WO2013070735A1 - Methods of treating hypertriglyceridemia - Google Patents
Methods of treating hypertriglyceridemia Download PDFInfo
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- WO2013070735A1 WO2013070735A1 PCT/US2012/063909 US2012063909W WO2013070735A1 WO 2013070735 A1 WO2013070735 A1 WO 2013070735A1 US 2012063909 W US2012063909 W US 2012063909W WO 2013070735 A1 WO2013070735 A1 WO 2013070735A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Definitions
- Cardiovascular disease is one of the leading causes of death in the United
- cardiovascular disease or disorder including but not limited to high blood pressure, coronary heart disease, dislipidemia, congestive heart failure and stroke.
- the present invention provides methods of treating and/or preventing cardiovascular-related diseases and, in particular, a method of blood lipid therapy comprising administering to a subject in need thereof a pharmaceutical composition comprising eicosapentaenoic acid or a derivative thereof.
- the composition contains not more than 10%, by weight, docosahexaenoic acid or derivative thereof, substantially no docosahexaenoic acid or derivative thereof, or no docosahexaenoic acid or derivative thereof.
- eicosapentaenoic acid ethyl ester comprises at least 96%>, by weight, of all fatty acids present in the composition; the composition contains not more than 4%, by weight, of total fatty acids other than
- the composition contains about 0.1% to about 0.6% of at least one fatty acid other than eicosapentaenoic acid ethyl ester and docosahexaenoic acid (or derivative thereof).
- a pharmaceutical composition useful in accordance with the invention comprises, consists of or consists essentially of at least 95% by weight ethyl eicosapentaenoate (EPA-E), about 0.2% to about 0.5% by weight ethyl octadecatetraenoate (ODTA-E), about 0.05% to about 0.25% by weight ethyl nonaecapentaenoate (NDPA-E), about 0.2% to about 0.45% by weight ethyl arachidonate (AA-E), about 0.3% to about 0.5% by weight ethyl eicosatetraenoate (ETA-E), and about 0.05% to about 0.32% ethyl heneicosapentaenoate (HPA-E).
- the composition is present in a capsule shell.
- the composition contains substantially no or no amount of docosahexaenoic acid (DHA) or derivative thereof such as ethyl
- the invention provides a method of treating moderate to severe hypertriglyceridemia comprising administering a composition as described herein to a subject in need thereof one to about four times per day.
- the invention provides a method of treating moderate to severe hypertriglyceridemia comprising administering to a subject about 2 g to about 4 g per day of EPA (e.g., ethyl)
- EPA e.g., ethyl
- eicosapentaenoate for example about 3.8 g to about 4 g per day.
- Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.
- the invention provides a method for treatment and/or prevention of a cardiovascular-related disease.
- 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.
- 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.
- 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.
- the present invention provides a method of blood lipid therapy comprising administering to a subject or subject group in need thereof a
- the subject or subject group has hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia and/or very high triglycerides.
- the subject or subject group being treated has a baseline triglyceride level (or median baseline triglyceride level in the case of a subject group), fed or fasting, of at least about 300 mg/dl, at least about 400 mg/dl, at least about 500 mg/dl, at least about 600 mg/dl, at least about 700 mg/dl, at least about 800 mg/dl, at least about 900 mg/dl, at least about 1000 mg/dl, at least about 1100 mg/dl, at least about 1200 mg/dl, at least about 1300 mg/dl, at least about 1400 mg/dl, or at least about 1500 mg/dl, for example about 400 mg/dl to about 2500 mg/dl, about 450 mg/dl to about 2000 mg/dl or about
- the subject or subject group being treated in accordance with methods of the invention has previously been treated with Lovaza® and has experienced an increase in, or no decrease in, LDL-C levels and/or non-HDL-C levels.
- Lovaza® therapy is discontinued and replaced by a method of the present invention.
- 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.
- 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%.
- free plasma EPA and/or total fatty acid levels are determined prior to initiating therapy.
- the subject or subject group being treated in accordance with methods of the invention exhibits a fasting baseline absolute plasma level of total fatty acid (or mean thereof) 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.
- 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 70 ⁇ g/ml, not greater than about 60 ⁇ g/ml, not greater than about 50 ⁇ g/ml, not greater than about 40 ⁇ g/ml, not greater than about 30 ⁇ g/ml, or not greater than about 25 ⁇ g/ml.
- 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.
- 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 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 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
- the subject or subject group upon treatment in accordance with the present invention, for example about 2g to about 4 g per day of a composition as described herein 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:
- DHA docosahexaenoic acid
- DP A docosapentaenoic acid
- AA arachidonic acid
- PA palmitic acid
- SA staeridonic acid
- OA oleic acid
- the subject upon administering a composition of the invention to a subject, the subject exhibits a decrease in triglyceride levels, an increase in the concentrations of EPA and DPA (n-3) in red blood cells, and an increase of the ratio of EPA: arachidonic acid in red blood cells.
- the subject upon administering a composition of the invention to a subject, the subject exhibits a decrease in triglyceride levels, an increase in the concentrations of EPA and DPA (n-3) in red blood cells, and an increase of the ratio of EPA: arachidonic acid in red blood cells.
- the subject upon administering a composition of the invention to a subject exhibits a decrease in triglyceride levels, an increase in the concentrations of EPA and DPA (n-3) in red blood cells, and an increase of the ratio of EPA: arachidonic acid in red blood cells.
- the subject upon administering a composition of the invention to a subject exhibits a decrease in triglyceride levels, an increase in
- methods of the present invention comprise measuring baseline levels of one or more markers set forth in (a) - (y) above prior to dosing the subject or subject group.
- the methods comprise administering a composition as disclosed herein to the subject after baseline levels of one or more markers set forth in (a) - (y) are determined, and subsequently taking an additional measurement of said one or more markers.
- composition of the present invention upon treatment with a composition of the present invention, for example about 2g to about 4 g per day of a composition as described herein, about 2 g to about 4 g per day of EPA (e.g., ethyl eicosapentaenoate), or about 3.8 g to about
- EPA e.g., ethyl eicosapentaenoate
- EPA e.g., ethyl eicosapentaenoate
- 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,
- EPA e.g., ethyl eicosapentaenoate
- the subject or subject group upon treatment with a composition of the present invention, exhibits one or more of the following outcomes:
- LDL particle concentration a reduction in small LDL particle concentration of at least about 3%, a reduction in small LDL particle concentration of at least about 6%, or a reduction small LDL particle concentration of at least about 9% (actual % change or median % change) compared to baseline or placebo control;
- a reduction in remnant-like particle 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%, or at least about 100% (actual % change or median % change) compared to baseline;
- FPG fasting plasma glucose
- Aic 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%o, or at least about 50% (actual % change or median % change) compared to baseline;
- methods of the present invention comprise measuring baseline levels of one or more markers set forth in (a) - (aa) prior to dosing the subject or subject group.
- the methods comprise administering a composition as disclosed herein to the subject after baseline levels of one or more markers set forth in (a) - (aa) are determined, and subsequently taking a second measurement of the one or more markers as measured at baseline for comparison thereto.
- compositions of the present invention upon treatment with a composition of the present invention, for example about 2 g to about 4 g per day of a composition as described herein, about 2 g to about 4 g per day of EPA (e.g., ethyl eicosapentaenoate), or about 3.8 g to about 4 g per day of EPA (e.g., ethyl eicosapentaenoate) 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
- Parameters (a) - (aa) can be measured in accordance with any clinically acceptable methodology.
- 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 Al, 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-6 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, 6 th Ed. (Burtis, Ashwood and Borter Eds.), WB Saunders Company.
- subjects fast for up to 12 hours prior to blood sample collection, for example about 10 hours.
- the present invention provides a method of treating or preventing primary hypercholesterolemia and/or mixed dyslipidemia (Fredrickson Types Ila and lib) in a patient in need thereof, comprising administering to the patient one or more compositions as disclosed herein.
- 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).
- 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.
- 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.
- 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.
- the present invention provides a method of treating subjects having very high serum triglyceride levels (e.g. greater than 1000 mg/dl or greater than 2000 mg/dl) and that are at risk of developing pancreatitis, comprising administering to the patient one or more compositions as disclosed herein.
- very high serum triglyceride levels e.g. greater than 1000 mg/dl or greater than 2000 mg/dl
- the present invention provides a method of treating subjects having very high serum triglyceride levels (e.g., greater than 1000 mg/dl or greater than 2000 mg/dl) comprising administering to the subject(s) about 2 g to about 4 g per day of EPA (e.g., ethyl eicosapentaenoate), for example about 3.8 g to about 4 g per day of EPA.
- very high serum triglyceride levels e.g., greater than 1000 mg/dl or greater than 2000 mg/dl
- EPA e.g., ethyl eicosapentaenoate
- the present invention provides a method of reducing large vLDL particle concentration in a subject having a fasting baseline triglyceride level of about 500 mg/dl to about 1500 mg/dl, the method comprising administering to the subject about 2 g to about 4 g per day, or about 3.8 g to about 4 g per day, of ethyl eicosapentaenoate thereby to produce a reduction in large vLDL particle concentration.
- the reduction is statistically significant.
- the reduction in large vLDL particle concentration is in comparison to a baseline large vLDL particle concentration prior to initiation of administration.
- the reduction in large vLDL particle concentration is at least a 2.5% reduction, at least a 10% reduction, at least a 20% reduction, or at least a 24% reduction.
- the subject is administered ethyl eicosapentaenoate for a period of 12 weeks.
- the present invention provides a method of reducing small LDL particle concentration in a subject having a fasting baseline triglyceride level of about 500 mg/dl to about 1500 mg/dl comprising, administering to the subject about 2 g to about 4 g per day of a pharmaceutical composition comprising at least about 96%, by weight, ethyl eicosapentaenoate thereby to produce a reduction in small LDL particle concentration by comparison with a baseline small LDL particle concentration prior to initiation of administration.
- the reduction in small LDL particle concentration is at least a 5% reduction or at least a 9% reduction.
- the subject is administered ethyl eicosapentaenoate for a period of 12 weeks.
- a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of eicosapentaenoic acid of about 2 g to about 4 g, about 3.8 g to about 4 g, 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,
- any of the methods disclosed herein are used in treatment or prevention of a subject or subjects that consume a traditional Western diet.
- 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.
- a composition for use in methods of the invention comprises eicosapentaenoic acid, or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof, or mixtures of any of the foregoing, collectively referred to herein as "EPA.”
- EPA eicosapentaenoic acid
- 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.
- the EPA comprises all-cis eicosa-5, 8,11,14, 17-pentaenoic acid.
- the EPA comprises an eicosapentaenoic acid ester.
- the EPA comprises a Ci - C 5 alkyl ester of eicosapentaenoic acid.
- the EPA comprises eicosapentaenoic acid ethyl ester, eicosapentaenoic acid methyl ester, eicosapentaenoic acid propyl ester, or eicosapentaenoic acid butyl ester.
- the EPA comprises In one embodiment, the EPA comprises all-cis eicosa-5, 8,11,14, 17-pentaenoic acid ethyl ester.
- the EPA is in the form of 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.
- EPA is present in a composition useful in accordance with methods of the invention 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,
- a composition useful in accordance with 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, docosahexaenoic acid (DHA), if any.
- DHA docosahexaenoic acid
- a composition of the invention contains substantially no docosahexaenoic acid.
- a composition useful in the present invention contains no docosahexaenoic acid and/or derivative thereof.
- EPA comprises at least 70%, at least 80%, at least
- a composition of the invention comprises ultra-pure EPA.
- ultra-pure refers to a composition comprising at least 95% by weight EPA (as the term “EPA” is defined and exemplified herein). Ultra- pure EPA comprises at least 96%> by weight EPA, at least 97% by weight EPA, or at least 98% by weight EPA, wherein the EPA is any form of EPA as set forth herein.
- a composition useful in accordance with methods of the invention contains 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, of any fatty acid other than EPA.
- fatty acid other than EPA examples include linolenic acid (LA), arachidonic acid (AA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), stearadonic acid (STA), eicosatrienoic acid (ETA) and/or docosapentaenoic acid (DP A).
- a composition useful in accordance with methods of the invention contains about 0.1% to about 4%, about 0.5% to about 3%, or about 1% to about 2%, by weight, of total fatty acids other than EPA and/or DHA.
- a composition useful in accordance with the invention has one or more of the following features: (a) eicosapentaenoic acid ethyl ester represents at least about 96%, at least about 97%, or at least about 98%, by weight, of all fatty acids present in the composition; (b) the composition contains not more than about 4%, not more than about 3%, or not more than about 2%, by weight, of total fatty acids other than eicosapentaenoic acid ethyl ester; (c) the composition contains not more than about 0.6%, not more than about 0.5%, or not more than about 0.4% 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
- the composition has a peroxide value of not more than about 5 meq/kg, not more than about 4 meq/kg, not more than about 3 meq/kg, or not more than about 2 meq/kg.
