Chronic hepatitis B: New potential therapeutic drugs target

Table 1 Developing new therapeutic drug targets for chronic hepatitis B

Drugs	Mechanism of action	Therapeutic class	Route of administration	Clinical trial	Results
HBV entry inhibitors
Bulevirtide (Myrcludex B)[49]	Competition with NTCP	Peptide	Subcutaneous injection	IIb	HBsAg loss in 27% of HBV/HDV co-infected patients after 48 wk of treatment with Bulevirtide + pegIFN-α and 24 wk treatment-free follow-up
cccDNA disruptors
CRISPR/Cas9[67]	Disruption of cccDNA	Gene editing	In vivo	Pre-clinical	Significantly improved survival of human hepatocytes in liver-humanized FRG mice and demonstrated a decreasing of total liver HBV-DNA and cccDNA
ZFNs[69]	Disruption of cccDNA	Gene editing	In vitro	Pre-clinical	Efficiently suppress the cellular template for HBV persistence and inhibit active HBV replication
Nucleocapsid assembly modulators
JNJ-632 and BAY41-4109[73]	Misdirecting the formation of capsid-like structures	Capsid assembly modulators	In vitro	Pre-clinical	Induce the formation of morphologically intact viral capsids and prevented formation of cccDNA
NVR3-778[78]	Misdirecting the formation of capsid-like structures	Capsid assembly modulator	In vivo	I/II	The largest mean reduction in serum HBV DNA levels was achieved from the combination treatment of 600 mg NVR3-778 BD + pegIFN 180 mg subcutaneous weekly (1.97 log10 IU/mL)
JNJ-6379[76]	Misdirecting the formation of capsid-like structures	Capsid assembly modulators	Oral	II	No clinically significant changes in levels of HBsAg were observed
ABI-H0731[77]	Misdirecting the formation of capsid-like structures	Capsid assembly modulators	Oral	I/II	Dose-dependent reduces in HBV DNA and HBV RNA not HBsAg was seen in both HBeAg-positive and HBeAg-negative patients
HBV transcription inhibitors
ARC-520[84]	Interference viral mRNA	Transcription inhibitor	Intravenous injection	II	CHB patients with high dose significantly reduced HBsAg and persisted for > 85 d after the last dose
GSK3389404[85]	Interference viral mRNA	Transcription inhibitor	Subcutaneous injection	I	Dose 120 mg for 4 wk was safe and well tolerate
RG7834[87]	Interference viral mRNA	Gene expression inhibitor	In vivo	Pre-clinical	Reduced WHsAg by a mean of 2.57 log10 and WHV DNA by a mean of 1.71 log10 from baseline. However, WHsAg and WHV DNA rebounded to baseline after stopped treatment and WHsAb was not observed.
HBsAg release inhibitors
REP 2055 and REP 2139-Ca[88]	HBsAg release inhibitors	NAPs	Intravenous injection	II	Substantially reduction of HBsAg levels, HBV DNA levels and increasing of serum HBsAb
REP 2139-Mg and REP 2165-Mg[90]	HBsAg release inhibitors	NAPs	Intravenous injection	II	Addition of NAPs to TDF + pegINFα-2a significantly increased rates of HBsAg loss during therapy and functional cure after therapy

cccDNA: Covalently closed circular DNA; CHB: Chronic hepatitis B; CRISPR/Cas9: Clustered regularly interspaced short palindromic repeats/CRISPR-associated 9; HBsAb: Hepatitis B surface antibody; HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; HDV: Hepatitis D virus; NAPs: Nucleic acid polymers; NTCP: Sodium taurocholate co-transporting polypeptide; pegIFN-α: Pegylated interferon-alpha; TDF: Tenofovir disoproxil fumarate; WHsAb: Woodchuck hepatitis surface antibody; WHsAg: Woodchuck hepatitis surface antigen; WHV: Woodchuck hepatitis virus.