Compositions and methods of targeting apolipoprotein B for the reduction of apolipoprotein C-III

• US 9,107,933 B2
• Filed: 03/16/2010
• Issued: 08/18/2015
• Est. Priority Date: 03/16/2009
• Status: Expired due to Fees

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation), Ionis Pharmaceuticals, Inc.
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation), ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Sacks, Frank M., Tribble, Diane
• Primary Examiner(s): ZARA, JANE J
• Application Number:
  US13/257,260
• Publication Number:
  US 20120129911A1
• Time in Patent Office: 1,981 Days
• Field of Search: 435/6, 435/91.1, 435/91.31, 435/455, 435/458, 435/6.1, 514/44, 536/23.1, 536/24.5
• US Class Current: 1/1
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

Disclosed herein are compositions and methods for lowering Apolipoprotein C-III (ApoC-III) in a subject in need thereof. Subjects in need of ApoC-III reduction include subjects with elevated ApoC-III levels, subjects with a condition associated with ApoC-III, subjects with diabetes, obese subjects and subjects with cardiovascular disease. Compositions to lower ApoC-III include compounds targeting Apolipoprotein B (ApoB) such as Mipomersen and other antisense compound targeting ApoB.

Claims

1. A method of lowering plasma apolipoprotein C-III levels in a human subject, comprising:

selecting a human subject with elevated apolipoprotein C-III levels or a condition associated with apolipoprotein C-III; and

administering to said human subject a therapeutically effective amount of a compound comprising a modified oligonucleotide having 12-30 linked nucleosides, or a salt thereof,

wherein said modified oligonucleotide is 100% complementary to a nucleic acid encoding human apolipoprotein B, and whereby plasma apolipoprotein C-III levels in said human subject are lowered.

11. The method of claim 1, wherein selection of the subject is based on a determination of elevated apolipoprotein C-III levels or a condition associated with apolipoprotein C-III.

12. The method of claim 11, wherein the selected subject is determined to have elevated plasma total cholesterol concentrations, elevated plasma LDL cholesterol, elevated plasma triglyceride concentrations, reduced plasma HDL cholesterol concentrations, elevated liver triglyceride concentrations, elevated apolipoprotein C-III concentrations in HDL cholesterol particles, elevated apolipoprotein C-III concentrations in VLDL cholesterol particles or elevated apolipoprotein C-III concentrations in cholesterol particles comprising apolipoprotein B.

13. The method of claim 11, wherein the modified oligonucleotide has a nucleobase sequence comprising at least an 8 nucleobase portion or at least a 12 nucleobase portion of SEQ ID NO:

10.

14. The method of claim 11, wherein the modified oligonucleotide has a nucleobase sequence comprising SEQ ID NO:

10.

15. The method of claim 11, wherein the modified oligonucleotide has a nucleobase sequence consisting of SEQ ID NO:

10.

16. The method of claim 11, wherein the modified oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar moiety, and/or at least one modified nucleobase.

17. The method of claim 16, wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.

18. The method of claim 16, wherein the modified sugar moiety is a bicyclic sugar moiety or a 2′

-substituted sugar moiety.

19. The method of claim 18, wherein the bicyclic sugar moiety comprises a 4′

-CH₂—

O-2′

bridge.

20. The method of claim 18, wherein the 2′

-substituted sugar moiety comprises a 2′

-O-methoxyethyl.

21. The method of claim 16, wherein the modified nucleobase is a 5-methylcytosine.

22. The method of claim 11, 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 moiety, wherein the modified oligonucleotide comprises at least one modified nucleobase, and wherein at least one internucleoside linkage is a phosphorothioate linkage.

23. The method of claim 22, wherein each modified sugar moiety is a 2′

-O-methoxyethyl sugar moiety or a bicyclic sugar moiety.

24. The method of claim 22, wherein the modified nucleobase is a 5-methylcytosine.

25. The method of claim 22, wherein the modified oligonucleotide comprises:

a gap segment consisting of ten 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 moiety, wherein each cytosine is a 5′

-methylcytosine, and wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

26. The method of claim 11, wherein the compound comprises a salt of the modified oligonucleotide.

27. The method of claim 11, wherein the compound is formulated as a composition comprising a pharmaceutically acceptable excipient, vehicle, carrier or diluent.

