HBV Hot topics 2019 HASLD

Robert G Gish MD Medical Director Hepatitis B Foundation

Robert G Gish Consultants LLC San Diego, California

2 2

Disclosures

• See robertgish.com

3 3

Outline

• Current standard of care to treat HBV

• qHBsAg utilization in practice today

• Biomarkers for HBV drug development

• New drugs for HBV cure

• HDV

• TDF, ETV difference in risk for HCC

4 4

HBV Disease Progression

5 5

• HBsAg = infection

• Anti-HBc = exposure = cccDNA

– No Vaccine boosting

– Educate about risk for reactivation

– Evaluate for occult HBV (OBI)

• Anti-HBs = immunity if anti-HBc is negative

• HBV is incurable

• There is no “natural immunity”

HBV Tests part I

6 6

– HBeAg

– Anti-HBe

– HDV antibody

– HCV antibody

– HIV

– qHBsAg

– HBV DNA quant

– HAV antibody

HBV Tests part II

7

Stage Liver Disease

• ALT/AST ratio

• Liver biopsy

• Elastography

• Fibrosure/Fibrotest

– serum makers of fibrosis

• Spleen size and PV

diameter

• Plt count

• APRI

• Fib4

Evaluating the HBsAg + patient Part III

• Alcohol history and current

use

• NASH risk and assessment

• Pregnancy

• Family testing for HBsAg

• HCC Risk/early detection

– AFP/ DCP AFP-L3%

– FH of HCC and cirrhosis

8

Profile 1 Profile 2 Profile 3 Profile 4 Profile 5 1. HBsAg Negative Negative Positive Negative Negative 2. Anti-HBc Negative Negative Positive Positive Positive 3. Anti HBs Negative Positive Negative Positive Negative Significance 1. No chronic

infection; not a hepatitis B carrier.

1. No chronic infection; not a hepatitis B carrier.

1. Has acute or flare (if HBc IgM+) or 99% chronic hepatitis B infection.

1. No hep B infection in the blood if HBV DNA negative

1. Subclinical infection at the moment if HBV DNA + OBI

2. Never been infected with hepatitis B virus.

2. Not infected with hep B virus.

2. Is infected with hep B virus. Has cccDNA in the liver

2. Has been infected with hep B virus.Has cccDNA in the liver

2. Has been infected with hep B virus.Has cccDNA in the liver

3. No immunity (no protection) against hep B.

3. Has immunity due to vaccination.

3. No immunity or protection against hep B.

3. Has cleared the blood of HBV infection (when combined with negative HBsAg) And has immune control

3. OBI: subclinical infection HBV DNA + and has risk of reactivation.

Action -- -- See Primary care provider for further tests. HBV DNA quant.

Watch for reactivation if becomes immune suppressed

Watch for risks of reactivation if patient become immune suppressed No vaccination boosting

Provide vaccination

No vaccination needed

No vaccination needed

No vaccination needed No vaccination needed

Interpretation HBV serologic test results for HBV infection and Further Actions

9

10

11 11

12 12

Who to Treat in chronic HBV infection

• HBV DNA > 2000

• ALT over 20-25 in women over 30-35 in men

• >F2 fibrosis by elastography, APRI, FIB4

• Elevated HCC biomarkers

• Any patient with cirrhosis with any HBV DNA + level

• Older age and active liver disease and DNA+

• High risk patients for HCC

– Family hx of HCC

– HCC diagnosis

13 13

• Monotherapy with ETV, TAF, TDF recommended based on high barrier to resistance

– PegIFN should only be considered as initial treatment for pts with mild/moderate CHB or selected

pts with compensated cirrhosis (no portal hypertension)

Chronic HBV Infection: Updated EASL Recommendations

EASL. HBV guidelines. 2017.

