Drug development for chronic hepatitis B functional cure: Recent progress

Table 1 Current available drugs for the treatment of chronic hepatitis B

Types of drugs	Name	Antiviral mechanism	Limitations/comments
Immunomodulators	IFN-2α and PEG-IFN-2α	Inhibit HBV replication Activate antiviral immune responses	Poor tolerability; Anti-PEG antibody mediated immune clearance[4]
Nucleoside analogue	ETV	HBV DNA polymerase inhibitor	High potency and low resistance
Nucleotide analogue	TDF	HBV DNA polymerase inhibitor	Potent, but with kidney and bone toxicity concern in long-term use
Nucleotide analogue	TAF	HBV DNA polymerase inhibitor	TDF analog with improved renal and bone safety profiles
Nucleotide analogue	ADV	HBV DNA polymerase inhibitor	Less potent, nephrotoxicity
Nucleoside analogue	3TC	HBV DNA polymerase inhibitor	Less potent, high rate of resistance
Nucleoside analogue	LdT	HBV DNA polymerase inhibitor	High rate of resistance

HBV: Hepatitis B virus; ETV: Entecavir; TAF: Tenofovir alafenamide; ADV: Adefovir dipivoxil; 3TC: Lamivudine; LdT: Telbivudine; TDF: Tenofovir disoproxil fumarate; IFN-2α: Interferon alpha-2α; PEG-IFN-2α: Pegylated IFN-2α.

Table 2 Current investigational drugs for the treatment of chronic hepatitis B

Types of drugs	Mechanism of action	Representative drugs	Global clinical R&D phase	Efficacy
HBV entry inhibitors	Acts on NTCP to inhibit virus entry into cells	Bulevirtide	Clinical phase II	Profound HDV RNA reduction but minimal HBsAg reduction
HBV monoclonal antibodies	Binding to HBV virus indicates that HBsAg binds and neutralizes the virus	Lenvervimab	Clinical phase II	HBsAg decreased after each administration but rebounded rapidly; 6 out of 27 patients had HBsAg loss when combined with siRNA and IFN-α
		Tobevibart (VIR-3434)	Clinical phase II
		HH-003	Clinical phase II	N/A on HBsAg loss rate; Efficacious against HDV
		BJT-778	Clinical phase II	N/A for HBsAg loss rate; Efficacious against HDV
RNA interference (siRNA)	Small interfering RNA targeted degradation of HBV mRNA	Daplusiran + tomligisiran (JNJ-3989)	Clinical phase II	Mean HBsAg reduction of 1.89 Log10 IU/mL after a 48-week therapy
		Elebsiran (VIR-2218)	Clinical phase II	11 out of 69 patients had HBsAg loss after different regimens of VIR-2218 plus IFN-α
		Imdusiran (AB-729)	Clinical phase II	4 out of 12 patients had HBsAg loss after 48 weeks Imdusiran plus 24 weeks IFN-α and ongoing nucleos(t)ide analogs
		RBD1016	Clinical phase I	HBsAg decline of 1.26 Log10 IU/mL by week 12 after two 3 mg/kg dosing
		Xalnesiran (RG6346)	Clinical phase II	30% HBsAg loss by Xalnesiran 200 mg and IFN-α combination at the end of 48-week treatment
RNA interference (ASO)	Targeted degradation of HBV mRNA by antisense oligonucleotides	Bepirovirsen	Clinical phase III	9%-10% patients had HBsAg loss after 300 mg weekly for 24 weeks
		AHB-137	Clinical phase II	62% patients had HBsAg loss after 12-week 300 mg dosing (interim results)
Inhibitor of capsid assembly	By affecting nucleocapsid formation, it reduces virus formation and cccDNA internal recruitment	JNJ-6379	Clinical phase I	HBV DNA reduction after a 28-day therapy, no HBsAg loss
		Morphothiadine (GLS4)	Clinical phase III	HBV DNA and RNA suppression. HBsAg decline but no HBsAg loss
		Canocapavir	Clinical phase II	HBV DNA and pregenomic RNA reduction after a 28-day therapy
		EDP-514	Clinical phase I	HBV DNA and RNA reduction in treatment-naïve and viral suppressed patients after a 28-day therapy
		ALG-000184	Clinical phase I	HBV DNA and RNA reduction, and modest HBsAg reduction after a 28-day monotherapy or ETV combination
HBsAg secretion inhibitors	Nucleic acid polymers interfere with the release of subviral particles by interacting with chaperone proteins, such as DNAJB12, and increase the intracellular degradation of subviral particles	REP 2139	Clinical phase II	14 of 40 patients had HBsAg loss after 48 weeks of combination therapy with TDF and peg-IFN
		REP 2165	Clinical phase II	14 of 40 patients had HBsAg loss after 48 weeks of combination therapy with TDF and peg-IFN
Direct-acting cccDNA drugs	Gene editing technology was used to knock out cccDNA	PBGENE-HBV	Clinical phase I	Reduction in HBsAg in 2 out of 3 patients after the first administration at 0.2 mg/kg dose
TLR-7 agonist	TLR-7 is activated to activate innate immune cells	Vesatolimod (GS-9620)	Clinical phase II	No patient has HBsAg loss after 12-week therapy with TDF combination
		TQ-A3334	Clinical phase II	N/A
TLR-8 agonist	TLR-8 is activated to activate innate immune cells	Selgantolimod	Clinical phase II	2 out of 39 achieved HBsAg loss after 24-week therapy
		HRS9950	Clinical phase II	N/A
		TQA3810	Clinical phase II	N/A
Immune checkpoint inhibitors	Anti-PD-1 antibody, by inhibiting PD-1, activates immune cells	Nivolumab	Clinical phase II	1 out of 12 patients had HBsAg loss after 12-week therapy
		Serplulimab	Clinical phase II	N/A
		Sintilimab	Clinical phase I	N/A
	Anti-PD-L1 antibody, by inhibiting PD-L1, activates immune cells	Envafolimab	Clinical phase II	3 out of 33 patients had HBsAg loss after 24-wekk therapy
Therapeutic vaccines	Enhanced T- and B-cell immunity	VBI-2601 (BRII-179)	Clinical phase II	A 9 doses regimen with HBV siRNA induced anti-HBs antibody (16/40) but no HBsAg loss
		VVX001	Clinical phase II	N/A
		CVI-HBV-002	Clinical phase II	2 out 18 patients had HBsAg loss after ChAdOx1-HBV on Day 0 and MVA-HBV on Day 28 (VTP-300)

HBV: Hepatitis B virus; HBsAg: Hepatitis B surface antigen; siRNA: Small interfering RNA; mRNA: Messenger RNA; ASO: Antisense oligonucleotide; TDF: Tenofovir disoproxil fumarate; IFN-2α: Interferon alpha-2α; PEG-IFN-2α: Pegylated IFN-2α; cccDNA: Covalently closed circular DNA; HDV: Hepatitis delta virus.