METHODS AND COMPOSITIONS FOR TREATING A BLEEDING EVENT IN A SUBJECT HAVING HEMOPHILIA
The invention relates to iRNA, e.g., double stranded ribonucleic acid (dsRNA), compositions targeting the Serpinc1 gene, and methods of using such iRNA, e.g., dsRNA, compositions to treat a bleeding event in a subject having a hemophilia (e.g., with or without inhibitors).
1 - 56 . (canceled)
57 . A method of treating a bleeding episode in a human patient with hemophilia A without inhibitors who is on routine prophylaxis for hemophilia with a double-stranded ribonucleic acid (dsRNA) molecule,
wherein the dsRNA molecule comprises a sense strand and an antisense strand;
wherein the sense strand comprises the nucleotide sequence 5′-GfsgsUfuAfaCfaCfCfAfuUfuAfcUfuCfaAf-3′ (SEQ ID NO:13) and the antisense strand comprises the nucleotide sequence 5′-usUfsgAfaGfuAfaAfuggUfgUfuAfaCfcsasg-3′ (SEQ ID NO:14), wherein a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U, respectively; Af, Cf, Gf and Uf are 2′-fluoro A, C, G, and U, respectively; and s is a phosphorothioate linkage; and
wherein a ligand is conjugated to the 3′ end of the sense strand as shown in the following schematic:
wherein X is O,
the method comprising the step of administering to the patient in need thereof a therapeutically effective amount of factor VIII, wherein the therapeutically effective amount of factor VIII is reduced as compared to the recommended effective amount of factor VIII.
58 . The method of claim 57 , wherein the therapeutically effective amount of factor VIII is
about 10 IU/kg per dose,
no more than about 20 IU/kg per dose, or
no more than about 20 IU/kg/24 hours.
59 . The method of claim 57 , further comprising repeating the administering step after no less than 24 hours.
60 . The method of claim 57 , wherein the bleeding episode
is non-surgery related;
results from trauma; or
is surgery related and wherein the factor VIII is administered perioperatively.
61 . The method of claim 57 , wherein the bleeding episode occurs in a joint, a muscle, or a skin or mucosal tissue, or occurs internally.
62 . The method of claim 57 , wherein the nucleotide sequence of the sense strand is 5′-GfsgsUfuAfaCfaCfCfAfuUfuAfcUfuCfaAf-3′ (SEQ ID NO:13) and the nucleotide sequence of the antisense strand is 5′-usUfsgAfaGfuAfaAfuggUfgUfuAfaCfcsasg-3′ (SEQ ID NO:14).
63 . The method of claim 62 , wherein the routine prophylaxis comprises a dose of about 30 mg to about 90 mg of the dsRNA molecule, or about 50 mg or about 80 mg of the dsRNA molecule, by subcutaneous injection at an interval of about once a month or about once every two months.
64 . A method of treating a bleeding episode in a human patient with hemophilia B without inhibitors who is on routine prophylaxis for hemophilia with a double-stranded ribonucleic acid (dsRNA) molecule,
wherein the dsRNA molecule comprises a sense strand and an antisense strand;
wherein the sense strand comprises the nucleotide sequence 5′-GfsgsUfuAfaCfaCfCfAfuUfuAfcUfuCfaAf-3′ (SEQ ID NO:13) and the antisense strand comprises the nucleotide sequence 5′-usUfsgAfaGfuAfaAfuggUfgUfuAfaCfcsasg-3′ (SEQ ID NO:14), wherein a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U, respectively; Af, Cf, Gf and Uf are 2′-fluoro A, C, G, and U, respectively; and s is a phosphorothioate linkage; and
wherein a ligand is conjugated to the 3′ end of the sense strand as shown in the following schematic:
wherein X is O, the method comprising administering to the patient in need thereof a therapeutically effective amount of factor IX, wherein the therapeutically effective amount of factor IX is reduced as compared to the recommended effective amount of factor IX.
65 . The method of claim 64 , wherein the factor IX is
(a) standard half-life factor IX, and wherein the therapeutically effective amount of the standard half-life factor IX is
about 20 IU/kg per dose,
no more than about 30 IU/kg per dose, or
no more than about 30 IU/kg/24 hours; or
(b) extended half-life factor IX, and wherein the therapeutically effective amount of the extended half-life factor IX is
about 20 IU/kg per dose,
no more than about 30 IU/kg, or
no more than about 30 IU/kg/5 days.