- composition useful in accordance with the invention comprises, consists of or consists essentially of at least 95% by weight ethyl
- eicosapentaenoate EPA-E
- ODTA-E ethyl octadecatetraenoate
- NDPA-E ethyl nonaecapentaenoate
- AA-E ethyl arachidonate
- ETA-E ethyl eicosatetraenoate
- HPA-E ethyl heneicosapentaenoate
- the composition is present in a capsule shell.
- compositions useful in accordance with the invention comprise, consist essential of, or consist of at least 95%>, 96%> or 97%>, by weight, ethyl eicosapentaenoate, about 0.2% to about 0.5% by weight ethyl octadecatetraenoate, about 0.05%) to about 0.25%> by weight ethyl nonaecapentaenoate, about 0.2%> to about 0.45%> by weight ethyl arachidonate, about 0.3% to about 0.5% by weight ethyl eicosatetraenoate, and about 0.05% to about 0.32% ethyl heneicosapentaenoate.
- the composition contains not more than about 0.06%>, about 0.05%>, or about 0.04%>, by weight, DHA or derivative there of such as ethyl-DHA. In one embodiment the composition contains substantially no or no amount of DHA or derivative there of such as ethyl-DHA.
- the composition further optionally comprises one or more antioxidants (e.g. tocopherol) or other impurities in an amount of not more than about 0.5% or not more than 0.05%.
- the composition comprises about 0.05%> to about 0.4%>, for example about 0.2%> by weight tocopherol.
- about 500 mg to about 1 g of the composition is provided in a capsule shell.
- compositions useful in accordance with the invention comprise, consist essential of, or consist of at least 96% by weight ethyl eicosapentaenoate, about 0.22% to about 0.4% by weight ethyl octadecatetraenoate, about 0.075% to about 0.20%) by weight ethyl nonaecapentaenoate, about 0.25%> to about 0.40%> by weight ethyl arachidonate, about 0.3% to about 0.4% by weight ethyl eicosatetraenoate and about 0.075% to about 0.25% ethyl heneicosapentaenoate.
- the composition contains not more than about 0.06%>, about 0.05%>, or about 0.04%>, by weight, DHA or derivative there of such as ethyl-DHA. In one embodiment the composition contains substantially no or no amount of DHA or derivative there of such as ethyl-DHA.
- the composition further optionally comprises one or more antioxidants (e.g. tocopherol) or other impurities in an amount of not more than about 0.5% or not more than 0.05%.
- the composition comprises about 0.05%> to about 0.4%>, for example about 0.2%> by weight tocopherol.
- 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 capsule and is packaged in blister packages of about 1 to about 20 capsules per sheet.
- compositions useful in accordance with the invention comprise, consist essential of, or consist of at least 96%>, 97% or 98%>, by weight, ethyl eicosapentaenoate, about 0.25%> to about 0.38%> by weight ethyl octadecatetraenoate, about 0.10%) to about 0.15%) by weight ethyl nonaecapentaenoate, about 0.25%> to about 0.35%> by weight ethyl arachidonate, about 0.31% to about 0.38%> by weight ethyl eicosatetraenoate, and about 0.08% to about 0.20% ethyl heneicosapentaenoate.
- the composition contains not more than about 0.06%>, about 0.05%>, or about 0.04%>, by weight, DHA or derivative there of such as ethyl-DHA. In one embodiment the composition contains substantially no or no amount of DHA or derivative there of such as ethyl-DHA.
- the composition further optionally comprises one or more antioxidants (e.g. tocopherol) or other impurities in an amount of not more than about 0.5% or not more than 0.05%.
- the composition comprises about 0.05%> to about 0.4%>, for example about 0.2%> by weight tocopherol.
- the invention provides a dosage form comprising about 500 mg to about 1 g of the foregoing composition in a capsule shell.
- a composition as described herein is administered to a subject once or twice per day.
- 1, 2, 3 or 4 capsules, each containing about 1 g of a composition as described herein are administered to a subject daily.
- 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.
- a subject being treated in accordance with methods of the invention is not otherwise on lipid-altering therapy, for example statin, fibrate, niacin and/or ezetimibe therapy.
- compositions useful in accordance with methods of the invention are orally deliverable.
- oral administration 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.
- oral administration includes buccal and sublingual as well as esophageal administration.
- 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.
- 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.
- 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.
- 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.
- the composition comprises about 1 g to about 4 g of eicosapentaenoic acid ethyl ester, wherein the composition contains substantially no docosahexaenoic acid.
- compositions of the invention upon storage in a closed container maintained at room temperature, refrigerated (e.g.
- the invention provides use of a composition as described herein in manufacture of a medicament for treatment of any of a cardiovascular-related disease.
- the subject is diabetic.
- a composition as set forth herein is packaged together with instructions for using the composition to treat a cardiovascular disorder.
- Example 1 Clinical study to evaluate TG levels in subjects treated with AMRlOl
- a multi-center, placebo-controlled randomized, double-blind, 12-week study with an open- label extension was performed to evaluate the efficacy and safety of AMRlOl in patients with fasting triglyceride levels >500 mg/dL.
- the primary objective of the study was to determine the efficacy of AMRlOl 2 g daily and 4 g daily, compared to placebo, in lowering fasting TG levels in patients with fasting TG levels >500 mg/dL and ⁇ 1500 mg/dL (>5.65 mmol/L and ⁇ 16.94 mmol/L).
- lipid-altering therapy Patients currently on statin therapy (with or without ezetimibe) were evaluated by the investigator as to whether this therapy could be safely discontinued at screening, or if it should be continued. If statin therapy (with or without ezetimibe) was to be continued, dose(s) must be stable for >4 weeks prior to randomization. Patients taking 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.
- statin therapy with or without ezetimibe
- the screening visit (Visit 1) occured for all patients at either 6 weeks (for patients not on lipid-altering therapy at screening or for patients who did not need to discontinue their current lipid-altering therapy) or 8 weeks (for patients who required washout of their current lipid-altering therapy at screening) before randomization, as follows: [0115] Patients who did not require a washout: The screening visit occured 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 instructions on how to follow this diet.
- NCEP National Cholesterol Education Program
- TLC Therapeutic Lifestyle Changes
- Eligible patients were randomly assigned at Visit 4 (Week 0) to receive orally AMRlOl 2 g daily, AMRlOl 4 g daily, or placebo for the 12-week double-blind treatment period.
- AMRlOl 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 AMRlOl .
- patients took 2 capsules (AMRlOl or matching placebo) in the morning and 2 in the evening for a total of 4 capsules per day.
- Patients in the AMRlOl 2 g/day treatment group received 1 AMRlOl 1 g capsule and 1 matching placebo capsule in the morning and in the evening.
- Patients in the AMRlOl 4 g/day treatment group received 2 AMRlOl 1 g capsules in the morning and evening.
- Patients in the placebo group received 2 matching placebo capsules in the morning and evening. During the extension period, patients received open-label AMRlOl 4 g daily. Patients took 2 AMRlOl 1 g capsules in the morning and 2 in the 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:
- TC total cholesterol
- HDL-C high-density lipoprotein cholesterol
- LDL-C low-density lipoprotein cholesterol
- non-HDL-C non-high-density lipoprotein cholesterol
- VLDL-C very low-density lipoprotein cholesterol
- the efficacy variable for the open-label extension period was percent change in fasting TG from extension baseline to end of treatment.
- Safety assessments included adverse events, clinical laboratory measurements (chemistry, hematology, and urinalysis), 12-lead electrocardiograms (ECGs), vital signs, and physical examinations
- 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 was 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.
- ANCOVA 2-way analysis of covariance
- the least-squares mean, standard error, and 2-tailed 95% confidence interval for each treatment group and for each comparison was estimated.
- the same 2-way ANCOVA model was used for the analysis of secondary efficacy variables.
- the primary efficacy variable was the percent change in fasting TG levels from baseline to Week 12.
- a sample size of 69 completed patients per treatment group provided >90% power to detect a difference of 30% between AMR101 and placebo in percent change from baseline in fasting TG levels, assuming a standard deviation of 45% in TG
- Example 2 Clinical study to evaluate lipoprotein particle concentration and size in subjects treated with AMR101
- Lipoprotein particle concentrations and sizes were measured with nuclear magnetic resonance spectroscopy in the above descriebd clinical trial. Lipoprotein particle size and concentration parameters were obtained from fasting blood samples. Lipoprotein particle size and concentrations are measured by nuclear magnetic resonance (NMR) spectroscopy at LipoScience, Inc. (Raleigh, NC) using the LipoProfile-3 algorithm. VLDL, LDL, and HDL subclasses of different size were quantified from the amplitudes of their spectroscopically- distinct lipid methyl group NMR signals.
- NMR nuclear magnetic resonance
- Efficacy analyses include the intent-to-treat (ITT) population, defined as all randomized patients who had a baseline efficacy measurement, received >1 dose of study drug, and had >1 postrandomization efficacy measurement. Subjects with missing baseline or Week 12 measurements, due to either missing laboratory samples or un-reportable values, were excluded from this analysis.
- the median difference of each lipoprotein particle variable (percent change from baseline) between each AMR101 treatment group and the placebo group was evaluated with a nonparametric test using the Hodges-Lehmann medians of the differences between treatment groups and the Wilcoxon rank-sum test (significance level 0.05). All statistical analyses were carried out using SAS 9.2 software.
- AMR101 2 g/day did not significantly change total, small, medium, or large VLDL particle concentration. See, Table 2.
- Neither AMRlOl dose significantly changed LDL or HDL particle size. See, Table 3.
Abstract
In various embodiments, the present invention provides methods of treating and/or preventing cardiovascular-related disease and, in particular, a method of blood lipid therapy comprising administering to a subject in need thereof a pharmaceutical composition comprising eicosapentaenoic acid or a derivative thereof.
Description
METHODS OF TREATING HYPERTRIGLYCERIDEMIA
BACKGROUND
[0001] 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, dislipidemia, congestive heart failure and stroke. A need exists for improved treatments for cardiovascular diseases and disorders.
SUMMARY
[0002] In various embodiments, the present invention provides methods of treating and/or preventing cardiovascular-related diseases and, in particular, a method of blood lipid therapy comprising administering to a subject in need thereof a pharmaceutical composition comprising eicosapentaenoic acid or a derivative thereof. In one embodiment, the composition contains not more than 10%, by weight, docosahexaenoic acid or derivative thereof, substantially no docosahexaenoic acid or derivative thereof, or no docosahexaenoic acid or derivative thereof. In another embodiment, eicosapentaenoic acid ethyl ester comprises at least 96%>, by weight, of all fatty acids present in the composition; the composition contains not more than 4%, by weight, of total fatty acids other than
eicosapentaenoic acid ethyl ester; and/or the composition contains about 0.1% to about 0.6% of at least one fatty acid other than eicosapentaenoic acid ethyl ester and docosahexaenoic acid (or derivative thereof).
[0003] In one embodiment, a pharmaceutical composition useful in accordance with the invention comprises, consists of or consists essentially of at least 95% by weight ethyl eicosapentaenoate (EPA-E), about 0.2% to about 0.5% by weight ethyl octadecatetraenoate (ODTA-E), about 0.05% to about 0.25% by weight ethyl nonaecapentaenoate (NDPA-E), about 0.2% to about 0.45% by weight ethyl arachidonate (AA-E), about 0.3% to about 0.5% by weight ethyl eicosatetraenoate (ETA-E), and about 0.05% to about 0.32% ethyl heneicosapentaenoate (HPA-E). In another embodiment, the composition is present in a
capsule shell. In another embodiment, the composition contains substantially no or no amount of docosahexaenoic acid (DHA) or derivative thereof such as ethyl-DHA (DHA-E).
[0004] In another embodiment, the invention provides a method of treating moderate to severe hypertriglyceridemia comprising administering a composition as described herein to a subject in need thereof one to about four times per day. In another embodiment, the invention provides a method of treating moderate to severe hypertriglyceridemia comprising administering to a subject about 2 g to about 4 g per day of EPA (e.g., ethyl
eicosapentaenoate), for example about 3.8 g to about 4 g per day.
[0005] These and other embodiments of the present invention will be disclosed in further detail herein below.
[0006] The foregoing summary, as well as the following detailed description of the disclosure, will be better understood when read in conjunction with the appended figures. For the purpose of illustrating the disclosure, shown in the figures are embodiments which are presently preferred. It should be understood, however, that the disclosure is not limited to the precise arrangements, examples and instrumentalities shown
BRIEF DESCRIPTION OF THE FIGURES
[0007] Figure 1 shows a graphical representation of atherogenic lipoprotein particle concentration plotted against apolipoprotein B (ApoB) at week 12 (N=177; r=0.79).
