药学学报

Drug	Company	Study type	Study result	Adverse event	NCT
Myrcludex B (bulevirtide)	Hepateral Ltd.	Phase II, multi-center, open-label, randomized clinical study to assess efficacy and safety of myrcludex B (2, 5, 10 mg) safety in combination with tenofovir compared to tenofovir alone in patients with chronic hepatitis D	HDV RNA negativation or decrease were observed in patients receiving myrcludex B and tenofovir. Hepatic cirrhosis was improved in receiving myrcludex B 5 mg or 10 mg	Blood and lymphatic system disorders, total bile acids increase, and ALT increase	03546621
Phase II, randomized, open-label substudy of daily myrcludex B plus PEG-IFNα-2a in patients with HBeAg negative chronic HBV co-infected with HDV	All chronically infected patients experienced reductions in serum HDV RNA level	Blood and lymphatic system disorders, AST and ALT increase, and influenza like illness	02637999
Phase II, randomized, comparative, parallel-arm study to assess efficacy and safety of myrcludex B in combination with PEG-IFNα-2a versus PEG-IFNα-2a alone in CHB patients	HBsAg levels reduction was observed in patients receiving myrcludex B in combination with PEG-IFNα-2a. No significative decrease in HBV DNA levels	Neutripenia, influenza like illness, thrombocytopenia, and total bile acids increase	02888106

Drug	Company	Study type	Study result	Adverse event	NCT
Myrcludex B (bulevirtide)	Hepateral Ltd.	Phase II, multi-center, open-label, randomized clinical study to assess efficacy and safety of myrcludex B (2, 5, 10 mg) safety in combination with tenofovir compared to tenofovir alone in patients with chronic hepatitis D	HDV RNA negativation or decrease were observed in patients receiving myrcludex B and tenofovir. Hepatic cirrhosis was improved in receiving myrcludex B 5 mg or 10 mg	Blood and lymphatic system disorders, total bile acids increase, and ALT increase	03546621
Phase II, randomized, open-label substudy of daily myrcludex B plus PEG-IFNα-2a in patients with HBeAg negative chronic HBV co-infected with HDV	All chronically infected patients experienced reductions in serum HDV RNA level	Blood and lymphatic system disorders, AST and ALT increase, and influenza like illness	02637999
Phase II, randomized, comparative, parallel-arm study to assess efficacy and safety of myrcludex B in combination with PEG-IFNα-2a versus PEG-IFNα-2a alone in CHB patients	HBsAg levels reduction was observed in patients receiving myrcludex B in combination with PEG-IFNα-2a. No significative decrease in HBV DNA levels	Neutripenia, influenza like illness, thrombocytopenia, and total bile acids increase	02888106

Drug	Company	Study type	Study result	Adverse event	NCT
GLS4	Sunshine Lake Pharma Co., Ltd.	Phase I, single-center, open label clinical study to evaluate the pharmacokinetic character of GLS4 combined with RTV or TAF alone or GLS4 and RTV and TAF combination administration in healthy subjects	HBV DNA levels were decreased by -1.42 log10 IU·mL^-1, -2.13 log10 IU·mL^-1 and -3.5 log10 IU·mL^-1 respectively for 28 days	AST and ALT elevation	04551261
Phase II clinical study to evaluate the safety, tolerability, and antiviral activity of GLS4 with RTV in combination with ETV in comparison with ETV alone in CHB patients	The antiviral efficacy of combination therapy of GLS4/RTV with ETV was remarkably superior to ETV alone	ALT elevation and hypertriglyceridemia	04147208
RO7049389	Hoffmann-La Roche	Phase I clinical study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of RO7049389 in healthy volunteers and CHB participants	RO7049389 was safe and well tolerated and demonstrated antiviral activity over 4 weeks in CHB patients	Headache, diarrhoea, upper respiratory tract infection, ALT elevation, and AST elevation	02952924
ZM-H1505R	Shanghai Zhimeng Biopharma, Inc.	Phase I, randomized, double-blind, placebo-controlled study following oral administration in healthy subjects to evaluate the safety, tolerability, and pharmacokinetics of ZM-H1505R	Multiple doses of up to 300 mg of ZM-H1505R were safe and well tolerated in healthy subjects	Gastrointestinal disorders	04220801
ALG-000184	Aligos Therapeutics	Phase I, double-blind, randomized, placebo-controlled study to evaluate safety, tolerability, pharmacokinetics and pharmacodynamic in healthy volunteers and CHB patients	ALG-000184 was safe, well tolerated and with no food effect, at single oral doses up to 500 mg in healthy volunteers	ALT elevation	04536337
JNJ-64530440 (JNJ-0440)	Alios Biopharma Inc.	Phase I, double-blind, randomized, placebo-controlled study of orally administered JNJ-0440 to evaluate the safety, tolerability, and pharmacokinetics after single ascending doses in healthy subjects and CHB subjects	JNJ-0440 750 mg once-daily or twice-daily for 28 days was well tolerated and achieved anti-HBV activity in CHB patients	ALT increase, blood potassium increase, neutrophil count decrease, and headache	03439488
ABI-H0731 (vebicorvir)	Assembly Biosciences	Phase IIa, multi-center, double-blind, placebo-controlled study to evaluate ABI-H0731 + ETV and ETV alone for the treatment of CHB patients	Declines of HBV DNA and RNA levels were more evident in the association therapy groups than with ETV alone	Upper respiratory tract infection, nervous system disorders, and skin and subcutaneous tissue disorders	03577171
Phase IIa, multi-center, double-blind, placebo-controlled study to evaluate ABI-H0731 as adjunctive therapy in virally-suppressed CHB patients	ABI-H0731 was demonstrated a favourable safety and tolerability profile for 24 weeks	Blood and lymphatic system disorders, gastrointestinal disorders, and upper respiratory tract infection	03576066
Phase IIa, multi-center, single-blind, placebo-controlled study to evaluate treatment intensification with ABI-H0731 in CHB patients	ABI-H0731 was well tolerated and achieved anti-HBV activity in CHB patients	HBV DNA and RNA levels were rebounded immediately after withdrawal ABI-H0731	04454567
ABI-H2158	Assembly Biosciences	Phase I study of the safety, tolerability, pharmacokinetics, and food effect of ABI-H2158 in healthy volunteers and CHB patients	ABI-H2158 had good safety and met the safety standard of once-daily dosing	ALT elevation and hypertriglyceridemia	03714152
Phase IIa, multicenter, single-blind, placebo-controlled, multiple cohort study to evaluate ABI-H2158-containing regimens in CHB patients	Assembly Biosciences discontinued development of hepatitis drug ABI-H2158	Grade 3/4 elevations in ALT	04398134
NVR-3-778	Novira Therapeutics, Inc.	Phase Ib, dose-ranging study to assess the safety, pharmacokinetics and initial antiviral efficacy of NVR 3-778 in patients with HBeAg-positive CHB infection	The mean reduction in HBV RNA was also greatest in the group given NVR 3-778 + PEG-IFN compared with the groups given NVR 3-778 or PEG-IFN alone	Fatigue, influenza-type illness, and injection site erythema	02401737
JNJ-56136379 (JNJ-6379)	Janssen Research & Development, LLC	Phase IIa, randomized, partially-blind, placebo-controlled study to assess the efficacy, safety, and pharmacokinetics of treatment with multiple doses of JNJ-6379 as monotherapy and in combination with a nucleos(t)ide analog in CHB subjects	The mean reduction in HBsAg was 0.4 log10 IU·mL^-1 in the group given JNJ-6379 + nucleos(t)ide analog	There were no discontinuations and no pattern of dose-related adverse effects with JNJ-6379	03361956
GST-HG141	Fujian Cosunter Pharmaceutical Co. Ltd.	Phase Ia, single-center, randomized, double-blind, placebo-controlled clinical trial to evaluate the tolerability and pharmacokinetics of GST-HG141 in healthy subjects	GST-HG141 was well-tolerated in healthy subjects	Renal and urinary disorders, neutropenia, and hypertriglyceridemia	04386915
QL-007	Qilu Pharmaceutical Co., Ltd.	Phase II, open-label study to evaluate safety and efficacy of QL-007 tablets in combination with ETV or TFV in CHB patients	Not available	Not available	04157257

Drug	Company	Study type	Study result	Adverse event	NCT
GLS4	Sunshine Lake Pharma Co., Ltd.	Phase I, single-center, open label clinical study to evaluate the pharmacokinetic character of GLS4 combined with RTV or TAF alone or GLS4 and RTV and TAF combination administration in healthy subjects	HBV DNA levels were decreased by -1.42 log10 IU·mL^-1, -2.13 log10 IU·mL^-1 and -3.5 log10 IU·mL^-1 respectively for 28 days	AST and ALT elevation	04551261
Phase II clinical study to evaluate the safety, tolerability, and antiviral activity of GLS4 with RTV in combination with ETV in comparison with ETV alone in CHB patients	The antiviral efficacy of combination therapy of GLS4/RTV with ETV was remarkably superior to ETV alone	ALT elevation and hypertriglyceridemia	04147208
RO7049389	Hoffmann-La Roche	Phase I clinical study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of RO7049389 in healthy volunteers and CHB participants	RO7049389 was safe and well tolerated and demonstrated antiviral activity over 4 weeks in CHB patients	Headache, diarrhoea, upper respiratory tract infection, ALT elevation, and AST elevation	02952924
ZM-H1505R	Shanghai Zhimeng Biopharma, Inc.	Phase I, randomized, double-blind, placebo-controlled study following oral administration in healthy subjects to evaluate the safety, tolerability, and pharmacokinetics of ZM-H1505R	Multiple doses of up to 300 mg of ZM-H1505R were safe and well tolerated in healthy subjects	Gastrointestinal disorders	04220801
ALG-000184	Aligos Therapeutics	Phase I, double-blind, randomized, placebo-controlled study to evaluate safety, tolerability, pharmacokinetics and pharmacodynamic in healthy volunteers and CHB patients	ALG-000184 was safe, well tolerated and with no food effect, at single oral doses up to 500 mg in healthy volunteers	ALT elevation	04536337
JNJ-64530440 (JNJ-0440)	Alios Biopharma Inc.	Phase I, double-blind, randomized, placebo-controlled study of orally administered JNJ-0440 to evaluate the safety, tolerability, and pharmacokinetics after single ascending doses in healthy subjects and CHB subjects	JNJ-0440 750 mg once-daily or twice-daily for 28 days was well tolerated and achieved anti-HBV activity in CHB patients	ALT increase, blood potassium increase, neutrophil count decrease, and headache	03439488
ABI-H0731 (vebicorvir)	Assembly Biosciences	Phase IIa, multi-center, double-blind, placebo-controlled study to evaluate ABI-H0731 + ETV and ETV alone for the treatment of CHB patients	Declines of HBV DNA and RNA levels were more evident in the association therapy groups than with ETV alone	Upper respiratory tract infection, nervous system disorders, and skin and subcutaneous tissue disorders	03577171
Phase IIa, multi-center, double-blind, placebo-controlled study to evaluate ABI-H0731 as adjunctive therapy in virally-suppressed CHB patients	ABI-H0731 was demonstrated a favourable safety and tolerability profile for 24 weeks	Blood and lymphatic system disorders, gastrointestinal disorders, and upper respiratory tract infection	03576066
Phase IIa, multi-center, single-blind, placebo-controlled study to evaluate treatment intensification with ABI-H0731 in CHB patients	ABI-H0731 was well tolerated and achieved anti-HBV activity in CHB patients	HBV DNA and RNA levels were rebounded immediately after withdrawal ABI-H0731	04454567
ABI-H2158	Assembly Biosciences	Phase I study of the safety, tolerability, pharmacokinetics, and food effect of ABI-H2158 in healthy volunteers and CHB patients	ABI-H2158 had good safety and met the safety standard of once-daily dosing	ALT elevation and hypertriglyceridemia	03714152
Phase IIa, multicenter, single-blind, placebo-controlled, multiple cohort study to evaluate ABI-H2158-containing regimens in CHB patients	Assembly Biosciences discontinued development of hepatitis drug ABI-H2158	Grade 3/4 elevations in ALT	04398134
NVR-3-778	Novira Therapeutics, Inc.	Phase Ib, dose-ranging study to assess the safety, pharmacokinetics and initial antiviral efficacy of NVR 3-778 in patients with HBeAg-positive CHB infection	The mean reduction in HBV RNA was also greatest in the group given NVR 3-778 + PEG-IFN compared with the groups given NVR 3-778 or PEG-IFN alone	Fatigue, influenza-type illness, and injection site erythema	02401737
JNJ-56136379 (JNJ-6379)	Janssen Research & Development, LLC	Phase IIa, randomized, partially-blind, placebo-controlled study to assess the efficacy, safety, and pharmacokinetics of treatment with multiple doses of JNJ-6379 as monotherapy and in combination with a nucleos(t)ide analog in CHB subjects	The mean reduction in HBsAg was 0.4 log10 IU·mL^-1 in the group given JNJ-6379 + nucleos(t)ide analog	There were no discontinuations and no pattern of dose-related adverse effects with JNJ-6379	03361956
GST-HG141	Fujian Cosunter Pharmaceutical Co. Ltd.	Phase Ia, single-center, randomized, double-blind, placebo-controlled clinical trial to evaluate the tolerability and pharmacokinetics of GST-HG141 in healthy subjects	GST-HG141 was well-tolerated in healthy subjects	Renal and urinary disorders, neutropenia, and hypertriglyceridemia	04386915
QL-007	Qilu Pharmaceutical Co., Ltd.	Phase II, open-label study to evaluate safety and efficacy of QL-007 tablets in combination with ETV or TFV in CHB patients	Not available	Not available	04157257

