Hepatitis B virus (HBV) dsRNA agent compositions and methods of use thereof

1. A method of treating a subject having a Hepatitis B virus (HBV)-associated disorder or a HBV infection, comprising administering to the subject a therapeutically effective amount of a double stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand forming a double stranded region, wherein the dsRNA agent is administered to the subject at a dose of 0.01 mg/kg to 10 mg/kg, 0.5 mg/kg to 50 mg/kg, or 50 to 900 mg, and wherein the antisense strand and the sense strand comprise the modified nucleotide sequences as set forth in, respectively:

(a)

(SEQ ID NO: 16)

5′-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca-3′;

(b)

(SEQ ID NO: 18)

5′-usGfsuga(Agn)gcgaaguGfdCAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca-3′;

(c)

(SEQ ID NO: 20)

5′-usGfsudGa(Agn)gCfGfaaguGfcAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca-3′;

(d)

(SEQ ID NO: 23)

5′-usGfsudGadAgdCGfaaguGfcAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca -3′;

(e)

(SEQ ID NO: 24)

5′-usGfsuga(Agn)dGCfGfaaguGfcAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca -3′;

(f)

(SEQ ID NO: 25)

5′-usGfsudGadAgdCGfaaguGfcAfdCacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca -3′;

or

(g)

(SEQ ID NO: 28)

5′-usGfsuga(Agn)gCfGfaaguGfdCAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca-3′;

wherein a, c, g, and u are 2′-O-methyladenosine-3′-phosphate, 2′-O-methylcytidine-3′-phosphate, 2′-O-methylguanosine-3′-phosphate, and 2′-O-methyluridine-3′-phosphate, respectively;

Af, Cf, Gf, and Uf are 2′-fluoroadenosine-3′-phosphate, 2′-fluorocytidine-3′-phosphate, 2′-fluoroguanosine-3′-phosphate, and 2′-fluorouridine-3′-phosphate, respectively;

dA, dC, dG, and dT are 2′-deoxyadenosine-3′-phosphate, 2′-deoxycytidine-3′-phosphate, 2′-deoxyguanosine-3′-phosphate, and 2′-deoxythymidine-3′-phosphate, respectively;

(Agn) is adenosine-glycol nucleic acid (GNA); and

s is a phosphorothioate linkage;

thereby treating the subject.

2. The method of claim 1 , wherein the HBV-associated disorder is chronic hepatitis and the subject is HBeAg positive.

3. The method of claim 1 , wherein the HBV-associated disorder is chronic hepatitis and the subject is HBeAg negative.

4. The method of claim 1 , wherein the dsRNA agent is administered to the subject at a dose of 3 mg/kg to 10 mg/kg.

5. The method of claim 1 , wherein the dsRNA agent is administered to the subject at a fixed dose of 50 mg to 200 mg.

6. The method of claim 1 , wherein the dsRNA agent is administered to the subject subcutaneously.

7. The method of claim 1 , wherein the dsRNA agent is administered to the subject in two or more doses.

8. The method of claim 1 , wherein the dsRNA agent is administered to the subject once per month, once every two months, or once every three months.

9. The method of claim 1 , wherein the dsRNA agent is administered to the subject no more than once per month.

10. The method of claim 5 , wherein the subject is being or has been administered one or more additional therapeutic agents.

11. The method of claim 10 , wherein the additional therapeutic agent is an antiviral agent, a reverse transcriptase inhibitor, an immune stimulator, a therapeutic vaccine, a viral entry inhibitor, an oligonucleotide that inhibits the secretion or release of HbsAg, a capsid inhibitor, a covalently closed circular (ccc) HBV DNA inhibitor, or a combination of any of the foregoing.

12. The method of claim 10 , wherein the additional therapeutic agent is a reverse transcriptase inhibitor.

13. The method of claim 10 , wherein the additional therapeutic agents are a reverse transcriptase inhibitor and an immune stimulator.

14. The method of claim 12 , wherein the reverse transcriptase inhibitor is Tenofovir disoproxil fumarate (TDF), Tenofovir alafenamide, Lamivudine, Adefovir dipivoxil, Entecavir (ETV), Telbivudine, AGX-1009, or any combination thereof.

15. The method of claim 13 , wherein the immune stimulator is pegylated interferon alfa 2a (PEG-IFN-α2a), Interferon alfa-2b, a recombinant human interleukin-7, a Toll-like receptor 7 (TLR7) agonist, or any combination thereof.

