NZ763702B2 - Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity - Google Patents
Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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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
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4875—Compounds of unknown constitution, e.g. material from plants or animals
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Abstract
Disclosed is the use of ethyl eicosapentaenoate in the manufacture of a medicament to treat or prevent stroke, myocardial infarction, or both in a subject on statin therapy, wherein (a) the subject has been identified as having a baseline triglyceride level of at least about 150 mg/dL and as allergic or hypersensitive to fish or seafood, and (b) the medicament is formulated to provide about 4 g of ethyl eicosapentaenoate to the subject per day, is substantially free of fish protein, and is encapsulated in one or more capsules. ic or hypersensitive to fish or seafood, and (b) the medicament is formulated to provide about 4 g of ethyl eicosapentaenoate to the subject per day, is substantially free of fish protein, and is encapsulated in one or more capsules.
Description
TITLE
LOW ERUCTATION COMPOSITION AND METHODS FOR TREATING AND/OR
PREVENTING CARDIOVASCULAR DISEASE IN A SUBJECT WITH FISH
ALLERGY/HYPERSENSITIVITY
This application is a divisional of New Zealand patent application 757815, itself a divisional
of New Zealand patent application 744990, itself a divisional of New Zealand patent
application 727980, itself a divisional of New Zealand patent application 712068, itself a
divisional of New Zealand patent application 611606, which is the national phase entry in
New Zealand of PCT international application (published as WO
2012/074930), filed 28 November 2011, all of which are incorporated herein by reference.
BACKGROUND
Cardiovascular disease is one of the leading causes of death in the United States
and most European countries. It is estimated that over 70 million people in the United States
alone suffer from a cardiovascular disease or disorder including but not limited to high blood
pressure, coronary heart disease, dislipidemia, congestive heart failure and stroke. A need
exists for improved treatments for cardiovascular diseases and disorders.
It is further estimated that more than 6 million Americans suffer from some form
of seafood allergy. Sicherer et al., Journal of Allergy and Clinical Immunology, Volume 114,
Issue 1, Pages 159-165. Therapies derived from fish oil have been proven effective at
lowering triglycerides, among other effects. Unfortunately, such products are contraindicated
in subjects that are allergic or hypersensitive to fish. It is an object of the present invention to
overcome the need in the art and/or to at least provide the public with a useful choice.
SUMMARY
[0002a] In a first aspect te present invention provides a use of ethyl eicosapentaenoate
in the manufacture of a medicament to treat or prevent stroke, myocardial infarction, or both
in a subject on statin therapy, wherein
(a) the subject has been identified as having a baseline triglyceride level of at least
about 150 mg/dL and as allergic or hypersensitive to fish or seafood, and
(b) the medicament is formulated to provide about 4 g of ethyl eicosapentaenoate to
the subject per day, is substantially free of fish protein, and is encapsulated in one or more
capsules.
[0002b] In a second aspect the present invention provides a use of ethyl
eicosapentaenoate in the manufacture of a medicament for treating hypertriglyceridemia in a
subject in need thereof, wherein
(a) the subject has been identified as having fasting baseline triglyceride level of at
least about 500 mg/dl and as allergic to fish or seafood, and
(b) the medicament is formulated to provide about 4 g of ethyl eicosapentaenoate to
the subject per day, is substantially free of fish protein, and is encapsulated in one or more
capsules.
In various embodiments, described are 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).
In various embodiments, described herein are pharmaceutical compositions and
methods of using such compositions to increase plasma, serum and/or red blood cell (RBC)
EPA levels and/or to treat or prevent cardiovascular-related diseases. In one embodiment, the
subject being treated is hypersentive and/or allergic to seafood, shellfish and/or fish. In other
embodiments, ingestion of the pharmaceutical composition causes no or reduced eructation as
compared to placebo and/or to commercially available omega-3 fatty acid blends (e.g.
Lovaza).
In a related embodiment, ingestion of the pharmaceutical composition as set forth
herein does not cause skin rash or causes reduced incidence of skin rash compared to placebo
and/or commercially available omega-3 fatty acid blends (e.g. Lovaza).
In one embodiment, described is a pharmaceutical composition comprising,
consisting of or consisting 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), for example not more than
about 0.06%, about 0.05%, or about 0.04%, by weight. In a related embodiment, the
composition is substantially free of or is free of allergens.
In another embodiment, described is a method of increasing serum, plasma and/or
red blood cell (RBC) EPA levels comprising administering a composition as described herein
to a subject in need of increased serum, plasma and/or RBC EPA levels.
In a related embodiment, the subject has a baseline EPA plasma, serum and/or
RBC level not greater than about 50 μg/g and upon administering the composition to the
subject for a period of at least about 6 weeks, the subject exhibits at least a 100%, at least a
150%, at least a 200%, at least a 250%, at least 300%, at least 350% or at least 400% increase
(change in EPA level divided by baseline EPA level) in plasma, serum and/or RBC EPA
levels compared to baseline or placebo control. In a related embodiment, the subject has a
baseline EPA plasma, serum and/or RBC level not greater than about 50 μg/g. In another
embodiment, the subject is provided with an amount of said composition effective to achieve
said increases in EPA levels. In another embodiment, the subject is provided with about 2 g
to about 4 g per day of said composition.