DETAILED DESCRIPTION
[0008] 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.
[0009] 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.
[0010] In one embodiment, the invention provides a method for treatment and/or prevention of a cardiovascular-related disease. 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.
[0011] 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.
[0012] 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.
[0013] In another embodiment, the subject or subject group being treated has a baseline triglyceride level (or median baseline triglyceride level in the case of a subject group), fed or fasting, of at least about 300 mg/dl, at least about 400 mg/dl, at least about 500 mg/dl, at least about 600 mg/dl, at least about 700 mg/dl, at least about 800 mg/dl, at least about 900 mg/dl, at least about 1000 mg/dl, at least about 1100 mg/dl, at least about 1200 mg/dl, at least about 1300 mg/dl, at least about 1400 mg/dl, or at least about 1500 mg/dl, for example about 400 mg/dl to about 2500 mg/dl, about 450 mg/dl to about 2000 mg/dl or about 500 mg/dl to about 1500 mg/dl.
[0014] In one embodiment, the subject or subject group being treated in accordance with methods of the invention has previously been treated with Lovaza® and has experienced an increase in, or no decrease in, LDL-C levels and/or non-HDL-C levels. In one such embodiment, Lovaza® therapy is discontinued and replaced by a method of the present invention.
[0015] 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.
[0016] 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 total fatty acid (or mean thereof) 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.
[0017] 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 70 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.
[0018] 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 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 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 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 of about 10 to about 60 mg/dl, for example 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 of about 50 to about 300 mg/dl, for example not less than about 100 mg/dl, not less than about 90 mg/dl, not less than about 80 mg/dl, not less than about 70 mg/dl, not less than about 60 mg/dl or not less than about 50 mg/dl.
[0019] In a related embodiment, upon treatment in accordance with the present invention, for example about 2g to about 4 g per day of a composition as described herein 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:
[0020] (a) reduced triglyceride levels compared to baseline;
[0021] (b) reduced Apo B levels compared to baseline;
[0022] (c) increased HDL-C levels compared to baseline;
[0023] (d) no increase in LDL-C levels compared to baseline;
[0024] (e) a reduction in LDL-C levels compared to baseline;
[0025] (f) a reduction in non-HDL-C levels compared to baseline;
[0026] (g) a reduction in vLDL levels compared to baseline;
[0027] (h) an increase in apo A-I levels compared to baseline;
[0028] (i) an increase in apo A-I/apo B ratio compared to baseline;
[0029] j) a reduction in lipoprotein A levels compared to baseline;
[0030] (k) a reduction in LDL particle number compared to baseline;
[0031] (1) an increase in LDL size compared to baseline;
[0032] (m) a reduction in remnant-like particle cholesterol compared to baseline;
[0033] (n) a reduction in oxidized LDL compared to baseline;
[0034] (o) no change or a reduction in fasting plasma glucose (FPG) compared to baseline;
[0035] (p) a reduction in hemoglobin Alc (HbAic) compared to baseline;
[0036] (q) a reduction in homeostasis model insulin resistance compared to baseline;
[0037] (r) a reduction in lipoprotein associated phospholipase A2 compared to baseline;
[0038] (s) a reduction in intracellular adhesion molecule- 1 compared to baseline;
[0039] (t) a reduction in interleukin-6 compared to baseline;
[0040] (u) a reduction in plasminogen activator inhibitor- 1 compared to baseline;
[0041] (v) a reduction in high sensitivity C-reactive protein (hsCRP) compared to baseline;
[0042] (w) an increase in serum or plasma EPA compared to baseline;
[0043] (x) an increase in red blood cell (RBC) membrane EPA compared to baseline; and/or
[0044] (y) a reduction or increase in one or more of serum phospholipid and/or red blood cell content of docosahexaenoic acid (DHA), docosapentaenoic acid (DP A), arachidonic acid (AA), palmitic acid (PA), staeridonic acid (SA) or oleic acid (OA) compared to baseline.
[0045] In one embodiment, upon administering a composition of the invention to a subject, the subject exhibits a decrease in triglyceride levels, an increase in the concentrations of EPA and DPA (n-3) in red blood cells, and an increase of the ratio of EPA: arachidonic acid in red blood cells. In a related embodiment the subject exhibits substantially no or no increase in RBC DHA.
[0046] In one embodiment, methods of the present invention comprise measuring baseline levels of one or more markers set forth in (a) - (y) 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) - (y) are determined, and subsequently taking an additional measurement of said one or more markers.
[0047] In another embodiment, upon treatment with a composition of the present invention, for example about 2g to about 4 g per day of a composition as described herein, about 2 g to about 4 g per day of EPA (e.g., ethyl eicosapentaenoate), or about 3.8 g to about
4 g per day of EPA (e.g., ethyl eicosapentaenoate) 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, any 24 or more, or all 25 of outcomes (a) - (y) described immediately above.
[0048] 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:
[0049] (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;
[0050] (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;
[0051] (c) 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;
[0052] (d) a less than 60% increase, a less than 50% increase, a less than 40% increase, a less than 30% increase, less than 20% increase, less than 10% increase, less than 5% increase or no increase in LDL-C levels or a reduction in LDL-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%, at least about 55% or at least about 75% (actual % change or median % change) as compared to baseline;
[0053] (e) a decrease in Apo B 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;
[0054] (f) a reduction in vLDL 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;
[0055] (g) a reduction in large (>60 nm e.g. as measured by NMR spectroscopy) vLDL particle concentration, a reduction in large vLDL particle concentration of at least about 10%, or a reduction in large vLDL particle concentration of at least about 20% (actual % change or median % change) compared to baseline or placebo control;
[0056] (h) a reduction in small (18 - 20.5 nm; e.g. as measured by NMR spectroscopy)
LDL particle concentration, a reduction in small LDL particle concentration of at least about 3%, a reduction in small LDL particle concentration of at least about 6%, or a reduction small LDL particle concentration of at least about 9% (actual % change or median % change) compared to baseline or placebo control;
[0057] (i) an increase in apo A-I 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;
[0058] (j) an increase in apo A-I/apo B ratio 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;
[0059] (k) a reduction in lipoprotein (a) 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;
[0060] (1) 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;
[0061] (m) an increase in mean LDL particle size 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;
[0062] (n) a reduction in remnant-like particle 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%, or at least about 100% (actual % change or median % change) compared to baseline;
[0063] (o) a reduction in oxidized LDL 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%o, 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;
[0064] (p) substantially no change, no significant change, or a reduction (e.g. in the case of a diabetic subject) in fasting plasma glucose (FPG) of at least about 5%, at least about 10%o, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%o, 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;
[0065] (q) substantially no change, no significant change or a reduction in hemoglobin
Aic (HbAic) 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%o, or at least about 50% (actual % change or median % change) compared to baseline;
[0066] (r) a reduction in homeostasis model index insulin resistance of at least about
5%o, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%o, 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;
[0067] (s) a reduction in lipoprotein associated phospholipase A2 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;
[0068] (t) a reduction in intracellular adhesion molecule- 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;
[0069] (u) a reduction in interleukin-6 of at least about 5%, at least about 10%, at least about 15%o, 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;
[0070] (v) a reduction in plasminogen activator inhibitor- 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;
[0071] (w) a reduction in high sensitivity C-reactive protein (hsCRP) 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;
[0072] (x) 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;
[0073] (y) 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%, r 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;
[0074] (z) 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; and/or
[0075] (aa) 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.
[0076] In one embodiment, methods of the present invention comprise measuring baseline levels of one or more markers set forth in (a) - (aa) 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) - (aa) are determined, and subsequently taking a second measurement of the one or more markers as measured at baseline for comparison thereto.
[0077] In another embodiment, upon treatment with a composition of the present invention, for example about 2 g to about 4 g per day of a composition as described herein, about 2 g to about 4 g per day of EPA (e.g., ethyl eicosapentaenoate), or about 3.8 g to about 4 g per day of EPA (e.g., ethyl eicosapentaenoate) 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, or all 27 or more of outcomes (a) - (aa) described immediately above.
[0078] Parameters (a) - (aa) 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 Al, 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-6 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.
[0079] In one embodiment, subjects fast for up to 12 hours prior to blood sample collection, for example about 10 hours.
[0080] In another embodiment, the present invention provides a method of treating or preventing primary hypercholesterolemia and/or mixed dyslipidemia (Fredrickson Types Ila and lib) 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).
[0081] 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.
[0082] 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.
[0083] 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.
[0084] In another embodiment, the present invention provides a method of treating subjects having very high serum triglyceride levels (e.g. greater than 1000 mg/dl or greater than 2000 mg/dl) and that are at risk of developing pancreatitis, comprising administering to the patient one or more compositions as disclosed herein.
[0085] In another embodiment, the present invention provides a method of treating subjects having very high serum triglyceride levels (e.g., greater than 1000 mg/dl or greater than 2000 mg/dl) comprising administering to the subject(s) about 2 g to about 4 g per day of EPA (e.g., ethyl eicosapentaenoate), for example about 3.8 g to about 4 g per day of EPA.
[0086] In another embodiment, the present invention provides a method of reducing large vLDL particle concentration in a subject having a fasting baseline triglyceride level of about 500 mg/dl to about 1500 mg/dl, the method comprising administering to the subject about 2 g to about 4 g per day, or about 3.8 g to about 4 g per day, of ethyl eicosapentaenoate thereby to produce a reduction in large vLDL particle concentration. In some embodiments, the reduction is statistically significant. In some embodiments, the reduction in large vLDL particle concentration is in comparison to a baseline large vLDL particle concentration prior to initiation of administration. In some embodiments, the reduction in large vLDL particle concentration is at least a 2.5% reduction, at least a 10% reduction, at least a 20% reduction, or at least a 24% reduction. In some embodiments, the subject is administered ethyl eicosapentaenoate for a period of 12 weeks.
[0087] In another embodiment, the present invention provides a method of reducing small LDL particle concentration in a subject having a fasting baseline triglyceride level of about 500 mg/dl to about 1500 mg/dl comprising, administering to the subject about 2 g to about 4 g per day of a pharmaceutical composition comprising at least about 96%, by weight, ethyl eicosapentaenoate thereby to produce a reduction in small LDL particle concentration by comparison with a baseline small LDL particle concentration prior to initiation of administration. In some embodiments, the reduction in small LDL particle concentration is at
least a 5% reduction or at least a 9% reduction. In some embodiments, the subject is administered ethyl eicosapentaenoate for a period of 12 weeks.
[0088] In one embodiment, a composition of the invention is administered to a subject in an amount sufficient to provide a daily dose of eicosapentaenoic acid of about 2 g to about 4 g, about 3.8 g to about 4 g, 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 or about 2500 mg, about 2750 mg, about 3000 mg, about 3250 mg, about 3500 mg, about 3750 mg, about 4000 mg, about 4250 mg, about 4500 mg, about 4750 mg, about 5000 mg, about 5500 mg, about 6000 mg, about 6500 mg, about 7000 mg, about 7500 mg, about 8000 mg, about 8500 mg, about 9000 mg, about 9500 mg, or about 10,000 mg.
[0089] In another embodiment, any of the methods disclosed herein are used in treatment or prevention 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.
[0090] In one embodiment, a composition for use in methods of the invention comprises eicosapentaenoic acid, or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof, or mixtures of any of the foregoing, collectively referred to herein as "EPA." 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.
[0091] In one embodiment, the EPA comprises all-cis eicosa-5, 8,11,14, 17-pentaenoic acid. In another embodiment, the EPA comprises an eicosapentaenoic acid ester. In another embodiment, the EPA comprises a Ci - C5 alkyl ester of eicosapentaenoic acid. In another embodiment, the EPA comprises eicosapentaenoic acid ethyl ester, eicosapentaenoic acid methyl ester, eicosapentaenoic acid propyl ester, or eicosapentaenoic acid butyl ester. In another embodiment, the EPA comprises In one embodiment, the EPA comprises all-cis eicosa-5, 8,11,14, 17-pentaenoic acid ethyl ester.
[0092] In another embodiment, the EPA is in the form of 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.
[0093] In another embodiment, EPA is present in a composition useful in accordance with methods of the invention 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.
[0094] In another embodiment, a composition useful in accordance with 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, docosahexaenoic acid (DHA), if any. In another embodiment, a composition of the invention contains substantially no docosahexaenoic acid. In still another embodiment, a composition useful in the present invention contains no docosahexaenoic acid and/or derivative thereof.
[0095] In another embodiment, EPA comprises at least 70%, at least 80%, at least
90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%, by weight, of all fatty acids present in a composition that is useful in methods of the present invention.