Drug	Company	Study type	Study result	Adverse event	NCT
AB-729	Arbutus Biopharma Corporation	Phase II, randomized, open-label, multicenter study to investigate AB-729, nucleos(t)ide analogue and PEG-IFNα-2a treatment in CHB subjects	Not available	Not available	04980482
ARB-001467	Arbutus Biopharma Corporation	Phase IIa, single-blind, randomized, placebo-controlled study to evaluate the safety, anti-HBV activity, and pharmacokinetics of ARB-001467 in CHB subjects receiving nucleos(t)ide analogue therapy	All subjects experienced a mean 1.4 log10 IU·mL^-1 reduction in HBsAg levels	Mild adverse events	02631096
GSK3228836(bepirovirsen)	GlaxoSmithKline	Phase II, open label, single arm study to mechanistically interrogate the therapeutic effect of GSK3228836 in CHB patients	Not available	Not available	04544956
Phase II, double-blinded, randomized, placebo-controlled, dose-escalation study to examine the safety, tolerability, pharmacokinetics and antiviral activity of GSK3228836 in CHB patients	HBV DNA and HBsAg reductions were obvious in patients receiving GSK3228836 300 mg	Blood and lymphatic system disorders, and gastrointestinal disorders	02981602
VIR-2218	Vir Biotechnology, Inc.	Phase I/II, randomized, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of VIR-2218	Decline in level of HBsAg was observed in CHB patients receiving VIR-2218 within 36 weeks	Mild adverse events	03672188
JNJ-73763989 (ARO-HBV)	Arrowhead Pharmaceuticals	Phase I, single-dose, open-label, parallel-group study to evaluate the effect of hepatic impairment on the pharmacokinetics of JNJ-3989	A single 200 mg dose of JNJ-3989 was in general safe and well-tolerated in participants with and without moderate hepatic impairment	Thrombocytopenia	04208386
Phase IIb, randomized, double blind, placebo-controlled study to evaluate efficacy, pharmacokinetics, and safety of JNJ 3989 + JNJ 6379 + nucleos(t)ide analog regimen in CHB participants	The combination therapy was well tolerated and decline of HBsAg was observed in CHB patients	ALT elevation and respiratory tract infection	04129554
Phase IIb, multicenter, double-blind, active-controlled, randomized study to investigate the efficacy and safety of different combination regimens including JNJ-3989 and/or JNJ-6379 for CHB infection	HBsAg change from baseline was -2.6 log10 IU·mL^-1 in patients receiving JNJ-3989 200 mg	ALT elevation and rhabdomyolysis	03982186
ARC-520	Arrowhead Pharmaceuticals	Phase I, randomized, double-blind, placebo-controlled, dose-escalating study to evaluate the safety, tolerability and pharmacokinetics of ARC-520 in healthy volunteers	It was safe and tolerated well in healthy volunteers receiving 2 mg·kg^-1 ARC-520	Mild adverse events	01872065
Phase II, multicenter study to determine the depth and duration of HBsAg reduction after single or multiple doses of ARC-520, in combination with ETV in CHB patients	Declines of HBsAg levels were more evident in HBeAg-positive patients	Gastrointestinal disorders, influenza like illness, and metabolism disorders	02065336

Drug	Company	Study type	Study result	Adverse event	NCT
AB-729	Arbutus Biopharma Corporation	Phase II, randomized, open-label, multicenter study to investigate AB-729, nucleos(t)ide analogue and PEG-IFNα-2a treatment in CHB subjects	Not available	Not available	04980482
ARB-001467	Arbutus Biopharma Corporation	Phase IIa, single-blind, randomized, placebo-controlled study to evaluate the safety, anti-HBV activity, and pharmacokinetics of ARB-001467 in CHB subjects receiving nucleos(t)ide analogue therapy	All subjects experienced a mean 1.4 log10 IU·mL^-1 reduction in HBsAg levels	Mild adverse events	02631096
GSK3228836(bepirovirsen)	GlaxoSmithKline	Phase II, open label, single arm study to mechanistically interrogate the therapeutic effect of GSK3228836 in CHB patients	Not available	Not available	04544956
Phase II, double-blinded, randomized, placebo-controlled, dose-escalation study to examine the safety, tolerability, pharmacokinetics and antiviral activity of GSK3228836 in CHB patients	HBV DNA and HBsAg reductions were obvious in patients receiving GSK3228836 300 mg	Blood and lymphatic system disorders, and gastrointestinal disorders	02981602
VIR-2218	Vir Biotechnology, Inc.	Phase I/II, randomized, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of VIR-2218	Decline in level of HBsAg was observed in CHB patients receiving VIR-2218 within 36 weeks	Mild adverse events	03672188
JNJ-73763989 (ARO-HBV)	Arrowhead Pharmaceuticals	Phase I, single-dose, open-label, parallel-group study to evaluate the effect of hepatic impairment on the pharmacokinetics of JNJ-3989	A single 200 mg dose of JNJ-3989 was in general safe and well-tolerated in participants with and without moderate hepatic impairment	Thrombocytopenia	04208386
Phase IIb, randomized, double blind, placebo-controlled study to evaluate efficacy, pharmacokinetics, and safety of JNJ 3989 + JNJ 6379 + nucleos(t)ide analog regimen in CHB participants	The combination therapy was well tolerated and decline of HBsAg was observed in CHB patients	ALT elevation and respiratory tract infection	04129554
Phase IIb, multicenter, double-blind, active-controlled, randomized study to investigate the efficacy and safety of different combination regimens including JNJ-3989 and/or JNJ-6379 for CHB infection	HBsAg change from baseline was -2.6 log10 IU·mL^-1 in patients receiving JNJ-3989 200 mg	ALT elevation and rhabdomyolysis	03982186
ARC-520	Arrowhead Pharmaceuticals	Phase I, randomized, double-blind, placebo-controlled, dose-escalating study to evaluate the safety, tolerability and pharmacokinetics of ARC-520 in healthy volunteers	It was safe and tolerated well in healthy volunteers receiving 2 mg·kg^-1 ARC-520	Mild adverse events	01872065
Phase II, multicenter study to determine the depth and duration of HBsAg reduction after single or multiple doses of ARC-520, in combination with ETV in CHB patients	Declines of HBsAg levels were more evident in HBeAg-positive patients	Gastrointestinal disorders, influenza like illness, and metabolism disorders	02065336

Drug	Company	Study type	Study result	Adverse event	NCT
GST-HG131	Fujian Cosunter Pharmaceutical Co. Ltd.	Phase I, single-center, randomized, double-blind, placebo-controlled clinical trial to evaluate the safety, tolerability and pharmacokinetics of GST-HG131 in healthy subjects	Not available	Not available	04499443
REP 2139-Ca	Replicor Inc.	Phase II study to evaluate safety and efficacy of combination treatment with REP 2139-Ca and Pegasys™ in patients with HBV/HDV co-infection	Long-term safety of REP 2139-Ca + PEG-IFNα-2a was observed in patients with HBV/HDV co-infection	ALT elevation and thrombocytopenia	02233075
REP 2139-Mg	Replicor Inc.	Phase II, open-label, randomized, active controlled study to evaluate REP 2139-Mg and REP 2165-Mg combination therapy in CHB subjects	The safety and tolerability were well in CHB subjects receiving REP 2139-Mg + TDF + PEG-IFNα-2a (90 μg)	ALT, AST and GGT elevation	02565719
ALG-010133	Aligos Therapeutics	Phase I, double-blind, randomized, placebo-controlled study of ALG-010133 drug to evaluate safety, tolerability, pharmacokinetics and pharmacodynamics after single and multiple doses in healthy volunteers and CHB subjects	No significative reduction on HBsAg levels in healthy volunteers receiving ALG-010133 at 400 mg dose level. And Aligos announced termination of clinical development of ALG-010133‎‎	Diarrhoea, erythema, headache and nausea	04485663

Drug	Company	Study type	Study result	Adverse event	NCT
GST-HG131	Fujian Cosunter Pharmaceutical Co. Ltd.	Phase I, single-center, randomized, double-blind, placebo-controlled clinical trial to evaluate the safety, tolerability and pharmacokinetics of GST-HG131 in healthy subjects	Not available	Not available	04499443
REP 2139-Ca	Replicor Inc.	Phase II study to evaluate safety and efficacy of combination treatment with REP 2139-Ca and Pegasys™ in patients with HBV/HDV co-infection	Long-term safety of REP 2139-Ca + PEG-IFNα-2a was observed in patients with HBV/HDV co-infection	ALT elevation and thrombocytopenia	02233075
REP 2139-Mg	Replicor Inc.	Phase II, open-label, randomized, active controlled study to evaluate REP 2139-Mg and REP 2165-Mg combination therapy in CHB subjects	The safety and tolerability were well in CHB subjects receiving REP 2139-Mg + TDF + PEG-IFNα-2a (90 μg)	ALT, AST and GGT elevation	02565719
ALG-010133	Aligos Therapeutics	Phase I, double-blind, randomized, placebo-controlled study of ALG-010133 drug to evaluate safety, tolerability, pharmacokinetics and pharmacodynamics after single and multiple doses in healthy volunteers and CHB subjects	No significative reduction on HBsAg levels in healthy volunteers receiving ALG-010133 at 400 mg dose level. And Aligos announced termination of clinical development of ALG-010133‎‎	Diarrhoea, erythema, headache and nausea	04485663

