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