[0096] In one embodiment, a composition of the invention comprises ultra-pure EPA.
The term "ultra-pure" as used herein with respect to EPA refers to a composition comprising at least 95% by weight EPA (as the term "EPA" is defined and exemplified herein). Ultra- pure EPA comprises at least 96%> by weight EPA, at least 97% by weight EPA, or at least 98% by weight EPA, wherein the EPA is any form of EPA as set forth herein.
[0097] In another embodiment, a composition useful in accordance with methods of the invention contains 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, of any fatty acid other than EPA. Illustrative examples of a "fatty acid other than EPA" include linolenic acid (LA), arachidonic acid (AA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), stearadonic acid (STA), eicosatrienoic acid (ETA) and/or docosapentaenoic acid (DP A). In another embodiment, a composition useful in accordance with methods of the invention contains about 0.1% to about 4%, about 0.5% to about 3%, or about 1% to about 2%, by weight, of total fatty acids other than EPA and/or DHA.
[0098] In another embodiment, a composition useful in accordance with the invention has one or more of the following features: (a) eicosapentaenoic acid ethyl ester represents at least about 96%, at least about 97%, or at least about 98%, by weight, of all fatty acids present in the composition; (b) the composition contains not more than about 4%, not more than about 3%, or not more than about 2%, by weight, of total fatty acids other than eicosapentaenoic acid ethyl ester; (c) the composition contains not more than about 0.6%, not more than about 0.5%, or not more than about 0.4% 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; (e) the composition contains not more than about 20 ppm, not more than about 15 ppm or not more than about 10 ppm heavy metals, (f) the composition contains not more than about 5 ppm, not more than about 4 ppm, not more than about 3 ppm, or not more than about
2 ppm arsenic, and/or (g) the composition has a peroxide value of not more than about 5 meq/kg, not more than about 4 meq/kg, not more than about 3 meq/kg, or not more than about 2 meq/kg.
[0099] In another embodiment, a composition useful in accordance with the invention comprises, consists of or consists essentially of at least 95% by weight ethyl
eicosapentaenoate (EPA-E), about 0.2% to about 0.5% by weight ethyl octadecatetraenoate (ODTA-E), about 0.05% to about 0.25% by weight ethyl nonaecapentaenoate (NDPA-E), about 0.2% to about 0.45% by weight ethyl arachidonate (AA-E), about 0.3% to about 0.5% by weight ethyl eicosatetraenoate (ETA-E), and about 0.05% to about 0.32% ethyl heneicosapentaenoate (HPA-E). In another embodiment, the composition is present in a capsule shell.
[00100] In another embodiment, compositions useful in accordance with the invention comprise, consist essential of, or consist of at least 95%>, 96%> or 97%>, by weight, ethyl eicosapentaenoate, about 0.2% to about 0.5% by weight ethyl octadecatetraenoate, about 0.05%) to about 0.25%> by weight ethyl nonaecapentaenoate, about 0.2%> to about 0.45%> by weight ethyl arachidonate, about 0.3% to about 0.5% by weight ethyl eicosatetraenoate, and about 0.05% to about 0.32% ethyl heneicosapentaenoate. Optionally, the composition contains not more than about 0.06%>, about 0.05%>, or about 0.04%>, by weight, DHA or derivative there of such as ethyl-DHA. In one embodiment the composition contains substantially no or no amount of DHA or derivative there of such as ethyl-DHA. The composition further optionally comprises one or more antioxidants (e.g. tocopherol) or other impurities 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.
[00101] In another embodiment, compositions useful in accordance with the invention comprise, consist essential of, or consist of at least 96% by weight ethyl eicosapentaenoate, about 0.22% to about 0.4% by weight ethyl octadecatetraenoate, about 0.075% to about 0.20%) by weight ethyl nonaecapentaenoate, about 0.25%> to about 0.40%> by weight ethyl arachidonate, about 0.3% to about 0.4% by weight ethyl eicosatetraenoate and about 0.075% to about 0.25% ethyl heneicosapentaenoate. Optionally, the composition contains not more than about 0.06%>, about 0.05%>, or about 0.04%>, by weight, DHA or derivative there of such as ethyl-DHA. In one embodiment the composition contains substantially no or no amount of DHA or derivative there of such as ethyl-DHA. The composition further optionally comprises one or more antioxidants (e.g. tocopherol) or other impurities 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 capsule and is packaged in blister packages of about 1 to about 20 capsules per sheet.
[0100] In another embodiment, compositions useful in accordance with the invention comprise, consist essential of, or consist of at least 96%>, 97% or 98%>, by weight, ethyl eicosapentaenoate, about 0.25%> to about 0.38%> by weight ethyl octadecatetraenoate, about 0.10%) to about 0.15%) by weight ethyl nonaecapentaenoate, about 0.25%> to about 0.35%> by weight ethyl arachidonate, about 0.31% to about 0.38%> by weight ethyl eicosatetraenoate, and about 0.08% to about 0.20% ethyl heneicosapentaenoate. Optionally, the composition contains not more than about 0.06%>, about 0.05%>, or about 0.04%>, by weight, DHA or derivative there of such as ethyl-DHA. In one embodiment the composition contains substantially no or no amount of DHA or derivative there of such as ethyl-DHA. The composition further optionally comprises one or more antioxidants (e.g. tocopherol) or other impurities 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.
[0101] 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.
[0102] In one embodiment, a subject being treated in accordance with methods of the invention is not otherwise on lipid-altering therapy, for example statin, fibrate, niacin and/or ezetimibe therapy.
[0103] 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.
[0104] 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.
[0105] 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.
[0106] In one embodiment, compositions of the invention, upon storage in a closed container maintained at room temperature, refrigerated (e.g. about 5 to about 5 -10 °C) temperature, or frozen for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, exhibit at least about 90%, at least about 95%, at least about 97.5%, or at least about 99% of the active ingredient(s) originally present therein.
[0107] In one embodiment, the invention provides use of a composition as described herein in manufacture of a medicament for treatment of any of a cardiovascular-related disease. In another embodiment, the subject is diabetic.
[0108] In one embodiment, a composition as set forth herein is packaged together with instructions for using the composition to treat a cardiovascular disorder.
EXAMPLES
Example 1 : Clinical study to evaluate TG levels in subjects treated with AMRlOl
[0109] A multi-center, placebo-controlled randomized, double-blind, 12-week study with an open- label extension was performed to evaluate the efficacy and safety of AMRlOl in patients with fasting triglyceride levels >500 mg/dL. The primary objective of the study was to determine the efficacy of AMRlOl 2 g daily and 4 g daily, compared to placebo, in lowering fasting TG levels in patients with fasting TG levels >500 mg/dL and≤1500 mg/dL (>5.65 mmol/L and≤16.94 mmol/L).
[0110] The secondary objectives of this study were the following:
1. To determine the safety and tolerability of AMRlOl 2 g daily and 4 g daily;
2. To determine the effect of AMRlOl on lipid and apolipoprotein profiles;
3. To determine the effect of AMRlOl on low-density lipoprotein (LDL) particle number and size;
4. To determine the effect of AMRlOl on oxidized LDL;
5. To determine the effect of AMRlOl on fasting plasma glucose (FPG) and hemoglobin Ale (HbAie);
6. To determine the effect of AMRlOl on insulin resistance;
7. To determine the effect of AMRlOl on high-sensitivity C-reactive protein (hsCRP);
8. To determine the effects of AMRlOl 2 g daily and 4 g daily on the incorporation of fatty acids into red blood cell membranes and into plasma phospholipids;
9. To explore the relationship between baseline fasting TG levels and the reduction in fasting TG levels; and
10. To explore the relationship between an increase in red blood cell membrane eicosapentaenoic acid (EPA) concentrations and the reduction in fasting TG levels.
[0111] The population for this study wass men and women (women of childbearing potential needed to be on contraception or practice abstinence) >18 years of age with a body mass index≤45 kg/m2 who were not on lipid-altering therapy or are currently on
lipid-altering therapy. Patients currently on statin therapy (with or without ezetimibe) were evaluated by the investigator as to whether this therapy could be safely discontinued at screening, or if it should be continued. If statin therapy (with or without ezetimibe) was to be continued, dose(s) must be stable for >4 weeks prior to randomization. Patients taking 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.
[0112] Approximately 240 patients were sought to be randomized at approximately 50 centers in North America, South America, Central America, Europe, India, and South Africa. The study was be a 58- to 60-week, Phase 3, multi-center study consisting of 3 study periods: (1) A 6- to 8-week screening period that included a diet and lifestyle stabilization and washout period and a TG qualifying period; (2) A 12-week, double-blind, randomized, placebo-controlled treatment period; and (3) A 40-week, open-label, extension period.
[0113] During the screening period and double-blind treatment period, all visits were to be within ±3 days of the scheduled time. During the open-label extension period, all visits were to be within ±7 days of the scheduled time. The screening period included a 4- or 6-week diet and lifestyle stabilization period and washout period followed by a 2-week TG qualifying period. Subjects must be stable for >4 weeks prior to randomization.
[0114] The screening visit (Visit 1) occured for all patients at either 6 weeks (for patients not on lipid-altering therapy at screening or for patients who did not need to discontinue their current lipid-altering therapy) or 8 weeks (for patients who required washout of their current lipid-altering therapy at screening) before randomization, as follows:
[0115] Patients who did not require a washout: The screening visit occured 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 instructions on how to follow this diet. Patients who required a washout: The screening visit occured at Visit 1 (Week -8). Eligible patients began a 6-week washout period at the screening visit. Patients received counseling regarding the NCEP TLC diet and received 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.
[0116] 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 TG qualifying period and had their fasting TG level measured at Visit 2 (Week -2) and Visit 3 (Week -1). Eligible patients must have had an average fasting TG level >500 mg/dL and≤1500 mg/dL (>5.65 mmol/L and≤16.94 mmol/L) to enter the 12-week double-blind treatment period. The TG level for qualification was based on the average (arithmetic mean) of the Visit 2 (Week - 2) and Visit 3 (Week -1) values. If a patient's average TG level from Visit 2 and Visit 3 fell outside the required range for entry into the study, an additional sample for fasting TG measurement could be 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.
[0117] After confirmation of qualifying fasting 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:
• AMR101 2 g daily,
• AMR101 4 g daily, or
• Placebo.
[0118] 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.
[0119] Patients who completed the 12-week double-blind treatment period were eligible to enter a 40-week, open-label, extension period at Visit 7 (Week 12). All patients were to receive open-label AMRlOl 4 g daily. From Visit 8 (Week 16) until the end of the study, changes to the lipid-altering regimen were permitted (e.g., initiating or raising the dose of statin or adding non-statin, lipid-altering medications to the regimen), as guided by standard practice and prescribing information. After Visit 8 (Week 16), patients were to return to the site every 12 weeks until the last visit at Visit 11 (Week 52).
[0120] Eligible patients were randomly assigned at Visit 4 (Week 0) to receive orally AMRlOl 2 g daily, AMRlOl 4 g daily, or placebo for the 12-week double-blind treatment period. AMRlOl 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 AMRlOl . During the double-blind treatment period, patients took 2 capsules (AMRlOl or matching placebo) in the morning and 2 in the evening for a total of 4 capsules per day. Patients in the AMRlOl 2 g/day treatment group received 1 AMRlOl 1 g capsule and 1 matching placebo capsule in the morning and in the evening. Patients in the AMRlOl 4 g/day treatment group received 2 AMRlOl 1 g capsules in the morning and evening.
[0121] Patients in the placebo group received 2 matching placebo capsules in the morning and evening. During the extension period, patients received open-label AMRlOl 4 g daily. Patients took 2 AMRlOl 1 g capsules in the morning and 2 in the evening.
[0122] 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), calculated low-density lipoprotein cholesterol (LDL-C), calculated non-high-density lipoprotein cholesterol (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-I), apolipoprotein B (apo B), and
apo A-I/apo B ratio from baseline to Week 12;
• Percent changes in lipoprotein(a) from baseline to Week 12 (selected sites only);
• Percent changes in LDL particle number and size, measured by nuclear magnetic resonance, from baseline to Week 12 (selected sites only);
• Percent change in remnant-like particle cholesterol from baseline to Week 12 (selected sites only);
• Percent change in oxidized LDL from baseline to Week 12 (selected sites only);
• Changes in FPG and HbAic 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 phospho lipase A2 from baseline to Week 12 (selected sites only);
• Change in intracellular adhesion molecule- 1 from baseline to Week 12 (selected sites only);
• Change in interleukin-6 from baseline to Week 12 (selected sites only);
• Change in plasminogen activator inhibitor- 1 from baseline to Week 12 (selected sites only);
• Change in hsCRP from baseline to Week 12 (selected sites only);
• Change in serum phospholipid EPA content from baseline to Week 12;
• Change in red blood cell membrane EPA content from baseline to Week 12; and
• Change in serum phospholipid and red blood cell membrane content in the following fatty acids from baseline to Week 12: docosapentaenoic acid, docosahexaenoic acid, arachidonic acid, palmitic acid, stearic acid, and oleic acid.
