# Patent

## Title
Compositions and methods for lowering triglycerides without raising LDL-C levels in a subject on concomitant statin therapy

## Abstract

In various embodiments, the present invention provides methods of lowering triglycerides in subject on statin therapy and having baseline fasting triglycerides of about 200 mg/dl to less than 500 mg/dl, the methods comprising administering to the subject a composition comprising ethyl eicosapentaenoate.

## Background
PRIORITY CLAIM
The present application claims priority to U.S. Provisional Patent Application Ser. No. 61/889,315, filed on Oct. 10, 2013, the entire contents of which are incorporated herein by reference and relied upon.


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.
SUMMARY
In various embodiments, the present invention provides pharmaceutical compositions and methods of using such compositions to treat and/or prevent cardiovascular-related diseases. In one embodiment, the subject is on concomitant statin therapy. In another embodiment, the subject on statin therapy has a baseline fasting serum triglyceride level of about 200 mg/dL to about 500 mg/dL.
In one embodiment, the invention provides a method of lowering triglycerides in a subject on statin therapy having baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl, the method comprising administering to the subject about 4 g of ethyl eicosapentaenoate per day.
In another embodiment, the invention provides a method of lowering triglycerides and LDL-C in a subject comprising, administering orally to a subject having fasting triglycerides of about 200 mg/dl to less than 500 mg/dl who is on stable statin therapy about 4 g per day of a pharmaceutical composition comprising at least about 90%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl eicosapentaenoate for a period of at least about 12 weeks.
In one embodiment, the invention provides a method of lowering triglycerides in a subject on stable statin therapy having baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl, the method comprising administering to the subject a pharmaceutical composition comprising polyunsaturated fatty acids, for example about 1 g to about 4 g of EPA per day, wherein upon administering the composition to the subject daily for a period of 12 weeks the subject exhibits at least 5% lower fasting triglycerides than a control subject maintained on stable statin therapy (optionally with placebo matching the EPA) without concomitant EPA for a period of 12 weeks wherein the control subject also has baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl. In another embodiment, upon administering the composition to the subject daily for a period of 12 weeks the subject exhibits no serum LDL-C increase, no statistically significant serum LDL-C increase, a serum LDL-C decrease, or the subject is statistically non-inferior to the control subjects (statin plus optional placebo) in regard to serum LDL-C elevation).
These and other embodiments of the present invention will be disclosed in further detail herein below.



BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 shows the correlation of atherogenic lipoproteins with Apo B after 12 weeks of treatment with ethyl eicosapentaenoate.
FIG. 2A displays placebo-adjusted percent changes in FADI parameters compared to baseline in plasma for both 2 g/day and 4 g/day doses of ethyl eicosapentaenoate.
FIG. 2B displays placebo-adjusted percent changes in FADI parameters compared to baseline in red blood cells for both 2 g/day and 4 g/day doses of ethyl eicosapentaenoate.
FIG. 3 displays median percent change in fasting triglycerides from baseline to week 12 in a modified intent-to-treat (“MITT”) study population.
FIG. 4 displays median percent change from baseline for selected endpoints.
FIG. 5A displays percent change in fasting triglycerides plotted against percent change in EPA concentration in plasma from baseline to week 12 for the MITT study population. FIG. 5B displays percent change in fasting triglycerides plotted against percent change in EPA concentration in red blood cells from baseline to week 12 for the MITT study population.
FIG. 6A displays a regression fit plot of atherogenic particle concentration to Apo B concentration at baseline for subjects assigned to placebo group (◯) or to a treatment group (+). FIG. 6B displays a regression fit plot of atherogenic particle concentration to Apo B concentration after 12 weeks of receiving placebo (◯) or 4 g per day of a composition consistent with the present disclosure (+). FIG. 6C displays a regression fit plot of total LDL particle concentration to Apo B concentration at baseline for subjects assigned to placebo group (◯) or to a treatment group (+). FIG. 6D displays a regression fit plot of total LDL particle concentration to Apo B concentration after 12 weeks of receiving placebo (◯) or 4 g per day of a composition consistent with the present disclosure (+).



