Background
It has been more than 50 years since the discovery of the Australia antigen which led to the identification of the Hepatitis B virus (HBV) [1, 2], and although there are effective treatments, no cure for this viral infection has yet been found. The HBV infects the liver causing acute and chronic inflammation, fibrosis, cirrhosis of the liver, hepatocellular carcinoma (HCC), and eventually death. Despite the fact that HBV can be effectively prevented through vaccination, an estimated 240 – 350 million people worldwide are chronically infected with HBV [3, 4], with 2.2 million living in the United States [5]. Current standard of care requires life-long treatment, not optimally accessible in many regions, making the search for a cure to this epidemic an urgent public health priority.
With the breakthroughs in Hepatitis C treatment (HCV) and cure [6, 7], industry, academia and patient communities shifted attention to find similarly effective therapeutic and curative alternatives for HBV [8]. However, the elimination of HBV in people who are chronically infected is challenging. The ultimate goal of HBV cure would be the eradication of cccDNA, also described as “absolute cure” [2]. Although in practice this is yet impossible [9], a functional cure, in which the patient returns to a state of health equivalent to that of a person who has recovered from HBV infection [1], may be achievable through other approaches [1, 9, 10], and may represent the first step towards the longer term goal of absolute cure.
The interest of pharmaceutical companies in developing new treatments and curative strategies is high, but the field remains challenged by the complexity of the approaches needed to achieve functional and/or absolute cures and the resulting implications for regulatory strategies. Stakeholders need a mechanism to advance the regulatory science for this field and increase the efficiency of drug development through evolving consensus and increasing clarity. Networking and opportunities for collaboration among all interested parties are key to reducing inefficiencies in processes such as biomarker identification, validation and acceptance.
The HBV Forum aims to advance the regulatory science for novel HBV therapeutic interventions and its associated morbidities in real time by providing an independent and neutral environment for ongoing multi-stakeholder dialogue. The goals of the HBV Forum are to:
- provide scientific guidance to facilitate discussion between the industry, regulatory bodies, the academic and patients’ communities and community advocates in the areas of HBV drug and diagnostic development, and
- facilitate evolving consensus, based on real-time scientific development in the areas of appropriate methodologies for novel therapeutic approaches, clinical trial design and standardization of definitions.
The Objectives of the HBV Forum are to:
- Provide a platform for ongoing and systematic dialogue to address the most relevant issues on innovative therapeutic and curative interventions.
- Produce recommendations, based on ongoing scientific review, to inform the regulatory path decision-making process; and
- Participate and collaborate with other initiatives to contribute to the advancement of the regulatory science of novel HBV therapeutic approaches.
Action Plan
The HBV Forum is led by a
Steering Committee and managed by Forum staff. The HBV Forum meets regularly with topic-specific working group conference calls and email/web-based communication and in-person meetings, as appropriate, in the intervening time.
HBV Forum members are recruited from regulatory and federal agencies, academia, professional societies, patient organizations, advocacy communities, and industry. The HBV Forum is open to all pharmaceutical, biotech and diagnostic companies involved in relevant clinical research, with industry members asked to contribute to the Forum's financial needs.
The HBV Forum agenda is set by the Steering Committee and includes discussion of topics such as:
Treatment
- Should people with immune tolerant disease or with HBeAg negative disease who are considered inactive be included in clinical trials with novel agents?
- Should they be included in current clinical trials and what is the long-term clinical benefit?
- What are the surrogate endpoints or long-term clinical outcomes?
- When to stop treatment (and potentially re-initiation of treatment)?
- What is an acceptable benefit-risk profile to support a development program?
- What are efficient models for monitoring long-term safety?
- When is it appropriate to start testing combination regimen and different therapeutic strategies?
- What is the goal of therapeutic vaccines moving forward?
Clinical Trials
- What are appropriate clinical trial designs for different interventions?
- What are appropriate populations to enroll?
- Inclusion and exclusion criteria for enrollment
- What are appropriate and acceptable control groups and comparator regimen?
- When is it appropriate to study combination regimens with different targets?
- What are the challenges for clinical trial design in the global setting, under different regulatory jurisdictions and standards of care?
- What are the regulatory expectations for post-marketing evaluations?
Endpoints
- Do current biomarkers accurately reflect disease progression and clearance?
- Is there room for improvement?
- Primary efficacy endpoints – HBV DNA suppression?
- Monitoring of HBsAg levels
- HBsAg clearance or seroconversion
- Durability of response
- What is needed for validating and accepting different endpoints for evaluating short and long-term treatment goals?
- What are the collaborative opportunities for improving the efficiency of regulatory acceptance of biomarkers and surrogate endpoints?
Working groups
Working groups have been developed to carry on the work of the HBV Forum by addressing priority areas identified by both the steering committee and HBV Forum members. Expected outcomes of the working groups include recommendations, position papers, reports, manuscripts for submission to peer-reviewed journals, and presentations at conferences. Throughout the year, working groups communicate and collaborate by conference calls, email, in-person meetings, and workshops as needed. There is no time requirement for participation; however, working group members are expected to be active participants and participate in as many calls and activities as possible.
| Ongoing Working Groups |
Completed Working Groups |
| Immune Checkpoint Inhibitors Working Group to advance the regulatory path for anti-PD-1 and anti-PD- L1 therapies in CHB patients by identifying major questions around risk-benefit with respect to immune- related adverse events and assessing lessons learned from the oncology space from which these therapies were initially approved. |
HDV RNA Assays sub-Writing Group published a Review summarizing available research-based and commercial HDV RNA assays, discussing technical features of assays that result in substantial variability in performance characteristics, and outlining implications for the use of HDV RNA assays in drug development and patient monitoring of HDV RNA levels in trials.
