METHODS FOR TREATING HYPERCHOLESTEROLEMIA

• US 20090318536A1
• Filed: 06/04/2009
• Published: 12/24/2009
• Est. Priority Date: 11/27/2006
• Status: Active Grant

• Current Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Original Assignee: ISS Pharmaceuticals Incorporated
• Inventors: Watt, Andrew T., FREIER, Susan M., Lemonidis, Kristina L., Graham, Mark J., Bhanot, Sanjay, Crooke, Rosanne M., Tribble, Diane
• Granted Patent: US 8,093,222 B2
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/351 Conjugate
• CPC Class Codes: C12N 2320/30 Special therapeutic applications

Abstract

Disclosed herein are antisense compounds and methods for decreasing LDL-C in an individual having elevated LDL-C. Additionally disclosed are antisense compounds and methods for treating, preventing, or ameliorating hypercholesterolemia and/or atherosclerosis. Further disclosed are antisense compounds and methods for decreasing coronary heart disease risk. Such methods include administering to an individual in need of treatment an antisense compound targeted to a PCSK9 nucleic acid. The antisense compounds administered include gapmer antisense oligonucleotides.

Claims

1. An antisense compound having the nucleotide sequence selected from the group consisting of:

SEQ ID NO;

248, SEQ ID NO;

250, SEQ ID NO;

65, SEQ ID NO;

28, SEQ ID NO;

188, SEQ ID NO;

352, SEQ ID NO;

60, SEQ ID NO;

381, SEQ ID NO;

400, SEQ ID NO;

212, SEQ ID NO;

62, SEQ ID NO;

59, SEQ ID NO;

237, SEQ ID NO;

288, SEQ ID NO;

50, SEQ ID NO;

402, SEQ ID NO;

394, SEQ ID NO;

180, SEQ ID NO;

8, and SEQ ID NO;

7.

2. The compound of claim 1 selected from the group consisting of:

SEQ ID NO;

248, SEQ ID NO;

28, SEQ ID NO;

59, SEQ ID NO;

60, SEQ ID NO;

62, SEQ ID NO;

250, SEQ ID NO;

352, SEQ ID NO;

381, SEQ ID NO;

400, and SEQ ID NO;

188.

3. The compound of claim 2, which is SEQ ID NO:

248.

4. The compound of claim 1, wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage.

5. The compound of claim 1, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

6. The compound of claim 1, wherein at least one nucleoside comprises a modified sugar.

7. The compound of claim 6, wherein the at least one modified sugar is a bicyclic sugar.

8. The compound of claim 7, wherein each of the at least one bicyclic sugar comprises a 4′

-CH(CH3)-O-2′

bridge.

9. The compound of claim 6, wherein the modified sugar comprises a 2′

-O-methoxyethyl moiety.

10. The compound of claim 1, comprising at least one tetrahydropyran modified nucleoside, wherein a tetrahydropyran ring replaces the furanose ring.

11. The compound of claim 10, wherein each of the at least one tetrahydropyran modified nucleoside has the structure:

12. The compound of claim 1, wherein at least one nucleoside comprises a modified nucleobase.

13. The compound of claim 12, wherein the modified nucleobase is a 5-methylcytosine.

14. The antisense compound of claim 1, wherein the antisense compound is a modified oligonucleotide comprising:

a gap segment consisting of linked deoxynucleosides;

a 5′

wing segment consisting of linked nucleosides; and

a 3′

wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′

wing segment and the 3′

wing segment; and

wherein each nucleoside of each wing segment comprises a modified sugar.

15. The antisense compound of claim 14, wherein the modified oligonucleotide comprises:

a gap segment consisting of ten linked deoxynucleosides;

a 5′

wing segment consisting of five linked nucleosides; and

a 3′

wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′

wing segment and the 3′

wing segment, wherein each nucleoside of each wing segment comprises a 2′

-O-methoxyethyl sugar; and

wherein each internucleoside linkage is a phosphorothioate linkage.

16. A composition comprising an antisense compound having the nucleotide sequence selected from the group consisting of:

SEQ ID NO;

248, SEQ ID NO;

250, SEQ ID NO;

65, SEQ ID NO;

28, SEQ ID NO;

188, SEQ ID NO;

352, SEQ ID NO;

60, SEQ ID NO;

381, SEQ ID NO;

400, SEQ ID NO;

212, SEQ ID NO;

62, SEQ ID NO;

59, SEQ ID NO;

237, SEQ ID NO;

288, SEQ ID NO;

50, SEQ ID NO;

402, SEQ ID NO;

394, SEQ ID NO;

180, SEQ ID NO;

8, and SEQ ID NO;

7, and a pharmaceutically acceptable carrier or diluent.