Management of NA Resistance

LAM resistance Switch to TDF or TAF

TBV resistance Switch to TDF or TAF

ETV resistance Switch to TDF or TAF

ADV resistance LAM naive Switch to ETV or TDF or TAF

LAM-R Switch to TDF or TAF

TDF or TAF resistance LAM naive Switch to ETV

LAM-R Add ETV

Multidrug resistance Switch to ETV + TDF or TAF combination

ETV or TAF Preferred Over TDF When:

Older than 60 yrs of age

Bone disease Chronic steroids or other meds that affect bone History of fragility fracture Osteoporosis

Renal abnormalities eGFR < 60 min/mL/1.73 m2

Albuminuria > 30 mg or moderate proteinuria Low phosphate (< 2.5 mg/dL) Hemodialysis

TAF over ETV if previous NA exposure No dose adjustment required for kidney disease or hemodialysis with TAF; ETV needs dose adjustment for eGFR < 50 mL/min

14

Adapted from: Lampertico P, Berg T. Hepatology 2018; 10.1002/hep.29821 HBsAg: hepatitis B surface antigen

TIME

Risk of severe flare?

ALT

Nucleos(t)ide analog (NA)

Lag-phase (<1-12

months)

HBV DNA

Reactivation phase ( 3 months)

Limit of HBV DNA detection

Consolidation phase ( 12 months)

Long-term outcome Treatment phase (> 3 years)

B) Sustained virologic response (true ‘healthy carrier‘ state) ± HBsAg level decline 20–30%

A) HBsAg loss ( 20% after 2–3 years of follow-up)

C) Indeterminate state not fulfilling immediate re-treatment criteria ( 10–20%)

D) Chronic hepatitis B requiring re-treatment ( 40%)

Potential outcome predictors

Age, time to undetectable HBV DNA, and duration of viral suppression under NA, HBsAg levels at NA baseline and NA cessation, type of NA (TDF vs. ETV), HBV DNA levels during reactivation phase, re-treament strategy,

and HBV genotype

Stopping NA therapy in HBeAg-negative patients before HBsAg loss, qHBsAg < 150 IU/mL predicted HBsAg loss

15 15

HBsAg in the Natural History of Chronic HBV Infection

• Gradient of qHBsAg

– Risk factor gradient for the development of hepatocellular carcinoma

compared with HBsAg(-) patients, compliments HBV DNA quant

• HBsAg clearance is a highly desirable treatment end point

– Improvement in survival

– Lower rates of hepatocellular carcinoma and liver decompensation

– “Functional cure”

• Spontaneous HBsAg clearance is infrequent

– Approximately 0.5% to 2% annually

• Lower rates seen in Asian patients who acquire HBV at birth or in very early

childhood

• Higher rates in GTA2, lower rates in GTB and C Fung J, et al. Expert Rev Anti Infect Ther. 2010;8:717-720.

16

HBV: Disease phase determination using qHBsAg

17

Application of qHBsAg proposed

18

67%

83%

100%

45%

23%

100%

0%

20%

40%

60%

80%

100%

Seroconversion e- active CHB e- inactive CHB

> 1 log IU/ml < 1 log IU/ml

HBsAg reduction > 1 log can predict good immune control in HBeAg-negative patients

17%

33%

71%

0% 0%

7%

0%

20%

40%

60%

80%

100%

Seroconversion e- active CHB e- inactive CHB

> 1 log IU/ml < 1 log IU/ml

#

#

#

# p< 0.05

HBV DNA < 2000 IU/ml

at last visit

HBsAg loss

at last visit

The patient with HBsAg loss without 1 log reduction in HBsAg has low titer of

HBsAg at baseline Chan HL, et al. Hepatology 2010

19 19

Can qHBsAg Levels Predict Spontaneous HBsAg Seroclearance?

• Matched case-control study in

patients with spontaneous HBsAg

seroclearance (n=46)

– Spontaneous HBeAg

seroconversion followed by >10

years of persistently normal ALT

– Genotype B: 75%

– Controls: age, sex, and HBV

genotype matched

• Decline of HBsAg to <100 IU/mL

can predict HBsAg seroclearance

in 1 to 3 years

Chen Y-C, et al. Clin Gastroenterol Hepatol. 2012;10:297-302.

PPV: positive predictive value.

NPV: negative predictive value.

