Is There a Best Direct Acting Antiviral Agent for HBV?

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1 Is There a Best Direct Acting Antiviral Agent for HBV? Fabien Zoulim Hepatology Department, Hospices Civils de Lyon INSERM U1052, Cancer Research Center of Lyon Lyon University, France

2 What targets for what drugs? Egress Inhibitors Entry inhibitors Targeting HBx RNA interference Targeting cccdna Polymerase/RNAseH inhibitors Core inhibitors Testoni and Zoulim, Hepatology 2015

3 Up- and/or Down- stream of cccdna? Potential to be curative? Zoulim, et al, Clin Gastroenterol Hepatol 2013

4 Entry inhibitors Entry inhibitors Myrcludex (pre-s1 peptide) Blank et al, J Hepatol 2016 Bogomolov et al, J Hepatol 2016 Ezetimibe Lucifora, Antiviral Res 2013 Proanthocyanidin Tsukuda, Hepatology 2017 Cyclosporin analogues Shimura, J Hepatol 2017 Li et al, elife 2012; Urban et al, Gastroenterology 2014

5 Pros & Challenges for entry inhibitors (Myrcludex-B) Inhibition of new rounds of infection Decrease the pool of cccdna on the long term pportunity to treat HBV/HDV coinfections SC administration Inhibition of NTCP and elevation of bile salts Slow kinetics of cccdna decay (need cell turnover); which combination with other DAAs?

6 Different classes of capsid assembly modulators Heteroaryldipyrimidine derivatives (HAP) Phenylpropenamide derivatives (AT series) Compounds in evaluation BAY HAP-12 AT-130 NVR3-778 JNJ-379 ABI-H0731 ABI-H0808 GLS4JHS HAP_R01 SBA_R01 AB-423

7 Core inhibitors inhibit viral genome replication and prevent cccdna formation when administered prior to HBV inoculation CpAMs Capsid inhibitors plasma membrane CpAMs Capsid inhibitors NUCs Polymerase inhibitors Berke et al. Antimicrob. Agents Chemother. 2017;61:e

8 HBV DNA Change from Baseline during JNJ-379 administration (HPB1001 Phase Ib study) HBV DNA change from baseline (log 10 IU/mL) * Pooled placebo (n=8) JNJ mg QD (n=8) JNJ mg QD (n=8) Time (weeks) *** *** * and *** refer respectively to 1 and 3 patients with HBV DNA <LLQ of the HBV DNA assay Will this be sufficient to accelerate cccdna decay? F Zoulim et al, AASLD 2017

9 Pros & challenges for CpAM Decrease the pool of cccdna on the long term pportunity to combine with NUCs, pegifn and other DAAs ral administration Long-term safety profile Mainly suppressive How to combine with other DAAs to be curative? Short-term safety profile

10 sirna Development Candidates Contains a hepatocyte targeted, reversibly masked membrane active peptide (NAG-MLP) Endosomal release of two synthetic sirnas PEG modification to inhibit membranolytic activity Journal of Controlled Release, Volume 209, 2015, Proprietary Lipid Nanoparticles 5 -sense 5 -AS P H N H N H N N H H N H N N H H N AcHN H AcHN AcHN H H H H H H H H ESC-GalNAc-Conjugate for subcutaneous administration And others

11 Decreased serum HBsAg levels in patients receiving ARC-520 every 4 weeks with daily entecavir HBeAg+ patients HBeAg- patients HBsAg [IU/mL] Single dose Cohort 7 Extension Cohort Week E Pos E Pos E Pos First dose of extension Last dose of extension HBsAg [IU/mL] Single dose Cohort 7 Extension Cohort Week E Neg E Neg E Neg E neg E Neg First dose of extension Last dose of extension - 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 2017 Yuen MF et al, EASL ILC 2017

12 Pros & challenges for sirna Decrease of HBsAg levels Possibility of immune restoration? pportunity 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 DAAs or immune Tx to be curative?

13 Nucleic acid polymers Nucleus cccdna Capsids Elimination of serum HBsAg NAPS Virions Replenishment of cccdna

14 Pros & challenges for NAPs Decrease of HBsAg levels Possibility of immune restoration, anti-hbs seroconversion? pportunity 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

15 Direct cccdna targeting IFNalpha /Lymphotoxin beta induced APBEC3A/B dependent degradation ; other cytokines Lucifora et al, Science 2014; Xia et al, Gastroenterology 2015 CRISPR/cas9 cleavage Seeger et al, Mol Ther Nucleic Acids & 2016 cccdna silencing through virus specific mechanims Belloni et al, JCI 2012; Liu et al, Plos Path 2013; Tropberger et al, PNAS 2015

16 HBV cure - New treatment concepts Will we need combination of DAA and immune therapy? SERUM HBV DNA change from baseline (log 10 c/ml) NUC Therapy Antivirals Capsid HBVDNA SiRNA Ag load Immune restoration TLR agonist HBsAg Check point inhibitors Tx Vaccine Anti-HBsAb Time LIVER cccdna cccdna degradation or permanent silencing

17 Acknowledgements Hepatology Unit INSERM U1052 Collaborations François Bailly Samir Benmaklouf Marie Ecochard Kerstin Hartig Fanny Lebossé Massimo Levrero Marianne Maynard Christian Trépo David Durantel Barbara Testoni Julie Lucifora Bernd Stadelmeyer Guada Martinez Maelle Locatelli Fleur Chapus Aurore Inchauspé Maud Michelet Judith Fresquet Marc Bonin Thomas Lahlali Lucyna Cova Romain Parent Anna Salvetti Birke Bartosch Eve Pecheur Boyan Grigorov Christophe Combet K. Lacombe, Paris F Carrat, Paris C Ferrari, Parma P Lampertico, Milan A Craxi, Palermo JP Quivy, Institut Curie M Dandri, Hamburg XX Zhang, Shanghai