Virtual ICE-HBV Workshop On Serum Biomarkers Session 1

ICE-HBV is organizing an virtual and interactive workshop on HBV biomarkers endorsed by the International HBV Meeting. The event is aimed at scientists, clinicians, pharmaceutical and diagnostic industry representatives.  The workshop, chaired by Anna Kramvis and Peter Revill, is put together by the ICE-HBV serum biomarkers working group. Both classic and future biomarkers will be discussed. The workshop will lead to a consensus statement on promising serum biomarkers. 

The workshop will be divided in two sessions, held on Monday Oct 5 and Monday Oct 12, 2020, via Zoom. Both sessions will start at 12PM GMT, go for approximately 2.5 hours each, and will be recorded. More information here.

Free registration is open here.

                               

Program

October 5th – 140 Minutes Total – Time in GMT

Session Co-Chairs: Timothy M. Block and Veronica Miller

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Timothy Block, Ph.D. is President and (with his wife, Joan and Paul and Jan Witte) co-founder of the Hepatitis B Foundation (HBF). He also founded its Baruch S. Blumberg (Research) Institute (BSBI) and Pennsylvania Biotechnology Center (PABC). He is Adjunct Professor, U. of Pennsylvania, formerly (1983-2006) Professor, Jefferson and Drexel Medical Schools. He and colleagues (Blumberg, Mehta, Dwek, Su) pioneered the use of glycoproteomics and “micro DNA” in the urine for detection of biomarkers of liver cancer risk, (with Guo) identified inhibitors of hepatitis B virus, which are in clinical phase testing. He has published >250 papers. Honors include (Hon. M.D.), election to Bulgarian National Academy, Fellow, American Association for the Advancement of Science, Glycobiology Institute (University of Oxford), US National Academy of Inventors. Named a “Visionary in Hepatitis” by the World Hepatitis Alliance.

Dr. Miller is an Adjunct Professor at the UC Berkeley School of Public Health. She developed and teaches a course on FDA and Drug Development based on case studies from the Forum’s rich history in facilitating drug development to Berkeley and Bay Area graduate students and post-docs. She mentors interns and fellows pursuing regulatory, biotech and translational medicine careers. Dr. Miller serves on numerous industry and government advisory boards, publishing over 100 peer-reviewed publications on HIV treatment strategies and regulatory strategies for HIV and HCV throughout her career. She joined the Forum in 2001 after directing the interdisciplinary HIV Research Group at the HIV Outpatient Clinic of the JW Goethe University in Frankfurt, Germany. Together with Joep Lange, she co-founded and chaired the Euro-Guidelines Group on HIV Drug Resistance, the first pan-European group established for the purpose of assuring a common standard-of-care for patients in all European states. Dr. Miller obtained a Bachelor of Science in Microbiology from the University of Manitoba, and a Doctor of Philosophy in Immunology from the University of Manitoba.

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Noon  Housekeeping Rules Capucine Penicaud
12:00-12:05pm 

Welcome and aims of the workshop. Introduction to Session Chairs Timothy M. Block  and Veronica Miller

Anna Kramvis
12:05-12:25pm  Summary of the Viral Serum Biomarker Landscape + Q&As

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Title: Summary of the Viral Serum Biomarker Landscape 

Date of presentation: October, 5th 2020 

Authors: Dr. Barbara TESTONI 

Affiliation: Cancer Research Center of Lyon (CRCL) – INSERM U1052 

Abstract Body: 

Chronic hepatitis B infection develops in severe liver disease and liver cancer. Viral persistence is due to the lack of therapies that can effectively target the hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in hepatocytes and by the presence of viral sequences integrated in the human genome. HBV integration does not sustain viral replication, but can transcribe for viral antigens and is associated to pathogenesis. As the unique viral genomic repository and matrix for full viral replication, cccDNA remains the utmost target for curing chronic HBV infections. Routine circulating biomarkers used for clinical monitoring of patients do not accurately reflect HBV intrahepatic activity. New emerging non-invasive biomarkers are therefore under evaluation for their relevance in reflecting liver viral activity, in improving the classification of patients with regards to their natural history and in the evaluation of novel compounds to assess target engagement and to define new virological endpoints.