60

70

80

90

100

Prediction of HBsAg Seroclearance

Perc

en

t

PPV

5 years prior

3 years prior

1 year prior

NPV PPV NPV

<200 IU/mL <100 IU/mL

81% 79%

82%

68%

81%

100%

82%

87% 86%

64%

73%

97%

Based on Decline to a HBsAg Level in the Years Prior to HBsAg Seroclearance

20 20

HBV - New Drugs - New Markers

• Looking for a functional cure at 40% level

– Sustained HBsAg loss and HBV DNA negativity

• Need to develop markets to accelerate drug development and approval

– Decrease cost of drug development

– Shorter time to medication approval

– Rapid access to new medications worldwide

• Increase compliance with starting therapy

• More patients treated

• Looking for HBV elimination by 2030

21 21 McNaughton et al, Gastroenterology

22 22 McNaughton, Gastro 2018

23

Patient with HBsAg Loss: Clinical Diagnostic & Biomarker Profiles

24 24

Potential Role of Quantitative Serology

Natural History Treatment

HBsAg

HBeAg

HBcrAg

HBV RNA

Subclassification of phases

Tolerance

Clearance/Reactive

Low replicative

Escape/HBeAg -ve

Correlations with:

cccDNA

viral load

HBsAg/HBeAg

BCP/PC mutations

Kinetics of decline on therapy

Potential prediction of:

HBsAg seroconversion

HBeAg seroconversion

Implications for

Treatment algorithms

Initiation

Stopping rules

Dose/Duration

Modified from Janssen, H. 2016

25 25

New Viral Targets

1. Entry and Pathways of Intrahepatic Spread

(Re-Entry)

2. Cytosolic Transport of Nucleocapsids

3. cccDNA Generation & Processing (HBcAg and

HBx)

4. HBV RNA

5. HBV Nucleocapsid Assembly (HBcAg)

6. Reverse Transcription

7. HBsAg

8. Putting It All Together

26

Short-term RNA interference therapy in chronic hepatitis B using JNJ-3989 brings majority of patients to HBsAg <100 IU/ml threshold

1. Jeng WJ, et al. Hepatology 2018;68:425-34.

Yuen MF, et al. ILC 2019; PS-080

RESULTS

• JNJ-3989 was well tolerated

• JNJ-3989 reduced viral products in

HBeAg+ and HBeAg-, NUC

experienced or naïve patients

• HBsAg was reduced as follows:

To <100 IU/mL in 88%

By ≥1 Log10 IU/mL in 100%

Both thresholds have been associated

with increased probability of HBsAg

clearance when stopping NUC

treatment1

METHODS

• Patients with chronic HBV received 3 SC doses

of JNJ-3989 weekly to monthly together with

ETV or TDF

• HBsAg levels were assessed in patients that

had ≥24 weeks of HBsAg data (n=40)

• Safety and tolerability were assessed in all

patients in these cohorts (n=56)

AIMS

• To explore the effect of 3 doses of JNJ-3989

(formerly ARO-HBV) on HBsAg reductions

below certain thresholds

27

Short-term RNA interference therapy in chronic hepatitis B using JNJ-3989 brings majority of patients to HBsAg <100 IU/ml threshold

Yuen MF, et al. ILC 2019; PS-080

CONCLUSIONS

JNJ-3989 exhibits

characteristics desirable for a

cornerstone therapy in finite

regimens aimed at HBsAg

seroclearance in patients

with chronic hepatitis B

infection

FIGURE Mean HBsAg reductions from baseline

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 )

Baseline HBsAg

Threshold N Percent

>100 IU/ml 37 of 40 93%

NADIR HBsAg

Threshold N Percent

≤100 IU/ml 35 of 40 88%

≤10 IU/ml 17 of 40 43%

28 28

RNA Interference Therapy with ARC-520 Injection Results in Long Term Off-Therapy Antigen Reductions in Treatment Naive, HBeAg Positive and Negative Patients with Chronic HBV