DETAILED DESCRIPTION
While the present invention is capable of being embodied in various forms, the description below of several embodiments is made with the understanding that the present disclosure is to be considered as an exemplification of the invention, and is not intended to limit the invention to the specific embodiments illustrated. Headings are provided for convenience only and are not to be construed to limit the invention in any manner. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.
The use of numerical values in the various quantitative values specified in this application, unless expressly indicated otherwise, are stated as approximations as though the minimum and maximum values within the stated ranges were both preceded by the word “about.” Also, the disclosure of ranges is intended as a continuous range including every value between the minimum and maximum values recited as well as any ranges that can be formed by such values. Also disclosed herein are any and all ratios (and ranges of any such ratios) that can be formed by dividing a disclosed numeric value into any other disclosed numeric value. Accordingly, the skilled person will appreciate that many such ratios, ranges, and ranges of ratios can be unambiguously derived from the numerical values presented herein and in all instances such ratios, ranges, and ranges of ratios represent various embodiments of the present invention.
In one embodiment, the invention provides a method for treatment and/or prevention of cardiovascular-related diseases. The term “cardiovascular-related disease” herein refers to any disease or disorder of the heart or blood vessels (i.e. arteries and veins) or any symptom thereof. Non-limiting examples of cardiovascular-related disease and disorders include hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, coronary heart disease, vascular disease, stroke, atherosclerosis, arrhythmia, hypertension, myocardial infarction, and other cardiovascular events.
The term “treatment” in relation a given disease or disorder, includes, but is not limited to, inhibiting the disease or disorder, for example, arresting the development of the disease or disorder; relieving the disease or disorder, for example, causing regression of the disease or disorder; or relieving a condition caused by or resulting from the disease or disorder, for example, relieving, preventing or treating symptoms of the disease or disorder. The term “prevention” in relation to a given disease or disorder means: preventing the onset of disease development if none had occurred, preventing the disease or disorder from occurring in a subject that may be predisposed to the disorder or disease but has not yet been diagnosed as having the disorder or disease, and/or preventing further disease/disorder development if already present.
In one embodiment, the present invention provides a method of blood lipid therapy comprising administering to a subject or subject group in need thereof a pharmaceutical composition as described herein. In another embodiment, the subject or subject group has hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia and/or very high triglycerides.
In another embodiment, the subject or subject group being treated has a baseline triglyceride level (or mean or median baseline triglyceride level in the case of a subject group), fed or fasting, of about 200 mg/dl to about 500 mg/dl. In another embodiment, the subject or subject group has a baseline LDL-C level (or mean or median baseline LDL-C level), despite stable statin therapy, of about 40 mg/dl to about 115 or about 40 to about 100 mg/dl.
In one embodiment, the subject or subject group being treated in accordance with methods of the invention is on concomitant statin therapy, for example atorvastatin, rosuvastatin or simvastatin therapy (with or without ezetimibe). In another embodiment, the subject is on concomitant stable statin therapy at time of initiation of ultra-pure EPA therapy.
In another embodiment, the subject or subject group being treated in accordance with methods of the invention has a body mass index (BMI or mean BMI) of not more than about 45 kg/m2.
In one embodiment, the invention provides a method of lowering triglycerides in a subject on stable statin therapy having baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl, the method comprising administering to the subject a pharmaceutical composition comprising about 1 g to about 4 g of EPA (e.g. ultra-pure EPA), wherein upon administering the composition to the subject daily for a period of about 12 weeks the subject exhibits 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%, or at least 75% lower fasting triglycerides than a control subject maintained on stable statin therapy (and optionally placebo matching the ultra-pure EPA) without concomitant ultra-pure EPA for a period of about 12 weeks, wherein the control subject also has baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl. The term “stable statin therapy” herein means that the subject, subject group, control subject or control subject group in question has been taking a stable daily dose of a statin (e.g. atorvastatin, rosuvastatin or simvastatin) for at least 4 weeks prior to the baseline fasting triglyceride measurement (the “qualifying period”). For example, a subject or control subject on stable statin therapy would receive a constant daily (i.e. the same dose each day) statin dose for at least 4 weeks immediately prior to baseline fasting triglyceride measurement. In one embodiment, the subject's and control subject's LDL-C is maintained between about 40 mg/dl and about 115 mg/dl or about 40 mg/dl to about 100 mg/dl during the qualifying period. The subject and control subject are then continued on their stable statin dose for the 12 week period post baseline.
In one embodiment, the statin is administered to the subject and the control subject in an amount of about 1 mg to about 500 mg, about 5 mg to about 200 mg, or about 10 mg to about 100 mg, for example about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg; about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg. In another embodiment, the subject (and optionally the control subject) has a baseline LDL-C level, despite stable statin therapy, of about 40 mg/dl to about 115 mg/dl or about 40 mg/dl to about 100 mg/dl. In another embodiment, the subject and/or control subject has a body mass index (BMI; or mean BMI) of not more than about 45 kg/m2.
In another embodiment, the invention provides a method of lowering triglycerides in a subject group on stable statin therapy having mean baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl, the method comprising administering to members of the subject group a pharmaceutical composition comprising about 1 g to about 4 g of ultra-pure EPA per day, wherein upon administering the composition to the members of the subject group daily for a period of about 12 weeks the subject group exhibits 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% lower mean fasting triglycerides than a control subject group maintained on stable statin therapy without concomitant ultra-pure EPA (optionally with matching placebo) for a period of about 12 weeks, wherein the control subject group also has mean baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl. In a related embodiment, the stable statin therapy will be sufficient such that the subject group has a mean LDL-C level about at least about 40 mg/dl and not more than about 100 mg/dl or about 40 mg/dl to about 100 mg/dl for the 4 weeks immediately prior to the baseline fasting triglyceride measurement.
In another embodiment, the invention provides a method of lowering triglycerides in subject group on stable statin therapy and having a mean baseline fasting triglyceride level of about 200 mg/dl to about 500 mg/dl, the method comprising administering to members of the subject group a pharmaceutical composition comprising about 1 g to about 4 g of ultra-pure EPA, wherein upon administering the composition to members of the subject group daily for a period of about 12 weeks the subject group exhibits: (a) 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% lower mean fasting triglycerides by comparison with a control subject group maintained on stable statin therapy without concomitant ultra-pure EPA (optionally with matching placebo) for a period of about 12 weeks, and (b) no serum LDL-C increase, no statistically significant serum LDL-C increase, a serum LDL-C decrease, or the subject is statistically non-inferior to the control subjects (statin plus optional placebo) in regard to serum LDL-C elevation) no increase in mean serum LDL-C levels compared to baseline, wherein the control subject also has mean baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl.
In another embodiment, the invention provides a method of lowering triglycerides in subject on stable statin therapy and having mean baseline fasting triglyceride level of about 200 mg/dl to about 500 mg/dl, the method comprising administering to the subject a pharmaceutical composition comprising about 1 g to about 4 g of ultra-pure EPA, wherein upon administering the composition to the subject daily for a period of about 12 weeks the subject exhibits (a) 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%, or at least 75% lower fasting triglycerides by comparison with a control subject maintained on stable statin therapy without concomitant ultra-pure EPA for a period of about 12 weeks and (b) no increase in serum LDL-C levels compared to baseline, wherein the control subject also has baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl.
In another embodiment, the invention provides a method of lowering triglycerides in subject group on stable statin therapy and having mean baseline fasting triglyceride level of about 200 mg/dl to about 500 mg/dl, the method comprising administering to members of the subject group a pharmaceutical composition comprising about 1 g to about 4 g of ultra-pure EPA, wherein upon administering the composition to the members of the subject group daily for a period of about 12 weeks the subject group exhibits: (a) 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% lower mean fasting triglycerides and (b) at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45% or at least 50% lower mean serum LDL-C levels by comparison with a control subject group maintained on stable statin therapy without concomitant ultra-pure EPA (optionally with matching placebo) for a period of about 12 weeks, no serum LDL-C increase, no statistically significant serum LDL-C increase, no statistically significant serum LDL-C increase, a serum LDL-C decrease, or the subject group is statistically non-inferior to the control subject group (statin plus optional placebo) in regard to serum LDL-C elevation), wherein the control subject group also has mean baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl.
In another embodiment, the invention provides a method of lowering triglycerides in subject group on stable statin therapy and having mean baseline fasting triglyceride level of about 200 mg/dl to about 500 mg/dl, the method comprising administering to members of the subject group a pharmaceutical composition comprising about 1 g to about 4 g of ultra-pure EPA, wherein upon administering the composition to the members of the subject group daily for a period of about 12 weeks the subject group exhibits (a) 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% lower mean fasting triglycerides and (b) at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45% or at least 50% lower mean serum LDL-C levels by comparison with a control subject group maintained on stable statin therapy without concomitant ultra-pure EPA (optionally with matching placebo) for a period of about 12 weeks, no serum LDL-C increase, no statistically significant serum LDL-C increase, no statistically significant serum LDL-C increase, a serum LDL-C decrease, or the subject group is statistically non-inferior to the control subject group (statin plus optional placebo) in regard to serum LDL-C elevation), wherein the control subject group also has mean baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl.
In another embodiment, the subject or subject group being treated in accordance with methods of the invention exhibits a fasting baseline absolute plasma level of free total fatty acid (or mean thereof) not greater than about 300 nmol/ml, not greater than about 250 nmol/ml, not greater than about 200 nmol/ml, not greater than about 150 nmol/ml, not greater than about 100 nmol/ml, or not greater than about 50 nmol/ml.
In another embodiment, the subject or subject group being treated in accordance with methods of the invention exhibits a fasting baseline absolute plasma level of free EPA (or mean thereof in the case of a subject group) not greater than about 0.70 nmol/ml, not greater than about 0.65 nmol/ml, not greater than about 0.60 nmol/ml, not greater than about 0.55 nmol/ml, not greater than about 0.50 nmol/ml, not greater than about 0.45 nmol/ml, or not greater than about 0.40 nmol/ml. In another embodiment, the subject or subject group being treated in accordance with methods of the invention exhibits a baseline fasting plasma level (or mean thereof) of free EPA, expressed as a percentage of total free fatty acid, of not more than about 3%, not more than about 2.5%, not more than about 2%, not more than about 1.5%, not more than about 1%, not more than about 0.75%, not more than about 0.5%, not more than about 0.25%, not more than about 0.2% or not more than about 0.15%. In one such embodiment, free plasma EPA and/or total fatty acid levels are determined prior to initiating therapy.
In another embodiment, the subject or subject group being treated in accordance with methods of the invention exhibits a fasting baseline absolute plasma level of free EPA (or mean thereof) not greater than about 1 nmol/ml, not greater than about 0.75 nmol/ml, not greater than about 0.50 nmol/ml, not greater than about 0.4 nmol/ml, not greater than about 0.35 nmol/ml, or not greater than about 0.30 nmol/ml.
In another embodiment, the subject or subject group being treated in accordance with methods of the invention exhibits a fasting baseline plasma, serum or red blood cell membrane EPA level not greater than about 150 μg/ml, not greater than about 125 μg/ml, not greater than about 100 μg/ml, not greater than about 95 μg/ml, not greater than about 75 μg/ml, not greater than about 60 μg/ml, not greater than about 50 μg/ml, not greater than about 40 μg/ml, not greater than about 30 μg/ml, or not greater than about 25 μg/ml.
In another embodiment, methods of the present invention comprise a step of measuring the subject's (or subject group's mean) baseline lipid profile prior to initiating therapy. In another embodiment, methods of the invention comprise the step of identifying a subject or subject group having one or more of the following: baseline non-HDL-C value (or mean) of about 200 mg/dl to about 400 mg/dl, for example at least about 210 mg/dl, at least about 220 mg/dl, at least about 230 mg/dl, at least about 240 mg/dl, at least about 250 mg/dl, at least about 260 mg/dl, at least about 270 mg/dl, at least about 280 mg/dl, at least about 290 mg/dl, or at least about 300 mg/dl; baseline total cholesterol value (or mean) of about 250 mg/dl to about 400 mg/dl, for example at least about 260 mg/dl, at least about 270 mg/dl, at least about 280 mg/dl or at least about 290 mg/dl; baseline vLDL-C value (or mean) of about 140 mg/dl to about 200 mg/dl, for example at least about 150 mg/dl, at least about 160 mg/dl, at least about 170 mg/dl, at least about 180 mg/dl or at least about 190 mg/dl; baseline HDL-C value (or mean) of about 10 to about 100 mg/dl, for example not more than about 90 mg/dl not, not more than about 80 mg/dl, not more than about 70 mg/dl, not more than about 60 mg/dl, not more than about 60 mg/dl, not more than about 50 mg/dl, not more than about 40 mg/dl, not more than about 35 mg/dl, not more than about 30 mg/dl, not more than about 25 mg/dl, not more than about 20 mg/dl, or not more than about 15 mg/dl; and/or baseline LDL-C value (or mean) of about 30 to about 300 mg/dl, for example not less than about 40 mg/dl, not less than about 50 mg/dl, not less than about 60 mg/dl, not less than about 70 mg/dl, not less than about 90 mg/dl or not less than about 90 mg/dl.
In a related embodiment, upon treatment in accordance with the present invention, for example over a period of about 1 to about 200 weeks, about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, the subject or subject group exhibits one or more of the following outcomes:
(a) reduced triglyceride levels compared to baseline or placebo control (e.g. a subject on stable statin plus placebo matching the EPA treatment group);
(b) reduced Apo B levels compared to baseline or placebo control;
(c) a decrease or an increase in HDL-C levels compared to baseline or placebo control;
(d) no increase in LDL-C levels compared to baseline or placebo control;
(e) a reduction in LDL-C levels compared to baseline or placebo control;
(f) a reduction in non-HDL-C levels compared to baseline or placebo control;
(g) a reduction in VLDL-C levels compared to baseline or placebo control;
(h) an increase, no change, or a decrease in Apo A-1 levels compared to baseline or placebo control;
(i) an decrease, no change, or an increase in Apo B/Apo A-1 ratio compared to baseline or placebo control;
(j) no increase or a reduction in lipoprotein A levels compared to baseline or placebo control;
(k) a reduction in LDL particle number compared to baseline or placebo control;
(l) an increase in LDL size compared to baseline or placebo control;
(m) a reduction in remnant-like particle cholesterol (RLP-C) compared to baseline or placebo control;
(n) a reduction in oxidized LDL compared to baseline or placebo control;
(o) an increase, no change, or a reduction in fasting plasma glucose (FPG) compared to baseline or placebo control;
(p) an increase, no change, or a reduction in hemoglobin A1c (HbA1c) compared to baseline or placebo control;
(q) an increase, no change, or a reduction in homeostasis model insulin resistance (HOMA-IR) compared to baseline or placebo control;
(r) a reduction in lipoprotein associated phospholipase A2 (Lp-PLA2) compared to baseline or placebo control;
(s) a reduction in intracellular adhesion molecule-1 (IAM-1) compared to baseline or placebo control;
(t) an increase, no change, or a reduction in interleukin-6 (IL-6) compared to baseline or placebo control;
(u) an increase, no change, or a reduction in plasminogen activator inhibitor-1 (PAI-1) compared to baseline or placebo control;
(v) a reduction in high sensitivity C-reactive protein (hsCRP) compared to baseline or placebo control;
(w) an increase in serum or plasma EPA compared to baseline or placebo control;
(x) an increase in red blood cell membrane EPA compared to baseline or placebo control;
(y) a reduction or increase in one or more of serum and/or red blood cell content of docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), arachidonic acid (AA), palmitic acid (PA), stearidonic acid (SA) or oleic acid (OA) compared to baseline or placebo control;
(z) a reduction in a fatty acid desaturation index (“FADI”) compared to baseline or placebo control;
(aa) a reduction in VLDL-TG compared to baseline or placebo control;
(bb) a reduction in total cholesterol compared to baseline or placebo control; and/or
(cc) an increase, no change, or a reduction in insulin compared to baseline or placebo control.
In one embodiment, methods of the present invention comprise measuring baseline levels of one or more markers set forth in (a)-(cc) above prior to dosing the subject or subject group. In another embodiment, the methods comprise administering a composition as disclosed herein to the subject after baseline levels of one or more markers set forth in (a)-(cc) are determined, and subsequently taking an additional measurement of said one or more markers.
In another embodiment, upon treatment with a composition of the present invention, for example over a period of about 1 to about 200 weeks, about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, the subject or subject group exhibits any 2 or more of, any 3 or more of, any 4 or more of, any 5 or more of, any 6 or more of, any 7 or more of, any 8 or more of, any 9 or more of, any 10 or more of, any 11 or more of, any 12 or more of, any 13 or more of, any 14 or more of, any 15 or more of, any 16 or more of, any 17 or more of, any 18 or more of, any 19 or more of, any 20 or more of, any 21 or more of, any 22 or more of, any 23 or more of, any 24 or more of, any 25 or more of, any 26 or more of, any 27 or more of, any 28 or more of, or all 29 of outcomes (a)-(cc) described immediately above.
In another embodiment, upon treatment with a composition of the present invention, the subject or subject group exhibits one or more of the following outcomes:
(a) a reduction in triglyceride level of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median % change) as compared to baseline or placebo control (e.g. a subject on statin and placebo matching the EPA treatment group);
(b) a less than 30% increase, less than 20% increase, less than 10% increase, less than 5% increase or no increase in non-HDL-C levels or a reduction in non-HDL-C levels of at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median % change) as compared to baseline or placebo control;
(c) an reduction in HDL-C levels of no greater than about 10%, no greater than about 5%, no greater than about 4%, no greater than about 3%, no greater than about 2%, no greater than about 1%, substantially no change in HDL-C levels, no change in HDL-C levels, or an increase in HDL-C levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median % change) as compared to baseline or placebo control;
(d) a less than 60% increase, a less than 50% increase, a less than 40% a increase, a less than 30% increase, a less than 20% increase, a less than 10% increase, a less than 5% increase, a less than 4% increase, a less than 3% increase, a less than 2% increase, in LDL-C levels, no increase in LDL-C levels, or a reduction in LDL-C levels of at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 55% or at least about 75% (actual % change or median % change) as compared to baseline or placebo control;
(e) an increase in Apo B levels of no more than about 5%, no more than about 4%, no more than about 3%, no more than about 2%, no more than about 1%, or no increase in Apo B levels, or a decrease in Apo B levels of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median % change) as compared to baseline or placebo control;
(f) an increase in VLDL-C levels of no more than about 5%, no more than about 4%, no more than about 3%, no more than about 2%, no more than about 1%, no increase in VLDL-C levels, or a reduction in VLDL-C levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or placebo control;
(g) an increase in Apo A-1 levels of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100%, substantially no change in Apo A-1 levels, no change in Apo A-1 levels, or a reduction in Apo A-1 levels of no greater than about 1%, no greater than about 2%, no greater than about 3%, no greater than about 4%, no greater than about 5%, no greater than about 6%, no greater than about 7%, no greater than about 8%, no greater than about 9%, or no greater than about 10% (actual % change or median % change) compared to baseline or placebo control;
(h) an increase in Apo B/Apo A-1 ratio of no more than about 5%, no more than about 4%, no more than about 3%, no more than about 2%, no more than about 1%, or no more than about 0.5%, no substantial change in Apo B/Apo A-1 ratio, no change in Apo B/Apo A-1 ratio, or an decrease in Apo B/Apo A-1 ratio of at least about 0.5%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or placebo control;
(i) an increase in lipoprotein (a) levels of no more than about 5%, no more than about 4%, no more than about 3%, no more than about 2%, no more than about 1%, no more than about 0.5%, no substantial change in lipoprotein (a) levels, no change in lipoprotein (a) levels, or a reduction in lipoprotein (a) levels of at least about 0.5%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or placebo control;
(j) an increase in LDL particle number of no more than about 5%, no more than about 4%, no more than about 3%, no more than about 2%, or no more than about 1%, no substantial change in LDL particle number, no change in LDL particle number, or a reduction in mean LDL particle number of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or placebo control;
(k) an increase in mean LDL particle size of at least about 0.5%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or placebo control;
(l) a reduction in remnant-like particle cholesterol (RLP-C) of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or placebo control;
(m) an increase in oxidized LDL of no more than about 5%, no more than about 4%, no more than about 3%, no more than about 2%, or no more than about 1%, no substantial change in oxidized LDL, no change in LDL, or a reduction in oxidized LDL of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or placebo control;
(n) an increase in fasting plasma glucose (FPG) of no more than about 10%, no more than about 9%, no more than about 8%, no more than about 7%, no more than about 6%, no more than about 5%, no more than about 4%, no more than about 3%, no more than about 2%, or no more than about 1%, substantially no change, no statistically significant change, or a reduction in fasting plasma glucose (FPG) of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or placebo control;
(o) an increase in hemoglobin A1c (HbA1c) of no more than about 2%, no more than about 1%, or no more than about 0.5%, substantially no change, no statistically significant change, a reduction in hemoglobin A1c (HbA1) of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50% (actual % change or median % change) compared to baseline or placebo control;
(p) an increase in homeostasis model index insulin resistance (HOMA-IR) of no more than about 5%, no more than about 4%, no more than about 3%, no more than about 2%, no more than about 1%, or no more than about 0.5%, no substantial change in HOMA-IR, no change in HOMA-IR, or a reduction in HOMA-IR of at least about 0.1%, at least about 0.5%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or placebo control;
(q) a reduction in lipoprotein associated phospholipase A2 (Lp-PLA2) of at least about 1%, at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or placebo control;
(r) an increase in intracellular adhesion molecule-1 (ICAM-1) of no more than about 5%, no more than about 4%, no more than about 3%, no more than about 2%, or no more than about 1%, no substantial change in ICAM-1, no change in ICAM-1, or a reduction in ICAM-1 of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or placebo control;
(s) an increase in interleukin-6 (IL-6) of no more than about 5%, no more than about 4%, no more than about 3%, no more than about 2%, no more than about 1%, or no more than about 0.5%, no substantial change in IL-6, no change in IL-6, or a reduction in IL-6 of at least about 0.1%, at least about 1%, at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or placebo control;
(t) an increase in plasminogen activator inhibitor-1 (PAI-1) of no more than about 15%, no more than about 10%, no more than about 5%, or no more than about 1%, no substantial change in PAI-1, no change in PAI-1, or a reduction in PAI-1 of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or placebo control;
(u) an increase in high sensitivity C-reactive protein (hsCRP) of no more than about 15%, no more than about 10%, no more than about 5%, or no more than about 1%, no substantial change in hsCRP, no change in hsCRP, or a reduction in hsCRP of at least about 1%, at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline or placebo control;
(v) an increase in serum, plasma and/or RBC EPA of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 100%, at least about 200% or at least about 400% (actual % change or median % change) compared to baseline or placebo control;
(w) an increase in serum phospholipid and/or red blood cell membrane EPA of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, at least about 100%, at least about 200%, or at least about 400% (actual % change or median % change) compared to baseline or placebo control;
(x) a reduction or increase in one or more of serum phospholipid and/or red blood cell DHA, DPA, AA, PA and/or OA of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median % change) compared to baseline or placebo control;
(y) a reduction in total cholesterol of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median % change) compared to baseline or placebo control;
(z) a reduction in a fatty acid desaturation index (“FADI”) of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or greater than about 95% (actual % change or median % change) compared to baseline or placebo control;
(aa) a reduction in VLDL-TG of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, or at least about 50% (actual % change or median % change) compared to baseline or placebo control;
(bb) an increase in total cholesterol of no more than about 5%, no more than about 4%, no more than about 3%, no more than about 2%, or no more than about 1%, no substantial change in total cholesterol, no change in total cholesterol, or a reduction in total cholesterol of at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, or at least about 20% (actual % change or median % change) compared to baseline or placebo control; and/or
(cc) an increase in insulin of no more than about 5%, no more than about 4%, no more than about 3%, no more than about 2%, no more than about 1%, or no more than about 0.5%, no substantial change in insulin, no change in insulin, or a decrease in insulin of at least about 0.1%, at least about 0.5%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, or at least about 5% (actual % change or median % change) compared to baseline or placebo control.
In one embodiment, methods of the present invention comprise measuring baseline levels of one or more markers set forth in (a)-(cc) prior to dosing the subject or subject group. In another embodiment, the methods comprise administering a composition as disclosed herein to the subject after baseline levels of one or more markers set forth in (a)-(cc) are determined, and subsequently taking a second measurement of the one or more markers as measured at baseline for comparison thereto.
