Coagulation factor V (F5) iRNA compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-12473550-B2
Application number	US-202318144276-A
Country	US
Kind code	B2
Filing date	May 8, 2023
Priority date	Nov 13, 2020
Publication date	Nov 18, 2025
Grant date	Nov 18, 2025

Abstract

The present invention relates to RNAi agents, e.g., dsRNA agents, targeting the Coagulation Factor V (F5) gene. The invention also relates to methods of using such RNAi agents to inhibit expression of an F5 gene and to methods of treating or preventing an F5-associated disease, e.g., a disorder associated with thrombosis, in a subject.

First claim

We claim:

1 . A method of inhibiting expression of a coagulation Factor V (F5) gene in a cell, the method comprising contacting the cell with a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of coagulation Factor V (F5) in a cell, or a pharmaceutically acceptable salt thereof,
wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, comprises a sense strand differing by no more than 4 unmodified or modified bases from the nucleotide sequence 5′-ascsaguuuuCfCfAfcuauuucucu-3′ of SEQ ID NO:2739 and an antisense strand differing by no more than 4 unmodified or modified bases from the nucleotide sequence 5′-asdGsagdAadAuagudGgAfaaacugususa-3′ of SEQ ID NO:2940, wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af and Cf, are 2′-fluoro A and C, respectively; s is a phosphorothioate linkage; dG is 2-deoxyguanosine-3′-phosphate; and dA is 2-deoxyadenosine-3-phosphate, thereby inhibiting expression of the F5 gene in the cell.

2 . A method of treating a subject having a disorder that would benefit from reduction in coagulation Factor V (F5) expression, the method comprising administering to the subject a therapeutically effective amount of a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of coagulation Factor V (F5) in a cell, or a pharmaceutically acceptable salt thereof,
wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, comprises a sense strand differing by no more than 4 unmodified or modified bases from the nucleotide sequence 5′-ascsaguuuuCfCfAfcuauuucucu-3′ of SEQ ID NO:2739 and an antisense strand differing by no more than 4 unmodified or modified bases from the nucleotide sequence 5′-asdGsagdAadAuagudGgAfaaacugususa-3′ of SEQ ID NO:2940, wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af and Cf, are 2′-fluoro A and C, respectively; s is a phosphorothioate linkage; dG is 2′-deoxyguanosine-3-phosphate; and dA is 2-deoxyadenosine-3-phosphate, thereby treating the subject having the disorder that would benefit from reduction in F5 expression.

3 . The method of claim 2 , wherein the disorder is an F5-associated disorder.

4 . The method of claim 3 , wherein the F5-associated disorder is a disorder associated with thrombosis.

5 . The method of claim 2 , wherein the subject is a human.

6 . The method of claim 2 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is administered to the subject subcutaneously.

7 . The method of claim 1 , wherein the cell is within a subject.

8 . The method of claim 7 , wherein the subject is a human.

9 . The method of claim 1 , wherein contacting the cell with the dsRNA agent, or a pharmaceutically acceptable salt thereof, inhibits the expression of F5 by at least 50%, 60%, 70%, 80%, 90%, or 95%.

10 . The method of claim 7 , wherein inhibiting expression of F5 causes a decrease in F5 protein levels in the subject's serum by at least 50%, 60%, 70%, 80%, 90%, or 95%.

11 . The method of claim 1 , wherein the sense strand differs by no more than 3 unmodified or modified bases from the nucleotide sequence 5′-ascsaguuuuCfCfAfcuauuucucu-3′ of SEQ ID NO:2739 and the antisense strand differs by no more than 3 unmodified or modified bases from the nucleotide sequence 5′-asdGsagdAadAuagudGgAfaaacugususa-3′ of SEQ ID NO:2940.

