CHRONIC HEPATITIS B - NATAP - HIV · CHRONIC HEPATITIS B Promising New Treatments Ed Gane NZ Liver...

CHRONIC HEPATITIS B Promising New Treatments

Ed Gane NZ Liver Transplant Unit

Auckland Hospital

Goals of treatment in CHB:

APASL Consensus Statement 2005

“The ultimate long-term goal is prevention

of cirrhosis, decompensation and HCC,

and prolong survival.

Sustained viral suppression is the key to

the reduction or prevention of hepatic

injury and disease progression.

Therefore, the primary goal of treatment

for chronic hepatitis B is to eliminate or

permanently suppress HBV….. ”

Liaw YF et al. Liver Int 2005

2015 update

May2015

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

2008 update Hepatol Int 2008;

2:263–83


2:263–83

2003 update JGH 2003;

18:239–45

2003 update JGH 2003;

18:239–45

1st version JGH 2000;

15:825–41

1st version JGH 2000;

15:825–41

2005 update Liver Intl 2005;

25:472–89

2005 update Liver Intl 2005;

25:472–89

Kick-off

March

1999


2:263–83


2:263–83

Thymosin- (China, India, Korea, Malaysia,

Singapore, Thailand, Vietnam)

Lamivudine

Adefovir PegIFN LdT

Tenofovir

1990s

Entecavir IFN-

2002 2006 1998 2005 2008

Clevudine (Korea)


In press


In press

Two randomized, double-blind, controlled trials in

HBeAg- (Study 102) and HBeAg+ (Study 103) CHB 1-3

– Rollover to open-label TDF at Week 48

– FTC allowed after Wk 72 if persistent viremia (DNA ≥69 IU/mL)

Chronic

HBV

patients

(HBeAg-

and

HBeAg+)

TDF 300 m g

( n= 250 , 17 6 )

ADV 10 mg

(n=125, 90)

Open - l a b e l TD F 30 0 m g Q D

8 5 4 3 0 1 2 Study Year

Biopsies

4

TDF 300 mg

(n=250, 176)

Benefits of Long-term Oral Antiviral Therapy:

Tenofovir in Studies 102 (HBeAg-) and 103 (HBeAg+)

1. Marcellin P, et al. J Hepatol. 2014 Jul 18; DOI: 10.1016/j.jhep.2014.07.019 (ePub ahead of print).


Viral Suppression (Observed)

5

99.6% overall response at Year 8

98% overall response at Year 8

Weeks Weeks

TDF-TDF

ADV-TDF

TDF-TDF

ADV-TDF

HBeAg- Patients HBeAg+ Patients

99.6% 98%

1. Marcellin P, et al. J Hepatol. 2014 Jul 18; DOI: 10.1016/j.jhep.2014.07.019 (ePub ahead of print).

Patients in Long-term Tenofovir Studies 102/103

‒ 348 had liver biopsies at baseline, 1 and 5 years

Marcellin P, et al. The Lancet 2013; 381(9865): 468-475.

Ishak Fibrosis

Scores

Pe

rce

nta

ge

of

pa

tie

nts

0

10

20

30

40

50

60

70

80

90

100

Baseline Year 1 Year 5

P < 0.001

P < 0.001

0

.

6

5

4

3

2

1

0


Fibrosis Regression over 5 years

28% 7%

18%

PLASMA

TFV X Tenofovir

(TFV)

GUT

HEPATOCYTE

A new Oral Antiviral: Tenofovir Alafenamide (TAF) Novel Prodrug of Tenofovir

7

TFV-MP

TFV-DP

TFV TDF TFV Tenofovir

disoproxil fumarate

(TDF)

– Enhances delivery of active drug (TFV-DP) to hepatocytes1

– Lower dose reduces circulating TFV levels >90% 2,3

– Lower risk of extrahepatic toxicity

TFV

Tenofovir

alafenamide (TAF)