Tolerability

• 7/8 patients reported at least one mild AE

• No AEs were rated as serious, severe or

caused withdrawal

• ARC-520 was more active in

HBeAg-positive patients,

presumably due to more cccDNA-

driven antigen production in

treatment naive HBeAg-positive

and a higher fraction of qHBsAg

from integrated DNA in HBeAg-

negative patients

• Mild ALT elevations off ARC-520

therapy coincided with sustained

host responses in 2/3 HBeAg-

positive and 2/5 HBeAg negative

patients

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

Log antigen reduction summary through 12 months of follow-up

NADIR Single Dose NADIR Extension

HBeAg pos HBeAg neg HBeAg pos HBeAg neg

Log

HB

sAg

red

uct

ion

fro

m

BL

Average -1.46 -0.33 -3.43 -1.10

SEM 0.06 0.02 1.04 0.33

Min -1.40 -0.25 -1.74 -0.58

Max -1.58 -0.37 -5.31 -2.37

Log

HB

eAg

red

uct

ion

fro

m

BL

Average -1.37 NA -2.86 NA

SEM 0.10 NA 0.70 NA

Min -1.20 NA -1.78 NA

Max -1.54 NA -4.18 NA

Log

HB

crA

g re

du

ctio

n f

rom

B

L

Average -1.17 -0.70 -4.19 -0.44

SEM 0.10 NA 1.25 NA

Min -1.04 NA -1.82 NA

Max -1.36 NA -6.08 NA

29

2.4kb S

HBV Transcripts Differ Between HBeAg+ and HBeAg- Chimps PacBio Single Molecule Real-Time (SMRT) Sequencing

DR

1

DR2 HBV Poly(A) signal

2.1kb S

HBeAg-

(88A010)

HBeAg+

(A2A004)

HBeAg- • Majority of S transcripts are fused

at the 3’ end to chimp sequence

• Fusion points typically between DR2 and DR1as expected if

transcripts arose from integrated HBV dslDNA

HBeAg+ • Most S transcripts terminate near

HBV poly(A) signal as expected

HBV-aligning HBV non-aligning

S ORFs

S transcripts in HBeAg- chimps often lack target sites for ARC-520

ARC-520 siRNAs

Wooddell, C et al. 2017. Sci Transl Med.;9(409):pii: eaan0241

30

A first-in-class orally available HBV cccDNA destabilizer ccc_R08 achieved sustainable HBsAg and cccDNA reduction in the HBV circle mouse model

Wang L, et al. ILC 2019; PS-074

CONCLUSIONS A novel small molecule

ccc_R08 can sustainably reduce serum

HBsAg and liver cccDNA levels in the HBV

circle mouse model

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

1

2

3

4

5

L L O Q

D a y s p o s t 1 s t d o s e

Lo

g1

0(

IU/m

l s

er

um

)

Treatment End HBsAg Treatment End HBeAg

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

0 . 5

1 . 0

1 . 5

2 . 0

2 . 5

3 . 0

L L O Q

D a y s p o s t 1 s t d o s e

Lo

g1

0(

NC

U/m

l s

er

um

)

Vehicl

e

Treatment End HBV DNA

ccc_R08

20 mg/kg

BID

Lo

g1

0 (

co

pie

s/u

l)

3

4

5

LLOQ

Vehicle

FIGURE‌ HBV circle mouse model: serum levels of HBsAg, HBeAg, and HBV DNA and

cccDNA levels in the liver

ccc_R08

20 mg/kg BID

Liver

cccDNA

level

31

HBV entry inhibition after IFN treatment hinders HBV rebound in hepatocytes negative for all HBV markers during IFN treatment

*MyrB treatment started 3 days before the last IFNα injection.

