The Hong Kong Association for the Study of Liver Diseases ...

New Therapies in the Treatment of HBV Infection

Man-Fung YuenDSc, MD, PhD

Chair ProfessorLi Shu Fan Medical Foundation Professor in Medicine

The University of Hong Kong

The Hong Kong Association for the Study of Liver Diseases














Chronic Hepatitis B: Globally Significant Disease

• In 2016– Worldwide estimated prevalence 3.5% (257 million)

• Western Pacific region 6.2% (115 million)• African region 6.1% (60 million)

• In 2015– Number of deaths due to

• Viral hepatitis 1.34 million• Tuberculosis 1.37 million• Malaria 0.44 million Seto WK… Yuen MF. The Lancet 2018;10161:2313-24

Yuen MF, et al. Nat Rev Dis Primers 2018;4:18035The Hong Kong Association for the Study of Liver Diseases














Chronic Hepatitis B Infection: Complex Disease

Complex Viral Life Cycle Complex Disease Phase

Seto WK… Yuen MF. The Lancet 2018;10161:2313-24The Hong Kong Association for the Study of Liver Diseases














HBV Treatment Goals and Definitions of Cure

4GLEM/SEBIVO/0022cThe Hong Kong Association for the Study of Liver Diseases














Current Goal: Partial Cure

Cessation of all treatment

Finite treatment duration

HBsAg+ but sustained normal ALT and low/undetectable HBV DNA

No activeliver disease















New Goal: Functional Cure



Absence of HBV DNA and HBsAg

• No activeliver disease

• No viral replication















Future Goal: Complete Cure

Clearance of cccDNA




• No viral replication

• No risk of reactivation
















Future Goal: Sterilising Cure




Clearance of cccDNA

Clearance of integrated HBV DNA


• No viralreplication

• No risk of reactivation

• No risk of HCCand no ongoing surveillance















• Important disease/ treatment milestone

– associated with better prognosis if it occurs at an early age

– treatment can be stopped

HBsAg Seroclearence = Functional Cure















Approved Treatment Agents For Chronic HBV Infection

Yuen MF et al., Nat Rev Dis Primers. 2018;4:18035 The Hong Kong Association for the Study of Liver Diseases














Slow HBsAg Decline by Long-term Entecavir Treatment

3.41 3.36 3.32 3.19 3.04 2.95 2.962.78

0

0.5

1

1.5

2

2.5

3

3.5

4Lo

g H

BsA

g(lo

g IU

/ml)

p <0.01

data on file from Lam YF… Yuen MF. Clin Transl Gastroenterol 2017; 8(10): e125The Hong Kong Association for the Study of Liver Diseases














HBsAg

HBcrAg

cccDNA

intrahepatic total HBVDNA

Serum HBV DNALoga

rithm

ic re

duct

ions

(log

IU/m

L or

cop

ies/

cell)

Baseline Year 1Year 6-12

(median 126 months)

0

-1

-2

-3

-4

-5

-6

Lai CL… Yuen MF. J Hepatol 2017;66:275-281

Slow HBsAg Decline by Long-term Nucleos(t)ide Treatment















Yuen MF et al., Nat Rev Dis Primers. 2018;4:18035

PEG - IFN2.4% at 5 years (n= 85, HBeAg+)8% at 3 years (n=230, HBeAg-) Wong V et al. Hepatology 2010;51(6):1945-53

Marcellin P et al. Gastroenterology 2009; 136(7):2169-79

Low Rate of HBsAg Seroclearance by Existing Treatment

Nucleos(t)ide Analogs















Decades of NUC Treatment Before Achieving HBsAg Seroclearance

Zoutendijk R, et al. J Infect Dis 2012;206:974–80.

10

3

42

18

0 20 40 60

HBeAg -ve

HBeAg +ve

Estimated years of Nuc therapy required to achieve HBsAg endpoints

HBsAg clearance

1 log decline in HBsAg from baseline















Possible Future Curative Regimen For CHB

NUC analogue Viral antigen inhibitor

Immune modulation

cccDNA inhibitor

+ + +

To control viral replication and

cccDNAre-amplification

To inhibit HBV life cycle processes (e.g. entry, mRNA transcription,

capsid assembly, viral protein secretion)

To activate orrestore HBV-targeting

immune responses

To silence or eliminate cccDNA

Functional cure

Complete cure?

