Toward a new era of hepatitis B virus therapeutics: The pursuit of a functional cure

Table 1 Direct-acting antivirals in the pipeline for chronic hepatitis B virus infection

	Compound	Class and action	Phase of development	Ref. or trial number
Entry Inhibitors	HBIG	Polyclonal antibodies neutralizing HBsAg	Available	Herrscher et al[29]
	GC1102	Monoclonal antibody neutralizing HBsAg	Phase II	NCT03801798
	HzKR359-1, HzKR127-3.2	Anti-preS1 monoclonal antibodies	Preclinical	Wi et al[30]
	Heparin, Suramin	Inhibition of HBV-HSPGs interaction	Preclinical	Herrscher et al[29] and Petcu et al[33]
	SALPs	Inhibition of HBV-HSPGs interaction	Preclinical	Krepstakies et al[32]
	PAC and analogs	Anti-preS1 oligomeric flavonoid analogs	Preclinical	Tsukuda et al[35]
	Conjugated bile acids (TCA, UDCA, TUDCA)	NTCP inhibitors	Preclinical	Yan et al[36]
	Ezetimibe, Irbesartan	NTCP inhibitors	Available	Lucifora et al[37] and Ko et al[38]
	Cyclosporine A analogs (SCY450, SCY995)	NTCP inhibitors	Preclinical	Watashi et al[39] and Shimura et al[40]
	Bulevirtide(Myrcludex B)	NTCP inhibitor	Phase III	Wedemeyer et al[41]
TargetingcccDNA	Interferons, TNF-α, Lymphotoxin-β receptor agonists	cccDNA degradation	Available	Bockmann et al[44] and Xia et al[45]
	ccc-R08	cccDNA destabilizer	Preclinical	Wang et al[46]
	Zinc finger nucleases	Gene editing technology	Preclinical	Cradick et al[47]
	TALENs	Gene editing technology	Preclinical	Chen et al[49]
	CRISPR‐associated (Cas) nucleases	Gene editing technology	Preclinical	Ramanan et al[48], Seeger and Sohn[50], and Martinez et al[51]
	C646	CBP and p300 inhibitorEpigenetic silencing	Preclinical	Cougot et al[54]
	GS-5801	Lysine demethylase 5 inhibitorEpigenetic silencing	Phase I	Gilmore et al[55]
	EYP001	FXR agonist	Phase II	Erken et al[56]
TargetingHBx	Nitazoxide	HBx-DDB1 interaction inhibitor	Phase II	Sekiba et al[58], Rossignol and Bréchot[59]
	Pevonedistat	NEDD8-activating enzyme inhibitor	Preclinical	Sekiba et al[60]
	AGK2	SIRT-2 inhibitor	Preclinical	Yu et al[61]
	CRV431	Cyclophilin inhibitor	Phase I	NCT03596697
RNA interference	JNJ-3989	siRNA	Phase II	Gane et al[66]
	VIR-2218 (or ALN-HBV)	siRNA	Phase II	Gane et al[67]
	ARB-1467	siRNA	Phase II	Streinu-Cerce et al[68]
	ARB-1740	siRNA	Phase I	Thi et al[191]
	AB-729	siRNA	Phase I	Yuen et al[69]
	RG6346 (or DCR-HBVS)	siRNA	Phase II	Yuen et al[70]
	GSK3228836, GSK33389404	ASOs	Phase II	Han et al[71] and Yuen et al[72]
	ALG-020572, ALG-020576	ASOs	Preclinical	Hong et al[74]
	RO7062931 (or RG6004)	Antisense LNA	Phase I	Yuen et al[75]
	Gapmers	Antisense LNA	Preclinical	Cortese et al[76]
	RG7834	RNA destabilizer	Preclinical	Mueller et al[77] and Zhou et al[78]
Core protein allosteric modulators (CpAMs)	RO7049389 (or RG7907)	Class I CpAM (HAP derivative)	Phase II	Gane et al[82]
	GLS4 (or morphothiadine)	Class I CpAM (HAP derivative)	Phase II	Zhao et al[83]
	KL060332	Class I CpAM (HAP derivative)	Phase I	Tai et al[84]
	NVR3-778	Class II CpAM (SBA derivative)	Phase I	Yuen et al[85]
	JNJ-6379	Class II CpAM (SBA derivative)	Phase II	Berke et al[86] and Janssen et al[87]
	AB-423	Class II CpAM (SBA derivative)	Phase I	Mani et al[192]
	EDP-514	Class II CpAM	Phase I	NCT04470388
	ABI-H0731	CpAM	Phase II	Fung et al[88] and Yuen et al[89]
	ABI-H2158	CpAM	Phase II	Agarwal et al[90]
	ABI-H3733	CpAM	Phase I	NCT04271592
	QL-007	CpAM	Phase I	NCT03770624
	ZM-H1505R	CpAM (Pyrazole derivative)	Phase I	NCT04220801
	ALG-001075, ALG-000184	Class II CpAMs	Preclinical	Zhang et al[193]
	GLP-26	Class II CpAM (SBA derivative)	Preclinical	Amblard et al[194]
	AT-61, AT-130	Class II CpAMs (PPA derivatives)	Preclinical	Delaney et al[195]
	Phthalazinone derivatives	CpAMs	Preclinical	Chen et al[196]
HBsAg inhibitors	REP 2139, REP 2156	NAPsSVP release inhibitors	Phase II	Bazinet et al[95]
	ALG-010133	STOPS	Phase I	Nie et al[94] and Gohil et al[96]