In another embodiment, upon treatment with a composition of the present invention, for example over a period of about 1 to about 200 weeks, about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, the subject or subject group exhibits any 2 or more of, any 3 or more of, any 4 or more of, any 5 or more of, any 6 or more of, any 7 or more of, any 8 or more of, any 9 or more of, any 10 or more of, any 11 or more of, any 12 or more of, any 13 or more of, any 14 or more of, any 15 or more of, any 16 or more of, any 17 or more of, any 18 or more of, any 19 or more of, any 20 or more of, any 21 or more of, any 22 or more of, any 23 or more of, any 24 or more of, any 25 or more of, any 26 or more of, any 27 or more of, any 28 or more of, or all 29 of outcomes (a)-(cc) described immediately above.
Parameters (a)-(z) can be measured in accordance with any clinically acceptable methodology. For example, triglycerides, total cholesterol, HDL-C and fasting blood sugar can be sample from serum and analyzed using standard photometry techniques. VLDL-TG, LDL-C and VLDL-C can be calculated or determined using serum lipoprotein fractionation by preparative ultracentrifugation and subsequent quantitative analysis by refractometry or by analytic ultracentrifugal methodology. Apo A1, Apo B and hsCRP can be determined from serum using standard nephelometry techniques. Lipoprotein (a) can be determined from serum using standard turbidimetric immunoassay techniques. LDL particle number and particle size can be determined using nuclear magnetic resonance (NMR) spectrometry. Remnants lipoproteins and LDL-phospholipase A2 can be determined from EDTA plasma or serum and serum, respectively, using enzymatic immunoseparation techniques. Oxidized LDL, intercellular adhesion molecule-1 and interleukin-2 levels can be determined from serum using standard enzyme immunoassay techniques. These techniques are described in detail in standard textbooks, for example Tietz Fundamentals of Clinical Chemistry, 6th Ed. (Burtis, Ashwood and Borter Eds.), WB Saunders Company.
In one embodiment, subjects fast for up to 12 hours prior to blood sample collection, for example about 10 hours.
In another embodiment, the subject being treated is in the highest risk category of Adult Treatment Panel (ATP) III Classification of LDL, Total, and HDL Cholesterol (mg/dL) (e.g. CHD or CHD Risk Equivalents (10-year risk>20%)). In another embodiment, the subject is in the ATP III Multiple (2+) risk factor category.
In one embodiment, the invention provides a method of lowering triglycerides in a subject in the highest risk category of Adult Treatment Panel (ATP) III Classification of LDL, Total, and HDL Cholesterol (mg/dL) (e.g. CHD or CHD Risk Equivalents (10-year risk>20%)). In another embodiment, the subject is in the ATP III Multiple (2+) risk factor category. In another embodiment, the method includes a step of identifying a subject in the ATP III Multiple (2+) risk factor category prior to administering ultra-pure E-EPA to the subject.
In another embodiment, the present invention provides a method of treating or preventing primary hypercholesterolemia and/or mixed dyslipidemia (Fredrickson Types IIa and IIb) in a patient in need thereof, comprising administering to the patient one or more compositions as disclosed herein. In a related embodiment, the present invention provides a method of reducing triglyceride levels in a subject or subjects when treatment with a statin or niacin extended-release monotherapy is considered inadequate (Frederickson type IV hyperlipidemia).
In another embodiment, the present invention provides a method of treating or preventing risk of recurrent nonfatal myocardial infarction in a patient with a history of myocardial infarction, comprising administering to the patient one or more compositions as disclosed herein.
In another embodiment, the present invention provides a method of slowing progression of or promoting regression of atherosclerotic disease in a patient in need thereof, comprising administering to a subject in need thereof one or more compositions as disclosed herein.
In another embodiment, the present invention provides a method of treating or preventing very high serum triglyceride levels (e.g. Types IV and V hyperlipidemia) in a patient in need thereof, comprising administering to the patient one or more compositions as disclosed herein.
In another embodiment, the present invention provides a method of lowering triglycerides and a fatty acid desaturation index (“FADI”) in a subject on statin therapy having baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl, the method comprising administering to the subject about 4 capsules per day, each capsule comprising about 1 g of ethyl eicosapentaenoate. In some embodiments, the subject has a baseline LDL-C level of about 40 mg/dl to about 115 mg/dl. In some embodiments, the method effects a reduction in serum LDL-C. In some embodiments, the method effects at least a 5% reduction in fasting triglycerides and a reduction in LDL-C. In some embodiments, the method effects at least a 5%, at least a 10%, or at least a 15% reduction in LDL-C. In some embodiments, the method effects at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or greater than about 95% reduction in the FADI (e.g., a ratio of palmitoleic acid to palmitic acid and/or a ratio of oleic acid to stearic acid). In some embodiments, the method effects a reduction in Apolipoprotein B, total cholesterol, and lipoprotein associated phospholipase A2. In some embodiments, the subject is on stable statin therapy (e.g., atorvastatin therapy, rosuvastatin therapy, or simvastatin therapy). In some embodiments, the subject has a baseline body mass index not greater than 45 kg/m2.
In another embodiment, the present invention provides a method of lowering triglycerides, LDL-C and a fatty acid desaturation index (“FADI”) in a subject comprising, administering orally to a subject having fasting triglycerides of about 200 mg/dl to less than 500 mg/dl who is on stable statin therapy about 4 g per day of a pharmaceutical composition comprising at least about 90%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl eicosapentaenoate for a period of at least about 12 weeks. In some embodiments, the method effects a reduction in fasting triglycerides and fasting LDL-C in the subject compared to fasting triglycerides and fasting LDL-C in a second subject on stable statin therapy who has not received the pharmaceutical composition. In some embodiments, the method effects a reduction in fasting non-HDL-C compared to fasting non-HDL-C in the second subject. In some embodiments, the method effects a reduction in fasting VLDL-C compared to fasting VLDL-C in the second subject. In some embodiments, the method effects a reduction in fasting Apolipoprotein B compared to fasting Apolipoprotein B in the second subject. In some embodiments, the method effects a reduction in fasting total cholesterol compared to fasting total cholesterol in the second subject. In some embodiments, the method effects at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, at least about 19%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or greater than about 95% reduction in the FADI (e.g., a ratio of palmitoleic acid to palmitic acid and/or a ratio of oleic acid to stearic acid).
In one embodiment, a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of EPA of about 1 mg to about 10,000 mg, 25 about 5000 mg, about 50 to about 3000 mg, about 75 mg to about 2500 mg, or about 100 mg to about 1000 mg, for example about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225 mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about 2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450 mg, about 2475 mg, about 2500 mg, about 2525 mg, about 2550 mg, about 2575 mg, about 2600 mg, about 2625 mg, about 2650 mg, about 2675 mg, about 2700 mg, about 2725 mg, about 2750 mg, about 2775 mg, about 2800 mg, about 2825 mg, about 2850 mg, about 2875 mg, about 2900 mg, about 2925 mg, about 2950 mg, about 2975 mg, about 3000 mg, about 3025 mg, about 3050 mg, about 3075 mg, about 3100 mg, about 3125 mg, about 3150 mg, about 3175 mg, about 3200 mg, about 3225 mg, about 3250 mg, about 3275 mg, about 3300 mg, about 3325 mg, about 3350 mg, about 3375 mg, about 3400 mg, about 3425 mg, about 3450 mg, about 3475 mg, about 3500 mg, about 3525 mg, about 3550 mg, about 3575 mg, about 3600 mg, about 3625 mg, about 3650 mg, about 3675 mg, about 3700 mg, about 3725 mg, about 3750 mg, about 3775 mg, about 3800 mg, about 3825 mg, about 3850 mg, about 3875 mg, about 3900 mg, about 3925 mg, about 3950 mg, about 3975 mg, about 4000 mg, about 4025 mg, about 4050 mg, about 4075 mg, about 4100 mg, about 4125 mg, about 4150 mg, about 4175 mg, about 4200 mg, about 4225 mg, about 4250 mg, about 4275 mg, about 4300 mg, about 4325 mg, about 4350 mg, about 4375 mg, about 4400 mg, about 4425 mg, about 4450 mg, about 4475 mg, about 4500 mg, about 4525 mg, about 4550 mg, about 4575 mg, about 4600 mg, about 4625 mg, about 4650 mg, about 4675 mg, about 4700 mg, about 4725 mg, about 4750 mg, about 4775 mg, about 4800 mg, about 4825 mg, about 4850 mg, about 4875 mg, about 4900 mg, about 4925 mg, about 4950 mg, about 4975 mg, about 5000 mg, about 5025 mg, about 5050 mg, about 5075 mg, about 5100 mg, about 5125 mg, about 5150 mg, about 5175 mg, about 5200 mg, about 5225 mg, about 5250 mg, about 5275 mg, about 5300 mg, about 5325 mg, about 5350 mg, about 5375 mg, about 5400 mg, about 5425 mg, about 5450 mg, about 5475 mg, about 5500 mg, about 5525 mg, about 5550 mg, about 5575 mg, about 5600 mg, about 5625 mg, about 5650 mg, about 5675 mg, about 5700 mg, about 5725 mg, about 5750 mg, about 5775 mg, about 5800 mg, about 5825 mg, about 5850 mg, about 5875 mg, about 5900 mg, about 5925 mg, about 5950 mg, about 5975 mg, about 6000 mg, about 6025 mg, about 6050 mg, about 6075 mg, about 6100 mg, about 6125 mg, about 6150 mg, about 6175 mg, about 6200 mg, about 6225 mg, about 6250 mg, about 6275 mg, about 6300 mg, about 6325 mg, about 6350 mg, about 6375 mg, about 6400 mg, about 6425 mg, about 6450 mg, about 6475 mg, about 6500 mg, about 6525 mg, about 6550 mg, about 6575 mg, about 6600 mg, about 6625 mg, about 6650 mg, about 6675 mg, about 6700 mg, about 6725 mg, about 6750 mg, about 6775 mg, about 6800 mg, about 6825 mg, about 6850 mg, about 6875 mg, about 6900 mg, about 6925 mg, about 6950 mg, about 6975 mg, about 7000 mg, about 7025 mg, about 7050 mg, about 7075 mg, about 7100 mg, about 7125 mg, about 7150 mg, about 7175 mg, about 7200 mg, about 7225 mg, about 7250 mg, about 7275 mg, about 7300 mg, about 7325 mg, about 7350 mg, about 7375 mg, about 7400 mg, about 7425 mg, about 7450 mg, about 7475 mg, about 7500 mg, about 7525 mg, about 7550 mg, about 7575 mg, about 7600 mg, about 7625 mg, about 7650 mg, about 7675 mg, about 7700 mg, about 7725 mg, about 7750 mg, about 7775 mg, about 7800 mg, about 7825 mg, about 7850 mg, about 7875 mg, about 7900 mg, about 7925 mg, about 7950 mg, about 7975 mg, about 8000 mg, about 8025 mg, about 8050 mg, about 8075 mg, about 8100 mg, about 8125 mg, about 8150 mg, about 8175 mg, about 8200 mg, about 8225 mg, about 8250 mg, about 8275 mg, about 8300 mg, about 8325 mg, about 8350 mg, about 8375 mg, about 8400 mg, about 8425 mg, about 8450 mg, about 8475 mg, about 8500 mg, about 8525 mg, about 8550 mg, about 8575 mg, about 8600 mg, about 8625 mg, about 8650 mg, about 8675 mg, about 8700 mg, about 8725 mg, about 8750 mg, about 8775 mg, about 8800 mg, about 8825 mg, about 8850 mg, about 8875 mg, about 8900 mg, about 8925 mg, about 8950 mg, about 8975 mg, about 9000 mg, about 9025 mg, about 9050 mg, about 9075 mg, about 9100 mg, about 9125 mg, about 9150 mg, about 9175 mg, about 9200 mg, about 9225 mg, about 9250 mg, about 9275 mg, about 9300 mg, about 9325 mg, about 9350 mg, about 9375 mg, about 9400 mg, about 9425 mg, about 9450 mg, about 9475 mg, about 9500 mg, about 9525 mg, about 9550 mg, about 9575 mg, about 9600 mg, about 9625 mg, about 9650 mg, about 9675 mg, about 9700 mg, about 9725 mg, about 9750 mg, about 9775 mg, about 9800 mg, about 9825 mg, about 9850 mg, about 9875 mg, about 9900 mg, about 9925 mg, about 9950 mg, about 9975 mg, or about 10,000 mg.
In another embodiment, any of the methods disclosed herein are used in treatment of a subject or subjects that consume a traditional Western diet. In one embodiment, the methods of the invention include a step of identifying a subject as a Western diet consumer or prudent diet consumer and then treating the subject if the subject is deemed a Western diet consumer. The term “Western diet” herein refers generally to a typical diet consisting of, by percentage of total calories, about 45% to about 50% carbohydrate, about 35% to about 40% fat, and about 10% to about 15% protein. A Western diet may alternately or additionally be characterized by relatively high intakes of red and processed meats, sweets, refined grains, and desserts, for example more than 50%, more than 60% or more or 70% of total calories come from these sources.
In another embodiment, any of the methods disclosed herein are used in treatment of a subject or subjects that consume less than (actual or average) about 150 g, less than about 125 g, less than about 100 g, less than about 75 g, less than about 50 g, less than about 45 g, less than about 40 g, less than about 35 g, less than about 30 g, less than about 25 g, less than about 20 g or less than about 15 g of fish per day.
In another embodiment, any of the methods disclosed herein are used in treatment of a subject or subjects that consume less than (actual or average) about 10 g, less than about 9 g, less than about 8 g, less than about 7 g, less than about 6 g, less than about 5 g, less than about 4 g, less than about 3 g, less than about 2 g per day of omega-3 fatty acids from dietary sources.
In another embodiment, any of the methods disclosed herein are used in treatment of a subject or subjects that consume less than (actual or average) about 2.5 g, less than about 2 g, less than about 1.5 g, less than about 1 g, less than about 0.5 g, less than about 0.25 g, or less than about 0.2 g per day of EPA and DHA (combined) from dietary sources.
In one embodiment, compositions useful in various embodiments of the invention comprise a polyunsaturated fatty acid as an active ingredient. In another embodiment, such compositions comprise EPA as an active ingredient. The term “EPA” as used herein refers to eicosapentaenoic acid (e.g. eicosa-5,8,11,14,17-pentaenoic acid) and/or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof, or mixtures of any of the foregoing.
In one embodiment, the EPA comprises all-cis eicosa-5,8,11,14,17-pentaenoic acid. In another embodiment, the EPA is in the form of an eicosapentaenoic acid ester. In another embodiment, the EPA comprises a C1-C5 alkyl ester of EPA. In another embodiment, the EPA comprises eicosapentaenoic acid ethyl ester, eicosapentaenoic acid methyl ester, eicosapentaenoic acid propyl ester, or eicosapentaenoic acid butyl ester. In still another embodiment, the EPA comprises all-cis eicosa-5,8,11,14,17-pentaenoic acid ethyl ester.
In still other embodiments, the EPA comprises ethyl-EPA, lithium EPA, mono, di- or triglyceride EPA or any other ester or salt of EPA, or the free acid form of EPA. The EPA may also be in the form of a 2-substituted derivative or other derivative which slows down its rate of oxidation but does not otherwise change its biological action to any substantial degree.
The term “pharmaceutically acceptable” in the present context means that the substance in question does not produce unacceptable toxicity to the subject or interaction with other components of the composition.
In one embodiment, EPA present in a composition suitable for use according to the invention comprises ultra-pure EPA. The term “ultra-pure” as used herein with respect to EPA refers to a composition comprising at least 96%, by weight, of all fatty acids (and/or derivatives thereof) present, EPA (as the term “EPA” is defined and exemplified herein). Ultra-pure EPA can comprise even higher purity EPA, for example at least 97%, at least 98%, or at least 99%, by weight, of all fatty acids (and/or derivatives thereof) present, EPA, wherein the EPA is any form of EPA as set forth herein. Ultra-pure EPA can further be defined (e.g. impurity profile) by any of the description of EPA provided herein.
In some embodiments, EPA is present in a composition in an amount of about 50 mg to about 5000 mg, about 75 mg to about 2500 mg, or about 100 mg to about 1000 mg, for example about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225 mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about 2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450 mg, about 2475 mg, about 2500 mg, about 2525 mg, about 2550 mg, about 2575 mg, about 2600 mg, about 2625 mg, about 2650 mg, about 2675 mg, about 2700 mg, about 2725 mg, about 2750 mg, about 2775 mg, about 2800 mg, about 2825 mg, about 2850 mg, about 2875 mg, about 2900 mg, about 2925 mg, about 2950 mg, about 2975 mg, about 3000 mg, about 3025 mg, about 3050 mg, about 3075 mg, about 3100 mg, about 3125 mg, about 3150 mg, about 3175 mg, about 3200 mg, about 3225 mg, about 3250 mg, about 3275 mg, about 3300 mg, about 3325 mg, about 3350 mg, about 3375 mg, about 3400 mg, about 3425 mg, about 3450 mg, about 3475 mg, about 3500 mg, about 3525 mg, about 3550 mg, about 3575 mg, about 3600 mg, about 3625 mg, about 3650 mg, about 3675 mg, about 3700 mg, about 3725 mg, about 3750 mg, about 3775 mg, about 3800 mg, about 3825 mg, about 3850 mg, about 3875 mg, about 3900 mg, about 3925 mg, about 3950 mg, about 3975 mg, about 4000 mg, about 4025 mg, about 4050 mg, about 4075 mg, about 4100 mg, about 4125 mg, about 4150 mg, about 4175 mg, about 4200 mg, about 4225 mg, about 4250 mg, about 4275 mg, about 4300 mg, about 4325 mg, about 4350 mg, about 4375 mg, about 4400 mg, about 4425 mg, about 4450 mg, about 4475 mg, about 4500 mg, about 4525 mg, about 4550 mg, about 4575 mg, about 4600 mg, about 4625 mg, about 4650 mg, about 4675 mg, about 4700 mg, about 4725 mg, about 4750 mg, about 4775 mg, about 4800 mg, about 4825 mg, about 4850 mg, about 4875 mg, about 4900 mg, about 4925 mg, about 4950 mg, about 4975 mg, or about 5000 mg.
In various embodiments, one or more antioxidants can be present in the EPA (e.g. E-EPA or ultra pure E-EPA). Non-limiting examples of suitable antioxidants include tocopherol, lecithin, citric acid and/or ascorbic acid. One or more antioxidants, if desired, are typically present in the EPA in an amount of about 0.01% to about 0.1%, by weight, or about 0.025% to about 0.05%, by weight.
In one embodiment, a composition of the invention contains not more than about 10%, not more than about 9%, not more than about 8%, not more than about 7%, not more than about 6%, not more than about 5%, not more than about 4%, not more than about 3%, not more than about 2%, not more than about 1%, or not more than about 0.5%, by weight, of all fatty acids (and/or derivatives thereof) present, docosahexaenoic acid or derivative thereof such as E-DHA, if any. In another embodiment, a composition of the invention contains substantially no docosahexaenoic acid or derivative thereof such as E-DHA. In still another embodiment, a composition of the invention contains no docosahexaenoic acid or E-DHA.
In another embodiment, EPA represents at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100%, by weight, of all fatty acids (and/or derivatives thereof) present in a composition useful in accordance with the invention.
In another embodiment, a composition of the invention contains less than 30%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5% or less than 0.25%, by weight of the total composition or by weight of the total fatty acid content (including or excluding derivatives of fatty acids), of any fatty acid other than EPA, or derivative thereof. Illustrative examples of a “fatty acid other than EPA” include linolenic acid (LA) or derivative thereof such as ethyl-linolenic acid, arachidonic acid (AA) or derivative thereof such as ethyl-AA, docosahexaenoic acid (DHA) or derivative thereof such as ethyl-DHA, alpha-linolenic acid (ALA) or derivative thereof such as ethyl-ALA, stearadonic acid (STA) or derivative thereof such as ethyl-SA, eicosatrienoic acid (ETA) or derivative thereof such as ethyl-ETA and/or docosapentaenoic acid (DPA) or derivative thereof such as ethyl-DPA.
In another embodiment, a composition of the invention has one or more of the following features: (a) eicosapentaenoic acid ethyl ester represents at least 96%, at least 97%, or at least 98%, by weight, of all fatty acids (and/or derivatives thereof) present in the composition; (b) the composition contains not more than 4%, not more than 3%, or not more than 2%, by weight, of all fatty acids (and/or derivatives thereof) present, of fatty acids other than eicosapentaenoic acid ethyl ester; (c) the composition contains not more than 0.6%, 0.5%, 0.4% or 0.3%, by weight, of all fatty acids (and/or derivatives thereof) present, of any individual fatty acid other than eicosapentaenoic acid ethyl ester; (d) the composition has a refractive index (20° C.) of about 1 to about 2, about 1.2 to about 1.8 or about 1.4 to about 1.5; (e) the composition has a specific gravity (20° C.) of about 0.8 to about 1.0, about 0.85 to about 0.95 or about 0.9 to about 0.92; (f) the composition contains not more than 20 ppm, 15 ppm or 10 ppm heavy metals, (g) the composition contains not more than 5 ppm, 4 ppm, 3 ppm, or 2 ppm arsenic, and/or (h) the composition has a peroxide value not more than 5, 4, 3, or 2 Meq/kg.
In another embodiment, a composition useful in accordance with the invention comprises, consists essentially of or consists of at least 95%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl eicosapentaenoate (EPA-E), about 0.2% to about 0.5%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl octadecatetraenoate (ODTA-E), about 0.05% to about 0.25%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl nonadecapentaenoate (NDPA-E), about 0.2% to about 0.45%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl arachidonate (AA-E), about 0.3% to about 0.5%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl eicosatetraenoate (ETA-E), and about 0.05% to about 0.32%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl heneicosapentaenoate (HPA-E). In another embodiment, the composition is present in a capsule shell. In still another embodiment, the capsule shell contains no chemically modified gelatin.
In another embodiment, compositions useful in accordance with the invention comprise, consist essentially of, or consist of at least 95%, 96% or 97%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl eicosapentaenoate, about 0.2% to about 0.5%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl octadecatetraenoate, about 0.05% to about 0.25%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl nonadecapentaenoate, about 0.2% to about 0.45%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl arachidonate, about 0.3% to about 0.5%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl eicosatetraenoate, and about 0.05% to about 0.32%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl heneicosapentaenoate. Optionally, the composition contains not more than about 0.06%, about 0.05%, or about 0.04%, by weight, of all fatty acids (and/or derivatives thereof) present, DHA or derivative thereof such as ethyl-DHA. In one embodiment the composition contains substantially no or no amount of DHA or derivative thereof such as ethyl-DHA. The composition further optionally comprises one or more antioxidants (e.g. tocopherol) in an amount of not more than about 0.5% or not more than 0.05%. In another embodiment, the composition comprises about 0.05% to about 0.4%, for example about 0.2% by weight tocopherol. In another embodiment, about 500 mg to about 1 g of the composition is provided in a capsule shell. In another embodiment, the capsule shell contains no chemically modified gelatin.
In another embodiment, compositions useful in accordance with the invention comprise, consist essentially of, or consist of at least 96%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl eicosapentaenoate, about 0.22% to about 0.4%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl octadecatetraenoate, about 0.075% to about 0.20%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl nonadecapentaenoate, about 0.25% to about 0.40%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl arachidonate, about 0.3% to about 0.4%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl eicosatetraenoate and about 0.075% to about 0.25%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl heneicosapentaenoate. Optionally, the composition contains not more than about 0.06%, about 0.05%, or about 0.04%, by weight, of all fatty acids (and/or derivatives thereof) present, DHA or derivative thereof such as ethyl-DHA. In one embodiment the composition contains substantially no or no amount of DHA or derivative thereof such as ethyl-DHA. The composition further optionally comprises one or more antioxidants (e.g. tocopherol) in an amount of not more than about 0.5% or not more than 0.05%. In another embodiment, the composition comprises about 0.05% to about 0.4%, for example about 0.2% by weight tocopherol. In another embodiment, the invention provides a dosage form comprising about 500 mg to about 1 g of the foregoing composition in a capsule shell. In one embodiment, the dosage form is a gel- or liquid-containing capsule and is packaged in blister packages of about 1 to about 20 capsules per sheet.
In another embodiment, compositions useful in accordance with the invention comprise, consist essentially of or consist of at least 96%, 97% or 98%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl eicosapentaenoate, about 0.25% to about 0.38%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl octadecatetraenoate, about 0.10% to about 0.15%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl nonadecapentaenoate, about 0.25% to about 0.35%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl arachidonate, about 0.31% to about 0.38% by weight ethyl eicosatetraenoate, and about 0.08% to about 0.20%, by weight, of all fatty acids (and/or derivatives thereof) present, ethyl heneicosapentaenoate. Optionally, the composition contains not more than about 0.06%, about 0.05%, or about 0.04%, by weight, of all fatty acids (and/or derivatives thereof) present, DHA or derivative thereof such as ethyl-DHA. In one embodiment the composition contains substantially no or no amount of DHA or derivative thereof such as ethyl-DHA. The composition further optionally comprises one or more antioxidants (e.g. tocopherol) in an amount of not more than about 0.5% or not more than 0.05%. In another embodiment, the composition comprises about 0.05% to about 0.4%, for example about 0.2% by weight tocopherol. In another embodiment, the invention provides a dosage form comprising about 500 mg to about 1 g of the foregoing composition in a capsule shell. In another embodiment, the capsule shell contains no chemically modified gelatin.
In another embodiment, a composition as described herein is administered to a subject once or twice per day. In another embodiment, 1, 2, 3 or 4 capsules, each containing about 1 g of a composition as described herein, are administered to a subject daily. In another embodiment, 1 or 2 capsules, each containing about 1 g of a composition as described herein, are administered to the subject in the morning, for example between about 5 am and about 11 am, and 1 or 2 capsules, each containing about 1 g of a composition as described herein, are administered to the subject in the evening, for example between about 5 pm and about 11 pm.
In one embodiment, a subject being treated in accordance with methods of the invention is not on fibrate or nitrate therapy.
In another embodiment, compositions useful in accordance with methods of the invention are orally deliverable. The terms “orally deliverable” or “oral administration” herein include any form of delivery of a therapeutic agent or a composition thereof to a subject wherein the agent or composition is placed in the mouth of the subject, whether or not the agent or composition is swallowed. Thus “oral administration” includes buccal and sublingual as well as esophageal administration. In one embodiment, the composition is present in a capsule, for example a soft gelatin capsule.
A composition for use in accordance with the invention can be formulated as one or more dosage units. The terms “dose unit” and “dosage unit” herein refer to a portion of a pharmaceutical composition that contains an amount of a therapeutic agent suitable for a single administration to provide a therapeutic effect. Such dosage units may be administered one to a plurality (i.e. 1 to about 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 2) of times per day, or as many times as needed to elicit a therapeutic response.
In another embodiment, the invention provides use of any composition described herein for treating moderate to severe hypertriglyceridemia in a subject in need thereof, comprising: providing a subject having a fasting baseline triglyceride level of about 500 mg/dl to about 1500 mg/dl and administering to the subject a pharmaceutical composition as described herein. In one embodiment, the composition comprises about 1 g to about 4 g of eicosapentaenoic acid ethyl ester, wherein the composition contains substantially no docosahexaenoic acid.
EXAMPLES
Example 1
Safety and Efficacy of Ultra-Pure EPA
A multi-center, placebo-controlled, randomized, double-blind, 12-week study was performed to evaluate the efficacy and safety of >96% E-EPA in patients with fasting triglyceride levels ≧200 mg/dl and <500 mg/dl despite statin therapy (the mean of two qualifying entry values needed to be ≧185 mg/dl and at least one of the values needed to be ≧200 mg/dl). The primary objective of the study was to determine the efficacy of >96% E-EPA 2 g daily and 4 g daily, compared to placebo, in lowering fasting TG levels in patients with high risk for cardiovascular disease and with fasting TG levels 2200 mg/dl and <500 mg/dl, despite treatment to LDL-C goal on statin therapy.
The secondary objectives of this study were the following:

