new anti-hbv drugs in the...

New anti-HBV drugs in the pipeline

Man-Fung YuenDSc, MD, PhD

Chair Professor

Li Shu Fan Medical Foundation Professor in Medicine

Chief, Division of Gastroenterology and Hepatology, Queen Mary Hospital

Deputy Head, Department of Medicine, The University of Hong Kong

Hong Kong

Yuen MF et al., Nat Rev Dis Primers. 2018;4:18035

Yuen MF, et al. Nat Rev Dis Primers 2018;4:18035

Chronic Hepatitis B: Approved Treatment Agents

Functional Cure = HBsAg seroclearance

Cessation of all treatment

Finite treatment duration

Absence of HBV DNA and HBsAg

• No activeliver disease

• No viral replication

Next HBV Treatment Goal

Better prognosis if HBsAg seroclearance at younger age

p=0.004

HBsAg seroclearance at age <50 years

HBsAg seroclearance at age ≥50 years

0

5

10

15

20

0 12 24 36 48 60 72 84 96 108 120

Cum

ula

tive r

isk o

f H

CC

(%

)

Months

Yuen MF. et al. Gastroenterology 2008;135:1192–9

Loss of HBsAg (HBsAg seroclearance): Good Outcome

Yuen MF et al., Nat Rev Dis Primers. 2018;4:18035

PEG - IFN

2.4% at 5 years (n= 85, HBeAg+)

8% at 3 years (n=230, HBeAg-)Wong V et al. Hepatology 2010;51(6):1945-53Marcellin P et al. Gastroenterology 2009; 136(7):2169-79

Low Rate of HBsAg Seroclearance by Existing Treatment

Nucleos(t)ide Analogs

Potential New Agents: Enhance “Functional Cure”

NUC analogues:• Already available

Nucleocapsid assembly inhibitors:• NVR 3-778• JNJ379• ABI-H0731• GLS4

HBsAg release inhibitors:• REP 2139• GC 1102

Immunomodulators:Therapeutic vaccines• GS-4774• ABX-203• TG-1050• INR-1800• FP-02.2Others• GS-9620• SB-9200 (Inarigivir)• AIC649• Birinapant

mRNA silencers:siRNA• ARC-520• ARO-HBV• ARB-1467Others• GSK3228836• RO7020322

cccDNA inhibitors:• Pending clinical

studies

Entry inhibitors:• Myrcludex B

Modified from Seto WK & Yuen MF. Clinical Liver Disease 2016;8:83-8

HBV virion

Knock Down Viral Proteins (HBsAg) by RNA Interference(RNAi)

RNAi

Antisense Therapeutic Approach

Adapted from Koller et al. Trends Pharmacol Sci. 2000;21:142–148.

DNA mRNA Disease-Associated

ProteinTranscription Translation

Antisense Drug(Oligonucleotide)

Transcription

No Disease-

Associated Proteins

Produced

No Translation

Translation

1) Short Single Stranded Anti-sense Oligonucleotide (DNA)

“Killing the

messenger”

Antisense Oligonucleotides: GSK3389404 and ISIS 505358

• ISIS 505358

• GSK3389404 is a GalNAc

conjugated prodrug of ISIS

505358 – intended to enhance

delivery to the hepatocyte

• target all 4 HBV mRNA

transcripts

• both are delivered by

subcutaneous injection

Paff, Melanie et al. Safety, Tolerability and Pharmacokinetics Results from the First Administration of GSK3389404, an Antisense Oligonucleotide, in Healthy Subjects. Singapore Hepatology Conference - 4th. 2017

Effective Reduction of HBsAg in Transgenic Mouse Model

GSK836 = ISIS 505358GSK404 = GSK3389404

Shihyun You et al (2016) Int.Hep.Conference, Korea

Natural Process of

RNAi

cleaved mRNA

Selective GeneSilencing

mRNAdegradation

dicerdicer

dsRNA

siRNAs

cleavage

RISC

strand separation

cleavage

Therapeutic Gene Silencing

complementary pairing

mRNA(A)n

SyntheticsiRNAs

2) Double Stranded RNA (siRNA)

ARC-520 consists of 2 vials

• Vial 1: ARC-520 Excipient

– contains a masked, hepatocyte-targeted peptide (NAG-MLP) that aids in the delivery of the HBV chol-siRNAs.

