitor (phase I) • Merck/Schering: protease + polymerase inhibitors

37. Remaining questions • Why doesn’t IFN work in some patients? • Is IFN necessary if you have two potent antivirals? • How many antiviral targets are needed and how long is therapy needed? • Target lipid metabolism?

38. Back to the case… • 43 yo Asian woman w/ chronic Hep C, GT 1, HCV RNA level of 2 million IU/ml • ALT 53, INR 1.0, Albumin 4.1 • Liver biopsy: grade 2 inflammation, stage 2 fibrosis • HTN • What to do next? • Treat now or wait?

39. Thanks! Larry Corey, MD Chia Wang, MD Dave Gretch, MD, PhD Erica Coppel Erica Seddig Wan Chong Qiu Steve Polyak, PhD Jean Michel Pawlotsky, MD Patients NIH/NCRR