The path towards the cure of HBV infection

Fabien Zoulim

Hepatology Department, Hospices Civils de Lyon

INSERM U1052, Cancer Research Center of Lyon

Lyon University, France

• 240 million CHB worldwide

• 1.7 million CHB treated worldwide

• Hepatocellular Carcinoma (HCC) : 2nd cause of cancer death worldwide

Chronic Hepatitis B (CHB) - a global health problemfrom viral suppression to cure

Elimination of HBV infection and HBV-related diseaes

HBV susceptible

Acute HBV

Chronic HBV

Cirrhosis/HCC

Vaccine

Universal precautions

Antiviral

treatment

Current treatments: virus suppression and sustained disease control

Liaw YF et al, N Engl J Med. 2004; Chang et al, Hepatology 2010; Marcellin et al, Lancet 2013;

Hosaka et al, Hepatology 2013; Kim et al, Cancer 2015; Papatheodoridis et al, J Hepatol 2015

Decreased inflammation/fibrosis

Decreased progression

Reversal of fibrosis

Decreased progression

Decreased incidence

but not eliminated

NUCs

Virus suppression

HBsAg loss rate

Max 10% after 5 years

UNTREATED

Liver

Blood

Rc-DNA

HBsAg

ccc-DNA

HBV-DNA

Normal Cirrhosis Hepatocellular

carcinoma

From viral suppression to cure

Liver

Blood

Rc-DNA

HBsAg

ccc-DNA

NUCs

Normal Cirrhosis Hepatocellular

carcinoma

Risk of HCC reduced

(after 5 yrs)

but not eliminated

Liver

Blood

ccc-DNA Liver

Blood

NMEs NMEs“Cure”

Direct Antiviral Agents

Immunomodulatory

strategies

Normal Cirrhosis Hepatocellular

carcinoma

Definition of HBV cure: what do we want to achieve ?

Therapy

HB

V D

NA

ch

an

ge

fro

m b

as

eli

ne (

log

10

c/m

L)

0.0

-1.0

-2.0

-3.0

-4.0

+1.0

Time

HBsAg

HBV DNA

cccDNA

SERUM

LIVER

+/- Anti-HBsAb

Lok et al, Hepatology / J Hepatol joint publication, in press; Testoni et al, Sem Liver Dis, in press.

Partial Cure

Functional

Cure

Complete Cure

Sterilizing

Cure

Virus

Suppression

Antivirals

Cure

Immunotherapy

Drug Discovery

Clinical development

Access to care

Biomarkers

Mechanisms of viral persistence

cccDNA reservoir

Antigenic load

Liver tolerance

Defective CD8+ response

Defective B cell response

Inefficient innate response

HBV persistence Defective immune responsesLocarnini, S. & Zoulim, F. et al. (2016) Global strategies are required to cure and eliminate HBV infectionNat. Rev. Gastroenterol. Hepatol.

Vaccine therapy

Check-point

inhibitors

TLR agonistsBlockade

of immune-

suppressive

cytokines

Chimeric antigen

Receptors (CAR)

Antiviral cytokines

Entry inhibitors

Core modulators

Targeting cccDNA

Polymerase

inhibitors

RNA

interference

Egress Inhibitors

Core modulators

Targeting

HBx

Testoni and Zoulim, Hepatology 2015

Persistence of intrahepatic viral DNA synthesisand cccDNA during Tenofovir therapy

(HIV-HBV cohort)

Boyd et al, J Hepatol 2016

New round of infection and/or replenishment of the cccDNA pool occur

despite « viral suppression »

Zoulim, et al, Clin Gastroenterol

Hepatol 2013

Lucifora et al, Science 2014

Belloni et al, JCI 2012

Koeniger etal, PNAS 2014

Durantel&Zoulim, J Hepatol 2016

cccDNA loss

cccDNA silencing

cccDNA

degradation

cccDNA

formation

Targeting cccDNA, the viral minichromosome

cccDNA

repleneshiment

cccDNA

repleneshiment

Billioud et al, Antiviral Res 2011; Klumpp K et al, PNAS 2015; Venkatakrishnan B et al, J Virol 2016

Targeting the HBV capsid with capsidassembly modulators

Phase 1b clinical trial: CpAM NVR 3-778 reduces serum HBV DNA and RNA

Pre-clinical evaluation in hepatocyte culture and chimeric mouse models

Serum HBV DNA: mean 1.7 log reduction (600 mg BID)

Serum HBV RNA: mean 0.86 log reduction (600 mg BID)

Cohort I: 600 mg BIDDecrease of circulating HBV RNA

contained in viral particles

Yuen M-F, et al. AASLD 2015, San Francisco. #LB-10

Combination trials with

NUCs and/or PegIFN

HBsAg targeting strategies

• HBsAg clearance an endpoint of therapy

• Decline in HBsAg levels may restore the antiviral activity of

exhausted T cells

• Several strategies in evaluation

- RNA interference (SiRNA): « gene silencing »

- Nucleic acid polymers (NAPs): HBsAg release

- HBs antibodies

SiRNA ARC-520 produces deep and durable knockdown of viral antigens and DNA in a phase II study

Yuen M-F, et al. AASLD 2015, San Francisco. #LB-9

S promoter X promoter Precore, core

promoters

Integrated HBV DNAS mRNA

S protein ARC-520 siRNAs

Host

chromosome

cccDNA

HBsAg reduction in ETV naive

patients with a single 4 mg dose

(cohort 7)

Will this result in restoration of immune

responses ?