Stopping Finite Therapies Working Group published a Viewpoints article on consensus in developing a framework for stopping novel agents and combination regimens for treatment of CHB when measuring off-treatment efficacy of investigational therapies. |
| Biomarkers Database Working Group to assess the range of diversity (demographic, clinical, biomarker) among patients being recruited into trials of novel therapeutic and combination regimens for chronic hepatitis B. Through collaborations with trial sponsors and the Forum’s Data & Analysis Center, develop a database of HBV clinical trial information to support future drug development and facilitate collective learning for all stakeholders. |
Capsid Assembly Modulators Working Group published a joint statement on behalf of both the HBV Forum and ICE-HBV on standardizing nomenclature of core protein-targeting antivirals, promoting definition consensus
Immune Monitoring Working Group published an article identifying a) a set of basic assays to facilitate cross-trial and cross-study comparison and b) biomarkers for immune-based interventions. |
HDV Co-Infection Working Group to facilitate HDV diagnostic and therapeutic development through discussions on standardization of HDV RNA, facilitating research through HDV sample biobanks, efficacy endpoint definitions, and other aspects of HDV drug development.
HDV Sample Biobank Working Group to facilitate development of HDV diagnostics and support evaluating the performance of available HDV diagnostic assays. The focus will be to discuss strategies and a path forward for establishing a biobank of HDV samples for use by sponsors working in HDV clinical development and by manufacturers developing diagnostics, screening tests, and treatment monitoring tests. |
Surrogate Endpoints Working Group published a meta-analysis to strengthen the link between surrogate markers and long-term clinical outcomes
Diagnostic/Biomarker sub-Working Group to develop clarity on what is needed for biomarker acceptance and validation for HBV drug/diagnostic development. Created the “Inventory of diagnostics approval status by US-FDA and the EU” |
| MAPPED Working Group (Mechanisms of Action and Patient Populations: Emphasizing Diversity) to understand relationship between HBV patient heterogeneity and drug mechanisms of action, assessing the assumptions made in clinical development programs, how assumptions evolve overtime based on results. Manuscript in progress. |
Treatment Combination Working Group to provide clarity on the requirements of novel agents in clinical development and to identify mechanisms to speed up the development of combination of different promising agents across companies
Liver Safety Monitoring sub-Working Group published an article to facilitate consensus on terminology and definitions to use when testing the safety and efficacy of novel therapeutic agents for chronic HBV when used alone or in combination with other investigational or approved anti-HBV agents |
Governance/Membership/Funding
The HBV Forum membership is by invitation only. Project members are recruited from academia, community, federal agencies, professional societies, and industry. Membership is open to scientific experts from pharmaceutical, biotech, and diagnostic industry organizations committed to and actively engaged in research and development in HBV.
Participation from industry is conditional on an annual sponsorship contribution. Industry members will be acknowledged as HBV Forum sponsors. Sponsorship includes participation in-person meetings, working groups, webinars, remote attendance, and project updates. Non-sponsoring industry will have access to information published on the HBV Forum’s website. Annual contributions from non-industry organizations are encouraged. Members from pharmaceutical, biotech, device, and diagnostic industry organizations must be scientific or regulatory experts actively engaged in research and development in the field of HBV. Industry members join as an organization. Commercial, marketing, and investment experts are not permitted to attend closed HBV Forum members meetings, but will be allowed to participate in any public meetings the Forum sponsors.
The Forum does not cover any honoraria or provides items of value (gifts) to any speakers or attendees. Membership cannot be combined/divided for participation in different disease specific projects at the Forum.
References
1. Gish, R.G., et al., Chronic hepatitis B: Virology, natural history, current management and a glimpse at future opportunities. Antiviral Res, 2015. 121: p. 47-58.
2. Block, T.M., et al., Chronic hepatitis B: what should be the goal for new therapies? Antiviral Res, 2013. 98(1): p. 27-34.
3. Ott, J.J., et al., Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine, 2012. 30(12): p. 2212-9.
4. CDC, Hepatitis B, in Epidemiology and Prevention of Vaccine-Preventable Diseases., J. Hamborsky, A. Kroger, and S. Wolfe, Editors. 2015, Public Health Foundation: Washington, DC. p. 149-174.
5. Kowdley, K.V., et al., Prevalence of chronic hepatitis B among foreign-born persons living in the United States by country of origin. Hepatology, 2012. 56(2): p. 422-33.
6. Pawlotsky, J.M., et al., From non-A, non-B hepatitis to hepatitis C virus cure. J Hepatol, 2015. 62(1 Suppl): p. S87-99.
7. Lucifora, J. and C. Trepo, Hepatitis: After HCV cure, HBV cure? Nat Rev Gastroenterol Hepatol, 2015. 12(7): p. 376-8.
8. Lok, A.S., Progress in Hepatitis B: A 30-Year Journey Through Three Continents. Hepatology, 2014. 60(1): p. 7.
9. Zeisel, M.B., et al., Towards an HBV cure: state-of-the-art and unresolved questions--report of the ANRS workshop on HBV cure. Gut, 2015. 64(8): p. 1314-26.
10. Locarnini, S., et al., Strategies to control hepatitis B: Public policy, epidemiology, vaccine and drugs. J Hepatol, 2015. 62(1 Suppl): p. S76-86.
Updated October 5th, 2021