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Barbara Testoni

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Barbara Testoni obtained her PhD in Genetics and Molecular Biology at the University of Milan, working on eukaryotic transcriptional regulation in the setting of skin development. Then, she moved to the University of Rome “La Sapienza”, where she began working on liver disease and type-I interferon signalling. At present, she is a PI in the “Viral Hepatitis” team at CRCL – INSERM U1052 in Lyon. Her research interests mainly include the investigation of the epigenetic mechanisms at the basis of host and viral gene regulation during HBV infection, with particular focus on the transcriptional regulation of the HBV minichromosome.

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12:25-12:45pm  Summary of Immunological Serum Biomarkers Landscape + Q&As

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Title: Summary of Immunological Serum Biomarkers Landscape 

Date of presentation:  October 5, 2020 

Authors:  Kyong-Mi Chang 

Affiliation:  University of Pennsylvania and Crescenz VA Medical Center 

Abstract Body: Liver disease in HBV infection is largely immune-mediated. Antiviral CD8 T-cells mediate both cytolytic and non-cytolytic virus control upon MHC class I-mediated recognition of virus-infected hepatocytes, with a key regulatory role for CD4 T-cells. However, in chronic hepatitis B, virus persists with dynamic variations in hepatocellular injury with inflammation versus disease and/or virus control, with the participation of multiple immune effector and regulatory pathways. Lacking safe and convenient access to the liver compartment, there is an interest to examine the peripheral compartment for immune markers to gain mechanistic as well as clinical and prognostic insights. This presentation will highlight aspects of HBV immune pathogenesis and summarize available literature on immunologically-based serum biomarkers with potential relevance to clinical outcomes of HBV infection and therapy.

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Kyong-Mi Chang

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Dr. Kyong-Mi Chang is a translational investigator with expertise in immune pathogenesis of human liver disease, including hepatitis B and C with progression to cirrhosis and cancer. Currently, she is Professor of Medicine in the Division of Gastroenterology at the University of Pennsylvania with an administrative leadership role as the Associate Chief of Staff and Associate Dean for Research at the Corporal Michael J. Crescenz VA Medical Center in Phliadelphia. Dr. Chang is also examining the genetic underpinnings of cardiometabolic disorders including liver disease among US Veteran participants in the Million Veteran Program.

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12:45-1pm  What is serum HBV RNA? + Q&As

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Title: What is serum HBV RNA?

Date of presentation: 5 October 2020

Authors: Florian van Bömmel

Affiliation: Leipzig University Medical Center, Department of Hepatology, Leipzig, Germany

Abstract Body: Serum HBV RNA is believed to be derived from cccDNA and there is a growing body of evidence that the circulating HBV RNA may serve as a new serum biomarker for cccDNA activity. Accordingly, HBV RNA in serum shows some correlation to other HBV markers as HBV DNA, HBeAg and HBcrAg. However, methods that were presented for quantification of HBV RNA are difficult to compare, and species and existence form of serum HBV RNA have not been thoroughly been characterized.  In recent studies, HBV RNA was found to be associated with HBV infection stages, treatment response and disease prognosis. Also, HBV RNA was found to be a marker for relapse of HBV replication after treatment cessation. Although to date it remains unclear whether serum HBV RNA is better than current biomarkers, HBV RNA possess potentials to be a new marker for chronic hepatitis B virus infection.

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Florian Van Bömmel

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Florian van Bömmel (MD) is Hepatologist and Gastroenterologist deputy head of the Department of Hepatology at the University of Leipzig, Germany. He has been involved in clinical and translational research in many studies in Hepatitis B. A special focus of his research is the development of novel serum markers of HBV replications.

