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UPDATES IN HBV
What is coming in 5-10 years?
Patrick T. F. Kennedy
Reader & Honorary Consultant Hepatologist
Blizard Institute, Barts and The London SMD, QMUL, London
EASL CPG 2017
EASL CPG 2017
Age limit of 30 years is arbitrary;
liver damage can be seen earlier
Representative patient: 23 year old male;
ALT 36 IU/L, HBV DNA 7.18 log IU/ml, HBsAg 3.59 log IU/ml
Ishak fibrosis stage 3/6
Evidence of liver damage in the ‘immune tolerant’ disease phase
Mason/Kennedy et al., Gastroenterology 2016
HBcAg HBsAg
HBsAg/HBcAg
Mason/Kennedy et al., Gastroenterology 2016
Nuclear core positive hepatocytes differentiate ‘immune tolerant’ disease
Nuclear core positive hepatocytes differentiate ‘immune tolerant’ disease
Mason/Kennedy et al., Gastroenterology 2016
Clonal hepatocyte expansion in ‘immune tolerant’ disease
Mason/Kennedy et al., Gastroenterology 2016
0
HBeAg Anti-HBe
HB
V D
NA
/HB
sA
g (
log
10 I
U/m
l)
ALT
(IU/L
)
CHRONIC INFECTION CHRONIC HEPATITIS CHRONIC INFECTION CHRONIC HEPATITIS
HBeAg POSITIVE HBeAg NEGATIVE
Natural History & Disease Phase
Adapted from Gill & Kennedy; Clin Med 2015
0
HBeAg Anti-HBe
HB
V D
NA
/HB
sA
g (
log
10 I
U/m
l)
ALT
(IU/L
)
CHRONIC INFECTION CHRONIC HEPATITIS CHRONIC INFECTION CHRONIC HEPATITIS
HBeAg POSITIVE HBeAg NEGATIVE
Natural History & Disease Phase
~10% ~50%
~25% - treated
~15% - worked-up
Adapted from Gill & Kennedy; Clin Med 2015
0
HBeAg Anti-HBe
HB
V D
NA
/HB
sA
g (
log
10 I
U/m
l)
ALT
(IU/L
)
CHRONIC INFECTION CHRONIC HEPATITIS CHRONIC INFECTION CHRONIC HEPATITIS
HBeAg POSITIVE HBeAg NEGATIVE
Natural History & Disease Phase
~10% ~50%
~25% - treated
~15% - worked-up
Adapted from Gill & Kennedy; Clin Med 2015
Treatment & management strategies
HBV Treatment regimes
Nucleos(t)ide Analogues (NUCs)
Marcellin et al, Lancet 2015; Chang, et al. Hepatology 2010
TENOFOVIR ENTECAVIR
Current therapies are non-curative
• Peg-IFN sustained immune control, but only in a minority
of patients1
• HBeAg positive & negative disease:
– limited decline in HBsAg during NUC monotherapy2
• Long-term viral suppression is achieved, but sustained
immune control following treatment cessation is limited3
1. EASL guidelines. J Hepatol 2012;57; 2. Zoutendijk R, et al. J Infect Dis 2011;
3. Hadziyannis SJ, et al. Gastroenterology 2012
The future prospects for HBV cure
Phase 3 Program: TAF 25 mg for HBV
Extended to *3 years; †5 years.
