Is Hepatitis B Curable? · 2020-06-06 · HBsA g subv iral partic les In tracel lu lar C o n v er...

Is Hepatitis B Curable?

Marion G. Peters, MD

Professor of Medicine

Chief of Hepatology Research

University of California San Francisco

San Francisco, California

Slide 3 of 48

Learning Objectives

After attending this presentation, learners will be able to:

▪ List the limitations of current therapies for HBV

▪ Describe types of HBV cure

▪ Describe HBV latency

▪ List mechanisms of action of putative new therapies for

HBV

Slide 4 of 48

ARS 1: HBV status in 2019: which is true?

1. Acute HBV in adults leads to loss of HBsAg usually

2. HBV infection can be cured

3. Currently available drugs lead to loss of HBsAg usually

4. HBV is not a latent virus

of 48

ARS 2: New drugs in Phase I/II: which is false?

1. Target Hepatitis B core protein

2. Target HBV entry into hepatocyte

3. Target cccDNA in nucleus

4. Target HBV mRNA

5. Target HBV secretion

Slide 6 of 48

Prevalence of HBV/HCV Coinfection in People with HIV

» 10% of HIV persons are HBsAg positive

• About 5% to 10% of anti-HCV-antibody–positive patients are HBsAg-positive

• Hepatitis C superinfection of chronic HBsAg carriers is common in HBV endemic regions, such as Southeast Asia

Fernandez-Montero JV, Soriano V. Best Pract Res Clin Gastroenterol. 2012;26:517-530; WHO 2019.

Estimated Number of Persons Infected

Worldwide, in Millions

HBV257

HIV/HCV/HBV0.5

HIV35

HCV71 HCV/HBV

15

Not to scale.

HBV HIV4-10

HIV HCV2-3

Slide 7 of 48

HBV is a life long, dynamic disease

• Changes over time

• Risk of end stage liver disease and cancer increases with ongoing inflammation and viremia in adults

• Fibrosis can be reversible

• Drugs can decrease fibrosis progression

• HBV can be controlled but not cured

• Reactivation can occur even in those who have lost HBsAg

• HBV infection in neonates and young children leads to chronicity >90-95%

• HBV infection in adults (HIV) leads to chronicity <5% (~20%)

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HBV Control

• Inflammatory: normalize serum ALT, biopsy

• Virologic: decrease HBV DNA

• Immune: seroconversion

–HBeAg to anti-HBe

–HBsAg to anti-HBs

• HBV as of 2019 not “cured” but controlled

Slide 9 of 48

Approved HBV treatments 2019

• Interferon alfa-2b – 1991

• Lamivudine – 1998

• Adefovir – 2002

• Entecavir – 2005

• Peginterferon alfa-2a – 2005

• Telbivudine – 2006

• Tenofovir Disoproxil– 2008

• Tenofovir alafenamide- 2017

Slide 10 of 48

Long-term Entecavir Treatment Improves Liver Histology and Fibrosis

Chang TT, et al. Hepatology. 2010;52:886-893 CCO Hepatitis.

73

96

0

20

40

60

80

Histologic improvement Fibrosis improvement

Coprimary Endpoints

Pati

en

ts (

%)

100

32

88

n = 41 55 158 50

Wk 48Long-term

biopsy >3y

of 48

Undetectable HBV DNA Over Time in

HBeAg Negative Patients

Lok AS, et al. Hepatology. 2009;50:661-662. Marcellin P, et al. AASLD 2008. Abstract 146. Marcellin P, et al. AASLD 2009. Abstract 481. Marcellin P, et al. Gastroenterology. 2009;136:2169-2179. Baqai S, et al. AASLD 2009. Abstract 476. Lai CL, et al. Hong Kong International Liver Congress 2006.

Extended Treatment With Nucleos(t)ide Analogues vs

1 Yr Peginterferon Treatment

Not head-to-head trials; different patient populations and trial designs

EntecavirTenofovirPeginterferon

Un

dete

cta

ble

HB

V D

NA

(%

)

90 938791

1 Yr 2 Yrs 3 Yrs

100

80

60

40

20

0

63

15 16

NA

100*

*Single center study.

