UPDATES IN HBV

What is coming in 5-10 years?

Patrick T. F. Kennedy

Reader & Honorary Consultant Hepatologist

Blizard Institute, Barts and The London SMD, QMUL, London

EASL CPG 2017

EASL CPG 2017

Age limit of 30 years is arbitrary;

liver damage can be seen earlier

Representative patient: 23 year old male;

ALT 36 IU/L, HBV DNA 7.18 log IU/ml, HBsAg 3.59 log IU/ml

Ishak fibrosis stage 3/6

Evidence of liver damage in the ‘immune tolerant’ disease phase

Mason/Kennedy et al., Gastroenterology 2016

HBcAg HBsAg

HBsAg/HBcAg

Mason/Kennedy et al., Gastroenterology 2016

Nuclear core positive hepatocytes differentiate ‘immune tolerant’ disease

Nuclear core positive hepatocytes differentiate ‘immune tolerant’ disease

Mason/Kennedy et al., Gastroenterology 2016

Clonal hepatocyte expansion in ‘immune tolerant’ disease

Mason/Kennedy et al., Gastroenterology 2016

0

HBeAg Anti-HBe

HB

V D

NA

/HB

sA

g (

log

10 I

U/m

l)

ALT

(IU/L

)

CHRONIC INFECTION CHRONIC HEPATITIS CHRONIC INFECTION CHRONIC HEPATITIS

HBeAg POSITIVE HBeAg NEGATIVE

Natural History & Disease Phase

Adapted from Gill & Kennedy; Clin Med 2015

0

HBeAg Anti-HBe

HB

V D

NA

/HB

sA

g (

log

10 I

U/m

l)

ALT

(IU/L

)

CHRONIC INFECTION CHRONIC HEPATITIS CHRONIC INFECTION CHRONIC HEPATITIS

HBeAg POSITIVE HBeAg NEGATIVE

Natural History & Disease Phase

~10% ~50%

~25% - treated

~15% - worked-up

Adapted from Gill & Kennedy; Clin Med 2015

0

HBeAg Anti-HBe

HB

V D

NA

/HB

sA

g (

log

10 I

U/m

l)

ALT

(IU/L

)

CHRONIC INFECTION CHRONIC HEPATITIS CHRONIC INFECTION CHRONIC HEPATITIS

HBeAg POSITIVE HBeAg NEGATIVE

Natural History & Disease Phase

~10% ~50%

~25% - treated

~15% - worked-up

Adapted from Gill & Kennedy; Clin Med 2015

Treatment & management strategies

HBV Treatment regimes

Nucleos(t)ide Analogues (NUCs)

Marcellin et al, Lancet 2015; Chang, et al. Hepatology 2010

TENOFOVIR ENTECAVIR

Current therapies are non-curative

• Peg-IFN sustained immune control, but only in a minority

of patients1

• HBeAg positive & negative disease:

– limited decline in HBsAg during NUC monotherapy2

• Long-term viral suppression is achieved, but sustained

immune control following treatment cessation is limited3

1. EASL guidelines. J Hepatol 2012;57; 2. Zoutendijk R, et al. J Infect Dis 2011;

3. Hadziyannis SJ, et al. Gastroenterology 2012

The future prospects for HBV cure

Phase 3 Program: TAF 25 mg for HBV

Extended to *3 years; †5 years.

Double Blind*

2:1 randomization

TAF 25 mg

TDF 300 mg

Study 110: HBeAg+ N=873 and Study 108: HBeAg− N=425

• Primary endpoint:

• HBV DNA <29 IU/mL at week 48

• Secondary safety endpoint:

• Bone: hip and spine bone mineral density change

• Renal: creatinine and eGFR change

Week

48

Open-label TAF†

Week

96

Week

120

Buti M et al. Lancet G&H 2016, Chan HLY et al. Lancet G&H 2016

TAF Phase 3: Week 96 Results

TAF Group Performance Relative to TDF Group

Week 48 Week 96

Viral Suppression Non-inferior Non-inferior

ALT Normalization Significantly Better Significantly Better

Bone Safety Significantly Better Significantly Better

Renal Safety Significantly Better Significantly Better

Viral Resistance None None

Harnessing innate and adaptive immunity

Gane EJ, J Hepatol, 2015

Lanford et al. Gastroenterology 2013

TLR agonists - GS-9620

• TLR-7/8 mediate innate immune

activation in human liver:

• CD56bright NK cells & MAITs

produce antiviral cytokine IFN-g

Jo et al. PLoS Path 2014

Virally Suppressed

Trial complete

1, 2, or 4 mg vs PBO qwk

N=156

Naïve/Off Treatment

Dosing complete

1, 2, or 4 mg vs PBO qwk

N=192

GS-9620: Pharmacodynamics and Efficacy

• Dose-dependent, reproducible ISG15 induction without systemic cytokines

• Minimal HBsAg changes at Week 24

0 2 2 1 2 2 2 8 2 9 4 9 5 0 7 7 7 8 8 4

0

5

1 0

1 5

2 0

2 5

-0 .4

-0 .2

0 .0

Wk 24 HBsAg Change from Baseline ISG15 Fold-Change Expression

Lo

g1

0 IU

/mL

Me

dia

n, IQ

R

PBO Study Day

Dose 1 4 8 12

PBO 1 mg 2 mg 4 mg

1 mg 2 mg 4 mg

Virally-suppressed

Schurich et al. PLoS Pathog. 2013; D, et al. Vaccine 2013;

Jo et al., PLoS Pathog. 2014; Isorce et al. Antiviral Res 2016.

TLR8 Cytokines Activate Antiviral Immunity

TLR8 TLR7

Neutrophil mDC B cell Macrophage Monocyte pDC Tregs

Innate

Immunity

IL-12

IL-18

Adaptive

immunity

pAPCs

Tregs

Antiviral

cytokines

TNF-α

IFN-γ

NK MAIT CD8+

Foxp3+

IL-12

TNF-α

Pre-systemic Mechanism of Action

Harnessing innate and adaptive immunity

TLR agonists - GS-9668

• Virally-suppressed, HBeAg negative CHB patients (single center NZ)

• Primary efficacy endpoint:

• Change in HBsAg log10 IU/mL levels 12 Weeks following nivolumab treatment

Baseline Week 4 Week 16 Week 12

Primary Endpoint

(12 weeks post-nivolumab)

Nivolumab 0.3 mg/kg Sentinel B, n=2

Sentinel A, n=2 Nivolumab 0.1 mg/kg

Cohort A, n=10 Nivolumab 0.3 mg/kg

Cohort B, n=10 + GS-4774 40 YU

Nivolumab 0.3 mg/kg

Anti-PD1 inhibitor - Nivolumab

Study Design

-5

-4

-3

-2

-1

-0 .8

-0 .6

-0 .4

-0 .2

0 .0

0 .2

-5

-4

-3

-2

-1

-0 .8

-0 .6

-0 .4

-0 .2

0 .0

0 .2

Nivolumab

0.1 mg/kg

Nivolumab

0.3 mg/kg

Nivolumab

0.3 mg/kg

+ GS-4774

Week 12 Week 24

HB

sA

g C

han

ge

fro

m B

L, L

og

10 IU

/mL

Nivolumab

0.1 mg/kg

Nivolumab

0.3 mg/kg

Nivolumab

0.3 mg/kg

+ GS-4774

• 2/22 (9%) at Week 12 and 3/22 (14%) at Week 24 with a >0.5 log10 reduction in

HBsAg • Only one patient with >1 log10 reduction in HBsAg at either timepoint

• No baseline demographic feature associated with >0.5 log10 reduction in HBsAg

HBsAg change from baseline

Anti-PD1 inhibitor - Nivolumab

HBV Capsid Assembly Modulators (CpAMs)