TAF

Tenofovir Alafenamide (TAF)

– Improved safety profile vs TDF in HIV patients4:

1. Babusis D, et al. Mol Pharmaceutics. 2013;10:459-66; 2. Markowitz M, et al. J Antimicrob Chemother. 2014;69:1362-9 ;

3. Agarwal K et al. J Hepatology 2015;62:533-40; 4. Sax P, et al. JAIDS 2014;67:52-8 8

Me

dia

n ∆

(Q

1,

Q3

) C

LC

r (m

L/m

in)

Time (Week)

Me

an

% ∆

in H

ip B

MD

TAF*

TDF*

Time (Week)

TAF*

TDF*

*p <0.001 *p=0.041

Loss of Bone Density Renal Dysfunction

3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0

-1 5

-1 2

-9

-6

-3

0

T A F 2 5 m g (n = 1 0 )

Me

an

Ch

an

ge

Fro

m

Ba

se

lin

e

CrC

L (

mL

/min

/1.7

3m

2)

T D F 3 0 0 m g (n = 1 0 )

S tu d y D a y

TAF Phase 1b in CHB: Key Findings

Creatinine Clearance Viral Suppression

TAF 25mg antiviral activity was similar to TDF 300mg

eGFR (CLCr) declined less with TAF vs TDF

Agarwal K et al. J Hepatology 2015;62:533-40

TAF HBV Phase IIII Study Design

Two phase 3, randomized, double-blind studies

Primary endpoint (non-inferiority margin of 10%)

– HBV DNA < 29 IU/mL at Week 48

Key secondary safety endpoints

– Bone mineral density at Week 48

– Renal parameters at Week 48

TAF 25mg

TDF 300mg

Open-label

2:1 TAF

25 mg

Study 108

HBeAg- (N=390)

Study 110

HBeAg+ (N=864)

Primary Endpoint

48 144 96 0 Week

1. High cost

2. Risk of viral rebound flares liver failure Non-adherence Emergence of resistance

3. Direct toxicity of oral antivirals Tenofovirbone disease, nephrotoxicity Entecavir risk of mutagenesis? Adefovir/Lamivudine risk of HCC

• A181T truncated S c-Raf-1/MAP kinase pathway

Disadvantages of Long-term Oral Antiviral Therapy

Yeh et al. BMC Cancer 2011, 11:398 -408

Hildt E, et al Recent Results Cancer Res 1998;154:315-29

Warner N, et al. Hepatology 2008; 48; 88-98

Confidential

Therapeutic Goal: Finite course of Therapy

Absence of HBV DNA and antigens

Cessation of all treatment

Finite treatment duration

13

TDF-Continue

TDF-Stop

Primary endpoint:

HBsAg loss by Wk 144

Wk 0 Wk 48 Wk 144

1:1

Ran

dom

iza

tion

CHB patients • HBeAg-negative

• ≥4 yrs TDF therapy

• noncirrhotic

Randomized N=45

TDF-Stop n=21

TDF-Continue n=21

Week 48 TDF-Restart

n=3

Week 48 TDF-Stop

n=18

Week 48 TDF-Continue

n=21

Withdrew consent n=3

FINITE CHB Study: Stopping TDF treatment after

long-term suppression in HBeAg-negative CHB

Berg T, et al. EASL 205, Vienna. #O119


TDF-Stop (n=21)

Patients requiring TDF re-initiation (n=3) Time TDF was restarted

HB

V D

NA

(lo

g 10 IU

/mL)

Weeks from baseline

4

0

5

6

7

8

9

10

3

2

1

20 40 0 A

LT (

U/L

)

Weeks from baseline

200

0

300

400

500

1000

100

20 40 0

559 U/L 983 U/L

FINITE CHB Study: Stopping TDF treatment after long-term suppression in HBeAg-negative CHB


TDF-Stop (n=21) TDF-Continue (n=20)