Allweiss L, et al. ILC 2019; PS-155

BACKGROUND & AIMS ‌

• IFNα treatment can exert both immunomodulatory and antiviral effects

• Aims:

– Investigate these antiviral effects in HBV-infected human hepatocytes in vivo and whether they can

persist after treatment cessation

– Employ HBV entry inhibition to assess the role of new infections in HBV rebound

METHODS ‌

• HBV-infected human liver chimeric mice were treated with PEG-IFNα for 6 weeks (n=13 + 5

untreated controls)

– Mice were either sacrificed (n=5) or treatment was stopped to assess serological/intrahepatic viral

changes for 6 further weeks, either in the presence (n=4) or absence of the entry inhibitor MyrB* (n=4)

– HBV load analyzed in serum and liver by qPCR

– RNA-ISH and immunofluorescence to visualize HBV transcription and presence of SMC6 (potential

marker of cccDNA suppression/clearance)

cccDNA

AAA AAA

Myrcludex B Chemically synthesized lipopeptides derived

from the envelope of HBV block virus infection in cell culture (HepaRG & PTH, PHH)

32

Myrcludex B: Acylated HBV preS1-derived peptides block HBV infection in vitro – entry inhibitor

33

• Clustered regularly interspaced short palindromic

repeats (CRISPR)/Cas9 platform for efficient

gene knockout

• Can inhibit HBV replication up to eight fold

• Inhibition due to introduction of mutations and

deletions in cccDNA from recruited Cas9 repaired

by non-homologous end joining (NHEJ)

• Inhibition not affected when IFN-α used in

combination

• Independently confirmed

Targeting Hepatitis B Virus with CRISPR/Cas9

Christophe Seeger and Ji A Sohn

34

Modulating Transcription: Epigenetics

Structure of Chromatin altered by post-translational modification of histones acetylation, phosphorylation, methylation and ubiquitylation

Relaxed Chromatin : Histone Acetylase (HAT)

transcription activation complex containing HATs HATs acetylate lysine residues of the histone tails

Compacted Chromatin : Histone Deacetylases (HDAC)

transcription repression complex containing HDAC HDACs deacetylate histone lysine tails

Conclusion acetylation status of HBV minichromosome (cccDNA-bound H3 & H4 histones) regulates HBV transcription/replication and is reflected in viral load

Activation of Gene Expression

Repression of Gene Expression

Haematologica. 2009;94(11):1618-22

Click to edit Master title style

35

In Vitro Antiviral Activity and Mode of Action of JNJ-64530440, a Novel Potent Hepatitis B Virus Capsid Assembly Modulator in Clinical Development

Stages of the HBV Life Cycle Regulated by HBc Protein

Berke JM, et al. AASLD 2018, San Francisco, USA. #402

Diab, A et al 2018. Antiviral Res;149:211–220

36

Interim safety and efficacy results of the phase 2a program of ABI-H0731 + Nuc therapy in treatment-naïve and treatment-suppressed patients with CHB

*Including follow-up at Weeks 2, 4 and then monthly; †Including HBV DNA, HBV RNA, HBsAg and HBeAg.

Ma X, et al. ILC 2019; LB-06

BACKGROUND & AIMS ‌

• Nucs are the standard of

care (SOC) for CHB

– But achieve low rates of

sustained response off

therapy

• The novel core inhibitor

ABI-H0731 (731) exhibited

potent anti-HBV activity over

28 days as monotherapy

• 731 + Nuc combo is being

evaluated in two double-

blind, placebo-controlled

phase 2a trials in patients

with CHB and F0–2 fibrosis

METHODS ‌

Study 201 47 HBeAg+ / 26 HBeAg-

Patients on SOC Nuc therapy

Nuc + 731

300 mg

Nuc +

placebo

R 3:2

24W

*

Extension study

Analyses • Clinical labs, safety and PK

• HBV biomarkers†

Primary efficacy endpoints • Log10 decline in HBsAg/

HBeAg at Week 24

≤1

year

Study 202 25 TN HBeAg+

Viraemia patients

ETV + 731

300 mg

ETV +

placebo

R 1:1

24W

*

Extension study

Analyses • Clinical labs, safety and PK

• HBV biomarkers†

Primary efficacy endpoints • Log10 decline in HBV DNA at

Weeks 12 and 24

≤1

year

37

Interim safety and efficacy results of the phase 2a program of ABI-H0731 + Nuc therapy in treatment-naïve and treatment-suppressed patients with CHB

*Target not detected using ASMB <5 copies/mL semi-quantitative PCR assay.