ASOs: Antisense oligonucleotides; CBP: CREB binding protein; cccDNA: Covalently closed circular DNA; CpAM: Core protein allosteric modulators; DDB1: DNA damage-binding protein 1; FXR: Farnesoid X receptor; HAP: Heteroaryldihydropyrimidine; HBIG: Hepatitis B immunoglobulin; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; HBx: Hepatitis B virus X protein; HSPGs: Heparan sulfate proteoglycans; LNA: Locked nucleic acid; NEDD8: Neural precursor cell expressed, developmentally downregulated-regulated 8; NTCP: Na+ - taurocholate cotransporting polypeptide; PAC: Proanthocyanidins; PPA: Phenylpropenamide; SALPs: Synthetic anti-lipopolysaccharide peptides; SBA: Sulfamoylbenzamide; siRNA: Small interfering RNA; SIRT-2: Sirtuin 2; STOPS: S-antigen transport inhibitory oligonucleotide polymers; SVP: Subviral particles; TALENs: Transcription activator-like effector nucleases; TCA: Taurocholic acid; TUDCA: Tauroursodeoxycholic acid; UDCA: Ursodeoxycholic acid.

Table 2 Candidate immunotherapies for chronic hepatitis B virus infection

	Compound	Class and action	Phase of development	Ref. or trial number
TLR agonists	GS-9620 (or Vesatolimod)	TLR-7 agonist	Phase II	Janssen et al[112] and Boni et al[113]
	RO7020531 (RG7854)	TLR-7 agonist	Phase II	Luk et al[116]
	JNJ-64794964	TLR-7 agonist	Phase I	Wu et al[117]
	APR002	TLR-7 agonist	Preclinical	Korolowizc et al[115]
	T7-EA	TLR-7 agonist	Preclinical	Hu et al[118]
	GS-9688 (or Selgantolimod)	TLR-8 agonist	Phase II	Mackman et al[121] and Janssen et al[122]
	ImmunoTAC™	ASGR1-TLR8 agonist conjugate	Preclinical	Baum et al[123]
RIG-I, NOD agonists	SB9200 (or Inarigivir)	RIG-I/NOD-2 agonist	Phase II	Yuen et al[129]
STING agonists	DMXAA (or Vadimezan or ASA404)	STING agonist	Preclinical	Guo et al[132]
T-cell engineering	TCR-engineered T cells	TCR-specific for MHC-I restricted HBV epitopes	Phase I	NCT03899415 NCT02719782 NCT02686372
	S-CAR engineered T cells	CAR targeting envelope proteins	Preclinical	Festag et al[145]
	IMC-I109V	ImmTAV targeting HLA-A restricted HBV epitopes	Phase II	EudraCT2019-004212-64
	ImmTAV-HLA-E	ImmTAV targeting HBV epitopes presented by HLA-E	Preclinical	Leonard et al[151]
Immune checkpoint inhibitors	Nivolumab	Monoclonal antibodyPD-1 inhibitor	Phase Ib	Gane et al[155]
	ASC22 (Envafolimab)	Monoclonal antibodyPD-L1 inhibitor	Phase II	NCT04465890
	HSV-1 glycoprotein D (gD)	BTLA-HVEM pathway inhibitor	Preclinical	Hasanpourghadi et al[158]
	APG-1387	IAP antagonist	Phase II	Zhang et al[159]
Vaccines	INO-1800	DNA vaccine	Phase I	NCT02431312
	HB110	DNA vaccine	Phase I	Yoon et al[164]
	JNJ-64300535	DNA vaccine	Phase I	NCT03463369
	AIC649	Viral vector vaccine (iPPVO)	Phase I	Addy et al[167]
	TG1050	Viral vector vaccine (Ad5)	Phase Ib	Zoulim et al[168]
	VTP-300	Viral vector vaccine (ChAdOx1)	Phase I	Vaccitech[169]
	HepTcell	T cell vaccine	Phase II	Lim et al[171] and Altimmune[172]
	GS-4774	Yeast-based, T-cell vaccine	Phase II	Boni et al[173]
	Chimigen® HBV (C-HBV)	Immune complex vaccine	Preclinical	Ma et al[177]
	YIC (HBsAg-HBIG)	Vaccine based on yeast-derived immune complexes	Phase II	Zhou et al[178] and Xu et al[179]
	ABX-203 (or Nasvac)	HBsAg and HBcAg	Phase III	Al Mahtab et al[183] and Yoshida et al[184]
	VBI-2601 (or BRII-179)	eVLP-based vaccine	Phase II	ACTRN-12619001210167
	NP-preS1	Nanoparticle-based vaccine	Preclinical	Wang et al[190]

Ad5: Adenovirus serotype 5; ASGR1: Asialoglycoprotein receptor 1; BTLA-HVEM: B and T lymphocyte attenuator/herpes virus entry mediator; CAR: Chimeric antigen receptor; ChAdOx1: Chimpanzee adenovirus Oxford 1; eVLP: enveloped virus-like particle; HBcAg: Hepatitis B core antigen; HBsAg: Hepatitis B surface antigen ; HBV: Hepatitis B Virus; HLA: Human leukocyte antigen; HSV: Herpes simplex virus; IAP: Inhibitors of apoptosis protein; ImmTAV: Immunomobilizing monoclonal T cell receptors against virus; iPPVO: Inactivated Parapoxvirus ovis; MHC: Major histocompatibility complex; NOD: Nucleotide-binding and oligomerization domain; PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; RIG-I: Retinoic acid-inducible gene I; STING: Stimulator of IFN genes; TCR: T cell receptor; YIC: Yeast-derived immune complexes