by author Novel approaches towards HBV cure

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1 Jörg Petersen Liver Unit IFI Institute at Asklepios Klinik St. Georg University of Hamburg Germany Novel approaches towards HBV cure New horizons in Hepatitis B,D, and E, ECCMID, Madrid, 24 April 2018

2 Disclosures Grant/research support: Bristol-Myers Squibb, Novartis, Roche Clinical studies: AbbVie, Arrowhead, Bristol-Myers Squibb, Eisai, Falk, Gilead Sciences, Hepatera, Hologic, Intercept, Janssen, Merck Sharp & Dohme, Roche, Siemens, Vertex Consultant/advisor: Abbott, AbbVie, Arrowhead, Assembly Pharma, Bristol-Myers Squibb, Contravir, Gilead Sciences, GlaxoSmithKline, Janssen, Kedrion, Merck Sharp & Dohme, Novira, Roche Sponsored lectures: Abbott, Bristol-Myers Squibb, Boehringer, Gilead Sciences, Janssen, Kedrion, Merck Sharp & Dohme, Merz, Novartis, Roche

3 Achievements and ongoing challenges Hepatitis B: From a treatable disease to a curable disease? Decrease hepatic inflammation and fibrosis Liaw YF, et al. N Engl J Med 2004;351: ; Marcellin P, et al. Lancet 2013;381: Dandri M, Petersen J. Clin Infect Dis 2016;62:281-8 Suppression of HBV replication Prevent/reduce complications of cirrhosis,reduction of HCCs Very good safety (10yrs) Hepatitis B treatment NA or PEG-IFN No HBV cure Will this become achievable in the future? S8JP14

4 Considerations for current tretment options Hepatitis B: From a treatable disease to a curable disease? Unlike in HCV drug development there is a very effective and safe therapy available which suppresses HBV DNA - generic ETV and TDF (and TAF as new NA player) On the global scale, people are still suffering from complications of chronic Hepatitis B and dying in large numbers because they do not receive any therapy in many parts of the world S8JP14

5 Globally, an estimated 250 million people are infected with HBV Region, ( % prevalence of HBsAg) African region (3.0) Region of the Americas (0.2) Eastern Mediterranean region (1.6) European region (0.4) South-East Asian region (0.7) Western Pacific region (0.9) It is estimated that 15 million people in Europe are living with HBV WHO. Global hepatitis report Available at: (accessed November 2017) HBsAg: hepatitis B surface antigen

6 HBV: Considerations for Current tretment options From a treatable disease to a curable disease? The HBV field remains complicated: Endpoints are currently being discussed Large number of new therapeutic targets and possible combination therapies especially at this years EASL meeting April 2018 in Paris have been presented Large pharmaceutical companies navigate back toward HBV with new drug combinations S8JP14

7 Why do our current treatment options not result in complete cure? cccdna pgrna AAA AAA Dandri M, Petersen J: Hepatitis B Virus DNA clearance: Killing for curing? Hepatology 2005;42:1453-8, Allweiss et al, Gut 2017 HBV NTCP Subgenomic RNAs AAA cccdna not affected by NA and not efficiently affected by PEG-IFN

8 What does cure of HBV mean? Several definitions are used Liver Achieved with NUCs Blood Nucleos(t)ide analogueinduced virus suppression (HBeAg seroconversion=20%) Virus suppression Modified from Durantel D, et al. J Hepatol 2016;64:S Achieved with IFN-based and NA therapy in a small proportion of patients Liver Blood Decreased viral RNA and protein synthesis, HBsAg loss +/- seroconversion Functional cure Liver Elimination of cccdna but persistence of integrated viral DNA Complete cure Blood Currently unachievable Sterilising cure cccdna: covalently closed circular DNA; HBeAg: hepatitis B e antigen

