EP-3700518-B1 - METHODS OF REDUCING THE RISK OF CARDIOVASCULAR EVENTS IN A SUBJECT WITH A COMPOSITION COMPRISING ICOSAPENT ETHYL

Inventors

• SONI, PARESH

Dates

Publication Date

20260513

Application Date

20190422

Claims (5)

1. A composition comprising icosapent ethyl (E-EPA), for use in a method of reducing risk of one or more of: myocardial infarction, stroke, cardiovascular death, unstable angina, coronary revascularization procedures and/or hospitalizations for unstable angina in a subject, the method comprising administering the composition to the subject daily, wherein the subject is on a high intensity statin regimen comprising 40 mg to about 80 mg per day of atorvastatin or 20 mg to 40 mg per day of rosuvastatin, wherein the subject has i) a fasting baseline triglyceride level of 135 mg/dL to 500 mg/dL; or ii) a fasting baseline triglyceride level of at least 200 mg/dL and a fasting baseline high density lipoprotein-C (HDL-C) level of 35 mg/dL or less, wherein: the subject i) has an established cardiovascular disease; or ii) is age 50 or older, has type I or type II diabetes mellitus and at least one additional risk factor for cardiovascular disease selected from: (a) is a male age 55 or older or a female age 65 or older; (b) is a cigarette smoker or was a cigarette smoker who stopped less than 3 months prior; (c) has hypertension; (d) has an HDL-C level of ≤ 40 mg/dL for men or ≤ 50 mg/dL for women; (e) has an hsCRP level of > 3.0 mg/L; (f) has renal dysfunction; (g) has retinopathy; (h) has microalbuminuria; (i) has macroalbuminuria; and/or (j) has an ankle-brachial index of < 0.9 without symptoms of intermittent claudication, and wherein the daily dose of E-EPA is 4g.
2. The composition for the use according to claim 1, wherein the subject is less than 65 years of age.
3. The composition for the use according to any preceding claim, wherein the subject has a high sensitivity reactive protein (hsCRP) level of 2 mg/L or less.
4. The composition for the use according to any preceding claim, wherein the subject has a fasting baseline triglyceride level of 135 mg/dL to 500 mg/dL.
5. The composition for the use according to any preceding claim, wherein the composition is administered for at least 2 years.

Description

BACKGROUND Cardiovascular disease is one of the leading causes of death in the United States and most European countries. It is estimated that over 70 million people in the United States alone suffer from a cardiovascular disease or disorder including but not limited to high blood pressure, coronary heart disease, dyslipidemia, congestive heart failure and stroke. Lovaza®, a lipid regulating agent, is indicated as an adjunct to diet to reduce triglyceride levels in adult patients with very high triglyceride levels. Unfortunately, Lovaza® can significantly increase LDL-C and/or non-HDL-C levels in some patients. A need exists for improved treatments for cardiovascular diseases and disorders. US2018/153846 discloses 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. US2010/311834 discloses methods of treating and/or preventing cardiovascular-related disease and, in particular, a method of blood lipid therapy comprising administering to a subject in need thereof, a pharmaceutical composition comprising Eicosapentaenoic acid or a derivative thereof. US2007/185198 discloses using a composition for preventing onset and/or recurrence of stroke which contains ethyl Eicosapentaenoic acid as its effective component to prevent onset and/or recurrence of stroke in a hyperlipidemia patient who has been treated with HMG-CoA R1. Brinton, Eliot et al. (2017) "Prescription omega-3 fatty acid products containing highly purified eicosapentaenoic acid (EPA)", Lipids in Health and Disease, vol. 16, no. 1, discloses that high-purity EPA products do not raise low-density lipoprotein cholesterol (LDL-C) levels, even in patients with TG levels >500 mg/ dL, in contrast to the increase in LDL-C levels with prescription omega-3 products that also contain DHA Balantyne, Christie et al. (2016) "Icosapent ethyl (eicosapentaenoic acid ethyl ester): Effects on remnant-like particle cholesterol from the MARINE and ANCHOR studies" ATHEROSCLEROSIS, vol. 253, pages 81-87, discloses studies wherein icosapent ethyl reduced TG and other atherogenic lipid parameter levels without increasing low-density lipoprotein cholesterol (LDL-C) levels. Furthermore, the paper evaluates the effects of icosapent ethyl on calculated and directly measured RLP-C. SUMMARY The present invention provides compositions for use in methods of reducing risk of cardiovascular diseases and disorders, as set forth in independent claim 1. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic of the study design according to an embodimentFigure 2 is a schematic showing disposition of patients according to an embodiment.Figures 3A and 3B are representative Kaplan-Meier event curves for the cumulative incidence of the primary composite endpoints. Figures 3A and 3B indicate a 25% relative risk reduction for the primary composite endpoint over the course of 5 years.Figure 4 is a representative forest plot of individual components of primary endpoints analyzed as time to first event of each individual endpoint and indicates that each component, individually, was reduced.Figures 5A and 5B are representative Kaplan-Meier event curves for the cumulative incidence of the key secondary composite endpoints. Figures 5A and 5B indicate that there was a 26% RRR for the key secondary composite endpoint over the course of 5 years.Figures 6 and 7 are representative forest plots of primary efficacy outcomes in select prespecified subgroups. Figures 6 and 7 indicate that a subject's baseline triglyceride levels (e.g., ≥150 vs. <150 mg/dL or ≥200 or <200 mg/dL) did not influence the primary endpoint outcomes.Figure 8 and 9 are representative forest plots of secondary efficacy outcomes in select prespecified subgroups. Figures 8 and 9 indicate that a subject's baseline triglyceride levels (e.g., ≥150 vs. <150 mg/dL or ≥200 or <200 mg/dL) did not influence the key secondary endpoint outcomes.Figures 10A and 10B are representative Kaplan-Meier curves of primary and key secondary endpoints by achieved triglyceride level at 1 year. Figures 10A and 10B indicate that patient's triglyceride levels had no influence on the efficacy of icosapent ethyl as compared with placebo with respect to the primary or key secondary efficacy endpoint outcomes.Figure 11 is a representative forest plot of prespecified hierarchical testing of endpoints and indicates that all individual and composite ischemic endpoints were significantly reduced by icosapent ethyl (AMR101).Figure 12 is a schematic of the study design according to an embodimentFigure 13 is a representative bar graph depicting the distribution of first, second, and recurrent isc