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Protease and Polymerase Inhibitors for the Treatment of Hepatitis C

Protease and Polymerase Inhibitors for the Treatment of Hepatitis C. Tarik Asselah MD, PhD Service d’Hépatologie & INSERM U773, CRB3 Hôpital Beaujon, Clichy tarik.asselah@bjn.aphp.fr. Protease and Polymerase Inhibitors for the Treatment of Hepatitis C. Unmet Needs

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Protease and Polymerase Inhibitors for the Treatment of Hepatitis C

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  1. Protease and Polymerase Inhibitors for the Treatment of Hepatitis C Tarik AsselahMD, PhD Service d’Hépatologie & INSERM U773, CRB3 Hôpital Beaujon, Clichytarik.asselah@bjn.aphp.fr

  2. Protease and Polymerase Inhibitors for the Treatment of Hepatitis C • Unmet Needs • Mechanisms of Non Response • Protease Inhibitors • Polymerase Inhibitors • Conclusion

  3. Progress in the Treatment of Hepatitis C 47% 63% 35 43% 18 23% 6 16% IFN PEG-IFN+Riba PEG-IFN IFN+Riba 1989 2009

  4. PEG-IFN-a + Ribavirin Incidence of Therapeutic Failure 58% PEG-IFN-a 2a + ribavirin (Fried et al., 2002) 54% 48% PEG-IFN-a 2a + ribavirin (Hadziyannis et al., 2004) 24% PEG-IFN-a 2b + ribavirin (Manns et al., 2001) 18% 16% Genotype 1 Genotypes 2/3 Manns et al. Lancet 2001; Fried et al. NEJM 2002; Hadziyannis et al. Ann Intern Med 2004.

  5. How These Drugs will be Evaluated ? Patterns of Virological Response Baseline Treatment Nonresponder Breakthrough HCV RNA Partialresponder Relapser Detection limit Sustained responder (cure) HCV RNA Undetectable 6 months Time

  6. Response-guided Therapy Requires Precise Definitions of on-Treatment Response * RVR = rapid virological response ** EVR = early virological response Marcellin et al. AASLD 2007

  7. Asselah T et al. Liver International 2009

  8. Asselah T et al. GUT 2009

  9. Prediction of Non response PEG-IFN-a + Ribavirin Interferon Stimulated Genes NR IFI6 IFI27 ISG15 IL8 OAS.. SVR Time Asselah T et al. GUT 2008 Feld et al. Hepatology 2007 Chen et al. Gastroenterology 2005

  10. Protease and Polymerase Inhibitors for the Treatment of HepatitisC • Unmet Needs • Mechanisms of Non Response • Protease Inhibitors • Polymerase Inhibitors • Conclusion

  11. Asselah T et al. Liver International 2009

  12. Enzyme Inhibitors • Protease Inhibitors • Telaprevir (Vertex-Tibotec) • Boceprevir (Schering Plough) • BI 201335 (Bohringer) • ITMN-191 (Intermune) • Polymerase Inhibitors • R7128 (Pharmasset-Roche)

  13. Telaprevir (Vertex-Tibotec) 1 0 -1 Peg-IFN + placebo -2 Reduction of viral load (Log 10 IU/mL) -3 VX-950 -4 -5 VX-950 + PEG-IFN -6 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Duration of treatment (days) Reesink et al. Gastroenterology 2006

  14. Telaprevir : Prove 2 PR48 (n = 82) Placebo + PEG-IFNα-2a + RBV TVR PEG-IFNα-2a RBV PEG-IFNα-2a RBV T12/PR24 (n = 81) TVR PEG-IFNα-2a RBV T12/PR12 (n = 82) TVR PEG-IFNα-2a T12/P12 (n = 78) 0 12 24 48 72 Zeuzem et al. AASLD 2008 – A243

  15. Telaprevir : Prove 2 SVR Relapse (%) p = 0.004* p = 0.12* % % 48 50 80 69 40 60 NS* 60 30 46 30 36 22 40 20 14 20 10 38/82 56/81 49/82 28/78 10/45 8/57 19/63 22/46 0 0 PR48 T12/PR24 T12/PR12 T12/P12(no RBV) PR48 T12/PR24 T12/PR12 T12/P12(no RBV) * vs PR48

  16. Telaprevir : Side Effects • Rash ( 10 % discontinuation for severe rash) • Pruritus • Anaemia • Nausea, Diarrhoea • Headaches • Fatigue