Ma X, et al. ILC 2019; LB-06

CONCLUSIONS Interim data suggest ABI-H0731+Nuc was well tolerated over the dosing period

and exhibited early and enhanced antiviral benefit in suppressing HBV DNA and HBV RNA levels to a

greater extent than seen with Nuc therapy. These interim data support the use of CIs in a next-

generation regimen as potential advance in treatment

RESULTS ‌

• Enrolment complete in both studies

• Few TEAEs or laboratory abnormalities; generally

mild or moderate

– 3 AEs (rash) “possibly related” or “related” to treatment

– None had associated systemic symptoms and none

required treatment interruption

– No discontinuations due to AE or ALT flares

• Significantly greater declines in HBV viraemia

(DNA/RNA) seen on combination therapy

• Individuals have shown decreases in HBeAg and

HBsAg, but no meaningful conclusions can be drawn

on antigen reductions at this early interim time point

Study 202 (TN HBeAg+ subjects), mean log10 declines

Marker Week ETV (n) 731+ETV (n) P values

RNA, copies/mL 12 0.44 (12) 2.27 (12) <0.005

24 0.61 (5) 2.54 (6) <0.005

DNA, IU/mL 12 3.29 (12) 4.54 (12) <0.011

24 3.99 (6) 5.94 (6) <0.005

Study 201 (Nuc-suppressed HBeAg+ subjects), mean log10 declines

Marker Week Nuc (n) 731+Nuc (n) P values

RNA, copies/mL 12 0.05 (18) 2.34 (23) <0.001

24 0.15 (4) 2.20 (6) 0.012

Study 201 (Available subjects at Week 24), HBV DNA (+/-)

DNA, PCR TND* 24 0 (4) 5 (6) N/A

38

39

Phase I

DrugName TradeName MOA

HBV Devlopment

Phase Company Country Url ABI-H0731 N/A Core Protein Allosteric

Modulator I Assembly Biosciences USA http://www.assemblybio.c

om/

AIC649 N/A therapeutic vaccine I AiCuris Germany www.aicuris.com

ALN-HBV N/A RNAi- based therapy I/II Alnylam Pharmaceuticals USA www.alnylam.com

birinapant, TL32711 N/A SMAC mimetic and IAP antagonist

I Medivir Sweden www.medivir.se

EYP001 N/A Farnesoid X Receptor agonist

I ENYO Pharma SA France http://www.enyopharma.com/

GC1102 N/A Recombinant hepatitis B immunoglobulin

I Green Cross Korea

HBAI20 Hepatitis B vaccine N/A therapeutic vaccine I CyTuVax The Netherlands http://www.cytuvax.com/

HepTcell, FP-02.2 HepTcell therapeutic vaccine I Altimmune USA www.altimmune

INO-1800 N/A therapeutic vaccine I Inovio Pharmaceuticals, Inc.

United States www.inovio.com

IONIS-HBV-LRx, IONIS-GSK6-LRx, IONIS-HBVRx

N/A Antisense HBV drug I Ionis Pharmaceuticals USA www.ionispharma.com

JNJ-56136379 N/A unknown I Johnson & Johnson USA www.jnj.com

NVR 3-778, NVR-1221 N/A Capsid protein inhibitor Ib Johnson & Johnson USA www.jnj.com

PIKA Hepatitis B vaccine N/A therapeutic vaccine I Yisheng Biopharma China http://www.yishengbio.com/

TG1050 N/A therapeutic vaccine I Transgene France www.transgene.fr

40

Phase II

DrugName TradeName MOA HBV Devlopment

Phase Company Country Url ABX203 N/A therapeutic vaccine II/III ABIVAX France http://www.abivax.com/

ARB-1467, TKM-HBV N/A RNAi- based therapy II Arbutus Biopharma

Canada www.arbutusbio.com

GS-4774, GI-13020 N/A therapeutic vaccine II GlobeImmune USA www.globeimmune.com

GS-9620, Vesatolimod N/A TLR7 agonist II Gilead Sciences USA www.gilead.com

IONIS-HBVRx, IONIS-GSK3Rx, ISIS-HBVRx, GSK3228836

N/A Antisense HBV drug; Viral protein inhibitors

II GlaxoSmithKline USA www.gsk.com

Lonafarnib Sarasar Prenylation inhibitor II Eiger Biopharma USA www.eigerbio,com

Myrcludex B Myrcludex B Entry inhibitor IIb Hepatera Russia http://www.hepatera.ru/

