IP Library › Granted Patent US 12,545,914
Granted Patent B2
US 12,545,914 · App. 17/823,980 · Granted Feb 10, 2026

Angiopoietin-like 3 (ANGPTL3) iRNA compositions and methods of use thereof

Inventors: Lucas D. BonDurant (Brookline, MA); Mark K. Schlegel (Boston, MA); Jeffrey Zuber (Somerville, MA); Lauren Blair Woods (Sharon, MA); Tyler Chickering (Needham, MA)
Assignee: Alnylam Pharmaceuticals, Inc.
C12N15/1136C12N2310/14C12N2310/315C12N2310/322C12N2310/344C12N2310/346
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Quick Facts
Patent No.
US 12,545,914
App. No.
17/823,980
Granted
Feb 10, 2026
Kind
B2
Abstract

The present invention relates to RNAi agents, e.g., double stranded RNA (dsRNA) agents, targeting the Angiopoietin-like 3 (ANGPTL3) gene. The invention also relates to methods of using such RNAi agents to inhibit expression of an ANGPTL3 gene and to methods of preventing and treating an ANGPTL3-associated disorder, e.g., a disorder of lipid metabolism, such as hyperlipidemia or hypertriglyceridemia.

Claims (122)

1 . A method of inhibiting expression of a Angiopoietin-like 3 (ANGPTL3) gene in a cell, the method comprising contacting the cell with a dsRNA agent, or salt thereof,

wherein the dsRNA agent, or salt thereof, comprises a sense strand and an antisense strand forming a double stranded region,

wherein the sense strand comprises at least 19 contiguous nucleotides of the nucleotide sequence 5′-AAGCUCCUUCUUUUUAUUGUU-3′ of SEQ ID NO:46 and the antisense strand comprises at least 21 contiguous nucleotides of the nucleotide sequence of 5′-AACAAUAAAAAGAAGGAGCUUGG-3′ of SEQ ID NO:661,

wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a modification, and

wherein at least one of the modifications is a 2′-deoxy-nucleotide modification, thereby inhibiting expression of the ANGPTL3 gene in the cell.

2 . The method of claim 1 , wherein contacting the cell with the dsRNA agent, or salt thereof, inhibits the expression of ANGPTL3 by at least 50%.

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

4 . The method of claim 3 , wherein the subject is a human.

5 . The method of claim 3 , wherein inhibiting expression of ANGPTL3 decreases ANGPTL3 protein level in serum of the subject by at least 50%.

6 . The method of claim 5 , wherein the subject has an ANGPTL3-associated disorder.

7 . The method of claim 6 , wherein the ANGPTL3-associated disorder is a disorder of lipid metabolism.

8 . The method of claim 7 , wherein the disorder of lipid metabolism is hyperlipidemia or hypertriglyceridemia.

9 . The method of claim 1 , wherein the double stranded region is 19-30 nucleotide pairs in length.

10 . The method of claim 1 , wherein the double stranded region is 21-23 nucleotide pairs in length.

11 . The method of claim 1 , wherein each strand is independently 19-30 nucleotides in length.

12 . The method of claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide.

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

14 . The method of claim 13 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent, or salt thereof.

15 . The method of claim 13 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.

16 . The method of claim 13 , wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent linker.

17 . The method of claim 16 , wherein the ligand is

18 . The method of claim 17 , wherein the dsRNA agent, or salt thereof, is conjugated to the ligand as shown in the following schematic

wherein X is O or S.

19 . The method of claim 18 , wherein X is O.

20 . The method of claim 1 , wherein the dsRNA agent, or salt thereof, further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.

21 . The method of claim 20 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 3′-terminus of one strand; the 5′-terminus of one strand; or at both the 5′- and 3′-terminus of one strand.

22 . The method of claim 1 , wherein the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length.

23 . The method of claim 1 , wherein the sense strand comprises the nucleotide sequence 5′-AAGCUCCUUCUUUUUAUUGUU-3′ of SEQ ID NO: 46.

24 . The method of claim 1 , wherein the sense strand comprises the nucleotide sequence 5′-AAGCUCCUUCUUUUUAUUGUU-3′ of SEQ ID NO: 46 and the antisense strand comprises the nucleotide sequence 5′-AACAAUAAAAAGAAGGAGCUUGG-3′ of SEQ ID NO:661.