1 3 5 -1

HBsAg (log10 reduction)

HBsAg reduction: mean 0.77log10

HBsAg loss in 2 pts (10%)

HBV DNA <2000 iu/mL in 14 (67%)

1 3 5 -1

HBsAg (log10 reduction)

* *

*

*TDF-Restart

FINITE CHB Study: Stopping TDF treatment after long-term suppression in HBeAg-negative CHB

HBsAg reduction: mean 0.11log10

HBsAg loss in no patients

Stopping OAV after >3.5 yrs in eAg neg CHB

•Safe if noncirrhotic

•Low rate of restarting TDF (Only 3/21)

•May result in HBsAg decline and loss

HBV CURE

New Targets for HBV “Cure”

Fabien Zoulim, and David Durantel Cold Spring Harb

Perspect Med 2015;5:a021501

cccDNA silencing Inhibit protein translation by siRNA • Arrowhead • Tekmira • Alnylam • GSK

Core inhibitors • Novira • Bayer • Assembly • Gilead • Janssen • Roche RT Pol Inhibitors

• Nucleotide analogues • Non-Nuc analogues • RNAseH inhibitrs

Entry Inhibitors

• Myrcludex

Immunodulators TLR agonists T-cell vaccines PD-1/PD-L1 blockade

HBsAg release Inhibitor • NAP



Core inhibitors • Novira • Bayer • Assembly • Gilead • Janssen • Roche


HBV Core Inhibitors Can Disrupt Multiple Steps Required for HBV Replication and Persistence

19

20

NVR 3-778 binds to HBV core & induces formation of abnormal capsids

NVR 3-778: Preclinical Profile

• NVR 3-778 induces rapid mis-assembly of HBV core

• NVR 3-778 is a potent inhibitor of HBV replication in standard HBV-producing call line HepG2.2.15: – EC50 = 0.24 μM, EC90 = 0.62 μM, similar to NUCs

• in vitro activity against HBV genotypes A, B, C and D

• Preclinical toxicology supports clinical testing:

– Negative genotoxicity assessments

– No organ toxicity in animal studies

• Oral administration

21

22

A; 50 mg

fasted dose

B; 150 mg

I

C; 400 mg

D; 800 mg

E; 14 day multidose

200 mg QD x 14 days

determined by SRC review of cohort A-D data

E2; optional 28 day multidose

Dose / frequency to be determined

SR

C

SR

C

SR

C

SR

C

SR

C

[SRC REVIEW ]

[SRC REVIEW]

[REVIEW after day 16]

[SRC REVIEW]

[SRC REVIEW]

Cohorts A-D: • Single doses after overnight fast, Day 1

• 7 days’ evaluations (inpatient days -1 to 4)

Food effect assessment with Cohort A • Subjects received a 2nd 50 mg dose with food

after washout

Cohort E multi-dose • 200 mg QD x 14 days

• Doses fasted

Healthy Volunteers • M or F, ages 18-65

• BMI 18-32 kg/m2

• 8 subjects/cohort

• Randomized 6:2, active:placebo

NOT DONE

NVR 3-778: Phase 1 MAD study in Healthy Subjects

23

Predictable dose-related exposure with little variability PK supports once daily oral dosing 200mg QD exceed inhibitory concentrations in HepG2 Doses 200 mg may afford continuous HBV inhibition

NO treatment-related AEs or Lab abnormalities

NVR 3-778: Phase 1 MAD study in Healthy Subjects

(i) Phase 1b MonoRx Dose-Ranging in HBeAg+ Patients (nuc-naïve)

F: 100 mg x 28 d

G: 200 mg x 28 d

I: >400 mg dose, or BD dosing

H: 400 mg x 28 d

Staggered initiation, Interim safety reviews at Week 2 for each cohort

NVR 3-778 Phase 1b Trial Design

24

Safety, PK, Preliminary Efficacy Initial NVR 3-778 3 monoRx dose cohorts Randomized 10:2 (active:placebo) 28 days treatment, with 28 days follow-up 4th monoRx cohort higher/lower dose

