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Rafael ESTEBAN

Rafael ESTEBAN. New Drugs for Chronic Hepatitis B. R. Esteban, M.D. Hospital General Universitario Valle de Hebron Barcelona. Nucleoside Analogues. Telbivudine.- Novartis/Idenix Emtricitabine (- FTC).- Gilead Science Clevudine (L-FMAU).- Bukwang Pharm. Co

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Rafael ESTEBAN

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  1. Rafael ESTEBAN

  2. New Drugs for Chronic Hepatitis B R. Esteban, M.D. Hospital General Universitario Valle de Hebron Barcelona

  3. Nucleoside Analogues • Telbivudine.- Novartis/Idenix • Emtricitabine (- FTC).- Gilead Science • Clevudine (L-FMAU).- Bukwang Pharm. Co • Valtorcitabine (Valyl-L-dC) Idenix-Novartis • Racevir (± FTC).- Pharmasset • Abacavir (GSK) • MIV-210 (FLG) Medivir/GSK

  4. O C H H N 3 O N O H O O H b-L-2’-deoxythymidine (LdT, telbuvidine) Telbivudine (LdT) • Specific inhibitor of HBV polymerase; not active against HIV or other viruses • Favorable preclinical toxicology • Once daily oral dosing indicated by PK • Phase I/II dose escalation results: • Marked HBV suppression after 4 weeks: 3.4 – 3.8 log10 with 400 – 800 mg/day • Excellent safety: no dose-related or dose-limiting toxicities

  5. Efficacy at Week 104 HBeAg-Positive 921 patients (ITT Population) Color designates P < 0.05, telbivudine vs lamivudine at Week 104 Lai CL, and others. Abstract 91. AASLD 2006.

  6. Efficacy at Week 104 HBeAg-Negative 446 Patients (ITT Population) Color designates P < 0.05, telbivudine vs lamivudine at Week 104 Lai CL, and others. Abstract 91. AASLD 2006.

  7. Emtricitabine (FTC) • Cytosine analog, oral 200 mg daily • Structurally similar to Lamivudine (3TC) • Potent activity against HIV and HBV in vitro and in vivo • Drug resistant mutations in YMDD motif • Phase III Clinical Trials

  8. Phase II study. Emtricitabine 200 mg dailyTwo years results in 77 Patients 100 85% 80 53% 60 33% 40 20 0 HBeAg seroconversion HBV DNA negative Normal ALT Drug resistance at year 2: 18% Gish R. J Hepatol 2005;43:60-68

  9. Emtricitabine Monotherapy in Chronic Hepatitis B • FTCB 301: double-blind, placebo-controlled, phase III trial • 248 patients HBeAg positive and negative randomized to receive: • Emtricitabine (200 mg/day) or placebo for 48 wks 100 P<.001 p<.001 p<.001 80 54% 65% 62% 60 40 25% 25% 20 2% 0 Histological Improvement HBV DNA negative <400 copies/mL Normal ALT Seroconversion antiHBe 12% both arms Drug resistance at year 1: 13% LIM SG et AL. Arch Intern Med 2006

  10. Emtricitabine Plus Adefovir • Emtricitabine resistance limits its use as monotherapy • Combination therapy may resolve this issue • FTC-201: double-blind, placebo-controlled, phase II study • 30 HBeAg-positive nucleoside-naive patients • Randomized to adefovir + emtricitabine or adefovir alone Lau G, et al. AASLD 2004. Abstract 245.

  11. Clevudine (L-FMAU) • Thymidine analog • In vitro activity against HBV and EBV but not HIV • Long half-life, more than 40 hours • Phase III study in South Corea

  12. Clevudine Phase 2 Trial Change from baseline serum HBV DNA after 4 weeks treatment 10 mg CLV 50 mg 0.00 100 mg 200 mg -0.50 -1.00 copies/mL) -1.50 Median Change in HBV DNA -2.00 10 -2.50 (log -3.00 -3.50 -4.00 0 2 4 6 12 18 24 28 Weeks 10 mg Cohort n: 5 3 4 4 4 4 4 50 mg Cohort n: 10 10 10 10 8 10 9 100 mg Cohort n: 10 10 10 10 10 10 10 200 mg Cohort n: 7 7 7 7 7 7 7 Marcellin P, Hepatology 2004;40:140-148