25 . The method of claim 1 , wherein the sense strand consists of the nucleotide sequence 5′-AAGCUCCUUCUUUUUAUUGUU-3′ of SEQ ID NO:46 and the antisense strand consists of the nucleotide sequence 5′-AACAAUAAAAAGAAGGAGCUUGG-3′ of SEQ ID NO:661.

26 . The method of claim 1 , wherein the nucleotide sequence of the sense strand differs by no more than 4 bases from the nucleotide sequence 5′-asasgcuccuUfCfUfuuuuauuguu-3′ of SEQ ID NO: 18 and the nucleotide sequence of the antisense strand differs by no more than 4 bases from the nucleotide sequence 5′-asdAscadAudAaaaadGaAfggagcuusgsg-3′ of SEQ ID NO:19,

wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; dA and dG, are 2′-deoxy A and G, respectively; Af, Cf and Uf are 2′-fluoro (2′-F) A, C and U, respectively; and s is a phosphorothioate linkage.

27 . The method of claim 1 , wherein the nucleotide sequence of the sense strand differs by no more than 3 bases from the nucleotide sequence 5′-asasgcuccuUfCfUfuuuuauuguu-3′ of SEQ ID NO: 18 and the nucleotide sequence of the antisense strand differs by no more than 3 bases from the nucleotide sequence 5′-asdAscadAudAaaaadGaAfggagcuusgsg-3′ of SEQ ID NO: 19,

wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; dA and dG, are 2′-deoxy A and G, respectively; Af, Cf and Uf are 2′-fluoro (2′-F) A, C and U, respectively; and s is a phosphorothioate linkage.

28 . The method of claim 1 , wherein the nucleotide sequence of the sense strand differs by no more than 2 bases from the nucleotide sequence 5′-asasgcuccuUfCfUfuuuuauuguu-3′ of SEQ ID NO: 18 and the nucleotide sequence of the antisense strand differs by no more than 2 bases from the nucleotide sequence 5′-asdAscadAudAaaaadGaAfggagcuusgsg-3′ of SEQ ID NO:19,

wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; dA and dG, are 2′-deoxy A and G, respectively; Af, Cf and Uf are 2′-fluoro (2′-F) A, C and U, respectively; and s is a phosphorothioate linkage.

29 . The method of claim 1 , wherein the nucleotide sequence of the sense strand differs by no more than 1 base from the nucleotide sequence 5′-asasgcuccuUfCfUfuuuuauuguu-3′ of SEQ ID NO: 18 and the nucleotide sequence of the antisense strand differs by no more than 1 base from the nucleotide sequence 5′-asdAscadAudAaaaadGaAfggagcuusgsg-3′ of SEQ ID NO:19,

wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; dA and dG, are 2′-deoxy A and G, respectively; Af, Cf and Uf are 2′-fluoro (2′-F) A, C and U, respectively; and s is a phosphorothioate linkage.

30 . The method of claim 1 , wherein the sense strand comprises the nucleotide sequence 5′-asasgcuccuUfCfUfuuuuauuguu-3′ of SEQ ID NO:18 and the antisense strand comprises the nucleotide sequence 5′-asdAscadAudAaaaadGaAfggagcuusgsg-3′ of SEQ ID NO:19,

wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; dA and dG, are 2′-deoxy A and G, respectively; Af, Cf and Uf are 2′-fluoro (2′-F) A, C and U, respectively; and s is a phosphorothioate linkage.

31 . The method of claim 1 , wherein the sense strand consists of the nucleotide sequence 5′-asasgcuccuUfCfUfuuuuauuguu-3′ of SEQ ID NO:18 and the antisense strand consists of the nucleotide sequence 5′-asdAscadAudAaaaadGaAfggagcuusgsg-3′ of SEQ ID NO:19,

wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; dA and dG, are 2′-deoxy A and G, respectively; Af, Cf and Uf are 2′-fluoro (2′-F) A, C and U, respectively; and s is a phosphorothioate linkage.

32 . The method of claim 1 , wherein the sense strand comprises the nucleotide sequence 5′-asasgcuccuUfCfUfuuuuauuguu-L96-3′ of SEQ ID NO:20 and the antisense strand comprises the nucleotide sequence 5′-asdAscadAudAaaaadGaAfggagcuusgsg-3′ of SEQ ID NO: 19,

wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; dA and dG, are 2′-deoxy A and G, respectively; Af, Cf and Uf are 2′-fluoro (2′-F) A, C and U, respectively; and s is a phosphorothioate linkage, and

wherein L96 is a ligand conjugated to the 3′-end of the sense strand as shown in the following schematic

wherein X is O.

