Hepatitis b combination therapies
Sequential administration of HBsAg lowering agents and CAMs addresses the inadequacies of current treatments for HBV and HDV infections by reducing viral load and preventing chronic infection through targeted viral inhibition.
Patent Information
- Authority / Receiving Office
- HK · HK
- Patent Type
- Applications
- Current Assignee / Owner
- ALIGOS THERAPEUTICS INC
- Filing Date
- 2026-05-18
- Publication Date
- 2026-07-10
AI Technical Summary
Current treatments for hepatitis B virus (HBV) and hepatitis D virus (HDV) infections are inadequate in effectively reducing viral load and preventing progression to chronic infection.
Administering a combination of HBV surface antigen (HBsAg) lowering agents and capsid assembly modulators (CAMs) in a sequential manner, with a delayed administration of the second agent following the first, to target and inhibit viral replication and assembly.
The sequential administration of HBsAg lowering agents and CAMs effectively reduces viral load and prevents chronic infection by targeting key stages of the viral life cycle, providing a therapeutic approach with improved efficacy.
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Abstract
Description
Abstract This article provides a method for treating hepatitis B virus and / or hepatitis D virus infection in subjects in need. In some embodiments, the method includes administering to a subject an effective amount of a first agent selected from the group consisting of: (i) an HBV surface antigen (HBsAg) lowering agent or a pharmaceutically acceptable salt thereof, and / or (ii) a capsid assembly modulator (CAM) or a pharmaceutically acceptable salt thereof, followed by administering to the subject an effective amount of a second agent selected from the group consisting of: (i) a CAM or a pharmaceutically acceptable salt thereof, and (ii) an HBV surface antigen (HBsAg) lowering agent or a pharmaceutically acceptable salt thereof, wherein when the first agent is an HBsAg lowering agent or a pharmaceutically acceptable salt thereof, the second agent is a CAM or a pharmaceutically acceptable salt thereof; and wherein when the first agent is a CAM or a pharmaceutically acceptable salt thereof, the second agent is an HBsAg lowering agent or a pharmaceutically acceptable salt thereof; and wherein the initial administration of the second agent is after a delayed period following the initial administration of the first agent.
Claims
WHAT IS CLAIMED IS:
1. A method of treating hepatitis B viral (HBV) and / or hepatitis D viral (HDV) infection in a subject in need thereof comprising: administering an effective amount of a first agent selected from the group consisting of (i) an HBV surface antigen (HBsAg) reducing agent, or a pharmaceutically acceptable salt thereof, and (ii) a capsid assembly modulator (CAM), or a pharmaceutically acceptable salt thereof, to the subject, followed by administering an effective amount of a second agent selected from the group consisting of (i) a CAM, or a pharmaceutically acceptable salt thereof, and (ii) an HBsAg reducing agent, or a pharmaceutically acceptable salt thereof, to the subject, wherein when the first agent is an HBsAg reducing agent, or a pharmaceutically acceptable salt thereof, the second agent is a CAM, or a pharmaceutically acceptable salt thereof; and wherein when the first agent is a CAM, or a pharmaceutically acceptable salt thereof, the second agent is an HBsAg reducing agent, or a pharmaceutically acceptable salt thereof; and wherein initial administration of the second agent is after a delay period following initial administration of the first agent.
2. The method of Claim 1, wherein the method is a method of treating an HBV infection.
3. The method of Claim 1, wherein the method is a method of treating an HDV infection.
4. The method of any one of Claims 1-3, wherein the first agent is an HBsAg reducing agent or a pharmaceutically acceptable salt thereof; and wherein the second agent is a CAM, or a pharmaceutically acceptable salt thereof.
5. The method of any one of Claims 1-3, wherein the first agent is a CAM, or a pharmaceutically acceptable salt thereof; and wherein the second agent is an HBsAg reducing agent, or a pharmaceutically acceptable salt thereof.
6. The method of any one of Claims 1-5, wherein the CAM is a Class A CAM (CAM-A), or a pharmaceutically acceptable salt thereof.
7. The method of any one of Claims 1-5, wherein the CAM is a Class E CAM (CAM-E), or a pharmaceutically acceptable salt thereof.
8. The method of any one of Claims 1-7, wherein the HBsAg reducing agent is a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO).