[0123] The efficacy variable for the open-label extension period was percent change in fasting TG from extension baseline to end of treatment. Safety assessments included adverse events, clinical laboratory measurements (chemistry, hematology, and urinalysis), 12-lead electrocardiograms (ECGs), vital signs, and physical examinations
[0124] For TG, TC, HDL-C, calculated 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 occured, Visit 3.1) measurements. Baseline for all other efficacy parameters was the Visit 4 (Week 0) measurement.
[0125] For TC, HDL-C, calculated 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 was the Visit 7 (Week 12) measurement.
[0126] 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 was estimated. The same 2-way ANCOVA model was used for the analysis of secondary efficacy variables.
[0127] The primary analysis was repeated for the per-protocol population to confirm the robustness of the results for the intent-to-treat population.
[0128] The primary efficacy variable was the percent change in fasting TG levels from baseline to Week 12. A sample size of 69 completed patients per treatment group provided >90% power to detect a difference of 30% between AMR101 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 <0.01. To accommodate a 15% drop-out rate from randomization to completion of the double-blind treatment period, a total of 240 randomized patients was planned (80 patients per treatment group). Top line esults of the study are shown in Table 1.
Example 2: Clinical study to evaluate lipoprotein particle concentration and size in subjects treated with AMR101
[0129] Lipoprotein particle concentrations and sizes were measured with nuclear magnetic resonance spectroscopy in the above descriebd clinical trial. Lipoprotein particle size and concentration parameters were obtained from fasting blood samples. Lipoprotein particle size and concentrations are measured by nuclear magnetic resonance (NMR) spectroscopy at LipoScience, Inc. (Raleigh, NC) using the LipoProfile-3 algorithm. VLDL, LDL, and HDL subclasses of different size were quantified from the amplitudes of their spectroscopically- distinct lipid methyl group NMR signals.
[0130] Concentrations of the following subclasses of lipoproteins were analyzed in this study: small LDL (18.0-20.5 nm), large LDL (20.5-23.0 nm), intermediate-density lipoprotein (IDL; 23.0-29.0 nm), large high-density lipoprotein (HDL; 9.4-14.0 nm), medium HDL (8.2-9.4 nm), small HDL (7.3-8.2 nm), large very-low-density lipoprotein (VLDL; >60 nm), medium VLDL (42-60 nm), and small VLDL (29-42nm).
[0131] Efficacy analyses include the intent-to-treat (ITT) population, defined as all randomized patients who had a baseline efficacy measurement, received >1 dose of study drug, and had >1 postrandomization efficacy measurement. Subjects with missing baseline or Week 12 measurements, due to either missing laboratory samples or un-reportable values, were excluded from this analysis. The median difference of each lipoprotein particle variable (percent change from baseline) between each AMR101 treatment group and the placebo group was evaluated with a nonparametric test using the Hodges-Lehmann medians of the differences between treatment groups and the Wilcoxon rank-sum test (significance level 0.05). All statistical analyses were carried out using SAS 9.2 software.
[0132] AMR101 4 g/day significantly reduced the concentration of large VLDL particles (-27.9%; P=0.0211) and increased the concentration of medium VLDL particles (+28.0%, P=0.0238) with no significant change in median concentration of total VLDL particles (+9.3%), P=0.2262). AMR101 2 g/day did not significantly change total, small, medium, or large VLDL particle concentration. See, Table 2.
[0133] AMR101 4 g/day and 2 g/day both significantly reduced small LDL particle concentration by 25.6% (P<0.0001) and 12.8% (P=0.0274), respectively, with no significant
changes in concentrations of large LDL or IDL particles. AMRlOl 4 g/day also reduced total LDL particle concentration (which included IDL particles, small LDL particles, and large LDL particles) by 16.3% (P=0.0006). AMR 101 2 g/day did not significantly change total LDL particle concentration (-1.1%, P=0.8202). See, Table 2.
[0134] AMRlOl 4 g/day significantly reduced total HDL particle concentration (-7.4%, P=0.0063); AMRlOl 2 g/day did not (-3.0%, P=0.2701). Neither dose of AMRlOl significantly changed concentrations of large, medium, or small HDL particles. See, Table 2.
[0135] AMRlOl 4 g/day was previously reported to significantly reduce median apolipoprotem B by 8.5% compared with placebo (P=0.0019), which was consistent with the reductions in the atherogenic particle concentrations observed in the present analysis. The concentration of all LDL and VLDL particles correlated with apolipoprotem B concentration at week 12 (r=0.79, PO.0001; see, Figure 1).
[0136] At study end and compared with placebo, AMRlOl 4 g/day significantly decreased VLDL particle size (-8.6%, P=0.0017). AMRlOl 2 g/day also decreased VLDL particle size, although not significantly so (-4.0%, P=0.0734). Neither AMRlOl dose significantly changed LDL or HDL particle size. See, Table 3.
Claims
1. A method of reducing large vLDL particle concentration in a subject having a fasting baseline triglyceride level of about 500 mg/dl to about 1500 mg/dl comprising administering to the subject about 2 g to about 4 g per day ethyl eicosapentaenoate thereby to produce a reduction in large vLDL particle concentration.
2. The method of claim 1 wherein said reduction is statistically significant.
3. The method of claim 1 wherein administering to the subject about 2 g to about 4 g per day of ethyl eicosapentaenoate produces a reduction in large vLDL particle concentration by comparison with a baseline large vLDL particle concentration prior to initiation of administration.
4. The method of claim 3 wherein the reduction in large vLDL particle concentration is at least a 2.5% reduction.
5. The method of claim 3 wherein the reduction in large vLDL particle concentration is at least a 10% reduction.
6. The method of claim 3 wherein the reduction in large vLDL particle concentration is at least a 20% reduction.
7. The method of claim 3 wherein the reduction in large vLDL particle concentration is at least about 24% reduction.
8. The method of any one of claims 1 to 7 wherein the subject is administered about 3.8 g to about 4 g per day of ethyl eicosapentaenoate.
9. The method of any one of claims 1 to 8 wherein the subject is administered ethyl eicosapentaenoate for a period of 12 weeks.
10. A method of reducing small LDL particle concentration in a subject having a fasting baseline triglyceride level of about 500 mg/dl to about 1500 mg/dl comprising, administering to the subject about 2 g to about 4 g per day of ethyl eicosapentaenoate thereby to produce a reduction in small LDL particle concentration by comparison with a baseline small LDL particle concentration prior to initiation of administration.
11. The method of claim 10 wherein the reduction in small LDL particle concentration is at least a 5% reduction.
12. The method of claim 10 wherein the reduction in small LDL particle concentration is at least a 9% reduction.
13. The method of any one of claims 10 to 12 wherein the subject is administered about 3.8 g to about 4 g per day of ethyl eicosapentaenoate.
14. The method of any one of claims 10 to 12 wherein the subject is administered ethyl eicosapentaenoate for a period of 12 weeks.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050187292A1 (en) * | 2004-02-19 | 2005-08-25 | Kowa Co., Ltd. | Hyperlipemia therapeutic agent |
US20100278879A1 (en) * | 2009-04-29 | 2010-11-04 | Amarin Pharma, Inc. | Stable pharmaceutical composition and methods of using same |
US20110034555A1 (en) * | 2009-06-15 | 2011-02-10 | Amarin Pharma , Inc. | Compositions and methods for lowering triglycerides without raising ldl-c levels in a subject on concomitant statin therapy |
US20110218243A1 (en) * | 2010-03-04 | 2011-09-08 | Amarin Pharma, Inc. | Compositions and methods for treating and/or preventing cardiovascular disease |
Family Cites Families (292)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU527784B2 (en) | 1978-05-26 | 1983-03-24 | Bang, Hans Olaf Dr. | Treatment of thromboembolic conditions withall-z)-5, 8, 11, 14, 17-eicosapentaenoic acid |
US4377526A (en) | 1981-05-15 | 1983-03-22 | Nippon Suisan Kaisha, Ltd. | Method of purifying eicosapentaenoic acid and its esters |
CA1239587A (en) | 1983-10-24 | 1988-07-26 | David Rubin | Combined fatty acid composition for lowering blood cholestrol and triglyceride levels |
US4526902A (en) | 1983-10-24 | 1985-07-02 | Century Laboratories, Inc. | Combined fatty acid composition for treatment or prophylaxis of thrombo-embolic conditions |
JPS6135356A (en) | 1984-07-27 | 1986-02-19 | Nippon Oil & Fats Co Ltd | Analyzing method of fatty acid in blood lipid |
EP0347509A1 (en) | 1988-06-21 | 1989-12-27 | Century Laboratories Inc. | A process of extraction and purification of polyunsaturated fatty acids from natural sources |
US4920098A (en) | 1986-09-17 | 1990-04-24 | Baxter International Inc. | Nutritional support or therapy for individuals at risk or under treatment for atherosclerotic vascular, cardiovascular, and/or thrombotic diseases |
ES2061519T3 (en) | 1986-12-26 | 1994-12-16 | Sagami Chem Res | PROCEDURE FOR THE PRODUCTION OF EICOSAPENTAENOIC ACID. |
JPS63185390A (en) | 1987-01-27 | 1988-07-30 | Suntory Ltd | Production of eicosapentaenoic acid by algae |
US5252333A (en) | 1987-04-27 | 1993-10-12 | Scotia Holdings Plc | Lithium salt-containing pharmaceutical compositions |
US5198468A (en) | 1987-06-24 | 1993-03-30 | Efamol Holdings Plc | Essential fatty acid composition |
US4843095A (en) | 1987-08-07 | 1989-06-27 | Century Laboratories, Inc. | Free fatty acids for treatment or propyhlaxis of rheumatoid arthritis arthritis |
GB8819110D0 (en) | 1988-08-11 | 1988-09-14 | Norsk Hydro As | Antihypertensive drug & method for production |
US5116871A (en) | 1988-09-13 | 1992-05-26 | Efamol Holdings Plc | Fatty acid therapy and compositions for the treatment of myalgic encephalomyelitis |
GB2223943A (en) | 1988-10-21 | 1990-04-25 | Tillotts Pharma Ag | Oral disage forms of omega-3 polyunsaturated acids |
US4935243A (en) | 1988-12-19 | 1990-06-19 | Pharmacaps, Inc. | Chewable, edible soft gelatin capsule |
JP2839276B2 (en) | 1989-01-23 | 1998-12-16 | 日本分光工業株式会社 | Supercritical fluid extraction / separation method and apparatus |
GB8906369D0 (en) | 1989-03-20 | 1989-05-04 | Tisdale Michael J | Eicosapentaenoic acid |