    
    
        1. To determine the safety and tolerability of >96% E-EPA 2 g daily and 4 g daily;
        2. To determine the effect of >96% E-EPA on lipid and apolipoprotein profiles including total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and very high density lipoprotein cholesterol (VHDL-C);
        3. To determine the effect of >96% E-EPA on lipoprotein associated phospholipase A2 (Lp-PLA2) from baseline to week 12;
        4. To determine the effect of >96% E-EPA on low-density lipoprotein (LDL) particle number and size;
        5. To determine the effect of >96% E-EPA on oxidized LDL;
        6. To determine the effect of >96% E-EPA on fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c);
        7. To determine the effect of >96% E-EPA on insulin resistance;
        8. To determine the effect of >96% E-EPA on high-sensitivity C-reactive protein (hsCRP);
        9. To determine the effects of >96% E-EPA 2 g daily and 4 g daily on the incorporation of fatty acids into red blood cell membranes and into plasma phospholipids;
        10. To explore the relationship between baseline fasting TG levels and the reduction in fasting TG levels; and
        11. To explore the relationship between changes of fatty acid concentrations in plasma and red blood cell membranes, and the reduction in fasting TG levels.
    
    


The population for this study was men and women >18 years of age with a body mass index ≦45 kg/m2 with fasting TG levels greater than or equal to 200 mg/dl and less than 500 mg/dl and on a stable does of statin therapy (with or without ezetimibe). The statin was atorvostatin, rosuvastatin or simvastatin. The dose of statin must have been stable for ≧4 weeks prior to the LDL-C/TG baseline qualifying measurement for randomization. The statin dose was optimized such that the patients are at their LDL-C goal at the LDL-C/TG baseline qualifying measurements. The same statin at the same dose was continued until the study ended.
Patients taking any additional non-statin, lipid-altering medications (niacin >200 mg/day, fibrates, fish oil, other products containing omega-3 fatty acids, or other herbal products or dietary supplements with potential lipid-altering effects), either alone or in combination with statin therapy (with or without ezetimibe), must have been able to safely discontinue non-statin, lipid-altering therapy at screening.
Patients at high risk for CVD, i.e., patients with clinical coronary heart disease (CHD) or clinical CHD risk equivalents (10-year risk>20%) as defined in the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) Guidelines were eligible to participate in this study. Those included patients with any of the following criteria: (1) Known CVD, either clinical coronary heart disease (CHD), symptomatic carotid artery disease (CAD), peripheral artery disease (PAD) or abdominal aortic aneurism; or (2) Diabetes Mellitus (Type 1 or 2).
Approximately 702 patients were randomized at approximately 80 centers in the U.S. The study was a 18- to 20-week, Phase 3, multi-center study consisting of 2 study periods: (1) A 6- to 8-week screening period that included a diet and lifestyle stabilization, a non-statin lipid-altering treatment washout, and an LDL-C and TG qualifying period and (2) A 12-week, double-blind, randomized, placebo-controlled treatment period.
During the screening period and double-blind treatment period, all visits were within ±3 days of the scheduled time. All patients continued to take the statin product (with or without ezetimibe) at the same dose they were taking at screening throughout their participation in the study.
The 6- to 8-week screening period included a diet and lifestyle stabilization, a non-statin lipid-altering treatment washout, and an LDL-C and TG qualifying period. The screening visit (Visit 1) occurred for all patients at either 6 weeks (for patients on stable statin therapy [with or without ezetimibe] at screening) or 8 weeks (for patients who will require washout of their current non-statin lipid-altering therapy at screening) before randomization, as follows:

    
    
        Patients who did not require a washout: The screening visit occurred at Visit 1 (Week −6). Eligible patients entered a 4-week diet and lifestyle stabilization period. At the screening visit, all patients received counseling regarding the importance of the National Cholesterol Education Program (NCEP) Therapeutic Lifestyle Changes (TLC) diet and received basic instructions on how to follow this diet.
        Patients who required a washout: The screening visit occurred at Visit 1 (Week −8). Eligible patients began a 6-week washout period at the screening visit (i.e. 6 weeks washout before the first LDL-C/TG qualifying visit). Patients received counseling regarding the NCEP TLC diet and received basic instructions on how to follow this diet. Site personnel contacted patients who did not qualify for participation based on screening laboratory test results to instruct them to resume their prior lipid-altering medications.
    
    


At the end of the 4-week diet and lifestyle stabilization period or the 6-week diet and stabilization and washout period, eligible patients entered the 2-week LDL-C and TG qualifying period and had their fasting LDL-C and TG levels measured at Visit 2 (Week −2) and Visit 3 (Week −1). Eligible patients must have had an average fasting LDL-C level ≧40 mg/dL and <100 mg/dL and an average fasting TG level 2200 mg/dL and <500 mg/dL to enter the 12-week double-blind treatment period. The LDL-C and TG levels for qualification were based on the average (arithmetic mean) of the Visit 2 (Week −2) and Visit 3 (Week −1) values. If a patient's average LDL-C and/or TG levels from Visit 2 and Visit 3 fell outside the required range for entry into the study, an additional fasting lipid profile was collected 1 week later at Visit 3.1. If a third sample was collected at Visit 3.1, entry into the study was based on the average (arithmetic mean) of the values from Visit 3 and Visit 3.1.
After confirmation of qualifying fasting LDL-C and TG values, eligible patients entered a 12-week, randomized, double-blind treatment period. At Visit 4 (Week 0), patients were randomly assigned to 1 of the following treatment groups:
>96% E-EPA 2 g daily,
>96% E-EPA 4 g daily, or
Placebo.
226 to 234 patients per treatment group were randomized in this study. Stratification was by type of statin (atorvastatin, rosuvastatin or simvastatin), the presence of diabetes, and gender.
During the double-blind treatment period, patients returned to the site at Visit 5 (Week 4), Visit 6 (Week 11), and Visit 7 (Week 12) for efficacy and safety evaluations.
Eligible patients were randomly assigned at Visit 4 (Week 0) to receive orally >96% E-EPA 2 g daily, >96% E-EPA 4 g daily, or placebo.
>96% E-EPA was provided in 1 g liquid-filled, oblong, gelatin capsules. The matching placebo capsule was filled with light liquid paraffin and contained 0 g of >96% E-EPA. >96% E-EPA capsules were to be taken with food (i.e. with or at the end of a meal).
During the double-blind treatment period, patients were to take 2 capsules (>96% E-EPA or matching placebo) in the morning and 2 capsules in the evening for a total of 4 capsules per day.

    
    
        Patients in the >96% E-EPA 2 g/day treatment group received 1>96% E-EPA 1 g capsule and 1 matching placebo capsule in the morning and in the evening.
        Patients in the >96% E-EPA 4 g/day treatment group received 2>96% E-EPA 1 g capsules in the morning and evening.
    
    


Patients in the placebo group received 2 matching placebo capsules in the morning and evening.
The primary efficacy variable for the double-blind treatment period was percent change in TG from baseline to Week 12 endpoint. The secondary efficacy variables for the double-blind treatment period included the following:

    
    
        Percent changes in total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), LDL-C, calculated non-HDL-C, and very low-density lipoprotein cholesterol (VLDL-C) from baseline to Week 12 endpoint;
        Percent change in very low-density lipoprotein TG from baseline to Week 12;
        Percent changes in apolipoprotein A-I (Apo A-1), apolipoprotein B (Apo B), and Apo A-1/Apo B ratio from baseline to Week 12;
        Percent changes in lipoprotein (a) from baseline to Week 12;
        Percent changes in LDL particle number and size, measured by nuclear magnetic resonance, from baseline to Week 12;
        Percent change in remnant-like particle cholesterol from baseline to Week 12;
        Percent change in oxidized LDL from baseline to Week 12;
        Changes in FPG and HbA1c from baseline to Week 12;
        Change in insulin resistance, as assessed by the homeostasis model index insulin resistance, from baseline to Week 12;
        Percent change in lipoprotein associated phospholipase A2 (Lp-PLA2) from baseline to Week 12;
        Change in intracellular adhesion molecule-1 from baseline to Week 12;
        Change in interleukin-2 from baseline to Week 12;
        Change in plasminogen activator inhibitor-1 from baseline to Week 12. Note: this parameter will only be collected at sites with proper storage conditions;
        Change in hsCRP from baseline to Week 12; and
        Change in plasma concentration and red blood cell membrane content of fatty acid from baseline to Week 12 including EPA, docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), arachidonic acid (AA), dihomo-γ-linolenic acid (DGLA), the ratio of EPA/AA, ratio of oleic acid/stearic acid (OA/SA), and the ratio of total omega-3 acids over total omega-6 acids.
    
    


Safety assessments included adverse events, clinical laboratory measurements (chemistry, hematology, and urinalysis), 12-lead electrocardiograms (ECGs), vital signs, and physical examinations.
For TG, TC, HDL-C, LDL-C, calculated non-HDL-C, and VLDL-C, baseline was defined as the average of Visit 4 (Week 0) and the preceding lipid qualifying visit (either Visit 3 [Week −1] or if it occurs, Visit 3.1) measurements. Baseline for all other efficacy parameters was the Visit 4 (Week 0) measurement.
For TG, TC, HDL-C, LDL-C, calculated non-HDL-C, and VLDL-C, Week 12 endpoint was defined as the average of Visit 6 (Week 11) and Visit 7 (Week 12) measurements.
Week 12 endpoint for all other efficacy parameters were the Visit 7 (Week 12) measurement.
The primary efficacy analysis was performed using a 2-way analysis of covariance (ANCOVA) model with treatment as a factor and baseline TG value as a covariate. The least-squares mean, standard error, and 2-tailed 95% confidence interval for each treatment group and for each comparison were estimated. The same 2-way ANCOVA model was used for the analysis of secondary efficacy variables.
The primary analysis was repeated for the per-protocol population to confirm the robustness of the results for the intent-to-treat population.
Non-inferiority tests for percent change from baseline in LDL-C were performed between >96% E-EPA doses and placebo using a non-inferiority margin of 6% and a significant level at 0.05.
For the following key secondary efficacy parameters, treatment groups were compared using Dunnett's test to control the Type 1 error rate: TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, Lp-PLA2, and Apo B. For the remaining secondary efficacy parameters, Dunnett's test was be used and the ANCOVA output were considered descriptive.
The evaluation of safety was based primarily on the frequency of adverse events, clinical laboratory assessments, vital signs, and 12-lead ECGs. The primary efficacy variable is the percent change in fasting TG levels from baseline to Week 12. A sample size of 194 completed patients per treatment group provided 90.6% power to detect a difference of 15% between >96% E-EPA and placebo in percent change from baseline in fasting TG levels, assuming a standard deviation of 45% in TG measurements and a significance level of p<0.05.
Previous data on fasting LDL-C show a difference in percent change from baseline of 2.2%, with a standard deviation of 15%, between study drug and placebo. A sample size of 194 completed patients per treatment group provided 80% power to demonstrate non-inferiority (p<0.05, one-sided) of the LDL-C response between >96% E-EPA 4 g daily and placebo, within a 6% margin. To accommodate a 10% drop-out rate from randomization to completion of the double-blind treatment period, a total of 648 randomized patients was planned (216 patients per treatment group); 702 subjects were randomized, as further described below.
Results
Of the 702 randomized subjects, 687 were in the intent-to-treat (“ITT”) population as follows:

    
    
        Ultra-pure EPA, 4 g/day: 226 subjects
        Ultra-pure EPA, 2 g/day: 234 subjects
        Placebo: 227 subjects
    
    


Lipids were extracted from plasma and red blood cell (“RBC”) suspensions and converted into fatty acid methyl esters for analysis using a standard validated gas chromatography/flame ionization detection method. Fatty acid parameters were compared between EPA treatment groups and placebo using an ANCOVA model with treatment, gender, type of statin therapy, and presence of diabetes as factors, and the baseline parameter value as a covariate. LSMs, SEs, and 2-tailed 95% confidence intervals for each treatment group and for each comparison were determined.
Baseline characteristics of the three ITT groups were comparable, with 61.4% of the ITT subjects being male, 96.3% being white, having a mean age of 61.4 years, a weight of 95.7 kg and a BMI of 32.9 kg/m2. ITT subjects with incomplete fatty acid data at baseline and/or at 12 weeks were excluded from the analyses described below.
As shown in Table 1 below, administration of 4 g per day of ethyl eicosapentaenoate (e.g., in a composition according to the present disclosure) reduced median concentrations of total VLDL by 12.2% over baseline when adjusted for placebo (P<0.001). Similarly, median concentrations of total LDL were reduced by 7.7% over baseline when adjusted for placebo (P<0.01). Median concentrations of total HDL were also reduced, by 7.4% over baseline when adjusted for placebo (P<0.0001). In addition, median concentrations of small LDL particles were reduced by 13.5% over baseline when adjusted for placebo control (P<0.0001).







TABLE 1







Placebo-Adjusted Effects of 4 g/day Ethyl Eicosapentaenoate


on Select Lipid Parameters Relative to Baseline.









Parameter
% Change
P












VLDL
−12.2%
<0.001


LDL
−7.7%
<0.01


HDL
−7.4%
<0.0001


Small LDL
−13.5%
<0.0001









Additional lipoprotein particle concentration data for 4 g/day and 2 g/day ethyl eicosapentaenoate groups is shown in Table 2.







TABLE 2







Median Change from Baseline to Study End in Lipoprotein Particle Concentrations












IPE 4 g/day (n = 216)
IPE 2 g/day (n = 222)
Placebo (n = 211)















Change

Change

Change
Median Change From Baseline




















End of
from

End of
from

End of
from
IPE 4 g/day
IPE 2 g/day



Base-
Treat-
Base-
Base-
Treat-
Base-
Base-
Treat-
Base-
vs Placebo
vs Placebo



line
ment
line %
line
ment
line %
line
ment
line %
%, P
%, P






















Total VLDL, nmol/L
116.7
110.0
−2.5
113.4
122.4
12.0
111.2
122.0
7.9
−12.2
1.8



(66.6)
(78.0)
(41.8)
(53.5)
(66.2)
(56.1)
(50.6)
(60.0)
(40.1)
0.0002
0.6102


Large VLDL, nmol/L
12.9
7.7
−41.9
12.1
10.0
−19.7
12.9
14.1
6.0
−46.4
−24.2



(10.7)
(7.6)
(57.2)
(8.3)
(9.9)
(72.5)
(9.7)
(13.2)
(101.1)
<0.0001
<0.0001


Medium VLDL, nmol/L
54.8
49.7
−6.9
52.6
59.6
7.9
53.3
58.8
9.2
−12.1
2.6



(37.2)
(41.8)
(59.3)
(33.4)
(39.0)
(69.6)
(29.9)
(36.1)
(56.3)
0.0068
0.5998


Small VLDL, nmol/L
43.9
46.8
8.3
43.1
49.6
22.1
41.4
45.3
8.5
2.8
16.5



(36.8)
(39.9)
(81.8)
(34.8)
(41.3)
(96.3)
(32.8)
(37.4)
(70.0)
0.6321
0.0058


Total LDL, nmol/L
1131
1191
3.8
1171
1215
4.7
1152
1287
11.9
−7.7
−7.5



(369.5)
(512.0)
(31.8)
(349.0)
(355.0)
(29.2)
(353.0)
(456.0)
(31.6)
0.0017
0.0013


IDL, nmol/L
51.5
63.0
23.7
45.0
63.5
10.5
55.0
55.0
0.0
10.0
8.6



(81.5
(94.0)
(173.7)
(94.0)
(122.0)
(200.7)
(88.0)
(102.0)
(194.8)
0.3051
0.3602


Large LDL, nmol/L
113.5
172.5
55.2
128.0
202.0
47.7
113.0
166.0
30.6
34.2
26.5



(198.5)
(226.0)
(241.0)
(190.0)
(242.0)
(207.2)
(215.0)
(271.0)
(200.4)
0.0076
0.0336


Small LDL, nmol/L
894.0
902.5
−1.1
944.0
920.5
−4.3
902.0
978.0
11.0
−13.5
−14.7



(266.5)
(387.5)
(36.1)
(310.0)
(313.0)
(32.0)
(323.0)
(387.0)
(39.0)
<0.0001
<0.0001


Total HDL, μmol/L
34.3
32.6
−4.0
34.3
34.7
0.7
34.8
35.5
4.7
−7.4
−3.1



(8.9)
(8.2)
(16.4)
(8.3)
(7.2)
(14.9)
(10.1)
(9.3)
(16.2)
<0.0001
0.0150


Large HDL, μmol/L
2.5
1.9
−21.6
2.5
2.4
−4.0
2.8
2.9
9.1
−31.0
−13.5



(1.8)
(2.0)
(58.1)
(2.0)
(2.3)
(63.3)
(2.0)
(2.3)
(50.4)
<0.0001
0.0017


Medium HDL, μmol/L
6.7
6.9
4.2
7.0
7.2
2.9
7.8
8.3
8.6
−6.5
−4.5



(6.0)
(4.8)
(69.4)
(5.6)
(5.2)
(93.8)
(5.6)
(7.3)
(81.8)
0.2245
0.4359


Small HDL, μmol/L
24.2
23.1
−3.9
24.0
23.8
−0.6
23.0
24.0
1.6
−2.8
−0.2



(6.4)
(6.7)
(21.9)
(6.7)
(6.4)
(24.8)
(8.1)
(7.4)
(25.4)
0.1267
0.9028





Data are presented as median (IQR) for end point values. Median placebo-adjusted percent changes are Hodges-Lehmann medians.






These data show that 4 g/day ethyl eicosapentaenoate significantly reduced median concentrations of total, large, and medium VLDL particles; total and small LDL particles; and total and large HDL particles. In addition, 4 g/day of ethyl eicosapentaenoate increased the concentration of large LDL particles compared to placebo.
As shown in FIG. 1, atherogenic lipoprotein particle (i.e., total VLDL and total LDL particles) concentrations correlated well with Apo B (N=649; R2=0.64; P<0.0001) at week 12. The shaded band corresponds to confidence limits of the mean, which is shown as a dark line.
Median changes in lipoprotein particle size from baseline are shown in Table 3 below for 4 g/day ethyl eicosapentaenoate, 2 g/day ethyl eicosapentaenoate, and placebo, along with placebo-adjusted median percent changes from baseline for both 4 g/day and 2 g/day ethyl-EPA dosages. Data is presents as median (IQR) for end point values, and as Hodges-Lehmann medians for placebo-adjusted percent changes.