16. The method of claim 1 , wherein the HBV-associated disorder is hepatitis D virus (HDV) infection.

17. The method of claim 1 , wherein the HBV-associated disorder is delta hepatitis, acute hepatitis B, acute fulminant hepatitis B, chronic hepatitis B, liver fibrosis, end-stage liver disease, or hepatocellular carcinoma.

18. The method of claim 1 , wherein the dsRNA agent is administered to the subject at a fixed dose of 200 mg.

19. A kit comprising:

(1) a double stranded ribonucleic acid (dsRNA) agent, comprising a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand and the sense strand comprise the modified nucleotide sequences as set forth in, respectively:

(a)

(SEQ ID NO: 16)

5′-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca-3′;

(b)

(SEQ ID NO: 18)

5′-usGfsuga(Agn)gcgaaguGfdCAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca-3′;

(c)

(SEQ ID NO: 20)

5′-usGfsudGa(Agn)gCfGfaaguGfcAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca-3′;

(d)

(SEQ ID NO: 23)

5′-usGfsudGadAgdCGfaaguGfcAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca -3′;

(e)

(SEQ ID NO: 24)

5′-usGfsuga(Agn)dGCfGfaaguGfcAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca -3′;

(f)

(SEQ ID NO: 25)

5′-usGfsudGadAgdCGfaaguGfcAfdCacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca -3′;

or

(g)

(SEQ ID NO: 28)

5′-usGfsuga(Agn)gCfGfaaguGfdCAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca-3′;

wherein a, c, g, and u are 2′-O-methyladenosine-3′-phosphate, 2′-O-methylcytidine-3′-phosphate, 2′-O-methylguanosine-3′-phosphate, and 2′-O-methyluridine-3′-phosphate, respectively;

Af, Cf, Gf, and Uf are 2′-fluoroadenosine-3′-phosphate, 2′-fluorocytidine-3′-phosphate, 2′-fluoroguanosine-3′-phosphate, and 2′-fluorouridine-3′-phosphate, respectively;

dA, dC, dG, and dT are 2′-deoxyadenosine-3′-phosphate, 2′-deoxycytidine-3′-phosphate, 2′-deoxyguanosine-3′-phosphate, and 2′-deoxythymidine-3′-phosphate, respectively;

(Agn) is adenosine-glycol nucleic acid (GNA); and

s is a phosphorothioate linkage; and

(2) instructions for use according to the method of claim 1 .

20. A method of treating a subject having a Hepatitis B virus (HBV)-associated disorder or a HBV infection, comprising administering to the subject:

(1) a therapeutically effective amount of a double stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand and the sense strand comprise the modified nucleotide sequences as set forth in, respectively:

(a)

(SEQ ID NO: 16)

5′-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca-3′;

(b)

(SEQ ID NO: 18)

5′-usGfsuga(Agn)gcgaaguGfdCAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca-3′;

(c)

(SEQ ID NO: 20)

5′-usGfsudGa(Agn)gCfGfaaguGfcAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca-3′;

(d)

(SEQ ID NO: 23)

5′-usGfsudGadAgdCGfaaguGfcAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca -3′;

(e)

(SEQ ID NO: 24)

5′-usGfsuga(Agn)dGCfGfaaguGfcAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca -3′;

(f)

(SEQ ID NO: 25)

5′-usGfsudGadAgdCGfaaguGfcAfdCacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca -3′;

or

(g)

(SEQ ID NO: 28)

5′-usGfsuga(Agn)gCfGfaaguGfdCAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca-3′;

wherein a, c, g, and u are 2′-O-methyladenosine-3′-phosphate, 2′-O-methylcytidine-3′-phosphate, 2′-O-methylguanosine-3′-phosphate, and 2′-O-methyluridine-3′-phosphate, respectively;

Af, Cf, Gf, and Uf are 2′-fluoroadenosine-3′-phosphate, 2′-fluorocytidine-3′-phosphate, 2′-fluoroguanosine-3′-phosphate, and 2′-fluorouridine-3′-phosphate, respectively;

dA, dC, dG, and dT are 2′-deoxyadenosine-3′-phosphate, 2′-deoxycytidine-3′-phosphate, 2′-deoxyguanosine-3′-phosphate, and 2′-deoxythymidine-3′-phosphate, respectively;

(Agn) is adenosine-glycol nucleic acid (GNA); and

s is a phosphorothioate linkage; and

(2) one or more additional therapeutic agents;

thereby treating the subject.

21. The method of claim 20 , wherein the additional therapeutic agent is an antiviral agent, a reverse transcriptase inhibitor, an immune stimulator, a therapeutic vaccine, a viral entry inhibitor, an oligonucleotide that inhibits the secretion or release of HbsAg, a capsid inhibitor, a covalently closed circular (ccc) HBV DNA inhibitor, or a combination of any of the foregoing.