CpAMs & ETV inhibit HBV replication

by distinct mechanisms

• CpAMs ABI-H0731 & GLS4 inhibit encapsidation of both viral DNA and pgRNA

• ETV in`hibited HBV DNA synthesis, but increased levels of pgRNA in intracellular

capsids by failing to create the RNA:DNA duplex digested by RNaseH

CpAMs inhibit cccDNA generation

in primary human hepatocytes

• CpAMs reduced viral HBV DNA levels and known surrogate markers for cccDNA

(HBeAg,HBsAg and pgRNA)

• ETV was highly effective at inhibiting HBV DNA levels, but exhibited limited effect

on cccDNA surrogates

Viral DNA, pgRNA, HBeAg and HBsAg in PHH

RNAi & Core Protein/Capsid Inhibtor

• Two novel agents in combination with SoC

• AB-423 (Core/Capsid Inhibitor)

-misdirects capsid assembly & inhibits pgRNA encapsidation

• ARB-1740 (RNA Inhibitor)

-Targets sAg produced by cccDNA & integrated DNA

RNAi & Core Protein/Capsid Inhibtor

• Two novel agents in combination with SoC

• AB-423 (Core/Capsid Inhibitor)

-misdirects capsid assembly & inhibits pgRNA encapsidation

• ARB-1740 (RNA Inhibitor)

-Targets sAg produced by cccDNA & integrated DNA

0 7 1 4 2 1 2 8 3 5 4 2

5

6

7

8

D a y

Se

rum

HB

V D

NA

(lo

g1

0c

op

ies

/mL

)

A B -4 2 3 + A R B -1 7 4 0 + P e g IF N

A B -4 2 3 + A R B -1 7 4 0 + E T V

LLOQ

RNAi & Core Protein/Capsid Inhibtor

• Combination of novel MOA agents

AB-423 (capsid inhibitor) and ARB-

1740 (RNAi) can enhance control of

HBV by current standard drugs

• These data support the hypothesis

that HBV antigen removal will

promote immune recognition and

viral control

Immune Recognition

Reduce viral

Antigens & DNA

GS-4774 (Tarmogen)

Stubbs, et al. Nat Med 2001; Cereda, et al. Vaccine 2011; Francis et al Vaccine 2015

CD4+

CD8+

GS-4774

APC

M X Large S (env) Core His

6

GS-4774 Recombinant Antigen

C8F17

fluorocarbon chain

DensigenTM

• ~ 30-40 amino acids long peptides

• CD4+/CD8+ T cell epitopes

• Net positive charge/Hydrophobicity

<70%

Current Trials of Therapeutic vaccination in HBV

Phase II in HBV patients suppressed on antivirals

Now to 5-10 years ahead; transition to functional cure

Gill & Kennedy, J Hepatol. 2017, In Press

Closing remarks

• Better understanding of HBV pathogenesis will be central to

better treatment outcomes

• Viral suppression now is just the starting point for HBV

care

• A new era in HBV management is emerging with strategies

to achieve functional cure

• Successful regimens for HBV cure will likely include

combination of direct antiviral suppression with immune

modulation

Acknowledgements

Dimitra Peppa, Lorenzo Micco,

Harsimran Singh, Mala Maini

Royal London Hospital

Louise Payaniandy, William Tong,

Deva Payaniandy, Sally Thomas,

Sandhia Naik

Graham Foster, Jyoti Hansi

Uppy Gill

Samuel Litwin, Yan Zhou,

Suraj Peri, William Mason

Fox Chase Cancer Centre Blizard Institute, QMUL

Rayne Institute, UCL

Duke, NUS/SICS A* Star

Elena Sandalova, Juandy Jo,

Adeline Chia, Antonio Bertoletti

ILS, Kings College

Oltin Pop,

Alberto Quaglia

University of Rome, TV

Luna Colagrossi, Romina Salpini,

Arianna Battistii, Lorenzo Piermatteo

Carlo Perno, Valentina Svicher