Methods of reducing the risk of a cardiovascular event in a subject on statin therapy

• US 10,278,939 B2
• Filed: 10/16/2018
• Issued: 05/07/2019
• Est. Priority Date: 06/29/2012
• Status: Active Grant

• Current Assignee: Amarin Pharmaceuticals Ireland Limited (Amarin Corporation plc)
• Original Assignee: Amarin Pharmaceuticals Ireland Limited (Amarin Corporation plc)
• Inventors: Soni, Paresh
• Primary Examiner(s): Vajda, Kristin A
• Application Number:
  US16/162,115
• Publication Number:
  US 20190076389A1
• Time in Patent Office: 203 Days
• Field of Search: 514549
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/232 having three or more double bonds, e.g. etretinate
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• 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 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• 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

Abstract

In various embodiments, the present invention provides methods of reducing the risk of a cardiovascular event in a subject on statin therapy and, in particular, a method of reducing the risk of a cardiovascular event in a subject on statin therapy having a fasting baseline triglyceride level of about 135 mg/dL to about 500 mg/dL, and administering to the subject a pharmaceutical composition comprising about 1 g to about 4 g of eicosapentaenoic acid ethyl ester or a derivative thereof.

Claims

1. A method of reducing risk of a cardiovascular event in a subject on statin therapy with residual atherogenic dyslipidemia and clinically evident cardiovascular disease, the method comprising administering to the subject about 2 g to about 4 g of a pharmaceutical composition comprising eicosapentaenoic acid and docosapentaenoic acid per day for a period of at least about 2 years, wherein said administration reduces risk of cardiovascular death, risk of unstable angina and/or need for coronary revascularization.

2. The method of claim 1, wherein the composition is administered to the subject in 1 to 4 dosage units per day.

3. The method of claim 1, wherein the eicosapentaenoic acid comprises at least about 90 wt. % of all omega-3 fatty acids in the pharmaceutical composition.

4. The method of claim 1, wherein the eicosapentaenoic acid comprises at least about 96 wt. % of all omega-3 fatty acids in the pharmaceutical composition.

5. The method of claim 1, wherein the docosapentaenoic acid comprises less than 10 wt. % of all omega-3 fatty acids in the pharmaceutical composition.

6. The method of claim 1, wherein the docosapentaenoic acid comprises less than 8 wt. % of all omega-3 fatty acids in the pharmaceutical composition.

7. The method of claim 1, wherein the docosapentaenoic acid comprises less than 5 wt. % of all omega-3 fatty acids in the pharmaceutical composition.

8. The method of claim 1, wherein the pharmaceutical composition further comprises less than 5% docosahexaenoic acid, by weight, of all omega-3 fatty acids in the pharmaceutical composition.

9. The method of claim 1 further comprising a step of measuring the subject'"'"'s baseline lipid profile prior to administering the pharmaceutical composition to the subject.

10. The method of claim 1, wherein the subject has one or more of:

a baseline non-HDL-C value of about 200 mg/dL to about 300 mg/dL;

a baseline total cholesterol value of about 250 mg/dL to about 300 mg/dL;

a baseline VLDL-C value of about 140 mg/dL to about 200 mg/dL;

a baseline HDL-C value of about 10 to about 30 mg/dL; and

/or a baseline LDL-C value of about 40 to about 100 mg/dL.

11. The method of claim 1, wherein the statin therapy comprises administering to the subject a statin and optionally ezetimibe.

12. The method of claim 1, wherein the subject:

(a) has not been administered 200 mg or more per day of niacin and/or fibrates for at least 28 days before administration of the pharmaceutical composition;

(b) has not been administered omega-3 fatty acid prescription for a period of time beginning 28 days prior to administration of the pharmaceutical composition;

or (c) has not ingested dietary supplements comprising omega-3 fatty acids for a period of time beginning 28 days prior to administration of the pharmaceutical composition.

