Hepatitis B cure: From discovery to regulatory approval

Abstract

The majority of persons currently treated for chronic hepatitis B require long-term or lifelong therapy. New inhibitors of hepatitis B virus entry, replication, assembly, or secretion and immune modulatory therapies are in development. The introduction of these novel compounds for chronic hepatitis B necessitates a standardized appraisal of the efficacy and safety of these treatments and definitions of new or additional endpoints to inform clinical trials. To move the field forward and to expedite the pathway from discovery to regulatory approval, a workshop with key stakeholders was held in September 2016 to develop a consensus on treatment endpoints to guide the design of clinical trials aimed at hepatitis B cure. The consensus reached was that a complete sterilizing cure, i.e., viral eradication from the host, is unlikely to be feasible. Instead, a functional cure characterized by sustained loss of hepatitis B surface antigen with or without hepatitis B surface antibody seroconversion, which is associated with improved clinical outcomes, in a higher proportion of patients than is currently achieved with existing treatments is a feasible goal. Development of standardized assays for novel biomarkers toward better defining hepatitis B virus cure should occur in parallel with development of novel antiviral and immune modulatory therapies such that approval of new treatments can be linked to the approval of new diagnostic assays used to measure efficacy or to predict response. Combination of antiviral and immune modulatory therapies will likely be needed to achieve functional hepatitis B virus cure. Limited proof-of-concept monotherapy studies to evaluate safety and antiviral activity should be conducted prior to proceeding to combination therapies. The safety of any new curative therapies will be paramount given the excellent safety of currently approved nucleos(t)ide analogues. (Hepatology 2017).

Figure 1.. Phases of chronic HBV infection.

1) Immune tolerant. HBeAg positive, high serum HBV DNA but normal ALT levels. 2) Immune clearance/HBeAg-positive chronic hepatitis. HBeAg positive, high serum HBV DNA and elevated ALT levels. HBeAg seroconversion to anti-HBe occurs after varying duration. 3) Inactive carrier. HBeAg-negative, serum HBV DNA low (generally <2000 IU/mL) or undetectable. 4) Reactivation/HBeAg-negative chronic hepatitis. HBeAg-negative, elevated levels of HBV DNA and ALT in serum, HBV precore and/or basal core promoter variant often present. Traditionally phases of chronic HBV infection are defined by HBeAg status, serum HBV DNA and ALT levels. Quantitative HBsAg levels are different in each phase and are generally highest in immune tolerant phase and lowest in inactive carrier phase. While most patients progress from one phase to the next, not all patients go through each phase, and reversion to an earlier phase can occur. Abbreviations: ALT, alanine aminotransferase; anti-HBe, hepatitis B e antibody; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen

Figure 2.. HBV lifecycle and antiviral targets.

1) HBV entry. Lipopeptides mimicking pre-S1 domain competing with Dane particle for binding to NTCP (e.g. Myrcludex B). Other small molecule inhibitors are in development. 2) Targeting cccDNA. Prevention of cccDNA formation. Damage and destruction via cytokines or cccDNA sequence-specific nucleases. Functional silencing via modulation of host cellular epigenetic-modifying enzymes by cytokines or inhibition of viral protein function. 3) HBV mRNAs. small interfering RNA approaches or anti-sense oligonucleotides to block viral replication and viral protein expression. 4) HBV Polymerase. Reverse transcriptase inhibitors include approved nucleos(t)ide analogues. RNAseH inhibitors are in preclinical evaluation. 5) Nucleocapsid assembly and pgRNA packaging. Capsid assembly modulators can affect nucleocapsid assembly, pgRNA encapsidation, and may affect the nuclear functions of HBc (cccDNA regulation and interferon stimulated gene expression). 6) Targeting HBsAg. Phosphorothioate oligonucleotides (NAPs) inhibiting HBsAg release and monoclonal antibodies to decrease circulating HBsAg load are under evaluation. Abbreviations: HBc, hepatitis B core protein; HBsAg, hepatitis B surface antigen; HBx, hepatitis B × protein; pgRNA, pregenomic RNA; NTCP, sodium taurocholate co-transporting polypeptide; cccDNA, covalently closed circular DNA.

Figure 3.. The immune liver microenvironment and immunotherapeutic targets

1) Innate immune responses. IFN-α exhibits antiviral activity in infected cells, but also contributes to cell-mediated immunity in vivo. TLR (TLR-7 and others) agonists to boost antiviral cytokine production and activation of NK cells, B cells and T-cells are in clinical evaluation. Drugs antagonizing cIAP can sensitize HBV-infected cells to TNF-mediated apoptosis. 2) HBV-specific T-cell exhaustion. Approaches to block inhibitory pathways (check point inhibitors: PD-1 blockade and others) and immunosuppressive cytokines (IL-10 and TGF-β) to achieve recovery of HBV-specific T cells and NK cells from chronic hepatitis B patients are currently in evaluation. 3) Engineering of redirected T cells via i) transfer of HBV-specific T-cell receptors or HBV-specific chimeric antigen receptors ex vivo in patient’s T cells, or ii) retargeting of immune effector cells towards HBV-infected cells using bispecific antibody constructs. 4) Therapeutic vaccines. Antigenic stimulation by diverse approaches are currently being evaluated in phase I/II clinical trials in association with nucleos(t)ide analogues to promote CD4+ and CD8+T cell antiviral activity and antibody responses. Abbreviations: cIAP, cellular inhibitor of apoptosis; NK, natural killer cells; HBsAg, hepatitis B surface antigen; PD-1, programmed cell death protein 1; TLR, Toll-like receptor; TNF, tumor necrosis factor.