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4 th Annual Clinical Care Options for Hepatitis Symposium: HCV Highlights

4 th Annual Clinical Care Options for Hepatitis Symposium: HCV Highlights. Interferon and Ribavirin: Mechanisms of Action, Resistance, and Why It Matters. Raymond T. Chung, MD Director of Hepatology Massachusetts General Hospital Associate Professor of Medicine Harvard Medical School

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4 th Annual Clinical Care Options for Hepatitis Symposium: HCV Highlights

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  1. 4th Annual Clinical Care Options for Hepatitis Symposium: HCV Highlights

  2. Interferon and Ribavirin:Mechanisms of Action, Resistance, and Why It Matters Raymond T. Chung, MDDirector of HepatologyMassachusetts General HospitalAssociate Professor of MedicineHarvard Medical School Boston, Massachusetts

  3. Innate Immunity: An IFN Amplification Loop Hepatitis Virus IFN- IFN- IFN-/ IFN- IFN- IFN signaling Jak-STAT IFN- IFN- IRF-3 activation IFN- TLR3 IFNAR-1 IFNAR-2 Viral PAMP: dsRNA Tyk2 Jak1 IRF-9 STAT 2 IRF-3 RIG-I IRF-7 STAT 1 IKK- JAK-STAT pathway TBK1 P P P P IRF-7 IRF-3 STAT 2 STAT 1 ISGF3 P P P IRF-7 IRF-7 IRF-3 P P P IRF-9 IRF-3 IRF-3 IRF-7 Cytoplasm ISRE IFN-stimulated genes: OAS, IRF-7, PKR, ISG56 etc PRD VRE IFN- IFN- Nucleus ISG expression; IFN amplification loop IRF-7 IFN- production Adapted from Gale M Jr, et al. Nature. 2005;436:939-945.

  4. CD8+ CTL The Adaptive (Cellular) Immune Response Finishes the Job Activation, Clonal expansion differentiation B cell Neutralizing HCV antibodies Th2 cytokines HCV (IL-4, IL-5, IL-6, Lysis Viral entry IL-9, IL-10, IL-13) MHC II CD4+ MHC I TCR Th cell Hepatocyte TCR CD8+ CTL CD4+ Th1 cytokines Clonal expansion cell Th (IFN-γTNF-α) (Th1 or Th2) IFN-a Adapted from Liang TJ, et al. Ann Intern Med. 2000;132;296-305.

  5. Viral Kinetics After IFN Therapy Viral kinetics IFN (efficacy = e) 0 1st phase: antiviral efficacy (r) (innate) -1 2nd phase: clearance ofinfected hepatocytes (d) (adaptive) HCV RNA (log IU mL-1) -2 Two phases ofviral decline -3 -4 -7 0 7 14 21 28 Days After Start of Therapy Adapted from Feld JJ, et al. Nature. 2005;436:967-972.

  6. Ribavirin • Initially developed as an antiviral–guanosine analogue • No antiviral activity but improved ALT when given as monotherapy • Combination with IFN improved ETR but greatly enhanced SVR rates by decreasing relapse • Does not alter 1st phase kinetics appreciably • Modest  of PEG-IFN antiviral effect (0.5-1.0 log) • Mechanistic models must explain clinical observations

  7. Ribavirin: Proposed Mechanisms of Action TH2 Defective HCV particles (decreased fitness) Ribavirin Immunomodulation (2nd phase) TH1 CTL IFN-, TNF- Hepatocyte RMP RDP RTP Ribavirin (-) IMP GMP RdRp HCV RNA HCV RNA RNA Mutagen IMPDH Replication GTP Inhibition of HCV RdRp (1st phase) Inhibition of IMPDH (1st phase) RNA mutagenesis (2nd phase) Adapted from Feld JJ, et al. Nature. 2005;436:967-972.

  8. P IRF-3 NF- NF- HCV NS3-4A Blocks IFN Induction at Multiple Levels TLR3 TRIF NS3/4A RIP-1 IRF-3 RIG-I IRF-3 MDA5 IKK- TBK1 IPS-1 RIP-1 P FADD IRF-3 l TRAF6 mitochondria P IKK IRF-3 P HCV NS3/4A l CBP/p300 IRF-3/NF- Target genes (IFN-b) P IRF-3 P CBP/p300 IRF-3 Adapted from Gale M Jr, et al. Nature. 2005;436:939-945.