96

Slide 12 of 48

HBsAg Loss Over Time in HBeAg Positive Patients

Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Buster EH, et al. Gastroenterology. 2008;135;459-467. Gish R, et al. Gastroenterology. 2007;133:1437-1444. Heathcote J. AASLD 2008. Abstract 158. Heathcote J, et al. AASLD 2009.

Abstract 483. Janssen HL, et al. Lancet. 2005;365:123-129; Marcellin Gastro 2016


Extended Treatment With Nucleos(t)ide Analogues*

vs 1 Yr Peginterferon Treatment

HB

sA

g L

oss (

%)

2 3 66

100

80

60

40

20

0

5 88

NA


*With sustained undetectable HBV DNA.

1.0 Yr 1.5-2.0 Yrs 3.0-4.0 Yrs

5

TDF +PEG 1y 9.3%37.5% geno A

Slide 13 of 48

Lai CL, et al. N Engl J Med. 2006;354:1011-1020. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Marcellin P, et al. AASLD 2008. Abstract 146. Shouval D, et al. J Hepatol. 2009;50:289-295.

Marcellin P, et al. AASLD 2009. Abstract 481. Brunetto M, et al. EASL 2008. Abstract 683.Marcellin Gastro 2016

HBsAg Loss Over Time in HBeAg Negative Patients

Extended Treatment With Nucleos(t)ide Analogues*

Vs 1 Yr Peginterferon Treatment


Pati

en

ts (

%)

< 1 04

0

100

80

60

40

20

0< 1

9

NA 07

1.0 Yr 1.5-2.0 Yrs 3.0-4.0 Yrs

*With sustained undetectable HBV DNA.


TDF +PEG 1y 5%33% geno A

of 48

RT

Mature HBV

virion

Mature

Nucleocapsid

Immature

Nucleocapsid

Core + pg RNA

+ Polymerase

HBsAg proteins:

HBsAg subviral

particles

Intracellular Conversion Pathway

cccDNA

RC-DNA

Precore mRNA

Pregenomic RNA

Pre-S1 mRNA Pre-S2/S mRNA

HBx mRNA

HBx

Smc 5/6

LHBsAg

MHBsAg

SHBsAg

DNA

Repair

TR

AN

SC

RIP

TIO

N

ENCAPSIDATION

Precore Protein (p25)

HBeAg

(P14-17) spherical

NUCLEAR

TRANSPORT

ASSEMBLY AND

SECRETION

Peters and Locarnini Gastro and Hep 2017

Slide 15 of 48

Viral Life Cycle- latent or “recovered” HBV

ER

cccDNA

Nucleus

HBsAg negAnti-HBsAnti-HBc

Immune system considers this “recovered”BUT cccDNA is template for viral replication

Slide 16 of 48

Types of HBV cure

Functional Cure- clinical resolution

Sustained, off drug:

• No inflammation: ALT and liver biopsy

• HBsAg loss

• +/- anti-HBs gain

Complete cure- virological cure

• All of above plus

• Loss of cccDNA in liver

Inactive state -an interim goal

• No inflammation: ALT and liver biopsy

• HBV DNA low or u/d

• HBsAg positive

of 48

RT

Mature HBV

virion

Mature

Nucleocapsid

Immature

Nucleocapsid

Core + pg RNA

+ Polymerase

HBsAg proteins:

HBsAg subviral

particles


cccDNA

RC-DNA

Precore mRNA

Pregenomic RNA


HBx mRNA

HBx

Smc 5/6

LHBsAg

MHBsAg

SHBsAg

DNA

Repair

TR

AN

SC

RIP

TIO

N

ENCAPSIDATION


HBeAg

(P14-17) spherical

NUCLEAR

TRANSPORT

ASSEMBLY AND

SECRETION

Peters and Locarnini Gastro and Hep 2017

Slide 18 of 48

Strategies to Eradicate HBVVirologic approaches

• Entry inhibitors

• Block cccDNA

• Transcription inhibitors

• RNA interference

• HBV capsid inhibitor

• Polymerase inhibitors

• Secretion inhibitors

Host immune approaches

• Interferons

• RIG-I agonists

• TLR-7

• PD-1/ PDL-1

• IL-7

• Therapeutic vaccines

– Immune complex vaccines

– Nasal HBV (NASVAC) vaccines

– DNA vaccines

– T cell vaccines

– Adenovirus based vaccines (TG1050)

