Table 2.
New hepatitis B virus treatment modalities and clinical trial phases
|
Class
|
Drug name
|
Mechanism
|
| HBV entry inhibitors | Hepcludex (Bulevirtid, formerly known as Myrcludex B) | Block HBV binding to NTCP receptor; clinical trial phase II |
| Betulin derivatives and cyclosporin derivatives | ||
| IFN-α, γ | Decreases cccDNA transcription via epigenetic modifications | |
| ZFNs | Site-specific cleavage of DNA creates DSBs to target the viral cccDNA; Pre-clinical phase | |
| Agents targeting cccDNA | TALENs | |
| CRISPR and CRISPR-Cas9 as EBT106 HBV CRISPR Cas9 lipid nanoparticle | Target and reduce the viral cccDNA reservoir; destroy the intrahepatic HBV genome and reduce HBsAg levels; reduction of intracellular pgRNA; preclinical phase | |
| Arginine methyltransferase 5 (PRMT5) | Restriction of HBV transcription and replication through cccDNA transcription suppression and pgRNA encapsidation inhibition | |
| Targeting HBx | SMC5/6 complex | Block all HBV mRNA transcription except HBx mRNA transcription |
| Nitazoxanide | Restore SMC5/6 protein levels and block HBV transcription by inhibiting the HBx-DDB1 binding; clinical trial phase II | |
| CRV-431 | Pan-cyclophilin inhibitor that inhibits liver HBV DNA and HBsAg; clinical trial phase I | |
| Agents targeting viral transcripts | ASO: IONIS-HBVRx (GSK3228836) IONIS-HBVLRx (GSK33389404) RG6004 RO7062931 | HBV RNA degradation, inhibit the expression of the corresponding gene, and bind viral mRNA to prevent viral protein production; clinical trial phase II |
| siRNAs: AB-729, ARB-1467, ARB-1740, Lunar-HB Vir-2218 (also known as ALN HBV02), JNJ-3989 (ARO-HBV), RG6346 (DCR-HBVS), GSK3228836 (IONIS-HBVRx), and Hepbarna (BB-HB-331) | HBV RNA degradation and reduce viremia, antigenemia, core, and HBx protein inside the hepatocyte; clinical trial phase I and II | |
| asRNA agent | Block HBV translation; clinical trial phase II | |
| Capsid assembly modulators (core protein assembly modulators) | HAPS as Morphothiadin (GLS4) | Core protein binding that inhibits encapsidation of pgRNA or nucleocapsid assembly, to an extent that the HBV pgRNA could not enter inside the capsid resulting in morphologically normal capsids with no nucleic acid content and therefore the virus will be noninfectious; clinical trial phase I and II |
| Phenylpropenamides derivatives as 3711, AT-61, and AT-130 | ||
| Sulfamoylbenzamide derivatives as AB-423, AB 506, JNJ-6379, JNJ-0440, NVR 3-778 | ||
| Morphothiadin, JNJ 56136379, and ABI-H0731 | Core protein binding led to a significant decrease in HBV DNA, but with smaller reductions of HBV RNA and HBsAg; clinical trial phase II | |
| RO7049389, ABI-H2158, GLS4JHS, ABI-H0731, ABI-H3733, RG7907, QL-007, EDP-514, CB-HBV-001 | Core protein binding; clinical trial phase I and II | |
| Targeting HBsAg | DNA based NAPs (REP-2055 and REP- 2031) or RNA-based NAPs (REP-2139 and REP-2165) | Block HBsAg release and improve the HBV-specific immune response; clinical trial phase II |
| NAPs: REP 301, REP 301-LFT and REP 401 | Functional cure in the form of undetectable HBV DNA and HBV RNA, decrease HBsAg and HBcrAg, normalize ALT levels, and detect anti-HBsAg; clinical trial phase II | |
| STOPS | Disrupt HBsAg secretion, ALG-010133; further development of this compound has been discontinued | |
| mAb against HBsAg, mAb E6F6A, and VIR-3434 | Overcome persistent HBV replication; clinical trial phase I and II | |
| E6F6 immunotherapy | Restore anti-HBV T cell response; clinical trial phase II | |
| GC1102 mAb and HBIg | Anti-HBs (against HBsAg) and boost humoral immunity; clinical trial phase II | |
| Apoptosis inducer as APG-1387 and Cyclophilin Inhibitor as CRV 431 (CPI 431-32) | Target host pathways; clinical trial phase II | |
| Immune modulators | ||