17. The composition of claim 16, wherein the antisense compound has the nucleotide sequence selected from the group consisting of:

SEQ ID NO;

248, SEQ ID NO;

28, SEQ ID NO;

59, SEQ ID NO;

60, SEQ ID NO;

62, SEQ ID NO;

250, SEQ ID NO;

352, SEQ ID NO;

381, SEQ ID NO;

400, and SEQ ID NO;

188.

18. The composition of claim 16, wherein the antisense compound has the nucleotide sequence of SEQ ID NO:

248.

19. The composition of claim 16, further comprising a pharmaceutical agent for separate, sequential, or simultaneous administration with said antisense compound.

20. The composition of claim 19, wherein the pharmaceutical agent is a lipid lowering compound.

21. The composition of claim 20, wherein the lipid lowering compound is a HMG-CoA reductase inhibitor, cholesterol absorption inhibitor, MTP inhibitor, antisense compound targeted to ApoB, or any combination thereof.

22. The composition of claim 21, wherein the HMG-CoA reductase inhibitor is atorvastatin, rosuvastatin, or simvastatin.

23. The composition of claim 21, wherein the cholesterol absorption inhibitor is ezetimibe.

24. The composition of claim 21, wherein the HMG-CoA reductase inhibitor is simvastatin, and the cholesterol absorption inhibitor is ezetimibe.

25. The composition of claim 16, wherein at least one internucleoside linkage in the antisense compound is a phosphorothioate internucleoside linkage.

26. The composition of claim 16, wherein each internucleoside linkage in the antisense compound is a phosphorothioate internucleoside linkage.

27. The composition of claim 16, wherein at least one nucleoside in the antisense compound comprises a modified sugar.

28. The composition of claim 27, wherein the at least one modified sugar is a bicyclic sugar.

29. The composition of claim 28, wherein each of the at least one bicyclic sugar comprises a 4′

-CH(CH3)-O-2′

bridge.

30. The composition of claim 27, wherein the modified sugar comprises a 2′

-O-methoxyethyl moiety.

31. The composition of claim 16, wherein the antisense compound comprises at least one tetrahydropyran modified nucleoside, wherein a tetrahydropyran ring replaces the furanose ring.

32. The composition of claim 31, wherein each of the at least one tetrahydropyran modified nucleoside has the structure:

33. The composition of claim 16, wherein at least one nucleoside in the antisense compound comprises a modified nucleobase.

34. The composition of claim 33, wherein the modified nucleobase is a 5-methylcytosine.

35. The composition of claim 16, wherein the antisense compound is a modified oligonucleotide comprising:

a gap segment consisting of linked deoxynucleosides;

a 5′

wing segment consisting of linked nucleosides; and

a 3′

wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′

wing segment and the 3′

wing segment; and

wherein each nucleoside of each wing segment comprises a modified sugar.

36. The composition of claim 35, wherein the modified oligonucleotide comprises:

a gap segment consisting of ten linked deoxynucleosides;

a 5′

wing segment consisting of five linked nucleosides; and

a 3′

wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′

wing segment and the 3′

wing segment, wherein each nucleoside of each wing segment comprises a 2′

-O-methoxyethyl sugar; and

wherein each internucleoside linkage is a phosphorothioate linkage.

37. A method comprising administering to an animal an antisense compound having the nucleotide sequence selected from the group consisting of:

SEQ ID NO;

248, SEQ ID NO;

250, SEQ ID NO;

65, SEQ ID NO;

28, SEQ ID NO;

188, SEQ ID NO;

352, SEQ ID NO;

60, SEQ ID NO;

381, SEQ ID NO;

400, SEQ ID NO;

212, SEQ ID NO;

62, SEQ ID NO;

59, SEQ ID NO;

237, SEQ ID NO;

288, SEQ ID NO;

50, SEQ ID NO;

402, SEQ ID NO;

394, SEQ ID NO;

180, SEQ ID NO;

8, and SEQ ID NO;

7.

38. The method of claim 37, wherein the antisense compound has the nucleotide sequence selected from the group consisting of:

SEQ ID NO;

248, SEQ ID NO;

28, SEQ ID NO;

59, SEQ ID NO;

60, SEQ ID NO;

62, SEQ ID NO;

250, SEQ ID NO;

352, SEQ ID NO;

381, SEQ ID NO;

400, and SEQ ID NO;

188.

39. The method of claim 37, wherein the antisense compound has the nucleotide sequence of SEQ ID NO:

248.

40. The method of claim 37, wherein the animal is a human.

41. The method of claim 37, wherein administering the compound slows progression and/or ameliorates hypercholesterolemia, acute coronary syndrome, polygenic hypercholesterolemia, mixed dyslipidemia, coronary heart disease, early onset coronary heart disease, type II diabetes, type II diabetes with dyslipidemia, hepatic steatosis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, hypertriglyceridemia, hyperfattyacidemia, hyperlipidemia, metabolic syndrome, atherosclerosis, or improves cardiovascular outcome, or any combination thereof.

