is there a best direct acting antiviral agent for...
TRANSCRIPT
Is There a Best Direct Acting Antiviral Agent for HBV?
Fabien ZoulimHepatology Department, Hospices Civils de LyonINSERM U1052, Cancer Research Center of Lyon
Lyon University, France
Entry inhibitors
Core inhibitors
Targeting cccDNA Polymerase/RNAseH inhibitors
RNA interference
Egress Inhibitors
Targeting HBx
Testoni and Zoulim, Hepatology 2015
What targets for what drugs?
Zoulim, et al, Clin Gastroenterol Hepatol 2013
Up- and/or Down- stream of cccDNA ?Potential to be curative ?
Li et al, elife 2012; Urban et al, Gastroenterology 2014
Entry inhibitors
Entry inhibitorsMyrcludex (pre-S1 peptide)Blank et al, J Hepatol 2016Bogomolov et al, J Hepatol 2016
EzetimibeLucifora, Antiviral Res 2013ProanthocyanidinTsukuda, Hepatology 2017Cyclosporin analogues Shimura, J Hepatol 2017
Pros & Challenges for entry inhibitors (Myrcludex-B)
Inhibition of new rounds of infection
Decrease the pool of cccDNA on the long term
Opportunity to treat HBV/HDV co-infections
SC administration
Inhibition of NTCP and elevationof bile salts
Slow kinetics of cccDNA decay(need cell turnover); whichcombination with other DAAs ?
Different classes of capsid assembly modulators
Compounds in evaluationBAY41-4109HAP-12AT-130NVR3-778JNJ-379ABI-H0731ABI-H0808GLS4JHSHAP_R01 SBA_R01AB-423
Heteroaryldipyrimidine derivatives (HAP) Phenylpropenamide derivatives (AT series)
Core inhibitors inhibit viral genome replication and prevent cccDNA formation when administered prior to HBV inoculation
NUCs“Polymerase inhibitors”
plasma
membrane
CpAMs“Capsid inhibitors”
CpAMs“Capsid inhibitors”
Berke et al. Antimicrob. Agents Chemother. 2017;61:e00560-17
***
*
HBV DNA Change from Baseline during JNJ-379 administration (HPB1001 Phase Ib study)
***
Pooled placebo (n=8)JNJ-379 25 mg QD (n=8)JNJ-379 75 mg QD (n=8)
0
–1
–2
–3
0 1 2 3 4
Time (weeks)
HBV
DN
A ch
ange
from
bas
elin
e(lo
g 10
IU/m
L)
* and *** refer respectively to 1 and 3 patients with HBV DNA <LLOQ of the HBV DNA assay
F Zoulim et al, AASLD 2017
Will this be sufficient to accelerate cccDNA decay ?
Pros & challenges for CpAM
Decrease the pool of cccDNA on the long term
Opportunity to combine with NUCs, pegIFN and other DAAs
Oral administration
Short-term safety profile
Long-term safety profile
Mainly suppressive
How to combine with other DAAsto be curative ?
siRNA Development Candidates
5′-AS
5′-senseHN
O
O
O
O
O
O
HN
HN
HN
HN
NH
NH
O
O
O
O
O
OO
O
N
O
HO
PO
OO
O OH
OHHO
AcHN
O OH
OHHO
AcHN
O OH
OHHO
AcHN
ESC-GalNAc-Conjugate for subcutaneous administration
Journal of Controlled Release, Volume 209, 2015, 57–66
• Contains a hepatocyte targeted,reversibly masked membrane activepeptide (NAG-MLP)
• Endosomal release of two syntheticsiRNAs
• PEG modification to inhibitmembranolytic activity
Proprietary Lipid Nanoparticles
And others…
Decreased serum HBsAg levels in patients receiving ARC-520 every 4 weeks with daily entecavir
Week
HB
sAg
[IU/m
L]
0 20 40 60 8010
100
1000
10000
10000001-7981 E Pos01-7982 E Pos01-7985 E Pos
First dose ofextension
Last dose ofextension
Single doseCohort 7
ExtensionCohort 10
01-7988 E Neg
Week
HB
sAg
[IU/m
L]0 20 40 60 80
0.1
1
10
100
1000
10000
First dose ofextensionLast dose ofextension
Single doseCohort 7
ExtensionCohort 10
01-7973 E neg01-7974 E Neg
01-7983 E Neg01-7986 E Neg
HBeAg+ patients HBeAg- patients
- Impact of integrated sequences on siRNA efficacy
- Will the decrease of viral antigen load result in restoration of immune responses ?Wooddel et al, Science Trans Med 2017Yuen MF et al, EASL ILC 2017
Pros & challenges for siRNA
Decrease of HBsAg levels
Possibility of immune restoration ?
Opportunity to combine with NUCs, pegIFN and other DAAs
Combination with immunotherapeutic approaches ?
IV infusion
Long-term safety profile
Mainly suppressive
Impact of integrated sequences
How to combine with other DAAsor immune Tx to be curative ?
Virions
NucleusNAPS
cccDNA
Capsids
Replenishment of cccDNA
Elimination ofserum HBsAg
Nucleic acid polymers
Pros & challenges for NAPs
Decrease of HBsAg levels
Possibility of immune restoration, anti-HBs seroconversion ?
Opportunity to combine with NUCs, pegIFN and other DAAs
Mode of action to be better defined
IV infusion
ALT elevation: good or bad ?
Long-term safety profile
Lucifora et al, Science 2014; Xia et al, Gastroenterology 2015
Direct cccDNA targeting
IFNalpha /Lymphotoxin beta induced APOBEC3A/B dependent
degradation ; other cytokines
CRISPR/cas9 cleavage
cccDNA silencing through virus specific mechanimsBelloni et al, JCI 2012; Liu et al, Plos Path 2013; Tropberger et al, PNAS 2015
Seeger et al, Mol Ther Nucleic Acids. 2014 & 2016
Therapy
HB
V D
NA
chan
ge fr
om b
asel
ine
(log
10c/
mL)
0.0
-1.0
-2.0
-3.0
-4.0
+1.0
Time
HBV cure - New treatment concepts – Will we need combination of DAA and immune therapy ?
HBsAgHBVDNA
cccDNA
SERUM
LIVER
Antivirals
NUCCapsid
SiRNAAg load
Immune restoration
TLR agonist
TxVaccine
Check point
inhibitors Anti-HBsAb
cccDNA degradationor permanent silencing
Acknowledgements
Hepatology Unit INSERM U1052 Collaborations
David DurantelBarbara TestoniJulie LuciforaBernd StadelmeyerGuada MartinezMaelle LocatelliFleur ChapusAurore InchauspéMaud MicheletJudith Fresquet
K. Lacombe, ParisF Carrat, ParisC Ferrari, ParmaP Lampertico, MilanA Craxi, PalermoJP Quivy, Institut CurieM Dandri, HamburgXX Zhang, Shanghai
Marc BoninThomas LahlaliLucyna CovaRomain ParentAnna SalvettiBirke BartoschEve PecheurBoyan GrigorovChristophe Combet
François BaillySamir BenmakloufMarie EcochardKerstin HartigFanny LebosséMassimo LevreroMarianne MaynardChristian Trépo