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 Valtorcitabine (Valyl-L-dC) Idenix-Novartis Racevir (± FTC).- Pharmasset Abacavir (GSK) MIV-210 (FLG) Medivir/GSK

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 log 10 with 400 – 800 mg/day Excellent safety: no dose-related or dose-limiting toxicities OH O OH N HN O O CH 3  -L-2’-deoxythymidine (LdT, telbuvidine)

Efficacy at Week 104 HBeAg-Positive 921 patients (ITT Population) TelbivudineLamivudine n Therapeutic response (%)6448 HBV DNA ↓ from baseline (mean log 10 ) – 5.7 – 4.4 HBV DNA non-detectable by PCR (%)5639 ALT normalization [≤1 × ULN] (%)7062 HBeAg loss (%)3529 HBeAg seroconversion (%)3025 Color Color designates P < 0.05, telbivudine vs lamivudine at Week 104 Lai CL, and others. Abstract 91. AASLD 2006.

Efficacy at Week 104 HBeAg-Negative 446 Patients (ITT Population) TelbivudineLamivudine n Therapeutic response (%)7866 HBV DNA ↓ from baseline (mean log 10 ) –5.0 –4.2 HBV DNA non-detectable by PCR (%)8257 ALT normalization [≤1 × ULN] (%)7870 Color Color designates P < 0.05, telbivudine vs lamivudine at Week 104 Lai CL, and others. Abstract 91. AASLD 2006.

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

Phase II study. Emtricitabine 200 mg daily Two years results in 77 Patients Gish R. J Hepatol 2005;43: % 85% 53% HBV DNA negativeNormal ALT HBeAgseroconversion Drug resistance at year 2: 18%

Emtricitabine Monotherapy in Chronic Hepatitis B LIM SG et AL. Arch Intern Med % 65% 54% HBV DNA negative <400 copies/mL Normal ALT Histological Improvement Seroconversion antiHBe 12% both arms Drug resistance at year 1: 13% 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 2% P<.001 p<.001 p< %

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 Abstract 245. Median Change in HBV DNA Adefovir, log 10 copies/mL (n = 14) Adefovir + Emtricitabine, log 10 copies/mL (n = 24) P Value Week Week

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

Clevudine Phase 2 Trial Change from baseline serum HBV DNA after Change from baseline serum HBV DNA after 4 weeks treatment Clevudine Phase 2 Trial Change from baseline serum HBV DNA after Change from baseline serum HBV DNA after 4 weeks treatment Median Change in HBV DNA (log 10 copies/mL) 10 mg 50 mg 100 mg 200 mg 10 mg Cohort n: mg Cohort n: mg Cohort n: mg Cohort n: Weeks CLV Marcellin P, Hepatology 2004;40:

HBV DNA (median log 10 copies /ml) Week 24 Week 48 (24 weeks off therapy) Yoo et al AASLD 2005 Clevudine in HBeAg+ve CHB Multicenter, randomized, phase 3 trial Patients received 24 weeks clevudine 30 mg/day (n = 243) or placebo (n = 61) CLV 30mg PLBCLV 30mg PLB

Clevudine: phase III study in HBeAg+ve HBeAg loss CLV 30mg PLB CLV 30mg PLB Week 24Week 48 (24wk off therapy) Patients (%) Yoo et al AASLD 2005

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 Abstract 183. Outcome Clevudine 30 mg/day (n = 63) Placebo (n = 23)P Value Change in HBV DNA, log 10 copies/mL End of treatment End of follow-up <.0001 Undetectable HBV DNA, % End of treatment End of follow-up <.0001 Normal ALT, % End of treatment End of follow-up

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 Chung YH, et al. EASL Abstract 53. Percentage With HBV DNA < 300 copies/mL Percentage With Normal Serum ALT HBeAg-Negative Patients (n = 15) HBeAg-Positive Patients (n = 40) Baseline (Week 0)Treatment End (Week 48)Follow-up (Week 60) HBeAg-Negative Patients (n = 15) HBeAg-Positive Patients (n = 40)

 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 HBV-Specific L-Nucleosides: Valtorcitabine (val-LdC) and Telbivudine (LdT) O R O OH N N NH 2 O Valtorcitabine (val-LdC) Telbivudine (LdT) OH O OH N HN O O CH 3

Effect of Valtorcitabine on Serum HBV DNA Lim SG, et al. EASL Study Week Placebo 600 mg/day 900 mg/day 1200 mg/day Serum HBV DNA Mean Log 10 Reduction From Baseline

Tennant et al. HepDart 2001 WHBV DNA Log 10 Genome Copies/ mL Weeks Telbivudine + Valtorcitabine  n = 5 per group  Once daily oral dosing for 12 weeks  Doses (mg/kg/day): Telbivudine, 10 Valtorcitabine,10 Telbivudine and Valtorcitabine are Synergistic in the Woodchuck Model  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

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

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. 40 th EASL. April Oral 75 Tenofovir disoproxil fumarate

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

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 Abstract 184. Undetectable HBV DNA Tenofovir 300 mg/day, % (n = 38) Adefovir 10 mg/day, % (n = 68) Month Month Month Outcome Tenofovir 300 mg/day, % (n = 38) Adefovir 10 mg/day, % (n = 68) loss4913 HBsAg loss196

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 log 10 copies/mL –Mean changes from baseline in HBV DNA log 10 copies/mL (range: -1.4 to -5.7) at 3 months -3.8 log 10 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 Abstract 1000.

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

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 Abstract 741. Week 48 Outcome Pradefovir Adefovir (n = 50) 5 mg/day (n = 47) 10 mg/day (n = 49) 20 mg/day (n = 48) 30 mg/day (n = 48) HBV DNA < 400 copies/mL, % ALT normalized HBeAg-positive patients, n HBeAg-negative patients, n HBeAg seroconversion, %

Pradefovir for Chronic Hepatitis B: Week 48 Analysis (cont’d) Lee KS, et al. EASL Abstract 741 Week Pradefovir 5 mg (n = 47) Mean (SE) Change in HBV DNA From Baseline (log 10 copies/mL) Adefovir 10 mg (n = 50) Pradefovir 10 mg (n = 49) Pradefovir 20 mg (n = 48) Pradefovir 30 mg (n = 48)

Alamifovir LY582563, MCC-478: bis(2,2,2-trifluoroethyl)[(2-{2-amino-6-[(4- methoxyphenyl) sulfanyl]-9H-purin- yl}ethoxy)methyl]phosphonate 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: log 10 at 2.5 mg QD log 10 at 10 mg QD Soon et al, J Hepatol 2004

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 Lai CL, et al. EASL (n = 13) 60 (n = 14) 90 (n = 14) 150 (n = 12) 240 (n = 12) Reduction in HBV DNA by Week 12 (log 10 copies/mL) ANA380 Dose

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