9. The method of Claim 6, wherein the CAM is a fused pyrazole compound, a fused pyrimidone compound, or a pyrrole compound, or a pharmaceutically acceptable salt of any of the foregoing.
10. The method of any one of Claims 1-9, wherein the CAM is selected from the group consisting of: N-methyl-4-[(11R)-12-[4-bromo-3-(trifluoromethyl)benzoyl]-5-(cyclopropylmethyl)- 11-methyl-8-oxo-2,3,7,12-tetrazatricyclo[7.4.0.0^2,6]trideca-1(9),3,5-trien-7- yl]benzamide (Compound 1); 4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but-3-en-2-yl)amino)-6- methyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)-N- methylbenzamide (Compound 2); N-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3,5-trimethyl-4-[2-oxo-2-[[(1S)-1- (hydroxymethyl)-1-methyl-prop-2-ynyl]amino]acetyl]pyrrole-2-carboxamide (Compound 3); [[2-[5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-1,2,4-trimethyl-pyrrol-3-yl]-2-oxo- acetyl]-(3-ethynyloxetan-3-yl)amino]methyl dihydrogen phosphate (Compound 4); N-(3-cyano-4-fluoro-phenyl)-4-[2-[(3-ethynyloxetan-3-yl)amino]-2-oxo-acetyl]- 1,3,5-trimethyl-pyrrole-2-carboxamide (Compound 5); (S)-2-(2-(5-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-1,2,4-trimethyl-1H- pyrrol-3-yl)-2-oxoacetamido)-2-methylbut-3-yn-1-yl dihydrogen phosphate (Compound 6); (R)-N-(2-chloropyridin-4-yl)-3-fluoro-1-methyl-4-(N-(1,1,1-trifluoropropan-2- yl)sulfamoyl)-1H-pyrrole-2-carboxamide (Compound 7); BAY 41-4109 (Compound 8); GLS4 (Compound 9); NVR 3-778 (Compound 10); RG7907 (Compound 11); ABI-H0731 (Compound 12); ABI-3773 (Compound 13);ABI-4334 (Compound 14); GLP-26 (Compound 15); KL-060332 (Compound 16); AB-836 (Compound 17); VNRX-9945 (Compound 18); (R)-N-(3-cyano-4-fluorophenyl)-1-methyl-4-(N-(1,1,1-trifluoropropan-2- yl)sulfamoyl)-1H-pyrrole-2-carboxamide (Compound 19); JNJ-64530440 (Compound 20); EDP-514 (Compound 21); (S)-N-(3-cyano-4-fluorophenyl)-7-methyl-3-vinyl-3,4-dihydro-2H,7H-pyrrolo[3,4- b][1,4,5]oxathiazepine-6-carboxamide 1,1-dioxide (Compound 22); ZM-H1505R (Compound 23); (R)-7-(4-bromo-3-chlorobenzoyl)-2-(4-cyclopropoxyphenyl)-6-methyl-3-oxo-N-(2- (pyrimidin-4-yl)benzyl)-2,3,5,6,7,8-hexahydroimidazo[1,5-a]pyrazine-1-carboxamide (Compound 24); (6R)-7-[4-bromo-3-(trifluoromethyl)benzoyl]-2-(3,5-dimethylpyrazol-1-yl)-6-methyl- 3-(3-methylimidazo[4,5-b]pyridin-6-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4- one (Compound 25); 4-[5-benzyl-12-(4-bromo-3-chloro-benzoyl)-8-oxo-2,3,7,12- tetrazatricyclo[7.4.0.0^2,6]trideca-1(9),3,5-trien-7-yl]-N-methyl-benzamide (Compound 26); and (6R)-7-[4-bromo-3-(trifluoromethyl)benzoyl]-2-(3,5-dimethylpyrazol-1-yl)-3-[4- [(2S)-2-hydroxypropoxy]phenyl]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin- 4-one (Compound 27), or a pharmaceutically acceptable salt of any of the foregoing.