Impact of integrated sequences on siRNA efficacy

Restoration of antiviral immunity

Bertoletti A, Gehring AJ (2013) Immune Therapeutic Strategies in Chronic Hepatitis B Virus Infection: Virus or

Inflammation Control?. PLoS Pathog

Gane et al, EASL ILC Amsterdam 2017 PS-044

A Phase 1 study evaluating anti-PD-1 treatment with or without GS-4774

in HBeAg negative chronic hepatitis B patients

Immune modulation

• Toll-like receptors agonists

• Anti-PD-1 mAb

• Vaccine therapy

• Redirection of T cells

RNA

interference

NUCs“Polymerase inhibitors”

Targeting

cccDNA

Entry inhibitors

CpAMs

“Capsid inhibitors”

plasma

membrane

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

HBV Virion

~10 ng/ml

HBV Sphere

~100 g/ml

HBV Filament

~1 g/ml

LHBsAg

HBsAg

MHBsAg

~1%

~90%

~10%

~5%

~85%

~10%

~10%

~80%

~10%

HIGH

COPY #

LOW

COPY #

Inhibitors

of HBsAg

release “exhaustion”

“high antigen

load” PD-1

CD8+

T cell

Dysfunctional

T-cell response Insufficient

B-cell response

B cell

The main targets & drug discovery efforts

Revill, Zoulim et al, Nature Reviews Gastro & Hepatol 2016 ; Levrero et al, Current Opinion Virology, 2016

Antivirals

Therapy

HB

V D

NA

ch

an

ge

fro

m b

as

eli

ne (

log

10

c/m

L)

0.0

-1.0

-2.0

-3.0

-4.0

+1.0

Time

HBV cure - New treatment concepts – Will we need combination of DAA and immune therapy ?

HBsAgHBVDNA

cccDNA

Immune

restoration

SERUM

LIVER

NUCCapsid

SiRNA

Ag loadTLR

agonist

Tx

Vaccine

Check

point

inhibitorsAnti-HBsAb

Testoni et al, Liver International 2017

• Collaboration between Academia, Industry and Stakeholders

• International HBV cure programs

HBV cure:An attainable goal within the next decade !

• Created in September 2016 by ANRS, Doherty Institute,

and The International HBV Conference.

• Aim#1: to support the discovery of a safe, affordable,

scalable and effective cure, available to all persons living

with CHB.

• Aim#2: to create an international, independent, research-

based and patient-centered forum in order to coordinate,

promote and foster collaborative partnerships working

towards a cure for HBV.

The International Coalition for the Eradication of HBV

ICE-HBV

www.ICE-HBV.org

www.ICE-HBV.org

Governing Board

Chairs: P Revill & F Zoulim

Scientific Working Group

Stakeholders Consulting

Group

Chairs: U Protzer, T Block,

V Miller

Virology

M Dandri

& H Guo

Immunology

A Ghering & R Thimme

Innovative Tools

J Hu & F Lu

Clinical SciencesH Janssen, P Lampertico, SG Lim

PartnersSponsors

What are we doing?

• Define research priorities to achieve a cure of HBV

infection and produce a position paper on a research

roadmap, similar to papers published in the HIV field

(Deeks et al. Nat. Med. 2016)

• Foster international collaborations on specific projects:• cccDNA assay standardization with ANRS and DZIF

• HBV cure mathematical modelling with Stanford

• Promote HBV cure initiatives to increase awareness and

funding for HBV research worldwide.• Contacts with NIAID, NCI, EU, etc.

• World Hepatitis Summit, Sao Paulo

www.ICE-HBV.org

Acknowledgements

Hepatology Unit INSERM U1052 Collaborations

David Durantel

Barbara Testoni

Julie Lucifora

Bernd Stadelmeyer

Guada Martinez

Maelle Locatelli

Fleur Chapus

Aurore Inchauspé

Maud Michelet

Judith Fresquet

C. Caux, Lyon CRCL

FL. Cosset, Lyon CIRI

K. Lacombe, Paris

F Carrat, Paris

C Ferrari, Parma

P Lampertico, Milan

A Craxi, Palermo

JP Quivy, Institut Curie

U Protzer, Munich

M Dandri, Hamburg

S Locarnini, Melbourne

XX Zhang, Shanghai

Marc Bonin

Thomas Lahlali

Lucyna Cova

Romain Parent

Anna Salvetti

Birke Bartosch

Eve Pecheur

Boyan Grigorov

Christophe Combet

François Bailly

Samir Benmaklouf

Marie Ecochard

Kerstin Hartig

Fanny Lebossé

Massimo Levrero

Marianne Maynard

Christian Trépo