REP 2139-Ca, REP 2139-Mg N/A HBsAg-release inhibitor II Replicor Canada http://replicor.com/

REP2165 N/A HBsAg-release inhibitor II Replicor Canada http://replicor.com/

RO6864018 N/A unknown II Roche USA www.roche.com

SB 9200 N/A RIG-I & NOD2 activator II Spring Bank Pharmaceuticals

USA www.springbankpharm.com

tenofovir exalidex, CMX157, conjugated tenofovir

N/A Non-nucleotiside reverse transcriptase

inhibitor

I/II ContraVir Pharmaceuticals

USA www.contravir.com

41 41

Thank you Simplified: 7 Pillars of HBV

• Test all adults, all immigrants, all patients with unknown HBV vaccine

status, all children born to mothers with HBV

• Anti-HBc = exposure, no vaccine, educate about reactivation risk (anti-

HBc false + rate is 2/1000 in low risk patients)

• Vaccinate all adults who are triple panel negative

• ALT over ULH (upper limits of healthy) or +fibrosis (APRI, FIB4, TE or bx)

and + DNA over 2000 = Nuc treatment,

– cirrhosis and any HBV DNA = Nuc treatment

• Treat until HBsAg loss + 12 months consolidation

• qHBsAg to use to manage patients with HBV infection

• Delta antibody testing in all patients with HBV

HDV

D is for deadly

43 43

44

HBV Global estimate is 292 M = 35 Million infected with HDV Total World Population 7.53 B If 1% are HDV seropositive = 70 million HDV+

15% of HBV patients are HDV sero positive

45 45

Vietnam HDV Prevalence

• anti-HDV < 1 % in one study Rural Vietnam

• HDV PCR < 1% in one study in Ho Chi Min City

www.vgcare.org

Vietnamese-German Centre for Excellence in Medical Research

46

www.vgcare.org

Vietnamese-German Centre for Excellence in Medical Research

0

5

10

15

Central North All cohort

HD

V R

NA

po

sit

ivit

y (

%)

* No sero testing performed

Regional HDV Prevalence ~ 10-13% Determined by PCR Testing

47

MyrB/IFNa combination show synergistic antiviral effects on HDV

Molecular Virology – Heidelberg

HBV Forum 15, Vienna, April 10th 2019

The Myr203-trial

Final results with follow up data in plenary III: GS-013

How can the strong synergistic effect between Myrcludex B and IFN on HDV RNA be explained ?

48

Myrcludex B with PEG-interferon α 2a: Safety and efficacy in patients with chronic HBV/HDV co-infection in a phase 2 trial (MYR203)

Wedemeyer H, et al. ILC 2019; GS-13

CONCLUSIONS ‌In contrast to PegIFNα2a monotherapy, MyrB + PegIFNα2a demonstrated high rates of HDV

RNA suppression. HBsAg loss was achieved in 27% of patients, indicating a potential role for MyrB in future

HBV cure regimens

RESULTS ‌

• Safety: MyrB was well tolerated, with 155 drug-

related AEs up to w72 (mild n=122, moderate n=28,

serious n=5), primarily increased total bile salts

– Most AEs (n=524) related to PegIFNα2a

– All cases resolved; bile salts returned to baseline by

follow-up Week 50

– Two SAEs (anal fistula and proctitis) not-related to

MyrB occurred in 1 patient of Arm B in follow-up

• Efficacy: MyrB + PegIFNα2a induced a significant

enhancement of HDV RNA response

– 40% (12/30) patients had undetectable HDV RNA at

Week 72

2 mg MyrB + PegIFNα2a induces HBsAg response

in HBeAg negative patients at Week 72

– 40% of patients experienced HBsAg response

– In this group 27% lost HBsAg and 20% seroconverted

RESULTS

HBsAg: 2 mg MyrB + PEG-IFNα Median HDV RNA

• Comparable activity to historical PEG IFN-alfa-2a

• Significantly better tolerated than PEG IFN-alfa-2a

• Durable response data at oral late-breaker (Etzion et al EASL 2019 Vienna)