33 . A method of treating a subject having a disorder that would benefit from reduction in Angiopoietin-like 3 (ANGPTL3) expression, comprising administering to the subject a therapeutically effective amount of a dsRNA agent, or salt thereof,

wherein the dsRNA agent, or salt thereof comprises a sense strand and an antisense strand forming a double stranded region,

wherein the sense strand comprises at least 19 contiguous nucleotides of the nucleotide sequence 5′-AAGCUCCUUCUUUUUAUUGUU-3′ of SEQ ID NO:46 and the antisense strand comprises at least 21 contiguous nucleotides of the nucleotide sequence of 5′-AACAAUAAAAAGAAGGAGCUUGG-3′ of SEQ ID NO:661,

wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a modification, and

wherein at least one of the modifications is a 2′-deoxy-nucleotide modification, thereby treating the subject having the disorder that would benefit from reduction in ANGPTL3 expression.

34 . The method of claim 33 , wherein the subject is a human.

35 . The method of claim 33 , wherein the disorder is an ANGPTL3-associated disorder.

36 . The method of claim 35 , wherein the ANGPTL3-associated disorder is a disorder of lipid metabolism.

37 . The method of claim 36 , wherein the disorder of lipid metabolism is hyperlipidemia or hypertriglyceridemia.

38 . The method of claim 33 , wherein the administration of the dsRNA agent, or salt thereof, to the subject causes a decrease in one or more serum lipid and/or a decrease in ANGPTL3 protein accumulation.

39 . The method of claim 33 , wherein the dsRNA agent, or salt thereof, is administered to the subject subcutaneously.

40 . The method of claim 33 , further comprising administering to the subject an additional therapeutic agent for treatment of an ANGPTL3-associated disorder.

41 . The method of claim 33 , wherein the double stranded region is 19-30 nucleotide pairs in length.

42 . The method of claim 33 , wherein the double stranded region is 21-23 nucleotide pairs in length.

43 . The method of claim 33 , wherein each strand is independently 19-30 nucleotides in length.

44 . The method of claim 33 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide.

45 . The method of claim 33 , wherein the dsRNA agent, or salt thereof, further comprises a ligand.

46 . The method of claim 45 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent, or salt thereof.

47 . The method of claim 45 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative.

48 . The method of claim 45 , wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent linker.

49 . The method of claim 48 , wherein the ligand is

50 . The method of claim 49 , wherein the dsRNA agent, or salt thereof, is conjugated to the ligand as shown in the following schematic

wherein X is O or S.

51 . The method of claim 50 , wherein X is O.

52 . The method of claim 33 , wherein the dsRNA agent, or salt thereof, further comprises at least one phosphorothioate or methylphosphonate internucleotide linkage.

53 . The method of claim 52 , wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 3′-terminus of one strand; the 5′-terminus of one strand; or at both the 5′- and 3′-terminus of one strand.

54 . The method of claim 33 , wherein the sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length.

55 . The method of claim 33 , wherein the sense strand comprises the nucleotide sequence 5′-AAGCUCCUUCUUUUUAUUGUU-3′ of SEQ ID NO:46.

56 . The method of claim 33 , wherein the sense strand comprises the nucleotide sequence 5′-AAGCUCCUUCUUUUUAUUGUU-3′ of SEQ ID NO:46 and the antisense strand comprises the nucleotide sequence 5′-AACAAUAAAAAGAAGGAGCUUGG-3′ of SEQ ID NO:661.

57 . The method of claim 33 , wherein the sense strand consists of the nucleotide sequence 5′-AAGCUCCUUCUUUUUAUUGUU-3′ of SEQ ID NO:46 and the antisense strand consists of the nucleotide sequence 5′-AACAAUAAAAAGAAGGAGCUUGG-3′ of SEQ ID NO:661.

58 . The method of claim 33 , wherein the nucleotide sequence of the sense strand differs by no more than 4 bases from the nucleotide sequence 5′-asasgcuccuUfCfUfuuuuauuguu-3′ of SEQ ID NO: 18 and the nucleotide sequence of the antisense strand differs by no more than 4 bases from the nucleotide sequence 5′-asdAscadAudAaaaadGaAfggagcuusgsg-3′ of SEQ ID NO:19,

wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; dA and dG, are 2′-deoxy A and G, respectively; Af, Cf and Uf are 2′-fluoro (2′-F) A, C and U, respectively; and s is a phosphorothioate linkage.