Drug	Company	Study type	Study result	Adverse event	NCT
ATI-2173	Antios Therapeutics, Inc.	Phase I, open-label, safety and tolerability, fixed-sequence study to investigate the potential interaction between ATI-2173 and TDF in healthy subjects	Not available	Not available	05137548
Phase I, double-blinded study for safety, tolerability, pharmacokinetics, and antiviral activity of ATI-2173 in healthy volunteers and CHB subjects	ATI-2173 at 10-50 mg orally per day had potent antiviral activity	There were no deaths, serious adverse events or discontinuations	04248426
Phase IIa, randomized, double-blinded, placebo-controlled study to evaluate safety and efficacy of ATI-2173 in combination with TDF in patients with HBV/HDV co-infection	Not available	Not available	04847440
Tenofovir exalidex (TXL)	ContraVir Pharmaceuticals, Inc.	Phase I, open-label study to investigate the effect of renal impairment on the pharmacokinetics of Tenofovir exalidex	Not available	Not available	03284164
Besifovir (BSV)	IlDong Pharmaceutical Co. Ltd.	Phase III, multi-center, randomized, double-blinded, parallel study to assess the antiviral activity and safety endpoints for the treatment of Besifovir 150 mg compared to TFV 300 mg in CHB patients	Not available	Not available	02792088
Phase III, multi-center, randomized, double-blinded, parallel study to assess the antiviral activity and safety of Besifovir 150 mg compared to TFV 300 mg in CHB patients for 48 weeks	Bone mineral density and eGFR were not reduced, and the safety was good after 192 weeks	Nasopharyngitis, dyspepsia, ALT elevation, dizziness, and headache	01937806
Phase IV, randomized, open-label, parallel, multi-center clinical trial to evaluate the efficacy and safety of switching to besifovir dipivoxil maleate from TDF in CHB patients	Not available	Not available	04202536
Phase IV, open-label, randomized, single-dose clinical trial to evaluate the food effect on pharmacokinetics of besifovir in healthy volunteers	Not available	Not available	03885778

Drug	Company	Study type	Study result	Adverse event	NCT
ATI-2173	Antios Therapeutics, Inc.	Phase I, open-label, safety and tolerability, fixed-sequence study to investigate the potential interaction between ATI-2173 and TDF in healthy subjects	Not available	Not available	05137548
Phase I, double-blinded study for safety, tolerability, pharmacokinetics, and antiviral activity of ATI-2173 in healthy volunteers and CHB subjects	ATI-2173 at 10-50 mg orally per day had potent antiviral activity	There were no deaths, serious adverse events or discontinuations	04248426
Phase IIa, randomized, double-blinded, placebo-controlled study to evaluate safety and efficacy of ATI-2173 in combination with TDF in patients with HBV/HDV co-infection	Not available	Not available	04847440
Tenofovir exalidex (TXL)	ContraVir Pharmaceuticals, Inc.	Phase I, open-label study to investigate the effect of renal impairment on the pharmacokinetics of Tenofovir exalidex	Not available	Not available	03284164
Besifovir (BSV)	IlDong Pharmaceutical Co. Ltd.	Phase III, multi-center, randomized, double-blinded, parallel study to assess the antiviral activity and safety endpoints for the treatment of Besifovir 150 mg compared to TFV 300 mg in CHB patients	Not available	Not available	02792088
Phase III, multi-center, randomized, double-blinded, parallel study to assess the antiviral activity and safety of Besifovir 150 mg compared to TFV 300 mg in CHB patients for 48 weeks	Bone mineral density and eGFR were not reduced, and the safety was good after 192 weeks	Nasopharyngitis, dyspepsia, ALT elevation, dizziness, and headache	01937806
Phase IV, randomized, open-label, parallel, multi-center clinical trial to evaluate the efficacy and safety of switching to besifovir dipivoxil maleate from TDF in CHB patients	Not available	Not available	04202536
Phase IV, open-label, randomized, single-dose clinical trial to evaluate the food effect on pharmacokinetics of besifovir in healthy volunteers	Not available	Not available	03885778

直接抗乙肝病毒候选药物的临床试验研究进展

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王美 ¹ , 刘林月 ¹ , 李传举 ¹ , 刘俊 ²^,^* , 贾海永 ¹^,^*

药学学报 | 专题报道Ⅰ：药物发现的新靶标、新策略与抗病毒药物研究 2022,57(10): 2972-2984

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药学学报 | 专题报道Ⅰ：药物发现的新靶标、新策略与抗病毒药物研究 2022, 57(10): 2972-2984

直接抗乙肝病毒候选药物的临床试验研究进展

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王美¹, 刘林月¹, 李传举¹, 刘俊²^,^*, 贾海永¹^,^*

作者信息

1.潍坊医学院药学院, 山东潍坊 261053

2.潍坊医学院护理学院, 山东潍坊 261053

通讯作者:

*刘俊, Tel: 86-536-8462493, E-mail: liujunangel@163.com;

贾海永, E-mail: 502378774@163.com

The recent advance of direct anti-HBV drug candidates in clinical trials

Mei WANG¹, Lin-yue LIU¹, Chuan-ju LI¹, Jun LIU²^,^*, Hai-yong JIA¹^,^*

Affiliations

1. School of Pharmacy, Weifang Medical University, Weifang 261053, China

2. School of Nursing, Weifang Medical University, Weifang 261053, China

出版时间: 2022-10-12 doi: 10.16438/j.0513-4870.2022-0318

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摘要

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乙型肝炎病毒感染是一个严重的全球公共卫生问题, 慢性乙肝感染能够导致肝硬化、肝代谢失常和肝癌等疾病, 严重威胁人类身体健康。已有的用于治疗慢性乙肝的核苷(酸) 类和干扰素类药物不能彻底清除共价闭合环状DNA (cccDNA) 和整合的HBV基因组DNA, 因而无法实现慢性乙肝的功能性治愈。目前, 一系列靶向于HBV生命周期的药物和免疫调节剂已进入临床试验阶段。本综述回顾了慢性乙肝的治疗现状, 以及直接抗病毒候选药物的最新研究进展。

关键词

乙型肝炎病毒 / 药物作用靶点 / 核苷(酸) 类似物 / 直接抗病毒药物

Abstract

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Hepatitis B virus (HBV) infection is a serious global public health problem. Chronic hepatitis B virus infection can cause health problems such as cirrhosis, liver metabolism disorders and hepatocellular carcinoma. Nucloes(t)ide analogues and interferon drugs used to treat chronic HBV infection do not completely eradicate covalently closed circular DNA (cccDNA) and integrated genome of HBV DNA, so that they cannot achieve the functional cure of chronic HBV infection. Currently, a series of drugs targeting the phases of HBV lifecycle and immunomodulators have entered clinical trials. Here, we review the current status of the therapeutic drugs as well as the recent advance of direct antiviral agents.

Key words

hepatitis B virus / drug target / nucloes(t)ide analogue / direct antiviral agent

引用本文

王美, 刘林月, 李传举, 刘俊, 贾海永. 直接抗乙肝病毒候选药物的临床试验研究进展. 药学学报, 2022 , 57 (10) : 2972 -2984 . DOI: 10.16438/j.0513-4870.2022-0318

Mei WANG, Lin-yue LIU, Chuan-ju LI, Jun LIU, Hai-yong JIA. The recent advance of direct anti-HBV drug candidates in clinical trials[J]. Acta Pharmaceutica Sinica, 2022 , 57 (10) : 2972 -2984 . DOI: 10.16438/j.0513-4870.2022-0318

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乙肝是由乙型肝炎病毒(hepatitis B virus, HBV) 引起的以肝脏炎症和坏死病变为主的一种感染性疾病, 具有较强的传染性、复杂的传播途径及较高的发病率。全世界有超过3.54亿人患有慢性肝炎, 每天有8 000多例乙型和丙型肝炎新感染病例, 每年有100多万人死于晚期肝病和肝癌^[1]。

根据欧洲肝脏研究协会(EASL)、美国肝脏疾病研究协会(AASLD)、中国肝病学会和中国传染病学会的指导方针, 目前治疗慢性乙肝患者的常用药物主要有两大类: 干扰素类(IFNα) 和核苷酸类似物(NAs)^{[2, 3]}。虽然这两类药物能够抑制HBV DNA的复制, 但是这些疗法无法清除乙肝病毒表面抗原(HBsAg), 从而使机体免疫系统受到影响, 导致患者出现细胞坏死和炎症等症状, 甚至引发肝硬化、肝癌等疾病。因此, 大力研发针对不同靶点的抗乙肝新药, 使慢性乙型肝炎(CHB) 的治疗具有更多选择, 同时联合使用不同机制的治疗方案, 在未来才有望实现CHB的功能性治愈。

1 乙肝病毒的生命周期及相关药物靶点

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乙肝病毒的生命周期包括吸附、穿入、脱壳、修复、转录、翻译、衣壳装配、DNA复制、包膜的形成及释放等步骤, 进而形成具有感染力的完整HBV病毒颗粒(图 1)^[4]。HBV感染宿主后, 经血液循环富集于肝脏附近, 病毒颗粒特异性结合肝细胞表面的硫酸乙酰肝素蛋白聚糖受体(HSPG), 继而病毒表面的PreS1区与肝细胞表面的牛磺胆酸钠协同转运多肽(NTCP) 结合, 病毒颗粒进入肝细胞^[5]。病毒脱去包膜裸露出核衣壳后被运输到细胞核, 病毒基因组通过核孔进入细胞核, 被宿主因子修复并转化为cccDNA^[6]。以cccDNA为模板, 经宿主的RNA聚合酶转录生成前基因组RNA (pgRNA) 及3种信使RNA (mRNA)。pgRNA作为乙肝病毒复制的主要中间体, 被输出到细胞质中, 它的5'端与HBV Pol结合并诱导包装过程。随后在核衣壳内, pgRNA被病毒聚合酶逆转录成为新的负链DNA, 进而形成半闭合环状双链线性DNA (dslDNA), 并在HBV DNA整合到宿主基因组中发挥重要作用。成熟的衣壳可以将rcDNA递送至细胞核中, 增加cccDNA的含量, 或者与内质网(ER) 中的HBV表面蛋白结合, 以病毒粒子的形式分泌到肝细胞外。

目前, 已出现了多种可以靶向HBV生命周期不同阶段的新型抑制剂(图 1), 包括阻断乙肝病毒进入细胞与NTCP结合的侵入抑制剂、干扰衣壳蛋白装配或加速衣壳蛋白降解的衣壳抑制剂、直接抑制乙肝病毒逆转录的RNA干扰类药物、永久沉默HBV复制模板的cccDNA抑制剂、抑制HBsAg释放继而免疫机制的HBsAg抑制剂、直接作用于病毒逆转录酶阻断HBV复制的聚合酶抑制剂。

2 已上市的两类抗HBV治疗药物

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2.1 核苷(酸) 类化合物

到目前为止, 被批准用于CHB的治疗药物, 主要包括PEG-IFNα和核苷类似物。其中, 恩替卡韦(ETV)、富马酸替诺福韦二吡呋酯(TDF) 和替诺福韦艾拉酚胺(TAF) 由于长期有效性和耐受性, 已成为治疗HBV最常用的药物^{[2, 3]}。

TDF和TAF作为前药可以改善替诺福韦(TFV) 不能通过肠壁被肠道吸收的缺陷。与TDF相比, TAF表现出更高的血浆稳定性, 并能发挥更显著的肝靶向能力。此外, 由于该药物能够更好地吸收到肝细胞和外周血单个核细胞, 与TDF 300 mg剂量相比, TAF 25 mg即可减少TFV的全身暴露90%以上^[7], 同时TAF也具有较低的不良反应发生率, 包括肾功能障碍和骨密度降低^[8]。免疫分析24周和48周时HBV DNA、乙肝e抗原(HBeAg) 和乙肝表面抗原(HBsAg) 水平的变化。48周后, 丙氨酸转氨酶(ALT) 归一化率为95.24% (40/42), 完全病毒学应答率(HBV DNA < 20 IU·mL^-1) 为69.05% (29/42), HBeAg血清转氨率为8.57% (3/35)。治疗48周后, HBV DNA和HBsAg水平分别从基线的5.49 ± 1.95降至1.26 ± 0.66 log10 IU·mL^-1, 从3.59 ± 0.81降至3.32 ± 0.55 log10 IU·mL^-1。与基线测量相比, 48周时肝脏硬度值(LSM) 显著降低, 从13.00 ± 8.15 kPa降至8.66 ± 4.45 kPa。因此, 研究结果证明了TAF治疗慢性乙型肝炎的有效性和安全性^[9]。