• Vial 2: ARC-520 API

– contains the HBV chol-siRNAs.

• The liquid in Vial 2 is used to dissolve the powder in Vial 1, resulting in ARC-520 for Injection (IV)

• DPC and the chol-siRNAs are targeted to the liver. When they are in the same endosome, the DPC facilitates chol-siRNA escape resulting in RNAi.

First siRNA (ARC-520) for chronic HBV infection

NAG

Vial 1

Vial 2

Single Dose ARC 520: First-in-patient Study

Wooddell CI, Yuen MF, et al. Sci Transl Med 2017;9:eann0241

HBeAg +ve patients HBeAg -ve patients

Multiple Dose of ARC-520 In HBeAg +ve Patient:Robust & Sustained Reduction of All Viral Antigens & HBV RNA

Yuen MF (data on file)

-8

-7

-6

-5

-4

-3

-2

-1

0

1

-6 0 6 12 18 24 30 36 42 48

Log

Red

uct

ion

Month

HBsAg

HBcrAg

HBeAg

HBV DNA

HBV RNA

Multiple dosesSingle dose

-8

Multiple Doses of ARC-520: Sustained HBsAg Reduction & HBsAg seroclearance

Yuen MF (data on file)

HBeAg negative pateints

-2,5

-2,0

-1,5

-1,0

-0,5

0,0

0,5

-6 0 6 12 18 24 30 36 42 48

HB

sAg

red

uct

ion

(Lo

g IU

/mL)

Month

Pt. 701Pt. 705Pt. 706Pt. 709Pt. 712

Single dose

-2.5

HBsAgseroconversion

-6

-5

-4

-3

-2

-1

0

1

-6 0 6 12 18 24 30 36 42 48

HB

sAg

red

uct

ion

(Lo

g IU

/mL)

Month

Pt. 708

Pt. 710

Pt. 711

Single dose

HBsAgseroconversion

-6

HBeAg positive pateints

Common Deleted Regions (Between DR2 & DR1) after HBV DNA Integration to Human DNA

HBeAg +ve

chimpanzee

HBeAg -ve

chimpanzee

Wooddell CI, Yuen MF, et al. Sci Transl Med 2017;9:eann0241

Target Sites for ARC-520 siRNAs can be Deleted in Integrated HBV DNA

Designed to reduce all transcripts from HBV cccDNA

host chromosome

integrated HBV DNA

host chromosome

ARC-520

HBV dslDNAS promoter X promoter

precore, core

promoters

Integration into host chromosome

S mRNA

DR1DR2DR2

S mRNA

ARC-520

• Addresses full HBV transcriptome

• Two hepatocyte targeted RNAi molecules

• Works for cccDNA and integrated-derived transcripts

• Previously shown to reduce HBV DNA, HBV RNA, HBsAg, HBeAg, & HBcrAg 1,2

• Multiple triggers to avoid resistance development and increase coverage of viral genomes

HBV Transcript Map

JNJ-3989 (ARO-HBV)

Linker

Chemistries

Targeting

Chemistries

Stabilization

Chemistries

2 Targeted RNAi Molecules

Yuen MF et al. ILC 12 April 2019, PS-080

1 Gane et al. 2018 Hepatology 68:6 LB-25 2 Gane et al. 2019 APASL Abstract 638

JNJ-3989/ ARO-HBVProfound HBsAg Reduction for both HBeAg +ve & -ve patients

Gane E...Yuen MF APASL 2019 (Abstract 638)