TABLE 3







Median Change from Baseline to Study End in Lipoprotein Particle Sizes









Placebo-Adjusted



Median Change



from Baseline













4 g/day E-EPA (n = 216)
2 g/day E-EPA (n = 222)
Placebo (n = 211)
4 g/d,
2 g/d,



















Baseline
End
% Δ
Baseline
End
% Δ
Baseline
End
% Δ
%, P
%, P






















VLDL, nm
56.3
51.2
−8.1
55.9
53.2
−5.0
56.5
55.9
−0.6
−7.7
−4.8


(IQR)
(8.3)
(8.4)
(13.7)
(8.7)
(9.2)
(14.1)
(10.0)
(11.3)
(14.3)
<0.0001
<0.0001


LDL*, nm
19.8
20.0
+0.5
19.8
20.0
+0.5
19.8
19.9
0.0
+0.5
+0.5


(IQR)
(0.5)
(0.6)
(2.5)
(0.5)
(0.6)
(2.5)
(0.6)
(0.5)
(2.5)
0.0031
0.0007


HDL, nm
8.7
8.6
−1.1
8.6
8.6
0.0
8.7
8.7
0.0
−1.2
0.0


(IQR)
(0.3)
(0.2)
(3.5)
(0.5)
(0.5)
(2.4)
(0.3)
(0.4)
(3.5)
0.0014
0.4171





*Patient numbers (n) for LDL data only were 215, 221, and 211 for IPE 4 g/day, IPE 2 g/day and placebo, respectively.






These data show that 4 g/day of ethyl eicosapentaenoate significantly reduced median VLDL and HDL particle sizes, with a modest but significant increase in LDL particle size compared to placebo.
As shown in Table 4 below, administration of 4 g per day of ethyl eicosapentaenoate (e.g., in a composition according to the present disclosure) significantly reduced median percent changes from baseline compared to placebo for both the FADI-16 ratio and the FADI-18 ratio.







TABLE 4







Placebo-Adjusted Effects of 4 g/day


Ethyl Eicosapentaenoate on FADI Ratios.












Plasma
RBCs














% 

% 



Parameter
Definition
Change
P
Change
P















FADI-16
Palmitoleic
−6.8%
<0.01
−15.7%
<0.0001



acid/Palmitic 







acid (C16:1/







C16:0)






FADI-18
Oleic acid/
−9.8%
<0.001
−3.1%
<0.01



Stearic







Acid (C18:1/







C18:0)









Corresponding FIG. 2 shows percent change in FADI parameters compared to placebo in both plasma (FIG. 2A) and in red blood cells (FIG. 2B). Data are placebo-adjusted least square means values.
Endpoint data for subjects who were randomized and took at least one dose of any study drug, had baseline laboratory efficacy measurement, and had at least one valid post-randomization laboratory efficacy measurement of any type is summarized below.
Endpoint data for a subset of the study population (a modified intent-to-treat group referred to herein as the “MITT” group) were also analyzed. The MITT group included 687 individuals, each of which took at least one dose of study drug, had a baseline laboratory efficacy measurement, and had at least one post-randomization laboratory efficacy measurement.
The baseline characteristics of the MITT subgroup were similar to those of the ITT population. The majority of subjects in the MITT population did not have coronary heart disease. A summary of the MITT subjects' diabetes and cardiovascular disease is shown in Table 5 below:







TABLE 5







Summary of diabetes and cardiovascular disease-MITT.












Placebo
2 g/day
4 g/day
Total














n, total
227
234
226
687


History of
52
49 
42 
143


diabetes and CVD*
(22.9%)
(20.9%)
(18.6%)
(20.8%)


History of 
113
122
123
358


diabetes; no CVD
(49.8%)
(52.1%)
(54.4%)
(52.1%)


No history 
62
63 
61 
186


of diabetes
(27.3%)
(26.9%)
(27.0%)
(27.1%)





*CVD defined as history of any of the following: MI, unstable angina, stable angina, angioplasty, bypass surgery, clinically significant myocardial ischemia, peripheral arterial disease, abdominal aortic aneurysm, TIA, stroke of carotid origin, or obstruction of carotid artery (>50%).






A summary of selected concomitant medications is shown in Table 6.







TABLE 6







Selected Concomitant medications-MITT.














AMR101 
AMR101 




Placebo
2 g/d
4 g/d




N = 233
N = 236
N = 233




n (%)
n (%)
n (%)
















HMG-CoA 
233 
236
232 



reductase inhibitors
(100.0)
(100.0)
(99.6)



Anti-hypertensive
190 
200
199 



agents
(81.5)
(84.7)
(85.4)



Anti-platelet agent 
141 
135 
138 



(excluding heparin)
(60.5)
(57.2)
(59.2)



Aspirin
135 
130 
133 




(57.9)
(55.1)
(57.1)



Clopidogrel
26 
20
18 




(11.2)
(8.5)
(7.7)



Asasantin
2
0
1




(0.9)

(0.4)



Cilostazol
1
0
0




(0.4)





Anti-diabetic 
139
138 
141 



agents
(59.7)
(58.5)
(60.5)







Concomitant medications were defined as those used during the double-blind treatment period.



1. In addition, 41 patients were on an HMG-CoA reductase inhibitor in combination with another medication.



2. Patient 0.57-061 (in the AMR101 4 g group) was not on a statin at randomization and did not inform site personnel until Visit 5 (Week 4) that he had stopped taking his statin 1 week prior to randomization. Patient 057-061 continued in the study; however, because the patient was not on a statin at the time baseline lipid measurements were drawn at Visit 4 (Week 0), the statin was not restarted following Visit 5.






A summary of statin use by MITT subjects (by intensity of therapy at randomization) is shown in Table 7.







TABLE 7







Statin use at randomization (by intensity)-MITT.












AMR101 
AMR101



Placebo
2 g/d
4 g/d



N = 227
N = 234
N = 226



n (%)
n (%)
n (%)













Lower intensity
14 (6.2)
15 (6.4)
16 (7.1)


Simvastatin 5 mg
4 (1.8)
4 (1.7)
2 (0.9)


Simvastatin 5 mg + eze* 
0
1 (0.4)
0


Simvastatin 10 mg
10 (4.4)
10 (4.3)
13 (5.8)


Simvastatin 15 mg
0
0
1 (0.4)


Medium intensity
140 (61.7)
147 (62.8)
141 (62.4)


Atorvastatin 10 mg
10 (4.4)
8 (3.4)
9 (4.0)


Atorvastatin 20 mg
14 (6.2)
18 (7.7)
15 (6.6)


Rosuvastatin 5 mg
9 (4.0)
7 (3.0)
8 (3.5)


Rosuvastatin 5 mg + eze
1 (0.4)
0
0


Rosuvastatin 10 mg
21 (9.3)
28 (12.0)
19 (8.4)


Rosuvastatin 10 mg + eze
1 (0.4)
0
1 (0.4)


Simvastatin 10 mg + eze
0
3 (1.3)
1 (0.4)


Simvastatin 20 mg
31 (13.7)
32 (13.7)
31 (13.7)


Simvastatin 20 mg + eze
5 (2.2)
3 (1.3)
4 (1.8)


Simvastatin 40 mg
47 (20.7)
48 (20.5)
53 (23.5)


Simvastatin 60 mg
1 (0.4)
0
0


Higher intensity
73 (32.2)
72 (30.8)
69 (30.5)


Atorvastatin 40 mg
16 (7.0)
9 (3.8)
12 (5.3)


Atorvastatin 40 mg + eze
1 (0.4)
2 (0.9)
0


Atorvastatin 60 mg
0
1 (0.4)
0


Atorvastatin 80 mg
4 (1.8)
4 (1.7)
4 (1.8)


Atorvastatin 80 mg + eze
0
1 (0.4)
1 (0.4)


Rosuvastatin 20 mg
20 (8.8)
15 (6.4)
21 (9.3)


Rosuvastatin 20 mg + eze
0
2 (0.9)
0


Rosuvastatin 40 mg
2 (0.9)
3 (1.3)
5 (2.2)


Rosuvastatin 40 mg + eze
0
2 (0.9)
0


Simvastatin 40 mg + eze
10 (4.4)
10 (4.3)
6 (2.7)


Simvastatin 80 mg + eze 
0
4 (1.7)
2 (0.9)





*Note: Ezetimibe includes patients on 5 mg or 10 mg






A summary of subjects' statin use before and during the study is shown in Table 8.







TABLE 8







Statin use-MITT.













AMR101 
AMR101 




Placebo
2 g/d
4 g/d
Total



N = 227
N = 234
N = 226
N = 687


Category
n (%)
n (%)
n (%)
n (%)














Patients taking a 
203 
212 
205 
620 


statin prior to screening
(89.4)
(90.6)
(90.7)
(90.2)


Continued statin after 
190 
198
194
582 


screening
(83.7)
(84.6)
(85.8)
(84.7)


Continued dose
187
194 
190 
571 



(82.4)
(82.9)
(84.1)
(83.1)


Changed dose
3 
4 
4
11 



(1.3)
(1.7)
(1.8)
(1.6)


Changed statin after 
13 
14 
11 
38 


screening
(5.7)
(6.0)
(4.9)
(5.5)


Patients not taking a 
24 
22 
21 
67 


statin prior to screening
(10.6)
(9.4)
(9.3)
(9.8)









As shown in Table 9 below, subjects in the MITT group receiving 4 g/day of study drug experienced a 17.5% median reduction in triglycerides compared to baseline, while MITT subjects receiving 2 g/day of study drug reduced median triglycerides by 2.6% compared to baseline. Placebo subjects' median triglycerides increased by 5.9% over baseline.







TABLE 9







Change in Fasting Triglycerides from Baseline to Week 12 - MITT.














Percent change




Baseline [2]
Week 12 EP [3]
from Baseline
Difference from placebo
















Treatment +

Median
Median
Median


Estimated




Statin
n [1]
(IQR)
(IQR)
(IQR)
(Q1, Q3)
p-value
median
95% CI
p-value



















Placebo
227
259.0 (81.0)
269.5 (149.5)
  5.9 (44.9)
(−13.5, 31.3)
0.0002
—
—
—


AMR101
234
254.0 (92.5)
244.3 (117.0)
−5.6 (34.5)
(−21.1, 13.4)
0.1111
−10.1
(−15.7, −4.5)
0.0005


2 g/d


AMR101
226
264.8 (93.0)
220.8 (92.0) 
−17.5 (31.0) 
(−30.5, 0.5) 
<0.0001
−21.5
(−26.7, −16.2)
<0.0001


4 g/d





[1]. Only patients with non-missing baseline and Week 12 endpoint values were included.


[2]. Baseline was defined as the average of Visit 4 (Week 0) and the preceding lipid qualifying visit (either Visit 3 [Week −1] or if it occurred, Visit 3.1) measurements. If the measurement at 1 visit was missing, the other visit was used. If the measurements at both visits were missing, the last valid measurement prior to dosing with study drug was used as the baseline value.


[3]. The Week 12 endpoint was defined as the average of Visit 6 (Week 11) and Visit 7 (Week 12) measurements. If the measurement at 1 visit was missing, the other visit was used. If the measurements at both visits were missing, the last valid post-baseline measurement during the double-blind treatment period was used as the endpoint measurement.


CI = confidence interval;


EP = endpoint;


IQR = interquartile range;


Q1 = first quartile;


Q3 = third quartile






Data for individual MITT subjects corresponding to Table 9 is shown in a box-and-whisker plot in FIG. 3.
Table 10 shows the percentage of subjects achieving triglyceride treatment goal (less than 150 mg/dL) at Week 12.







TABLE 10







Percentage of Subjects Achieving 


Triglyceride Goal at Week 12.













Placebo
2 g/day
4 g/day
















Total n
227
234
226



Achieved TG 
13
9
16



Goal






Percentage 
5.7%
3.8%
7.1%



Achieving






TG Goal










Table 11 shows changes in lipid parameters by statin type in the MITT group.







TABLE 11





Changes in Lipid Parameters by Statin Type - MITT.


















Pbo + statin
AMR 101 2 g + statin























Median




Median






BL [2]
EOT [3]
% chg




% chg






Median
Median
from
p from



from
p from


Parameter
Statin
n [1]
(IQR)
(IQR
BL
BL
n [1]
BL [2]
EOT [3]
BL
BL





TG
Atorva
45
247
266.0
7.8
0.1729
43
235.0
245.0
−0.5
0.5764





(71.0)
(142.5)



(89.0)
(125.0)



Simva
128
262.0
274.5
6.0
0.0016
134
256.5
241.3
−8.8
0.0176





(97.8)
(148.3)



(102.0)
(133.0)



Rosuva
54
258.8
268.3
−0.6
0.1437
57
258.0
252.5
−5.8
0.9656





(69.0)
(147.0)



(93.5)
(99.0)


LDL-C
Atorva
45
85.0
88.0
6.8
0.1239
43
82.0
88.0
4.9
0.0264





(24.0)
(32.0)



(21.0)
(29.0)



Simva
127
83.0
88.0
8.6
0.0003
133
85.0
88.0
1.8
0.0954





(30.0)
(31.0)



(25.0)
(25.0)



Rosuva
54
81.0
89.5
10.5
0.0016
57
78.0
87.0
4.3
0.0365





(28.0)
(30.0)



(25.)
(34.0)


Non-HDL-C
Atorva
45
132.0
141.0
4.2
0.0139
42
128.0
135.0
10.5
<0.0001





(30.0)
(39.0)



(37.0)
(46.0)



Simva
128
128.0
135.0
9.2
<0.0001
134
128.0
133.5
0.0
0.0862





(37.5)
(45.0)



(34.0)
(41.0)



Rosuva
54
126.0
145
12.8
<0.0001
57
125.0
133.0
2.7
0.0659





(25.0)
(40.0)



(30.0)
(44.0)













AMR 101




2 g + statin
AMR 101 4 g + statin






















p



Median








Diff
value



% chg

Diff
p value





from
from



from
p from
from
from



Parameter
Statin
pbo
pbo [4]
n [1]
BL [2]
EOT [3]
BL
BL
pbo
pbo [4]







TG
Atorva
−2.4
0.6642
41
281.5
216.0
−23.9
<0.0001
−28.4
<0.0001








(59.0)
(82.5)




Simva
−14.3
0.0004
131
262.0
228.0
−14.7
<0.0001
−18.8
<0.001








(106.0)
(114.5)




Rosuva
−5.7
0.2512
54
250.8
204.0
−20.5
0.0001
−23.4
<0.0001








(85.5)
(77.0)



LDL-C
Atorva
1.1
0.8477
40
78.5
82.5
9.0
0.0358
2.5
0.6188








(24.5)
(29.5)




Simva
−4.8
0.0844
131
82.0
83.0
1.5
0.2468
−5.4
0.0539








(24.0)
(27.0)




Rosuva
−4.2
0.3482
54
85.0
82.5
−3.8
0.3532
−14.8
0.0033








(33.0)
(40.0)



Non-HDL-C
Atorva
2.0
0.7259
41
131.0
122.0
−6.3
0.0936
−13.5
0.0071








(30.0)
(32.0)




Simva
−6.8
0.0067
131
128.0
125.0
−4.3
0.3514
−11.1
<0.0001








(35.0)
(38.0)




Rosuva
−9.0
0.0481
54
128.5
118.0
−5.5
0.0240
−20.0
<0.0001








(28.0)
(42.0)







The median differences between the treatment groups were estimated with the Hodges-Lehmann method.



[1]. Only patients with both baseline and Week 12 endpoint values are included.



[2]. Baseline for TG was defined as the average of the measurements at Visit 4 (Week 0) and the preceding lipid qualifying visit (either Visit 3 [Week−1] or if it occurred, Visit 3.1) measurements. If the measurement at 1 visit was missing, the other visit measurement was used. If the measurements at both visits were missing, the last valid measurement prior to dosing with study drug was used as the baseline value. Baseline for other parameters were defined as the Visit 4 (Week 0) measurement. If missing, the last valid measurement prior to dosing with study drug was used.



[3]. For TG: the Week 12 endpoint was defined as the average of measurements at Visit 6 (Week 11) and Visit 7 (Week 12). If the measurement at 1 visit was missing, the other visit measurement was used. If the measurements at both visits were missing, the last valid post-baseline measurement during the double-blind treatment period was used as the endpoint measurement. For other lipid parameters, the Week 12 endpoint was defined as the Visit 7 (Week 12) measurement. If missing, the LOCF method was used.



[4]. P-value is from the Wilcoxon rank-sum test.



BL = Baseline;



pbo = placebo;



EOT = end of treatment (Week 12 endpoint);



IQR = interquartile range;



LOCF = last observation carried forward;



Q1 = first quartile;



Q3 = third quartile.






Table 12 shows changes in lipid parameters by statin regimen intensity in the MITT group.







TABLE 12





Changes in Lipid Parameters by Statin Regimen Intensity - MITT.


