  17. Boceprevir : Sprint 1 P + R P + R + B FU 44 w. n = 103 Lead-in P + R P + R + B FU 24 w. n = 103 FU 44 w. P + R + B n = 107 No Lead-in P + R + B FU 24 w. n = 103 P + R (LD) + B FU24 w. Low dose RBV P + R (SOC) FU 24 w. SOC n = 104 0 4 weeks 28 48 72 Kwo et al. AASLD 2008 –A LB16

  18. Boceprevir : Sprint 1 Virological Response 12 to 24 weeksafter end of treatment (ITT) 100 74 80 66 56 55 60 % patients with HCV RNA undetectable 38 40 20 0 n = 104 n = 107 n = 103 n = 103 n = 103 P/R 48 w(n = 104) P/R/B 28 w(n = 107) P/R/ 4 w →P/R/B 24 w(n = 103) P/R/B 48 w(n = 103) P/R 4 w → P/R/B 44 w(n = 103) Kwo et al. AASLD 2008 –A LB16

  19. Boceprevir : Side Effetcs • Fatigue, • Nausea, • Headache • Dysgeusia • Anaemia (45 % receiving erythropoietin)

  20. BI 201335 (Bohringer) BI 201335 or placebo BI 201335 + PEG-IFNα-2a + RBV BI 201335 1 20 mg /j 48 mg /j 0 120 mg /j 240 mg /j -1 Placebo -2 HCV RNA Log 10 UI/ml -3 -4 -5 0 1 2 3 4 6 10 14 21 28 Days Manns et al. AASLD 2008 –A 1849

  21. BI 201335 PEG-IFNα + RBV treatment-experienced patients with Genotype 1 108 107 106 105 104 103 102 Limit of detection 25 1 0 1 2 3 4 6 10 14 21 28 Manns et al. AASLD 2008 –A 1849

  22. ITMN-191 (Intermune) 7 Placebo 6 100 mg/12h 5 100 mg/8h HCV RNA log10 (UI/ml) 4 300 mg/12h (NR) 200 mg/8h 3 200 mg/12h 2 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Jours (NR) : non-responders to PEG-IFNα + RBV Forestier et al. AASLD 2008 –A1847

  23. R7128 (Pharmasset-Roche) HCV GT 1 Naifs , RVR 100% 88% 85% 80% 75% HCV RNA <15 UI/mL 60% 45% 40% 30% 20% 20% 10% 10% 10% 0% 1 2 3 4 Weeks of Treatment PR PR+R 500mg/12h PR+R 1000mg/12h PR+R 1500mg/12h Lalezari et al. EASL 2008. Pharmasset. Press Release Sept 2008

  24. R7128 0 -1 G 2 & 3 NR or Relapsers -2  Mean HCV RNA -3 -4 -5 -6 0 1 2 3 4 Weeks SOC 1 500 mg 2x/j + SOC Gane EJ et al. AASLD 2008 –A LB10

  25. HCV resistance NS2–NS3 proteinase NS3 protease C E2 p7 NS2 NS3 4A NS4B NS5A NS5B E1 Serine protease domain RNA-dependent RNA polymerase Core Envelope T54 R155 A156 D168 V36 S96 N142 S282 C316 M414 M419 P495 T423 R1479(R1626) VX-950; SCH 503034 VX-950; BILN 2061 Valopicitabine VX-950; BILN 2061; SCH 503034 HCV-796 BILN 2061 Nonnucleosides VX-950 Sarrazin et al. Gastroenterology. 2007.Tong et al. Antiviral Res. 2006. De Francesco and Migliaccio. Nature. 2005.Le Pogam et al. Virology. 2006.Villano et al. Hepatology. 2006.

  26. Combination of Enzyme Inhibitors in the Replicon System + + + EASL 2007- Howe AY - Kenilworth, USA, Abstract 432 EASL 2007- Ralston R - Kenilworth, USA, Abstract 793 EASL 2007- McCown M – Palo Alto, USA, Abstract 790

  27. Potential Antiviral Targets and Approaches Antiviral Targets Enzymes Immune System Protease Inhibitors Polymerase Inhibitors Ribavirine PEG-IFN Potential use in Combination

  28. Conclusion Enzyme Inhibitor + SOC (PEG-IFN + RBV) in Genotype 1 Naïve Patients • Increase SVR from 50 to  70 % • Shorten the Duration of Treatment • New Definitions of Response • Resistance occurs Rapidly • Toxicity Concern

  29. Perspectives Combination of Enzyme Inhibitors • Increase SVR • Decrease Treatment Duration • Side Effects • Minimize Resistance • Avoid Ribavirin, avoid PEG-IFN, When ? • Studies in other Populations : NR, other Genotypes, HIV-HCV Coinfected patients, Liver Transplant patients…

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