(ii) 28-day Phase 1b Combination Assessment(s)

pegIFN

NVR 3-778 + pegIFN

Randomize 24 pts 1:1

Nuc (TNF or ETV)

NVR 3-778 + Nuc

Randomize 24 pts 1:1

by protocol amendment

NVR 3-778 assessed at maximal effect dose, in combination regimens



Entry Inhibitors

• Myrcludex

HBsAg release Inhibitor • NAP


Entry Inhibitors in CHB

Urban et al. Gastroenterology 2014; 147: 48-64

• Myrcludex B is synthetic N-acylated preS1 lipopeptide which

blocks receptor functions of NTCP and virus entry

• Ongoing clinical studies in HBV and HDV infection

Nucleic Acid Polymers (NAPs) in CHB

• NAPs are oligonucleotides that interact with multiple intracellular amphipathic targets

• NAPs have multiple anti-HBV mechanisms – Block HBV entry – Post-entry activity

• Blocks subviral particle (SVP) formation – Restore host immune response

• NAPs may also have anti-delta effects – block HDV entry – Block HDV production from a SVP-related assembly

mechanism – “liberated” anti-HBs directly target HDV

Nucleic Acid Polymers (NAPs) (i) HBeAg+ CHB

10

8

6

4

4

6

8

10

LLD LLD

BL 12 20–24 IM f/u

HB

V D

NA

(lo

g cp

m)

HB

V R

NA

(log cp

m)

Responders (n=9)

Jansen L, et al. EASL 2015, Vienna. #O114

12 HBeAg+ pts in Moldova

Rep 2139-Ca IV 500mg weekly

Continued for 20-38 weeks

9 responded (fall in HBV DNA)

REP 2139-Ca

Entecavir

Add-on F/u

20–24 wks 13–26 wks 21 wks (range 7–27)

HBsAg non-responders (n=3)

HBsAg responders (n=9)

BL 12 20–24 IM add-on f/u

LLD

0

2

4

6 600

400

200

0

An

ti-HB

s

HB

sAg

(lo

g IU

/mL)

BL 12 20–24 IM f/u

REP 2139-Ca

At f/u, 4/9 patients had HBsAg <0.05 IU/mL and anti-HBs+

Long-term safety?

REP 2139-Ca

500mg qW IV 15 wks REP 2139-Ca

250mg qW IV 15 wks

Peg-IFN

180 m qW SC 48 wks

Follow-up

4, 12 and 24 wks

Nucleic Acid Polymers (NAPs) (ii) HBV/HDV coinfection

12 HDV pts in Moldova

Anti-HDV/RNA +

HBsAg >1000

Non-cirrhotic

500mg REP 2139-Ca qW

250 mg REP 2139-Ca qW

180 ug Pegasys® qW

1.E-03

1.E-02

1.E-01

1.E+00

1.E+01

1.E+02

1.E+03

1.E+04

1.E+05

-5 0 5 10 15 20 25 30

Se

rum

HB

sA

g (

IU /

ml)

Weekly doses received(≤ 0 = pre-treatment baseline)

001-01001-02001-03001-06001-09001-11001-14001-17001-20001-22001-24001-26LLOQno HBsAg detectedstart of dosingstart Pegasys

500mg REP 2139-Ca qW

250 mg REP 2139-Ca qW

180 ug Pegasys® qW

1.E-01

1.E+00

1.E+01

1.E+02

1.E+03

1.E+04

1.E+05

1.E+06

1.E+07

1.E+08

-5 0 5 10 15 20 25 30

Se

rum

HD

V R

NA

(U

/ m

l)

Weekly doses received(≤ 0 = pre-treatment baseline)

001-01001-02001-03001-06001-09001-11001-14001-17001-20001-22001-24001-26LLOQno target detectedstart of dosingstart Pegasys

Vaillant A, et al. EASL 2015, Vienna. #LO2

Results: (1) HBsAg (2) HDV RNA

Prenylation Inhibitors for HDV

*J. Glenn et al., J Virol. 1998 Nov;72(11):9303-6.