11. The method of any one of Claims 1-10, wherein the HBsAg reducing agent is an siRNA.
12. The method of Claim 11, wherein the siRNA is a compound selected from the group consisting of RG6346 (Roche / Dicerna), ARC-520 (Arrowhead), ARC-521 (Arrowhead), ALN-HBV (Alnylam / VIR), VIR-2218 (Alnylam / VIR), AB-729 (Arbutus), and JNJ3989 (Arrowhead / JNJ).
13. The method of Claim 11, wherein the siRNA has a nucleic acid sequence as set forth in SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO:
7.
14. The method of any one of Claims 1-10, wherein the HBsAg reducing agent is an ASO.
15. The method of Claim 14, wherein the ASO is a compound selected from the group consisting of GSK-404 (Isis / GlaxoSmithKline), GSK-836 (Isis / GlaxoSmithKline), and RG6004 (Roche).
16. The method of Claim 14, wherein the ASO has a nucleic acid sequence as set forth in SEQ ID NO:
1.
17. The method of any one of Claims 1-16, wherein initial administration of the second agent occurs after HBsAg levels have been reduced in the subject by administration of the first agent.
18. The method of Claim 17, wherein initial administration of the second agent occurs after HBsAg levels have been reduced to a nadir in the subject by administration of the first agent.
19. The method of Claim 18, wherein the nadir comprises a period of at least one week including at least one additional dose of the first agent, wherein the at least one additional dose results in no statistically significant reduction of HBsAg levels.
20. The method of any one of claims Claim 1-19, wherein initial administration of the second agent occurs after the first agent has been continuously administered for at least one month.
21. The method of any of Claims 1-20, wherein the delay period is greater than approximately 50 days.
22. The method of any of Claims 1-21, wherein the delay period is greater than approximately 2 months.
23. The method of any one of Claims 1-22, wherein the delay period is between approximately 21 days and approximately 168 days.
24. The method of any one of Claims 1-23, wherein the delay period is between approximately 28 days and approximately 91 days.
25. The method of any one of Claims 1-24, wherein the delay period is between approximately 8 weeks and approximately 18 weeks.
26. The method of any one of Claims 1-25, wherein the delay period is approximately 50 days.
27. The method of any one of Claims 1-26, wherein the first agent is administered at least three times at regular intervals, before administration of the second agent.
28. The method of any one of Claims 1-27, wherein the second agent is Compound 1, the first agent is an siRNA having the nucleic acid sequences set forth in SEQ ID NO: 2 and SEQ ID NO: 3, and wherein the delay period comprises 50 days.
29. The method of any one of Claims 1-28, wherein the delay period is determined based on measurement of the subject’s plasma HBsAg levels.
30. The method of any one of Claims 1-29, wherein the delay period extends until the subject’s HBsAg levels are reduced as compared to baseline HBsAg levels.
31. The method of any one of Claims 1-30, wherein the delay period extends until the subject’s plasma HBsAg levels reach a nadir.
32. The method of any one of Claims 1-31, wherein (a) the first agent is Compound 4, or pharmaceutically acceptable salt thereof, and the second agent is an siRNA having the nucleic acid sequences set forth in SEQ ID NO: 6 and SEQ ID NO: 7; or wherein (b) the first agent is an siRNA having the nucleic acid sequences set forth in SEQ ID NO: 6 and SEQ ID NO: 7, and the second agent is Compound 4, or a pharmaceutically acceptable salt thereof.
33. The method of any one of Claims 1-32, further comprising administering an additional agent selected from the group consisting of an interferon, a nucleoside analog, a nucleotide analog, a sequence specific oligonucleotide, a nucleic acid polymer, an entry inhibitor and a small molecule immunomodulator, or a pharmaceutically acceptable salt of any of the foregoing.
34. The method of Claim 33, wherein the additional agent is selected from the group consisting of recombinant interferon alpha 2b, IFN-Į, PEG-IFN-Į-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, and tenofovir disoproxil and an additional siRNA, or a pharmaceutically acceptable salt of any of the foregoing.