- 4

- 3

- 2

- 1

0

Lo

g

HB

sA

g

fr

om

d

ay

1

H B e A g p o s i t i v e

H B e A g n e g a t i v e

• Range of HBsAg NADIR: -1.3 to -3.8 Log10

• Mean HBsAg NADIR: -2.0 Log10

• All CHB patient’s HBsAg responded

• Mean HBeAg positive (n=11): -2.5 Log10

• Mean HBeAg negative (n=13): -1.8 Log10

All patients receiving 3 monthly doses have achieved > 1 log

reduction in HBsAg

• NADIR in HBsAg is reached around 4 months post start of therapy

• Duration of pharmacologic effect persisted for > 4 months after last dose

0 1 2 3 4 5 6 7 8

- 2 . 5

- 2 . 0

- 1 . 5

- 1 . 0

- 0 . 5

0 . 0

M o n t h s

Lo

g

HB

sA

g

fr

om

D

ay

1

3 0 0 m g ( C 4 b )

2 0 0 m g ( C 3 b )

1 0 0 m g ( C 2 b )

4 0 0 m g ( C 5 b )

3 0 0 m g E + ,

N U C n a ï v e ( C 8 )

3 0 0 m g E + ,

N U C e x p ( C 9 )

Yuen MF et al. EASL 2019, PS-080

Mean HBsAg reductions from baseline

Ba

se

l in

e

NA

DI R

0 . 0 1

0 . 1

1

1 0

1 0 0

1 0 0 0

1 0 0 0 0

1 0 0 0 0 0

1 0 0 0 0 0 0

HB

sA

g

(I

U/

mL

)

Distribution of quantitative HBsAg pre and post

3 doses of JNJ-3989/ARO-HBV

Median: 1263 IU/mLMin: 7.0 IU/mLMax: 392,800 IU/mL

Baseline

Median: 14.5 IU/mLMin: 0.05 IU/mLMax: 8950 IU/mL

NADIR

Yuen MF et al. EASL 2019, PS-080

Individual changes in HBV DNA, HBV RNA, HBeAg and HBcrAg

in patients receiving 3-dose siRNA (ARO-HBV)

Individual Changes in HBV DNA, HBeAg, HBcrAg and HBV RNA

- 2 0 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0

1 01

1 02

1 03

1 04

1 05

1 06

1 07

1 08

1 09

1 01 0

H B V D N A

D a y

HB

V

DN

A

[I

U/

mL

]

* < 2 0 I U / m L

**

L L O Q

- 2 0 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0

0 . 1

1

1 0

1 0 0

1 0 0 0

1 0 0 0 0

H B e A g

D a y

HB

eA

g

[P

EI

U/

mL

]

L L O Q

- 2 0 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0

1 01

1 02

1 03

1 04

1 05

1 06

1 07

H B c r A g

D a y

HB

cr

Ag

[

kU

/m

L]

L L O Q

- 2 0 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0

1

2

3

4

5

6

7

8

9

1 0

L o g H B V R N A

D a y

Lo

g

HB

V

RN

A

[L

og

U

/m

L]

L L O Q

* < 1 . 6 5 L o g U / m L

****** * *

Gane E...Yuen MF APASL 2019 (Abstract 638)

HBcAg inhibition: Core Protein Allosteric Modulator (CpAM)

HBV capsid assembly pathway and examples of capsid inhibitors

HAP: heteroaryldihydropyrimidines; | SBA: sulfamoylbenzamides; | PP: phenylpropenamides

Class l Class llForms empty

capsid devoid of pgRNA/rcDNA

Assembly

rcDNA-containingnucleocapsid

polGAA

HAP

PP

AB-423

JNJ-6379

AB-506

ABI-H0731

RG7907

GLS-4

NVR 3-778HAP

BAY-41-4109AT-130

Lower stem

Upper stem

Looptyrosine

Retrotranscription + DNA replication

SBA

Forms aberrant non-capsid polymers Core +

pgRNARO7049389

NaCl controlRO7049389 Class II CpAMNaCl controlRO7049389 Class II CpAM

CpAM: Dual Mechanism of Action

RNA containing particle(pgRNA,spliced RNA)

Dane particle (infectious DNA containing)

Subviral particles (HBsAg)

xx

Berke JM et al. AASLD 2016; Abstract 234

xx

“Secondary” mechanismInhibition of the de-novo formation of cccDNA, potentially by interfering

with the capsid disassembly process (early step in viral life cycle)JNJ-6379 median EC50/EC90 = 876 nM/4019 nM

JNJ-6379 is a CAM that binds to HBV core protein and disrupts early and late-stage processes in the HBV life-cycle