Pbo + statin
AMR 101 2 g + statin























Median




Median






BL [2]
EOT [3]
% chg




% chg




Statin

Median
Median
from
p from



from
p from


Parameter
Potency
n [1]
(IQR)
(IQR
BL
BL
n [1]
BL [2]
EOT [3]
BL
BL





TG
Low
14
315.0
304.5
19.4
0.9515
15
256.0
208.5
−18.8
0.6387





(148.5)
(158.5)



(64.0)
(162.0)



Medium
140
257.3
268.3
4.6
0.0047
148
253.8
248.0
−5.3
0.3500





(83.5)
(131.3)



(83.0
(116.0)



High
73
257.5
266.0
6.5
0.0210
71
256.5
239.5
−5.8
0.2668





(76.5)
(160.0)



(103.5)
(115.0)


LDL-C
Low
14
101.5
98.0
−4.4
0.2661
15
91.0
95.0
0.9
0.6788





(35.0)
(41.0)



(30.0)
(20.0)



Medium
140
83.0
91.5
9.9
<0.0001
147
82.0
85.0
2.4
0.0168





(26.0)
(34.0)



(23.0)
(25.0)



High
72
83.0
84.0
8.3
0.0133
71
83.0
91.0
3.1
0.0205





(27.0)
(26.0)



(26.0)
(35.0)


Non-HDL-C
Low
14
150
152
1.5
0.7609
15
139
135
−2.2
0.5614





(50.0)
(45.0)



(20.0)
(28.0)



Medium
140
128
140
10.5
<0.0001
148
127
133
1.7
0.0094





(35.0)
(43.0)



(36.0)
(40.0)



High
73
126
134
12.3
<0.0001
71
128
142
5.4
0.0030





(27.0)
(41.0)



(31.0)
(47.0)













AMR 101




2 g + statin
AMR 101 4 g + statin






















p



Median








Diff
value



% chg

Diff
p value




Statin
from
from



from
p from
from
from



Parameter
Potency
pbo
pbo [4]
n [1]
BL [2]
EOT [3]
BL
BL
pbo
pbo [4]







TG
Low
−13.8
0.6784
16
267.8
256.8
0.5
0.6387
−13.1
0.5467








(87.0)
(131.5)




Medium
−8.7
0.0139
141
269.0
221.0
−15.8
<0.0001
−20.1
<0.0001








(96.5)
(91.0)




High
−11.7
0.0200
69
254.5
214.5
−20.2
<0.0001
−26.0
<0.0001








(92.5)
(87.0)



LDL-C
Low
7.1
0.4450
16
78.5
84.5
7.8
0.0934
12.4
0.0483








(14.5)
(20.0)




Medium
−5.9
0.0231
140
85.0
84.0
−2.2
0.9545
−10.0
0.0006








(28.0)
(35.0)




High
−1.7
0.6410
69
79.0
82.0
5.4
0.1139
−2.9
0.4910








(22.0)
(29.0)



Non-HDL-C
Low
3.3
0.7107
16
128
131
−1.4
0.5282
2.4
0.6326








(24.0)
(37.0)




Medium
−7.1
0.0031
141
129
124
−4.3
0.0618
−13.9
<0.0001








(35.0)
(40.0)




High
−3.5
0.3266
69
128
118
−6.3
0.0212
−15.8
<0.0001








(31.0)
(38.0)







The median differences between the treatment groups were estimated with the Hodges-Lehmann method. Low intensity was defined as simvastatin 5-10 mg; medium intensity was defined as rosuvastatin 5 10 mg, atorvastatin 10-20 mg, simvastatin 20-40 mg, or simvastatin 10-20 mg + ezetimibe 5-10 mg; High intensity was defined as rosuvastatin 20-40 mg, atorvastatin 40-80 mg, simvastatin 80 mg, or simvastatin 40-80 mg + ezetimibe 5-10 mg.



[1]. Only patients with both baseline and Week 12 endpoint values are included.



[2]. Baseline for TG was defined as the average of the measurements at Visit 4 (Week 0) and the preceding lipid qualifying visit (either Visit 3 [Week−1] or if it occurred, Visit 3.1) measurements. If the measurement at 1 visit was missing, the other visit measurement was used. If the measurements at both visits were missing, the last valid measurement prior to dosing with study drug was used as the baseline value. Baseline for other parameters were defined as the Visit 4 (Week 0) measurement. If missing, the last valid measurement prior to dosing with study drug was used.



[3]. For TG: the Week 12 endpoint was defined as the average of measurements at Visit 6 (Week 11) and Visit 7 (Week 12). If the measurement at 1 visit was missing, the other visit measurement was used. If the measurements at both visits were missing, the last valid post-baseline measurement during the double-blind treatment period was used as the endpoint measurement. For other lipid parameters, the Week 12 endpoint was defined as the Visit 7 (Week 12) measurement. If missing, the LOCF method was used.



[4]. P-value is from the Wilcoxon rank-sum test.



BL = Baseline;



pbo = placebo;



EOT = end of treatment (Week 12 endpoint);



IQR = interquartile range;



LOCF = last observation carried forward;



Q1 = first quartile;



Q3 = third quartile.






Table 13 shows changes in lipid parameters by TG tertile in the MITT group.







TABLE 13





Changes in Lipid Parameters by TG Tertile-MITT.


















Pbo + statin
AMR 101 2 g + statin























Median




Median




Baseline

BL [2]
EOT [3]
% chg




% chg



TG

Median
Median
from
p from



from
p from


Parameter
tertile
n [1]
(IQR)
(IQR
BL
BL
n [1]
BL [2]
EOT [3]
BL
BL





TG
Lowest
72
203.8
214.5
7.9
0.0055
84
205.8
207.8
0.7
0.1560





(31.5)
(71.5)



(33.0)
(74.5)



Middle
80
257.8
263.5
3.3
0.3629
76
257.0
228.3
−13.0
0.0092





(30.3)
(112.3)



(30.5)
(83.5)



Highest
75
340.5
380.5
5.2
0.0039
74
348.5
320.3
−8.7
0.0914





(94.0)
(165.5)



(75.0)
(119.0)


LDL-C
Lowest
72
85.5
95.0
9.2
0.0002
84
84.5
92.0
3.1
0.0656





(23.5)
(28.0)



(28.0)
(32.0)



Middle
80
86.5
90.0
7.3
0.0012
76
82.0
86.5
3.1
0.0161





(27.0)
(26.5)



(25.0)
(23.5)



Highest
74
80.0
80.0
9.2
0.0821
73
81.0
85.0
1.7
0.1876





(33.0)
(37.0)



(24.0)
(26.0)


Non-HDL-C
Lowest
72
117
134
12.1
<0.0001
84
121
129
6.9
0.0001





(23.0)
(32.0)



(32.0)
(38.0)



Middle
80
132
138
6.0
0.0004
76
129
132
−1.2
0.7214





(26.0)
(36.0)



(30.0)
(35.0)



Highest
75
140
149
12.2
<0.0001
74
140
150
3.0
0.0183





(48.0)
(60.0)



(44.0)
(51.0)












AMR 101 4 g + statin


















Median






Baseline
AMR 101 2 g + statin

% chg

Diff
p value


















TG
Diff from
p value from



from
p from
from
from


Parameter
tertile
pbo
pbo [4]
n [1]
BL [2]
EOT [3]
BL
BL
pbo
pbo [4]





TG
Lowest
−4.1
0.3694
68
207.8
183.5
−10.9
0.1127
−14.4
0.0020







(28.0)
(67.5)



Middle
−9.9
0.0324
81
261.5
205.0
−19.3
<0.0001
−17.9
<0.0001







(26.0)
(74.5)



Highest
−16.9
0.0043
77
346.5
260.0
−21.8
<0.0001
−31.1
<0.0001







(75.5)
(110.5)


LDL-C
Lowest
−5.7
0.0889
68
82.5
83.0
−3.9
0.3336
−12.2
0.0007







(25.0)
(30.5)



Middle
−2.6
0.4097
80
81.5
82.5
2.1
0.3260
−5.8
0.1345







(29.5)
(34.0)



Highest
−2.0
0.6672
77
82.0
83.0
4.8
0.0289
0
0.9970







(25.0)
(24.0)


Non-HDL-C
Lowest
−4.2
0.1926
68
116
118
−2.0
0.4390
−13.8
<0.0001







(26.0)
(31.0)



Middle
−7.0
0.0169
81
127
124
−4.0
0.5345
−9.5
0.0039







(31.0)
(42.0)



Highest
−5.0
0.2151
77
142
130
−6.9
0.0030
−17.6
<0.0001







(36.0)
(48.0)





The median differences between the treatment groups were estimated with the Hodges-Lehmann method.


Baseline TG tertiles were <230.5 mg/dL, 230.5 to <289.5 mg/dL, and ≧289.5 mg/dL.


[1]. Only patients with both baseline and Week 12 endpoint values are included.


[2]. Baseline for TG was defined as the average of the measurements at Visit 4 (Week 0) and the preceding lipid qualifying visit (either Visit 3 [Week−1] or if it occurred, Visit 3.1) measurements. If the measurement at 1 visit was missing, the other visit measurement was used. If the measurements at both visits were missing, the last valid measurement prior to dosing with study drug was used as the baseline value. Baseline for other parameters were defined as the Visit 4 (Week 0) measurement. If missing, the last valid measurement prior to dosing with study drug was used.


[3]. For TG: the Week 12 endpoint was defined as the average of measurements at Visit 6 (Week 11) and Visit 7 (Week 12). If the measurement at 1 visit was missing, the other visit measurement was used. If the measurements at both visits were missing, the last valid post-baseline measurement during the double-blind treatment period was used as the endpoint measurement. For other lipid parameters, the Week 12 endpoint was defined as the Visit 7 (Week 12) measurement. If missing, the LOCF method was used.


[4]. P-value is from the Wilcoxon rank-sum test.


BL = Baseline;


pbo = placebo;


EOT = end of treatment (Week 12 endpoint);


IQR = interquartile range;


LOCF = last observation carried forward;


Q1 = first quartile;


Q3 = third quartile.






Table 14 shows changes in lipid parameters by non-statin washout status in the MITT group.







TABLE 14





Changes in Lipid Parameters by Non-Statin Washout Status-MITT.


















Pbo + statin
AMR 101 2 g + statin



















Non-



Median




Median




statin

BL [2]
EOT [3]
% chg




% chg




washout

Median
Median
from
p from



from
p from


Parameter
(Yes/No)
n [1]
(IQR)
(IQR
BL
BL
n [1]
BL [2]
EOT [3]
BL
BL





TG
Yes
100
258.3
267.5
3.9
0.0075
109
262.5
249.5
−4.2
0.4771


(mg/dL)


(81.8)
(175.5)



(95.5)
(120.5)



No
127
259.0
272.0
6.2
0.0105
125
247.5
229.0
−7.9
0.1416





(85.5)
(131.5)



(87.0)
(114.5)


LDL-C
Yes
100
82.0
84.5
9.5
0.0002
109
82.0
85.0
2.2
0.1289


(mg/dL)


(27.5)
(27.5)



(24.0)
(23.0)



No
126
85.0
90.0
7.3
0.0007
124
84.0
91.5
3.5
0.0024





(25.0)
(35.0)



(26.0)
(32.5)


Non-HDL-
Yes
100
124
136
10.7
<0.0001
109
127
133
0.0
0.0239


C (mg/dL)


(31.0)
(40.0)



(30.0)
(38.0)



No
127
129
140
9.6
<0.0001
125
129
135
3.8
0.0020





(35.0)
(44.0)



(35.0)
(44.0)












AMR 101 4 g + statin















Non-


Median






statin
AMR 101 2 g + statin

% chg

Diff
p value


















washout
Diff from
p value from



from
p from
from
from


Parameter
(Yes/No)
pbo
pbo [4]
n [1]
BL [2]
EOT [3]
BL
BL
pbo
pbo [4]





TG
Yes
−9.5
0.0292
92
269.3
220.8
−17.7
<0.0001
−22.4
<0.0001


(mg/dL)




(92.8)
(80.8)



No
−10.7
0.0060
134
263.0
220.0
−16.7
<0.0001
−20.8
<0.0001







(90.5)
(100.0)


LDL-C
Yes
−6.3
0.0423
91
82.0
80.0
−1.4
0.4932
−7.5
0.0428


(mg/dL)




(28.0)
(33.0)



No
−1.2
0.6549
134
82.0
83.5
2.5
0.2283
−5.1
0.0692







(25.0)
(30.0)


Non-HDL-
Yes
−6.9
0.0345
92
129
124
−5.4
0.0900
−14.4
<0.0001


C (mg/dL)




(35.0)
(36.0)



No
−4.6
0.0847
134
128
122
−4.9
0.0522
−4.8
<0.0001







(32.0)
(42.0)





The median differences between the treatment groups were estimated with the Hodges-Lehmann method.


[1]. Only patients with both baseline and Week 12 endpoint values are included.


[2]. Baseline for TG was defined as the average of the measurements at Visit 4 (Week 0) and the preceding lipid qualifying visit (either Visit 3 [Week−1] or if it occurred, Visit 3.1) measurements. If the measurement at 1 visit was missing, the other visit measurement was used. If the measurements at both visits were missing, the last valid measurement prior to dosing with study drug was used as the baseline value. Baseline for other parameters were defined as the Visit 4 (Week 0) measurement. If missing, the last valid measurement prior to dosing with study drug was used.


[3]. For TG: the Week 12 endpoint was defined as the average of measurements at Visit 6 (Week 11) and Visit 7 (Week 12). If the measurement at 1 visit was missing, the other visit measurement was used. If the measurements at both visits were missing, the last valid post-baseline measurement during the double-blind treatment period was used as the endpoint measurement. For other lipid parameters, the Week 12 endpoint was defined as the Visit 7 (Week 12) measurement. If missing, the LOCF method was used.


[4]. P-value is from the Wilcoxon rank-sum test.


BL = Baseline;


pbo = placebo;


EOT = end of treatment (Week 12 endpoint);


IQR = interquartile range;


LOCF = last observation carried forward;


Q1 = first quartile;


Q3 = third quartile.






Table 15 shows changes in lipid parameters by diabetes status in the MITT group.







TABLE 15





Changes in Lipid Parameters by Diabetes Status-MITT.


















Pbo + statin
AMR 101 2 g + statin























Median




Median






BL [2]
EOT [3]
% chg




% chg



Diabetes

Median
Median
from
p from



from
p from


Parameter
(Yes/No)
n [1]
(IQR)
(IQR)
BL
BL
n [1]
BL [2]
EOT [3]
BL
BL





TG
Yes
165
259.0
275.5
6.2
0.0002
171
253.5
244.0
−1.5
0.7846


(mg/dL)


(78.0)
(153.5)



(87.0)
(116.5)



No
62
258.8
258.5
4.3
0.3134
63
256.5
245.0
−12.1
0.0075





(123.5)
(138.0)



(96.0)
(121.5)


LDL-C
Yes
164
84.0
87.5
8.8
<0.0001
170
82.0
87.0
2.2
0.0063


(mg/dL)


(25.5)
(31.0)



(24.0)
(26.0)



No
62
85.5
90.0
8.5
0.0060
63
83.0
88.0
2.6
0.0674





(33.0)
(31.0)



(29.0)
(35.0)


Non-HDL-
Yes
165
128
136
10.7
<0.0001
171
125
135
5.1
<0.0001


C (mg/dL)


(34.0)
(44.0)



(33.0)
(41.0)



No
62
129
143
8.3
0.0001
63
135
133
−0.7
0.7421





(33.0)
(36.0)



(31.0)
(42.0)












AMR 101 4 g + statin
















Median






AMR 101 2 g + statin

% chg

Diff
p value


















Diabetes
Diff from
p value from



from
p from
from
from


Parameter
(Yes/No)
pbo
pbo [4]
n [1]
BL [2]
EOT [3]
BL
BL
pbo
pbo [4]





TG
Yes
−9.8
0.0074
165
262.0
216.5
−18.7
<0.0001
−23.2
<0.0001


(mg/dL)




(92.0)
(88.0)



No
−10.8
0.0261
61
271.5
234.5
−15.0
<0.0001
−16.8
0.0005







(114.5)
(90.0)


LDL-C
Yes
−3.8
0.1482
165
81.0
83.0
2.0
0.2403
−6.3
0.0227


(mg/dL)




(26.0)
(29.0)



No
−3.1
0.3161
60
83.0
83.5
1.4
0.4317
−5.3
0.1402







(23.0)
(37.0)


Non-HDL-
Yes
−4.4
0.0723
165
128
121
−5.5
0.0317
−14.4
<0.0001


C (mg/dL)




(35.0)
(40.0)



No
−8.6
0.0108
61
131
126
−0.9
0.3032
−11.3
0.0003







(38.0)
(38.0)





The median differences between the treatment groups were estimated with the Hodges-Lehmann method.


[1]. Only patients with both baseline and Week 12 endpoint values are included.


[2]. Baseline for TG was defined as the average of the measurements at Visit 4 (Week 0) and the preceding lipid qualifying visit (either Visit 3 [Week−1] or if it occurred, Visit 3.1) measurements. If the measurement at 1 visit was missing, the other visit measurement was used. If the measurements at both visits were missing, the last valid measurement prior to dosing with study drug was used as the baseline value. Baseline for other parameters were defined as the Visit 4 (Week 0) measurement. If missing, the last valid measurement prior to dosing with study drug was used.


[3]. For TG: the Week 12 endpoint was defined as the average of measurements at Visit 6 (Week 11) and Visit 7 (Week 12). If the measurement at 1 visit was missing, the other visit measurement was used. If the measurements at both visits were missing, the last valid post-baseline measurement during the double-blind treatment period was used as the endpoint measurement. For other lipid parameters, the Week 12 endpoint was defined as the Visit 7 (Week 12) measurement. If missing, the LOCF method was used.


[4]. P-value is from the Wilcoxon rank-sum test.


BL = Baseline;


pbo = placebo;


EOT = end of treatment (Week 12 endpoint);


IQR = interquartile range;


LOCF = last observation carried forward;


Q1 = first quartile;


Q3 = third quartile.






Table 16 shows lipid changes in placebo-treated subjects in various clinical trials in the MITT group.







TABLE 16





Lipid changes in placebo-treated subjects in various clinical trials-MITT.



























Central




Study/Active


Background
Lead-in
tendency
Duration


drug
Population
Placebo
statin therapy
period
measure
of PBO
n










Very high TG population (≧500 mg/dL)














MARINE
TG 500-2000 mg/dL
Mineral
25% on
4 to 6 wks
Median %
  12 wks
75


Icosapent Ethyl1

oil
statin

CFB


Harris Pownall
TG 500-2000 mg/dL
Corn oil
No
6 wks
Median %
6-16 wks
42


pooled analysis/




CFB


Omega 3 acid


Ethyl Esters2,3


Goldberg4/
TG 500-1500 mg/dL
Yes
No
6 to 12
Mean %
  8 wks
44


Fenofibrate



weeks
CFB







High TG population (200-500 mg/dL)














ANCHOR
TG 200-499 mg/dL
Mineral
Simva
6 to 8 wks
Median %
  12 wks
227


Icosapent

oil
Atorva
Stopped all
CFB


Ethyl5


Rosuva +/−
lipid meds





Eze
except statin


COMBOS/
TG 200-499 mg/dL
Corn oil
Simva 40 mg
8 wks stopped
Median %
  8 wks
132


Omega 3 Ethyl



all lipid meds
CFB


Esters6



start simva 40


Goldberg/
TG 350-499 mg/dL
Yes
No
6 to 12
Mean %
  8 wks
28






weeks
CFB


Simvastatin8
Type IV LDL-
Yes
No
4 weeks
Median %
  6 weeks
74



C < 160



CFB



TG > 200


Atorvastatin9
Type IV
Yes
No
Yes duration
Median %
NR
12






not specified
CFB


Rosuvastatin10
Primary htg
Yes
No
6 week
Median %
  6 wks
26







CFB


Niacin ER11
Primary
Yes
No
Not
Mean %
  16 wks
73



hyperlipidemia


specified
CFB



and mixed



dyslipidemia


FIRST/
Mixed
Yes
Atorva up to
2 to 10
Mean %
  24 mos
329


Fenofibric acid12
dyslipidemia

40 mg
weeks
CFB



TG ≧ 150



HDL-C ≦ 45



M or ≦ 55



FLDL-C ≦ 100



















Study/Active










drug
TG
LDLc
nHDLc
TC
HDLc
VLDLc
apo B













Very high TG population (≧500 mg/dL)
















MARINE
+9.7
−3.0
+7.8
+7.7
 0.0
+13.7
+4.3



Icosapent Ethyl1



Harris Pownall
+6.7
−4.8
−3.6
−1.7
 0.0
−0.9
NR



pooled analysis/



Omega 3 acid



Ethyl Esters2,3



Goldberg4/
+7.2
−4.2
NR
+0.4
+5.0
+11.0
NR



Fenofibrate









High TG population (200-500 mg/dL)
















ANCHOR
+5.9
+8.8
+9.8
+9.1
+4.8
+15.0
+7.1



Icosapent



Ethyl5



COMBOS/
−6.3
−2.8
−2.2
−1.7
−1.2
−7.2
−1.9



Omega 3 Ethyl



Esters6



Goldberg/
−0.5
+12.0 
NR
+2.8
+4.0
+5.8
NR



Simvastatin8
−9
+1  
+1
+2
+3  
−7
NR



Atorvastatin9
−12.4
+3.6
−2.8
−2.3
+3.8
−1.0
NR



Rosuvastatin10
+0.8
+4.5
+1.7
+1.2
−2.9
+2.1
−0.2



Niacin ER11
+12
+1  
NR
+2
+2  
NR
+1  



FIRST/
−2*
+2* 
*0
NR
+3* 
NR
NR



Fenofibric acid12
Median




% CFB







NR: not reported;



% CFB: percent change from baseline;



*Results at 13 week timepoint



1Bays HE et al. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multi-center, placebo-controlled, Randomized, double-blind, 12-week study with an open-label Extension MARINE. Am J Cardiol. 2001; 108(5): 682-90.



