Administering antisense oligonucleotides complementary to human apolipoprotein B

• US 9,347,061 B2
• Filed: 03/24/2008
• Issued: 05/24/2016
• Est. Priority Date: 03/24/2007
• Status: Expired due to Fees

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Geary, Richard S., Yu, Zhengrong, Wedel, Mark K., Tribble, Diane
• Primary Examiner(s): ANGELL, JON E
• Application Number:
  US12/532,602
• Publication Number:
  US 20100297105A1
• Time in Patent Office: 2,983 Days
• US Class Current: 1/1
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• 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
• CPC Class Codes: C12N 2320/32 Special delivery means, e.g. tissue-specific

Abstract

Methods for long-term lowering of lipid levels in human subjects and for the treatment of conditions associated with elevated LDL-cholesterol and elevated ApoB are provided.

Claims

1. A method comprising administering to a subject a pharmaceutical composition comprising an antisense oligonucleotide complementary to a nucleic acid encoding human apolipoprotein B-100, wherein the administering comprises an induction phase, wherein a 210 mg dose of the antisense oligonucleotide per week is administered in two or more administrations for at least 13 weeks, followed by a maintenance phase, wherein a 210 mg dose of the antisense oligonucleotide per week is administered in two or more administrations.

2. The method of claim 1, wherein tolerability or effectiveness of the antisense oligonucleotide are assessed during or at the end of the induction phase, or a portion thereof.

3. The method of claim 1, wherein said administration comprises subcutaneous administration.

4. The method of claim 1, wherein effectiveness of the antisense oligonucleotide is assessed by monitoring ApoB, LDL-C, VLDL-C, IDL-C, non-HDL-C, serum triglycerides, liver triglycerides, Lp(a), Ox-LDL-C, or small dense LDL particle concentration in the plasma of said subject.

5. The method of claim 1, wherein said subject has hypercholesterolemia.

6. The method of claim 5, wherein said subject has polygenic hypercholesterolemia.

7. The method of claim 5, wherein said subject has familial hypercholesterolemia.

8. The method of claim 7, wherein said subject has homozygous familial hypercholesterolemia.

9. The method of claim 7, wherein said subject has heterozygous familial hypercholesterolemia.

10. The method of claim 1, wherein said subject has mixed dyslipidemia.

11. The method of claim 1, wherein said subject has been treated by a statin.

12. The method of claim 11, wherein said subject failed to meet LDL-cholesterol target on statin therapy.

13. The method of claim 1, wherein said administering of said pharmaceutical composition results in ApoB reduction of at least 10%.

14. The method of claim 13 wherein said ApoB reduction is between 10% and 80%, between 20% and 70%, between 30% and 60%, or between 30% and 70%.

15. The method of claim 1, wherein said administering of said pharmaceutical composition results in a LDL-cholesterol reduction of at least 10%.

16. The method of claim 15, wherein said LDL-cholesterol reduction is 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%.

17. The method of claim 1, wherein said administering of said pharmaceutical composition results in Lp(a) reduction of at least 10%.

18. The method of claim 1, wherein said administering of said pharmaceutical composition results in a small LDL-particle reduction of at least 10%.

19. The method of claim 1, wherein said administering of said pharmaceutical composition results in a non-HDL-cholesterol reduction of at least 10%.

20. The method of claim 1, wherein said administering of said pharmaceutical composition results in reduced coronary heart disease risk in the subject.

21. The method of claim 1, wherein said administering of said pharmaceutical composition slows or stops the progression of atherosclerosis in the subject.

22. The method of claim 1, wherein said administering of said pharmaceutical composition results in improved cardiovascular outcome the subject.

23. The method of claim 22, wherein said improved cardiovascular outcome is increased HDL-cholesterol.

24. The method of claim 22, wherein said administering results in reductions in LDL-cholesterol, triglycerides, or small LDL particles, or a combination thereof.

25. The method of claim 1, wherein the antisense oligonucleotide is at least 90% complementary to a nucleic acid encoding human ApoB.

26. The method of claim 1, wherein the antisense oligonucleotide is ISIS 301012.

27. A method comprising administering to a subject a pharmaceutical composition comprising a 210 mg dose of an antisense oligonucleotide complementary to a nucleic acid encoding human apolipoprotein B-100 per week in two or more administrations, wherein the antisense oligonucleotide is ISIS 301012, wherein said administering of said pharmaceutical composition results in antisense oligonucleotide plasma trough levels between 5 and 100 ng/mL.

28. The method of claim 27, wherein said administering of said pharmaceutical composition results in antisense oligonucleotide plasma trough levels between 5 and 50 ng/mL.

29. The method of claim 27, wherein said administering of said pharmaceutical composition results in antisense oligonucleotide plasma trough levels between 10 and 40 ng/mL.

30. The method of claim 27, wherein said administering of said pharmaceutical composition results in antisense oligonucleotide plasma trough levels between 15 and 35 ng/mL.

31. The method of claim 27, wherein said administering of said pharmaceutical composition results in antisense oligonucleotide plasma trough levels between 20 and 30 ng/mL.