– Yeast based vaccines

Slide 19 of 48



• Block cccDNA







• Interferons

• RIG-I agonists

• TLR-7

• PD-1/ PDL-1

• IL-7




– DNA vaccines

– T cell vaccines



of 48

Figure 6

Gastroenterology 2014 147, 48-64DOI: (10.1053/j.gastro.2014.04.030) Copyright © 2014 Urban Gastro review

HBV entry through NTCP receptor

Slide 21 of 48

HBV Targeting cell entry

Small molecule compounds binding to Sodium taurocholate

cotransporting polypeptide (NTCP)

• HBV pre-S1-derived lipopeptide Myrcludex-B competes with

HBV/HDV for binding to NTCP

– Prevents HBV/HDV entry

– Blocks entry at pM concentrations increased serum bile acids

– Stops new infection of hepatocytes

Zeisel Gut 2015Urban AASLD 2016; Gastro 2014

Slide 22 of 48

Mean ALT levels

Primary endpoint: <2 log HDV RNA decline or undetectable Week 24

Multicentre, open-label Phase 2b clinical trial to assess safety and efficacy of Myrcludex B + TDF in chronic HBV/HDV coinfection

Wedemeyer H, et al. ILC 2018, #GS-005

• 120 HBeAg negative HDV patients in 4 arms were treated in the MYR 202 study for 24 weeks

• Excellent safety in 239 subjects dosed so far (2, 5, 10 mg sq +TDF 24 w)

• No persistent, drug-related AEs/SAEs

• Primary endpoint was met: HDV RNA >2 log decline or undetectable

• Strong on-treatment decrease in ALT, liver stiffness, intrahepatic HDV RNA

• Relapse in most patients in the follow-up: ?? longer treatment needed

TDF MyrB/TDF TDF

150

ALT

(U

/L)

50

100

0

Weeks

30 504020–10–15 100

HD

V R

NA

de

cre

ase

by

>2 lo

g in %

5 m

g M

yrB

/TD

F

10

mg M

yrB

/TD

F

100

40

80

TD

F

0

2 m

g M

yrB

/TD

F

20

60 **

*

Median RNA log10 change to BL

Week 24 Week 48

2 mg MyrB/TDF –1.75 –0.35

5 mg MyrB/TDF –1.60 –0.12

10 mg MyrB/TDF –2.70 –0.39

TDF –0.18 +0.07

TDF TDF

10 mg MyrB /TDF5 mg MyrB /TDF2 mg MyrB /TDFTDF

Negligible effects on qHBsAg*p<0.001

of 48 Peters and Locarnini Gastro and Hep 2017

RT

Mature HBV

virion

Mature

Nucleocapsid

Immature

Nucleocapsid

Core + pg RNA

+ Polymerase

HBsAg proteins:

HBsAg subviral

particles


cccDNA

RC-DNA

Precore mRNA

Pregenomic RNA


HBx mRNA

HBx

Smc 5/6

LHBsAg

MHBsAg

SHBsAg

DNA

Repair

TR

AN

SC

RIP

TIO

N

ENCAPSIDATION


HBeAg

(P14-17) spherical

NUCLEAR

TRANSPORT

ASSEMBLY AND

SECRETION

MYR

Slide 24 of 48



• Block cccDNA







• Interferons

• RIG-I agonists

• TLR-7

• PD-1/ PDL-1

• IL-7




– DNA vaccines

– T cell vaccines



Slide 25 of 48

cccDNA inhibitors

Drug Class Antiviral agent Trials Manufacturer

cccDNABlocking

Disubstituted sulphonamides Preclinical

cccDNADegradation

RNA guided nucleasesCRISPR/CAS9)