“Primary” mechanism (“empty capsid” CAM)Interference with capsid assembly kinetics, preventing encapsidation of

(pg)RNA and blocking HBV replication (late step in viral life cycle)JNJ-6379 median EC50/EC90 = 102 nM/376 nM

NAs block HBV replication butdo not inhibit the production of

RNA-containing particles

Placebo

100 mg QD NVR 3-778

200 mg QD NVR 3-778

400 mg QD NVR 3-778

600 mg BD NVR 3-778

1000 mg BD NVR 3-778

600 mg BD NVR 3-778+ PegIFN

Placebo+ PegIFN

Ran

do

miz

ed t

reat

men

t ar

ms

0

-0.5

-1.0

-1.5

-2.0

-2.5

0.5

1 7 14 21 28 1 7 14 21 28

Mean HBV DNA change Mean HBV RNA change

log 1

0IU

/mL

Time (days)

Yuen MF et al. Gastroenterology 2019;156:1392-1403

Effects of First-in-class CpAM (NVR3-778) +/- Peg IFN onHBV DNA and HBV RNA

JNJ-6379: HBV DNA Change

Placebo QD

25 mg QD

75 mg QD

150 mg QD

250 mg QD

-4

-3

-2

-1

0

1

Mea

n (

±SD

) H

BV

DN

A c

han

ge f

rom

bas

elin

e (l

og 1

0 IU

/mL)

1 2 3 4

Time (weeks)

6 8 10 12

Follow-up period

-0.57 (0.62)

-0.77 (0.69)

-1.39 (1.18)e

-0.06 (0.93)

-0.08 (0.42)

LLOQ = Lower limit of quantification (20 IU/mL) of the HBV DNA assay

No patients had values <LLOQe One patient started tenofovir at Week 8

Zoulim F et al. AASLD 2018 (Abstract 74)

ABI-H0731: HBV DNA Change in HBeAg +ve patients

Yuen MF et al. Lancet Gastroenterol Hepatol 2019 (in press)

ABI-H0731: HBV DNA Change in HBeAg –ve patients


ABI-H0731: HBV RNA Change


HBV DNA decline after 28 days of RO7049389 treatment

• After 4 weeks of treatment with RO7049389, a robust HBV DNA decline was observed across all five cohorts with a median reduction of 2.66-3.20 Log10 IU/mL.

• 13/16 (81.3%) patients who were HBeAg negative at baseline achieved HBV DNA levels lower than LLOQ (<20 IU/mL).

Median HBV DNA decline from baseline over time

a. Only include patients who completed 28 days treatment. One patient in each group was excluded from efficacy analysis. These two patients were discontinued early and were replaced.

Median HBV DNA change from baseline at the end of treatment (Day 28)

HBV DNA Log10IU/mL

Cohort n (Baseline HBeAg +/-)

Baseline Median(range)

Change from Baseline on Day 28

200mg BID N=6 (3/3) 4.5 (1.9-8.3) -2.66 (-3.4, -0.6)

400mg BID N=6 (3/3) 7.8 (4.0-8.5) -3.20 (-5.3, -2.2)

200mg QD N=6 (5/1) 7.14 (3.9-8.5) -3.0 (-3.6, -2.3)

600mg QD N=6 (2/4) 4.43 (3.3-8.4) -2.92 (-3.7, -2.0)

1000mg QD N=6 (1/5)a 5.1 (4.1-8.7) -3.17 (-3.8, -2.8)

Placebo N=6 (2/3)a 5.94 (4.8-8.2) -0.26 (-1.2, 0.2)

-4,0

-3,5

-3,0

-2,5

-2,0

-1,5

-1,0

-0,5

0,0

0,5

BL 8 15 22 28 35 56 84 112

200 mg BID 400 mg BID 200 mg QD600 mg QD 1000 mg QD Placebo

Me

dia

n H

BV

DN

A d

eclin

e

fro

m b

ase

line

(Log

10

IU/m

l)

Visit dayEOT Follow-up

Yuen MF et al. EASL (abstract 219) 2019

Median HBV RNA decline from baseline over time

a. LLOQ=4.04 Log10 copies/mL.