9 Overall transplant-free survival (%) Cumulative incidence of hepatocellular carcinoma (%) Why is functional HBV cure important? If you cannot kill HBV, inactivate the disease as much as possible HBsAg loss improves survival and lowers HCC incidence in patients who are currently on oral antiviral therapy Kim GA, et al. Gut 2014;63: HBsAg seroclearance (n=93) No HBsAg seroclearance (n=372) P=0.02 HR 0.10; 95% CI Time after treatment initiation (years) HBsAg seroclearance (n=93) No HBsAg seroclearance (n=372) P<0.01 HR 0.06; 95% CI Time after treatment initiation (years) CI: confidence interval; HCC: hepatocellular carcinoma; HR: hazard ratio

10 HBsAg loss as endpoint of CHB therapy HBsAg loss with, or without, anti-hbs seroconversion, is an optimal endpoint The ultimate goal would be achievement of HBsAg loss with a finite course of oral antiviral therapy Immune control of the disease is important the role of flares is being debated But: In HBeAg negative patients, HBsAg may be produced from integrated DNA too and not exclusively from cccdna EASL. J Hepatol 2017;67:370 98, Wooddell CI et al, Wooddell C, et al. Sci Transl Med 2017 Sep 27 doi: /scitranslmed.aan0241

11 NA discontinuation before HBsAg loss a new concept? Really? Recommendation: Discontinuation of NAs in selected non-cirrhotic HBeAg-negative patients who have achieved long-term (3 years) virological suppression under NA(s) may be considered if close post-na monitoring can be guaranteed. In some parts of the world, due to restricted budget situation limited duration of therapy with NAs is already part of some guidelines (APASL) EASL. J Hepatol 2017;67:370 98, APASL Hepatol Intern 2016;10:1-98

12 New HBV targets what pathways or approaches might we take? Stimulation of innate and / or adaptive immunity Targeting cccdna preclinical stage Petersen J, et al. J Hepatol 2016;65: Entry inhibitors RNA interference (sirna) Capsid assembly modulators Inhibition of HBsAg release

13 Safety, pharmacokinetics and antiviral activity of novel capsid assembly modulator (CAM) JNJ (JNJ-6379) in treatment-naive CHB patients without cirrhosis Aim: Evaluate safety, PK, and antiviral activity of multiple ascending doses of novel CAM JNJ-6379 in CHB pts Zoulim F, et al. EASL 2018, Paris. #LBO-004 NVR GLS4-JHS JNJ-6379 Company J & J HEC Pharma J & J Dose 60 mg QD 120 mg QD 240 mg QD 25 mg QD / 75 mg QD 150 mg QD Mean DNA reduction (log) Mean RNA reduction (log) 0.86 NA NA Other CpAM in development include: ABI-H0731; ABI-H2158; ABI-Nx; SBA-R01; AB-423; AB-506; GLP-26 Session 8 (8 drug; 4 placebo) Session 9 (8 drug; 4 placebo) Session 10 (9 drug; 3 placebo) 100 mg QD 75 mg QD 150 mg QD 25 mg QD 8-week follow-up 8 week follow-up 8 week follow-up 0 1 Dosing period (days) 28 Follow-up phase 84

14 Mean (SD) HBV DNA change from BL (log 10 IU/mL) Safety, pharmacokinetics and antiviral activity of novel capsid assembly modulator (CAM) JNJ (JNJ-6379) in treatment-naive CHB patients without cirrhosis Baseline characteristics ITT analysis Zoulim F, et al. EASL 2018, Paris. #LBO mg QD (n=12)* 75 mg QD (n=12)* 150 mg QD (n=12)** Mean age, years (SD) 39.5 (11.6) 36.5 (10.2) 45.8 (9.9) Sex Male, n (%) 11 (92) 10 (83) 9 (75) Race White, n (%) 6 (50) 12 (100) 10 (83.3) ALT Grade, n (%) Grade 0 9 (75) 9 (75) 9 (75) Grade 1 3 (25) 3 (25) 3 (25) Metavir fibrosis stage n, (%) F0 4 (33) 5 (42) 5 (42) F1 6 (50) 4 (33) 7 (58) F2 2 (17) 3 (25) 0 HBeAg positive, n (%) 6 (50) 3 (25) 0 Mean HBV DNA log 10 IU/mL (SD) 6.41 (1.99) 5.36 (1.54) 4.84 (1.43) Mean HBsAg log 10 IU/mL (SD) 4.07 (0.96) 3.95 (0.55) 3.91 (0.70) HBV genotype D, n (%) 5 (42) 10 (83) 8 (67) *Sessions 8 and 9: JNJ-6379 (n=8); PBO (n=4) **Session 10: JNJ-6379 (n=9); PBO (n=3) including one pt with recombinant genotype C/D Mean HBV DNA change from BL up to 4 weeks f/u Pooled PBO (n=11) f/u period Time (weeks) 25 mg (n=8) 75 mg (n=8) 150 mg (n=9) Each * refers to 1 pt with HBV DNA <LLQ * *** *** *** **** *** ** * n=9 n=8 n=5 n=3 **