EBT106Anti‐HBV sgRNA

Preclinical Excision Biotherapeutics

Silencing histone acetyltransferase (HAT) inhibitors HBx targeting drugs


RT

Mature HBV

virion

Mature

Nucleocapsid

Immature

Nucleocapsid

Core + pg RNA

+ Polymerase

HBsAg proteins:

HBsAg subviral

particles


cccDNA

RC-DNA

Precore mRNA

Pregenomic RNA


HBx mRNA

HBx

Smc 5/6

LHBsAg

MHBsAg

SHBsAg

DNA

Repair

TR

AN

SC

RIP

TIO

N

ENCAPSIDATION


HBeAg

(P14-17) spherical

NUCLEAR

TRANSPORT

ASSEMBLY AND

SECRETION

MYR

Preclin

Slide 27 of 48



• Block cccDNA







• Interferons

• RIG-I agonists

• TLR-7

• PD-1/ PDL-1

• IL-7




– DNA vaccines

– T cell vaccines



Slide 28 of 48

RNA interference Antiviral agent Trials Manufacturer

ALN‐HBV (siRNA) Phase I‐II Alnylam

ARC‐520 (siRNA) Terminated Arrowhead pharmaceuticals

ARB‐1467 (siRNA) Phase II Arbutus Biopharma

ARB‐1740 (siRNA) Preclinial Arbutus Biopharma

RO7020322 (RG7834) (small molecule mRNA inhibitors)

Phase I Roche

IONIS-HBVRx (GSK3228836) (antisense molecule)

Phase I Ionis Pharma/GSK

IONIS‐HBVLRx (GSK33389404) (antisense molecule)

Phase I Ionis Pharma/GSK

AB‐452 (RNA destabilizer) Preclinical Arbutus Biopharma

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Silencing HBV gene expression using RNAi-based therapy

• ARC-520 is a combination of siRNAs directed against conserved HBV RNA sequences and efficiently knocks down HBV RNA, proteins and DNA levels.

• 2 siRNAs (cover 99.6% of known HBV sequences) conjugated to cholesterol and hepatocyte-targeted ligands

• Taken up by endosomes in hepatocyte then released into cytoplasm after lysis of endosomal membrane

– Given (Arrowhead Hepdart 2015)

– Arbutus ARB-1740 decreases HBsAg, HBeAg, HDV RNA (AASLD 2016)

– ARO-HBV EASL 2018

– 1 month human dataZeisel Gut 2015

Slide 30 of 48

RNA interference therapy with ARC-520 injection –Case 1: HBeAg positive patient flared when ARC-520 stopped

Yuen M-F, et al. EASL 2018, Paris. #FRI-362

3.2 log10 HBsAg reduction from baseline to 46 IU/mL

4.7 log10 HBcrAg reduction

2.6 log10 HBeAg and 3.0 log10 HBV RNA reduction to BLOQ

HBeAg seroclearance post therapy coincides with HBV RNA drop to BLOQ

Biphasic reduction of HBV DNA by >7.5 log10 to BLOQ

ALT elevations coinciding with antigen, RNA and DNA reductions & also after ARC-520 stopped

HBsAg - ALT HBcrAg- HBV DNA- HBeAg

HBV RNA - DNAWeek

HB

sA

g[I

U/

mL

]

AL

T[I U

/L

]

0 50 100

10

100

1000

10000

100000

0

20

40

60

80

100HBsAg [IU/mL]

ALT

Single dose

Cohort 7

Multi-dose

Cohort 10

Sustained host

response

Week

HB

cr

Ag

[IU

/m

L]

HB

eA

g[

PE

IU

/m

L]

Lo

gH

BV

RN

A[

Lo

gU

/m

L]

0 50 100

10 0

10 1

10 2

10 3

10 4

10 5

10 6

10 7

2

4

6

8

LLOQ

Single dose

Cohort 7

Multi-dose

Cohort 10

HBeAg [PEIU/mL]