  13. Clevudine in HBeAg+ve CHBMulticenter, randomized, phase 3 trialPatients received 24 weeks clevudine 30 mg/day (n = 243) or placebo (n = 61) CLV 30mg PLB CLV 30mg PLB 0 -0.27 HBV DNA (median log10 copies /ml) -1 -0.68 -2 -2.02 -3 -4 -5 -5.10 Week 24 Week 48 (24 weeks off therapy) -6 Yoo et al AASLD 2005

  14. 30 25 20 15 15 12 12 10 10 5 0 Clevudine: phase III study in HBeAg+veHBeAg loss Week 24 Week 48 (24wk off therapy) Patients (%) PLB CLV 30mg CLV 30mg PLB Yoo et al AASLD 2005

  15. Clevudine Treatment in HBeAg-Negative Patients • Multicenter, randomized, phase 3 trial • Patients received 24 weeks clevudine 30 mg/day (n = 63) or placebo (n = 23) • Follow-up, 24 weeks Yoo et al. AASLD 2005. Abstract 183.

  16. Open-Label, Phase III Study of Clevudine: Year 1 results • Clevudine 30 mg/day for 24 weeks, then 10 mg/day through Week 48, then 12 weeks follow-up off treatment (N = 55) • All patients with HBV DNA < 300 copies/mL at Week 24 had sustained virologic, biochemical responses through Week 48 Baseline (Week 0) Treatment End (Week 48) Follow-up (Week 60) 100 100 100 100 100 100 89 86 80 80 68 60 60 Percentage WithHBV DNA < 300 copies/mL Percentage With Normal Serum ALT 40 40 27 25 23 20 20 0 0 0 0 HBeAg-Positive Patients (n = 40) HBeAg-Negative Patients (n = 15) HBeAg-Positive Patients (n = 40) HBeAg-Negative Patients (n = 15) Chung YH, et al. EASL 2006. Abstract 53.

  17. N H O 2 C H N H N 3 O N O N O H O H O O R O O H Telbivudine (LdT) Valtorcitabine (val-LdC) HBV-Specific L-Nucleosides: Valtorcitabine (val-LdC) and Telbivudine (LdT) • Small-molecule HBV polymerase inhibitors • Valtorcitabine is a valine esther prodrug of L-dC (poor bioavailability) • Phosphorylated intracellularly • High intracellular triphosphate concentrations • Renally cleared • HBV-specific • Once daily oral dosing • Favorable toxicology

  18. 900 mg/day Effect of Valtorcitabine on Serum HBV DNA 1 0 Placebo 600 mg/day -1 Serum HBV DNA Mean Log10 Reduction From Baseline 1200 mg/day -2 -3 -4 0 1 2 3 4 5 Study Week Lim SG, et al. EASL 2005.

  19. Valtorcitabine Telbivudine 13 13 13 13 12 12 12 12 11 11 11 11 10 10 10 10 9 9 9 9 8 8 8 8 7 7 7 7 6 6 6 6 5 5 5 5 4 4 4 4 3 0 4 8 12 16 20 24 3 3 3 2 2 2 2 Telbivudine + Valtorcitabine 1 1 1 1 Placebo 0 4 8 12 16 20 24 0 0 4 4 8 8 12 12 16 16 20 20 24 24 Telbivudine and Valtorcitabine are Synergistic in the Woodchuck Model • n = 5 per group • Once daily oral dosing for 12 weeks • Doses (mg/kg/day): • Telbivudine, 10 • Valtorcitabine,10 WHBV DNA Log10 Genome Copies/mL • Potentially complementary mechanisms of action on 1st and 2nd-strand HBV DNA synthesis • Combination has potent synergistic antiviral activity in vitro and in woodchuck HBV model • Both compounds have excellent safety profiles Tennant et al. HepDart 2001 Weeks

  20. Nucleotide Analogues • Tenofovir.- Gilead Sciences • Pradefovir.- Valeant/Schering Plough • Alamifovir.- Eli Lilly • ANA 380.- Anadys Pharmaceuticals

  21. Tenofovir disoproxil fumarate • Acyclic nucleotide approved for HIV infection (as pro-drug TDF) • Anti-hepadnaviral activity in vitro • Potent suppression of HIV and HBV in co-infected patients • Maybe effective against adefovir- and FTC- and ETV-resistant HBV Qi et al. 40th EASL. April 2005. Oral 75

  22. Tenofovir vs Adefovir in patients with lamivudine resistanceHBV-DNA <400 copies/ml Weeks Van Bommel et al 2004

  23. Tenofovir vs Adefovir in LAM-Refractory Patients • Retrospective analysis: LAM-refractory patients switched to tenofovir 300 mg/day (n = 38) or adefovir 10 mg/day (n = 68) • More patients receiving tenofovir exhibited HBeAg and HBsAg loss vs adefovir after up to 2 years van Bömmel F, et al. AASLD 2005. Abstract 184.