*J. Glenn et al., Science. 1992 May 29;256(5061):1331-3.

post-translational modification via inhibition of farnesyltransferase

(prenylation, site-specific lipid modification of proteins)

Preventing prenylation abolishes virus particle formation.

Review: Hughes, Wedemeyer, Harrison Lancet 2011

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0 5 10 15 20 25 30 35 40 45

LNF 100 mg BID + PEG IFN 180 mcg QW

LNF 100 mg BID + RTN 100 mg QD

HIDIT-2: PEG IFN ± tenofovir QD (N=91)

Me

an

VL C

ha

ng

e (

Lo

g IU

/mL

)

Week

(N=3)

(N=3)

Yurdaydin et al., O118 EASL 2015 Dahari et al., LP36 EASL 2015 Yurdaydin et al., O118 EASL 2015 Dahari et al., LP36 EASL 2015

15 HDV pts in Turkey treated with oral lonafarnib for 8 weeks

–200/300mg bid vs. 100mg bid +PEG vs. 100mg OD + ritonavir

Ritonavir boosting increased efficacy and reduced GI side-effects

Log decline HDV RNA

Prenylation Inhibitors in HDV coinfection Lonafarnib



New Targets for HBV “Cure” Immunodulators TLR agonists T-cell vaccines PD-1/PD-L1 blockade

Confidential

Strategies of Immune Modulation for CHB

Adaptive Immunity1-3

M X Large S (env) Core

GS-4774

1. Fisicaro P, et al. Gastroenterology 2012;143:1576-85; 2. Liu J, et. al. PLOS Pathogens 2014; 10; 1; 3. Martinet J, et

al. Gastroenterology 2012;143:1586-96; 4. Xu N, et al. Inflamm Res 2012;61:997-1004; 5. Vincent IE, et al.

PLoS One 2011;6:e26315.

HBV T-cell Vaccine

Day 1 8 15 29 85

GS-4774

(10 YU, 40 YU or 80 YU) Weekly

Immunology

Assessment

GS-4774

Administration

GS-4774

(10 YU, 40 YU or 80 YU) Monthly

57 36

GS-4774: Phase 1 Study in Healthy Volunteers

Lymphocyte Proliferation Assay (LPA)

• Immunogenicity to HBsAg, HBcAg and HBx

• Well tolerated with mild injection site reactions

Gaggar A, et al. Vaccine. 2014;32:4925-31

Confidential

n=27 Antiviral Antiviral

n=51 Antiviral + 2 YU GS-4774 Antiviral



GS-4774: Phase 2 Study in CHB Patients

Noncirrhotic CHB pts on oral antiviral treatment for >1yr • GS-4774 subcut every 4 weeks x 6 doses

Primary efficacy endpoint: HBsAg decline at Week 24 • Secondary endpoint: HBsAg loss at Week 48

Exploratory assessments of HBV-specific host immune responses • Flow cytometry, Pentamer, IFN-γ Elispot • Serum cytokines, RNAs

Wk 0 Wk 24 Wk 48

GS-4774 Administration

Confidential

Strategies of Immune Modulation for CHB

Innate Immunity4,5

GS-9620

(Oral TLR-7 Agonist)

1. Fisicaro P, et al. Gastroenterology 2012;143:1576-85; 2. Liu J, et. al. PLOS Pathogens 2014; 10; 1; 3. Martinet J, et

al. Gastroenterology 2012;143:1586-96; 4. Xu N, et al. Inflamm Res 2012;61:997-1004; 5. Vincent IE, et al.

PLoS One 2011;6:e26315.