22. The method of claim 20 , wherein the additional therapeutic agent is a reverse transcriptase inhibitor.

23. The method of claim 20 , wherein the additional therapeutic agents are a reverse transcriptase inhibitor and an immune stimulator.

24. The method of claim 23 , wherein the reverse transcriptase inhibitor is Tenofovir disoproxil fumarate (TDF), Tenofovir alafenamide, Lamivudine, Adefovir dipivoxil, Entecavir (ETV), Telbivudine, AGX-1009, or any combination thereof.

25. The method of claim 23 , wherein the immune stimulator is pegylated interferon alfa 2a (PEG-IFN-α2a), Interferon alfa-2b, a recombinant human interleukin-7, a Toll-like receptor 7 (TLR7) agonist, or any combination thereof.

26. The method of claim 20 , wherein the HBV-associated disorder is chronic hepatitis and the subject is HBeAg positive.

27. The method of claim 20 , wherein the HBV-associated disorder is chronic hepatitis and the subject is HBeAg negative.

28. The method of claim 20 , wherein the HBV-associated disorder is hepatitis D virus (HDV) infection.

29. The method of claim 20 , wherein the HBV-associated disorder is delta hepatitis, acute hepatitis B, acute fulminant hepatitis B, chronic hepatitis B, liver fibrosis, end-stage liver disease, or hepatocellular carcinoma.

30. A method of treating a subject having a Hepatitis B virus (HBV)-associated disorder or a HBV infection, comprising administering to a subject:

one or more fixed doses of 200 mg of a double stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand and the sense strand comprise the modified nucleotide sequences as set forth in, respectively:

(a)

(SEQ ID NO: 16)

5′-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca-3′;

(b)

(SEQ ID NO: 18)

5′-usGfsuga(Agn)gcgaaguGfdCAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca-3′;

(c)

(SEQ ID NO: 20)

5′-usGfsudGa(Agn)gCfGfaaguGfcAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca-3′;

(d)

(SEQ ID NO: 23)

5′-usGfsudGadAgdCGfaaguGfcAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca -3′;

(e)

(SEQ ID NO: 24)

5′-usGfsuga(Agn)dGCfGfaaguGfcAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca -3′;

(f)

(SEQ ID NO: 25)

5′-usGfsudGadAgdCGfaaguGfcAfdCacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca -3′;

or

(g)

(SEQ ID NO: 28)

5′-usGfsuga(Agn)gCfGfaaguGfdCAfcacsusu-3′

and

(SEQ ID NO: 29)

5′-gsusguGfcAfCfUfucgcuucaca-3′;

wherein a, c, g, and u are 2′-O-methyladenosine-3′-phosphate, 2′-O-methylcytidine-3′-phosphate, 2′-O-methylguanosine-3′-phosphate, and 2′-O-methyluridine-3′-phosphate, respectively;

Af, Cf, Gf, and Uf are 2′-fluoroadenosine-3′-phosphate, 2′-fluorocytidine-3′-phosphate, 2′-fluoroguanosine-3′-phosphate, and 2′-fluorouridine-3′-phosphate, respectively;

dA, dC, dG, and dT are 2′-deoxyadenosine-3′-phosphate, 2′-deoxycytidine-3′-phosphate, 2′-deoxyguanosine-3′-phosphate, and 2′-deoxythymidine-3′-phosphate, respectively;

(Agn) is adenosine-glycol nucleic acid (GNA); and

s is a phosphorothioate linkage;

wherein the subject is being or has been administered one or more additional therapeutic agents comprising a reverse transcriptase inhibitor and an immune stimulator, wherein:

(1) the reverse transcriptase inhibitor is Tenofovir disoproxil fumarate (TDF), Tenofovir alafenamide, Lamivudine, Adefovir dipivoxil, Entecavir (ETV), Telbivudine, AGX-1009, or a combination thereof; and

(2) the immune stimulator is pegylated interferon alfa 2a (PEG-IFN-α2a), Interferon alfa-2b, a recombinant human interleukin-7, a Toll-like receptor 7 (TLR7) agonist, or any combination thereof;

thereby treating the subject.

31. The method of claim 30 , wherein the HBV-associated disorder is hepatitis D virus (HDV) infection.

32. The method of claim 30 , wherein the HBV-associated disorder is delta hepatitis, acute hepatitis B, acute fulminant hepatitis B, chronic hepatitis B, liver fibrosis, end-stage liver disease, or hepatocellular carcinoma.