15 Safety, pharmacokinetics and antiviral activity of novel capsid assembly modulator (CAM) JNJ (JNJ-6379) in treatment-naive CHB patients without cirrhosis Pharmacokinetics Following repeat administration, exposure increased in a dose-dependent manner Safety On-treatment AEs (28 days) Zoulim F, et al. EASL 2018, Paris. #LBO-004 Session 8 25 mg (n=8) Session 9 75 mg (n=8) Session mg (n=9) Pooled placebo (n=11) At least one AE 5 (63) 4 (50) 6 (67) 7 (64) Worst reported grade of AE, n (%) Grade 1 3 (38) 2 (25) 3 (33) 5 (46) Grade 2 1 (13) 1 (13) 2 (22) 2 (18) Grade 3 1 (13) 1 (13) * 0 0 Grade (11) 0 SAEs, n (%) ** 0 AEs leading to treatment discontinuation (%) (11) 0 JNJ-6379 (administered for 28 days) was generally well tolerated and resulted in potent antiviral activity at all doses evaluated Data warrant additional evaluation of compound in Phase 2a * 1 pt had isolated Gr1 and 2 ALT and Gr 1 AST elevations on treatment that raised to Gr3 and 4 ALT and Gr3 AST elevations during f/u, without other lab changes or clinical symptoms; ** 1 SAE observed during f/u: right frontal lobe mass, unrelated to study drug; 1 pt receiving 150 mg JNJ-6379 QD had isolated ALT/AST elevation without any other lab changes or clinical symptoms

16 Durable inhibition of HBV replication and antigenemia using a subcutaneously administered sirna agent in preclinical models ARB-1467: RNA interference product (IV) with a 3-trigger design inhibiting HBV replication, reducing HBV transcripts, and lowering HBV antigens, delivered via proprietary lipid nanoparticle (LNP) technology (P2) Here second generation preclinical: AB-729: Novel RNA interference agent (SC), N-acetylgalactosamine (GalNAc) conjugate liver targeting technology, pan-genotypic activity, multi-month duration of surface antigen inhibition after a single SC dose, 10-fold larger dose for HBsAg reduction Lee A, et al. EASL 2018, Paris. #PS-029 sirna delivery is mediated by a conjugated targeting ligand; GalNAc Cell uptake via GalNAc interaction with ASGPR Asialoglycoprotein Receptor Highly expressed in/on hepatocytes High rate of uptake 15 min recycling time Conserved across species

17 S e r u m H B s A g ( L o g I U / m L ) Durable inhibition of HBV replication and antigenemia using a subcutaneously administered sirna agent in preclinical models Asialoglycoprotein receptor interaction demonstrated in vitro (PHH or immortalized hepatocytes) dose sirna Weeks W e e k s after A f t e r Oone n e S C SC D odose s e Lee A, et al. EASL 2018, Paris. #PS-029 Analyzed expanded panel panel of HBV of markers at Day 14 (right HBV panel, markers & next slide) at Day 14 L L O Q S a l i n e 1 m g / k g 3 m g / k g 9 m g / k g Clear dose response, achieved max effect detectable in this model Supports clinical dosing frequency of 1 month (or more) Controls Liver sections stained for HBsAg 200 µm 729 Treatment

