IP Library › Granted Patent US 12,473,550
Granted Patent B2
US 12,473,550 · App. 18/144,276 · Granted Nov 18, 2025

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

Inventors: Mark Keating (Weston, MA); James D. McIninch (Burlington, MA); Mark K. Schlegel (Boston, MA)
Assignee: Alnylam Pharmaceuticals, Inc.
C12N15/113A61K9/0019A61K45/06A61K47/549A61P7/02C12N2310/11C12N2310/3125C12N2310/313
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Quick Facts
Patent No.
US 12,473,550
App. No.
18/144,276
Granted
Nov 18, 2025
Kind
B2
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.

Claims (71)

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 SEQ ID NO:2940.

28 . The method of claim 2 , 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.

29 . The method of claim 2 , 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.

30 . The method of claim 2 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, further comprises a ligand.

31 . The method of claim 30 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent.

32 . The method of claim 30 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.

33 . The method of claim 32 , wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent linker.

34 . The method of claim 33 , wherein the ligand is

35 . The method of claim 34 , 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.

36 . The method of claim 35 , wherein X is O.

37 . The method of claim 2 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is present in a pharmaceutical composition.

38 . 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 comprising the nucleotide sequence 5′-ascsaguuuuCfCfAfcuauuucucu-3′ of SEQ ID NO: 2739 and an antisense strand comprising 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,

wherein the 3′-end of the sense strand of the dsRNA agent, or a pharmaceutically acceptable salt thereof, is conjugated to a ligand as shown in the following schematic

wherein X is O,

thereby treating the subject having the disorder that would benefit from reduction in F5 expression.

39 . The method of claim 38 , wherein the disorder is an F5-associated disorder.

40 . The method of claim 39 , wherein the F5-associated disorder is a disorder associated with thrombosis.

41 . The method of claim 40 , 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.

42 . The method of claim 38 , wherein the subject is a human.

43 . The method of claim 38 , wherein the dsRNA agent is administered to the subject subcutaneously.

44 . The method of claim 38 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is present in a pharmaceutical composition.

45 . The method of claim 38 , wherein the dsRNA agent is in a salt form.

46 . The method of claim 45 , wherein the dsRNA agent is in a sodium salt form.

47 . 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 consisting of the nucleotide sequence 5′-ascsaguuuuCfCfAfcuauuucucu-3′ of SEQ ID NO: 2739 and an antisense strand consisting of 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,

wherein the 3′-end of the sense strand of the dsRNA agent, or a pharmaceutically acceptable salt thereof, is conjugated to a ligand as shown in the following schematic

wherein X is O,

thereby treating the subject having the disorder that would benefit from reduction in F5 expression.

48 . The method of claim 47 , wherein the disorder is an F5-associated disorder.

49 . The method of claim 48 , wherein the F5-associated disorder is a disorder associated with thrombosis.

50 . The method of claim 49 , 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.

51 . The method of claim 47 , wherein the subject is a human.

52 . The method of claim 47 , wherein the dsRNA agent is administered to the subject subcutaneously.

53 . The method of claim 47 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is present in a pharmaceutical composition.

54 . The method of claim 46 , wherein the dsRNA agent is in a salt form.

55 . The method of claim 54 , wherein the dsRNA agent is in a sodium salt form.

Assignments (2)
SECURITY INTEREST Recorded Oct 1, 2025
From: ALNYLAM PHARMACEUTICALS, INC.; SIRNA THERAPEUTICS, INC.
To: BANK OF AMERICA, N.A.
Reel/Frame 072996/0337 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 23, 2023
From: KEATING, MARK; MCININCH, JAMES D.; SCHLEGEL, MARK K.
To: ALNYLAM PHARMACEUTICALS, INC.
Reel/Frame 063730/0606 →
Continuity (5)
Continuation PCTUS2021059047 · Nov 12, 2021
Provisional Application 63271872 · Oct 26, 2021
Provisional Application 63146115 · Feb 5, 2021
Provisional Application 63113282 · Nov 13, 2020
Related Publication 20240209358A1 · Jun 27, 2024
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