28. The method of claim 11, wherein the therapeutically effective amount is delivered in a plurality of doses of the compound.

29. The method of claim 28, wherein the plurality of doses results in a plasma trough concentration of the compound from about 12 ng/mL to about 40 ng/mL in the plasma of the human subject or a plasma trough AUC of the compound from about 12 μ

g·

hr/mL to about 60 μ

g·

hr/mL in the plasma of the human subject.

30. The method of claim 29, wherein the compound is mipomersen.

31. The method of claim 30, wherein each of the plurality of doses is 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, at least about 100 mg, at least about 200 mg, about 200 mg to about 400 mg, about 100 mg, about 200 mg, about 300 mg, or about 400 mg of mipomersen.

32. The method of claim 28, wherein at least one dose of said plurality of doses is administered daily, about twice a week, about once a week, about once every other week or about once a month.

33. The method of claim 11, wherein the plasma apolipoprotein C-III levels are reduced at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 54%, at least about 60% or at least about 62% relative to the amount of plasma apolipoprotein C-III observed in the subject prior to administration of the compound.

34. The method of claim 1, wherein the selected subject is determined to have elevated plasma total cholesterol concentrations, elevated plasma LDL cholesterol, elevated plasma triglyceride concentrations, reduced plasma HDL cholesterol concentrations, elevated liver triglyceride concentrations, elevated apolipoprotein C-III concentrations in HDL cholesterol particles, elevated apolipoprotein C-III concentrations in VLDL cholesterol particles or elevated apolipoprotein C-III concentrations in cholesterol particles comprising apolipoprotein B.

2. A method for treating, reducing the incidence of, or ameliorating a symptom of diabetes in a human subject, comprising administering to said human subject a therapeutically effective amount of a compound comprising a modified oligonucleotide having 12-30 linked nucleosides, or a salt thereof, wherein said modified oligonucleotide is 100% complementary to a nucleic acid encoding human apolipoprotein B, and wherein plasma apolipoprotein C-III levels in said human subject are lowered, whereby the diabetes is treated, the incidence reduced or the symptom ameliorated.

3. The method of claim 2, wherein said subject is selected based on a determination of elevated plasma apolipoprotein C-III concentrations, elevated plasma total cholesterol concentrations, elevated plasma LDL cholesterol, elevated plasma triglyceride concentrations, reduced plasma HDL cholesterol concentrations, elevated liver triglyceride concentrations, elevated apolipoprotein C-III concentrations in HDL cholesterol particles, elevated apolipoprotein C-III concentrations in VLDL cholesterol particles or elevated apolipoprotein C-III concentrations in cholesterol particles comprising apolipoprotein B.

4. The method of claim 3, wherein said subject has or is at risk of having diabetic dyslipidemia or mixed dyslipidemia.

8. The method of claim 3, wherein the human subject is obese.

5. A method for treating, reducing the incidence of, or ameliorating a symptom of coronary heart disease in a human subject, comprising administering to said human subject a therapeutically effective amount of a compound comprising a modified oligonucleotide having 12-30 linked nucleosides, or a salt thereof, wherein said modified oligonucleotide is 100% complementary to a nucleic acid encoding human apolipoprotein B, and wherein plasma apolipoprotein C-III levels in said human subject are lowered, whereby the coronary heart disease is treated, the incidence reduced or the symptom ameliorated.

6. The method of claim 5, wherein said subject is selected based on a determination of elevated plasma apolipoprotein C-III concentrations, elevated plasma total cholesterol concentrations, elevated plasma LDL cholesterol, elevated plasma triglyceride concentrations, reduced plasma HDL cholesterol concentrations, elevated liver triglyceride concentrations, elevated apolipoprotein C-III concentrations in HDL cholesterol particles, elevated apolipoprotein C-III concentrations in VLDL cholesterol particles or elevated apolipoprotein C-III concentrations in cholesterol particles comprising apolipoprotein B.

7. The method of claim 6, wherein said subject has or is at risk of having diabetic dislipidemia or mixed dyslipidemia.

9. The method of claim 6, wherein the human subject is obese.

10. The method of claim 6, wherein the human subject is diabetic.