JPWO2020232024A5 - - Google Patents

Claims (37)

1. A pharmaceutical composition comprising siRNA for the treatment of chronic HBV infection or HBV-related disease in a subject,
(a) the siRNA has a sense strand containing 5′-gsusguGfcAfCfUfucgcuucacaL96-3′ (SEQ ID NO: 5) and an antisense strand containing 5′-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3′ (SEQ ID NO: 6);
(wherein a, c, g and u are respectively 2′-O-methyladenosine-3′-phosphate, 2′-O-methylcytidine-3′-phosphate, 2′-O-methylguanosine-3′- phosphate and 2′-O-methyluridine-3′-phosphate;
Af, Cf, Gf and Uf are respectively 2′-fluoroadenosine-3′-phosphate, 2′-fluorocytidine-3′-phosphate, 2′-fluoroguanosine-3′-phosphate and 2′-fluorouridine-3′ - is a phosphate;
(Agn) is adenosine-glycol nucleic acid (GNA);
s is a phosphorothioate linkage; and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol)
(b) the subject is also administered PEG-INFα;
pharmaceutical composition . 2. The pharmaceutical composition of claim 1 , wherein the siRNA and PEG-IFNα are administered to the patient over the same period of time. 2. The pharmaceutical composition of claim 1 , wherein the siRNA is administered to the subject for a period of time before the PEG-IFNα is administered to the subject. 2. The pharmaceutical composition of claim 1 , wherein the PEG-IFNα is administered to the subject for a period of time before the siRNA is administered to the subject. 2. The pharmaceutical composition of claim 1 , wherein the subject has been administered PEG-IFNα prior to administration of the siRNA. 6. The pharmaceutical composition of claim 1, 2 or 5 , wherein the subject is administered PEG-IFNα during the same period of time that the subject is administered the siRNA. 7. The pharmaceutical composition of any of claims 1-6 , wherein the subject is subsequently administered PEG-IFN. 8. The pharmaceutical composition of any of claims 1-7 , wherein the subject is also administered an NRTI. 9. The pharmaceutical composition of any of claims 1-8 , wherein the subject has been administered an NRTI prior to administration of the siRNA. 10. The pharmaceutical composition of any of claims 1-9 , wherein the subject has been administered an NRTI at least 2 months or at least 6 months prior to administration of the siRNA. 11. The pharmaceutical composition of any of claims 1-10 , wherein the subject is administered the NRTI during the same period of time that the siRNA is administered. 12. The pharmaceutical composition of any of claims 1-11 , wherein the subject is subsequently administered an NRTI. Use of siRNA and PEG-IFNα in the manufacture of a medicament for the treatment of chronic HBV infection or HBV-related disease in a subject , wherein the siRNA comprises a sense strand comprising 5′-gsusguGfcAfCfUfucgcuucacaL96-3′ (SEQ ID NO:5) and 5 having an antisense strand containing '-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' (SEQ ID NO: 6), use
(wherein a, c, g and u are respectively 2′-O-methyladenosine-3′-phosphate, 2′-O-methylcytidine-3′-phosphate, 2′-O-methylguanosine-3′- phosphate and 2′-O-methyluridine-3′-phosphate;
Af, Cf, Gf and Uf are respectively 2′-fluoroadenosine-3′-phosphate, 2′-fluorocytidine-3′-phosphate, 2′-fluoroguanosine-3′-phosphate and 2′-fluorouridine-3′ - is a phosphate;
(Agn) is adenosine-glycol nucleic acid (GNA);
s is a phosphorothioate linkage; and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol). Use of siRNA, PEG-IFNα and NRTI in the manufacture of a medicament for the treatment of chronic HBV infection or HBV-related disease in a subject , wherein the siRNA comprises 5'-gsusguGfcAfCfUfucgcuucacaL96-3' (SEQ ID NO: 5) sense strand and 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' (SEQ ID NO: 6).