35. A method of maintaining low plasma HBsAg levels in a subject having an HBV and / or an HDV infection, comprising: administering an effective amount of a first agent selected from the group consisting of (i) an HBV surface antigen (HBsAg) reducing agent, or a pharmaceutically acceptable salt thereof, and (ii) a capsid assembly modulator (CAM), or a pharmaceutically acceptable salt thereof, to the subject, followed by administering an effective amount of a second agent selected from the group consisting of (i) a CAM, or a pharmaceutically acceptable salt thereof, and (ii) an HBsAg reducing agent, or a pharmaceutically acceptable salt thereof, to the subject, wherein when the first agent is an HBsAg reducing agent, or a pharmaceutically acceptable salt thereof, the second agent is a CAM, or a pharmaceutically acceptable salt thereof; and wherein when the first agent is a CAM, or a pharmaceutically acceptable salt thereof, the second agent is an HBsAg reducing agent, or a pharmaceutically acceptable salt thereof; wherein initial administration of the second agent is after a delay period following initial administration of the first agent.
36. The method of Claim 35, wherein the method is a method of treating an HBV infection.
37. The method of Claim 35, wherein the method is a method of treating an HDV infection.
38. The method of any one of Claims 35-37, wherein the first agent is an HBsAg reducing agent or a pharmaceutically acceptable salt thereof; and wherein the second agent is a CAM, or a pharmaceutically acceptable salt thereof.
39. The method of any one of Claims 35-37, wherein the first agent is a CAM, or a pharmaceutically acceptable salt thereof; and wherein the second agent is an HBsAg reducing agent, or a pharmaceutically acceptable salt thereof.
40. The method of Claim 36, wherein the first agent is a short interfering RNA (siRNA), and wherein the second agent is a Class A capsid assembly modulator (CAM-A) or a Class E capsid assembly modulator (CAM-E), or a pharmaceutically acceptable salt of any of the foregoing.
41. The method of Claim 39, wherein the first agent is a Class A capsid assembly modulator (CAM-A) or a Class E capsid assembly modulator (CAM-E), or a pharmaceutically acceptable salt of any of the foregoing, and wherein the second agent is a short interfering RNA (siRNA).
42. The method of any one of Claims 35-41, wherein (a) the first agent is Compound 4, or pharmaceutically acceptable salt thereof, and the second agent is an siRNA having the nucleic acid sequences set forth in SEQ ID NO: 6 and SEQ ID NO: 7; or wherein (b) the first agent is an siRNA having the nucleic acid sequences set forth in SEQ ID NO: 6 and SEQ ID NO: 7, and the second agent is Compound 4, or a pharmaceutically acceptable salt thereof.
43. The method of any one of Claims 35-42, further comprising administering an additional agent selected from the group consisting of an interferon, a nucleoside analog, a nucleotide analog, a sequence specific oligonucleotide, a nucleic acid polymer, an entry inhibitor and a small molecule immunomodulator, or a pharmaceutically acceptable salt of any of the foregoing.
44. The method of Claim 43, wherein the additional agent is selected from the group consisting of recombinant interferon alpha 2b, IFN-Į, PEG-IFN-Į-2a, lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, and tenofovir disoproxil and an additional siRNA, or a pharmaceutically acceptable salt of any of the foregoing.
45. An improved method of treating a hepatitis B viral and / or a hepatitis D viral infection in a subject for whom therapy with a first agent selected from the group consisting of (i) an HBV surface antigen (HBsAg) reducing agent, or a pharmaceutically acceptable salt thereof, and (ii) a capsid assembly modulator (CAM), or a pharmaceutically acceptable salt thereof, has been initiated, the improved method comprising administering an effective amount of a second agent selected from the group consisting of (i) a CAM, or a pharmaceutically acceptable salt thereof, and (ii) an HBsAg reducing agent, or a pharmaceutically acceptable salt thereof, to the subject, wherein when the first agent is an HBsAg reducing agent, or a pharmaceutically acceptable salt thereof, the second agent is a CAM, or a pharmaceutically acceptable salt thereof; and wherein when the first agent is a CAM, or a pharmaceuticallyacceptable salt thereof, the second agent is an HBsAg reducing agent, or a pharmaceutically acceptable salt thereof; wherein initial administration of the second agent is after a delay period following initial administration of the first agent.
46. The improved method of Claim 45, wherein the improved method is an improved method of treating a hepatitis B viral infection.
47. The improved method of Claim 45, wherein the improved method is an improved method of treating a hepatitis D viral infection.