12 . The method of claim 1 , wherein the sense strand differs by no more than 2 unmodified or modified bases from the nucleotide sequence 5′-ascsaguuuuCfCfAfcuauuucucu-3′ of SEQ ID NO:2739 and the antisense strand differs by no more than 2 unmodified or modified bases from the nucleotide sequence 5′-asdGsagdAadAuagudGgAfaaacugususa-3′ of SEQ ID NO:2940.

13 . The method of claim 1 , wherein the sense strand differs by no more than 1 unmodified or modified base from the nucleotide sequence 5′-ascsaguuuuCfCfAfcuauuucucu-3′ of SEQ ID NO:2739 and the antisense strand differs by no more than 1 unmodified or modified base from the nucleotide sequence 5′-asdGsagdAadAuagudGgAfaaacugususa-3′ of SEQ ID NO:2940.

14 . The method of claim 1 , wherein the sense strand comprises the nucleotide sequence 5′-ascsaguuuuCfCfAfcuauuucucu-3′ of SEQ ID NO:2739 and the antisense strand comprises the nucleotide sequence 5′-asdGsagdAadAuagudGgAfaaacugususa-3′ of SEQ ID NO: 2940.

15 . The method of claim 1 , wherein the sense strand consists of the nucleotide sequence 5′-ascsaguuuuCfCfAfcuauuucucu-3′ of SEQ ID NO:2739 and the antisense strand consists of the nucleotide sequence 5′-asdGsagdAadAuagudGgAfaaacugususa-3′ of SEQ ID NO: 2940.

16 . The method of claim 1 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, further comprises a ligand.

17 . The method of claim 16 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent.

18 . The method of claim 16 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.

19 . The method of claim 18 , wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent linker.

20 . The method of claim 19 , wherein the ligand is

21 . The method of claim 20 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof is conjugated to the ligand as shown in the following schematic

wherein X is O or S.

22 . The method of claim 21 , wherein X is O.

23 . The method of claim 1 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is present in a pharmaceutical composition.

24 . The method of claim 4 , wherein the disorder associated with thrombosis is selected from the group consisting of venous thrombosis, deep vein thrombosis, genetic thrombophilia, Factor V leiden, prothrombin thrombophilia, plurpura fulminans, acquired thrombophilia, antiphospholipid syndrome, systemic lupus erythematosus, drug induced thrombophilia, arterial thrombosis, myocardial infarction, peripheral arterial disease, thromboembolic disease, pulmonary embolus embolic, ischemic stroke, atrial fibrillation, post-surgery deep vein thrombosis, cancer thrombosis and infectious disease thrombosis.

25 . The method of claim 2 , wherein the sense strand differs by no more than 3 unmodified or modified bases from the nucleotide sequence 5′-ascsaguuuuCfCfAfcuauuucucu-3′ of SEQ ID NO:2739 and the antisense strand differs by no more than 3 unmodified or modified bases from the nucleotide sequence 5′-asdGsagdAadAuagudGgAfaaacugususa-3′ of SEQ ID NO:2940.

26 . The method of claim 2 , wherein the sense strand differs by no more than 2 unmodified or modified bases from the nucleotide sequence 5′-ascsaguuuuCfCfAfcuauuucucu-3′ of SEQ ID NO:2739 and the antisense strand differs by no more than 2 unmodified or modified bases from the nucleotide sequence 5′-asdGsagdAadAuagudGgAfaaacugususa-3′ of SEQ ID NO:2940.

27 . The method of claim 2 , wherein the sense strand differs by no more than 1 unmodified or modified base from the nucleotide sequence 5′-ascsaguuuuCfCfAfcuauuucucu-3′ of SEQ ID NO:2739 and the antisense strand differs by no more than 1 unmodified or modified base from the nucleotide sequence 5′-asdGsagdAadAuagudGgAfaaacugususa-3′ of

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

• Keating Mark
• Mcininch James D
• Schlegel Mark K

Classifications

• C12N2310/313

  Phosphorodithioates · CPC title

• C12N2310/3125

  Methylphosphonates · CPC title

• C12N2310/11

  Antisense · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title