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New Anti-HCV Drugs Other Drugs?

New Anti-HCV Drugs Other Drugs?. Yves Benhamou Hôpital Pitié Salpêtrière Paris. Challenges for New Anti-HCV Therapies. Improve SVR Role of direct antivirals (enzyme inhibitors) Potency – Safety – Resistance profile Improve acceptability and tolerability of current SOC

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New Anti-HCV Drugs Other Drugs?

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  1. New Anti-HCV DrugsOther Drugs? Yves Benhamou Hôpital Pitié Salpêtrière Paris

  2. Challenges for New Anti-HCV Therapies • Improve SVR • Role of direct antivirals (enzyme inhibitors) • Potency – Safety – Resistance profile • Improve acceptability and tolerability of current SOC • Better tolerated and more convenient IFNs • Better tolerated RBV analogues • Reduction of treatment duration (STAT-C) • IFN/RBV sparing regimens ? • Role of combinations with STAT-C ?

  3. « Non STAT-C Anti HCV » Valeant Taribavirin

  4. « Non STAT-C Anti HCV » Valeant Taribavirin

  5. CYCLOPHILIN INHIBITOR

  6. Debio 025 • Synthetic first-in-class Cyp inhibitor (binding) • Cyp host cell protein that confer advantages to HCV replication • Preclinical studies show anti-HCV effects • Anti-HCV activity in monotherapy FLisiak et al. Hepatology 2008.

  7. Debio 025 Phase IIa, double-blinded, randomized, trial 90 HCV naive patients : GT 1/4 (n=60) and 2/3 (n=30) F. up PEG-IFNα-2a (180 µg/wk.) Debio 025 (200 mg/qd) PEG-IFNα-2a(180 µg/wk) Debio 025 (600 mg/qd) PEG-IFNα-2a(180 µg/wk) Debio 025 (1 000 mg qd) Debio 025 (1 000 mg qd) PEG-IFNα-2a(180 µg/wk+ placebo 29 days 21 days EASL 2008 – Flisiak et al. EASL 2008

  8. Debio 025 Virologic Response (HCV RNA <LOQ) at day 29 % 100 PEG + placebo 80 Debio 025 1 000 mg 60 PEG + Debio 025 200 mg PEG + Debio 025 600 mg 40 PEG + Debio 025 1 000 mg 20 0 Genotype 1/4(12 patients in each dose group) Genotype 2/3(6 patients in each dose group) EASL 2008 – Flisiak et al. EASL 2008

  9. NITAZOXANID

  10. Nitazoxanid (NTZ)STEALTH C-1 : HCV GT 4 Naive Patients 5: HCV RNA reduction > 1 log 1 patient undetectable SVR 48 wk. PEG-IFN-2a + ribavirin n = 40 12 wk. + 36 wk. NTZ NTZ + PEG-IFN-2a n = 28 NTZ NTZ + PEG-IFN-2a + ribavirin n = 28 VHC RNA during NTZ Monotherapy phase 6 5.75 HCV RNA reduction - 0,26 log UI/ml Log10 UI/ml 5.5 5.25 5 JO S4 S8 S12 Rossignol F. et al. EASL 2008

  11. Nitazoxanid (NTZ)STEALTH C-1 : HCV GT 4 Naive Patients 100 86 82 79 75 80 71 70 68 64 61 60 54 50 38 40 20 0 RVR EVR EOT SVR Virologic Response p = 0,023 p = 0,048 PEG-IFN + RBV PEG-IFN + NTZ PEG-IFN + RBV + NTZ Rossignol F. et al. EASL 2008

  12. Nitazoxanid (NTZ)STEALTH C-1 : HCV GT 4 NR Patients 12 wk. + 36 wk. NTZ NTZ + PEG-IFN-2a n = 12 NTZ NTZ + PEG-IFN-2a + ribavirin n = 12 Virologic Response 75 60 50 % 42 % 42 % 42 % PEG-IFN + NTZ 45 PEG-IFN + RBV + NTZ 25 % 25 % 25 % 30 8 % 15 0 RVR EVR EOT SVR Rossignol F. et al. EASL 2008

  13. ALBINTERFERON

  14. Molecular Model ofAlbinterferon Alfa-2b (alb-IFN) Genetic Fusion HA gene IFNa gene Molecular weight: 85.7 kDa IFNa-2b HA A single polypeptide molecule that combines the therapeutic activity of interferon-α (IFNα) with the long half-life of human albumin (HA) Zeuzem S. et al. Hepatology 2008