HBcrAg [kU/mL]

LLOQ

Log HBV RNA [Log U/mL]

Sustained host

response

Week

HB

VD

NA

[ IU

/m

L]

HB

VR

NA

[L

og

U/

mL

]

0 50 100

10 2

10 3

10 4

10 5

10 6

10 7

10 8

10 9

2

3

4

5

6

7

8

9

HBV DNA [IU/mL]

LLOQ

Single dose

Cohort 7

Multi-dose

Cohort 10

First dose of

extension

Last dose of

extensionLLOQ

Log HBV RNA [Log U/mL]

Sustained host

response

First dose of

extension

Last dose of

extension

First dose of

extension

Last dose of

extension

HB

sAg

[IU

/mL]

ALT [IU

/L]

HB

crA

g[I

U/m

LH

BeA

g[P

EI U

/mL]

Log HB

V R

NA

[log U/m

L]

HB

V D

NA

[IU

/mL]

Log HB

V R

NA

[log U/m

L]

Slide 31 of 48

Bi-weekly Dosing of ARB-1467 LNP siRNA in HBeAg Negative, Virally

Suppressed Patients with Chronic HBV Infection Leads to Deeper Declines in

HBsAg and Potential Association with IL28b

KoshAgarwal et al. AASLD 2017

Phase 2a Single-Blind Study in HBV PatientsDuration of treatment: 3-month follow-up, 12 months after the first dose

HBeAg negativeARB-1467 0.2mg/kg monthly

N=8 (6 active, 2 placebo)

HBeAg negativeARB-1467 0.4mg/kg monthly


HBeAg positiveARB-1467 0.4mg/kg monthly


HBeAg negativeARB-1467 0.4mg/kg bi-weekly

N=12 (12 active)

0.4mg/kg monthlyResponders only: HBsAg

<1000IU/mL and >1log dec from bl

Wk 0 Wk 8 Wk 12 Wk 24 Wk 48

Study design

Mean changes from baseline in HBsAg (monthly vs. biweekly)

Steeper HBsAg median declines from baseline in subjects with more frequent dosing (biweekly vs. monthly)5/7 responders (71%) reached HBsAg<50IU/mLBaseline HBsAg and IL28b GT CC were significantly associated with response Most AEs mild and transient


RT

Mature HBV

virion

Mature

Nucleocapsid

Immature

Nucleocapsid

Core + pg RNA

+ Polymerase

HBsAg proteins:

HBsAg subviral

particles


cccDNA

RC-DNA

Precore mRNA

Pregenomic RNA


HBx mRNA

HBx

Smc 5/6

LHBsAg

MHBsAg

SHBsAg

DNA

Repair

TR

AN

SC

RIP

TIO

N

ENCAPSIDATION


HBeAg

(P14-17) spherical

NUCLEAR

TRANSPORT

ASSEMBLY AND

SECRETION

MYR

Preclin

siRNAs Ph1-2

Slide 33 of 48



• Block cccDNA







• Interferons

• RIG-I agonists

• TLR-7

• PD-1/ PDL-1

• IL-7




– DNA vaccines

– T cell vaccines



Slide 34 of 48

Core is essential for • HBV genome packaging • Reverse transcription• Intracellular trafficking• Maintenance of chronic infection as encapsidated HBV genomes

are imported into the nucleus.

pgRNA-RT

HBV core protein dimers

Class II CpAM

Heteroarylpyrimidinederivatives

Phenylpropenamideand

sulfamoylbenzamidederivatives

Aberrant core protein aggregates that are subsequently degradede.g. GLS-4, Bay-41

Functional nucleocapsids

Empty capsidse.g AT-130, AB, JNJ,

Class I CpAM

CpAM: core protein allosteric modulator- Roche, ABICAM: capsid assembly modulator - J&J, Roche

of 48

Antiviral agent Trials Manufacturer

GLS‐4 Phase II HEC Pharm, Sunshine

NVR 3‐778 Phase Ia NoviraPharmaceuticals/Janssen

BAY41‐4109 Phase I

JNJ56136379 Phase II JnJ Janssen

Core protein allosteric modulators (CpAMs)