Double Blind*
2:1 randomization
TAF 25 mg
TDF 300 mg
Study 110: HBeAg+ N=873 and Study 108: HBeAg− N=425
• Primary endpoint:
• HBV DNA <29 IU/mL at week 48
• Secondary safety endpoint:
• Bone: hip and spine bone mineral density change
• Renal: creatinine and eGFR change
Week
48
Open-label TAF†
Week
96
Week
120
Buti M et al. Lancet G&H 2016, Chan HLY et al. Lancet G&H 2016
TAF Phase 3: Week 96 Results
TAF Group Performance Relative to TDF Group
Week 48 Week 96
Viral Suppression Non-inferior Non-inferior
ALT Normalization Significantly Better Significantly Better
Bone Safety Significantly Better Significantly Better
Renal Safety Significantly Better Significantly Better
Viral Resistance None None
Harnessing innate and adaptive immunity
Gane EJ, J Hepatol, 2015
Lanford et al. Gastroenterology 2013
TLR agonists - GS-9620
• TLR-7/8 mediate innate immune
activation in human liver:
• CD56bright NK cells & MAITs
produce antiviral cytokine IFN-g
Jo et al. PLoS Path 2014
Virally Suppressed
Trial complete
1, 2, or 4 mg vs PBO qwk
N=156
Naïve/Off Treatment
Dosing complete
1, 2, or 4 mg vs PBO qwk
N=192
GS-9620: Pharmacodynamics and Efficacy
• Dose-dependent, reproducible ISG15 induction without systemic cytokines
• Minimal HBsAg changes at Week 24
0 2 2 1 2 2 2 8 2 9 4 9 5 0 7 7 7 8 8 4
0
5
1 0
1 5
2 0
2 5
-0 .4
-0 .2
0 .0
Wk 24 HBsAg Change from Baseline ISG15 Fold-Change Expression
Lo
g1
0 IU
/mL
Me
dia
n, IQ
R
PBO Study Day
Dose 1 4 8 12
PBO 1 mg 2 mg 4 mg
1 mg 2 mg 4 mg
Virally-suppressed
Schurich et al. PLoS Pathog. 2013; D, et al. Vaccine 2013;
Jo et al., PLoS Pathog. 2014; Isorce et al. Antiviral Res 2016.
TLR8 Cytokines Activate Antiviral Immunity
TLR8 TLR7
Neutrophil mDC B cell Macrophage Monocyte pDC Tregs
Innate
Immunity
IL-12
IL-18
Adaptive
immunity
pAPCs
Tregs
Antiviral
cytokines
TNF-α
IFN-γ
NK MAIT CD8+
Foxp3+
IL-12
TNF-α
Pre-systemic Mechanism of Action
Harnessing innate and adaptive immunity
TLR agonists - GS-9668
• Virally-suppressed, HBeAg negative CHB patients (single center NZ)
• Primary efficacy endpoint:
• Change in HBsAg log10 IU/mL levels 12 Weeks following nivolumab treatment
Baseline Week 4 Week 16 Week 12
Primary Endpoint
(12 weeks post-nivolumab)
Nivolumab 0.3 mg/kg Sentinel B, n=2
Sentinel A, n=2 Nivolumab 0.1 mg/kg
Cohort A, n=10 Nivolumab 0.3 mg/kg
Cohort B, n=10 + GS-4774 40 YU
Nivolumab 0.3 mg/kg
Anti-PD1 inhibitor - Nivolumab
Study Design
-5
-4
-3
-2
-1
-0 .8
-0 .6
-0 .4
-0 .2
0 .0
0 .2
-5
-4
-3
-2
-1
-0 .8
-0 .6
-0 .4
-0 .2
0 .0
0 .2
Nivolumab
0.1 mg/kg
Nivolumab
0.3 mg/kg
Nivolumab
0.3 mg/kg
+ GS-4774
Week 12 Week 24
HB
sA
g C
han
ge
fro
m B
L, L
og
10 IU
/mL
Nivolumab
0.1 mg/kg
Nivolumab
0.3 mg/kg
Nivolumab
0.3 mg/kg
+ GS-4774
• 2/22 (9%) at Week 12 and 3/22 (14%) at Week 24 with a >0.5 log10 reduction in
HBsAg • Only one patient with >1 log10 reduction in HBsAg at either timepoint
• No baseline demographic feature associated with >0.5 log10 reduction in HBsAg
HBsAg change from baseline
Anti-PD1 inhibitor - Nivolumab
HBV Capsid Assembly Modulators (CpAMs)