59 . The method of claim 33 , wherein the nucleotide sequence of the sense strand differs by no more than 3 bases from the nucleotide sequence 5′-asasgcuccuUfCfUfuuuuauuguu-3′ of SEQ ID NO: 18 and the nucleotide sequence of the antisense strand differs by no more than 3 bases from the nucleotide sequence 5′-asdAscadAudAaaaadGaAfggagcuusgsg-3′ of SEQ ID NO: 19,

wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; dA and dG, are 2′-deoxy A and G, respectively; Af, Cf and Uf are 2′-fluoro (2′-F) A, C and U, respectively; and s is a phosphorothioate linkage.

60 . The method of claim 33 , wherein the nucleotide sequence of the sense strand differs by no more than 2 bases from the nucleotide sequence 5′-asasgcuccuUfCfUfuuuuauuguu-3′ of SEQ ID NO: 18 and the nucleotide sequence of the antisense strand differs by no more than 2 bases from the nucleotide sequence 5′-asdAscadAudAaaaadGaAfggagcuusgsg-3′ of SEQ ID NO:19,

wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; dA and dG, are 2′-deoxy A and G, respectively; Af, Cf and Uf are 2′-fluoro (2′-F) A, C and U, respectively; and s is a phosphorothioate linkage.

61 . The method of claim 33 , wherein the nucleotide sequence of the sense strand differs by no more than 1 base from the nucleotide sequence 5′-asasgcuccuUfCfUfuuuuauuguu-3′ of SEQ ID NO: 18 and the nucleotide sequence of the antisense strand differs by no more than 1 base from the nucleotide sequence 5′-asdAscadAudAaaaadGaAfggagcuusgsg-3′ of SEQ ID NO:19,

wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; dA and dG, are 2′-deoxy A and G, respectively; Af, Cf and Uf are 2′-fluoro (2′-F) A, C and U, respectively; and s is a phosphorothioate linkage.

62 . The method of claim 33 , wherein the sense strand comprises the nucleotide sequence 5′-asasgcuccuUfCfUfuuuuauuguu-3′ of SEQ ID NO:18 and the antisense strand comprises the nucleotide sequence 5′-asdAscadAudAaaaadGaAfggagcuusgsg-3′ of SEQ ID NO:19,

wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; dA and dG, are 2′-deoxy A and G, respectively; Af, Cf and Uf are 2′-fluoro (2′-F) A, C and U, respectively; and s is a phosphorothioate linkage.

63 . The method of claim 33 , wherein the sense strand consists of the nucleotide sequence 5′-asasgcuccuUfCfUfuuuuauuguu-3′ of SEQ ID NO: 18 and the antisense strand consists of the nucleotide sequence 5′-asdAscadAudAaaaadGaAfggagcuusgsg-3′ of SEQ ID NO:19,

wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; dA and dG, are 2′-deoxy A and G, respectively; Af, Cf and Uf are 2′-fluoro (2′-F) A, C and U, respectively; and s is a phosphorothioate linkage.

64 . The method of claim 33 , wherein the sense strand comprises the nucleotide sequence 5′-asasgcuccuUfCfUfuuuuauuguu-L96-3′ of SEQ ID NO:20 and the antisense strand comprises the nucleotide sequence 5′-asdAscadAudAaaaadGaAfggagcuusgsg-3′ of SEQ ID NO:19,

wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; dA and dG, are 2′-deoxy A and G, respectively; Af, Cf and Uf are 2′-fluoro (2′-F) A, C and U, respectively; and s is a phosphorothioate linkage, and

wherein L96 is a ligand conjugated to the 3′-end of the sense strand as shown in the following schematic

wherein X is O.