2Pownall HJ et al. Correlation of serum triglyceride and its reduction by omega-3 fatty acids with lipid transfer activity and the neutral lipid compositions of high-density and low-density lipoproteins. Atherosclerosis 1999; 143: 285-97.



3Harris WS et al. Safety and efficacy of Omacor in severe hypertriglyceridemia. J Cardiovasc Risk 1997; 4(5-6): 385-91.



4Goldberg AC et al. Fenofibrate for the treatment of type IV and type V hyperlipoproteinemias: a double-blind, placebo-controlled multicenter US study. Clin Ther. 1989; 11(1): 69-83.



5Ballantyne CM et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am j Cardiol. 2012; 110(7): 984-92.



6Davidson MH et al. COMBination of prescription Omega-3 with Simvastatin (COMBOS) Investigators. Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week randomized, double-blind, placebo-controlled study. Clin Ther. 2007; 29(7); 1354-67.



7Goldberg AC et al. Fenofibrate for the treatment of type IV and type V hyperlipoproteinemias: a double-blind, placebo-controlled multicenter US study. Clin Ther. 1989; 11(1): 69-83.



8Zocor (simvastatin) Prescribing Information, 2012. Merck Sharp & Dohme Ltd.



9Lipitor (atorvastatin calcium) Prescribing information, 2013. Pfizer Inc.



10Crestor (rosuvastatin calcium) Prescribing information, 2013. AstraZeneca



11NIASPAN (niacin extended-release) Prescribing information, 2013. AbbVie LTD.



12Davidson MH et al. Results from the fenofibric acid on carotid intima-media thickness in subjects with Type IIb dyslipidemia with residual risk in addition to atorvastatin (FIRST) trial. J Am Col Cardiol. 2013; 61(10-2): E1434.






Table 17 shows percent change from baseline and difference from placebo for secondary endpoints in the MITT group.







TABLE 17







Percent change from baseline and difference from placebo for secondary endpoints-MITT.













Week 12




Treat-
Baseline [2]
EP [3]
Percent change from Baseline
Difference from placebo
















ment +

Median
Median
Median


Estimated

Adjusted


Statin
n [1]
(IQR)
(IQR)
(IQR)
(Q1, Q3)
p-value
median
95% CI
p-value [4]










LDL-C (mg/dL)
















Placebo
226
84.0 (27.0)
88.5 (31.0)
8.8 (31.0)
(−7.8, 23.2)
<0.0001
—
—
—


AMR101
234
82.0 (24.0)
87.0 (27.0)
2.4 (26.1)
(−8.3, 17.7)
0.0010
−3.6
(−7.9, 0.5) 
0.0867


2 g/d


AMR101
225
82.0 (25.0)
83.0 (31.0)
1.5 (26.6)
(−11.6, 15.0) 
0.1733
−6.2
(−10.5, −1.7) 
0.0067


4 g/d







Non-HDL-C (mg/dL)
















Placebo
227
128.0 (34.0) 
138.0 (43.0) 
9.8 (27.6)
(−3.5, 24.1)
<0.0001
—
—
—


AMR101
234
128.0 (33.0) 
134.0 (41.0) 
2.4 (26.1)
(−7.0, 19.0)
0.0001
−5.5
(−9.4, −1.7)
0.0140


2 g/d


AMR101
226
128.0 (32.0) 
122.0 (39.0) 
−5.0 (21.3) 
(−13.5, 7.8) 
0.0106
−13.6 
(−17.2, −9.9) 
0.0001


4 g/d







Apo B (mg/dL)
















Placebo
219
91.0 (24.0)
98.0 (25.0)
7.1 (23.2)
(−4.7, 18.6)
<0.0001
—
—
—


AMR101
227
91.0 (22.0)
95.0 (24.0)
1.6 (20.7)
(−6.4, 14.3)
0.0001
−3.8
(−6.9, −0.7)
0.0170


2 g/d


AMR101
217
93.0 (23.0)
90.0 (25.0)
−2.2 (16.4) 
(−10.2, 6.2) 
0.0759
−9.3
(−12.3, −6.1) 
0.0001


4 g/d







VLDL-C (mg/dL)
















Placebo
226
42.0 (21.0)
49.0 (28.0)
15.0 (58.8) 
(−10.9, 47.8) 
<0.0001
—
—
—


AMR101
233
43.0 (21.0)
44.0 (25.0)
1.6 (54.6)
(−20.0, 34.5) 
0.0287
−10.5 
(−18.3, −2.5) 
0.0170


2 g/d


AMR101
225
44.0 (21.0)
38.0 (22.0)
−12.1 (47.9) 
(−31.3, 16.7) 
0.0043
−24.4 
(−31.9, −17.0)
0.0001


4 g/d







Lp-PLA2 (mg/mL)
















Placebo
213
185.0 (58.0) 
200.0 (71.0) 
6.7 (24.0)
(−6.4, 17.6)
<0.0001
—
—
—


AMR101
224
190.0 (55.5) 
183.5 (57.5) 
−1.8 (23.1) 
(−12.7, 10.4) 
0.2686
−8.0
(−11.6, −4.5) 
0.0004


2 g/d


AMR101
217
180.0 (56.0) 
160.0 (57.0) 
−12.8 (18.5) 
(−22.1, −3.6) 
<0.0001
−19.0 
(−22.2, −15.7)
0.0001


4 g/d





[1]. Only patients with non-missing baseline and Week 12 endpoint values were included.


[2]. Baseline was defined as the Visit 4 (Week 0) measurement. If missing, the last valid measurement prior to dosing with study drug was used.


[3]. The Week 12 endpoint was defined as the Visit 7 (Week 12) measurement. If missing, the LOCF method was used.


[4]. The adjusted p-value was obtained from applying Hommel's multiple comparison procedure to the p-value from the treatment comparison between the AMR101 4 g or 2 g with placebo with exception of LDL-C


CI = confidence interval;


EP = endpoint;


IQR = interquartile range;


Q1 = first quartile;


Q3 = third quartile






Table 18 shows percent change from baseline and difference from placebo for lipid exploratory endpoints in the MITT group.







TABLE 18







Percent Change from Baseline and Difference from Placebo for Lipid Exploratory Endpoints-MITT Population.













Week 12





Baseline [2]
EP [3]
Percent change from Baseline
Difference from placebo
















Treatment +

Median
Median
Median


Estimated




Statin
n [1]
(IQR)
(IQR)
(IQR)
(Q1, Q3)
p-value
median
95% CI
p-value










Total cholesterol (mg/dL)
















Placebo
227
168.0 (38.0) 
181.0 (46.0)
9.1 (20.8)
(−1.4, 19.4)
<0.0001
—
—
—


AMR101
234
169.0 (34.0) 
175.0 (44.0)
2.1 (19.6)
(−4.4, 15.2)
<0.0001
−4.8
 (−7.8, −1.8)
0.0019


2 g/d


AMR101
226
167.0 (38.0) 
162.0 (38.0)
−3.2 (16.8) 
(−11.3, 5.5) 
0.0023
−12.0 
(−14.9, −9.2)
<0.0001 


4 g/d







HDL-C (mg/dL)
















Placebo
227
39.0 (12.0)
 40.0 (14.0)
4.8 (22.0)
(−7.7, 14.3)
<0.0001
—
—
—


AMR101
234
38.0 (13.0)
 38.0 (11.0)
  0 (19.5)
(−7.7, 11.8)
0.0164
−2.2
(−4.9, 0.5)
0.1265


2 g/d


AMR101
226
37.0 (12.0)
 37.0 (13.0)
−1.0 (18.2) 
(−8.7, 9.5) 
0.8474
−4.5
(−7.4, −1.8)
0.0013


4 g/d







VLDL-TG (mg/dL)
















Placebo
226
183.0 (94.0) 
 196.0 (136.0)
8.9 (63.8)
(−19.3, 44.5) 
<0.0001
—
—
—


AMR101
233
185.0 (86.0) 
168.0 (98.0)
−2.1 (48.9) 
(−26.3, 22.6) 
0.8897
−11.3 
(−19.4, −3.4)
0.0049


2 g/d


AMR101
225
190.0 (99.0) 
147.0 (88.0)
−19.2 (46.2) 
(−39.2, 7.0) 
<0.0001
−26.5 
 (−33.9, −19.0)
<0.0001 


4 g/d







Apo A1 (mg/dL)
















Placebo
219
140.0 (35.0) 
145.0 (34.0)
3.6 (14.9)
(−2.1, 12.1)
<0.0001
—
—
—


AMR101
227
140.0 (26.0) 
141.0 (26.0)
2.0 (13.0)
(−4.0, 9.0) 
0.0007
−1.7
(−3.7, 0.3)
0.0943


2 g/d


AMR101
217
141.0 (31.0) 
137.0 (29.0)
−2.9 (12.6) 
(−9.6, 3.1) 
<0.0001
−6.9
 (−8.9, −4.9)
<0.0001 


4 g/d







Apo B/ApoA1 ratio
















Placebo
219
0.7 (0.2)
 0.7 (0.2)
2.4 (21.7)
(−7.8, 13.9)
0.0028
—
—
—


AMR101
227
0.7 (0.2)
 0.7 (0.2)
0.1 (18.3)
(−7.9, 10.4)
0.2523
−2.0
(−5.0, 0.9)
0.1886


2 g/d


AMR101
217
0.7 (0.2)
 0.7 (0.2)
−0.7 (20.3) 
(−8.1, 12.2)
0.4097
−2.4
(−5.4, 0.8)
0.1333


4 g/d







Lp(a) (mg/dL)
















Placebo
83
12.0 (31.0)
 12.0 (37.0)
0.0 (35.0)
(−8.3, 26.7)
0.0452
—
—
—


AMR101
83
11.0 (33.0)
 12.0 (33.0)
0.0 (24.9)
(−2.5, 22.4)
0.0011
 0.0
(−2.5, 8.3)
0.5466


2 g/d


AMR101
81
 7.0 (33.0)
 9.0 (31.0)
0.0 (10.0)
(−6.5, 3.4) 
0.4722
 0.0
(−8.3, 0.0)
0.3626


4 g/d







RLP-C (mg/dL)
















Placebo
86
14.0 (7.0) 
13.0 (9.0)
8.0 (66.9)
(−29.4, 37.5) 
0.1316
—
—
—


AMR101
84
15.0 (7.0) 
11.0 (7.0)
−11.1 (40.0) 
(−30.0, 10.0) 
0.0124
−16.7 
(−30.0, 10.0)
0.0153


2 g/d


AMR101
82
13.5 (6.0) 
10.0 (6.0)
−24.0 (45.5) 
(−45.5, 0.0) 
0.0002
−25.8 
 (−39.9, −12.4)
0.0001


4 g/d







Oxidized LDL (U/L)
















Placebo
84
51.8 (16.8)
 59.7 (18.1)
11.6 (28.1) 
(−4.0, 24.1)
<0.0001
—
—
—


AMR101
75
54.0 (17.8)
 55.8 (22.8)
2.6 (18.3)
(−4.5, 13.8)
0.0245
−5.8
(−11.9, 0.9) 
0.0946


2 g/d


AMR101
78
54.0 (14.6)
 51.4 (17.5)
−4.8 (19.6) 
(−11.5, 8.1) 
0.0610
−13.3 
(−19.3, −7.5)
<0.0001 


4 g/d





[1]. Only patients with non-missing baseline and Week 12 endpoint values were included.


[2]. Baseline was defined as the Visit 4 (Week 0) measurement. If missing, the last valid measurement prior to dosing with study drug was used.


[3]. The Week 12 endpoint was defined as the Visit 7 (Week 12) measurement. If missing, the LOCF method was used.


CI = confidence interval;


EP = endpoint;


IQR = interquartile range;


Q1 = first quartile;


Q3 = third quartile






Table 19 shows change from baseline and difference from placebo for LDL Particle Concentration and Size in the MITT group.







TABLE 19







Change from Baseline and Difference from Placebo for LDL Particle


Concentration and Size-MITT Population.












Baseline
Week 12 EP
Percent change from Baseline
Difference from placebo
















Treatment +

[2] Median
[3] Median
Median


Estimated




Statin
n [1]
(IQR)
(IQR)
(IQR)
(Q1, Q3)
p-value
median
95% CI
p-value










LDL Particle Concentration (nmol/L)
















Placebo
211
1152.0
1287.0
11.9 (31.6)
(−3.0, 28.6)
<0.0001
—
—
—




(353.0)
(456.0)


AMR101
222
1170.5
1215.0
 4.7 (29.2)
(−10.3, 18.9)
0.0008
−7.5
(−12.1, −2.9)
0.0013


2 g/d

(349.0)
(355.0)


AMR101
216
1130.5
1190.5
 3.8 (31.8)
(−11.0, 20.8)
0.0016
−7.7
(−12.3, −2.8)
0.0017


4 g/d

(369.5)
(512.0)







LDL Particle Size (nm)
















Placebo
211
19.8
19.9
0.0 (2.5)
(−1.0, 1.5)
0.3037
—
—
—




(0.6)
(0.5)


AMR101
221
19.8
20.0
0.5 (2.5)
(−0.5, 2.0)
<0.0001
 0.5
(0.5, 1.0)
0.0007


2 g/d

(0.5)
(0.6)


AMR101
215
19.8
20.0
0.5 (2.5)
(−0.5, 2.0)
<0.0001
 0.5
(0.0, 1.0)
0.0031


4 g/d

(0.5)
(0.6)





[1]. Only patients with non-missing baseline and Week 12 endpoint values were included.


[2]. Baseline was defined as the Visit 4 (Week 0) measurement. If missing, the last valid measurement prior to dosing with study drug was used.


[3]. The Week 12 endpoint was defined as the Visit 7 (Week 12) measurement. If missing, the LOCF method was used.


CI = confidence interval;


EP = endpoint;


IQR = interquartile range;


Q1 = first quartile;


Q3 = third quartile






Table 20 shows change from baseline and difference from placebo for glucose metabolism exploratory endpoints in the MITT group.







TABLE 20







Change from baseline and difference from placebo for glucose metabolism


exploratory endpoints-MITT.











Week 12 EP
Mean Change from Baseline
Difference from placebo
















Treatment +

Baseline [2]
[3] Mean
LS Mean


LS Mean




Statin
n [1]
Mean (SD)
(SD)
(SE)
(95% CI)
p-value
(SE)
95% CI
p-value










Fasting plasma glucose (mg/dL)
















Placebo
219
128.9 (35.2) 
133.7 (38.5) 
 4.2 (2.1)
(0.0, 8.4)
0.0032
—
—
—


AMR101
226
134.8 (42.6) 
138.0 (44.9) 
 3.6 (2.1)
(−0.5, 7.7)
0.0042
−0.6 (3.0) 
(−6.5, 5.3)
0.8408


2 g/d


AMR101
217
133.1 (37.0) 
141.9 (51.1) 
 8.9 (2.1)
(4.7, 13.1)
0.0007
4.7 (3.0)
(−1.2, 10.6)
0.1200


4 g/d







HbA1c (%)
















Placebo
218
6.5 (0.9)
6.7 (1.1)
 0.2 (0.04)
(0.1, 0.2)
<0.0001
—
—
—


AMR101
228
6.7 (1.1)
6.8 (1.2)
 0.2 (0.04)
(0.1, 0.2)
<0.0001
−0.0 (0.05)
(−0.1, 0.1)
0.9392


2 g/d


AMR101
220
6.6 (0.9)
6.9 (1.1)
0.3 (0.04)
(0.2, 0.3)
<0.0001
 0.1 (0.05)
(−0.0, 0.3)
0.0899


4 g/d







Insulin (μIU/mL)
















Placebo
215
23.0 (33.1)
20.1 (17.5)
−1.2 (0.9)
(−2.9, 0.6)
0.1568
—
—
—


AMR101
217
18.6 (11.5)
18.6 (11.0)
−1.2 (0.9)
(−3.0, 0.5)
0.5685
−0.1 (1.3) 
(−2.6, 2.4)
0.9567


2 g/d


AMR101
215
19.6 (16.0)
19.0 (16.2)
−1.1 (0.9)
(−2.9, 0.6)
0.9601
0.0 (1.3)
(−2.5, 2.5)
0.9874


4 g/d







HOMA-IR
















Placebo
215
 8.1 (16.4)
6.9 (6.9)
−0.4 (0.4)
(−1.2, 0.3)
0.4806
—
—
—


AMR101
217
6.4 (4.8)
6.4 (4.5)
−0.6 (0.4)
(−1.3, 0.2)
0.4192
−0.1 (0.5) 
(−1.2, 0.9)
0.8022


2 g/d


AMR101
213
6.8 (7.0)
6.9 (6.7)
−0.1 (0.4)
(−0.8, 0.7)
0.2462
0.3 (0.6)
(−0.7, 1.4)
0.5225


4 g/d





[1]. Only patients with non-missing baseline and Week 12 endpoint values were included.


[2]. Baseline was defined as the Visit 4 (Week 0) measurement. If missing, the last valid measurement prior to dosing with study drug was used.


