Methods for the treatment of alpha-1 antitrypsin deficiency (AATD)
AssigneeArrowhead Pharmaceuticals, Inc.
InventorsBruce Given, Dawn Christianson, James C. Hamilton, Zhen Li, Rui Zhu, Christine I. Wooddell, Tao Pei
Life of this patent
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Abstract
Described are methods for treating alpha-1 antitrypsin deficiency (AATD) in a human patient in need of treatment, using pharmaceutical compositions that include AAT RNAi agents. The pharmaceutical compositions disclosed herein that include AAT RNAi agents, when administered to a human patient in need thereof, treat liver diseases associated with AAT deficiency such as chronic hepatitis, cirrhosis, increased risk of hepatocellular carcinoma, transaminitis, cholestasis, fibrosis, fulminant hepatic failure, and other liver-related diseases.
Claims22
A method of treating alpha-1 antitrypsin deficiency (AATD) in a human subject in need thereof, the method comprising administering by subcutaneous injection to the subject doses of a pharmaceutical composition comprising about 5 mg to about 300 mg of an AAT RNAi Drug Substance, wherein the AAT RNAi Drug Substance comprises:
- a sense strand comprising the structure of (NAG37) s (invAb) sagcguuuaGfGfCfauguuuaacas (invAb) (SEQ ID NO:6) and an antisense strand comprising the structure of usGfsuUfaAfacaugCfcUfaAfaCfgCfsu (SEQ ID NO:2), wherein the sense and antisense strands are annealed to form a duplex,
- wherein a, c, g, and u represent 2′-O-methyl adenosine, 2′-O-methyl cytidine, 2′-O-methyl guanosine, and 2′-O-methyl uridine, respectively;
- Af, Cf, Gf, and Uf represent 2′-fluoro adenosine, 2′-fluoro cytidine, 2′-fluoro guanosine, and 2′-fluoro uridine, respectively;
- s represents a phosphorothioate linkage;
- (invAb) represents an inverted abasic deoxyribose residue;
- and
- (NAG37) s represents the structure of
- or both,
- wherein the pharmaceutical composition is administered once every 28 days.
A method of treating alpha-1 antitrypsin deficiency (AATD) in a human subject in need thereof, the method comprising administering by subcutaneous injection to the subject doses of a pharmaceutical composition comprising about 5 mg to about 300 mg of an AAT RNAi Drug Substance, wherein the AAT RNAi Drug Substance comprises:
- a sense strand comprising the structure of (NAG37) s (invAb) sagcguuuaGfGfCfauguuuaacas (invAb) (SEQ ID NO:6) and an antisense strand comprising the structure of usGfsuUfaAfacaugCfcUfaAfaCfgCfsu (SEQ ID NO:2), wherein the sense and antisense strands are annealed to form a duplex,
- wherein a, c, g, and u represent 2′-O-methyl adenosine, 2′-O-methyl cytidine, 2′-O-methyl guanosine, and 2′-O-methyl uridine, respectively;
- Af, Cf, Gf, and Uf represent 2′-fluoro adenosine, 2′-fluoro cytidine, 2′-fluoro guanosine, and 2′-fluoro uridine, respectively;
- s represents a phosphorothioate linkage;
- (invAb) represents an inverted abasic deoxyribose residue;
- and
- (NAG37) s represents the structure of
- or both,
- wherein the pharmaceutical composition is administered once every 84 days.
A method of treating alpha-1 antitrypsin deficiency (AATD) in a human subject in need thereof, the method comprising administering to the subject by subcutaneous administration doses of a pharmaceutical composition comprising about 5 mg to about 300 mg of an AAT RNAi Drug Substance, wherein the AAT RNAi Drug Substance comprises:
- a sense strand comprising the structure of (NAG37) s (invAb) sagcguuuaGfGfCfauguuuaacas (invAb) (SEQ ID NO:6) and an antisense strand comprising the structure of usGfsuUfaAfacaugCfcUfaAfaCfgCfsu (SEQ ID NO:2), wherein the sense and antisense strands are annealed to form a duplex,
- wherein a, c, g, and u represent 2′-O-methyl adenosine, 2′-O-methyl cytidine, 2′-O-methyl guanosine, and 2′-O-methyl uridine, respectively;
- Af, Cf, Gf, and Uf represent 2′-fluoro adenosine, 2′-fluoro cytidine, 2′-fluoro guanosine, and 2′-fluoro uridine, respectively;
- s represents a phosphorothioate linkage;
- (invAb) represents an inverted abasic deoxyribose residue;
- and
- (NAG37) s represents the structure of
- or both,
- wherein the administration comprises:
- a. administering to the subject an initial dose of the pharmaceutical composition,
- b. administering to the subject a second dose of the pharmaceutical composition about 28 days after the initial dose, and
- c. administering to the subject a third dose of the pharmaceutical composition about 84 days after the second dose.
A method of treating alpha-1 antitrypsin deficiency (AATD) in a human subject in need thereof, the method comprising administering to the subject by subcutaneous administration doses of a pharmaceutical composition comprising about 200 mg of an AAT RNAi Drug Substance, wherein the AAT RNAi Drug Substance comprises:
- a sense strand comprising the structure of (NAG37) s (invAb) sagcguuuaGfGfCfauguuuaacas (invAb) (SEQ ID NO:6) and an antisense strand comprising the structure of usGfsuUfaAfacaugCfcUfaAfaCfgCfsu (SEQ ID NO:2), wherein the sense and antisense strands are annealed to form a duplex, wherein a, c, g, and u represent 2′-O-methyl adenosine, 2′-O-methyl cytidine, 2′-O-methyl guanosine, and 2′-O-methyl uridine, respectively;
- Af, Cf, Gf, and Uf represent 2′-fluoro adenosine, 2′-fluoro cytidine, 2′-fluoro guanosine, and 2′-fluoro uridine, respectively;
- s represents a phosphorothioate linkage;
- (invAb) represents an inverted abasic deoxyribose residue;
- and (NAG37) s represents the structure of
- or both,
- wherein the administration comprises:
- a. administering to the subject an initial dose of the pharmaceutical composition,
- b. administering to the subject a second dose of the pharmaceutical composition comprising about 28 days after the initial dose, and
- c. administering to the subject a third dose of the pharmaceutical composition comprising about 84 days after the second dose.
Dependencies are inferred from the claim text.