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.