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Table 1. New HBV Therapeutics Not Acting Through HBV Polymerase Inhibition Undergoing Clinical Trials in Humans
Target Name Compounds Sponsor Stage of Development Reference
Viral antigen HBV mRNA ARC‐520 siRNA Arrowhead Pharmaceuticals Phase 2
NCT02065336
NCT02604212
ARB‐1467 siRNA Arbutus Biopharma Phase 2a NCT02631096
GSK 3228836 Antisense oligonucleotide GlaxoSmithKline Phase 1 Company Web site
RO7020322 Small‐molecule viral expression inhibitor Roche Phase 1 NCT02604355
Nucleocapsid assembly NVR 3‐778 HBV core inhibitor Johnson & Johnson Phase 1b
NCT02112799
NCT02401737
JNJ379 Capsid assembly modulator Johnson & Johnson Phase 1 NCT02662712
GLS4 (Morphothiadin) HAPs HEC Pharm Phase 2 Company Web site
HBV entry Myrcludex‐B HBV pre‐S1‐derived lipopeptide affecting NTCP Hepatera Phase 2 Company Web site
HBsAg release REP 2139 Phosphorothioated oligonucleotides Replicor Inc. Phase 2
NCT02646189
NCT02565719
GC 1102 Recombinant hepatitis B human immunoglobulin that neutralizes HBsAg Green Cross Corporation Phase 2 NCT02304315
Immune modulation Therapeutic vaccine GS‐4774 Recombinant antigen containing X, Env, Core epitopes Gilead Phase 2
NCT01943799
NCT02174276
ABX‐203 Recombinant antigen containing HBsAg and HBcAg Abivax Phase 2 NCT02249988
TG‐1050 Nonreplicative adenovirus encoding a large fusion protein (truncated Core, modified Pol, and t wo Env domains) Transgene Phase 1 NCT02428400
INO‐1800 DNA plasmids encoding HBsAg and HBcAg Inovio Phase 1 NCT02431312
FP‐02.2 (HepTCell) Peptide encoding CD4+ and CD8+ epitopes Altimmune Phase 1 NCT02496897
pDC stimulation GS‐9620 Oral TLR7 agonist Gilead Phase 2
NCT02166047
NCT02579382
Immune stimulation SB‐9200 Small molecular nucleic acid hybrid activating RIG‐I and NOD2 pathways Spring Bank Pharmaceuticals Phase 2 NCT02751996
AIC649 Proprietary inactivated parapox virus AiCuris Phase 1 Company Web site
Apoptosis protein cellular inhibitor Birinapant SMAC inhibitor Tetralogic Phase 1 NCT02288208
Abbreviations: HAPs, heteroaryldihydropyrimidine; HBcAg, hepatitis B core antigen; NOD, nucleotide‐binding oligomerization domain; RIG‐I, retinoic acid‐inducible gene‐I; SMAC, second mitochondria‐derived activator of caspases.
Figure 1
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The HBV life cycle and therapeutics currently undergoing clinical trials in humans.
Targeting HBV Messenger RNA Transcription
One promising antiviral target is viral messenger RNA (mRNA) transcription. Chronic HBV infection is characterized by excess HBsAg‐containing subviral particle production. The continued exposure of T cells to viral antigens results in the functional T cell impairment of immune response commonly seen in HBV infection. If viral mRNA transcription were controlled, this will lead to a profound reduction in viral antigens, followed by host immune reconstitution, HBsAg seroclearance, and finally a functional cure.3 This whole action can be augmented with the simultaneous suppression of viral replication via nucleos(t)ide therapy, which indirectly controls cccDNA amplification. One such example is ARC‐520, which is a small interfering RNA (siRNA) that can be successfully delivered to the cytosol of hepatocytes. Viral RNAs contain overlapping sequences, and a single RNA interference can theoretically suppress all related viral protein production. A phase 2a study involving one to two doses of intravenous ARC‐520, when in combination with entecavir, resulted in a profound and durable reduction of viral antigens (Fig. 2).4 Other siRNAs (e.g., ARB‐1467) and other viral mRNA inhibitors achieving satisfactory suppression of HBV viral antigens in preclinical studies are also entering clinical development (Table 1).5
Figure 2
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Reduction in serum HBsAg levels after one dose of ARC‐520 in treatment‐naive chronic hepatitis B patients.4 Entecavir was also given in combination. Reproduced with permission from Arrowhead Pharmaceuticals. |
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发表于 2018-9-20 19:42
