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

Patent metadata

Field	Value
Publication number	US-12331297-B2
Application number	US-202418586689-A
Country	US
Kind code	B2
Filing date	Feb 26, 2024
Priority date	Nov 13, 2020
Publication date	Jun 17, 2025
Grant date	Jun 17, 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 double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of coagulation Factor V (F5) in a cell, or a pharmaceutically acceptable salt thereof, comprising 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.

2. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , comprising a sense strand differing by no more than 3 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 3 unmodified or modified bases from the nucleotide sequence 5′-asdGsagdAadAuagudGgAfaaacugususa-3′ of SEQ ID NO:2940.

3. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , comprising a sense strand differing by no more than 2 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 2 unmodified or modified bases from the nucleotide sequence 5′-asdGsagdAadAuagudGgAfaaacugususa-3′ of SEQ ID NO:2940.

4. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , comprising a sense strand differing by no more than 1 unmodified or modified base from the nucleotide sequence 5′-ascsaguuuuCfCfAfcuauuucucu-3′ of SEQ ID NO:2739 and an antisense strand differing by no more than 1 unmodified or modified base from the nucleotide sequence 5′-asdGsagdAadAuagudGgAfaaacugususa-3′ of SEQ ID NO:2940.

5. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , comprising 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.

6. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , comprising 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.

7. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 , further comprising a ligand.

8. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 7 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent.

9. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 7 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.

10. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 9 , wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent linker.

11. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 10 , wherein the ligand is

12. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 11 , 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.

13. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 12 , wherein X is O.

14. An isolated cell containing the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 .

15. A pharmaceutical composition, comprising the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 1 .

16. The pharmaceutical composition of claim 15 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is in an unbuffered solution.

17. The pharmaceutical composition of claim 16 , wherein the unbuffered solution is saline or water.

18. The pharmaceutical composition of claim 15 , wherein the dsRNA agent, or a pharmaceutically acceptable salt thereof, is in a buffer solution.

19. The pharmaceutical composition of claim 18 , wherein the buffer solution comprises acetate, citrate, prolamine, carbonate, or phosphate or any combination thereof.

20. The pharmaceutical composition of claim 19 , wherein the buffer solution is phosphate buffered saline (PBS).

21. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of coagulation Factor V (F5) in a cell, or a pharmaceutically acceptable salt thereof, comprising 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 is conjugated to a ligand as shown in the following schematic

and wherein X is O.

22. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 21 , which is in a sodium salt form.

23. An isolated cell containing the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 21 .

24. A pharmaceutical composition comprising the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 21 .

25. A double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of coagulation Factor V (F5) in a cell, or a pharmaceutically acceptable salt thereof, consisting of 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 is conjugated to a ligand as shown in the following schematic

and wherein X is O.

26. The dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 25 , which is in a sodium salt form.

27. An isolated cell containing the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 25 .

28. A pharmaceutical composition comprising the dsRNA agent, or a pharmaceutically acceptable salt thereof, of claim 25 .

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