US5457130A (en) | 1989-03-20 | 1995-10-10 | Cancer Research Campaign Technology Limited | Eicosapentaenoic acid used to treat cachexia |
CA2043615C (en) | 1990-06-04 | 2001-08-14 | Kazuhiko Hata | Method of producing eicosapentaenoic acid or the ester derivative thereof |
GB9012651D0 (en) | 1990-06-06 | 1990-07-25 | Efamol Holdings | Essential fatty acid treatment |
JP3103588B2 (en) | 1990-11-16 | 2000-10-30 | 持田製薬株式会社 | Lipoprotein (a) lowering agent |
SE9101642D0 (en) | 1991-05-30 | 1991-05-30 | Kabi Pharmacia Ab | phospholipids |
US5215630A (en) | 1991-06-04 | 1993-06-01 | Nippon Suisan Kaisha, Ltd. | Method of purifying eicosapentaenoic acid or the ester derivative thereof by fractional distillation |
AU2384292A (en) | 1991-07-30 | 1993-03-02 | North Carolina State University | Method and apparatus for measuring blood lipoprotein levels by nmr spectroscopy |
DE4133694C2 (en) | 1991-10-11 | 1993-10-07 | Fresenius Ag | Use of an emulsion with polyunsaturated fatty acids for i.v. administration for the treatment of skin diseases |
JP3400466B2 (en) | 1991-10-28 | 2003-04-28 | 日本水産株式会社 | Method for producing high-purity eicosapentaenoic acid or ester thereof |
JPH0649479A (en) | 1992-07-28 | 1994-02-22 | Maruha Corp | Stabilization of omega,3-unsaturated fatty acid compound |
US5888541A (en) | 1992-08-21 | 1999-03-30 | Scotia Holdings Plc | Fatty acid treatment |
GB9217780D0 (en) | 1992-08-21 | 1992-10-07 | Efamol Holdings | Fatty acid treatment |
GB9300125D0 (en) | 1993-01-06 | 1993-03-03 | Scotia Holdings Plc | Compositions containing esters of unsaturated fatty acids |
WO1994028891A1 (en) | 1993-06-04 | 1994-12-22 | Martek Biosciences Corporation | Method of treating coronary vascular disease using docosahexaenoic acid |
GB9318611D0 (en) | 1993-09-08 | 1993-10-27 | Sandoz Nutrition Ltd | Improvements in or relating to organic compounds |
JP3325995B2 (en) | 1994-02-28 | 2002-09-17 | ミサワホーム株式会社 | Panel joint structure |
GB9403857D0 (en) | 1994-03-01 | 1994-04-20 | Scotia Holdings Plc | Fatty acid derivatives |
GB9404483D0 (en) | 1994-03-08 | 1994-04-20 | Norsk Hydro As | Refining marine oil compositions |
US5385929A (en) | 1994-05-04 | 1995-01-31 | Warner-Lambert Company | [(Hydroxyphenylamino) carbonyl] pyrroles |
US5760081A (en) | 1994-05-10 | 1998-06-02 | The General Hospital Corporation | Omega 3 fatty acids in the prevention of ventricular fibrillation |
JP3368100B2 (en) | 1994-06-02 | 2003-01-20 | キヤノン株式会社 | Toner for developing electrostatic images |
AU711482B2 (en) | 1994-06-28 | 1999-10-14 | Scotia Holdings Plc | Compositions for treatment of diabetic complications |
IT1274734B (en) | 1994-08-25 | 1997-07-24 | Prospa Bv | PHARMACEUTICAL COMPOSITIONS CONTAINING POLYUNSATURATED FATTY ACIDS, THEIR ESTERS OR SALTS, WITH VITAMINS OR ANTIOXIDANT PROVITAMINS |
JP2780154B2 (en) | 1995-02-17 | 1998-07-30 | 株式会社ヤクルト本社 | Yogurt |
MY118354A (en) | 1995-05-01 | 2004-10-30 | Scarista Ltd | 1,3-propane diol derivatives as bioactive compounds |
GB9509764D0 (en) | 1995-05-15 | 1995-07-05 | Tillotts Pharma Ag | Treatment of inflammatory bowel disease using oral dosage forms of omega-3 polyunsaturated acids |
GB9519661D0 (en) | 1995-09-27 | 1995-11-29 | Scotia Holdings Plc | Fatty acid treatment |
US5763496A (en) | 1995-11-27 | 1998-06-09 | The Research Foundation Of State University Of New York | Prevention of atherosclerosis using NADPH oxidase inhibitors |
AU2738497A (en) | 1996-04-24 | 1997-11-12 | Brigham And Women's Hospital | Omega-3 fatty acids and omega-3 phosphatidylcholine in the treatment of bipolar disorder |
US6077828A (en) | 1996-04-25 | 2000-06-20 | Abbott Laboratories | Method for the prevention and treatment of cachexia and anorexia |
US6248398B1 (en) | 1996-05-22 | 2001-06-19 | Applied Materials, Inc. | Coater having a controllable pressurized process chamber for semiconductor processing |
TW425285B (en) | 1996-06-10 | 2001-03-11 | Viva America Marketing Inc | Fish oil and garlic nutritive supplement |
US5861399A (en) | 1996-07-17 | 1999-01-19 | Heart Care Partners | Methods and compositions for the rapid and enduring relief of inadequate myocardial function |
US20020055539A1 (en) | 1996-10-02 | 2002-05-09 | Bockow Barry I. | Compositions and methods for treating cardiovascular conditions |
KR100657642B1 (en) | 1996-10-11 | 2006-12-19 | 스카리스타 리미티드 | Oil comprising eicosapentaenoic acid and/or stearidonic acid |
DE69622722T2 (en) | 1996-11-20 | 2003-02-27 | Nutricia Nv | Dietary composition containing fats for the treatment of metabolic syndrome |
US20010006644A1 (en) | 1997-07-31 | 2001-07-05 | David J. Bova | Combinations of hmg-coa reductase inhibitors and nicotinic acid and methods for treating hyperlipidemia once a day at night |
EP1025842B1 (en) | 1997-10-30 | 2004-07-21 | Morishita Jintan Co., Ltd. | Double-leyered capsule of unsaturated fatty acid or derivative thereof and process for producing the same |
CA2303864A1 (en) | 1997-11-25 | 1999-06-03 | Warner-Lambert Company | Inhibition of lipoprotein oxidation |
EP1039893B1 (en) | 1997-12-10 | 2011-02-02 | Cyclosporine Therapeutics Limited | Pharmaceutical compositions containing an omega-3 fatty acid oil |
NZ500703A (en) | 1998-11-04 | 2001-06-29 | F | Preparation of food-grade marine edible oils by treatment with silica, vacuum steam deodorisation and addition of a herb extract |
US20020055529A1 (en) | 1998-12-02 | 2002-05-09 | Bisgaier Charles Larry | Method for treating alzheimer's disease |
GB9901809D0 (en) | 1999-01-27 | 1999-03-17 | Scarista Limited | Highly purified ethgyl epa and other epa derivatives for psychiatric and neurological disorderes |
CA2260397A1 (en) | 1999-01-29 | 2000-07-29 | Atlantis Marine Inc. | Method of converting rendered triglyceride oil from marine sources into bland, stable food oil |
US20030104048A1 (en) | 1999-02-26 | 2003-06-05 | Lipocine, Inc. | Pharmaceutical dosage forms for highly hydrophilic materials |
US6193999B1 (en) | 1999-03-01 | 2001-02-27 | Banner Pharmacaps, Inc. | Gum acacia substituted soft gelatin capsules |
PT1156814E (en) | 1999-03-03 | 2004-01-30 | Eurovita A S | PHARMACEUTICAL COMPOUNDS DIETETIC SUPPLEMENTS AND COSMETIC COMPOSITIONS COMPREHENSING A FATTY ACID AND GINGER |
KR100423013B1 (en) | 1999-03-04 | 2004-03-12 | 산토리 가부시키가이샤 | Utilization of material containing docosapentaenoic acid |
US7112609B2 (en) | 1999-06-01 | 2006-09-26 | Drugtech Corporation | Nutritional supplements |
US6207699B1 (en) | 1999-06-18 | 2001-03-27 | Richard Brian Rothman | Pharmaceutical combinations for treating obesity and food craving |
CA2311974A1 (en) | 1999-06-28 | 2000-12-28 | Nisshin Flour Milling Co., Ltd. | Processes of selectively separating and purifying eicosapentaenoic and docosahexaenoic acids or their esters |
GB9916536D0 (en) | 1999-07-14 | 1999-09-15 | Scarista Limited | Nutritional or pharmaceutical compositions |
EP1072198B1 (en) | 1999-07-28 | 2008-05-14 | SWISS CAPS Rechte und Lizenzen AG | Preparation for use as medicament and/or nutritional supplement |
WO2001015552A1 (en) | 1999-08-30 | 2001-03-08 | Ocean Nutrition Canada Ltd. | A nutritional supplement for lowering serum triglyceride and cholesterol levels |
EP1125914A1 (en) | 2000-02-14 | 2001-08-22 | Nisshin Flour Milling Co., Ltd. | Process for separating and purifying eicosapentaenoic acid or its ester |
DK1157692T3 (en) | 2000-05-22 | 2006-02-06 | Pro Aparts Investimentos E Con | Composition of fatty acids containing at least 80% by weight of EPA and DHA, derivatives thereof and pharmaceutical use thereof |
US6620821B2 (en) | 2000-06-15 | 2003-09-16 | Bristol-Myers Squibb Company | HMG-CoA reductase inhibitors and method |
GB0016045D0 (en) | 2000-06-29 | 2000-08-23 | Laxdale Limited | Therapeutic combinations of fatty acids |
GB0016452D0 (en) | 2000-07-04 | 2000-08-23 | Kilgowan Limited | Vitamin K and essential fatty acids |
JP4391673B2 (en) | 2000-08-08 | 2009-12-24 | 花王株式会社 | Oil composition |
BR0113200A (en) | 2000-08-15 | 2003-09-16 | Pfizer Prod Inc | Therapeutic combination |
GB0101198D0 (en) | 2001-01-17 | 2001-02-28 | Scherer Technologies Inc R P | Ingestible compositions containing an odoriferous oil |
ITMI20010129A1 (en) | 2001-01-25 | 2002-07-25 | Pharmacia & Upjohn Spa | ESSENTIAL FATTY ACIDS IN THE THERAPY OF HEART INSUFFICIENCY AND HEART FAILURE |
GB0111282D0 (en) | 2001-05-09 | 2001-06-27 | Laxdale Ltd | Potentiation of therapeutic effects of fatty acids |
SK14502003A3 (en) | 2001-05-30 | 2004-10-05 | Laxdale Ltd | Coenzyme Q and eicosapentaenoic acid |
US20120214771A1 (en) | 2001-07-27 | 2012-08-23 | Fontini Sampalis | Compositions for treatment of cardiometabolic disorders |
ITMI20012384A1 (en) | 2001-11-12 | 2003-05-12 | Quatex Nv | USE OF POLYUNSATURATED FATTY ACIDS FOR THE PRIMARY PREVENTION OF MAJOR CARDIOVASCULAR EVENTS |
US20030144219A1 (en) | 2001-11-15 | 2003-07-31 | Phinney Stephen Dodge | Formulations and methods for treatment or amelioration of inflammatory conditions |
ITMI20020269A1 (en) | 2002-02-12 | 2003-08-12 | Victorix Assets Ltd | USE OF OMEGA-3 POLYUNSATURATED ACID ETHYL STERES IN PATIENTS WITH HEART INSUFFICIENCY |
JP2003306690A (en) | 2002-02-18 | 2003-10-31 | Nooburu:Kk | Oil-and-fat composition containing polyunsaturated fatty acid |
US20030166614A1 (en) | 2002-03-01 | 2003-09-04 | Harrison Stanley F. | Method for reducing cholesterol and triglycerides |
AU2003229993B2 (en) | 2002-05-03 | 2008-07-24 | Pronova Biopharma Norge As | Use of EPA and DHA in secondary prevention |
EP1549299B1 (en) | 2002-06-05 | 2014-08-20 | IVAX Pharmaceuticals s.r.o. | Reduction of gelatin cross-linking |
US7157235B2 (en) | 2002-06-17 | 2007-01-02 | St. Vincent's Hospital Sydney Limited | Methods of diagnosis, prognosis and treatment of cardiovascular disease |
US20040001874A1 (en) | 2002-06-24 | 2004-01-01 | Vital Living, Inc. | Safe and effective nutritional supplement formulations and associated regimens adapted to prevent and/or treat targeted diseases or medical or health conditions, and related methods |
JP2005532394A (en) | 2002-07-02 | 2005-10-27 | ガリレオ ファーマシューティカルズ, インコーポレイティド | Compositions and methods for reduction of inflammatory symptoms and / or biomarkers in female subjects |
US20060211761A1 (en) | 2002-07-08 | 2006-09-21 | Yatendra Kumar | Hmg-coa-reductase inhibitors |
US20080200453A1 (en) | 2002-07-29 | 2008-08-21 | Cincotta Anthony H | Methods of treating metabolic syndrome using dopamine receptor agonists |
EP1547588B1 (en) | 2002-08-20 | 2013-12-11 | Kowa Company, Ltd. | Soft capsule preparation |
DE20214847U1 (en) | 2002-09-24 | 2004-02-19 | Voss Automotive Gmbh | Connection device for pipes |
