Investigational therapies for chronic hepatitis B : will anything really work? This presentation will:

Describe the basis of therapies for chronic HBV Describe the new therapies in the pipeline for HBV

• Conflicts:• Arbutus BioPharma (grant)• Contravir Pharma (Board Member)

The secret lives of the hepatitis virus and hepatitis!

webmd.com

The Liver and hepatitis B

Liver Weight:3-4 lbs ~1.5 kg

Weight of Kidney:

0.26 lbs ~130g

webmd.com

The Liver and hepatitis B

Liver Weight:3-4 lbs ~1.5 kg

Weight of Kidney:

0.26 lbs ~130g

Revill, Testoni, Zoulim, Locarnini (2016) Nat Revs Gast&Hep

Virions (DNA containing)

HBs (sAg)HBs (sAg)

Revill, Testoni, Zoulim, Locarnini (2016) Nat Revs Gast&Hep

Virions (DNA containing)

HBs (sAg)HBs (sAg)

Target the virus

Revill, Testoni, Zoulim, Locarnini (2016) Nat Revs Gast&Hep

Virions (DNA containing)

HBs (sAg)HBs (sAg)

Target the host

Slide 8

Immuneescape

< <> >

ALT

HBV-DNA

Inactive (carrier)state*

HBeAg –ve active chronic hepatitis

HBeAg +ve chronic hepatitis

Immune tolerance

Immuneclearance

Immunecontrol

The phases of chronic hepatitis B

*Previously considered to be ‘healthy carriers’

HBsAg

HBsAb

Treatment goals Clinically: reduce (eliminate) the clinical consequences of chronic hepatitis B

Surrogate end points: Eliminate detectable viremia

Normalize circulating levels of liver derived enzymes (ALT, AST)

Reduce HBs antigenemia

Sustained, off drug, beneficial antiviral affect

New DAAs: HBs suppressed

Slide 8

< <

>

>

ALT

HBV-DNA

Immune tolerance Immuneclearance

Immunecontrol

Chronic hepatitis B following Successful Treatment

*Previously considered to be ‘healthy carriers’

HBsAg

HBsAb

>

DAA

IndirectHost modifier

IndirectImmunomodulator

ARC520 RNAi

Isis HBV antisense

Rep2139 sAg

?Bay41109

capsid

GS4774 vac

DV501 Vac

Editope

Chimgene HBV

InovioHBV

TTP sAg

Pre-clinical Human Phase Trials

The HBV Investigational Development Landscape as of 4. 2005

*HDV active

DAA

IndirectHost modifier

IndirectImmunomodulator

TAFARC520 RNAi

Isis HBV antisense

Rep2139 sAg

?Bay41109

capsid

GS4774 vac

DV501 Vac

Briniprint

SMAC

NV100

Editope

HDAC

Chimgene HBV

Benzacapsid

CpAMScapsid

InovioHBV

TTP sAg

Pre-clinical Human Phase Trials

The HBV Investigational Development Landscape as of 4. 2010

ALN-HBV

*HDV active

CAR

ARB-423

capsid

HepTcell

Lonafarnib*

Roche 7834 (sAg)

DAA

IndirectHost modifier

IndirectImmunomodulator

TAFARC520 RNAiIsis HBV

antisense

Rep2139 sAg

?Bay41109

capsid

GS4774 vac

GS9620 TLR7

DV501 Vac

Briniprint

SMACNV100

Editope

HDAC

Chimgene HBV

AGX1009 prodrug

NVR1221

capsid

GLS-4 capsid

Benzacapsid

CpAMScapsid

InovioHBV

TTP sAg

STING

cccDNA

forma

Pre-clinical Human Phase Trials

The HBV Therapeutic Development Landscape as of 4. 2015

ddRNAiHBV

ALN-HBV

*HDV active

Roche 7795

CAR

ABI 7031 capsid

DVR capsid

ARB-423

capsid

HepTcell

TG1050Tomega

vax

CRISPCAS

(intel)

SB9200Lonafar

nib*

Roche 7834

ARB1740,&1467

CTR431

TLX prodrug

MycBentry*

Roche 7834 (sAg)

RNaseHi

EntryPre-clinical Human Phase Trials

• Pros:• Clinical validation• Anti-HDV• Stops life cycle

from the beginning

HepteraContravir

• Cons:• Doesn’t affect

established infection

• MyrB: NTCP receptor targeted (?affect on bile)

• CTR432: cell chaperons affected (tox?)

