Rafael ESTEBAN
New Drugs for Chronic Hepatitis B
R. Esteban, M.D.Hospital General Universitario Valle de
HebronBarcelona
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 log10 with 400 – 800 mg/day
• Excellent safety: no dose-related or dose-limiting toxicities
OH
OOHN
HN
O
O
CH3
-L-2’-deoxythymidine(LdT, telbuvidine)
Efficacy at Week 104 HBeAg-Positive 921 patients (ITT Population)
Telbivudine Lamivudine
n 458 463
Therapeutic response (%) 6464 4848
HBV DNA ↓ from baseline (mean log10) – – 5.75.7 – – 4.44.4
HBV DNA non-detectable by PCR (%) 5656 3939
ALT normalization [≤1 × ULN] (%) 70 62
HBeAg loss (%) 35 29
HBeAg seroconversion (%) 30 25
ColorColor 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)
Telbivudine Lamivudine
n 222 224
Therapeutic response (%) 78 66
HBV DNA ↓ from baseline (mean log10) ––5.05.0 ––4.24.2
HBV DNA non-detectable by PCR (%) 8282 5757
ALT normalization [≤1 × ULN] (%) 78 70
ColorColor 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 dailyTwo years results in 77 Patients
Gish R. J Hepatol 2005;43:60-68
33%
85%53%
0
20
40
60
80
100
HBV DNA negative Normal ALT HBeAgseroconversion
Drug resistance at year 2: 18%
Emtricitabine Monotherapy in Chronic Hepatitis B
LIM SG et AL. Arch Intern Med 2006
62%65%54%
0
20
40
60
80
100
HBV DNA negative<400 copies/mL
Normal ALT HistologicalImprovement
Seroconversion antiHBe 12% both armsDrug resistance at year 1: 13%
FTCB 301: double-blind, placebo-controlled, phase III trial248 patients HBeAg positive and negative randomized to receive:
Emtricitabine (200 mg/day) or placebo for 48 wks
2%
P<.001 p<.001 p<.001
25% 25%
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.
Median Change in HBV DNA
Adefovir, log10 copies/mL
(n = 14)
Adefovir + Emtricitabine, log10 copies/mL
(n = 24)P Value
Week 24 -3.19 -5.08 --
Week 48 -3.40 -5.44 .03
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 TrialClevudine Phase 2 Trial Change from baseline serum HBV DNA after Change from baseline serum HBV DNA after
4 weeks treatment4 weeks treatment
Clevudine Phase 2 TrialClevudine Phase 2 Trial Change from baseline serum HBV DNA after Change from baseline serum HBV DNA after
4 weeks treatment4 weeks treatment
-4.00
-3.50
-3.00
-2.50
-2.00
-1.50
-1.00
-0.50
0.00
0 2 4 6 12 18 24 28
Med
ian
Ch
ang
e in
HB
V D
NA
(l
og
10 c
op
ies/
mL
)
10 mg 50 mg 100 mg 200 mg
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 10200 mg Cohort n: 7 7 7 7 7 7 7
Weeks
CLV
Marcellin P, Hepatology 2004;40:140-148
HBV DNA (median log10 copies /ml)
Week 24 Week 48
(24 weeks off therapy)
Yoo et al AASLD 2005
Clevudine in HBeAg+ve CHBMulticenter, randomized, phase 3 trial
Patients received 24 weeks clevudine 30 mg/day (n = 243) or placebo (n = 61)
CLV 30mg PLB CLV 30mg PLB
-0.68
-2.02
-0.27
-5.10
-6
-5
-4
-3
-2
-1
0
Clevudine: phase III study in HBeAg+ve
HBeAg loss
CLV30mg
PLB CLV30mg
PLB
Week 24 Week 48(24wk off therapy)
Patients(%)
Yoo et al AASLD 2005
15
101212
0
5
10
15
20
25
30
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.
Outcome
Clevudine 30 mg/day (n = 63)
Placebo (n = 23) P Value
Change in HBV DNA, log10 copies/mL• End of treatment• End of follow-up
-4.25-3.11
-0.48-0.66
< .0001< .0001
Undetectable HBV DNA, %• End of treatment• End of follow-up
9216
00 < .0001
Normal ALT, %• End of treatment• End of follow-up
7571
3329
.006
.007
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 2006. Abstract 53.