US7511131B2 (en) | 2002-11-13 | 2009-03-31 | Genzyme Corporation | Antisense modulation of apolipoprotein B expression |
US8017651B2 (en) | 2002-11-22 | 2011-09-13 | Bionexus, Ltd. | Compositions and methods for the treatment of HIV-associated fat maldistribution and hyperlipidemia |
AU2003284617A1 (en) | 2002-11-22 | 2004-06-18 | Nippon Suisan Kaisha, Ltd. | Composition containing organic substance having double bond with improved oxidation stability |
GB0228079D0 (en) | 2002-12-02 | 2003-01-08 | Laxdale Ltd | Huntington's Disease |
US8124582B2 (en) | 2002-12-06 | 2012-02-28 | Fibrogen, Inc. | Treatment of diabetes |
GB0301701D0 (en) | 2003-01-24 | 2003-02-26 | Ensay Ltd | Psoriasis and Eicosapentaenoic acid |
WO2004068970A2 (en) | 2003-01-31 | 2004-08-19 | The Procter & Gamble Company | Means for improving the appearance of mammalian keratinous tissue |
JP5362944B2 (en) | 2003-02-07 | 2013-12-11 | 持田製薬株式会社 | Prognostic agent for subarachnoid hemorrhage |
CA2516333C (en) | 2003-02-21 | 2011-08-23 | Mochida Pharmaceutical Co., Ltd. | Drug for reducing side effects in ribavirin / interferon combination therapy |
JP2006519244A (en) | 2003-03-05 | 2006-08-24 | ゾルファイ ファーマスーティカルズ ゲゼルシャフト ミット ベシュレンクテル ハフツング | Use of omega-3-fatty acids in the treatment of diabetic patients |
EP1605781A1 (en) | 2003-03-18 | 2005-12-21 | Novartis AG | Compositions comprising fatty acids and amino acids |
US7598227B2 (en) | 2003-04-16 | 2009-10-06 | Isis Pharmaceuticals Inc. | Modulation of apolipoprotein C-III expression |
US6846942B2 (en) | 2003-05-20 | 2005-01-25 | David Rubin | Method for preparing pure EPA and pure DHA |
US7205329B2 (en) | 2003-05-30 | 2007-04-17 | Microbia, Inc. | Modulators of CRTH2 activity |
WO2004112777A1 (en) | 2003-06-20 | 2004-12-29 | Mochida Pharmaceutical Co., Ltd. | Composition for prevention/treatment for varicose vein |
US20050042214A1 (en) | 2003-07-15 | 2005-02-24 | Gershwin M. Eric | Discovery of the microorganism that causes the human autoimmune disease, primary biliary cirrhosis |
EP1558220B1 (en) | 2003-07-24 | 2010-02-10 | Wockhardt Limited | Oral compositions for treatment of diabetes |
EP1685239B1 (en) | 2003-11-12 | 2014-05-21 | E.I. Du Pont De Nemours And Company | Delta-15 desaturases suitable for altering levels of polyunsaturated fatty acids in oilseed plants and oleaginous yeast |
ITMI20032247A1 (en) | 2003-11-19 | 2005-05-20 | Tiberio Bruzzese | INTERACTION OF POLAR DERIVATIVES OF COMPOUNDS INSATURATED WITH INORGANIC SUBSTRATES |
SE0303513D0 (en) | 2003-12-19 | 2003-12-19 | Pronova Biocare As | Use of a fatty acid composition comprising at least one of epa and any or any combination thereof |
GB2409644B (en) | 2003-12-31 | 2005-12-21 | Igennus Ltd | Formulation comprising eicosapentaenoic acid or an ester thereof and a triterpene or an ester thereof |
GB0403247D0 (en) | 2004-02-13 | 2004-03-17 | Tillotts Pharma Ag | A pharmaceutical composition |
EP1591114A1 (en) | 2004-03-12 | 2005-11-02 | Fournier Laboratories Ireland Limited | Use of metformin and orlistat for the treatment or prevention of obesity |
US20050215640A1 (en) | 2004-03-26 | 2005-09-29 | Baxter Jeffrey H | HMB compositions and uses thereof |
US7923043B2 (en) | 2004-03-30 | 2011-04-12 | Theta Biomedical Consulting & Development Co., Inc. | Method for protecting humans against superficial vasodilator flush syndrome |
US20050244367A1 (en) | 2004-05-03 | 2005-11-03 | Ilypsa, Inc. | Phospholipase inhibitors localized in the gastrointestinal lumen |
WO2005114190A2 (en) | 2004-05-19 | 2005-12-01 | Ppd Biomarker Discovery Sciences, Llc | Methods of identifying biomarkers |
TW200613009A (en) | 2004-06-11 | 2006-05-01 | Ono Pharmaceutical Co | Capsule having chewing stability |
GB0413730D0 (en) | 2004-06-18 | 2004-07-21 | Tillotts Pharma Ag | A pharmaceutical composition and its use |
GB0413729D0 (en) | 2004-06-18 | 2004-07-21 | Tillotts Pharma Ag | A pharmaceutical composition and its use |
JP2007284350A (en) | 2004-07-27 | 2007-11-01 | Takeda Chem Ind Ltd | Therapeutic agent for diabetes |
ITRM20040395A1 (en) | 2004-08-03 | 2004-11-03 | Sigma Tau Ind Farmaceuti | COMPOSITION INCLUDING STATINES AND FATTY ACIDS OMEGA 3. |
WO2006017627A2 (en) | 2004-08-06 | 2006-02-16 | Barry Sears | Dietary compositions comprising docosahexaenoic acid and eicosapentaenoic acid and use thereof for treating insulin resistance |
JP2008509154A (en) | 2004-08-06 | 2008-03-27 | トランスフオーム・フアーマシユーチカルズ・インコーポレーテツド | Novel statin drug compositions and related treatment methods |
US20090042979A1 (en) | 2004-08-06 | 2009-02-12 | Transform Pharmaceuticals Inc. | Novel Statin Pharmaceutical Compositions and Related Methods of Treatment |
CA2577345C (en) | 2004-08-18 | 2013-02-19 | Hiroki Ueshima | Jelly composition |
EP2404605B1 (en) | 2004-08-25 | 2015-04-22 | Essentialis, Inc. | Pharmaceutical formulations of potassium ATP channel openers and uses thereof |
CN1759834B (en) | 2004-09-17 | 2010-06-23 | 中国医学科学院医药生物技术研究所 | Application of berberine or associated with Simvastatin in preparing product for preventing or curing disease or symptom related to blood fat |
CA2581775A1 (en) | 2004-09-27 | 2006-04-06 | Sigmoid Biotechnologies Limited | Dihydropyrimidine microcapsule - formulations |
WO2006085144A2 (en) | 2004-10-15 | 2006-08-17 | Photonz Corporation Limited | Compositions containing high omega-3 and low saturated fatty acid levels |
FR2878747B1 (en) | 2004-12-03 | 2007-03-30 | Pierre Fabre Medicament Sa | USE OF OMEGA-3 FATTY ACID (S) FOR THE TREATMENT OF HYPERCHOLESTEROLEMIA CAUSED BY ANTI-RETROVIRAL TREATMENT IN HIV INFECTED PATIENTS |
MX2007006707A (en) | 2004-12-06 | 2008-01-16 | Reliant Pharmaceuticals Inc | Omega-3 fatty acids and dyslipidemic agent for lipid therapy. |
US20070191467A1 (en) | 2004-12-06 | 2007-08-16 | Reliant Pharmaceutical, Inc. | Statin and omega-3 fatty acids for lipid therapy |
CN101098690A (en) | 2004-12-06 | 2008-01-02 | 瑞莱恩特医药品有限公司 | Omega-3 fatty acids and dyslipidemic agent for lipid therapy |
US20090239927A1 (en) | 2004-12-06 | 2009-09-24 | George Bobotas | Statin and Omega-3 Fatty Acids For Lipid Therapy |
US20060135610A1 (en) | 2004-12-22 | 2006-06-22 | Bortz Jonathan D | Cardiovascular compositions |
GB2421909A (en) | 2004-12-23 | 2006-07-12 | Laxdale Ltd | Pharmaceutical compositions comprising EPA and methods of use |
WO2006073147A1 (en) | 2005-01-04 | 2006-07-13 | Mochida Pharmaceutical Co., Ltd. | Remedial agent for fat toxicity |
US20080200707A1 (en) | 2005-01-04 | 2008-08-21 | Mochida-Pharmaceuticals Pharmaceutical Co., Ltd. | Lipotoxicity Relieving Agent |
WO2006072881A1 (en) | 2005-01-10 | 2006-07-13 | Cortendo Invest Ab | Methods and compositions for treating diabetes, metabolic syndrome and other conditions |
US20060172012A1 (en) | 2005-01-28 | 2006-08-03 | Finley John W | Anti-inflammatory supplement compositions and regimens to reduce cardiovascular disease risks |
US20060189682A1 (en) | 2005-02-02 | 2006-08-24 | Payne Joseph E | Water soluble prodrugs of COX-2 inhibitors |
CA2598273A1 (en) | 2005-02-17 | 2006-08-24 | Merck & Co., Inc. | Method of treating atherosclerosis, dyslipidemias and related conditions |
US20100254951A1 (en) | 2005-02-22 | 2010-10-07 | Mochida Pharmaceutical Co., Ltd. | Nerve Regeneration Promoting Agent |
CN101208083A (en) | 2005-03-08 | 2008-06-25 | 瑞莱恩特医药品有限公司 | Treatment with statin and Omega-3 fatty acids and a combination product thereof |
EP1790339B1 (en) | 2005-07-08 | 2014-06-04 | Mochida Pharmaceutical Co., Ltd. | Composition for prevention of occurrence of cardiovascular event |
WO2007011886A2 (en) | 2005-07-18 | 2007-01-25 | Reliant Pharmaceuticals, Inc. | Treatment with azetidinone-based cholesterol absorption inhibitors and omega-3 fatty acids and a combination product thereof |
RU2290185C1 (en) | 2005-07-26 | 2006-12-27 | Дмитрий Николаевич Мясников | Composition for normalization of lipid metabolism and reducing body mass and method for its preparing |
EA200800451A1 (en) | 2005-07-28 | 2008-08-29 | Релайэнт Фармасьютикалз, Инк. | TREATMENT OF DIHYDROPYRIDINE BLOCKERS OF CALCIUM CHANNELS AND FATTY ACIDS OF OMEGA-3 AND THEIR COMBINED PRODUCT |
ITMI20051560A1 (en) | 2005-08-10 | 2007-02-11 | Tiberio Bruzzese | COMPOSITION OF N-3 FATTY ACIDS WITH HIGH CONCENTRATION OF EPA AND E-O DHA AND CONTAINING N-6 FATTY ACIDS |
US7405302B2 (en) | 2005-10-11 | 2008-07-29 | Amira Pharmaceuticals, Inc. | 5-lipoxygenase-activating protein (FLAP) inhibitors |
EP1948168A4 (en) | 2005-10-28 | 2010-10-06 | Numerate Inc | Compositions and treatments for inhibiting kinase and/or hmg-coa reductase |
US20070105793A1 (en) | 2005-11-04 | 2007-05-10 | Curt Hendrix | Compositions and methods using nicotinic acid for treatment of hypercholesterolemia, hyperlipidemia nd cardiovascular disease |
US20070104779A1 (en) | 2005-11-07 | 2007-05-10 | Rongen Roelof M | Treatment with omega-3 fatty acids and products thereof |
BRPI0618455A2 (en) | 2005-11-11 | 2011-08-30 | Mochida Pharm Co Ltd | jelly composition |
WO2007058523A1 (en) | 2005-11-17 | 2007-05-24 | N.V. Nutricia | Composition with docosapentaenoic acid |
RU2395280C2 (en) | 2005-11-21 | 2010-07-27 | Тева Фармасьютикл Индастриес Лтд. | Pharmaceutical medical form of atorvastatin |
JP2009520824A (en) | 2005-12-20 | 2009-05-28 | セネストラ エルエルシー | Omega 3 fatty acid preparation |
ATE509624T1 (en) | 2005-12-23 | 2011-06-15 | Nutricia Nv | COMPOSITION CONTAINING POLYUNSATURATED FATTY ACIDS, PROTEINS, MANGANEOUS AND/OR MOLYBDENES AND NUCLEOTIDES/NUCLEOSIDES, FOR THE TREATMENT OF DEMENTIA |
WO2007081773A2 (en) | 2006-01-05 | 2007-07-19 | Reliant Pharmaceuticals, Inc | Treatment of fatty liver |
EP1905424A3 (en) | 2006-02-02 | 2008-04-30 | Ranbaxy Laboratories Limited | Process for the preparation of a pharmaceutical composition comprising stabilized statin particles |
WO2007091338A1 (en) | 2006-02-07 | 2007-08-16 | Mochida Pharmaceutical Co., Ltd. | Composition for prevention of recurrence of stroke |
BRPI0707794A2 (en) | 2006-02-14 | 2011-05-10 | Intercept Pharmaceuticals Inc | bile acid derivatives, formulations and pharmaceutical compositions, as well as use of said compounds |
US8784886B2 (en) | 2006-03-09 | 2014-07-22 | GlaxoSmithKline, LLC | Coating capsules with active pharmaceutical ingredients |
WO2007128801A1 (en) | 2006-05-08 | 2007-11-15 | Novartis Ag | Combination of organic compounds |
EP2777701A1 (en) | 2006-05-31 | 2014-09-17 | Mochida Pharmaceutical Co., Ltd. | Composition for preventing the occurrence of a cardiovascular event in multiple risk patient comprising the ethyl ester of all-cis-5,8,11,14,17-icosapentaenoic acid |
CA2656311C (en) | 2006-07-05 | 2016-06-21 | Photonz Corporation Limited | Ultra pure epa and polar lipids produced in largely heterotrophic culture |