48. The improved method of any one of Claims 45-47, wherein the first agent is an HBsAg reducing agent, or a pharmaceutically acceptable salt thereof; and wherein the second agent is a CAM, or a pharmaceutically acceptable salt thereof.
49. The improved method of any one of Claims 45-47, wherein the first agent is a CAM, or a pharmaceutically acceptable salt thereof; and wherein the second agent is an HBsAg reducing agent, or a pharmaceutically acceptable salt thereof.
50. The improved method of any one of Claims 45-49, wherein the CAM is a Class A CAM (CAM-A), or a pharmaceutically acceptable salt thereof.
51. The improved method of any one of Claims 45-49, wherein the CAM is a Class E CAM (CAM-E), or a pharmaceutically acceptable salt thereof.
52. The improved method of any one of Claims 45-51, wherein the HBsAg reducing agent is a small interfering RNA (siRNA) or an antisense oligonucleotide (ASO).
53. The improved method of any one of Claims 45-52, wherein the CAM is a fused pyrazole compound or a fused pyrimidone compound, or a pharmaceutically acceptable salt of any of the foregoing.
54. The improved method of any one of Claims 45-53, wherein the CAM is selected from the group consisting of: N-methyl-4-[(11R)-12-[4-bromo-3-(trifluoromethyl)benzoyl]-5-(cyclopropylmethyl)- 11-methyl-8-oxo-2,3,7,12-tetrazatricyclo[7.4.0.0^2,6]trideca-1(9),3,5-trien-7- yl]benzamide (Compound 1); 4-((R)-7-(4-bromo-3-(trifluoromethyl)benzoyl)-2-(((S)-but-3-en-2-yl)amino)-6- methyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H)-yl)-N- methylbenzamide (Compound 2);N-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3,5-trimethyl-4-[2-oxo-2-[[(1S)-1- (hydroxymethyl)-1-methyl-prop-2-ynyl]amino]acetyl]pyrrole-2-carboxamide (Compound 3); [[2-[5-[(3-cyano-4-fluoro-phenyl)carbamoyl]-1,2,4-trimethyl-pyrrol-3-yl]-2-oxo- acetyl]-(3-ethynyloxetan-3-yl)amino]methyl dihydrogen phosphate (Compound 4); N-(3-cyano-4-fluoro-phenyl)-4-[2-[(3-ethynyloxetan-3-yl)amino]-2-oxo-acetyl]- 1,3,5-trimethyl-pyrrole-2-carboxamide (Compound 5); (S)-2-(2-(5-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-1,2,4-trimethyl-1H- pyrrol-3-yl)-2-oxoacetamido)-2-methylbut-3-yn-1-yl dihydrogen phosphate (Compound 6); (R)-N-(2-chloropyridin-4-yl)-3-fluoro-1-methyl-4-(N-(1,1,1-trifluoropropan-2- yl)sulfamoyl)-1H-pyrrole-2-carboxamide (Compound 7); BAY 41-4109 (Compound 8); GLS4 (Compound 9); NVR 3-778 (Compound 10); RG7907 (Compound 11); ABI-H0731 (Compound 12); ABI-3773 (Compound 13); ABI-4334 (Compound 14); GLP-26 (Compound 15); KL-060332 (Compound 16); AB-836 (Compound 17); VNRX-9945 (Compound 18); (R)-N-(3-cyano-4-fluorophenyl)-1-methyl-4-(N-(1,1,1-trifluoropropan-2- yl)sulfamoyl)-1H-pyrrole-2-carboxamide (Compound 19); JNJ-64530440 (Compound 20); EDP-514 (Compound 21); (S)-N-(3-cyano-4-fluorophenyl)-7-methyl-3-vinyl-3,4-dihydro-2H,7H-pyrrolo[3,4- b][1,4,5]oxathiazepine-6-carboxamide 1,1-dioxide (Compound 22); ZM-H1505R (Compound 23);(R)-7-(4-bromo-3-chlorobenzoyl)-2-(4-cyclopropoxyphenyl)-6-methyl-3-oxo-N-(2- (pyrimidin-4-yl)benzyl)-2,3,5,6,7,8-hexahydroimidazo[1,5-a]pyrazine-1-carboxamide (Compound 24); (6R)-7-[4-bromo-3-(trifluoromethyl)benzoyl]-2-(3,5-dimethylpyrazol-1-yl)-6-methyl- 3-(3-methylimidazo[4,5-b]pyridin-6-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4- one (Compound 25); 4-[5-benzyl-12-(4-bromo-3-chloro-benzoyl)-8-oxo-2,3,7,12- tetrazatricyclo[7.4.0.0^2,6]trideca-1(9),3,5-trien-7-yl]-N-methyl-benzamide (Compound 26); and (6R)-7-[4-bromo-3-(trifluoromethyl)benzoyl]-2-(3,5-dimethylpyrazol-1-yl)-3-[4- [(2S)-2-hydroxypropoxy]phenyl]-6-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin- 4-one (Compound 27), or a pharmaceutically acceptable salt of any of the foregoing.