2.2 干扰素类化合物

干扰素(IFN) 是一类在抗病毒防御中发挥关键作用的细胞因子。PEG-IFNα已被证明具有直接抗病毒和免疫调节作用。相比于IFNα, PEG-IFNα的药代动力学改善和半衰期延长, 逐渐取代IFNα成为慢性HBV感染的一线治疗药物^[10]。将IFNα-2a与PEG移植可减弱肾滤过, 从而降低血清中IFN的清除率。与IFNα-2a相比, PEG-IFNα-2a不仅减少了注射次数, 而且轻微提高了患者的依从性和反应率^[11]。

非活性HBsAg携带者(IHCs) 可通过PEG-IFNα-2b为基础的抗病毒治疗, 然而, 这种治疗方法的研究还不够充分。在19例接受PEG-IFNα-2b治疗的患者中, 16例(84.2%) 在72周时出现HBsAg丢失, 13例(68.4%) 出现HBsAg血清转换。治疗组的所有患者在停药时均表现出病毒学应答(HBV DNA < 10 IU·mL^-1), 对照组患者观察期内无HBsAg丢失。治疗期间无严重不良事件发生, 治疗耐受性良好, 研究表明短期PEG-IFNα-2b治疗IHCs具有较高的功能性治愈率和良好的安全性, PEG-IFNα-2b治疗可能是部分IHCs临床治疗的最佳选择^[12]。

鉴于慢性HBV感染会导致免疫损伤和耐受, 与NAs相比, IFN作为一种基于免疫的治疗方法, 在抗病毒免疫调节方面具有独特的机制优势, 并可能破坏免疫耐受状态。IFN治疗需要更多新颖可靠的生物标记物来改善临床管理方案, 新的联合策略和IFN自身的优化, 如新的IFN亚型和给药方式, 有望大幅提高慢性乙型肝炎的治疗效果^[13]。

3 在研的抗HBV治疗药物

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目前, 针对HBV生命周期各个阶段的直接抗病毒药物(DAA) 正在研究中, 如HBV侵入抑制剂、病毒基因表达抑制剂、衣壳组装修饰剂、HBsAg释放抑制剂等, 下面将详细介绍当前处于不同临床试验阶段的抗乙肝新药。

3.1 侵入抑制剂

侵入抑制剂是一种新型抗乙型肝炎病毒感染的药物。首个可以灭活HBV和HDV受体的侵入抑制剂myrcludex B (bulevirtide) (表 1), 是一种由HBV表面蛋白前S1结构域的47个氨基酸组成的脂肪肉豆蔻醇化肽^[14], 可以和天然乙肝表面抗原竞争结合NTCP从而抑制病毒进入^[15]。Myrcludex B已在2020年下半年获得欧盟批准用于治疗HBV/HDV合并感染。

一项多中心、开放、随机、比较、平行对照的II期研究(NCT02888106) 中, 评估了myrcludex B联合PEG-IFNα-2a与单独使用PEG-IFNα-2a治疗慢性乙型肝炎合并丁型肝炎药物的疗效和安全性, 在48周时, 80%的myrcludex B 2 mg + PEG-IFNα-2a患者血清中检测不到HDV RNA, 比单独使用myrcludex B或PEG-IFNα-2a的患者比例高; 丙氨酸转氨酶(ALT) 恢复正常的患者中, 仅服用myrcludex B 2 mg的患者最常见(73.3%), 46.7% myrcludex B 2 mg + PEG-IFNα-2a 180 μg患者HBsAg水平下降(> 1 log10 IU·mL^-1), 单独用药治疗组无变化^[16]。72周时, 相比于myrcludex B治疗(534例vs 152例), PEG-IFNα-2a的不良反应发生率更高。超过40%的研究患者出现轻度不良反应, 多为总胆盐增加、中性粒细胞减少、血小板减少、白细胞减少和ALT升高等。目前, 一项多中心、开放标签、随机III期临床研究(NCT03852719) 正在进行中, 旨在评估myrcludex B对慢性丁型肝炎患者的疗效和安全性, 预计2024年7月完成。

近日, 全球首个针对HBV和HDV的口服NTCP抑制剂A2342已进入临床前研究阶段, 体外实验表明A2342可以有效地抑制NTCP胆汁酸的转运活性, 在不影响细胞活性的前提下能够有效阻止HBV进入人体肝细胞, 预计2022年底开展I期临床研究。

3.2 衣壳蛋白抑制剂

乙肝病毒颗粒的核衣壳是由HBcAg组成的二十面体结构, 包裹着rcDNA。同时, 核衣壳被L-HBsAg、M-HBsAg和S-HBsAg组成的包膜所包裹。研究表明, 一些新型衣壳抑制剂(表 2) 可以影响HBV复制周期中衣壳形成、cccDNA逆转录和宿主基因的表达等多个步骤。衣壳抑制剂基于衣壳和配体相互作用机制可分为两类, 一类是核心蛋白异构调节剂, 可以诱导核衣壳变形, 以杂芳基二氢嘧啶(HAP) 为代表的GLS4和Bay 41-4109; 另一类是衣壳组装调节剂, 如苯基丙烯酰胺(PPA) 或氨磺酰基苯甲酰胺(SBA), 代表性研究药物有NVR-3-778、AB-423、AT-130、JNJ-632^[17]。

我国东阳光药业自主研发的GLS4, 是一种靶向乙肝病毒衣壳成熟的异芳基二氢嘧啶衍生物, 可诱导产生异常的核衣壳结构^[18]。120 mg GLS4给药28天后, 75% (18/24) 患者出现不良反应, 多为ALT升高, 未发生严重AEs的患者出现HBV DNA和RNA水平降低, 尤其是低于基线ALT水平5倍的患者^[19]。此外, 在一些患者中也观察到HBsAg、HBeAg和HBcrAg的减少。一项评估GLS4/RTV + ETV的安全性、耐受性和抗病毒活性的II期临床试验(NCT04147208) 正在研究中, 中期研究结果表明, GLS4/RTV + ETV方案的治疗效果明显优于ETV单药治疗, 支持了进一步对联合治疗的安全性和有效性的研究。目前, 该公司已启动了一项多中心、随机、双盲、平行、安慰剂对照IIIa期临床试验, 以评估GLS4/RTV与核苷类药物联合用药方案在CHB患者中的有效性和安全性, 主要观察指标为治疗48周后患者的HBV DNA情况。

由Roche制药公司开发的HBV核心蛋白异构调节剂RO7049389, 可以诱导异常HBcAg聚集体的形成, 导致存有缺陷的衣壳组装进而抑制HBV复制, 同时, 该药物可能恢复宿主对HBV的免疫应答。在体外细胞和体内动物模型的测定中, RO7049389对HBV复制具有显著抑制作用。一项随机、盲法、安慰剂对照、单/多剂量递增的Ia期临床研究(NCT02952924), 评估RO7049389在健康志愿者及慢性乙肝患者中的安全性、耐受性、药代动力学和药效学特性。RO7049389对健康受试者具有良好的安全性和耐受性, 在血浆中吸收和消除迅速, 并且对CYP3A的抑制作用较弱(< 20%)^[20]。未经治疗的HBeAg阳性和阴性CHB患者接受4周的RO7049389 (200~1 000 mg) 或安慰剂治疗后, 抗病毒作用较好, 但未出现病毒学突破^[21]。目前, 一项采用RO7049389 + RO7020531 + 核苷类药物联合用药方案对肝功能完好且无明显纤维化/肝硬化的CHB患者的安全性、耐受性和有效性的II期临床试验(NCT04225715) 正在进行中。

ZM-H1505R, 作为一种具有新型吡唑结构的小分子HBV衣壳组装调节剂, 由我国上海挚盟医药科技有限公司自主研发, 它对大多数对于I类或II类HBV衣壳调节剂耐药的HBV变异具有活性。目前, 在一项随机、双盲、安慰剂对照、单/多剂量递增(SAD/MAD) 的I期临床研究(NCT04220801) 中, 在健康受试者口服后评价ZM-H1505R的安全性、耐受性和药代动力学。在连续14天的口服给药75、150或300 mg期间, ZM-H1505R被发现安全且耐受性良好。多剂量给予ZM-H1505R后, 患者血浆AUC和C_max以剂量成比例的方式增加。300 mg的ZM-H1505R在健康志愿者中是安全且耐受性良好, 目前正被评估用于慢性乙型肝炎患者的治疗。

ALG-000184是Aligos公司的衣壳组装调节剂候选乙肝药物, 主要通过干扰乙肝病毒的衣壳组装和病毒复制过程, 导致非感染性空病毒颗粒形成, 从而抑制乙肝病毒感染。作为前体药物, ALG-000184具有更高的水溶性及高的渗透性, 小鼠模型可迅速吸收并转化为有效的ALG-001075^[22]。在健康志愿者和慢性乙肝受试者中评价单/多剂量给药后的安全性、耐受性、药代动力学和药效学的I期临床研究(NCT04536337) 正在进行中。根据2021年美国肝病学会年会报道, ALG-000184 100 mg给药28天后耐受性良好, 表现出可预测的药代动力学特性, 并导致多数CHB受试者HBV DNA和RNA水平低于LLOQ。目前, 正在对HBeAg阴性受试者进行ALG-000184 10 mg剂量评估中。

JNJ-64530440 (JNJ-0440) 是Janssen公司旗下一款正在进行研究用于慢性乙型肝炎治疗的衣壳组装调节剂, 能使乙肝病毒衣壳空壳化。一项随机、双盲、安慰剂对照的I期临床研究(NCT03439488) 部分研究结果如下, 在健康志愿者中, 单剂量(50 mg或4 000 mg) 和多次递增剂量(750 mg每日一次或两次, 或2 000 mg每日一次) 的JNJ-0440具有良好的耐受性, 且未发生严重的不良事件、治疗中断或剂量限制性毒性^[23]。随后在CHB患者中进行长达28天的Ib期评估中, JNJ-0440 750 mg普遍耐受性良好, 并导致HBV DNA和HBV RNA较基线显著降低, 患者未观察到严重的不良事件, 主要是疲劳、ALT升高、中性粒细胞计数下降和头痛等轻度不良事件^[24]。

ABI-H0731 (vebicorvir) 是Assembly Biosciences开发的用于治疗CHB的第一代HBV核心抑制剂^[25]。体外研究已经确定了ABI-H0731在HBV复制周期中的多个靶点, 其可以有效地抑制HBV RNA和HBV DNA在衣壳中的包装, 还可以降低HBV感染的HepG2-NTCP细胞中HBeAg和HBsAg的产生^[26]。一项IIa期多中心、双盲、安慰剂对照研究(NCT03577171), 第12周时, ABI-H0731 + ETV组患者HBV DNA和RNA下降幅度较大。目前, 已经启动IIa期三联疗法临床试验, 研究方向包括: ABI-H0731 + NUC与其他互补机制结合、ABI-H0731 + NUC + PEG-IFNα、ABI-H0731 + NUC + AB-729。

ABI-H2158是Assembly公司第二代有效核心抑制剂候选药。研究证明在300 mg QD稳态给药时, ABI-H2158在抗病毒抑制和预防cccDNA建立的作用方面明显增强^[27]。在该II期研究中, 2名接受ABI-H2158治疗的患者出现了4级ALT升高, 2名接受ABI-H2158治疗的患者出现了3级ALT升高, ABI-H2158具有严重的肝毒性进而做出停止开发的决定。