18 Serum S e r u m HBsAg H B s A g (log IU/mL) (L o g IU / m L ) Durable inhibition of HBV replication and antigenemia using a subcutaneously administered sirna agent in preclinical models Log L O G inhibition In h ib itio n # # L iv e r 3.5 k b H B V R N A Inhibition h it ioof n omultiple f M u le HBV H B V markers M a r k e r s bby y ' L iv e r T o ta l H B V R N A Next generation sirna agent with long half-life, SC route, demonstrating suppression of replication and reduction of antigenemia Lee A, et al. EASL 2018, Paris. #PS-029 L iv e r H B s A g S e r u m H B s A g 14 days after single dose treatment in AAV mice (mean of n=5 ±SD) # relative to baseline (serum readouts) or saline control (liver readouts) *indicates signal for 1 animal below LLOQ * S e ru m H B e A g C o n tro l s ir N A 9 m g / k g ' m g / k g ' m g / k g ' m g / k g * S e ru m H B V D N A * * AB-729 has longer duration of activity than ARB Weeks W e e k s after A r administration A d m is a tio n Ain A V AAV M ic emice Dose responsive effects on all measured HBV markers cccdna not significantly present in this model; not expected to be directly impacted by RNAi Next step: Safety studies L L O Q S a lin e A R B , 0.3 m g / k g IV A B , 3 m g / k g S C

19 New HBV targets what pathways or approaches might we take? Innate Cytokine therapy, IFN TLR agonists (TLR7, TLR8) RIG-I agonists Adaptive Therapeutic vaccine Checkpoint inhibitors (PD-1, PD-L1) Petersen J, et al. J Hepatol 2016;65: Stimulation of innate and / or adaptive immunity (Partial) immune restoration through inhibition of viral antigens

20 Pros and cons of novel approaches to HBV cure Entry inhibitors RNA interference Capsid assembly modulators Immune modulators cccdna impairment Pros Prevents HBV spreading from human hepatocytes in vivo Slows amplification of the cccdna pool by blocking the dynamics of hepatocyte infection Liver-specific reduction in HBV replication and protein expression demonstrated Might show benefit of reducing expression of cccdna and core proteins Dysregulate or inhibit pgrna encapsidation and/or nucleocapsid assembly Oral, combo therapies Cons Lack of data Most interest for HBV/HDV at this stage Parenteral Next speaker will talk about HDV Sustainability of response still to be demonstrated antibodies? Parenteral, second generation sc not iv anymore Potential for systemic effects and resistance Evidence of efficacy and tolerability Potential for systemic effects, animal models do not necessarily reflect potential and/or safety profile in humans May be able to destroy or damage the major HBV transcriptional template Revill P, et al. Nat Rev Gastroenterol 2016;13:239 48; Durantel D, et al. J Hepatol 2016;64:S117 31; Petersen J, et al. J Hepatol 2016;65: Challenging to identify small molecules Currently at the preclinical stage so safety profile needs to be established

21 Considerations for current tretment options Hepatitis B: From a treatable disease to a curable disease? The HBV field remains complicated: Endpoints are currently being discussed Large number of new therapeutic targets and possible combination therapies Probably different therapies for different subpopulations of patients (no one fits all therapies) New biomarker needed to measure success (DNA suppressed patient on NA followed by add-on CPAM) Becoming more invasive again? (Biopsies in subsets of patients in phase 2 studies) S8JP14

22 Invasive biomarker and the need for biopsies cccdna As a key molecule of the viral life cycle, cccdna represents the major target for next-generation therapeutics Besides questions in respect to cccdna dynamics and standardisation, HBV infection of the liver is likely to become increasingly heterogenous during long-term infection and antiviral treatment o Q: does a small biopsy reflect the whole liver? Furthermore, we need to balance the benefits vs risks with this invasive procedure Chi H, et al. Eur J Gastroenterol Hepatol 2017;29:36 41 Liver biopsies are not without a risk for the patient 5.6% complications (pain, bleeding) 1.7% severe (hospitalisation >2 days, intervention needed) 0.06% of patients died (1/1806)