Seto WK & Yuen MF. Clinical Liver Disease 2016;8(4):83-8The Hong Kong Association for the Study of Liver Diseases














Agents Under Clinical Trials to Enhance “Functional Cure”

NUC analogues:• Already available

Nucleocapsid assembly inhibitors:• NVR 3-778• JNJ379• ABI-H0731• GLS4

HBsAg release inhibitors:• REP 2139• GC 1102

Immunomodulators:Therapeutic vaccines• GS-4774• ABX-203• TG-1050• INR-1800• FP-02.2Others• GS-9620• SB-9200 (Inarigivir)• AIC649• Birinapant

mRNA silencers:siRNA• ARC-520• ARO-HBV• ARB-1467Others• GSK3228836• RO7020322

cccDNA inhibitors:• Pending clinical

studies

Entry inhibitors:• Myrcludex B

Modified from Seto WK & Yuen MF. Clinical Liver Disease 2016;8(4):83-8

HBV virion















GLEM

/SEB

IVO

/002

2c

17

Simplified Theory of HBV siRNA Therapeutic

Silence Entire HBV Genome

1. “HBsAg Theory”• Reducing HBsAg enables

host immune system de-repression and long term control of virus

2. Destabilizing Viral Function• Silencing all antigens could

destabilize normal viral function

• Enable host immune system de-repression and long term control of virus















-6

-5

-4

-3

-2

-1

0

1

-20 0 20 40 60 80 100 120 140 160

Log

HBsA

g re

duct

ion

Weeks

Pt. 017981 EPosPt. 017982 EPos

HBsAg Reduction by Multiple Doses of siRNA (ARC-520)

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

-20 0 20 40 60 80 100 120 140 160Lo

g HB

sAg

redu

ctio

nWeeks

Pt. 017973 EnegPt. 017974 ENegPt. 017988 ENeg

HBsAg Seroclearance

HBeAg +ve HBeAg -ve

Yuen MF (unpublished data)The Hong Kong Association for the Study of Liver Diseases














Mean Log HBsAg change from day 1 (n=4 per cohort)

0 2 0 4 0 6 0 8 0 1 0 0 1 2 0

- 2 . 5

- 2 . 0

- 1 . 5

- 1 . 0

- 0 . 5

0 . 0

D a y

Lo

g H

Bs

Ag

fr

om

Da

y 1

3 0 0 m g q 4 w x 3 ( C 4 b )

2 0 0 m g q 4 w x 3 ( C 3 b )

1 0 0 m g q 4 w x 3 ( C 2 b )

4 0 0 m g q 4 w x 3 ( C 5 b )

3 0 0 m g q 4 w x 3 E + , N U C n a ï v e ( C 8 )

3 0 0 m g q 4 w x 3 E + , N U C e x p ( C 9 )

NADIR HBsAg responses for patients with > 6 weeks of HBsAg data• > 1 log (90%) reduction 100%• > 1.5 log (97%) reduction 83%• > 2 log (99%) reduction 38%• > 3 log (99.9%) reduction 3%

Profound HBsAg Reduction with 3-dose siRNA (ARO-HBV)

Gane E...Yuen MF AASLD 2018 (LB 25)The Hong Kong Association for the Study of Liver Diseases














Individual changes in HBV DNA, HBV RNA, HBeAg and HBcrAg

in patients receiving 3-dose siRNA (ARO-HBV)

- 2 0 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0

1 0 1

1 0 2

1 0 3

1 0 4

1 0 5

1 0 6

1 0 7

1 0 8

1 0 9

1 0 1 0

H B V D N A

D a y

HB

V D

NA

[IU

/mL

]

* < 2 0 I U / m L**

L L O Q

- 2 0 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0

0 . 1

1

1 0

1 0 0

1 0 0 0

1 0 0 0 0

H B e A g

D a y

HB

eA

g [

PE

IU/m

L]

L L O Q

- 2 0 0 2 0 4 0 6 0 8 0 1 0 0

1 0 1

1 0 2

1 0 3

1 0 4

1 0 5

1 0 6

1 0 7

H B c r A g

D a y

HB

cr

Ag

[k

U/m

L]