NVR-3-778是首个在HBV感染患者中证明有抗病毒活性的II类衣壳组装调节剂。作为一种氨磺酰基苯甲酰胺衍生物, 它与核苷类似物在体内的结合后产生附加的或协同的抗病毒活性, 可以抑制传染性HBV DNA病毒颗粒的产生, 具有抗病毒能力(EC₅₀ = 0.40 μmol·L^-1), 还抑制pgRNA包膜、病毒复制和产生HBV DNA和HBV RNA颗粒^[28]。在具有人源化肝脏的HBV感染小鼠模型中, NVR-3-778展示了较高的抗病毒活性, 与PEG-IFNα联合使用比单独使用ETV更能阻止病毒复制和HBV RNA产生^[29]。在HBeAg阳性的慢性HBV感染患者的I期研究(NCT02112799、NCT02401737) 中, NVR-3-778与PEG-IFNα联合使用时, 可以大幅度地降低血清HBV DNA (1.97 log10 IU·mL^-1) 和HBV RNA (2.09 log10 IU·mL^-1) 水平^[30]。

JNJ-56136379 (JNJ-6379) 在I期临床研究(NCT02662712) 中, 56% (23/41) 服用JNJ-6379 (25、75、150或250 mg) 的患者在治疗期间出现至少1个不良事件, 而63% (10/16) 服用安慰剂的患者治疗期间出现至少1个不良事件, 且治疗期间未出现严重的不良事件^[31]。在HBeAg阳性和阴性的患者中, JNJ-6379具有良好的耐受性和强效抗病毒活性^[32]。相比单独使用核苷类药物, JNJ-6379 250 mg + 核苷类药物治疗导致未经治疗的HBeAg阳性患者体内HBsAg平均下降0.4 log10 IU·mL^-1。以上研究数据支持了正在进行的JNJ-6379 + JNJ-3989 + 核苷类药物II期REEF-1研究(NCT03982186) 继续评估。目前, 一项开放标签、单组、多中心II期研究(NCT04667104), 评估JNJ-3989 + JNJ-6379 + PEG-IFNα-2a + 核苷类似物联合治疗CHB感染者的安全性、有效性、耐受性及药代动力学特性正在进行中。

GST-HG141是由福建广生堂药业股份有限公司自主研发的一种新型口服HBV衣壳装配抑制剂。GST-HG141可以加速HBV核心蛋白组装, 在临床前药效学研究中表现出较好的抗病毒活性和HBV DNA抑制活性(EC₅₀ = 0.93 ± 0.11 μmol·L^-1)。在游离腺相关病毒(AAV) 模型中, GST-HG141给药28天后, 小鼠血清(~3.0 log10 IU·mL^-1) 和肝脏(0.9 log10 IU·mL^-1) 内HBV DNA水平显著降低。一项双盲、随机、安慰剂对照Ia期研究(NCT04536337), GST-HG141在健康受试者中安全性和耐受性良好, 常见的不良事件是尿路感染、血清肌酐水平升高及中性粒细胞计数下降等, 未发现与剂量有关的不良反应^[33]。以上结果为评估GST-HG141对CHB患者疗效的Ib期临床试验(NCT04868981) 提供了支持。

QL-007是齐鲁药业研发的新型衣壳蛋白抑制剂, 符合对人体安全性和一定疗效, 已经顺利得到国家药品监督管理局批准开展临床试验。QL-007主要与当前一线核苷酸类似物联合, 从而起到协同抑制HBV复制作用。目前, QL-007 + TDF联合用药方案对初治CHB患者的安全性和有效性的一项开放标签II期研究(NCT04157257) 正在进行中。

3.3 RNA干扰类

RNA干扰技术主要通过诱导mRNA降解和翻译抑制, 显著降低HBsAg水平, 进而抑制HBV的复制, 在肿瘤及慢性传染性疾病的治疗中应用十分广泛。目前, 用于乙肝治疗的RNA干扰类药物(表 3) 正处于I期或II期临床研究中, 并显示出良好的抗病毒效果。

ARB-001467 (ARB-1467) 是一种脂质纳米颗粒(LNP), 通过靶向病毒基因组中三个不同且高度保守的位点, 进而抑制由cccDNA和整合DNA产生的HBV蛋白的转录后基因。在一项单盲、安慰剂对照、多剂量IIa期临床试验(NCT02631096) 中, 在非肝硬化、病毒抑制的受试者中评估ARB-1467为期12周的安全性和有效性。结果表明, 治疗总体上安全性、耐受性良好, 在一些患者中观察到HBcAg和HBV RNA减少, 但仅有少数试验者对ARB-1467获得较好应答, 多数试验者未实现预期的治疗目标。因此, Arbutus公司宣布不会继续深入推进对ARB-1467研究, 将研究重点转向第二代RNAi药物AB-729。

AB-729是Arbutus Biopharma公司正在开发的一种N-乙酰半乳糖胺(GalNAc) 偶联的单触发RNA干扰在研乙肝新药, 可阻断包括HBx的所有HBV RNA转录产物, 从而抑制乙肝病毒复制和所有病毒抗原的水平。研究表明, 重复给药AB-729后, HBsAg水平持续显著性下降, 74% (25/34) 参与本研究的CHB患者都达到了HBsAg < 100 IU·mL^-1。在接受核苷(酸) 类似物治疗的慢性乙肝受试者中, 停用AB-729后, 受试者的HBsAg依然保持在低水平^[34]。目前, AB-729正进行多项联合用药的IIa期临床试验中, 包括AB-729 + 核苷类/PEG-IFNα-2a、AB-729 + vebicorvir + 核苷类、AB-729 + ATI-2173 + TDF、AB-729 + VTP-300 + 核苷类。

GSK3228836 (bepirovirsen, ISIS 505358) 是英国葛兰素史克公司(GSK) 正在开发的一款反义寡核苷酸, 可以和N-乙酰半乳糖胺(GalNAc) 结合, 通过肝细胞表达的去唾液酸糖蛋白递送至肝脏。一项双盲、随机、安慰剂对照、剂量递增II期研究(NCT02981602) 中, 相比于安慰剂对照组, GSK3228836 300 mg高剂量组中未接受过治疗的患者血清中HBsAg和HBV DNA水平显著降低(> 1 log10 IU·mL^-1), 大多为轻/中度不良事件, 部分患者具有良好的治疗效果, 未检测到HBsAg或HBV DNA, 停止治疗后, 出现反弹, 血清中HBsAg上升。这些研究结果表明GSK3228836具有较好的安全性, 其安全性和活性需要在更大的慢乙肝患者群体中进一步调查^[35]。目前, 一项针对GSK3228836在HBeAg阴性CHB患者中使用重复肝细针穿刺进行稳定核苷治疗的治疗机制多中心开放标签的IIa期探索性研究(NCT04544956) 正在进行中。

VIR-2218是一款由Alnylam和Vir Biotechnology公司合作研发的RNAi类乙肝新药, 被临床开发用于功能性治愈慢性乙肝病毒感染。VIR-2218在健康志愿者中显示出良好的药代动力学特性, 支持慢性HBV感染患者的皮下给药和持续发展^[36]。在一项正在进行的开放标签的II期临床研究(NCT04412863) 中, 与VIR-2218单药治疗相比, VIR-2218与PEG-IFNα联合用药组出现ALT升高的患者较多且HBsAg下降更快更显著, 平均值为2.9 log10 IU·mL^{-1 [37]}。该研究结果支持了VIR-2218的抗病毒活性可以通过免疫调节剂如PEG-IFNα来增强的假设。

JNJ-3763989 (JNJ-3989, ARO-HBV) 由Arrowhead和Janssen公司合作开发, 通过诱导缺乏基因组物质的病毒衣壳形成, 从而抑制乙肝病毒复制。在一项多中心、主动对照的IIb期研究(NCT03982186) 中, 使用JNJ-3989 200 mg (最高剂量组) 48周后, 19.1%的受试者达到主要终点, HBsAg水平从基线下降幅度最大(2.6 log10 IU·mL^-1), 74.7%的患者达到HBsAg < 100 IU·mL^{-1 [38]}。目前, 涉及不同作用机制的JNJ-3989联合用药方案正在研究中。

ARC-520是由Arrowhead公司开发的首款用于CHB治疗并进入临床试验的RNA干扰制剂。在一项针对非人类灵长类动物进行的安全性研究中, 观察到EX1给药制剂具有致命毒性, 该药物试验因严重的毒性而被终止。近日, Gupta等^[39]开发了一个新型多室药代动力学-药效学模型, 并使用HBV动力学数据对其进行校准, 观察接受ARC-520治疗的HBeAg阳性患者体内HBV DNA、HBsAg和HBeAg水平。结果表明, 单剂量的ARC-520在第1天抑制HBsAg和HBeAg的有效性超过96%, 并在1~4个月内逐渐消失至50%。单剂量的ARC-520和ETV对HBV DNA的抑制水平随着时间的推移是恒定的, 疗效超过99.8%。因此, ETV介导了HBV DNA的持续下降, ARC-520介导了HBsAg和HBeAg暂时性的下降。该建模框架可能有助于评估正在进行的用于HBV感染的RNAi药物开发, 基于RNAi疗法有可能会降低HBsAg水平并诱导功能性治愈。

RG6346 (RO7445482, DCR-HBVS) 是Dicerna Pharmaceuticals公司与Roche公司正在合作开发的用于CHB治疗的一种新型GalXC^TM RNAi疗法。Ib/IIa期临床试验中未观察到严重的不良事件或剂量限制毒性, 表明RG6346治疗HBeAg阳性或阴性患者总体是安全的且具有良好的耐受性, 可导致血清HBsAg水平显著及持久下降^[40]。目前, Roche公司已经开展了RG6346治疗HBV感染的II期联合试验(NCT04225715), 将评估RG6346与多种具有不同作用机制的其他药物联合使用的有效性和安全性。2021年3月, 已启动了RG6346与核苷类逆转录酶抑制剂进行联合用药方案, 并与本公司的CPAM抑制剂或TLR7激动剂或PEG-IFNα-2a进行三联疗法研究。

3.4 HBsAg抑制剂

目前, 全球基于HBsAg为靶点的在研乙肝新药(表 4) 尚且处于临床研究阶段, 还没有一款在研的HBsAg药物获批上市。国内方面, 我国福建广生堂药业股份有限公司的一款HBsAg抑制剂GST-HG131, 正进行I期临床研究中。国外方面, 以抑制HBsAg释放为靶点的候选药物有Aligos Therapeutics公司的一款S-抗原转运抑制寡核苷酸聚合物(STOPS^TM分子) ALG-010133, 正在进行Ib期临床研究中; Replicor公司的REP2139/2165, 目前它们正在进行II期联合给药临床研究中。

GST-HG131是由福建广生堂药业股份有限公司自主研发的针对HBV基因表达的小分子抑制剂, 可以抑制HBsAg分泌, 与TENT4B结合和抑制进而导致HBV mRNA多聚腺苷酸尾缩短, 从而加速其降解。作为一种新型、口服生物可利用的HBV基因表达抑制剂, 它在AAV-HBV小鼠模型中可以显著降低HBsAg和HBV DNA的水平, 具有良好的体外抗病毒活性和耐受性^[41]。目前, GST-HG131在健康受试者单中心、随机、双盲、安慰剂对照Ia期临床试验(NCT04499443) 中, 进行安全性、耐受性和药代动力学研究。