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1-1:15pm  What is core related antigen? + Q&As

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Title: What is core related antigen? (Characterization of Hepatitis B core-related Antigens and Their Applications in HBV-infected Patients and Animal Models)  

Date of presentation: October 5, 2020 

Authors: Xupeng Hong1, Laurie Luckenbaugh1, Megan Mendenhall1, Stefan Wieland2, Renae Walsh3, Liza Cabuang3, Sally Soppe3, Peter Revill3, Dara Burdette4, Becket Feierbach4, William Delaney4, Stephan Menne5, Jianming Hu1 

Affiliation: 1. Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA. 2. Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland. 3. Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Melbourne, Australia. 4. Gilead Sciences, Inc., Foster City, California, USA. 5. Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, USA. 

Abstract Body: 

Current therapies rarely cure chronic hepatitis B virus (HBV) infection due to the persistence of the viral episome, covalently closed circular DNA (cccDNA), in hepatocytes. The so-called hepatitis B core-related antigen (HBcrAg), a composite antigen found in the blood of infected patients, has emerged as one potential marker to monitor the intrahepatic cccDNA and define new meaningful treatment endpoints. In this study, we aimed to comprehensively characterize the compositions of HBcrAg and its equivalents in the woodchuck hepatitis virus (WHV) and investigate their kinetics during the natural infection and antiviral treatments. We have found that components of HBcrAg included the classical hepatitis B core antigen (HBcAg or HBc) and hepatitis B e antigen (HBeAg), and additionally, the PreCore-related antigen (PreC) that retain the N-terminal signal peptide sequence. Both HBeAg and PreC antigens displayed heterogeneous proteolytic processing at their C-terminus resulting in multiple species. HBeAg was the predominant form of HBcrAg in HBeAg-positive patients. HBc, but not HBeAg or PreC proteins, were found as the main component of capsids in DNA-containing or empty virions. The woodchuck hepatitis virus (WHV) core related antigen also included the WHcAg, WHeAg, and WHV PreC proteins analogous to HBV PreC proteins. WHeAg and PreC proteins, but not HBeAg or PreC, were N-glycosylated. A positive correlation was found between the serum WHeAg and intrahepatic cccDNA. Analysis of the kinetics of each HBcrAg component (HBeAg, HBc, and PreC) in HBV-infected chimpanzees and analogous WHV antigens in WHV-infected woodchucks revealed multiple distinct phases of decline during the natural resolution of HBV and WHV infection and in response to different antiviral treatments. Careful monitoring of each component of HBcrAg, i.e., HBc, HBeAg, and PreC proteins, along with other classical markers such as viral DNA and HBV surface antigen will help understand intrahepatic HBV gene expression and replication, including cccDNA levels and activity, so as to elucidate natural resolution mechanisms as well as guide antiviral development.

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Jianming Hu

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MD: Wuhan University School of Medicine 

PhD: Penn State University College of Medicine 

Currently: Professor, Department of Microbiology and Immunology, Penn State University College of Medicine 

Research interest: HBV replication and persistence, virus-host interactions, antivirals, biomarkers 

Co-Chair, ICE-HBV Working Group – Innovative Tools 

Member, ICE-HBV Working Group – Virology

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1:15-1:35pm  Utility of serum biomarkers to follow natural history and treatment of chronic hepatitis B + Q&As

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Title: Utility of serum biomarkers to follow clinical phases and treatment of chronic hepatitis B 

Date of presentation: October 5, 2020 

Authors: Harry L.A. Janssen and Hannah Choi 

Affiliation: Toronto Centre for Liver Disease, University of Toronto 

Abstract Body: 

The management of chronic HBV infection is challenging, owing to the varying natural course of infection and persistence of cccDNA. Thus, it is essential to monitor HBV biomarkers for diagnosis and effective management of the disease. Although serum HBVDNA and HBsAg remain the most well-characterized, clinically relevant biomarkers in chronic hepatitis B, supplemental, or even superior, biomarkers may be needed for disease monitoring, especially with HBV genome integration. Moreover, in the current era of effective NA therapy leading to complete HBV DNA suppression and to explore new treatment modalities which bring functional cure, HBV RNA and HBcrAg may serve as important additional markers of viral activity and immune control. Combinations of these biomarkers will likely be required to evaluate treatment efficacy, determine prognosis, and define true, (sterilizing) cure. In my lecture, the clinical utility of both established and emerging biomarkers will be appraised regarding the course of infection, disease progression, and response to established and new treatment.