L L O Q

- 2 0 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0

1

2

3

4

5

6

7

8

9

1 0

L o g H B V R N A

D a y

Lo

g H

BV

RN

A [

Lo

g U

/mL

]

L L O Q

* < 1 . 6 5 L o g U / m L

****** * *

Gane E...Yuen MF AASLD 2018 (LB 25)The Hong Kong Association for the Study of Liver Diseases














CpAM under Clinical TrialsHBV capsid assembly pathway and examples of capsid inhibitors

HAP: heteroaryldihydropyrimidines; | SBA: sulfamoylbenzamides; | PP: phenylpropenamides

Class l Class llForms empty capsid

devoid of pgRNA/rcDNA

Assembly

rcDNA-containingnucleocapsid

polGAA

HAP

PP

AB-423

JNJ-6379

AB-506

ABI-H0731

RG7907

GLS-4

NVR 3-778HAP

BAY-41-4109AT-130

Lower stemUpper stem

Looptyrosine

Retrotranscription + DNA replication

SBA

Forms aberrant non-capsid polymers Core +

pgRNARO7049389















CpAM: Dual mechanism of action

RNA containing particle(pgRNA,spliced RNA)

Dane particle (infectious DNA containing)

Subviral particles (HBsAg)

x x

Berke JM et al. AASLD 2016; Abstract 234

xx

“Secondary” mechanismInhibition of the de-novo formation of cccDNA, potentially by interfering

with the capsid disassembly process (early step in viral life cycle)JNJ-6379 median EC50/EC90 = 876 nM/4019 nM

JNJ-6379 is a CAM that binds to HBV core protein and disrupts early and late-stage processes in the HBV life-cycle

“Primary” mechanism (“empty capsid” CAM)Interference with capsid assembly kinetics, preventing encapsidation of

(pg)RNA and blocking HBV replication (late step in viral life cycle)JNJ-6379 median EC50/EC90 = 102 nM/376 nM

NAs block HBV replication butdo not inhibit the production of

RNA-containing particles















JNJ-6379: Study Design

AP Asia-Pacific; EU Europe

Objective: To evaluate the antiviral activity, safety and PK of escalating doses of JNJ-6379 following 4 weeks’ oral administration in treatment-naïve adults with CHB who meet the following criteria:

▪ HBeAg-positive or -negative

▪ Plasma HBV DNA >2,000 IU/mL

▪ Non-cirrhotics (F0–F2)

▪ ALT less than 2.5x ULN

Dosing phase (days)1 280 84Follow-up phase (days)

100 mg

75 mg QD

150 mg QD

25 mg QDSession 8 (EU)(8 drug; 4 placebo)

Session 9 (EU)(8 drug; 4 placebo)

Session 10 (EU/AP)(9 drug; 3 placebo)

Session A (EU/AP)(9 drug; 3 placebo)

Session 11 (AP)(7 drug; 2 placebo)

8-week follow-up

8-week follow-up

8-week follow-up

250 mg QD 8-week follow-up

75 mg QD 8-week follow-up

Data being presented

today

Sessions 1 to 7 were performed in healthy volunteers (Zoulim F et al., AASLD 2017; Abstract LB-15) Zoulim F et al. AASLD 2018 (Abstract 74)The Hong Kong Association for the Study of Liver Diseases














HBV DNA Change

Placebo QD

25 mg QD75 mg QD

150 mg QD

250 mg QD

-4

-3

-2

-1

0

1

Mea

n (±

SD) H

BV D

NA

chan

ge fr

om b

asel

ine

(log 1

0 IU

/mL)

1 2 3 4

Time (weeks)

6 8 10 12

Follow-up period

-0.57 (0.62)-0.77 (0.69)

-1.39 (1.18)e

-0.06 (0.93)-0.08 (0.42)

LLOQ = Lower limit of quantification (20 IU/mL) of the HBV DNA assay

No patients had values <LLOQe One patient started tenofovir at Week 8

Zoulim F et al. AASLD 2018 (Abstract 74)The Hong Kong Association for the Study of Liver Diseases














25

ABI-H0731: Study Design

• Once-daily oral dosing

• HBeAg Pos and Neg patients (stratified 7:5)

400 mg (n=2)