  15. AlbInterferon Phase 2a StudyPharmacokinetics Balan, et. al. AASLD 2004

  16. Exposure comparison AlbInterferon vs PegIFN a-2aandPegIFN a-2b Cmax of albumin-IFNα 5 fold greater compared to PegIFN α-2a and 86 fold greater compared to PegIFN α-2b Exposure (AUC) 3.5 to 7 fold greater for albumin-IFNα Source: Albumin-IFNα data is from Bain, V.G. et. al. A phase 2 study to evaluate the antiviral activity, safety and pharmacokinetics of recombinant human albumin-interferon alfa fusions protein in genotype 1 chronic hepatitis c patients. Journal of Hepatology. In preparation, and Bain, et. al., 2005 EASL, Abstract #18. Pegasys data is from its label (PDR).

  17. AlbInterferon Phase 2a StudyViral Dynamics (HCV GT1) 23% (6/26) patients in the 900-1200 µg cohorts had undetectable virus at Day 42 Bain, VG. et al. in preparation

  18. AlbInterferon: Phase 2b trial in HCV Naïve GT1Study Design Randomized, open label, active control, phase 2b Conducted at 82 sites in 8 countries 4 groups stratified by: HCV RNA: < or ≥ 800,000 IU/mL BMI: < or ≥ 25 kg/m2 wk 0 wk 12 wk 24 wk 48 wk 72 SVR Follow-up Treatment n = 114 PEG-IFNα-2a 180 µg qwk + RBVa n = 118 alb-IFN 900 µg q2wk + RBVa 458 Gt 1Patients n = 110 alb-IFN 1200 µg q2wk + RBVa n = 116 alb-IFN 1200 µg q4wk + RBVa aOral ribavirin (RBV) 1000─1200 mg/d based on body weight.BMI, body mass index; HCV, hepatitis C virus; PEG, pegylated; SVR, sustained virologic response. Zeuzem S. et al. Hepatology 2008

  19. Virologic Response: ITT Analyses PEG-IFNα-2a 180 µg qwk alb-IFN 900 µg q2wk alb-IFN 1200 µg q2wk alb-IFN 1200 µg q4wk HCV RNA <LOQ Zeuzem S. et al. Hepatology 2008

  20. Effect of Adherence to Therapya on SVR Rates PEG-IFNα-2a 180 µg qwk alb-IFN 900 µg q2wk alb-IFN 1200 µg q2wk alb-IFN 1200 µg q4wk HCV RNA <LOQ aPatients receiving ≥80% of planned full dose of IFN and RBV. Zeuzem S. et al. Hepatology 2008

  21. Summary of Safety and Dose Reductions AE, adverse event. Zeuzem S. et al. Hepatology 2008

  22. ACHIEVE 2/3AlbInterferon: Phase 3 trial in HCV Naïve GT2/3Study Design Randomized, multi center, active controlled non -inferiority, phase 3 trial wk 0 wk 24 wk 48 SVR Follow-up Treatment n = 310 PEG-IFNα-2a 180 µg qwk + RBVa 933 Gt 2/3 Naïve Patients n = 312 alb-IFN 900-mcg q2wk + RBVa n = 310 alb-IFN 1200-mcg q2wk + RBVa • Jan 2008: DMC recommendation (pulmonary SAEs); patients rdz in 1200-mcg q2wk had their dose reduced to 900-mcg q2wk. • All patients had completed at least 12 weeks of treatment at the time of the dose modification. • Data from all three treatment groups in the ACHIEVE 2/3 study were analyzed according to the original dose assignment aOral ribavirin (RBV) 800 mg/d

  23. ACHIEVE 2/3SVR (ITT Analysis) P*=0.0059 P*=0.0086 * p value for non inferiority Human Genome Sciences. Press release December 8, 2008.

  24. ACHIEVE 2/3SVR by Region (ITT Analysis) Human Genome Sciences. Press release December 8, 2008.

  25. ACHIEVE 2/3Adverse Events and Discontinuation Human Genome Sciences. Press release December 8, 2008.

  26. Potent Scenario for anti-HCV Therapy 2012 2017 2020 2022? IFN - RBV Cyclophilin inhibitor ? STAT-C STAT-C Entry inhibitor ? STAT-C Combinations Therapeutic vaccine ? Cytokines ? other immunomodulators IFN Sparing Regimens

  27. Conclusion • New anti-HCV drugs: • STAT-C • IFN and RBV (may be for ever) • Short term : AlbInterferon (Taribavirin?) • Role of drugs (vaccine) with different MOA ? (more difficult to treat patients – multiple Rx failure …) • Highly Active Anti HCV Therapy (« HAACT ») combining drugs with different MOA: Futur SOC?

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