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Harry Janssen

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Harry Janssen is Professor of Medicine at the University of Toronto, Ontario, Canada, where he holds the Francis Family Chair in Hepatology. He currently works at Toronto General Hospital as Chief of Hepatology and Director of the Toronto Centre for Liver Disease. 

Dr. Janssen has coordinated numerous clinical and translational studies on treatment for chronic viral hepatitis and other liver diseases. His main research interest is cure of chronic hepatitis B. He has published more than 500 original peer-reviewed papers and many book chapters. His H-index is over 100 and he has been cited 45,000 times (Google Scholar). He has received several prestigious international awards and has mentored over 50 PhD students, of whom many have taken leadership positions in the field of Hepatology or Virology.

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Panel Co-Chairs: Adam Gehring and Ulrike Protzer

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Adam Gehring received his Ph.D. at Case Western Reserve University in Cleveland, Ohio.  His training included a Postdoctoral Fellowship in the Institute of Hepatology at University College London and a position of Senior Research Fellow, and subsequently Assistant Principal Investigator, at the Singapore Institute for Clinical Sciences with Antonio Bertoletti. During his postdoctoral training Dr. Gehring was instrumental in developing TCR gene therapy for chronic HBV. His foundational work resulted in human application of engineered T cells for HBV-related HCC tumors expressing viral antigen. Dr. Gehring moved to Saint Louis University as an Assistant Professor in the Molecular Microbiology and Immunology department in March 2013 before joining the Toronto Center for Liver Disease as Biology Lead in February 2016.  

Dr. Gehring is currently Co-Chair for the Immune Monitoring Workgroup of the HBV Forum. He is Co-Chair for the International HBV Meeting being organized in Toronto in September, 2021. 

Dr. Gehring runs a translational HBV immunology research lab focused on liver pathogenesis and sex-based differences in disease progression. His primary interest lies in defining the mechanisms driving liver inflammation during HBV-related flares using functional and transcriptomic approaches in liver biopsies. He has established an internal immune monitoring core within his lab to process and analyze immune responses in Phase 2 clinical studies for HBV. 

Ulrike Protzer is an expert clinical virologist with many years of research in molecular virology, virus-host interaction and immunology mostly focusing on hepatitis B virus (HBV). Ulrike studied medicine in Germany, South Africa and Switzerland. She did a clinical training in infectious diseases, gastroenterology and hepatology before she went into virology, and has passed board exams in Internal Medicine as well as in Microbiology and Virology. 

Her scientific efforts focus on understanding the interaction between viruses and their hosts and on translating this knowledge into novel therapeutic approaches. She developed cell culture and mouse models of HBV infection to understand how HBV persists and how the nuclear HBV persistence form, the so called cccDNA, can be attacked. Her scientific work indicates that immune stimulation is required to keep cccDNA in check. Her group is exploiting therapeutic vaccines, adoptive T cell therapies and antibodies to reconstitute HBV-specific immunity and finally cure HBV. More recently, she also focusses on SARS-coronavirus. 

Since 2007, Ulrike Protzer holds the Chair of Virology at the Technical University of Munich (TUM)and is director of the Institutes of Virology at TUM and at Helmholtz Zentrum Muenchen. She serves in numerous advisory and supervisory boards and is vice dean of the School of Medicine. She leads two national and an international research consortium, was member of the executive board of the German Center for Infection Research and now is the speaker of its Thematic Translational Unit “Viral Hepatitis”.