  9. HCV Blocks IFN Signal Transduction IFN- IFN- IFN-/ IFN- IFN- IFN- IFN- HCV proteins Core Core IFNAR-1 IFNAR-2 Tyk2 Jak1 SOCS-1 SOCS Inhibition of Jak-STAT signaling STAT 1 STAT 2 SOCS-3 Inhibit P-STAT1 Degrade STAT1 IRF-9 Cytoplasm P P Block STAT function STAT 1 STAT 2 PP2A PIAS ISGF3 Nucleus ISG expression attenuated IRF-9 IL-8 NS5A ISRE Adapted from Gale M Jr, et al. Nature. 2005;436:939-945.

  10. IFN-Stimulated Genes as the Antiviral Workhorses Antiviral Actions of Interferon IFN IFN Oligoadenylate synthetase OAS Protein kinase PKRInactive Inactive NS5A dsRNA ssRNA E2 Oligoadenylate synthetase OASActive(multiple forms: nuclear and cytoplasmic) Protein kinase PKRActive(Ribosome associated) Phosphorylatedinitiation factorelF-2a P InitiationfactorelF-2a 2’, 5’-oligoadenylic acid ATPAMP Pi (2, 5 A) Phosphodiesterase Phosphatase(Soluble) Paucity of recognition sites RNase LActive RNase LInactive mRNA translationinhibition HCV RNA degradation Microarray studies have identified > 100 IFN-stimulated genes Adapted from Samuel CE. Clin Microbiol Rev. 2001;14:778-809.

  11. Treatment of Hepatitis C inBlacks: SVR PEG-IFN -2a 180 g/ wk + RBV 1000-1200 mg/d x 48 wks 100% genotype 1 PEG-IFN -2b 1.5 g/ kg/wk x 48 weeks + RBV 1000 800 mg/d 100% genotype 1 PEG-IFN -2a 180 g/wk + RBV 1000-1200 mg/d x 48 wks 98% genotype 1 Virologic Response Rates (%) 100 Black 80 White P < .001 P < .001 60 52% 52% 39% 40 28% 26% 19% 20 n = 196 n = 205 n = 100 n = 100 n = 78 n = 28 0 Virahep-C[3] Muir et al[1] Jeffers et al[2] 1. Muir AJ, et al. N Engl J Med. 2004;350:2265-227. 2. Jeffers LJ, et al. Hepatology. 2004;39:1702-1708. 3. Conjeevaram H, et al. AASLD 2005. Abstract 199.

  12. Impaired Host Antiviral Responses as the Basis for Inferior SVR Rates? • Differences between A-A and C-A appear to reside primarily in 1st phase viral decay • These findings suggest intrinsic defects in innate immunity (signal transduction or ISGs) • Search for genetic polymorphisms in innate immunity underway (Virahep-C)

  13. Obesity and Impaired Antiviral Response Rates • Obesity also associated with impaired antiviral response rates (likely related to steatosis) • SOCS-3 as key mediator • Upregulated in obesity • Increased by HCV • Promotes degradation of IRS1 and IRS2  insulin resistance Kawaguchi T, et al. Am J Path. 2004;165:1499-1508. Walsh MJ, et al. Gut. 2006;55:529-535.

  14. Higher-Dose IFN or Further Refinements in IFN PK • Theory: overcome intrinsic blocks to IFN action with higher doses of exogenous IFN • High dose PEG-IFN + RBV: recent studies showing modest SVR rates in prior PEG-IFN/RBV nonresponders • Albumin-IFN: extend half-life of IFN to permit extended dosing interval • Limitations: tolerability, toxicities, downstream block

  15. Strategies to Improve or Replace RBV • IMPDH inhibitors • Likely not major mechanism of RBV against HCV • Antiviral effect may be offset by immunosuppressive effects • Higher RBV doses • Further decreases in relapse among genotype 1 patients? • Prodrugs • Permit targeted dosing of RBV (viramidine)