23 Circulating viral antigens and particles Adapted from Lucifora J, Protzer U. Hepatitis B Virus X Protein: A Key Regulator of the Virus Life Cycle. Available at: (accessed November 2017)

24 (Novel) HBV serum markers qhbsag (established) HBcrAg Circulating viral RNAs HBcrAg: hepatitis core-related antigen

25 Quantitative HBsAg tests total HBsAg Abbott linear range IU/mL Elecsys linear range ,000 IU/mL Abbot linear range , ,000 1,000,000 HBsAg Level (IU/mL) Zacher BJ, et al. Clin Vaccine Immunol 2011;18: Package insert: Elecsys HBsAg II quant Elecsys linear range Linear ranges covering clinically relevant HBsAg levels

26 HBV RNA (pgrna) in circulating viral particles First described in 1996 in the serum of infected patients Can be released into serum as enveloped 3.5kb pregenomic RNA containing virions Amount of circulating pgrna strongly correlates with the amount of pgrna present in the whole liver and with transcriptionally active cccdna in humanised mice Marker to study the transcriptional activity of cccdna Wang J, et al. J Hepatol 2016;65:700 10; Giersch K, et al. J Hepatol 2017;66:460 2; Butler K, et al. AASLD 2017; Poster #1915 No commercially available test yet, but performance of an automated prototype assay for the detection and quantification of hepatitis B pregenomic RNA in chronic HBV patients receiving nucleo(t)side analogue therapy

27 Serum HBV pgrna can serve as clinical marker for cccdna activity with HBV mono and HBV/HDV co-infection (in humanised mice and patients) HBV-monoinfection (+/- IFN-treatment) HBV/HDV-coinfection DNA RNA Allweiss L, et al. ILC 2017; Poster #SAT-176; Giersch K, et al. J Hepatol 2017;66:460 2 IFN-treated untreated IFN-treated

28 Serum HBV pgrna can serve as clinical marker for cccdna activity with HBV mono and HBV/HDV co-infection (in humanised mice and patients) HBV-monoinfection (+/- IFN-treatment) HBV/HDV-coinfection Allweiss L, et al. ILC 2017; Poster #SAT-176; Giersch K, et al. J Hepatol 2017;66:460 2 DNA RNA IFN-treated untreated IFN-treated IFN lowers levels of pgrna in serum; very good correlations between serum pgrna and intrahepatic pgrna (=cccdna activity) but not with cccdna amounts in mice treated with IFN (due to reduced cccdna activity) or in HDV coinfected mice

29 How to use these markers? Petersen J, et al. J Hepatol 2016;65:835 48

30 The problem of suboptimal HBV-DNA suppression Several recent studies demonstrated persistence of HBV-DNA or intrahepatic HBV- DNA synthesis during NA treatment, although qpcr showed undetectable DNA levels No prevention of cccdna synthesis from incoming virus/replenishment Combo NA plus CpAMs (sirna): Expect to improve inhibition of viral genomes within hepatocytes But how to measure here efficacy if biopsies unavailable? pgrna? HBcrAg? Boyd A, et al. J Hepatol 2016;65:683 91; Petersen J, personal opinion CpAM: core protein allosteric modifier

31 HBV: Considerations for Current tretment options From a treatable disease to a curable disease? The HBV field remains complicated: What are the correct populations with HBV to be treated? Easiest to show an effect? Patient with highest need? Inactive carriers / Immunotolerant patients NUC suppressed patients Challenging times ahead of us S8JP14

32 Summary Ultimate goal in management of CHB is to completely cure the virus Currently, only a small proportion of patients will achieve functional cure (HBsAg loss); complete virological cure is still not possible Knowledge of the HBV replication cycle has resulted in identification of new agents that may have the potential to (functionally) cure more HBV patients in the future Today s view is that combining new treatment targets appears to be necessary to achieve higher rates of functional cure in the future Demonstration of the long-term safety profile of all new treatment targets is of utmost importance With new therapies comes need to proof success of treatment HBcrAg and HBV mrna

33 Jörg Petersen Liver Unit IFI Institute at Asklepios Klinik St. Georg University of Hamburg Thank you for your attention