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1:35-2:20pm Industry Panel Discussion – What are the virological and immunological gaps that need to be addressed? What biomarkers are most needed to meet HBV cure endpoints?  Gavin Cloherty, Jenny Yang, Bill Delaney, Oliver Lenz, Harry Janssen and MF Yuen

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Jenny Yang, PharmD is a Senior Director of Clinical Research at Gilead Sciences.  After working on the global development and registration of Gilead’s HCV marketed products including Sovaldi®, Harvoni®, and Vosevi®, she now leads the HBV Cure clinical development program at Gilead.  Prior to her 13-year experience in drug development at Gilead and Novartis, she completed her PharmD at the University at Buffalo, School of Pharmacy and Pharmaceutical Sciences. 

William Delaney, PhD joined Assembly Biosciences as Chief Scientific Officer, Virology in May 2020. Prior to joining Assembly, he most served as Executive Director, Biology at Gilead. During his 20-year career at the Gilead, he headed the Viral Hepatitis & Herpes Discovery Biology Groups and served as the Research Therapeutic Area Head for HBV. He began his career as a Research Scientist, Clinical Virology at Gilead and later transitioned into Drug Discovery where he held positions of increasing responsibility. Over the course of his career, he has contributed to the development of several marketed products, including Hepsera®, Viread®, and Vemlidy® for HBV and Sovaldi®, Harvoni®, Epclusa®, and Vosevi® for HCV. He earned a BS in Biotechnology from the University of Delaware and a PhD in Cell and Molecular Biology from the Penn State College of Medicine. In addition, he was a Postdoctoral Fellow at the Victorian Infectious Diseases Reference Laboratory (VIDRL), Department of Research & Molecular Development. 

Oliver Lenz, PhD is Scientific Director Clinical Microbiology and Immunology at Janssen Infectious Diseases, part of the Janssen Pharmaceutical Companies of Johnson & Johnson. He is the global virology lead for the development of HBV therapeutics from pre-clinical through clinical development. Prior to his work in HBV he was involved in the discovery of the HCV protease inhibitor simeprevir which he supported subsequently through clinical development until registration. Oliver Lenz completed his PhD at the University of Marburg, Germany, mainly working on hemorrhagic fever viruses and did a postdoctoral fellowship at the European Molecular Biology Laboratory (EMBL) at Grenoble, France, on HIV GP41 structural biology. He is author of 70 peer reviewed papers and co-chair of the HBV Forum surrogate endpoints working group.   

Harry Janssen is Professor of Medicine at the University of Toronto, Ontario, Canada, where he holds the Francis Family Chair in Hepatology. He currently works at Toronto General Hospital as Chief of Hepatology and Director of the Toronto Centre for Liver Disease. 

Dr. Janssen has coordinated numerous clinical and translational studies on treatment for chronic viral hepatitis and other liver diseases. His main research interest is cure of chronic hepatitis B. He has published more than 500 original peer-reviewed papers and many book chapters. His H-index is over 100 and he has been cited 45,000 times (Google Scholar). He has received several prestigious international awards and has mentored over 50 PhD students, of whom many have taken leadership positions in the field of Hepatology or Virology. 

Professor Yuen obtained his first bachelor degree of medicine in 1992. He further pursued his academic excellence through the achievement of obtaining 3 doctoral degrees including Doctor of Medicine with Sir Patrick Manson Gold Medal in 2001, Doctor of Philosophy in 2005 and Doctor of Science in 2017.  

Professor Yuen’s research interests include prevention, natural history, molecular virology and treatment of chronic hepatitis B and C, and hepatocellular carcinoma. He is one of the top internationally renowned researchers in the field of hepatitis B disease. He has now published more than 440 papers in world renowned medical journals.  

At present, he is the pioneering clinical researcher leading numerous studies on novel antiviral and immunomodulatory agents for the treatment of chronic hepatitis B. He is also actively performing cutting edge research on novel markers for hepatitis B infection and occult hepatitis B infection.  

As a specialist of Gastroenterology and Hepatology, Professor Yuen have been providing clinical care and services for patients in Queen Mary Hospital, The University of Hong Kong for more than 20 years. He is also serving as medical advisor and consultant for different health related units of the Government of Hong Kong, many academic centres and commercial enterprises for different aspects related to the diseases of Gastroenterology and Hepatology.  

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