NZ774866B2 - Angiopoietin-like 3 (ANGPTL3) iRNA compositions and methods of use thereof - Google Patents

Abstract

The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the ANGPTL3 gene, as well as methods of inhibiting expression of ANGPTL3 and methods of treating subjects having a disorder of lipid metabolism, such as hyperlipidemia or hypertriglyceridemia, using such dsRNA compositions.

Claims (31)

We claim:

1. A double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of angiopoietin-like 3 (ANGPTL3), or a salt thereof, wherein the dsRNA agent, or a salt thereof, comprises a sense strand and an antisense 5 strand g a double stranded region, wherein the sense strand comprises the nucleotide sequence 5’ – UGUCACUUGAACUCAACUCAA - 3’ of SEQ ID NO:296 and the antisense strand comprises the nucleotide sequence 5’ – UUGAGUUGAGUUCAAGUGACAUA – 3’ of SEQ ID NO: 308, 10 wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a tide modification selected from the group consisting of a 2’-O-methyl nucleotide modification and a oro nucleotide cation, wherein the sense strand comprises no more than four 2’-fluoro nucleotide modifications, and the antisense strand ses no more than six 2’-fluoro nucleotide 15 modifications, and wherein a ligand comprising an N-acetylgalactosamine (GalNAc) derivative is conjugated to at least one strand of the dsRNA agent.

2. The RNAi agent, or a salt thereof, of claim 1, w herein the sense strand is 21 20 tides in length and the antisense strand is 23 nucleotides in length.

3. The dsRNA agent, or a salt f, of claim 1 or 2, wherein at least one strand comprises a 3’ overhang of at least 1 nucleotide.

4. The dsRNA agent, or a salt thereof, of any one of claims 1-3, wherein at least one strand comprises a 3’ overhang of at least 2 nucleotides.

5. The dsRNA agent, or a salt thereof, of any one of claims 1-4, wherein at least one of the 5’-end or the 3’-end of the sense strand of the dsRNA agent, or a salt thereof, is a 30 blunt end. 21329397_1 (GHMatters) P107021.NZ.1

6. The dsRNA agent, or a salt f, of any one of claims 1-5, further comprising at least one phosphorothioate internucleotide linkage.

7. The dsRNA agent, or a salt f, of claim 6, wherein the phosphorothioate or methylphosphonate internucleotide linkage is at the 3’-terminus of one strand. 5

8. The dsRNA agent, or a salt thereof, of claim 7, wherein the strand is the antisense strand.

9. The dsRNA agent, or a salt thereof, of claim 6, wherein the dsRNA agent, or a 10 salt thereof, comprises 6-8 phosphorothioate internucleotide linkages.

10. The dsRNA agent, or a salt thereof, of any one of claims 1-9, wherein the ligand is conjugated to the 3’ end of the sense strand of the dsRNA, or a salt thereof.

11. The dsRNA agent, or a salt thereof, of any one of claims 1-10, wherein the ligand comprising the GalNAc derivative is attached to the dsRNA agent, or a salt thereof, through a linker.

12. The dsRNA agent, or a salt thereof, of claim 11, n the ligand 20 comprising the GalNAc derivative is attached to the dsRNA agent, or a salt f, through a bivalent or trivalent .

13. The dsRNA agent, or a salt thereof, of claim 12, wherein the ligand is HO OH O H H HO O N N O HO OH O H H HO O N N O O O O HO OH HO O N N O AcHN H H O . 25 21329397_1 (GHMatters) P107021.NZ.1

14. The dsRNA agent, or a salt thereof, of claim 13, wherein the dsRNA agent, or a salt thereof, is conjugated to the ligand as shown in the following schematic , wherein X is O or S.

15. An isolated cell containing the dsRNA agent, or a salt thereof, of any one of 5 claims 1-14.

16. A pharmaceutical composition for ting expression of an ANGPTL3 gene comprising the dsRNA agent, or a salt f, of any one of claims 1-14.

17. An in vitro method of inhibiting ANGPTL3 expression in a cell, the method comprising: (a) contacting the cell with the dsRNA agent, or a salt thereof, of any one of claims 1-14 or the pharmaceutical composition of claim 16; and (b) ining the cell produced in step (a) for a time sufficient to obtain 15 degradation of the mRNA transcript of an ANGPTL3 gene, thereby inhibiting expression of the 3 gene in the cell.

18. Use of the dsRNA agent, or a salt thereof, of any one of claims 1-14 or the pharmaceutical composition of claim 16, in the manufacture of a medicament for treating a 20 human subject having a disorder that would benefit from a ion in ANGPTL3 expression.

19. The use of claim 18, wherein the disorder is a disorder of lipid metabolism. 21329397_1 (GHMatters) P107021.NZ.1

20. The use of claim 19, wherein the disorder of lipid metabolism is selected from the group consisting of hypertriglyceridemia, obesity, hyperlipidemia, atherosclerosis, diabetes, cardiovascular disease, or coronary artery disease.

21. The use of claim 19, n the disorder of lipid metabolism is 5 hyperlipidemia or hypertriglyceridemia.

22. The use of any one of claims 18-21, wherein the use further comprises use of an additional therapeutic.

23. The use of claim 22, wherein the additional therapeutic is a statin.

24. The use of any one of claims 18-23, wherein the dsRNA agent, or a salt thereof, or ceutical composition is for subcutaneous administration.

25. The use of any one of claims 18-24, wherein the dsRNA agent, or a salt thereof, or pharmaceutical composition is for administration at a dose of about 0.01 mg/kg to about 50 mg/kg.

26. The use of any one of claims 18-25, wherein administration of the dsRNA 20 agent, or a salt thereof, or pharmaceutical composition causes a decrease in one or more serum lipid and/or a decrease in ANGPTL3 protein accumulation.

27. Use of the dsRNA agent, or a salt thereof, of any one of claims 1-14 or the pharmaceutical composition of claim 16, in the cture of a medicament for ting 25 the expression of ANGPTL3 in a human subject.

28. The use of claim 27, n the subject has a disorder of lipid metabolism.

29. The use of any one of claims 27-28, n the use further comprises use of 30 an onal therapeutic.

30. The use of claim 29, wherein the additional therapeutic is a statin. 21329397_1 (GHMatters) P107021.NZ.1

31. The use of any one of claims 27-30, wherein the dsRNA agent, or a salt thereof, or pharmaceutical composition is for subcutaneous administration. 97_1 (GHMatters) P107021.NZ.1 None set by na MigrationNone set by kirstena Unmarked set by kirstena None set by kirstena MigrationNone set by kirstena Unmarked set by kirstena \\\\\\\\\” Optimized ~§\\\‘ 10 ANG—GaINAc ...................... “““““““