Median HBV RNA change from baseline at the end of treatment (Day 28)

Media

n H

BV

RN

A d

eclin

e

from

baselin

e

(Log

10

IU/m

l)

-4,0

-3,5

-3,0

-2,5

-2,0

-1,5

-1,0

-0,5

0,0

0,5

BL 8 15 22 28 35 56 84 112

200 mg BID 400 mg BID 200 mg QD600 mg QD 1000 mg QD Placebo

Follow-upEOT

Visit Day

HBV RNA in patients with Baseline HBV RNA ≥ LLOQ a

Log10 copies/mL

Cohort n (Baseline HBeAg +/-)

Baseline Median(range)

Change from Baseline on Day 28

200mg BID n=2 (2/0) 6.37 (5.7-7.1) -2.09 (-2.5, -1.6)

400mg BID n=4 (3/1) 7.01 (6.5-7.4) -2.55 (-4.0, -2.0)

200mg QD n=5(5/0) 6.9 (4.5-7.5) -2.55 (-3.1, -0.4)

600mg QD n=2(2/0) 7.02 (6.8-7.2) -2.54 (-2.9, -2.2)

1000mg QD n=2 (1/1) 4.64 (4.3-7.4) -2.43 (-3.0, -1.9)

Placebo n=3 (2/1) 6.37 (4.7-7.3) -0.26 (-0.5, 0.2)

• After 4 weeks of treatment with RO7049389, a robust HBV RNA decline was observed across all five cohorts with a median reduction of d 2.09-2.55 Log10 copies/mL.

HBV RNA decline after 28 days of RO7049389 treatment

Yuen MF et al. EASL (abstract 219) 2019

I N A R I G I V I R : A N O V E L , O R A L S E L E C T I V E

I M M U N O M O D U L AT O R W I T H A D U A L M E C H A N I S M O F A C T I O N

HBV, hepatitis B virus; IFN, interferon; pgRNA, pregenomic RNA; RIG-I, retinoic acid-inducible gene-I.

Sato et al. Immunity. 2015;42:123-132.

INARIGIVIR is a RIG–I AGONIST which is

designed to:

• Restore hepatic selective innate and

adaptive immune response stimulating the

production of type I and III IFNs

• Inhibit the HBV replication complex via a

direct acting anti-viral effect

• Result in significant anti-HBV activity with

reduction in HBV DNA, HBV RNA, HBsAg

and cccDNA

RIG-I

RIG-I

TYPE III IFNs

OATP1

DAA EFFECT TARGETING REPLICATION COMPLEX

HBV pgRNA

5’ 3’

HBV pgRNA

5’ 3’

Dual antiviral effect against HBV

HBV polymerase

Reverse transcription

Viral replication

ε ε

INARIGIVIR

Hepatocyte

RIG-I ACTIVATION AND BINDING TO

HBV PGRNA

PRIMARYENDPOINT

SECONDARYENDPOINT

Safety and antiviral activity at 12 weeks

PK, change in serum HBV DNA, HBsAg, HBV RNA and HBeAg from baseline to weeks 6, 12, 14, 16, and 24

Up to 80 non-cirrhotic

HBV subjects, randomized 4:1

between inarigivir

and placebo (Adaptive trial

design)

Inarigivir - 200 mg

Placebo

Inarigivir - 100 mg

Inarigivir - 50 mg

Inarigivir - 25 mg

Viread® 300 mg

All patients switch to Gilead’s Viread®

300 mg monotherapy

12 weeks (inarigivir monotherapy QD)

12 weeks

Clinical trial collaboration with Gilead to evaluate inarigivir followed by tenofovir 300 mg

Achieve Phase 2 Monotherapy Dose Escalation Study

Responders: > 0.5 log HBsAg reduction at week 12

Yuen MF et al. EASL 2019 (Abstract 75)

Mean Change from Baseline in HBV DNA to Week 12 in Placebo (PL) and IRIG cohorts

PL 25 50 100 200

-2.0

-1.5

-1.0

-0.5

0.0

IRIG Dose (mg)