CpAMs & ETV inhibit HBV replication
by distinct mechanisms
• CpAMs ABI-H0731 & GLS4 inhibit encapsidation of both viral DNA and pgRNA
• ETV in`hibited HBV DNA synthesis, but increased levels of pgRNA in intracellular
capsids by failing to create the RNA:DNA duplex digested by RNaseH
CpAMs inhibit cccDNA generation
in primary human hepatocytes
• CpAMs reduced viral HBV DNA levels and known surrogate markers for cccDNA
(HBeAg,HBsAg and pgRNA)
• ETV was highly effective at inhibiting HBV DNA levels, but exhibited limited effect
on cccDNA surrogates
Viral DNA, pgRNA, HBeAg and HBsAg in PHH
RNAi & Core Protein/Capsid Inhibtor
• Two novel agents in combination with SoC
• AB-423 (Core/Capsid Inhibitor)
-misdirects capsid assembly & inhibits pgRNA encapsidation
• ARB-1740 (RNA Inhibitor)
-Targets sAg produced by cccDNA & integrated DNA
RNAi & Core Protein/Capsid Inhibtor
• Two novel agents in combination with SoC
• AB-423 (Core/Capsid Inhibitor)
-misdirects capsid assembly & inhibits pgRNA encapsidation
• ARB-1740 (RNA Inhibitor)
-Targets sAg produced by cccDNA & integrated DNA
0 7 1 4 2 1 2 8 3 5 4 2
5
6
7
8
D a y
Se
rum
HB
V D
NA
(lo
g1
0c
op
ies
/mL
)
A B -4 2 3 + A R B -1 7 4 0 + P e g IF N
A B -4 2 3 + A R B -1 7 4 0 + E T V
LLOQ
RNAi & Core Protein/Capsid Inhibtor
• Combination of novel MOA agents
AB-423 (capsid inhibitor) and ARB-
1740 (RNAi) can enhance control of
HBV by current standard drugs
• These data support the hypothesis
that HBV antigen removal will
promote immune recognition and
viral control
Immune Recognition
Reduce viral
Antigens & DNA
GS-4774 (Tarmogen)
Stubbs, et al. Nat Med 2001; Cereda, et al. Vaccine 2011; Francis et al Vaccine 2015
CD4+
CD8+
GS-4774
APC
M X Large S (env) Core His
6
GS-4774 Recombinant Antigen
C8F17
fluorocarbon chain
DensigenTM
• ~ 30-40 amino acids long peptides
• CD4+/CD8+ T cell epitopes
• Net positive charge/Hydrophobicity
<70%
Current Trials of Therapeutic vaccination in HBV
Phase II in HBV patients suppressed on antivirals
Now to 5-10 years ahead; transition to functional cure
Gill & Kennedy, J Hepatol. 2017, In Press
Closing remarks
• Better understanding of HBV pathogenesis will be central to
better treatment outcomes
• Viral suppression now is just the starting point for HBV
care
• A new era in HBV management is emerging with strategies
to achieve functional cure
• Successful regimens for HBV cure will likely include
combination of direct antiviral suppression with immune
modulation
Acknowledgements
Dimitra Peppa, Lorenzo Micco,
Harsimran Singh, Mala Maini
Royal London Hospital
Louise Payaniandy, William Tong,
Deva Payaniandy, Sally Thomas,
Sandhia Naik
Graham Foster, Jyoti Hansi
Uppy Gill
Samuel Litwin, Yan Zhou,
Suraj Peri, William Mason
Fox Chase Cancer Centre Blizard Institute, QMUL
Rayne Institute, UCL
Duke, NUS/SICS A* Star
Elena Sandalova, Juandy Jo,
Adeline Chia, Antonio Bertoletti
ILS, Kings College
Oltin Pop,
Alberto Quaglia
University of Rome, TV
Luna Colagrossi, Romina Salpini,
Arianna Battistii, Lorenzo Piermatteo
Carlo Perno, Valentina Svicher