TLR-7/8 Agonist)

Toll-like Receptor 7 (TLR7) for HBV

NK IFN-

CD8+

APCs

IFN-α

Innate Immunity - Kill infected cells - Antiviral cytokines (e.g. IFN-γ)

Adaptive immunity - Kill infected cells - Antiviral cytokines (e.g. IFN-γ) - Neutralizing antibodies

Antiviral cytokines

Intrahepatic TLR7+ Cells

B cells

pDCs

B cell

IFN-α

IL-6

pDC, Plasmacytoid dendritic cell

APC, Antigen presenting cell.

IFN, interferon

TLR7-induced Cytokines Exert Anti-HBV Effects

in Vitro and Animal Studies

Niu C et al. AASLD 2014..

Viral parameters (20 days p.i.)

HBV-infected PHH (3 or 13 days p.i.)

Dilution

(1/100) TLR7 Agonist Compound A

PBMCs

pDC

B cell Mock DMSO

Conditioned media (CM)

HB

eA

g (

% c

on

tro

l)

3 -2 0 3 -2 0 3 -2 0 1 3 -2 0

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

1 4 0

N o T x M o c k T L R 7 -C M

HB

sA

g (

%c

on

tro

l)

3 -2 0 3 -2 0 3 -2 0 1 3 -2 0

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

1 4 0


Nu

cle

i c

ou

nt

(% c

on

tro

l)

3 -2 0 3 -2 0 3 -2 0 1 3 -2 0

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

1 4 0


D a y s (p .i.)

HB

V D

NA

(%

co

ntr

ol)

3 -2 0 3 -2 0 3 -2 0 1 3 -2 0

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

1 4 0


HB

V R

NA

(%

co

ntr

ol)

3 -2 0 3 -2 0 3 -2 0 1 3 -2 0

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

1 4 0


AK

ac

tiv

ity

(%

co

ntr

ol)

3 -2 0 3 -2 0 3 -2 0 1 3 -2 0

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

1 4 0


D a y s (p .i.)

HB

eA

g (

% c

on

tro

l)

3 -2 0 3 -2 0 3 -2 0 1 3 -2 0

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

1 4 0


HB

sA

g (

%c

on

tro

l)

3 -2 0 3 -2 0 3 -2 0 1 3 -2 0

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

1 4 0


Nu

cle

i c

ou

nt

(% c

on

tro

l)

3 -2 0 3 -2 0 3 -2 0 1 3 -2 0

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

1 4 0


D a y s (p .i.)

HB

V D

NA

(%

co

ntr

ol)

3 -2 0 3 -2 0 3 -2 0 1 3 -2 0

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

1 4 0


HB

V R

NA

(%

co

ntr

ol)

3 -2 0 3 -2 0 3 -2 0 1 3 -2 0

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

1 4 0


AK

ac

tiv

ity

(%

co

ntr

ol)

3 -2 0 3 -2 0 3 -2 0 1 3 -2 0

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

1 4 0


D a y s (p .i.)

In woodchucks and chimps, GS-9620 for 4-8 weeks lead to

sustained HBV DNA suppression, HBsAg loss and HCC

GS-9620 Phase 1 SAD/MAD study in CHB Patients

ISG15 (mRNA) Induction

(b) 2 Doses (Day 1 and 8)

Time (hr)

ISG

15 m

RN

A

mean

fo

ld c

han

ge

0 24 48 72 96 120 144 168 192 216 240 264 288 312 3360.25

0.5

1

2

4

8

16

32

64

128

Time (hr)

ISG

15 m

RN

A

mean

fo

ld c

han

ge

0 24 48 72 96 120 144 168 192 216 240 264 288 312 3360.25

0.5

1

2

4

8

16

32

64

128 Treatment-Naïve Patients Virally Suppressed Patients

GS-9620 dosing

T im e (h r )