  16. New Therapies for Chronic Hepatitis C: Rational Drug Design Gary Davis, MDDirector, Division of HepatologyBaylor University Medical CenterMedical Director, Liver TransplantationBaylor Regional Transplant InstituteDallas, Texas

  17. Role of New Agents in Treating HCV • Primary aim should remain eradication • Chronic suppression may be achievable • Interferon likely to remain foundation of therapy • Combination therapy will be key • Other agents may allow lower doses or shorter duration of poorly tolerated drugs • New agents will be able to target different processes of the HCV replication cycle

  18. Target: Infection of the Hepatocyte

  19. Polyclonal preparations[1] Neutralize infectious inoculae ex vivo Inhibit or prevent infection in chimps Studies in man disappointing to date Monoclonal antibodies[2] Anti-E2 human monoclonal XTL Mild HCV RNA suppression with daily dosing Vaccine-derived anti-E1E2[3] Neutralizing antibody In vitro inhibition of CD81 and VSV pseudovirions Therapeutics: Infection of the Hepatocyte 1. Davis, et al. Liver Transpl 2005. Willems, et al. J Hepatol. 2002. 2. Schiano, et al. Hepatol. 2005. 3. DiBisceglie, et al. Hepatol. 2005.

  20. Therapeutics: Infection of the Hepatocyte (cont’d) • N-glycans in envelope glycoprotein (E1E2) are essential for protein folding, secretion/assembly, antigenicity, receptor binding, and cell entry • Mutations in E2 eliminate infectivity[1] • E2N2, E2N4 by blocking cell entry • MX-3256 (celgosivir, Migenix)[2] • In vitro synergy with interferon-ribavirin • No reduction in HCV RNA 1. Goffard, et al. J Virol. 2005. 2. Yoshida, et al. Gastroenterology. 2006.

  21. 5’ 3’ Target: RNA Transport to the ER

  22. Therapeutics: RNA Transport to the ER • Oligonucleotides • Ribozymes • Antisense oligos • siRNA

  23. mRNA Ribozyme Antisense oligo Translation arrest Endogenous ribonucleases destroy ineffective mRNA Therapeutics: RNA Transport to the ER (cont’d)

  24. Therapeutics: siRNA • Ancient host process of gene silencing, probably evolved for antiviral defense/genome protection • siRNA • Exogenous short synthetic ds nucleic acid molecules • Highly modified to increase stability (nuclease resistance), prolong half-life, and reduce nonspecific (off-target) effects • Incorporated into RNA-induced splicing complex (RISC) which pairs it with target mRNA • Destruction of mRNA by RNase

  25. Target: Translation and Protein Processing

  26. Therapeutics: Translation and Protein Processing Serine protease (trans) HCV polyprotein NS2 NS3 NS4A NS4B NS5A NS5B E1 E2 p7 C Serine protease (cis)

  27. Therapeutics: Translation and Protein Processing (cont’d) • Conclusions • Potent antivirals • Orally bioavailable • Well tolerated • Synergy with IFN; increased IFN sensitivity • Require maintenance of trough concentration • May be able to shorten course of therapy • Other PI in development: ITMN B (InterMune)

  28. 3’ +RNA 5’ 3’ +RNA 5’ 3’ 3’ +RNA +RNA 5’ 5’ Target: Viral RNA Transcription -RNA 5’ 3’ Subcellular Membrane -RNA 5’ 3’ Subcellular Membrane

  29. Therapeutics: Viral RNA Transcription • HCV polymerase inhibitors in development • NM-283 (valopicitabine, Idenix) • R1626 (Roche) • HCV-796 (Viropharma)

  30. Target: Virus Assembly

  31. Therapeutics: Virus Assembly • N-glycans in envelope glycoprotein (E1E2) are essential for protein folding, secretion/assembly, antigenicity, receptor binding, and cell entry • Imino sugars inhibit α-glucosidases and prevent proper glycosylation of viral envelope proteins; may inhibit secretion and infectivity of viruses • Zitzmann, et al. PNAS 1999; Mehta, et al. FEBS Ltr 1998

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