Peptide, ivSmall mol, oral

H Weidemeyer,S Urban AASLD, 2018

?Bay41109

capsid

J&J capsid

GLS-4 capsid

Benzacapsid

CpAMScapsid

Pre-clinical Human Phase Trials

ABI 7031 capsid

ARB-423

capsid

Roche

Programs:AssemblyBlumberg/Arbutus,NovartisNoviraRocheSunshine

Novartis

ProsMultiple, Essential viral functionValidated clinicallyExtra-virological affects?Escape mutants rare

Cons?replication inhibitorResistance possible

Capsid/Core modifiers/uncoating

Wang J, et al. AASLD 2018, Washington DC. #937

Capsid/Core modifiers/uncoating

HBs Ag inhibitors

DAARep2139 sAgTTP sAg

Pre-clinical Human Phase Trials

BSBI 259 sAg

Programs:Blumberg/Arbutus,ContravirReplicor

See: Al-Mahtab M, BazinetM, Vaillant A (2016) PLoSONE 11(6):e0156667

REP 2139 on-treatment antiviral response

Courtesy: A Vailliant

HBs

HBV DNA

HBsAb

CRV431

HBV integration

RNA Degrading

Zhou et al, AVR (2017) Mueller et al, , J.Hep (2017)

Hu-mouse

0 1 2 3 4 5 6 71

1 0

1 0 0

S tu d y D a y

Se

rum

HB

sA

g(%

Ba

selin

e)

U n tre a te dV e h ic le0 .1 m g /k g0 .3 m g /k g1 m g /k g

AB452Roche DHQ

Arbutus

Pre-clinical

siRNA

DAAARC RNAi

cccDNA

forma

Pre-clinical

ALN-HBV

CRISPCAS

(intel)

ARB1467

Human Phase Trials

ARC RNAi

ARB 1467 Human Clinical Study

ARB1467

siRNA

Arrowhead Human Clinical Study

RNAi + Therapeutic vaccination (AAV model)

reduces HBsinduces HBsAb & T cell activity

T. Michler AASLD 2018

Arrowhead Pharma

cccDNA

Programs:?Gilead, ?Arbutus, Assembly, ?OthersBlumberg, Fox Chase, Duke, Rockefeller

Pre-clinical Human Phase Trials

CRISPCAS

(intel)iaCRISPR CoCrys

tal

BSBI (JT Guo)

GS4774 vac

GS9620 TLR7

DV501 Vac

Chimgene HBV

InovioHBVSTING

Pre-clinical Human Phase Trials

Immune Modulators as of Jan, 2017

Roche 7795

CARHepTcell

TG1050Tomega

vax

SB9200

Programs:AkshayaArbutus/BlumbergBMSDynavaxGileadHepTcellInovioRocheSpringbankTomegvax

Opdivo+

GS4774

Chang & Liu, 2016

Ulrike Protzer, Mala K. Maini & Percy A. Knolle Nature Reviews Immunology 12, 201-213 (March 2012)

Normal induction of immune clearance

Angus W. Thomson & Percy A. Knolle Nature Reviews Immunology 10, 753-766 (November 2010)

Homeostatic Tolerance

GS-9620 (vesatolimod), TLR 7 agonist, in CHB pts (not on antiviral Rx)

Springbank’sputative

RIGI/STING acting small

molecule first in class in people

Yuen et al, AASLD, 2018

Checkpoint intervention

Bertoletti, A. and Le Bert, N., 2018. Immunotherapy for chronic hepatitis B virus infection. Gut and liver, 12(5), p.497.

Nivolumab (Anti PDL-1) in HBe neg CHBM-2N=12N=10 (GS 4774+

Combination for efficacy, not to repress resistance

Repress viremia and antigenemia (2 complimentary DAAs)This could be sufficient for a large % of people

Enhance host Immune mediated antiviral responsepatient selectafter antigen control

DAARNAi

HBV antisen

se

HBs inhib

Capsid II

Capsid/CPAM

I cccDN

A inhibt

Capsid CPAM

III

CRISPCAS

(intel)

RNA degrad

Better Pol

inhibt

vac Innate host

ISG activat

or

aPD1/Opdivo + GS4774

+

Stair way to a cure!!!Each new drug will be a step up clinical benefit

5%

New Drug Introduction / Event / time% H

Bs L

oss /

Sus

tain

ed o

ff dr

ug b

enef

its

100%

Acknowledgement Thanks to the following scientists for providing slides or allowing for presentation of their data:

Chari Cohen (Hepatitis B Foundation) Ju-Tao Guo (Blumberg) Tianlun Zhou (Blumberg) Jinhong Chang (Blumberg) Bruce Givens (Arrowhead) Anuj Gaggar (Gilead) Chris Moore (Arbutus) Mike Sofia (Arbutus) Andrew Valient (Replicor) Stephan Urban (Heidelburg) Phil Pang (Vir)

Thanks to: The Hepatitis B Foundation, committed to improving

the lives of those affected by hepatitis B