[3]. The Week 12 endpoint was defined as the Visit 7 (Week 12) measurement. If missing, the LOCF method was used.


LS means, SE, CI, and p-values are from linear contrasts of an ANCOVA model of change from baseline to Week 12 EP with treatment as a factor and baseline value as a covariate.


CI = confidence interval;


EP = endpoint;


SE = standard error;


SD = standard deviation






Table 21 shows change from baseline and difference from placebo for inflammatory biomarkers in the MITT group.







TABLE 21





Change from Baseline and Difference from Placebo for Inflammatory


Biomarkers-MITT.




















Baseline
Week 12 EP
Percent change from Baseline
Difference from placebo
















Treatment +

[2] Median
[3] Median
Median


Estimated




Statin
n [1]
(IQR)
(IQR)
(IQR)
(Q1, Q3)
p-value
median
95% CI
p-value










ICAW-1 (ng/mL)
















Placebo
83
269.0 (122.0)
257.0 (131.0)
 9.0 (31.0)
(−6.0, 25.0)
0.0085
—
—
—


AMR101
74
267.0 (97.0) 
268.5 (89.0) 
 1.5 (37.0)
(−15.0, 22.0)
0.3718
−6.0
(−15.0, 3.0)
0.2086


2 g/d


AMR101
78
273.0 (96.0) 
270.0 (110.0)
 2.5 (40.0)
(−18.0, 22.0)
0.4487
−6.0
(−16.0, 4.0)
0.1910


4 g/d







IL-6 (pg/mL)
















Placebo
83
3.2 (3.2)
2.9 (3.0)
0.1 (1.8)
(−0.8, 0.9)
0.6566
—
—
—


AMR101
74
2.4 (2.0)
2.7 (2.3)
0.2 (1.3)
(−0.4, 0.9)
0.1344
0.1
(−0.3, 0.6)
0.5979


2 g/d


AMR101
78
2.7 (2.6)
2.6 (2.1)
0.1 (1.8)
(−1.0, 0.8)
0.9920
−0.1
(−0.6, 0.4)
0.7608


4 g/d







PAI-1 (ng/mL)
















Placebo
54
72.2 (62.0)
86.4 (60.7)
−1.7 (73.3)
(−29.1, 44.2)
0.8618
—
—
—


AMR101
50
28.1 (58.1)
90.3 (67.4)
14.6 (38.8)
(−8.7, 30.1)
0.0551
12.1
(−9.1, 29.4)
0.2631


2 g/d


AMR101
55
84.7 (73.5)
85.6 (86.3)
−3.1 (45.2)
(−24.2, 21.0)
0.9967
0.6
(−16.7, 17.8)
0.9420


4 g/d










hsCRP (mg/L)[4]


















Baseline
Week 12 EP
Median %







Treatment +

[2] Median
[3] Median
Chg from


Estimated


Statin
n[1]
(IQR)
(IQR)
BL
(Q1, Q3)
p-value
median
95% CI
p-value





Placebo
219
2.2 (4.0)
2.6 (4.7)
 17.1 (108.0)
(−26.5, 81.5)
<0.0001
—
—
—


AMR101
227
1.9 (2.9)
2.5 (3.4)
10.3 (88.6)
(−24.3, 64.3)
<0.0001
−6.8
(−20.0, 6.0)
0.2889


2 g/d


AMR101
217
2.2 (2.7)
2.0 (3.0)
−2.4 (62.8)
(−29.4, 33.3)
0.5544
−22.0
(−34.1, −9.4)
0.0005


4 g/d





[1]. Only patients with non-missing baseline and Week 12 endpoint values were included.


[2]. Baseline was defined as the Visit 4 (Week 0) measurement. If missing, the last valid measurement prior to dosing with study drug was used.


[3]. The Week 12 endpoint was defined as the Visit 7 (Week 12) measurement. If missing, the LOCF method was used.


4. Post-hoc analysis of hsCRP based on median percent change from baseline p-values are from Wilcoxon rank-sum test. When hsCRP = <0.2, 0.1 was imputed for the analysis.


CI = confidence interval;


EP = endpoint;


IQR = interquartile range;


Q1 = first quartile;


Q3 = third quartile






Table 22 shows changes in EPA concentration from baseline to week 12 in the MITT group.







TABLE 22





Changes in EPA Concentration from Baseline to Week 12 - MITT.


















Placebo












Week 12
LS Mean
AMR101 2 g
















Baseline [2]
Endpoint [3]
Change (SE)

Baseline [3]
Week 12




Mean
Mean
[4] From

Mean
Endpoint [4]


Parameter
n [1]
(SD)
(SD)
Baseline
n [1]
(SD)
Mean (SD)





Plasma EPA concentration
81
28.1 (28.01)
30.6 (27.90)
8.1 (6.59)
73
28.1 (13.71)
123.8 (67.82)


(μg/mL)


RBC EPA concentration
79
11.2 (6.64) 
9.9 (5.70)
0.4 (2.38)
71
10.9 (5.21) 
 43.7 (16.84)


(μg/mL)













AMR101 2 g
AMR101 4 g















LS Mean



LS Mean




Change (SE) [5]

Baseline [3]
Week 12
Change (SE) [5]




From

Mean
Endpoint [4]
From



Parameter
Baseline
n [2]
(SD)
Mean (SD)
Baseline







Plasma EPA concentration
100.5 (6.83)
71
28.1 (18.79)
182.6 (71.73)
159.5 (6.95)



(μg/mL)



RBC EPA concentration
 34.6 (2.48)
69
11.6 (5.56) 
 72.7 (31.49)
 62.8 (2.55)



(μg/mL)







Outliers were identified within each treatment group as percent change values <Q1 − 1.5 * IQR or >Q3 + 1.5 * IQR. Patients with outliers were excluded from the analysis.



When LLOQ was <10.0, 5 μg/mL was imputed for analysis. When LLOQ was <5.00, 2.5 μg/mL was imputed for analysis.



[1]. Only patients with non-missing baseline and Week 12 endpoint values were included.



[2]. Baseline was defined as the Visit 4 (Week 0) measurement. If missing, the last valid measurement prior to dosing with study drug was used.



[3]. The Week 12 endpoint was defined as the Visit 7 (Week 12) measurement. If missing, the LOCF method was used.



[4]. Least-squares means and SEs were from linear contrasts of an ANCOVA model of change from baseline to Week 12 endpoint, with treatment, gender, type of stain, and presence of diabetes as factors and baseline value as a covariate.



ANCOVA = analysis of covariance;



EPA = eicosapentaenoic acid;



IQR = interquartile range;



LLOQ = lower limit of quantitation;



LOCF = last observation carried forward;



LS = least squares;



Q1 = first quartile;



Q3 = third quartile;



RBC = red blood cell;



SD = standard deviation;



SE = standard error.






These data demonstrate that administration of 4 g per day of ethyl eicosapentaenoate for 12 weeks resulted in atherogenic particle concentrations that correlate with Apo B and, compared with placebo and relative to baseline, reduce key atherogenic lipoprotein particle concentrations and produce potentially beneficial reductions in FADI in statin-treated subjects at high atherosclerotic coronary heart disease risk.
Example 2
Effects of High Purity Ethyl-EPA on Lipoprotein Particle Concentration and Size
The reductions in lipoprotein particle concentration and size for all randomized subjects in the populations of Example 1 who had a baseline triglyceride primary efficacy end point measurement, received at least one dose of the ethyl EPA study drug or placebo, and had at least one post-randomization efficacy measurement were studied.
As shown in Table 23, this subset of subjects had similar baseline triglycerides, LDL-C, non-HDL-C, HDL-C and Apo-B levels to the ITT population of Example 1. Subjects in this subset who received 4 g/day of >96% ethyl-EPA of Example 1 (“IPE”) experienced similar significant reductions in triglycerides, LDL-C, non-HDL-C, HDL-C and Apo-B versus placebo at 12 weeks that the larger ITT population of Example 1 experienced in the same time period.







TABLE 23







Median Changes in Selected Lipid End Points After 12 Weeks - Patients


with Lipoprotein Data.













Median





Change



IPE 4 g/day
Placebo
From



(n = 216)
(n = 211)
Baseline

















Change


Change
IPE 4 g/day


Lipid End Point

End of
From

End of
From
vs Placebo,


(mg/dL)
Baseline
Treatment
Baseline, %
Baseline
Treatment
Baseline, %
%, P

















TG
264.8
219.3
−17.5
258.0
267.5
4.8
−21.1



(90.3)
(91.3)
(30.4)
(80.5)
(141.0)
(43.6)
<0.0001


LDL-C*
82.0
83.0
2.1
84.0
88.0
7.7
−5.2



(24.0)
(31.0)
(27.0)
(27.0)
(31.0)
(31.2)
0.0225


Non-HDL-C
128.0
122.0
−5.1
128.0
136.0
9.8
−13.5



(32.5)
(37.0)
(21.4)
(34.0)
(42.0)
(27.2)
<0.0001


HDL-C
38.0
36.5
−2.2
39.0
40.0
5.2
−5.0



(12.0)
(13.0)
(18.5)
(12.0)
(14.0)
(22.0)
0.0005


Apo-B
92.5
90.0
−2.2
92.0
98.0
7.0
−8.8



(23.5)
(25.5)
(16.5)
(25.0)
(25.0)
(23.0)
<0.0001





Data are presented as median (interquartile range) for end point values.


Median percent changes versus placebo are Hodges-Lehmann medians.


Apo-B, apolipoprotein B;


HDL-C, high-density lipoprotein cholesterol;


IPE, icosapent ethyl;


LDL-C, low-density lipoprotein cholesterol;


TG, triglycerides.


*n = 210 for placebo.






As shown in Table 24, subjects receiving 4 g/day of the >96% ethyl-EPA composition for 12 weeks also had significantly reduced concentrations of total VLDL particles, large VLDL particles, medium VLDL particles, total LDL particles, small LDL particles, total HDL particles and large HDL particles compared to placebo. The treated subjects also had significantly increased large LDL particle concentration compared to placebo after 12 weeks. Treated subjects also had significantly reduced VLDL particle size, significantly reduced HDL particle size, and slightly increased LDL particle size compared to placebo after 12 weeks.







TABLE 24







Median Changes in Lipoprotein Particle Concentration and Size After


12 Weeks-Patients with Lipoprotein Data.











IPE 4 g/day
Placebo
Median



(n = 216)
(n = 211)
Change From

















Change


Change
Baseline




End of
From

End of
From
IPE 4 g/day vs



Baseline
Treatment
Baseline, %
Baseline
Treatment
Baseline, %
Placebo, %, P











Lipoprotein Particle Concentration














Total VLDL,
116.7
110.0
−2.5
111.2
122.0
7.9
−12.2


nmol/L
(66.6)
(78.0)
(41.8)
(50.6)
(60.0)
(40.1)
0.0002


Large
12.9
7.7
−41.9
12.9
14.1
6.0
−46.4


VLDL,
(10.7)
(7.6)
(57.2)
(9.7)
(13.2)
(101.1)
<0.0001


nmol/L


Medium
54.8
49.7
−6.9
53.3
58.8
9.2
−12.1


VLDL,
(37.2)
(41.8)
(59.3)
(29.9)
(36.1)
(56.3)
0.0068


nmol/L


Small
43.9
46.8
8.3
41.4
45.3
8.5
2.8


VLDL,
(36.8)
(39.9)
(81.8)
(32.8)
(37.4)
(70.0)
0.6321


nmol/L


Total LDL,
1131
1191
3.8
1152
1287
11.9
−7.7


nmol/L
(369.5)
(512.0)
(31.8)
(353.0)
(456.0)
(31.6)
0.0017


IDL,
51.5
63.0
23.7
55.0
55.0
0.0
10.0


nmol/L
(81.5)
(94.0)
(173.7)
(88.0)
(102.0)
(194.8)
0.3051


Large LDL,
113.5
172.5
55.2
113.0
166.0
30.6
34.2


nmol/L
(198.5)
(226.0)
(241.0)
(215.0)
(271.0)
(200.4)
0.0076


Small LDL,
894.0
902.5
−1.1
902.0
978.0
11.0
−13.5


nmol/L
(266.5)
(387.5)
(36.1)
(323.0)
(387.0)
(39.0)
<0.0001


Total HDL,
34.3
32.6
−4.0
34.8
35.5
4.7
−7.4


μmol/L
(8.9)
(8.2)
(16.4)
(10.1)
(9.3)
(16.2)
<0.0001


Large HDL,
2.5
1.9
−21.6
2.8
2.9
9.1
−31.0


μmol/L
(1.8)
(2.0)
(58.1)
(2.0)
(2.3)
(50.4)
<0.0001


Medium
6.7
6.9
4.2
7.8
8.3
8.6
−6.5


HDL,
(6.0)
(4.8)
(69.4)
(5.6)
(7.3)
(81.8)
0.2245


μmol/L


Small HDL,
24.2
23.1
−3.9
23.0
24.0
1.6
−2.8


μmol/L
(6.4)
(6.7)
(21.9)
(8.1)
(7.4)
(25.4)
0.1267







Lipoprotein Particle Size














VLDL,
56.3
51.2
−8.1
56.5
55.9
−0.6
−7.7


nm
(8.3)
(8.4)
(13.7)
(10.0)
(11.3)
(14.3)
<0.0001


LDL,*
19.8
20.0
0.5
19.8
19.9
0.0
0.5


nm
(0.5)
(0.6)
(2.5)
(0.6)
(0.5)
(2.5)
0.0031


HDL,
8.7
8.6
−1.1
8.7
8.7
0.0
−1.2


nm
(0.3)
(0.2)
(3.5)
(0.3)
(0.4)
(3.5)
0.0014





Data are presented as median (interquartile range) for end point values.


Median percent change versus placebo are Hodges-Lehmann medians.


Diameter as follows: large VLDL (>60 nm); medium VLDL (42-60 nm); small VLDL (29-42 nm); IDL (23-29 nm); large LDL (20.5-23.0 nm); small LDL (18.0-20.5 nm); large HDL (9.4-14.0 nm); medium HDL (8.2-9.4 nm); and small HDL (7.3-8.2 nm).


HDL, high-density lipoprotein;


IDL, intermediate-density lipoprotein;


IPE, icosapent ethyl;


LDL, low-density lipoprotein;


VLDL, very-low-density lipoprotein.


*n = 215 for IPE 4 g/day.






Atherogenic particle concentration (e.g., concentration of all VLDL and LDL particles) correlated well with ApoB concentrations at both baseline (FIG. 6A) and after 12 weeks (FIG. 6B). Similarly, total LDL particle concentrations correlated strongly with ApoB concentrations at both baseline (FIG. 6C) and after 12 weeks (FIG. 6D).

## Claims

1. A method of lowering triglycerides in a subject on statin therapy having baseline fasting triglycerides of about 200 mg/dl to less than 500 mg/dl, the method comprising determining a baseline fasting triglyceride level and a baseline fasting apolipoprotein B (“Apo B”) level of about 217 mg/dl or about 227 mg/dl associated with the subject; and thereafter administering to the subject about 2 grams or about 4 grams per day of ethyl eicosapentaenoate, wherein after the administering an Apo B level associated with the subject is lower than the baseline fasting Apo B level compared to a second subject who has received statin therapy but not the ethyl eicosapentaenoate.

2. The method of claim 1 further comprising determining a baseline fasting low-density lipoprotein cholesterol (“LDL-C”) level associated with the subject before the administering, wherein an LDL-C level associated with the subject after the administering is not increased compared to the baseline fasting LDL-C level.

3. The method of claim 1, wherein the subject is administered about 2 grams per day of ethyl eicosapentaenoate, and wherein the triglycerides are lowered by about 10% compared to a second subject who has received statin therapy but not the ethyl eicosapentaenoate.

4. The method of claim 2, wherein the subject is administered about 2 grams per day of ethyl eicosapentaenoate, and wherein the triglycerides are lowered by about 10% compared to a second subject who has received statin therapy but not the ethyl eicosapentaenoate.

5. The method of claim 1, wherein the subject is administered about 4 grams per day of ethyl eicosapentaenoate, and wherein the triglycerides are lowered by about 21% compared to a second subject who has received statin therapy but not the ethyl eicosapentaenoate.

6. The method of claim 2, wherein the subject is administered about 4 grams per day of ethyl eicosapentaenoate, and wherein the triglycerides are lowered by about 21% compared to a second subject who has received statin therapy but not the ethyl eicosapentaenoate.

7. A method of lowering triglycerides in a subject on statin therapy having baseline fasting triglycerides of about 200 mg/dl to less than 500 mg/dl, the method comprising determining a baseline fasting triglyceride level and a baseline fasting very low-density lipoprotein cholesterol (“VLDL-C”) level of about 225 mg/dl or about 233 mg/dl associated with the subject, and thereafter administering to the subject about 2 grams or about 4 grams per day of ethyl eicosapentaenoate, wherein after the administering an VLDL-C level associated with the subject is lower than the baseline fasting VLDL-C level compared to a second subject who has received statin therapy but not the ethyl eicosapentaenoate.

8. A method of lowering triglycerides in a subject on statin therapy having baseline fasting triglycerides of about 200 mg/dl to less than 500 mg/dl, the method comprising determining a baseline fasting triglyceride level and a baseline fasting lipoprotein-associated phospholipase A2 (“LP-PLA2”) level of about 217 mg/dl or about 224 mg/dl associated with the subject, and thereafter administering to the subject about 2 grams or about 4 grams per day of ethyl eicosapentaenoate, wherein after the administering an LP-PLA2 level associated with the subject is lower than the baseline fasting LP-PLA2 level compared to a second subject who has received statin therapy but not the ethyl eicosapentaenoate.

9. A method of lowering triglycerides in a subject on statin therapy having baseline fasting triglycerides of about 200 mg/dl to less than 500 mg/dl, the method comprising determining a baseline fasting triglyceride level, a baseline fasting LDL-C level of about 82 mg/dl, a fasting baseline Apo B level of about 217 mg/dl or about 227 mg/dl, a fasting baseline VLDL-C level of about 225 mg/dl or about 233 mg/dl, and a fasting baseline Lp-PLA2 level of about 217 mg/dl or about 224 mg/dl associated with the subject, wherein after the administering levels of LDL-C, Apo B, VLDL-C and Lp-PLA2 associated with the subject are lower than the baseline fasting levels compared to a second subject who has received statin therapy but not the ethyl eicosapentaenoate.

10. The method of claim 9, wherein the subject receives about 2 grams of ethyl eicosapentaenoate per day.

11. The method of claim 9, wherein the subject receives about 4 grams of ethyl eicosapentaenoate per day.

12. The method of claim 2, wherein the subject has a baseline fasting LDL-C level of about 82 mg/dl.