-3

-2.5

-2

-1.5

0

-0.5

-1

Mean 180…

Mean 120…

0 4 8 12 16 20 24 28 32 36 40 44 48

Week 48 N Mean VL Decline ≥ 2 Log Decline

120 mcg* 14/17 -1.5 log 6 of 14 (42.9%)

180 mcg* 10/16 -2.4 log 6 of 10 (60.0%)

Change in

Log HDV-

RNA

40% sustained off treatment HDV RNA(-)

49

Pegylated interferon lambda for HDV

50 50

Great news !!!

Source: Polaris Observatory (http://cdafound.org/Polaris/ accessed June 14, 2018

51

HBV VACCINE

Vaccinate all triple negative patients HBV markers

52

HCC

Major controversy !!!!

• Is TDF safer then ETV ? HCC RISK?

• 3 studies to-date

• All have design flaws

53

Tenofovir treatment has lower risk of hepatocellular carcinoma than entecavir in patients with chronic hepatitis B

*Before (aHR 0.36, p=0.042) and after MI, with (weighted HR 0.36, p=0.013) and without (aHR 0.32, p=0.002) PS weighting.

Yip TCF, et al. ILC 2019; LB-03

BACKGROUND & AIMS ‌

• TDF and ETV have potent hepatitis B antiviral effects and are recommended first-line for CHB

• Aim: To compare TDF and ETV on HCC risk in a territory-wide CHB cohort

METHODS ‌

• Adult CHB patients initially treated with ETV or TDF for ≥6 months between 01/2008–06/2018

– In/out-patient data from all Hong Kong public hospitals and clinics

– Exclusions: patients with cancers or LT before or within first 6 months of treatment

– Missing data replaced by MI by chained equations, then PS weighted to balance BL clinical characteristics

RESULTS ‌

• 29,350 CHB patients identified (mean age 52.9 ± 13.2 years; 63.7% male)

– 1,309 (4.5%) and 28,041 (95.5%) first received TDF and ETV, respectively

• At a median 3.6 years FU, 8 (0.6%) TDF and 1,386 (4.9%) ETV-treated patients developed

HCC

– TDF associated with lower HCC risk than ETV*

54

Tenofovir treatment has lower risk of hepatocellular carcinoma than entecavir in patients with chronic hepatitis B

*Log-transformed in the model; †p=0.002 for TDF vs. ETV; ‡p=0.003 for TDF vs. ETV;

All others p<0.001.

Yip TCF, et al. ILC 2019; LB-03

CONCLUSIONS TDF treatment associated

with lower HCC risk than ETV in a

territory-wide CHB cohort

Parameters

Univariate analysis†

Multivariable

analysis†

SHR 95% CI Adjusted SHR 95% CI

TDF vs. ETV 0.15 0.07–0.29 0.32 0.16–0.65

Age 1.06 1.06–1.06 1.05 1.04–1.05

Male sex 2.17 1.90–2.47 2.42 2.11–2.76

Cirrhosis 5.73 5.16–6.36 2.30 2.01–2.64

Platelet* 0.35 0.31–0.40 0.54 0.49–0.60

Albumin 0.91 0.91–0.92 0.97 0.97–0.98

ALT* 0.81 0.77–0.84 0.87 0.83–0.91

Total bilirubin* 1.48 1.41–1.56 – –

HBeAg+‡ 0.82 0.73–0.93 1.44 1.26–1.65

TABLE ‌ HCC risk analysis

Cu

mu

lative

in

cid

en

ce

of H

CC

(%

)

Follow-up duration (years)

7.0% 95% CI 6.6–7.3%

1.1% 95% CI 0.5–2.3%

FIGURE 5-year cumulative HCC incidence

‌ ETV

TDF

Gray’s test, p<0.001