66 . The method of claim 64 , further comprising repeating the administering step after
(a) no less than 24 hours if the factor IX is standard half-life factor IX, or
(b) no less than 5-7 days if the factor IX is extended half-life factor IX.
67 . The method of claim 64 , wherein the bleeding episode
is non-surgery related;
results from trauma; or
is surgery related and wherein the factor IX is administered perioperatively.
68 . The method of claim 64 , wherein the bleeding episode occurs in a joint, a muscle, or a skin or mucosal tissue, or occurs internally.
69 . The method of claim 64 , wherein the nucleotide sequence of the sense strand is 5′-GfsgsUfuAfaCfaCfCfAfuUfuAfcUfuCfaAf-3′ (SEQ ID NO:13) and the nucleotide sequence of the antisense strand is 5′-usUfsgAfaGfuAfaAfuggUfgUfuAfaCfcsasg-3′ (SEQ ID NO:14).
70 . The method of claim 69 , wherein the routine prophylaxis comprises a dose of about 30 mg to about 90 mg of the dsRNA molecule, or about 50 mg or about 80 mg of the dsRNA molecule, by subcutaneous injection at an interval of about once a month or about once every two months.
71 . A method of treating a bleeding episode in a human patient with hemophilia A or B with inhibitors who is on routine prophylaxis for hemophilia with a double-stranded ribonucleic acid (dsRNA) molecule,
wherein the dsRNA molecule comprises a sense strand and an antisense strand;
wherein the sense strand comprises the nucleotide sequence 5′-GfsgsUfuAfaCfaCfCfAfuUfuAfcUfuCfaAf-3′ (SEQ ID NO:13) and the antisense strand comprises the nucleotide sequence 5′-usUfsgAfaGfuAfaAfuggUfgUfuAfaCfcsasg-3′ (SEQ ID NO:14), wherein a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U, respectively; Af, Cf, Gf and Uf are 2′-fluoro A, C, G, and U, respectively; and s is a phosphorothioate linkage; and
wherein a ligand is conjugated to the 3′ end of the sense strand as shown in the following schematic:
wherein X is O, the method comprising administering to the patient in need thereof a therapeutically effective amount of a bypassing agent, wherein the therapeutically effective amount of the bypassing agent is reduced as compared to the recommended effective amount of the bypassing agent.
72 . The method of claim 71 , wherein the bypassing agent is
(a) activated prothrombin complex concentrate (aPCC), wherein the therapeutically effective amount of the aPCC is
about 30 U/kg per dose,
no more than about 50 U/kg per dose, or
no more than about 50 U/kg/24 hours; or
(b) recombinant factor VIIa (rFVIIa), wherein the therapeutically effective amount of the rFVIIa is
no more than about 45 μg/kg per dose, or
no more than about 45 μg/kg/2 hours.
73 . The method of claim 71 , further comprising repeating the administering step after
(a) no less than 24 hours if the bypassing agent is aPCC, or
(b) no less than about 2 hours if the bypassing agent is rFVIIa.
74 . The method of claim 71 , wherein the bleeding episode
is non-surgery related;
results from trauma; or
is surgery related and wherein the bypassing agent is administered perioperatively.
75 . The method of claim 71 , wherein the bleeding episode occurs in a joint, a muscle, or a skin or mucosal tissue, or occurs internally.
76 . The method of claim 71 , wherein the nucleotide sequence of the sense strand is 5′-GfsgsUfuAfaCfaCfCfAfuUfuAfcUfuCfaAf-3′ (SEQ ID NO:13) and the nucleotide sequence of the antisense strand is 5′-usUfsgAfaGfuAfaAfuggUfgUfuAfaCfcsasg-3′ (SEQ ID NO:14).
77 . The method of claim 76 , wherein the routine prophylaxis comprises a dose of about 30 mg to about 90 mg of the dsRNA molecule, or about 50 mg or about 80 mg of the dsRNA molecule, by subcutaneous injection at an interval of about once a month or about once every two months.