  24. Tenofovir Use in Patients With Incomplete Response to Adefovir • Retrospective analysis (N = 20) of tenofovir in patients with chronic hepatitis B who had suboptimal response to adefovir • At tenofovir initiation, the mean HBV DNA was 6.6 log10 copies/mL • Mean changes from baseline in HBV DNA • -3.2 log10 copies/mL (range: -1.4 to -5.7) at 3 months • -3.8 log10 copies/mL (range: -1.4 to -6.7) at 6 months • 18 of 20 (90%) patients achieved HBV DNA < 400 copies/mL after a mean of 4 months (range: 1-9) • 3 patients lost HBeAg after 3-5 months van Bömmel F, et al. AASLD 2005. Abstract 1000.

  25. Pradefovir • Liver-targeting pro-drug of PMEA • activated by the P450 enzyme • CYP3A4 which is expressed exclusively in the liver • In HBV transgenic mouse studies resulted in a 40-fold increase relative to PMEA in drug delivery to the liver • Phase I: HBV DNA reduction at 28 days • - 2 log10 decrease in 5-mg group • - 3 log10 decrease in 60-mg group Remofovir, MB6866 Chao et al, AASLD 2004

  26. Pradefovir for Chronic Hepatitis B: Week 48 Analysis • Phase II randomized, open-label, multicenter trial of ADV-naive patients (N = 244) • Patients received adefovir 10 mg/day or pradefovir 5, 10, 20, or 30 mg/day for 48 weeks • Genotype C: 67% – Asian: 100% – HBeAg positive: 70% Lee KS, et al. EASL 2006. Abstract 741.

  27. Pradefovir for Chronic Hepatitis B: Week 48 Analysis (cont’d) 0 -1 -2 Mean (SE) Change in HBV DNA From Baseline (log10 copies/mL) -3 Pradefovir 5 mg (n = 47) -4.09 -4 Adefovir 10 mg (n = 50) -4.19 Pradefovir 10 mg (n = 49) -4.84 -5 Pradefovir 20 mg (n = 48) -4.89 Pradefovir 30 mg (n = 48) -5.54 -6 0 4 12 18 24 36 48 Week Lee KS, et al. EASL 2006. Abstract 741

  28. Alamifovir • Prodrug of PMEA • Novel mechanism of action? • Interferes with packaging of pregenomic RNA into viral capsids • Dose-ranging study: Reduction in HBV DNA at 28 days in QD or BID regimes: • - 1.52 log10 at 2.5 mg QD • - 2.63 log10 at 10 mg QD LY582563, MCC-478: bis(2,2,2-trifluoroethyl)[(2-{2-amino-6-[(4-methoxyphenyl) sulfanyl]-9H-purin-yl}ethoxy)methyl]phosphonate Soon et al , J Hepatol 2004

  29. ANA380 (LB80380) in HBeAg-Positive Patients With LAM Resistance • Phase II, multicenter, dose-escalating study (N = 65) • HBeAg-positive Asian patients • 5 dose escalation groups • ANA380 (30, 60, 90, 150, or 240 mg/day) + LAM for 4 weeks followed by 8 weeks ANA380 monotherapy ANA380 Dose 30 (n = 13) 60 (n = 14) 90 (n = 14) 150 (n = 12) 240 (n = 12) 0 -1 Reduction in HBV DNA by Week 12 (log10 copies/mL) -2 -3 -2.8 -3.2 -4 -3.9 -3.9 -4.1 -5 Lai CL, et al. EASL 2006.

  30. Combination therapy for CH-B • Different targets or mechanisms • Goals, more effective in • Suppression of HBV replication • Induction of HBeAg seroconversion • Durable post-treatment responses • Reduction of drug-resistant mutants

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