Treatment (28 days)

100 mg (n=10 + 2 PBO)

200 mg (n=10 + 2 PBO)

300 mg (n=10 + 2 PBO)

Primary • Dose-related safety and

tolerabilitySecondary • Steady state human PK • Dose-related antiviral effects

• HBV DNA/RNA • HBsAg and HBeAg • Pre-existing and emergent

resistance

Objectives

Off Treatment Follow up (28 days)

Yuen MF et al. AASLD 2018 (Abstract 73)The Hong Kong Association for the Study of Liver Diseases














26

HBV DNA Change

Change from BaselineLog10 HBV DNA (IU/mL)

Patients HBeAg Pos HBeAg Neg

Dose (mg) N Mean(Range) N Mean

(Range)

100 mg 6 1.3(0.8 - 1.7) 4 2.2

(0.7 - 3.6)

200 mg 5 1.9(1.0 - 2.6) 5 2.4

(1.5 - 3.8)

300 mg 6 2.9(1.8 - 3.9) 3* 2.5*

(0.8 – 4.1)

400 mg 0 NA 2 3.9(3.9 –4)

• Dose responsive declines; Reductions of up to 4 logs at 300 and 400 mg PO QD• All subjects rebounded post therapy

*Excludes subject with known resistance at baselineThe Hong Kong Association for the Study of Liver Diseases














27

Parallel Reductions in HBV RNA Levels

Changes from Baseline

Patients HBeAg Pos

Dose (mg) N Mean Copies/ uL(Range)*

100 mg 6 1.2(0.7 - 1.6)

200 mg 5 1.7(1.1 - 2.2)

300 mg 6 2.3(1.7 – 2.6)

400 mg 0 NA

• HBV RNA reductions (1-2 logs) seen at all dose levels, and correlated with HBV DNA reductions (p <0.001)• Mechanism-based reduction in viral RNA levels is a differentiating feature of Core inhibitors

*Internal HBV RNA RT-qPCR assay, for HBeAg positive: LOQ = 10 copies/µL

HBeAg Neg patients• RNA levels were lower

at baseline and more difficult to quantitate

• All subjects with detectable RNA at baseline had RNA declines on treatment















I N A R I G I V I R : A N O V E L , O R A L S E L E C T I V E I M M U N O M O D U L AT O R W I T H A D U A L M E C H A N I S M O F A C T I O N

HBV, hepatitis B virus; IFN, interferon; pgRNA, pregenomic RNA; RIG-I, retinoic acid-inducible gene-I.

Sato et al. Immunity. 2015;42:123-132.

INARIGIVIR is a RIG–I AGONIST which is designed to:

• Restore hepatic selective innate and adaptive immune response stimulating the production of type I and III IFNs

• Inhibit the HBV replication complex via a direct acting anti-viral effect

• Result in significant anti-HBV activity with reduction in HBV DNA, HBV RNA, HBsAg and cccDNA

RIG-I

RIG-I

TYPE III IFNs

OATP1

DAA EFFECT TARGETING REPLICATION COMPLEX

HBV pgRNA5’ 3’

HBV pgRNA5’ 3’

Dual antiviral effect against HBV

HBV polymerase

Reverse transcription

Viral replication

ε ε

INARIGIVIR

Hepatocyte

RIG-I ACTIVATION AND BINDING TO

HBV PGRNA















DNA, deoxyribonucleic acid; HBeAg, hepatitis B e antigen; RNA, ribonucleic acid; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; QD, once daily.

PRIMARYENDPOINT

SECONDARYENDPOINT

Safety and antiviral activity at 12 weeks

PK, change in serum HBV DNA, HBsAg, HBV RNA and HBeAg from baseline to weeks 6, 12, 14, 16, and 24

Up to 80 non-cirrhotic

HBV subjects, randomized 4:1

between inarigivir

and placebo (Adaptive trial

design)

Inarigivir - 200 mg

Placebo

Inarigivir - 100 mg

Inarigivir - 50 mg

Inarigivir - 25 mg

Viread® 300 mg

All patients switch to Gilead’s Viread®

300 mg monotherapy

12 weeks (inarigivir monotherapy QD)

12 weeks

Clinical trial collaboration with Gilead to evaluate inarigivir followed by tenofovir 300 mg