‎Replicor公司的REP 2139, 可选择性靶向非传染性乙肝病毒的亚病毒颗粒组装或分泌, 进而阻止HBsAg释放^{[42, 43]}。已有研究证明, REP 2139可以直接与丁型肝炎病毒抗原(HDAg) 相互作用, 这与其他寡核苷酸与HDAg的非特异性相互作用是一致的^[44]。在慢性HDV/HDV合并感染的肝硬化患者中, REP 2139-Mg + TDF + PEG-IFNα 90 μg联合用药方案可实现HBsAg清除率增加、治疗性转氨酶清除以及HBV和HDV的功能性治愈^[45]。

ALG-010133是一种采用专有寡核苷酸抑制HBsAg转运的寡核苷酸聚合物(STOPSM^TM) 分子。目前, 正在进行I期双盲、随机、安慰剂对照的首次皮下给药的人体研究(NCT04485663), 以评估在健康志愿者、CHB患者中单/多剂量递增后的安全性、耐受性、药代动力学和药效学特征。到目前为止, 已经有72名健康志愿者接受ALG-010133治疗, ALG-010133单剂量200 mg和多剂量180 mg治疗3周后患者具有可以接受的安全性和药代动力学特性, 未出现严重不良事件或导致过早停药的不良事件^[46], 有利于在CHB患者中进一步研究。近日, 有研究报道ALG-010133在预期有效剂量400 mg (肝暴露水平为EC₉₀的3倍) 几乎无降低HBsAg活性, 预计最高可行剂量600 mg几乎不能降低90% (1 log10 IU·mL^-1) HBsAg, 进而Aligos公司宣布终止对ALG-010133‎‎的临床开发。

3.5 cccDNA抑制剂

作为HBV转录和复制的模板, cccDNA通常以游离形式存在于肝细胞核中。目前尚无治疗手段消除cccDNA或永久沉默cccDNA, 因而无法实现慢性乙肝的功能性治愈。基于其潜在研发方向, cccDNA抑制剂可分为直接基因编辑剂、表观遗传修饰剂及DNA失稳剂等^[47]。

PBGENE-HBV是由Precision BioSciences公司基于ARCUS平台开发的一种新型基因编辑药物。在这项临床前研究中, ARCUS平台有效地靶向并降解HBV cccDNA, 并使HBV感染的原代人肝细胞中的HBsAg表达下降77%。研究人员开发了一种小鼠和非人类灵长类动物模型, 将部分HBV基因组的AAV作为cccDNA的替代物以评估ARCUS平台的体内活性, 发现两种附加型模型中AAV拷贝数显著减少, 剩余AAV中的高靶向编辑, 小鼠模型中HBsAg水平持续性减少96%^[48]。由此来看, PBGENE-HBV具有靶向和降解cccDNA的能力, 将在2024年提交新药临床试验申请以开展I期临床研究评估PBGENE-HBV对人体的安全性和有效性。

近几年, 基因组编辑工具锌指核糖核酸酶(ZFN)、转录激活因子样效应物核酸酶(TALENs) 和天然免疫系统CRISPR-Cas, 在生物医学研究领域展现了巨大的潜力^[49]。所面临的问题是, 这些核酸酶在模拟非人类灵长类动物等人类疾病模型中的功效和安全性尚无充分的证据去证实。其中, ZFN可以直接靶向cccDNA, 依据这一策略可以在细胞培养模型中成功编辑HBV的cccDNA。处于临床前研究阶段的TALENs和CRISPR-Cas系统, 有望在将来的科学研究中应用于治疗HBV感染。

3.6 聚合酶抑制剂

聚合酶抑制剂(NRTIs), 即核苷(酸) 类似物, 通过阻断HBV DNA聚合酶并导致链终止进而抑制HBV复制。虽然长期的核苷(酸) 类似物治疗可以逆转肝硬化情况、降低肝癌的风险, 但目前HBV已经对部分使用拉米夫定(3TC)、替比夫定(LDT)、阿德福韦(ADF) 的患者产生了耐药性突变。为了克服这一缺陷, 许多优化的核苷(酸) 类药物(表 5) 正在临床研究中。

ATI-2173是Antios公司研发的乙肝II期临床候选药物, 也是临床开发中唯一的活性位点聚合酶抑制剂核苷酸(ASPIN)。ATI-2173单用或联用TDF的临床前数据表明, 在治疗中具有持续抑制HBV DNA的潜力^[50]。HEP DART 2021大会报道了ATI-2173Ib期实验结果, ATI-2173具有良好的抗HBV活性(-2.7 log10 IU·mL^-1), 观察期间未出现严重不良事件, 并且在治疗28天后显著减少3TC全身性暴露。ATI-2173治疗结束时, 65%受试者的HBV DNA水平低于定量限, 停药后4~24周观察到持续的停药反应^{[51, 52]}。目前, ATI-2173已经进入随机、双盲、安慰剂对照、多中心的IIa期临床研究(NCT04847440) 中, 旨在评估ATI-2173 25 mg + TDF 50 mg治疗HBV/HDV合并感染者90天的安全性和有效性。

Besifovir (BSV) 是一种新型无环核苷酸磷酸酯, 与AFV和TFV的化学结构相似, 通过一种活性代谢物(三磷酸鸟苷的核苷酸类似物) 抑制HBV复制^[53]。在一项多中心、随机、双盲、平行III期研究(NCT01937806) 中, 192周后BSV-BSV组和TDF-BSV组的病毒学应答率分别为92.50%和93.06%。BSV治疗不降低骨密度和eGFR, 具有良好的安全性。因此, BSV可以作为一种潜在的新型慢性乙型肝炎的治疗方法, 特别是用于肾和骨相关疾病的高风险患者^[54]。然而, BSV治疗组最常见的不良事件是肉碱耗竭, 定期服用左旋肉碱给患者带来了巨大的经济压力^[55]。2021年美国肝病研究协会报道了BSV的IV期临床试验(NCT04202536) 数据, 从TDF转为BSV的慢性乙型肝炎患者中, BSV组1例发生严重不良事件, TDF组6例; BSV组骨转换生物标志物具有统计学意义上的改善, 表现出非劣于TDF组的抗病毒疗效并提高了安全性^[56]。

4 总结与展望

收起

通过对HBV生命周期的深入了解, 人们设计了一系列新型的直接作用的抗病毒药物, 这些抗病毒药物通过多种机制发挥其功能, 包括抑制病毒侵入、RNA干扰、抑制cccDNA、干扰衣壳组装和阻断HBsAg释放。此外, 一些间接作用的抗病毒药物发展迅速, 如TLR激动剂、FXR激动剂、PD-1抑制剂等。HBV相关疾病可以通过现有的核苷类或干扰素类药物来加以控制, 但慢性乙肝的治疗仍然充满挑战, 慢性乙肝的功能性治愈目标是实现停药后持续的HBV DNA抑制和HBsAg清除, 这可以通过两种手段来实现: 一是在不杀死受感染肝细胞情况下, 利用新型抗乙肝药物清除cccDNA; 二是采用现有的免疫干预手段进行临床研究, 或开发新的免疫调节剂来安全清除受感染的肝细胞。目前, 已开展了新药与现有药物(NAs和PEG-IFNα) 联合用药方案, 提高乙肝临床治愈率指日可待。

作者贡献: 王美负责查阅文献和文章初稿的撰写; 刘林月、李传举负责查阅文献和修改文章; 刘俊、贾海永负责构思文章框架, 指导文章撰写、修改并最后定稿。

利益冲突: 所有作者均声明不存在利益冲突。

基金

收起

国家自然科学基金资助项目(81903468)
山东省自然科学基金资助项目(ZR2019BH068)
山东省医药卫生科技发展计划项目(2018WS061)

参考文献

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文献

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2022年第57卷第10期

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文章信息

doi: 10.16438/j.0513-4870.2022-0318

接收时间：2022-03-15
首发时间：2025-12-24
出版时间：2022-10-12

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文章信息

作者

出版历史

收稿日期：2022-03-15
修回日期：2022-04-08

基金

国家自然科学基金资助项目(81903468)

山东省自然科学基金资助项目(ZR2019BH068)

山东省医药卫生科技发展计划项目(2018WS061)

作者信息

1.潍坊医学院药学院, 山东潍坊 261053

2.潍坊医学院护理学院, 山东潍坊 261053

通讯作者:

*刘俊, Tel: 86-536-8462493, E-mail: liujunangel@163.com;

贾海永, E-mail: 502378774@163.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Drug	Company	Study type	Study result	Adverse event	NCT
Myrcludex B (bulevirtide)	Hepateral Ltd.	Phase II, multi-center, open-label, randomized clinical study to assess efficacy and safety of myrcludex B (2, 5, 10 mg) safety in combination with tenofovir compared to tenofovir alone in patients with chronic hepatitis D	HDV RNA negativation or decrease were observed in patients receiving myrcludex B and tenofovir. Hepatic cirrhosis was improved in receiving myrcludex B 5 mg or 10 mg	Blood and lymphatic system disorders, total bile acids increase, and ALT increase	03546621
Phase II, randomized, open-label substudy of daily myrcludex B plus PEG-IFNα-2a in patients with HBeAg negative chronic HBV co-infected with HDV	All chronically infected patients experienced reductions in serum HDV RNA level	Blood and lymphatic system disorders, AST and ALT increase, and influenza like illness	02637999
Phase II, randomized, comparative, parallel-arm study to assess efficacy and safety of myrcludex B in combination with PEG-IFNα-2a versus PEG-IFNα-2a alone in CHB patients	HBsAg levels reduction was observed in patients receiving myrcludex B in combination with PEG-IFNα-2a. No significative decrease in HBV DNA levels	Neutripenia, influenza like illness, thrombocytopenia, and total bile acids increase	02888106

Drug

Company

Study type

Study result

Adverse event

NCT

Myrcludex B (bulevirtide)

Hepateral Ltd.

Phase II, multi-center, open-label, randomized clinical study to assess efficacy and safety of myrcludex B (2, 5, 10 mg) safety in combination with tenofovir compared to tenofovir alone in patients with chronic hepatitis D

HDV RNA negativation or decrease were observed in patients receiving myrcludex B and tenofovir. Hepatic cirrhosis was improved in receiving myrcludex B 5 mg or 10 mg

Blood and lymphatic system disorders, total bile acids increase, and ALT increase

03546621

Phase II, randomized, open-label substudy of daily myrcludex B plus PEG-IFNα-2a in patients with HBeAg negative chronic HBV co-infected with HDV

All chronically infected patients experienced reductions in serum HDV RNA level

Blood and lymphatic system disorders, AST and ALT increase, and influenza like illness

02637999

Phase II, randomized, comparative, parallel-arm study to assess efficacy and safety of myrcludex B in combination with PEG-IFNα-2a versus PEG-IFNα-2a alone in CHB patients

HBsAg levels reduction was observed in patients receiving myrcludex B in combination with PEG-IFNα-2a. No significative decrease in HBV DNA levels

Neutripenia, influenza like illness, thrombocytopenia, and total bile acids increase