13. The method of claim 1, wherein the subject is administered about 3 g or about 4 g of the pharmaceutical composition per day for at least about 3 years.

14. The method of claim 1, wherein the pharmaceutical composition is formulated to delay onset of a first said cardiovascular event of said subject compared with control subjects, wherein each said control subject is on stable statin therapy, has a fasting baseline triglyceride level of about 135 mg/dL to about 500 mg/dL, and has established cardiovascular disease.

15. The method of claim 14, wherein the medicament is formulated to delay onset of a second said cardiovascular event of said subject compared with control subjects.

16. The method of claim 14, wherein the subject has diabetes mellitus and the control subjects each have diabetes mellitus or the subject has metabolic syndrome and the control subjects each have metabolic syndrome.

17. The method of claim 1, wherein the administration further reduces the risk of stroke and/or risk of myocardial infarction.

18. A method of reducing risk of a cardiovascular event in a subject on statin therapy with residual atherogenic dyslipidemia and clinically evident cardiovascular disease, the method comprising administering to the subject about 2 g to about 4 g of a pharmaceutical composition comprising eicosapentaenoic acid and docosapentaenoic acid per day for a period of at least about 2 years, wherein said administration reduces risk of cardiovascular death, need for coronary revascularization, risk of unstable angina, risk of stroke and/or risk of myocardial infarction.

19. The method of claim 18, wherein the composition is administered to the subject in 1 to 4 dosage units per day.

20. The method of claim 18, wherein the eicosapentaenoic acid comprises at least about 90 wt. % of all omega-3 fatty acids in the pharmaceutical composition.

21. The method of claim 18, wherein the eicosapentaenoic acid comprises at least about 96 wt. % of all omega-3 fatty acids in the pharmaceutical composition.

22. The method of claim 18, wherein the docosapentaenoic acid comprises less than 10 wt. % of all omega-3 fatty acids in the pharmaceutical composition.

23. The method of claim 18, wherein the docosapentaenoic acid comprises less than 8 wt. % of all omega-3 fatty acids in the pharmaceutical composition.

24. The method of claim 18, wherein the docosapentaenoic acid comprises less than 5 wt. % of all omega-3 fatty acids in the pharmaceutical composition.

25. The method of claim 18, wherein the pharmaceutical composition further comprises less than 5% docosahexaenoic acid, by weight, of all omega-3 fatty acids in the pharmaceutical composition.

26. The method of claim 18 further comprising a step of measuring the subject'"'"'s baseline lipid profile prior to administering the pharmaceutical composition to the subject.

27. The method of claim 18, wherein the subject has one or more of:

a baseline non-HDL-C value of about 200 mg/dL to about 300 mg/dL;

a baseline total cholesterol value of about 250 mg/dL to about 300 mg/dL;

a baseline VLDL-C value of about 140 mg/dL to about 200 mg/dL;

a baseline HDL-C value of about 10 to about 30 mg/dL; and

/or a baseline LDL-C value of about 40 to about 100 mg/dL.

28. The method of claim 18, wherein the subject:

(a) has not been administered 200 mg or more per day of niacin and/or fibrates for at least 28 days before administration of the pharmaceutical composition;

(b) has not been administered omega-3 fatty acid prescription for a period of time beginning 28 days prior to administration of the pharmaceutical composition;

or (c) has not ingested dietary supplements comprising omega-3 fatty acids for a period of time beginning 28 days prior to administration of the pharmaceutical composition.

29. The method of claim 18, wherein the subject is administered about 3 g or about 4 g of the pharmaceutical composition per day for at least about 3 years.

30. The method of claim 18, wherein the pharmaceutical composition is formulated to delay onset of a first said cardiovascular event of said subject compared with control subjects, wherein each said control subject is on stable statin therapy, has a fasting baseline triglyceride level of about 135 mg/dL to about 500 mg/dL, and has established cardiovascular disease.