| -Therapeutic vaccination | GS-4774 | Enhance antiviral cytokine production by HBV-specific T cells as CD8+ cells; clinical trial phase III |
| DNA vaccines as INO-1800, HB-110, and JNJ-64300535 | Encode HBsAg, HBcAg, and polymerase proteins; clinical trial phase I | |
| NASVAC, Sci-B-Vac derivative BRII-179, and HepTcell | T cell vaccines; clinical trial phase I and II | |
| TG1050/T101 and TomegaVax HBV | Non-replicative adenovirus serotype 5 encode three HBV proteins; clinical trial phase II | |
| ChAdOx1 HBV | Adjuvanted ChAd and MVA vector; clinical trial phase I | |
| AIC 649 | iPPVO nonspecific vaccine; clinical trial phase I | |
| ABX-203 | Contain both HBsAg and HBcAg; clinical trial phase I | |
| -Checkpoint inhibitors | Tim-3, CTLA-4 (anti-CTLA-4), Nivolumab, ASC22 (KN035), and Cemiplimab (REGN2810) | Anti-PD-1/anti-PD-L1 antibodies that restore virus-specific CD8+ T cell responses that boost adaptive immunity; clinical trial phase I and II |
| -Genetically engineered T cells | cTCR with anti-HBs antibody or HBV specific T cell receptor gene | Recognize HBV-infected cells carrying HBV proteins on their surfaces resulting in disappearance of HBV-infected cells and decreasing cccDNA; Pre-clinical trial |
| LTCR-H2-1 and CAR-T cells | LTCR-H2-1 targets TCR gene transfer, which boosts adaptive immunity; Preclinical trial | |
| -Pathogen recognition receptors | Vesatolimod (GS-9620), RO7020531 (RG7854), RO6864018 (RG7795), ANA773, and JNJ-4964 (AL-034/TQ-A3334) | TLR-7 agonists activate intrahepatic dendritic cells, NK cells, and mucosal-associated invariant T cells and trigger the production of type I and II IFNs causing inhibition of HBV replication and boost innate immunity; clinical trial phase I and II |
| Selgantolimod (GS-9688) | TLR-8 agonists activate intrahepatic dendritic cells, NK cells, and mucosal-associated invariant T cells and enhance the production of antiviral cytokines (IL-12/IL-18) and boost innate immunity; clinical trial phase II | |
| STING agonist and RIG-I and NOD2 agonist as Inarigivir (SB9200) | Induce production of IFN-stimulated genes and proinflammatory cytokines that can cytopathically or noncytopathically clear virus, inhibit HBV replication, and boost innate immunity; clinical trial phase II | |
| -Other immune approaches | IMC-I109V | Immune mobilizing monoclonal T cell receptors against the virus; clinical trial phase I |
ALT: Alanine aminotransferase; ASO: Antisense oligonucleotides; asRNA: Antisense RNA; CAR: Chimeric antigen receptor; cccDNA: Covalently closed circular DNA; CRISPR: Clustered regularly interspaced short palindromic repeats; CRISPR-Cas9: CRISPR-associated protein nine nuclease; cTCR: Chimeric T-cell receptor; CTLA-4: Cytotoxic T-lymphocyte associated protein 4; PDSBs: Double stranded breaks; HAPS: Heteroaryldihydropyrimidines; HBcAg: Hepatitis B core antigen; HBcrAg: Hepatitis B core-related antigen; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; HBx: Hepatitis B virus X protein; IFN-α: Interferon-alpha; IL: Interleukin; iPPVO: Inactivated parapoxvirus; mAb: Monoclonal antibody; NAPs: Nucleic acid polymers; NK: Natural killer; NOD2: Nucleotide-binding oligomerization domain-containing protein 2; NTCP: Sodium taurocholate cotransporting polypeptide; PD-1: Programmed cell death protein 1; PD-L1: Programmed death ligand 1; pgRNA: Pre-genomic RNA; PRMT5: Protein arginine methyltransferase 5; RIG-I: Cytosolic retinoic acid inducible gene I; siRNAs: Small interfering RNAs; SMC5/6: structural maintenance of chromosomes protein 5 and 6; STING: Stimulator of interferon genes; STOPS: S-antigen transport-inhibiting oligonucleotide polymers; TALENs: Transcription activator-like effector nucleases; Tim3: T cell immunoglobulin and mucin containing 3; TLR: Toll-like receptor; ZFNs: Zinc finger nucleases.