02888106

Drug	Company	Study type	Study result	Adverse event	NCT
GLS4	Sunshine Lake Pharma Co., Ltd.	Phase I, single-center, open label clinical study to evaluate the pharmacokinetic character of GLS4 combined with RTV or TAF alone or GLS4 and RTV and TAF combination administration in healthy subjects	HBV DNA levels were decreased by -1.42 log10 IU·mL^-1, -2.13 log10 IU·mL^-1 and -3.5 log10 IU·mL^-1 respectively for 28 days	AST and ALT elevation	04551261
Phase II clinical study to evaluate the safety, tolerability, and antiviral activity of GLS4 with RTV in combination with ETV in comparison with ETV alone in CHB patients	The antiviral efficacy of combination therapy of GLS4/RTV with ETV was remarkably superior to ETV alone	ALT elevation and hypertriglyceridemia	04147208
RO7049389	Hoffmann-La Roche	Phase I clinical study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of RO7049389 in healthy volunteers and CHB participants	RO7049389 was safe and well tolerated and demonstrated antiviral activity over 4 weeks in CHB patients	Headache, diarrhoea, upper respiratory tract infection, ALT elevation, and AST elevation	02952924
ZM-H1505R	Shanghai Zhimeng Biopharma, Inc.	Phase I, randomized, double-blind, placebo-controlled study following oral administration in healthy subjects to evaluate the safety, tolerability, and pharmacokinetics of ZM-H1505R	Multiple doses of up to 300 mg of ZM-H1505R were safe and well tolerated in healthy subjects	Gastrointestinal disorders	04220801
ALG-000184	Aligos Therapeutics	Phase I, double-blind, randomized, placebo-controlled study to evaluate safety, tolerability, pharmacokinetics and pharmacodynamic in healthy volunteers and CHB patients	ALG-000184 was safe, well tolerated and with no food effect, at single oral doses up to 500 mg in healthy volunteers	ALT elevation	04536337
JNJ-64530440 (JNJ-0440)	Alios Biopharma Inc.	Phase I, double-blind, randomized, placebo-controlled study of orally administered JNJ-0440 to evaluate the safety, tolerability, and pharmacokinetics after single ascending doses in healthy subjects and CHB subjects	JNJ-0440 750 mg once-daily or twice-daily for 28 days was well tolerated and achieved anti-HBV activity in CHB patients	ALT increase, blood potassium increase, neutrophil count decrease, and headache	03439488
ABI-H0731 (vebicorvir)	Assembly Biosciences	Phase IIa, multi-center, double-blind, placebo-controlled study to evaluate ABI-H0731 + ETV and ETV alone for the treatment of CHB patients	Declines of HBV DNA and RNA levels were more evident in the association therapy groups than with ETV alone	Upper respiratory tract infection, nervous system disorders, and skin and subcutaneous tissue disorders	03577171
Phase IIa, multi-center, double-blind, placebo-controlled study to evaluate ABI-H0731 as adjunctive therapy in virally-suppressed CHB patients	ABI-H0731 was demonstrated a favourable safety and tolerability profile for 24 weeks	Blood and lymphatic system disorders, gastrointestinal disorders, and upper respiratory tract infection	03576066
Phase IIa, multi-center, single-blind, placebo-controlled study to evaluate treatment intensification with ABI-H0731 in CHB patients	ABI-H0731 was well tolerated and achieved anti-HBV activity in CHB patients	HBV DNA and RNA levels were rebounded immediately after withdrawal ABI-H0731	04454567
ABI-H2158	Assembly Biosciences	Phase I study of the safety, tolerability, pharmacokinetics, and food effect of ABI-H2158 in healthy volunteers and CHB patients	ABI-H2158 had good safety and met the safety standard of once-daily dosing	ALT elevation and hypertriglyceridemia	03714152
Phase IIa, multicenter, single-blind, placebo-controlled, multiple cohort study to evaluate ABI-H2158-containing regimens in CHB patients	Assembly Biosciences discontinued development of hepatitis drug ABI-H2158	Grade 3/4 elevations in ALT	04398134
NVR-3-778	Novira Therapeutics, Inc.	Phase Ib, dose-ranging study to assess the safety, pharmacokinetics and initial antiviral efficacy of NVR 3-778 in patients with HBeAg-positive CHB infection	The mean reduction in HBV RNA was also greatest in the group given NVR 3-778 + PEG-IFN compared with the groups given NVR 3-778 or PEG-IFN alone	Fatigue, influenza-type illness, and injection site erythema	02401737
JNJ-56136379 (JNJ-6379)	Janssen Research & Development, LLC	Phase IIa, randomized, partially-blind, placebo-controlled study to assess the efficacy, safety, and pharmacokinetics of treatment with multiple doses of JNJ-6379 as monotherapy and in combination with a nucleos(t)ide analog in CHB subjects	The mean reduction in HBsAg was 0.4 log10 IU·mL^-1 in the group given JNJ-6379 + nucleos(t)ide analog	There were no discontinuations and no pattern of dose-related adverse effects with JNJ-6379	03361956
GST-HG141	Fujian Cosunter Pharmaceutical Co. Ltd.	Phase Ia, single-center, randomized, double-blind, placebo-controlled clinical trial to evaluate the tolerability and pharmacokinetics of GST-HG141 in healthy subjects	GST-HG141 was well-tolerated in healthy subjects	Renal and urinary disorders, neutropenia, and hypertriglyceridemia	04386915
QL-007	Qilu Pharmaceutical Co., Ltd.	Phase II, open-label study to evaluate safety and efficacy of QL-007 tablets in combination with ETV or TFV in CHB patients	Not available	Not available	04157257

Drug

Company

Study type

Study result

Adverse event

NCT

GLS4

Sunshine Lake Pharma Co., Ltd.

Phase I, single-center, open label clinical study to evaluate the pharmacokinetic character of GLS4 combined with RTV or TAF alone or GLS4 and RTV and TAF combination administration in healthy subjects

HBV DNA levels were decreased by -1.42 log10 IU·mL^-1, -2.13 log10 IU·mL^-1 and -3.5 log10 IU·mL^-1 respectively for 28 days

AST and ALT elevation

04551261

Phase II clinical study to evaluate the safety, tolerability, and antiviral activity of GLS4 with RTV in combination with ETV in comparison with ETV alone in CHB patients

The antiviral efficacy of combination therapy of GLS4/RTV with ETV was remarkably superior to ETV alone

ALT elevation and hypertriglyceridemia

04147208

RO7049389

Hoffmann-La Roche

Phase I clinical study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of RO7049389 in healthy volunteers and CHB participants

RO7049389 was safe and well tolerated and demonstrated antiviral activity over 4 weeks in CHB patients

Headache, diarrhoea, upper respiratory tract infection, ALT elevation, and AST elevation

02952924

ZM-H1505R

Shanghai Zhimeng Biopharma, Inc.

Phase I, randomized, double-blind, placebo-controlled study following oral administration in healthy subjects to evaluate the safety, tolerability, and pharmacokinetics of ZM-H1505R

Multiple doses of up to 300 mg of ZM-H1505R were safe and well tolerated in healthy subjects

Gastrointestinal disorders

04220801

ALG-000184

Aligos Therapeutics

Phase I, double-blind, randomized, placebo-controlled study to evaluate safety, tolerability, pharmacokinetics and pharmacodynamic in healthy volunteers and CHB patients

ALG-000184 was safe, well tolerated and with no food effect, at single oral doses up to 500 mg in healthy volunteers

ALT elevation

04536337

JNJ-64530440 (JNJ-0440)

Alios Biopharma Inc.

Phase I, double-blind, randomized, placebo-controlled study of orally administered JNJ-0440 to evaluate the safety, tolerability, and pharmacokinetics after single ascending doses in healthy subjects and CHB subjects

JNJ-0440 750 mg once-daily or twice-daily for 28 days was well tolerated and achieved anti-HBV activity in CHB patients

ALT increase, blood potassium increase, neutrophil count decrease, and headache

03439488

ABI-H0731
(vebicorvir)

Assembly Biosciences

Phase IIa, multi-center, double-blind, placebo-controlled study to evaluate ABI-H0731 + ETV and ETV alone for the treatment of CHB patients

Declines of HBV DNA and RNA levels were more evident in the association therapy groups than with ETV alone

Upper respiratory tract infection, nervous system disorders, and skin and subcutaneous tissue disorders

03577171

Phase IIa, multi-center, double-blind, placebo-controlled study to evaluate ABI-H0731 as adjunctive therapy in virally-suppressed CHB patients

ABI-H0731 was demonstrated a favourable safety and tolerability profile for 24 weeks

Blood and lymphatic system disorders, gastrointestinal disorders, and upper respiratory tract infection

03576066

Phase IIa, multi-center, single-blind, placebo-controlled study to evaluate treatment intensification with ABI-H0731 in CHB patients

ABI-H0731 was well tolerated and achieved anti-HBV activity in CHB patients

HBV DNA and RNA levels were rebounded immediately after withdrawal ABI-H0731

04454567

ABI-H2158

Assembly Biosciences

Phase I study of the safety, tolerability, pharmacokinetics, and food effect of ABI-H2158 in healthy volunteers and CHB patients

ABI-H2158 had good safety and met the safety standard of once-daily dosing

ALT elevation and hypertriglyceridemia

03714152

Phase IIa, multicenter, single-blind, placebo-controlled, multiple cohort study to evaluate ABI-H2158-containing regimens in CHB patients

Assembly Biosciences discontinued development of hepatitis drug ABI-H2158

Grade 3/4 elevations in ALT

04398134

NVR-3-778

Novira Therapeutics, Inc.

Phase Ib, dose-ranging study to assess the safety, pharmacokinetics and initial antiviral efficacy of NVR 3-778 in patients with HBeAg-positive CHB infection

The mean reduction in HBV RNA was also greatest in the group given NVR 3-778 + PEG-IFN compared with the groups given NVR 3-778 or PEG-IFN alone

Fatigue, influenza-type illness, and injection site erythema

02401737

JNJ-56136379 (JNJ-6379)

Janssen Research & Development, LLC

Phase IIa, randomized, partially-blind, placebo-controlled study to assess the efficacy, safety, and pharmacokinetics of treatment with multiple doses of JNJ-6379 as monotherapy and in combination with a nucleos(t)ide analog in CHB subjects

The mean reduction in HBsAg was 0.4 log10 IU·mL^-1 in the group given JNJ-6379 + nucleos(t)ide analog

There were no discontinuations and no pattern of dose-related adverse effects with JNJ-6379

03361956

GST-HG141

Fujian Cosunter Pharmaceutical Co. Ltd.

Phase Ia, single-center, randomized, double-blind, placebo-controlled clinical trial to evaluate the tolerability and pharmacokinetics of GST-HG141 in healthy subjects

GST-HG141 was well-tolerated in healthy subjects

Renal and urinary disorders, neutropenia, and hypertriglyceridemia

04386915

QL-007

Qilu Pharmaceutical Co., Ltd.

