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Protease and Polymerase Inhibitors for the Treatment of Hepatitis C Tarik Asselah MD, PhD Service d’Hépatologie & INSERM U773, CRB3 Hôpital Beaujon, Clichy.

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Presentation on theme: "Protease and Polymerase Inhibitors for the Treatment of Hepatitis C Tarik Asselah MD, PhD Service d’Hépatologie & INSERM U773, CRB3 Hôpital Beaujon, Clichy."— Presentation transcript:

1 Protease and Polymerase Inhibitors for the Treatment of Hepatitis C Tarik Asselah MD, PhD Service d’Hépatologie & INSERM U773, CRB3 Hôpital Beaujon, Clichy

2 Unmet NeedsUnmet Needs Mechanisms of Non ResponseMechanisms of Non Response Protease InhibitorsProtease Inhibitors Polymerase InhibitorsPolymerase Inhibitors ConclusionConclusion Protease and Polymerase Inhibitors for the Treatment of Hepatitis C

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

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

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

6 ResponseDefinition RVR* HCV RNA negative at week 4 EVR** Complete EVR HCV RNA positive at week 4 but negative at week 12 Partial EVR HCV RNA positive at week 4 and 12 but  2 log 10 drop from baseline at week 12 Non-EVR < 2 log 10 drop from baseline at week 12 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 InterferonStimulatedGenes PEG-IFN-a + Ribavirin Time NR SVR IFI6IFI27ISG15IL8OAS.. Asselah T et al. GUT 2008 Feld et al. Hepatology 2007 Chen et al. Gastroenterology 2005 Prediction of Non response

10 Unmet NeedsUnmet Needs Mechanisms of Non ResponseMechanisms of Non Response Protease InhibitorsProtease Inhibitors Polymerase InhibitorsPolymerase Inhibitors ConclusionConclusion Protease and Polymerase Inhibitors for the Treatment of HepatitisC

11 Asselah T et al. Liver International 2009

12

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

14 Duration of treatment (days) Reduction of viral load (Log 10 IU/mL) VX PEG-IFN VX-950 Peg-IFN + placebo Telaprevir (Vertex-Tibotec) Reesink et al. Gastroenterology 2006

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

16 SVR PR48T12/PR24T12/PR12 T12/P12 (no RBV) 46 % /8256/8149/8228/78 NS* p = 0.004* p = 0.12* * vs PR48 Relapse (%) PR48T12/PR24T12/PR12 T12/P12 (no RBV) 22 % /458/5719/6322/46 40 Telaprevir : Prove 2

17 Telaprevir : Side Effects Rash (  10 % discontinuation for severe rash)Rash (  10 % discontinuation for severe rash) PruritusPruritus AnaemiaAnaemia Nausea, Diarrhoea HeadachesHeadaches FatigueFatigue

18 Kwo et al. AASLD 2008 –A LB16 Lead-in No Lead-in Low dose RBV SOC n = 103 n = 107 n = 104 P + R P + R + B FU 44 w. FU 24 w. P + R + B FU 44 w. FU 24 w. P + R (LD) + BFU 24 w. P + R (SOC)FU 24 w. n = 103 Boceprevir : Sprint weeks0

19 Boceprevir : Sprint 1 Virological Response 12 to 24 weeks after end of treatment (ITT) % patients with HCV RNA undetectable n = 104n = 107n = 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

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

21 BI (Bohringer) Manns et al. AASLD 2008 –A mg /j 48 mg /j 120 mg /j 240 mg /j Placebo BI Days HCV RNA Log 10 UI/ml BI or placeboBI PEG-IFNα-2a + RBV

22 Manns et al. AASLD 2008 –A 1849 BI Limit of detection PEG-IFNα + RBV treatment-experienced patients with Genotype 1

23 Forestier et al. AASLD 2008 –A1847 ITMN-191 (Intermune) Placebo 100 mg/12h 100 mg/8h 200 mg/12h 200 mg/8h 300 mg/12h (NR) 7 HCV RNA log 10 (UI/ml) Jours 6 (NR) : non-responders to PEG-IFNα + RBV

24 Lalezari et al. EASL Pharmasset. Press Release Sept 2008 HCV GT 1 Naifs, RVR R7128 (Pharmasset-Roche) 10% 20% 30% 88% 10% 45% 75% 85% 0% 20% 40% 60% 80% 100% 1234 Weeks of Treatment HCV RNA <15 UI/mL PRPR+R 500mg/12hPR+R 1000mg/12hPR+R 1500mg/12h

25 R7128 Gane EJ et al. AASLD 2008 –A LB  Mean HCV RNA Weeks SOC mg 2x/j + SOC G 2 & 3 NR or Relapsers

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

27 Combination of Enzyme Inhibitors in the Replicon System Protease InhibitorsPolymerase InhibitorsReplicon System SCH HCV -796 Increase Anti-viral Decrease Resistance SCH NM 107 Increase Anti-viral Decrease Resistance VX-950R1479 Increase Anti-viral Decrease Resistance EASL Howe AY - Kenilworth, USA, Abstract 432 EASL Ralston R - Kenilworth, USA, Abstract 793 EASL McCown M – Palo Alto, USA, Abstract 790

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

29 Increase SVR from 50 to  70 %Increase SVR from 50 to  70 % Shorten the Duration of TreatmentShorten the Duration of Treatment New Definitions of ResponseNew Definitions of Response Resistance occurs RapidlyResistance occurs Rapidly Toxicity ConcernToxicity ConcernConclusion Enzyme Inhibitor + SOC (PEG-IFN + RBV) in Genotype 1 Naïve Patients

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


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