Per
cen
tag
e W
ith
HB
V D
NA
< 3
00
co
pie
s/m
L
Per
cen
tag
e W
ith
N
orm
al S
eru
m A
LT
25 27
89100
86
100
HBeAg-Negative Patients (n = 15)
HBeAg-Positive Patients (n = 40)
0
20
40
60
80
100
Baseline (Week 0) Treatment End (Week 48) Follow-up (Week 60)
HBeAg-Negative Patients (n = 15)
HBeAg-Positive Patients (n = 40)
00
68
100
23
100
0
20
40
60
80
100
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)
OR
OOHN
N
NH2
O
Valtorcitabine
(val-LdC)
Telbivudine
(LdT)
OH
OOHN
HN
O
OCH3
Effect of Valtorcitabine on Serum
HBV DNA
Lim SG, et al. EASL 2005.
-4
-3
-2
-1
0
1
0 1 2 3 4 5
Study Week
Placebo600 mg/day900 mg/day1200 mg/day
Ser
um
HB
V D
NA
Mea
nL
og
10 R
edu
ctio
n F
rom
Bas
elin
e
Tennant et al. HepDart 2001
WHBVDNALog10
GenomeCopies/
mL
Weeks
123456789
10111213
0 4 8 12 16 20 24
Placebo
0 4 8 12 16 20 24123456789
10111213 Telbivudine
Telbivudine +Valtorcitabine
0 4 8 12 16 20 24
123456789
10111213
n = 5 per group
Once daily oral dosing for 12 weeks
Doses (mg/kg/day):Telbivudine, 10Valtorcitabine,10
Telbivudine and Valtorcitabine are Synergistic in the Woodchuck Model
Valtorcitabine
0 4 8 12 16 20 24123456789
10111213
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 380.- 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 N
NN
N
NH2
OPO
HO
HO
CH3
Qi et al. 40th EASL. April 2005. Oral 75
Tenofovir disoproxil fumarate
Tenofovir vs Adefovir in patients with lamivudine resistanceHBV-DNA <400 copies/ml
Van Bommel et al 2004
Weeks
22%
44%44%
78%94%
33%44%
100%
0%
20%
40%
60%
80%
100%
12 24 36 48
ADV Tenofovir
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.
Undetectable HBV DNATenofovir 300 mg/day,
%(n = 38)
Adefovir 10 mg/day, %
(n = 68)Month 12 94 32Month 18 100 35Month 24 100 49
OutcomeTenofovir 300 mg/day,
%(n = 38)
Adefovir 10 mg/day, %
(n = 68)loss 49 13HBsAg loss 19 6
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.
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
Cl
P
O
OO
O
N
NN
N
NH2
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 2006. 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, % 45 63 56 71 36
ALT normalized• HBeAg-positive patients, n• HBeAg-negative patients, n
6457
6481
6565
6967
6479
HBeAg seroconversion, % 18 12 10 19 17
Pradefovir for Chronic Hepatitis B: Week 48 Analysis (cont’d)
Lee KS, et al. EASL 2006. Abstract 741
Week
-4.09
-5.54
Pradefovir 5 mg (n = 47)
0 4 12 18 24 36 48
-4.19
-4.89
-4.84
0
-1
-2
-3
-4
-5
-6Mea
n (
SE
) C
han
ge
in H
BV
DN
A
Fro
m B
asel
ine
(lo
g10
co
pie
s/m
L)
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:
- 1.52 log10 at 2.5 mg QD- 2.63 log10 at 10 mg QD
N
NN
N
S
MeO
NH2O
P
O O
O
CF3
CF3
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 2006.
-5
-2.8-3.2
-3.9 -3.9 -4.1-4
-3
-2
-1
0
30(n = 13)
60(n = 14)
90(n = 14)
150(n = 12)
240(n = 12)
Red
uct
ion
in H
BV
DN
A b
y W
eek
12
(lo
g10
co
pie
s/m
L)
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