Phase II, open-label study to evaluate safety and efficacy of QL-007 tablets in combination with ETV or TFV in CHB patients

Not available

04157257

Drug	Company	Study type	Study result	Adverse event	NCT
AB-729	Arbutus Biopharma Corporation	Phase II, randomized, open-label, multicenter study to investigate AB-729, nucleos(t)ide analogue and PEG-IFNα-2a treatment in CHB subjects	Not available	Not available	04980482
ARB-001467	Arbutus Biopharma Corporation	Phase IIa, single-blind, randomized, placebo-controlled study to evaluate the safety, anti-HBV activity, and pharmacokinetics of ARB-001467 in CHB subjects receiving nucleos(t)ide analogue therapy	All subjects experienced a mean 1.4 log10 IU·mL^-1 reduction in HBsAg levels	Mild adverse events	02631096
GSK3228836(bepirovirsen)	GlaxoSmithKline	Phase II, open label, single arm study to mechanistically interrogate the therapeutic effect of GSK3228836 in CHB patients	Not available	Not available	04544956
Phase II, double-blinded, randomized, placebo-controlled, dose-escalation study to examine the safety, tolerability, pharmacokinetics and antiviral activity of GSK3228836 in CHB patients	HBV DNA and HBsAg reductions were obvious in patients receiving GSK3228836 300 mg	Blood and lymphatic system disorders, and gastrointestinal disorders	02981602
VIR-2218	Vir Biotechnology, Inc.	Phase I/II, randomized, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of VIR-2218	Decline in level of HBsAg was observed in CHB patients receiving VIR-2218 within 36 weeks	Mild adverse events	03672188
JNJ-73763989 (ARO-HBV)	Arrowhead Pharmaceuticals	Phase I, single-dose, open-label, parallel-group study to evaluate the effect of hepatic impairment on the pharmacokinetics of JNJ-3989	A single 200 mg dose of JNJ-3989 was in general safe and well-tolerated in participants with and without moderate hepatic impairment	Thrombocytopenia	04208386
Phase IIb, randomized, double blind, placebo-controlled study to evaluate efficacy, pharmacokinetics, and safety of JNJ 3989 + JNJ 6379 + nucleos(t)ide analog regimen in CHB participants	The combination therapy was well tolerated and decline of HBsAg was observed in CHB patients	ALT elevation and respiratory tract infection	04129554
Phase IIb, multicenter, double-blind, active-controlled, randomized study to investigate the efficacy and safety of different combination regimens including JNJ-3989 and/or JNJ-6379 for CHB infection	HBsAg change from baseline was -2.6 log10 IU·mL^-1 in patients receiving JNJ-3989 200 mg	ALT elevation and rhabdomyolysis	03982186
ARC-520	Arrowhead Pharmaceuticals	Phase I, randomized, double-blind, placebo-controlled, dose-escalating study to evaluate the safety, tolerability and pharmacokinetics of ARC-520 in healthy volunteers	It was safe and tolerated well in healthy volunteers receiving 2 mg·kg^-1 ARC-520	Mild adverse events	01872065
Phase II, multicenter study to determine the depth and duration of HBsAg reduction after single or multiple doses of ARC-520, in combination with ETV in CHB patients	Declines of HBsAg levels were more evident in HBeAg-positive patients	Gastrointestinal disorders, influenza like illness, and metabolism disorders	02065336

Drug

Company

Study type

Study result

Adverse event

NCT

AB-729

Arbutus Biopharma Corporation

Phase II, randomized, open-label, multicenter study to investigate AB-729, nucleos(t)ide analogue and PEG-IFNα-2a treatment in CHB subjects

Not available

04980482

ARB-001467

Arbutus Biopharma Corporation

Phase IIa, single-blind, randomized, placebo-controlled study to evaluate the safety, anti-HBV activity, and pharmacokinetics of ARB-001467 in CHB subjects receiving nucleos(t)ide analogue therapy

All subjects experienced a mean 1.4 log10 IU·mL^-1 reduction in HBsAg levels

Mild adverse events

02631096

GSK3228836(bepirovirsen)

GlaxoSmithKline

Phase II, open label, single arm study to mechanistically interrogate the therapeutic effect of GSK3228836 in CHB patients

Not available

04544956

Phase II, double-blinded, randomized, placebo-controlled, dose-escalation study to examine the safety, tolerability, pharmacokinetics and antiviral activity of GSK3228836 in CHB patients

HBV DNA and HBsAg reductions were obvious in patients receiving GSK3228836 300 mg

Blood and lymphatic system disorders, and gastrointestinal disorders

02981602

VIR-2218

Vir Biotechnology, Inc.

Phase I/II, randomized, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of VIR-2218

Decline in level of HBsAg was observed in CHB patients receiving VIR-2218 within 36 weeks

Mild adverse events

03672188

JNJ-73763989
(ARO-HBV)

Arrowhead Pharmaceuticals

Phase I, single-dose, open-label, parallel-group study to evaluate the effect of hepatic impairment on the pharmacokinetics of JNJ-3989

A single 200 mg dose of JNJ-3989 was in general safe and well-tolerated in participants with and without moderate hepatic impairment

Thrombocytopenia

04208386

Phase IIb, randomized, double blind, placebo-controlled study to evaluate efficacy, pharmacokinetics, and safety of JNJ 3989 + JNJ 6379 + nucleos(t)ide analog regimen in CHB participants

The combination therapy was well tolerated and decline of HBsAg was observed in CHB patients

ALT elevation and respiratory tract infection

04129554

Phase IIb, multicenter, double-blind, active-controlled, randomized study to investigate the efficacy and safety of different combination regimens including JNJ-3989 and/or JNJ-6379 for CHB infection

HBsAg change from baseline was -2.6 log10 IU·mL^-1 in patients receiving JNJ-3989 200 mg

ALT elevation and rhabdomyolysis

03982186

ARC-520

Arrowhead Pharmaceuticals

Phase I, randomized, double-blind, placebo-controlled, dose-escalating study to evaluate the safety, tolerability and pharmacokinetics of ARC-520 in healthy volunteers

It was safe and tolerated well in healthy volunteers receiving 2 mg·kg^-1 ARC-520

Mild adverse events

01872065

Phase II, multicenter study to determine the depth and duration of HBsAg reduction after single or multiple doses of ARC-520, in combination with ETV in CHB patients

Declines of HBsAg levels were more evident in HBeAg-positive patients

Gastrointestinal disorders, influenza like illness, and metabolism disorders

02065336

Drug	Company	Study type	Study result	Adverse event	NCT
GST-HG131	Fujian Cosunter Pharmaceutical Co. Ltd.	Phase I, single-center, randomized, double-blind, placebo-controlled clinical trial to evaluate the safety, tolerability and pharmacokinetics of GST-HG131 in healthy subjects	Not available	Not available	04499443
REP 2139-Ca	Replicor Inc.	Phase II study to evaluate safety and efficacy of combination treatment with REP 2139-Ca and Pegasys™ in patients with HBV/HDV co-infection	Long-term safety of REP 2139-Ca + PEG-IFNα-2a was observed in patients with HBV/HDV co-infection	ALT elevation and thrombocytopenia	02233075
REP 2139-Mg	Replicor Inc.	Phase II, open-label, randomized, active controlled study to evaluate REP 2139-Mg and REP 2165-Mg combination therapy in CHB subjects	The safety and tolerability were well in CHB subjects receiving REP 2139-Mg + TDF + PEG-IFNα-2a (90 μg)	ALT, AST and GGT elevation	02565719
ALG-010133	Aligos Therapeutics	Phase I, double-blind, randomized, placebo-controlled study of ALG-010133 drug to evaluate safety, tolerability, pharmacokinetics and pharmacodynamics after single and multiple doses in healthy volunteers and CHB subjects	No significative reduction on HBsAg levels in healthy volunteers receiving ALG-010133 at 400 mg dose level. And Aligos announced termination of clinical development of ALG-010133‎‎	Diarrhoea, erythema, headache and nausea	04485663

Drug

Company

Study type

Study result

Adverse event

NCT

GST-HG131

Fujian Cosunter Pharmaceutical Co. Ltd.

Phase I, single-center, randomized, double-blind, placebo-controlled clinical trial to evaluate the safety, tolerability and pharmacokinetics of GST-HG131 in healthy subjects

Not available

04499443

REP
2139-Ca

Replicor Inc.

Phase II study to evaluate safety and efficacy of combination treatment with REP 2139-Ca and Pegasys™ in patients with HBV/HDV co-infection

Long-term safety of REP 2139-Ca + PEG-IFNα-2a was observed in patients with HBV/HDV co-infection

ALT elevation and thrombocytopenia

02233075

REP
2139-Mg

Replicor Inc.

Phase II, open-label, randomized, active controlled study to evaluate REP 2139-Mg and REP 2165-Mg combination therapy in CHB subjects

The safety and tolerability were well in CHB subjects receiving REP 2139-Mg + TDF + PEG-IFNα-2a (90 μg)

ALT, AST and GGT elevation

02565719

ALG-010133

Aligos Therapeutics

Phase I, double-blind, randomized, placebo-controlled study of ALG-010133 drug to evaluate safety, tolerability, pharmacokinetics and pharmacodynamics after single and multiple doses in healthy volunteers and CHB subjects

No significative reduction on HBsAg levels in healthy volunteers receiving ALG-010133 at 400 mg dose level. And Aligos announced termination of clinical development of ALG-010133‎‎

Diarrhoea, erythema, headache and nausea

04485663

Drug	Company	Study type	Study result	Adverse event	NCT
ATI-2173	Antios Therapeutics, Inc.	Phase I, open-label, safety and tolerability, fixed-sequence study to investigate the potential interaction between ATI-2173 and TDF in healthy subjects	Not available	Not available	05137548
Phase I, double-blinded study for safety, tolerability, pharmacokinetics, and antiviral activity of ATI-2173 in healthy volunteers and CHB subjects	ATI-2173 at 10-50 mg orally per day had potent antiviral activity	There were no deaths, serious adverse events or discontinuations	04248426
Phase IIa, randomized, double-blinded, placebo-controlled study to evaluate safety and efficacy of ATI-2173 in combination with TDF in patients with HBV/HDV co-infection	Not available	Not available	04847440
Tenofovir exalidex (TXL)	ContraVir Pharmaceuticals, Inc.	Phase I, open-label study to investigate the effect of renal impairment on the pharmacokinetics of Tenofovir exalidex	Not available	Not available	03284164
Besifovir (BSV)	IlDong Pharmaceutical Co. Ltd.	Phase III, multi-center, randomized, double-blinded, parallel study to assess the antiviral activity and safety endpoints for the treatment of Besifovir 150 mg compared to TFV 300 mg in CHB patients	Not available	Not available	02792088
Phase III, multi-center, randomized, double-blinded, parallel study to assess the antiviral activity and safety of Besifovir 150 mg compared to TFV 300 mg in CHB patients for 48 weeks	Bone mineral density and eGFR were not reduced, and the safety was good after 192 weeks	Nasopharyngitis, dyspepsia, ALT elevation, dizziness, and headache	01937806
Phase IV, randomized, open-label, parallel, multi-center clinical trial to evaluate the efficacy and safety of switching to besifovir dipivoxil maleate from TDF in CHB patients	Not available	Not available	04202536
Phase IV, open-label, randomized, single-dose clinical trial to evaluate the food effect on pharmacokinetics of besifovir in healthy volunteers	Not available	Not available	03885778

Drug

Company

Study type

Study result

Adverse event

NCT

ATI-2173

Antios Therapeutics, Inc.

Phase I, open-label, safety and tolerability, fixed-sequence study to investigate the potential interaction between ATI-2173 and TDF in healthy subjects

Not available

05137548

Phase I, double-blinded study for safety, tolerability, pharmacokinetics, and antiviral activity of ATI-2173 in healthy volunteers and CHB subjects

ATI-2173 at 10-50 mg orally per day had potent antiviral activity

There were no deaths, serious adverse events or discontinuations

04248426

Phase IIa, randomized, double-blinded, placebo-controlled study to evaluate safety and efficacy of ATI-2173 in combination with TDF in patients with HBV/HDV co-infection

Not available

04847440

Tenofovir exalidex (TXL)

ContraVir Pharmaceuticals, Inc.

Phase I, open-label study to investigate the effect of renal impairment on the pharmacokinetics of Tenofovir exalidex

Not available

03284164

Besifovir
(BSV)

IlDong Pharmaceutical Co. Ltd.

Phase III, multi-center, randomized, double-blinded, parallel study to assess the antiviral activity and safety endpoints for the treatment of Besifovir 150 mg compared to TFV 300 mg in CHB patients

Not available

02792088

Phase III, multi-center, randomized, double-blinded, parallel study to assess the antiviral activity and safety of Besifovir 150 mg compared to TFV 300 mg in CHB patients for 48 weeks

Bone mineral density and eGFR were not reduced, and the safety was good after 192 weeks

Nasopharyngitis, dyspepsia, ALT elevation, dizziness, and headache

01937806

Phase IV, randomized, open-label, parallel, multi-center clinical trial to evaluate the efficacy and safety of switching to besifovir dipivoxil maleate from TDF in CHB patients

Not available

04202536

Phase IV, open-label, randomized, single-dose clinical trial to evaluate the food effect on pharmacokinetics of besifovir in healthy volunteers

Not available

03885778