Methods for treating hypercholesterolemia

• US 8,084,437 B2
• Filed: 11/27/2007
• Issued: 12/27/2011
• Est. Priority Date: 11/27/2006
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Freier, Susan M., Crooke, Rosanne M., Graham, Mark J., Bhanot, Sanjay, Tribble, Diane, Watt, Andrew T., Lemonidis, Kristina M.
• Primary Examiner(s): GIBBS, TERRA C
• Application Number:
  US12/516,457
• Publication Number:
  US 20100144834A1
• Time in Patent Office: 1,491 Days
• Field of Search: 536/23.1, 536/24.3, 536/24.33, 536/24.5, 514/44
• US Class Current: 514/44
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/0375 Animal model for cardiovascular diseases
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• 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 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/3525 MOE, methoxyethoxy

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 hypercholesterolemia, or alternatively for treating or preventing 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. A single-stranded modified oligonucleotide compound consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising a portion which consists of at least 8 contiguous nucleobases complementary to an equal-length portion of 1004-1023 or 1920-1939 of SEQ ID NO:

1, wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO;

1.

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

3. The compound of claim 2, wherein at least one nucleoside comprises a modified sugar.

4. The compound of claim 3, wherein at least one modified sugar is a bicyclic sugar.

5. The compound of claim 4, wherein at least one modified sugar comprises a 2′

-O-methoxyethyl.

6. The compound of claim 2, wherein at least one nucleoside comprises a modified nucleobase.

7. The compound of claim 6, wherein the modified nucleobase is a 5-methylcytosine.

8. The compound of claim 1, wherein the modified oligonucleotide comprises:

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.

9. The compound of claim 8, 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.

10. The compound of claim 8, wherein the compound is a chimeric oligonucleotide consisting of a gap segment consisting of from 10 to 18 linked 2′

-deoxynucleosides;

a 5′

wing segment consisting of from 1 to 5 linked nucleosides; and

a 3′

wing segment consisting of from 1 to 5 linked nucleosides;

wherein each nucleoside of the 5′

wing segment is a sugar-modified nucleoside, each nucleoside of the 3′

wing segment is a sugar-modified nucleoside, and each internucleoside linkage is a phosphorothioate internucleoside linkage.

11. A composition comprising the modified oligonucleotide compound of any of claims 1, 2, or 3-10, or a salt thereof and a pharmaceutically acceptable carrier or diluent.

17. The compound of claim 1, wherein the modified oligonucleotide comprises:

a gap segment consisting of 10 linked deoxynucleosides;

a 5′

wing segment consisting of 5 linked nucleosides; and

a 3′

wing segment consisting of 5 linked nucleosides;

wherein the gap segment is positioned between the 5′

wing segment and the 3′

wing segment;

wherein the compound consists of the nucleobase sequence set forth in SEQ ID NO;

28, SEQ ID NO;

59, SEQ ID NO;

248, SEQ ID NO;

250, SEQ ID NO;

394, SEQ ID NO;

400, or SEQ ID NO;

402.

18. The compound of claim 1, wherein the modified oligonucleotide comprises:

a gap segment consisting of 14 linked deoxynucleosides;

a 5′

wing segment consisting of 3 linked nucleosides; and

a 3′

wing segment consisting of 3 linked nucleosides;

wherein the gap segment is positioned between the 5′

wing segment and the 3′

wing segment;

wherein the compound consists of the nucleobase sequence set forth in SEQ ID NO;

28, SEQ ID NO;

59, SEQ ID NO;

248, SEQ ID NO;

250, SEQ ID NO;

394, SEQ ID NO;

400, or SEQ ID NO;

402.

19. The compound of claim 17, wherein each internucleoside linkage is a phosphorothioate linkage;

wherein each nucleoside of each wing segment comprises a 2′

-O-methoxyethyl sugar; and

wherein the compound consists of the nucleobase sequence set forth in SEQ ID NO;

402.

12. A method comprising administering to a human with hypercholesterolemia, polygenic hypercholesterolemia, mixed dyslipidemia, coronary heart disease, acute coronary syndrome, 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, elevated ApoB, elevated cholesterol, elevated LDL-cholesterol, elevated VLDL-cholesterol, or elevated non-HDL cholesterol, a therapeutically effective amount of a composition comprising a single-stranded oligonucleotide compound consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases complementary to an equal-length portion of 1004-1023 or 1920-1939 of SEQ ID NO:

1, wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO;

1.

13. The method of claim 12, wherein the elevated LDL-cholesterol level is above a target level of at least about 100 mg/dL, 130 mg/dL, 160 mg/dL, or 190 mg/dL.

14. The method of claim 13, wherein administering said composition results in an 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.

15. The method of claim 12, wherein administering said composition results in a reduction of ApoB, LDL-cholesterol, VLDL-cholesterol, Lp(a), small LDL-particle, small VLDL-particle, non-HDL-cholesterol, liver triglyceride level, serum triglycerides, serum phospholipids, or any combination thereof.

16. The method of claim 15, wherein at least one of the ApoB reduction, the LDL-cholesterol reduction, the, VLDL-cholesterol reduction, the Lp(a) reduction, the small LDL-particle reduction, the small VLDL-particle reduction, the non-HDL-cholesterol reduction, the liver triglyceride level reduction, the serum triglycerides reduction, or serum phospholipids reduction is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.