Log10 -0.02

-0.58-0.73

-0.95

-1.54


Mean Change from Baseline in HBV RNA to Week 12 in Placebo (PL) and IRIG cohorts

IRIG DOSE

Log10

-1.5

-1.0

-0.5

0.0

PL 25mg 50mg 100mg 200mg

-0.1

-1.0

-0.8 -0.81

-1.14


Mean Change in HbsAgWeek 12: 0.4log10

Range 0.1 – 0.9log10

Week 24: 0.72log10

Range 0.15 - 1.4log10

HBeAg +HBeAg -

Quantitative HBsAg in Responder Patients > 0.5log10 Reduction at Week 12 or Week 24 from Baseline

HBsAglog10

WEEK 0 12 24Inarigivir Tenofovir

1

2

3

4

5

6


HBsAg release inhibitor Nucleic Acid Polymer (NAP) : REP 2139/2165

• 40 nucleotide phosphorothioate oligoribonucleotide (RNA)

• Hydrophobic interactions drive delivery to the liver and provide pharmacologic effect

NAPs block subviral particle release(cccDNA and integration derived)

Efficient HBsAg clearance from blood

REP 2139/2165 + Tenofovir + Peg-IFN

Initial follow up scheduled 4, 12, 24 and 48 weeks after all treatment is stopped

40

REP 2139-Mg / REP 2165-Mg (1:1)

Pegasys

TDF

Patients with

< 3 log HBsAg

response at

49 weeks

Pegasys

TDF

Pegasys

TDFW

ee

k 1

Wee

k 2

5

Wee

k 4

9

Wee

k 7

3

Wee

k 9

7

Fo

llow

-up

Fo

llow

-up

Fo

llow

-up

EXPERIMENTAL

(20 patients)

ADAPTIVE

COMPARATOR

CONTROL

(20 patients)

TDF

REP 2139-Mg / REP 2165-Mg (1:1)Dosing:

• TDF 300mg PO qD• Pegasys 180ug SC qW• NAPs: REP 2139-Mg or REP 2165-Mg 250mg IV qW• REP 2165 = REP 2139 variant with improved tissue clearance Valliant A et al., AASLD 2018

REP 401HBeAg negative treatment naïve

chronic HBV infection

REP 2139/2165 + Tenofovir + Peg-IFNNAPs + TDF + pegIFNTDF TDF + pegIFNAdaptive control

NAPs + TDF + pegIFNTDFExperimental

LLOQ(<0.05 IU/mL)

Protective immunity(10 mIU/mL)

Absent(< 0.1 mIU/mL)

TND(0.00 IU/mL)

LLOQ(< 10 IU/mL)TND

Patients entered into trial 40

End of treatment HBsAg response

> 1 log from baseline 36 (90%)< 1 IU/mL 27 (67%)

≤ 0.05 IU/mL 24 (60%)Patients currently completed treatment and

24-48 weeks of follow-up34

Stable, inactive HBV(HBV DNA ≤ 2000 IU/mL, normal ALT)

15 (44%)

Functional cure(HBsAg and HBV DNA target not detected)

14 (41%)

Therapy not indicated (AASLD / EASL guidelines)Clinical benefit

(Low risk of fibrosis progression and HCC)29 (85%)

REP 401 Treatment and Follow-up Summary

Valliant A et al., AASLD 2018

Conclusions

• RNA inhibition (IV or SC)

• Profound effect on HBsAg level (also HBeAg/ HBcrAg)

and HBV RNA

• Cases of HBsAg seroclearance were observed

• Capid protein modulation/ inhibition (oral)

• Proven efficacy on HBV DNA and HBV RNA reduction

• According to the MOA, reduction on cccDNA expected

• HBsAg release inhibition (IV or ? SC)

• Profound effect on HBsAg level

• Able to achieve full blown HBsAg seroconversion

(detectable anti-HBs)

• RIG-I agonist (oral)

• Positive effects on HBV DNA and HBV RNA

• Effects on HBsAg reduction maintained/ potentiated

even after switching to NUC monotherapy

Most of the new HBV agents have now undergone/ completed phase II studies

Coming HBV agents to the clinic

new anti-hbv drugs in the...

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