(wherein a, c, g and u are respectively 2′-O-methyladenosine-3′-phosphate, 2′-O-methylcytidine-3′-phosphate, 2′-O-methylguanosine-3′- phosphate and 2′-O-methyluridine-3′-phosphate;
Af, Cf, Gf and Uf are respectively 2′-fluoroadenosine-3′-phosphate, 2′-fluorocytidine-3′-phosphate, 2′-fluoroguanosine-3′-phosphate and 2′-fluorouridine-3′ - is a phosphate;
(Agn) is adenosine-glycol nucleic acid (GNA);
s is a phosphorothioate linkage; and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol). 15. The composition or use of any of claims 1-14 , wherein the dose of siRNA is 0.8 mg/kg, 1.7 mg/kg, 3.3 mg/kg, 6.7 mg/kg or 15 mg/kg. 16. The composition or use of any of claims 1-15 , wherein the dose of siRNA is 20 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg or 450 mg. 17. The composition or use of any of claims 1-16 , wherein the siRNA is administered weekly or more than once, each administration separated by 2, 3 or 4 weeks. 18. The composition of any of claims 1-17, wherein the siRNA is administered 2, 3, 4, 5, 6 or more times, each administration separated by 1 week, 2 weeks, 3 weeks or 4 weeks. thing or use. ( a) the subject has received at least 200 mg of siRNA having a sense strand comprising 5'-gsusguGfcAfCfUfucgcuucacaL96-3' (SEQ ID NO: 5) and an antisense strand comprising 5'-usGfsuga(Agn)gCfGfaaguGfcAfcacsusu-3' (SEQ ID NO: 6); administered more than once
(wherein a, c, g and u are respectively 2′-O-methyladenosine-3′-phosphate, 2′-O-methylcytidine-3′-phosphate, 2′-O-methylguanosine-3′- phosphate and 2′-O-methyluridine-3′-phosphate;
Af, Cf, Gf and Uf are respectively 2′-fluoroadenosine-3′-phosphate, 2′-fluorocytidine-3′-phosphate, 2′-fluoroguanosine-3′-phosphate and 2′-fluorouridine-3′ - is a phosphate;
(Agn) is adenosine-glycol nucleic acid (GNA);
s is a phosphorothioate linkage; and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol); and
(b) the subject is administered a nucleoside/nucleotide reverse transcriptase inhibitor (NRTI);
19. The composition or use of any of claims 1-18 , wherein the subject is HBeAg-negative or HBeAg-positive. 20. The composition or use of any of claims 1-19 , wherein six 200 mg doses of siRNA are administered. 20. The composition or use of any of claims 1-19 , wherein two 400 mg doses of siRNA are administered. 22. The composition or use of any of claims 1-21 , wherein the siRNA is administered by subcutaneous injection. 23. The composition or use of claim 22 , wherein administering the siRNA comprises administering by one, two or three subcutaneous injections per administration. 24. The composition or use of any of claims 1-23 , wherein the dose of PEG-IFNα is 50 μg, 100 μg, 150 μg or 200 μg. 25. The composition or use of any of claims 1-24 , wherein PEG-IFNα is administered weekly. 26. The composition or use of any of claims 1-25 , wherein PEG-IFNα is administered by subcutaneous injection. NRTIs tenofovir, tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), lamivudine, adefovir, adefovir dipivoxil, entecavir (ETV), telbivudine, AGX-1009, emtricitabine (FTC), clevudine, ritonavir, dipivoxil , lobucavir, famvir, N-acetyl-cysteine (NAC), PC1323, theradigm-HBV, thymosin-alpha, ganciclovir, besifovir (ANA-380/LB-80380) or tenofvir-exaliades (TLX/CMX157) The composition or use of any of 8-12 and 14-26 . 28. The composition or use of claim 27 , wherein the NRTI is entecavir (ETV). 28. The composition or use of Claim 27 , wherein the NRTI is tenofovir. 28. The composition or use of claim 27 , wherein the NRTI is lamivudine. 28. The composition or use of claim 27 , wherein the NRTI is adefovir or adefovir dipivoxil. 32. The composition or use of any of claims 1-31 , wherein the subject is HBeAg negative. 32. The composition or use of any of claims 1-31 , wherein the subject is HBeAg positive. 34. The composition or use of any of claims 1-33, wherein the subject has a chronic HBV infection. 34. The composition or use of any of claims 1-33, wherein the subject has an HBV-related disease and the HBV-related disease is hepatitis D virus (HDV) infection. A kit comprising a pharmaceutical composition comprising the siRNA of any one of claims 1 to 12 and a pharmaceutically acceptable additive; and a pharmaceutical composition comprising PEG-IFNα and a pharmaceutically acceptable additive. 37. The kit of claim 36 , further comprising NRTIs and pharmaceutically acceptable excipients.