US20090304784A1 (en) | 2006-07-28 | 2009-12-10 | V. Mane Fils | Seamless capsules containing high amounts of polyunsaturated fatty acids and a flavouring component |
CN101553221A (en) | 2006-10-10 | 2009-10-07 | 瑞莱恩特医药品有限公司 | Statin and omega-3 fatty acids for reduction of APO-B levels |
US20080085911A1 (en) | 2006-10-10 | 2008-04-10 | Reliant Pharmaceuticals, Inc. | Statin and omega-3 fatty acids for reduction of apo-b levels |
JP2010506920A (en) | 2006-10-18 | 2010-03-04 | リライアント・ファーマシューティカルズ・インコーポレイテッド | Omega-3 fatty acids for reducing LP-PLA2 concentration |
US20080125490A1 (en) | 2006-11-03 | 2008-05-29 | My Svensson | Treatment and prevention of cardiovascular disease in patients with chronic kidney disease by administering Omega-3 Fatty Acids |
US20080306154A1 (en) | 2006-11-03 | 2008-12-11 | My Svensson | Treatment and prevention of major adverse cardiovascular events or major coronary evens by administering Omega-3 fatty acids |
WO2008088030A1 (en) | 2007-01-17 | 2008-07-24 | Mochida Pharmaceutical Co., Ltd. | Composition for prevention or treatment of disease associated with thrombus or embolus |
WO2008091338A1 (en) | 2007-01-23 | 2008-07-31 | Reddy Us Therapeutics, Inc. | Methods and compositions for the treatment of insulin resistance, diabetes, and diabetes-associated dyslipidemia |
US20080185198A1 (en) | 2007-02-02 | 2008-08-07 | Steven Mark Jones | Next generation hybrid III parallel/series hybrid system |
ES2561482T3 (en) | 2007-02-15 | 2016-02-26 | Centre De Recherche Sur Les Biotechnologies Marine | Monoglycerides of polyunsaturated fatty acid, derivatives, and their uses |
WO2008106787A1 (en) | 2007-03-06 | 2008-09-12 | Bioriginal Food & Science Corporation | Soft gelatin capsule shells containing oil soluble flavoring and methods of making the same |
WO2008115529A1 (en) | 2007-03-20 | 2008-09-25 | Reliant Pharmaceuticals, Inc. | Compositions comprising omega-3 fatty acids and cetp inhibitors |
WO2008145170A1 (en) | 2007-05-31 | 2008-12-04 | Siemens Aktiengesellschaft | Method for configuring an automation system |
US20080299187A1 (en) | 2007-06-01 | 2008-12-04 | Joar Opheim | Substances for Reducing Occurence of Major Cardiac Events in Humans |
AU2008272135B2 (en) | 2007-06-29 | 2013-10-31 | Takeda Pharmaceutical Company Limited | Seamless capsule |
US8969400B2 (en) | 2007-10-01 | 2015-03-03 | Duke University | Pharmaceutical compositions of 5-hydroxytryptophan and serotonin-enhancing compound |
AU2008343689A1 (en) | 2007-12-20 | 2009-07-09 | Abbott Laboratories | Stable nutritional powder |
US8361534B2 (en) | 2007-12-20 | 2013-01-29 | Abbott Laboratories | Stable nutritional powder |
JP5421126B2 (en) | 2008-01-10 | 2014-02-19 | 武田薬品工業株式会社 | Capsule formulation |
US20090182049A1 (en) | 2008-01-16 | 2009-07-16 | Joar Arild Opheim | Pharmaceutical Composition and Method for Treating Hypertriglyceridemia and Hypercholesterolemia in Humans |
EP2291499B1 (en) | 2008-05-15 | 2020-02-12 | Basf As | Krill oil process |
CA2724983A1 (en) | 2008-05-20 | 2009-11-26 | Mochida Pharmaceutical Co., Ltd. | Composition for preventing cardiovascular event in high-risk patient |
WO2009151125A1 (en) | 2008-06-13 | 2009-12-17 | 持田製薬株式会社 | Diagnosis and treatment of hepatic disorder |
WO2009151116A1 (en) | 2008-06-13 | 2009-12-17 | 持田製薬株式会社 | Prophylactic/ameliorating or therapeutic agent for non-alcoholic steatohepatitis |
JPWO2009154230A1 (en) | 2008-06-17 | 2011-12-01 | 持田製薬株式会社 | Non-alcoholic steatohepatitis prevention / improvement / treatment drug |
EP2308493A4 (en) | 2008-07-07 | 2013-05-01 | Mochida Pharm Co Ltd | Ameliorating or therapeutic agent for dyslipidemia |
US20110236476A1 (en) | 2008-09-02 | 2011-09-29 | Amarin Corporation Plc. | Pharmaceutical composition comprising eicosapentaenoic acid and nicotinic acid and methods of using same |
CA2738985A1 (en) | 2008-09-30 | 2010-04-08 | Mochida Pharmaceutical Co., Ltd. | Therapeutic agent for hepatitis c |
US20100130608A1 (en) | 2008-10-01 | 2010-05-27 | Martek Biosciences Corporation | Compositions and methods for reducing triglyceride levels |
US20120035105A1 (en) | 2009-01-09 | 2012-02-09 | Sdg, Inc. | Insulin Therapies for the Treatment of Diabetes, Diabetes Related Ailments, and/or Diseases or Conditions Other Than Diabetes or Diabetes Related Ailments |
CA2750561C (en) | 2009-01-26 | 2017-10-10 | Protiva Biotherapeutics, Inc. | Compositions and methods for silencing apolipoprotein c-iii expression |
KR20140007973A (en) | 2009-02-10 | 2014-01-20 | 아마린 파마, 인크. | Methods of treating hypertriglyceridemia |
US8241672B2 (en) | 2009-03-11 | 2012-08-14 | Stable Solutions Llc | Omega-3 enriched fish oil-in-water parenteral nutrition emulsions |
US20120046251A1 (en) | 2009-04-06 | 2012-02-23 | The Regents Of The University Of California | Inhibitors of soluble epoxide hydrolase to inhibit or prevent niacin-induced flushing |
NZ624963A (en) | 2009-04-29 | 2016-07-29 | Amarin Pharmaceuticals Ie Ltd | Pharmaceutical compositions comprising epa and a cardiovascular agent and methods of using the same |
JP5313343B2 (en) | 2009-05-22 | 2013-10-09 | 持田製薬株式会社 | Self-emulsifying composition of ω3 fatty acid |
RU2402326C1 (en) | 2009-06-22 | 2010-10-27 | Учреждение Российской академии медицинских наук Дальневосточный научный центр физиологии и патологии дыхания Сибирского отделения Российской академии медицинских наук (ДНЦ ФПД СО РАМН) | Method for insulin resistance correction in metabolic syndrome |
US8557275B2 (en) | 2009-07-23 | 2013-10-15 | U.S. Nutraceuticals, LLC | Composition and method to alleviate joint pain using a mixture of fish oil and fish oil derived, choline based, phospholipid bound fatty acid mixture including polyunsaturated EPA and DHA |
BR112012004677A2 (en) | 2009-09-01 | 2020-11-03 | Catabasis Pharmaceuticals, Inc. | niacin fatty acid conjugates and their uses |
WO2011038122A1 (en) | 2009-09-23 | 2011-03-31 | Amarin Corporation Plc | Pharmaceutical composition comprising omega-3 fatty acid and hydroxy-derivative of a statin and methods of using same |
EP2488022B1 (en) | 2009-10-16 | 2018-01-10 | Mochida Pharmaceutical Co., Ltd. | Compositions |
WO2011046204A1 (en) | 2009-10-16 | 2011-04-21 | 持田製薬株式会社 | Marker associated with non-alcoholic steatohepatitis |
WO2011085211A1 (en) | 2010-01-08 | 2011-07-14 | Catabasis Pharmaceuticals, Inc. | Fatty acid fumarate derivatives and their uses |
US20110178105A1 (en) | 2010-01-15 | 2011-07-21 | E.I. Du Pont De Nemours And Company | Clinical benefits of eicosapentaenoic acid in humans |
US8846321B2 (en) | 2010-03-12 | 2014-09-30 | President And Fellows Of Harvard College | Association of levels of HDL-cholesterol apolipoprotein CIII with the risk of coronary heart disease and cardiovascular events |
US8663704B2 (en) | 2010-04-30 | 2014-03-04 | U.S. Nutraceuticals, LLC | Composition and method to improve blood lipid profiles and optionally reduce low density lipoprotein (LDL) per-oxidation in humans |
AU2011249630B2 (en) | 2010-05-05 | 2014-01-23 | St. Giles Foods Limited | Edible compositions and methods of manufacturing edible compositions |
ES2710540T5 (en) | 2010-06-30 | 2022-08-26 | Mochida Pharm Co Ltd | Omega-3 fatty acid compound preparation |
WO2012054555A2 (en) | 2010-10-20 | 2012-04-26 | Glycomark, Inc. | Improved identification of pre-diabetes using a combination of mean glucose and 1,5-anhydroglucitol markers |
CN104814950A (en) | 2010-11-09 | 2015-08-05 | 持田制药株式会社 | Agent for inhibiting elevation in postprandial blood glucose level |
NZ744990A (en) | 2010-11-29 | 2019-10-25 | Amarin Pharmaceuticals Ie Ltd | Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity |
KR101310710B1 (en) | 2011-03-23 | 2013-09-27 | 한미약품 주식회사 | Oral complex composition comprising omega-3 fatty acid ester and hmg-coa reductase inhibitor |
US20120264824A1 (en) | 2011-04-15 | 2012-10-18 | Mochida Pharmaceutical Co., Ltd. | Compositions and methods for treating non-alcoholic steatohepatitis |
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KR102488648B1 (en) | 2015-01-21 | 2023-01-12 | 모치다 세이야쿠 가부시키가이샤 | SELF-EMULSIFYING COMPOSITION OF ω-3 FATTY ACID |
EP3248599B1 (en) | 2015-01-21 | 2022-07-06 | Mochida Pharmaceutical Co., Ltd. | Omega-3 fatty acid self-emulsifying composition |
US20180028480A1 (en) | 2015-03-02 | 2018-02-01 | Richard Preston Mason | Methods of reducing or preventing oxidative modification of membrane polyunsaturated fatty acids |
US20170151202A1 (en) | 2015-09-09 | 2017-06-01 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing or preventing oxidation of small dense ldl or membrane polyunsaturated fatty acids |
US10406130B2 (en) | 2016-03-15 | 2019-09-10 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing or preventing oxidation of small dense LDL or membrane polyunsaturated fatty acids |
HUE053081T2 (en) | 2016-07-29 | 2021-06-28 | Kowa Co | Methods of preventing cardiovascular events in residual risk dyslipidemic populations |
-
2012
- 2012-11-07 US US13/671,197 patent/US20130131170A1/en not_active Abandoned
- 2012-11-07 EP EP12847246.1A patent/EP2775837A4/en not_active Withdrawn
- 2012-11-07 WO PCT/US2012/063909 patent/WO2013070735A1/en active Application Filing
-
2015
- 2015-11-09 US US14/936,295 patent/US10537544B2/en active Active
-
2019
- 2019-06-10 US US16/436,364 patent/US10632094B2/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050187292A1 (en) * | 2004-02-19 | 2005-08-25 | Kowa Co., Ltd. | Hyperlipemia therapeutic agent |
US20100278879A1 (en) * | 2009-04-29 | 2010-11-04 | Amarin Pharma, Inc. | Stable pharmaceutical composition and methods of using same |
US20110034555A1 (en) * | 2009-06-15 | 2011-02-10 | Amarin Pharma , Inc. | Compositions and methods for lowering triglycerides without raising ldl-c levels in a subject on concomitant statin therapy |
US20110218243A1 (en) * | 2010-03-04 | 2011-09-08 | Amarin Pharma, Inc. | Compositions and methods for treating and/or preventing cardiovascular disease |
Non-Patent Citations (3)
Title |
---|
MOSTAD ET AL.: "Effects of marine n-3 fatty acid supplementation on lipoprotein subclasses measured by nuclear magnetic resonance in subjects with type II diabetes", EUROPEAN JOURNAL OF CLINICAL NUTRITION, vol. 62, 2008, pages 419 - 429, XP055151453 * |
NOHARA ET AL.: "Eicosapentaenoic Acid Add-on to Atorvastatin Normalizes Pre-'1-HDL Levels", CIRCULATION, vol. 122, 2010, pages A17785, XP055151458 * |
See also references of EP2775837A4 * |
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Also Published As
Publication number | Publication date |
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EP2775837A1 (en) | 2014-09-17 |
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