Phase I (ABI‐H0731)IND enabling (ABI‐H2158)Clinical candidate (ABI‐Nx)

Assembly Biosciences

AB‐423 Phase I Arbutus Biopharma

AB‐506 IND enabling Arbutus Biopharma

Nucleocapsid assembly inhibitors/ modulators

Slide 36 of 48

Antiviral Activity of JNJ-56136379, a novel HBV

Nucleocapsid Inhibitor

Zoulim F et al. AASLD #LBO-004, 2017

Session 8JNJ-379 100mg or placebo (Day 1)25mg (D2-28) or placebo (D2-28), QD

Session 9JNJ-379 75mg or placebo, QD

Session 10 JNJ-379 150mg or placebo, QD

Session 11JNJ-379 75mg or placebo

Sessions 8 and 9n=12 per session

(8 active/4 placebo)28 days of treatment followed by 8 weeks of follow-up

56% with one AE, no SAEs, treatment d/c or deathsOne patients with Grade III elevations in ALT and AST- TDF started

HBV DNA

Baseline Day 29

Treatment Arm N Mean (SD), log10IU/mL

Mean (SD) change from baseline log10IU/mL

<LLOQ

25mg QD 8 6.90 (1.91) -2.16 (0.49) 0

75mg QD 8 5.26 (1.50) -2.89 (0.48) 3

Pooled placebo 8 5.49 (1.77) -0.01 (0.31) 0

An oral dose regimen of 250 mg daily for 28 days is being evaluated Phase 2a study is ongoing in treatment-naïve and virologically suppressed CHB patients (NCT03361956)

Slide 37 of 48 Peters and Locarnini Gastro and Hep 2017

RT

Mature HBV

virion

Mature

Nucleocapsid

Immature

Nucleocapsid

Core + pg RNA

+ Polymerase

HBsAg proteins:

HBsAg subviral

particles


cccDNA

RC-DNA

Precore mRNA

Pregenomic RNA


HBx mRNA

HBx

Smc 5/6

LHBsAg

MHBsAg

SHBsAg

DNA

Repair

TR

AN

SC

RIP

TIO

N

ENCAPSIDATION


HBeAg

(P14-17) spherical

NUCLEAR

TRANSPORT

ASSEMBLY AND

SECRETION

MYR

Preclin

siRNAs Ph1-2CpCAM

of 48



• Block cccDNA







• Interferons

• RIG-I agonists

• TLR-7

• PD-1/ PDL-1

• IL-7




– DNA vaccines

– T cell vaccines



Slide 39 of 48

HBsAg inhibitors

Antiviral agent Trials Manufacturer

REP2139 & REP2165 Phase II Replicor

BM601 (benzimidazole derivative)

Preclinical

Slide 40 of 48

Participants entered into trialN=40

(20 with NAPs following

24 weeks of pegIFN*)

Participants currently completed treatment

and ≥ 24 weeks of follow-up34

Functional cure

(HBsAg negative, HBV DNA TND)

14/34

(41%)

Inactive chronic HBV state

(HBV DNA < 2000 IU/mL, normal ALT)

15/34

(44%)

Global summary of follow-up responses after removal of all therapy (2018)

REP 2139-Mg and REP 2165-Mg Combination Therapy in CHB (REP 401 - NCT02565719)

Personal communication, Vaillant A et al. 2018ACTG


RT

Mature HBV

virion

Mature

Nucleocapsid

Immature

Nucleocapsid

Core + pg RNA

+ Polymerase

HBsAg proteins:

HBsAg subviral

particles


cccDNA

RC-DNA

Precore mRNA

Pregenomic RNA


HBx mRNA

HBx

Smc 5/6

LHBsAg

MHBsAg

SHBsAg

DNA

Repair

TR

AN

SC

RIP

TIO

N

ENCAPSIDATION


HBeAg

(P14-17) spherical

NUCLEAR

TRANSPORT

ASSEMBLY AND

SECRETION

MYR

Preclin

siRNAs Ph1-2CpCAM

NAP

NAP

Slide 42 of 48



• Block cccDNA







• Interferons

• Rig-I agonist- modest

• TLR-7- no effect on HBsAg but increased IFN-γ and IL-2

• PD-1/ PDL-1

• IL-7

• Birinapant selectively induces TNF mediated apoptosis (Pelligrini WEHI)




– DNA vaccines

– T cell vaccines



Slide 43 of 48



• Block cccDNA







• Interferons

• Rig-I agonist- modest

• TLR-7- no effect on HBsAg but increased IFN-γ and IL-2

• PD-1/ PDL-1

• IL-7

• Birinapant selectively induces TNF mediated apoptosis (Pelligrini WEHI)

• Therapeutic vaccines– Immune complex vaccines


– DNA vaccines

– T cell vaccines



of 48

qHBsAg change on anti-PD1 0.3mg/kg (Nivolumab)

19/22 decreasedqHBsAg

PD-1 receptor occupancy up to 84 d post anti PD-1: yeast vaccine Verdon et al AASLD 2017

NB:240 mg IVQ2w for RCC, SC lungMelanoma

ACTG

Slide 45 of 48

Emerging DAAs against HBV

Many currently in the pipe-line• Novel polymerase inhibitors

• Capsid inhibitors

• cccDNA inhibition or eradication

• Core protein packaging inhibitors

• Small interfering RNA (siRNA)-based strategies


• Immune activators

Combination therapy will likely be required for cure

• Inhibitors of polymerase, entry, core, cccDNA etc

• IFN, immune stimulant, TLR 7

• Checkpoint inhibitors PD-1/L1

BUTZeizel Gut 2015

Slide 46 of 48

Emerging DAAs against HBV

Many currently in the pipe-line• Novel polymerase inhibitors

• Capsid inhibitors

• cccDNA inhibition or eradication

• Core protein packaging inhibitors

• Small interfering RNA (siRNA)-based strategies

• Immune activators

Combination therapy will likely be required for cure

• Inhibitors of polymerase, entry, core, cccDNA etc

• IFN, immune stimulant, TLR 7

• Checkpoint inhibitors PD-1/L1

BUT Selection of HBV patient will be critical

Optimization of HBV endpoints neededZeizel Gut 2015

of 48

ARS 2: HBV status in 2019: which is true?

1. Acute HBV in adults leads to loss of HBsAg usually

2. HBV infection can be cured

3. Currently available drugs lead to loss of HBsAg usually

4. HBV is not a latent virus

Slide 48 of 48

ARS 2: New drugs in Phase I/II: which is false?

1. Target Hepatitis B core protein2. Target HBV entry into hepatocyte3. Target cccDNA in nucleus4. Target HBV mRNA5. Target HBV secretion

Slide 49 of 48 Peters and Locarnini Gastro and Hep 2017

RT

Mature HBV

virion

Mature

Nucleocapsid

Immature

Nucleocapsid

Core + pg RNA

+ Polymerase

HBsAg proteins:

HBsAg subviral

particles


cccDNA

RC-DNA

Precore mRNA

Pregenomic RNA


HBx mRNA

HBx

Smc 5/6

LHBsAg

MHBsAg

SHBsAg

DNA

Repair

TR

AN

SC

RIP

TIO

N

ENCAPSIDATION


HBeAg

(P14-17) spherical

NUCLEAR

TRANSPORT

ASSEMBLY AND

SECRETION

MYR Ph 2

Preclinical

siRNAs Ph1-2CpCAM Ph 1-2

NAP Ph 2

of 48

Question-and-Answer

Is Hepatitis B Curable? · 2020-06-06 · HBsA g subv iral partic les In tracel lu lar C o n v er...

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Transcript of Is Hepatitis B Curable? · 2020-06-06 · HBsA g subv iral partic les In tracel lu lar C o n v er...