ISG

15

me

an

fo

ld c

ha

ng

e g

en

e e

xp

re

ss

ion

0 2 4 4 8 7 2 9 6 1 2 0 1 4 4 1 6 8

0 .2 5

0 .5

1

2

4

8

1 6

3 2

6 4

1 2 8

T im e (h r )

ISG

15

me

an

fo

ld c

ha

ng

e g

en

e e

xp

res

sio

n

0 2 4 4 8 7 2 9 6 1 2 0 1 4 4 1 6 8

0 .2 5

0 .5

1

2

4

8

1 6

3 2

6 4

1 2 8Treatment-Naïve Patients Virally Suppressed Patients

(a) Single Dose

Gane EJ, et al. J Hepatol 2015 (in press)

Safety – Safe and well tolerated,

– No systemic IFN, no flares, no cytopenias

Phase II study: 150 pts with 4-12 weekly doses

HBV “Cure” is the aim!



cccDNA silencing

Can we eliminate cccDNA?

• cccDNA is the transcription template for all mRNAs, and is responsible for chronicity in an infected cell and rebound after OAV withdrawal.

• cccDNA is the reservoir which prevents cure

• cccDNA formation utilises the host cell’s own nuclear enzyme/DNA repair machinery

• Strategies which could eliminate cccDNA include

– cccDNA silencing by specific small molecules but against virus not host targets to avoid toxicity

– cccDNA depletion through increased hepatocyte turnover (but potential risk of hepatocarcinogenesis)

– cccDNA cleavage through by CRISPR-Cas9 nucleases

• Guide RNA sequences deliver Cas9 nuclease to conserved regions within HBV cccDNA, induce ds DNA breaks cccDNA, gene expression and DNA replication

ORF Targets

S 35

C 27

X 28

P 126

www.nature.com/scientificreports.DOI:1038/srep10833

http://www.nature.com/scientificreports

• Has potential to eliminate persistent HBV infection but will need to target EVERY infected hepatocyte

• Need safe and effective in vivo drug delivery system (AAV vector) • Extensive genome-wide profiling to exclude off-target Cas-9 cutting

(but little homology between HBV and human DNA)

Rel

ativ

e cc

cDN

A

Rel

ativ

e H

BV

DN

A

www.nature.com/scientificreports.DOI:1038/srep10833

http://www.nature.com/scientificreports

HBV CURE Conclusions

• Viral suppression with oral antiviral therapy can prevent disease progression and liver-related complications

• Current duration of OAV is lifelong with high cost and risk of breakthrough from non-adherence/resistance

• Future therapies will aim to induce HBsAg loss and enable discontinuation of long-term therapy

• Ultimate goal of CHB management will be to develop a new targeted therapy which can provide “HBV Cure” after a finite duration of treatment

HBV CURE: Conclusions

• HBV Cure programs stem from better understanding of HBV lifecycle and identification of new targets

• Several promising candidates already in preclinical and early clinical development

• Target patient population still undefined wrt phase of HBV infection, stage of disease, suppressed on OAV vs. treatment naïve vs. “immune tolerant”

• Safety will be the priority for these new therapies, in order to avoid severe hepatitis flares and other toxicity

• Convenient administration important (oral, subcut)

• HBV cure will ultimately require combinations which inactivate cccDNA and restore host immune responses

46

CD8+

T cell

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 #

B cell

Deplete or silence

cccDNA

Activate

antiviral

immunity

CONFIDENTIAL

HBV CURE: A Multi-Step Approach

NUCs Core inhibitors siRNAs

Special thanks to

Professor Stephen Locarnini, VIDRL

Dr W Ray Kim, Mayo Clinic

Dr Brian McMahon, Alaska

John Hornell, Chris Moyes, Helen Purcell, Hepatitis Foundation NZ

CHRONIC HEPATITIS B - NATAP - HIV · CHRONIC HEPATITIS B Promising New Treatments Ed Gane NZ Liver...

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