ACHIEVE PHASE 2 (PART A) MONOTHERAPY DOSE ESCALATION STUDY

Cohort 1

Cohort 2

Cohort 3

Cohort 4

HBsAg predefined response: > 0.5 log HBsAg reduction at week 12 or 24















I N A R I G I V I R D E M O N S T R AT E S A C O N T I N U I N G P O S I T I V E D O S E R E S P O N S E I N H B e A g - V E PAT I E N T S AT W E E K 1 2

HBV DNA HBV RNA

Placebo 25 mg 50 mg and 100 mg

4

2

-2

-4

0

-6

2

1

-1

-2

0

-3

Placebo 25 mg 50 mg 100 mg

All groupsp<0.01

All groups p<0.01

5 patients undetectable HBV RNA at baseline

Inarigivir DoseInarigivir Dose

Log 1

0 De

clin

e HB

V DN

A

Log 1

0 De

clin

e HB

V RN

AYuen MF et al. AASLD 2018 (Abstract 75)The Hong Kong Association for the Study of Liver Diseases














HBV DNA1

0

-1

-2Placebo 25 mg 50 mg 100 mg Placebo 25 mg 50 mg 100 mg

HBV RNA0.5

0.0

-1.0

-1.5

-0.5

-2.0

Inarigivir 100 mg vs PL*p<0.05

* #

Inarigivir vs PL*p<0.03#p<0.02

Inarigivir Inarigivir

Log 1

0 De

clin

e HB

V DN

A

Log 1

0 De

clin

e HB

V RN

A

Inarigivir Dose Inarigivir Dose

I N A R I G I V I R D E M O N S T R AT E S A C O N T I N U I N G P O S I T I V E D O S E R E S P O N S E I N H B e A g + V E PAT I E N T S AT W E E K 1 2















HBV DNA HBV RNAlog10 log10

Inarigivir to week 12 Tenofovir week 12 - 24 Inarigivir to week 12 Tenofovir week 12 - 24

HBeAg negative patients (n=10) – Inarigivir effect on HBV RNA persists on TDF

BL 12 14 240

2

4

6

8

BL 12 14 240

1

2

3

4

5

6 patients LLOQ















BL 12 242

3

4

5

BL 12 245

6

7

8

HBsAg decline in HBeAg positive responders

HBV RNA decline in HBeAg positive responders

Inarigivir Tenofovir

log10 log10

Inarigivir Tenofovir

-0.9log10-1.5log10

HBeAg Positive Responder Patients > 0.5 log10 Reduction















S i m m a r y o f H B s A g R e s p o n s e

• Overall, 13 of 47 (28%) patients experienced a 0.5 log10 reduction on inarigivir alone or at 24 weeks after TDF switch

• HBsAg response seen in 6 out of 32 HBeAg +ve and 7 out of 15 HBeAg –ve patients

• Mean and median HBsAg reduction 0.8 log10 (range 0.5 – 1.4 log10) in 13 responder patients















Summary for New Agents

• RNA inhibition (IV or SC)

• Profound effect on HBsAg level

(also HBeAg/ HBcrAg) and HBV RNA

• Cases of HBsAg seroclearance were observed

• Capid protein modulation/ inhibition (oral)

• Proven efficacy on HBV DNA and HBV RNA reduction

• According to the MOA, reduction on cccDNA expected

• RIG-I agonist (oral)

• Positive effects on HBV DNA and HBV RNA

• Effects on HBsAg reduction maintained/ potentiated even after switching to NUC monotherapy

Most of the new HBV agents have now undergone/ completed phase II studies

Coming HBV agents to the clinic















Shortening the Time of CHB Treatment by New Agents

NUCs Viral suppressionundetectable HBV DNA

Functional control/cureHBsAg loss

Complete curecccDNA clearance

For now

1-3 yrs ? >10 yrs ? >30-40 yrs

Slow HBsAg decline Natural hepatocyte turn-over

For the future

NUCs Viral suppressionundetectable HBV DNA

Functional control/cureHBsAg loss

Complete curecccDNA clearance

1-3 yrs ?3 yrs ? 10, 20 yrs

RNA knock-down

NAP + Immune modulators

RIG-I agonistCpAM















Thank you















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