55. The improved method of any one of Claims 45-54, wherein the HBsAg reducing agent is an siRNA.
56. The improved method of Claim 55, wherein the siRNA is a compound selected from the group consisting of RG6346 (Roche / Dicerna), ARC-520 (Arrowhead), ARC-521 (Arrowhead), ALN-HBV (Alnylam / VIR), VIR-2218 (Alnylam / VIR), AB-729 (Arbutus), and JNJ3989 (Arrowhead / JNJ).
57. The improved method of Claim 55, wherein the siRNA has a nucleic acid sequence as set forth in SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO:
7.
58. The improved method of any one of Claims 45-54, wherein the HBsAg reducing agent is an ASO.
59. The improved method of Claim 58, wherein the ASO is a compound selected from the group consisting of GSK-404 (Isis / GlaxoSmithKline), GSK-836 (Isis / GlaxoSmithKline), and RG6004 (Roche).
60. The improved method of Claim 58, wherein the ASO has a nucleic acid sequence as set forth in SEQ ID NO:
1.
61. The improved method of any one of Claims 45-60, wherein initial administration of the second agent occurs after the first agent has been continuously administered for at least one month.
62. The improved method of any one of Claims 45-61, wherein the delay period is greater than approximately 50 days.
63. The improved method of any one of Claims 45-62, wherein the delay period is greater than approximately 2 months.
64. The improved method of any one of Claims 45-63, wherein the delay period is between approximately 21 days and approximately 168 days.
65. The improved method of any one of Claims 45-64, wherein the delay period is between approximately 28 days and approximately 91 days.
66. The improved method of any one of Claims 45-65, wherein the delay period is between approximately 8 weeks and approximately 18 weeks.
67. The improved method of any one of Claims 45-66, wherein the first agent is administered at least three times at regular intervals before administration of the second agent.
68. The improved method of any one of Claims 45-67, wherein the CAM is Compound 1, or a pharmaceutically acceptable salt thereof, the HBsAg reducing agent is an siRNA having the nucleic acid sequences set forth in SEQ ID NO: 2 and SEQ ID NO: 3, and the delay period comprises 50 days.
69. The improved method of any one of Claims 45-68, wherein the hepatitis B viral infection is a chronic hepatitis B viral infection.
70. The improved method of any one of Claims 45-69, wherein (a) the first agent is Compound 4, or pharmaceutically acceptable salt thereof, and the second agent is an siRNA having the nucleic acid sequences set forth in SEQ ID NO: 6 and SEQ ID NO: 7; or wherein (b) the first agent is an siRNA having the nucleic acid sequences set forth in SEQ ID NO: 6 and SEQ ID NO: 7, and the second agent is Compound 4, or a pharmaceutically acceptable salt thereof.
71. The improved method of any one of Claims 45-70, further comprising administering an additional agent selected from the group consisting of an interferon, a nucleoside analog, a nucleotide analog, a sequence specific oligonucleotide, a nucleic acid polymer, an entry inhibitor and a small molecule immunomodulator, or a pharmaceutically acceptable salt of any of the foregoing.
72. The improved method of Claim 72, wherein the additional agent is selected from the group consisting of recombinant interferon alpha 2b, IFN-Į, PEG-IFN-Į-2a,lamivudine, telbivudine, adefovir dipivoxil, clevudine, entecavir, tenofovir alafenamide, and tenofovir disoproxil and an additional siRNA, or a pharmaceutically acceptable salt of any of the foregoing.