Drugs in Development for Hepatitis B

Abstract

With high morbidity and mortality worldwide, there is great interest in effective therapies for chronic hepatitis B (CHB) virus. There are currently several dozen investigational agents being developed for treatment of CHB. They can be broadly divided into two categories: (1) direct-acting antivirals (DAAs) that interfere with a specific step in viral replication; and (2) host-targeting agents that inhibit viral replication by modifying host cell function, with the latter group further divided into the subcategories of immune modulators and agents that target other host functions. Included among the DAAs being developed are RNA interference therapies, covalently closed circular DNA (cccDNA) formation and transcription inhibitors, core/capsid inhibitors, reverse transcriptase inhibitors, hepatitis B surface antigen (HBsAg) release inhibitors, antisense oligonucleotides, and helioxanthin analogues. Included among the host-targeting agents are entry inhibitors, cyclophilin inhibitors, and multiple immunomodulatory agents, including Toll-like receptor agonists, immune checkpoint inhibitors, therapeutic vaccines, engineered T cells, and several cytokine agents, including recombinant human interleukin-7 (CYT107) and SB 9200, a novel therapy that is believed to both have direct antiviral properties and to induce endogenous interferon. In this review we discuss agents that are currently in the clinical stage of development for CHB treatment as well as strategies and agents currently at the evaluation and discovery phase and potential future targets. Effective approaches to CHB may require suppression of viral replication combined with one or more host-targeting agents. Some of the recent research advances have led to the hope that with such a combined approach we may have a functional cure for CHB in the not distant future.

Fig. 1

Novel therapies targeting hepatitis B virus with virologic approaches [, , , –179]. cccDNA covalently closed circular DNA, HBV hepatitis B virus, NTCP sodium taurocholate co-transporting polypeptide

Fig. 2

Novel therapies targeting hepatitis B virus with immunological approaches [, , , , , –179]. Among the therapies currently being assessed as possible agents to counter hepatitis B virus with host-targeting approaches, including (a) entry inhibitors: myrcludex B, ciclosporin (cyclosporine A) and several ciclosporin derivatives (including SCYX618806, SCYX827830, and SCYX1454139), alisporivir, bendroflumethiazide, ezetimibe, irbesartan, losartan, nefazodone, nifedipine, ritonavir, simvastatin, epigallocatechin-3-gallate, Ro41-5253, vanitaracin A, and the nucleic acid polymer REP 2005; (b) cyclophilin inhibitors: ciclosporin, alisporivir, NIM811, SCY-635, and NVP018; (c) Toll-like receptor agonists: GS-9620; (d) engineered T cells: T cells engineered with a chimeric antigen receptor specific for HBV envelope proteins; (e) immune checkpoint inhibitors: nivolumab; (f) therapeutic vaccines: (1) protein/peptide-based: vaccination that combines HBsAg and HBcAg, (2) DNA vaccines: DNA vaccine encoding for S and preS2 domains of HBV envelope proteins, DNA prime and viral vector boost vaccines, and DNA vaccine encoding HBV proteins and modified human IL-12, (3) viral vector-based vaccines: TG1050 vaccine, recombinant retroviral vector vaccine expressing HBcAg, DNA/MVA prime/boost vaccine, and DNA prime-adenovirus boost vaccine, (4) cell-based vaccines: dendritic cell vaccines; and (g) other immune modulators: recombinant human IL-7 (CYT107), recombinant human IL-12, and SB 9200. HBcAg hepatitis B core antigen, HBsAg hepatitis B surface antigen, HBV hepatitis B virus, IL interleukin, MVA modified vaccinia virus Ankara

Fig. 3

The main features of the HBV life cycle and potential antiviral targets [, –192]. (1) HBV entry inhibitors. Lipopeptides mimicking pre-S1 domain competing with Dane particle for binding to NTCP (e.g., myrcludex B™). Other small molecules are under evaluation. (2) Targeting cccDNA. Damage and destruction of cccDNA 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 antisense oligonucleotides to block viral replication and viral protein expression. (4) HBV Pol inhibitors. Reverse transcriptase inhibitors of the nucleos(t)ide analog family are part of the standard of care. RNAse H inhibitors are in preclinical evaluation. (5) Core modulators. Nucleocapsid assembly and pgRNA packaging. Capsid assembly modulators can affect nucleocapsid assembly, pgRNA encapsidation, and the nuclear functions of HBc (cccDNA regulation and interferon stimulated gene expression). (6) Egress inhibitors. Phosphorothioate oligonucleotides inhibiting HBsAg release and monoclonal antibodies to decrease circulating HBsAg load are under evaluation. Reproduced with permission from Revill et al. [189]. cccDNA covalently closed circular DNA, dslDNA double-stranded linear DNA, HBc hepatitis B core protein, HBe hepatitis e antigen, HBs hepatitis B surface, HBsAg hepatitis B surface antigen, HBV hepatitis B virus, HBx hepatitis B x protein, HSC hepatic stellate cell, IFNβ interferon-β, IL6 interleukin-6, KC Kuppfer cell, LSEC liver sinusoidal endothelial cells, mRNA messenger RNA, NTCP sodium taurocholate co-transporting polypeptide, pgRNA pregenomic RNA, Pol polymerase, RC DNA relaxed circular DNA, TGFβ transforming growth factor-β, MVB multivesicular bodies, SVP subviral envelope particles