Complement component iRNA compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10465194-B2
Application number	US-201615176231-A
Country	US
Kind code	B2
Filing date	Jun 8, 2016
Priority date	Dec 12, 2013
Publication date	Nov 5, 2019
Grant date	Nov 5, 2019

Abstract

The invention relates to iRNA, e.g., double-stranded ribonucleic acid (dsRNA), compositions targeting the complement factor B (CFB) gene, the complement component C3 gene, and the complement component C9 gene and methods of using such iRNA, e.g., dsRNA, compositions to inhibit expression of CFB, C9 and/or C3 and to treat subjects having a complement component-associated disease, e.g., paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.

First claim

We claim:

1. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement factor B (CFB) in a cell, wherein said dsRNA agent comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises the nucleotide sequence 5′-AfsgsCfaAfcAfuGfUfGfuUfcAfaAfgUfcAf-3′ (SEQ ID NO:482) and the antisense strand comprises the nucleotide sequence 5′-usGfsaCfuUfuGfaAfcacAfuGfuUfgCfuscsa-3′ (SEQ ID NO:485),
wherein a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U; Af, Cf, Gf, and Uf are 2′-fluoro A, C, G, and U; and s is a phosphorothioate linkage, and
wherein the sense strand is conjugated to a ligand attached at the 3′-terminus.

2. The dsRNA agent of claim 1 , wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker.

3. The dsRNA agent of claim 1 , wherein the ligand is

4. An isolated cell containing the dsRNA agent of claim 1 .

5. A pharmaceutical composition for inhibiting expression of complement factor B (CFB) comprising the dsRNA agent of claim 1 .

6. The dsRNA agent of claim 3 , wherein the dsRNA agent is conjugated to the ligand as shown in the following schematic

7. The pharmaceutical composition of claim 5 , wherein dsRNA agent is formulated in a buffered solution.

8. The dsRNA agent of claim 1 , wherein the sense strand consists of the nucleotide sequence 5′-AfsgsCfaAfcAfuGfUfGfuUfcAfaAfgUfcAfL96-3′ (SEQ ID NO:482) and the antisense strand consists of the nucleotide sequence 5′-usGfsaCfuUfuGfaAfcacAfuGfuUfgCfuscsa-3′ (SEQ ID NO:485),
wherein a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U; Af, Cf, Gf, and Uf are 2′-fluoro A, C, G, and U; s is a phosphorothioate linkage; and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol.

9. The pharmaceutical composition of claim 5 , wherein dsRNA agent is formulated in an unbuffered solution.

10. A pharmaceutical composition for inhibiting expression of complement factor B (CFB), comprising a double stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand forming a double stranded region,
wherein the sense strand comprises the nucleotide sequence 5′-AfsgsCfaAfcAfuGfUfGfuUfcAfaAfgUfcAfL96-3′ (SEQ ID NO:482) and the antisense strand comprises the nucleotide sequence 5′-usGfsaCfuUfuGfaAfcacAfuGfuUfgCfuscsa-3′ (SEQ ID NO:485),
wherein a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U; Af, Cf, Gf, and Uf are 2′-fluoro A, C, G, and U; s is a phosphorothioate linkage; and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol.

11. A pharmaceutical composition for inhibiting expression of complement factor B (CFB), comprising a double stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand forming a double stranded region,
wherein the sense strand consists of the nucleotide sequence 5′-AfsgsCfaAfcAfuGfUfGfuUfcAfaAfgUfcAfL96-3′ (SEQ ID NO:482) and the antisense strand consists of the nucleotide sequence 5′-usGfsaCfuUfuGfaAfcacAfuGfuUfgCfuscsa-3′ (SEQ ID NO:485),
wherein a, c, g, and u are 2′-O-methyl (2′-OMe) A, C, G, and U; Af, Cf, Gf, and Uf are 2′-fluoro A, C, G, and U; s is a phosphorothioate linkage; and L96 is N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinol.

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

• Borodovsky Anna
• Bettencourt Brian

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title