42. The method of claim 37 further comprising administering at least one pharmaceutical agent.

43. The method of claim 42, wherein the pharmaceutical agent is administered separately, sequentially, or simultaneously with the antisense compound.

44. The method of claim 42, wherein the compound and the pharmaceutical agent are administered in the same or separate formulation.

45. The method of claim 42, wherein the pharmaceutical agent is a lipid lowering pharmaceutical agent.

46. The method of claim 45, wherein the lipid lowering pharmaceutical agent is a HMG-CoA reductase inhibitor, cholesterol absorption inhibitor, MTP inhibitor, or antisense compound targeted to ApoB, or any combination thereof.

47. The method of claim 46, wherein the HMG-CoA reductase inhibitor is atorvastatin, rosuvastatin, or simvastatin.

48. The method of claim 46, wherein the cholesterol absorption inhibitor is ezetimibe.

49. The method of claims 46, wherein the HMG-CoA reductase inhibitor is simvastatin, and the cholesterol absorption inhibitor is ezetimibe.

50. The method of claim 37, wherein the administering is parenteral administration.

51. The method of claim 50, wherein the parenteral administration comprises subcutaneous or intravenous administration.

52. The method of claim 37, wherein the administering comprises oral administration.

53. The method of claim 37, wherein the animal has an elevated LDL-cholesterol level above a target level of at least about 100 mg/dL, 130 mg/dL, 160 mg/dL, or 190 mg/dL.

54. The method of claim 37, wherein the administering the compound to the animal reduces LDL-cholesterol levels.

55. The method of claim 54, wherein administering the compound reduces the LDL-cholesterol level below a target level of at least about 190 mg/dL, 160 mg/dL, 130 mg/dL, 100 mg/dL, 70 mg/dL, or 50 mg/dL.

56. The method of claim 37, wherein administering the compound results in reduced coronary heart disease risk, or slows, stops or ameliorates progression of atherosclerosis, or any combination thereof.

57. The method of claim 40, wherein administering the compound results in improved cardiovascular outcome of the human.

58. The method of claim 57, wherein the improved cardiovascular outcome is improved carotid intimal media thickness, improved atheroma thickness, increased HDL-cholesterol, or any combination thereof.

59. The method of claim 37, wherein administering the compound ameliorates hepatic steatosis, results in lipid lowering, improves LDL/HDL ratio, or any combination thereof.

60. The method of claim 37, wherein at least one internucleoside linkage in the antisense compound is a phosphorothioate internucleoside linkage.

61. The method of claim 60, wherein each internucleoside linkage in the antisense compound is a phosphorothioate internucleoside linkage.

62. The method of claim 37, wherein at least one nucleoside in the antisense compound comprises a modified sugar.

63. The method of claim 62, wherein the at least one modified sugar is a bicyclic sugar.

64. The method of claim 63, wherein each of the at least one bicyclic sugar comprises a 4′

-CH(CH3)-O-2′

bridge.

65. The method of claim 62, wherein the modified sugar comprises a 2′

-O-methoxyethyl moiety.

66. The method of claim 37, wherein the antisense compound comprises at least one tetrahydropyran modified nucleoside, wherein a tetrahydropyran ring replaces the furanose ring.

67. The method of claim 66, wherein each of the at least one tetrahydropyran modified nucleoside has the structure:

68. The method of claim 37, wherein at least one nucleoside in the antisense compound comprises a modified nucleobase.

69. The method of claim 68, wherein the modified nucleobase is a 5-methylcytosine.

70. The method of claim 37, wherein the antisense compound is a modified oligonucleotide comprising:

a gap segment consisting of linked deoxynucleosides;

a 5′

wing segment consisting of linked nucleosides; and

a 3′

wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′

wing segment and the 3′

wing segment; and

wherein each nucleoside of each wing segment comprises a modified sugar.

71. The method of claim 70, wherein the modified oligonucleotide comprises:

a gap segment consisting of ten linked deoxynucleosides;

a 5′

wing segment consisting of five linked nucleosides; and

a 3′

wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′

wing segment and the 3′

wing segment, wherein each nucleoside of each wing segment comprises a 2′

-O-methoxyethyl sugar; and

wherein each internucleoside linkage is a phosphorothioate linkage.

72. A modified antisense oligonucleotide having the nucleotide sequence of SEQ ID NO:

248, wherein the modified oligonucleotide comprises;

a gap segment consisting of ten linked deoxynucleosides;

a 5′

wing segment consisting of five linked nucleosides; and

a 3′

wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′

wing segment and the 3′

wing segment, wherein each nucleoside of each wing segment comprises a 2′

-O-methoxyethyl sugar;

wherein each internucleoside linkage is a phosphorothioate linkage, and wherein each cytosine nucleoside in the modified antisense oligonucleotide is a 5-methylcytosine.