65 . A method of treating a subject having a disorder that would benefit from reduction in Angiopoietin-like 3 (ANGPTL3) expression, comprising administering to the subject a therapeutically effective amount of a dsRNA agent, or salt thereof,

wherein the dsRNA agent, or salt thereof, comprises a sense strand and an antisense strand forming a double stranded region,

wherein the sense strand comprises the nucleotide sequence 5′-asasgcuccuUfCfUfuuuuauuguu-L96-3′ of SEQ ID NO:20 and the antisense strand comprises the nucleotide sequence 5′-asdAscadAudAaaaadGaAfggagcuusgsg-3′ of SEQ ID NO:19,

wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; dA and dG, are 2′-deoxy A and G, respectively; Af, Cf and Uf are 2′-fluoro (2′-F) A, C and U, respectively; and s is a phosphorothioate linkage, and

wherein L96 is a ligand conjugated to the 3′-end of the sense strand as shown in the following schematic

wherein X is O, thereby treating the subject.

66 . The method of claim 65 , wherein the subject is human.

67 . The method of claim 66 , wherein the disorder is an ANGPTL3-associated disorder.

68 . The method of claim 67 , wherein the ANGPTL3-associated disorder is a disorder of lipid metabolism.

69 . The method of claim 68 , wherein the disorder of lipid metabolism is hyperlipidemia or hypertriglyceridemia.

70 . The method of claim 65 , wherein the administration of the agent to the subject causes a decrease in one or more serum lipid and/or a decrease in ANGPTL3 protein accumulation.

71 . The method of claim 65 , wherein the dsRNA agent, or salt thereof, is administered to the subject subcutaneously.

72 . The method of claim 65 , further comprising administering to the subject an additional therapeutic agent for treatment of an ANGPTL3-associated disorder.

73 . The method of claim 65 , wherein the dsRNA agent is in a salt form.

74 . The method of claim 65 , wherein the dsRNA agent, or salt thereof, is present in a pharmaceutical composition.

75 . A method of treating a subject having a disorder that would benefit from reduction in Angiopoietin-like 3 (ANGPTL3) expression, comprising administering to the subject a therapeutically effective amount of a dsRNA agent, or salt thereof,

wherein the dsRNA agent, or salt thereof, comprises a sense strand and an antisense strand forming a double stranded region,

wherein the sense strand consists of the nucleotide sequence 5′-asasgcuccuUfCfUfuuuuauuguu-L96-3′ of SEQ ID NO:20 and the antisense strand consists of the nucleotide sequence 5′-asdAscadAudAaaaadGaAfggagcuusgsg-3′ of SEQ ID NO:19,

wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; dA and dG, are 2′-deoxy A and G, respectively; Af, Cf and Uf are 2′-fluoro (2′-F) A, C and U, respectively; and s is a phosphorothioate linkage, and

wherein L96 is a ligand conjugated to the 3′-end of the sense strand as shown in the following schematic

wherein X is O, thereby treating the subject.

76 . The method of claim 75 , wherein the subject is human.

77 . The method of claim 76 , wherein the disorder is an ANGPTL3-associated disorder.

78 . The method of claim 77 , wherein the ANGPTL3-associated disorder is a disorder of lipid metabolism.

79 . The method of claim 78 , wherein the disorder of lipid metabolism is hyperlipidemia or hypertriglyceridemia.

80 . The method of claim 75 , wherein the administration of the agent to the subject causes a decrease in one or more serum lipid and/or a decrease in ANGPTL3 protein accumulation.

81 . The method of claim 75 , wherein the dsRNA agent, or salt thereof, is administered to the subject subcutaneously.

82 . The method of claim 75 , further comprising administering to the subject an additional therapeutic agent for treatment of an ANGPTL3-associated disorder.

83 . The method of claim 75 , wherein the dsRNA agent is in a salt form.

84 . The method of claim 75 , wherein the dsRNA agent, or salt thereof, is present in a pharmaceutical composition.

Assignments (3)
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 Sep 28, 2022
From: BONDURANT, LUCAS D.; SCHLEGEL, MARK K; ZUBER, JEFFREY; WOODS, LAUREN BLAIR; CHICKERING, TYLER
To: ALNYLAM PHARMACEUTICALS, INC.
Reel/Frame 061242/0843 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 28, 2022
From: BONDURANT, LUCAS D.; SCHLEGEL, MARK K.; ZUBER, JEFFREY
To: ALNYLAM PHARMACEUTICALS, INC.
Reel/Frame 061242/0808 →
Continuity (5)
Continuation 17689034 · Mar 8, 2022
Continuation PCTUS2022018630 · Mar 3, 2022
Provisional Application 63308668 · Feb 10, 2022
Provisional Application 63156476 · Mar 4, 2021
Related Publication 20230133637A1 · May 4, 2023
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