In another embodiment, described is a method of treating a cardiovascular-related
disease in a subject in need thereof, comprising administering a composition as described
herein to the subject. In a related embodiment, the subject has a baseline EPA plasma, serum
and/or RBC level not greater than about 50 μg/g and upon administering the composition to
the subject for a period of at least about 6 weeks, the subject exhibits at least about a 100%, at
least about a 150%, at least about a 200%, at least about a 250%, at least about a 300%, at
least about a 350% or at least about a 400% increase in plasma, serum and/or RBC EPA
levels compared to baseline or placebo control. In a related embodiment, the subject has a
baseline EPA plasma, serum and/or RBC level not greater than about 50 μg/g. In another
embodiment, the subject is provided with about 2 g to about 4 g per day of said composition.
These and other embodiments of the present invention will be disclosed in further
detail herein below.
DETAILED DESCRIPTION
While the present invention is capable of being embodied in various forms, the
description below of several embodiments is made with the understanding that the present
disclosure is to be considered as an exemplification of the invention, and is not intended to
limit the invention to the specific embodiments illustrated. Headings are provided for
convenience only and are not to be construed to limit the invention in any manner.
Embodiments illustrated under any heading may be combined with embodiments illustrated
under any other heading.
The use of numerical values in the various quantitative values specified in this
application, unless expressly indicated otherwise, are stated as approximations as though the
minimum and maximum values within the stated ranges were both preceded by the word
“about.” Also, the disclosure of ranges is intended as a continuous range including every
value between the minimum and maximum values recited as well as any ranges that can be
formed by such values. Also disclosed herein are any and all ratios (and ranges of any such
ratios) that can be formed by dividing a disclosed numeric value into any other disclosed
numeric value. Accordingly, the skilled person will appreciate that many such ratios, ranges,
and ranges of ratios can be unambiguously derived from the numerical values presented
herein and in all instances such ratios, ranges, and ranges of ratios represent various
embodiments of the present invention.
In one embodiment, described are pharmaceutical compositions comprising
eicosapentaenoic acid or a derivative thereof. In one embodiment, such compositions
comprise 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.
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 C – C 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 all-cis eicosa-5,8,11,14,17-pentaenoic acid ethyl
ester.
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.
In another embodiment, described is a composition comprising EPA for the
treatment of hypertriglyceridemia in a subject or subjects that is/are allergic to fish. In one
embodiment, a subject is diagnosed as allergic to fish (e.g. by prior history, allergic
challenge, shellfish mix skin prick test or fish mix skin prick test) or other methodology)
prior to or after initiation of administration of the composition described herein to said
subject or subjects.
In another embodiment, described is a composition comprising EPA as defined
herein for the treatment of hypertriglyceridemia in a subject or subjects that is susceptible to
eructation or that experiences eructation while on other commercially available omega-3 fatty
acid therapy (e.g. Lovaza).
In another embodiment, the composition is present in a dosage unit (e.g. a capsule)
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 or about 2500 mg.
In another embodiment, a composition useful herein contains not more than about
%, 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) or derivative thereof such as ethyl-DHA, if any. In another
embodiment, a composition described herein contains substantially no DHA or ethyl-DHA.
In still another embodiment, a composition useful herein contains no DHA or derivative
thereof such as DHA-E.
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 described herein.
In another embodiment, a composition useful herein 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 or derivative thereof
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 (DPA). In
another embodiment, a composition useful herein 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.
In another embodiment, a composition described herein 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.
In another embodiment, described is a composition comprising, consisting
essentially of, or consisting 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.
In another embodiment, described is a composition comprising, consisting of or
consisting essentially 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,
described is a dosage form comprising about 500 mg to about 1 g of the foregoing
composition in a capsule shell.
In another embodiment, described is a composition comprising, consisting of, or
consisting essentially 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,
described is a dosage form comprising about 500 mg to about 1 g of the foregoing
composition in a capsule shell.
In another embodiment, described is a method of increasing serum, plasma and/or
red blood cell (RBC) EPA levels comprising administering a composition as described herein
to a subject in need of such treatment. In one embodiment, upon orally administering a
composition as set forth herein to a subject for a period of at least about 5, about 10, about 15,
about 20, about 25, about 30, about 35, about 40, about 42, about 45 or about 50 days, the
subject exhibits at least about a 2-fold, at least about a 3-fold, at least about a 3.5-fold, at least
about a 3.75-fold or at least about a 4-fold change (final absolute EPA level divided by
baseline EPA level) in serum, plasma and/or RBC EPA. In one embodiment, the method
comprises a step of identifying a patient in need of an increase in serum, plasma and/or red
blood cell (RBC) EPA prior to said administration step. In a related embodiment, the subject
has a baseline EPA plasma, serum and/or RBC level not greater than about 50 μg/g. In
another embodiment, the subject is provided with about 2 g to about 4 g per day of said
composition. In another embodiment, upon administering the composition to the subject as
per above, the subject exhibits a decrease in DHA, AA and/or DGLA plasma, serum and/or
RBC levels. In another embodiment, upon administering the composition to the subject as
per above, the subject exhibits an increase in DPA plasma, serum and/or RBC levels. In still
another embodiment, upon administering the composition to the subject as per above, DHA
plasma, serum and/or RBC levels decrease by at least 16%, DGLA plasma, serum and/or
RBC levels decrease by at least 31%, AA plasma, serum and/or RBC levels decrease by at
least 20%, and/or DPA plasma, serum and/or RBC levels increase by greater than 130%.
In another embodiment, described is a method of increasing serum, plasma and/or
red blood cell (RBC) EPA levels comprising administering a composition as described herein
to a subject in need of increased serum, plasma and/or RBC EPA levels. In a related
embodiment, upon administering the composition to the subject for a period of at least about
, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 42, about 45, or
about 50 days, the subject exhibits at least about a 100%, at least about a 150%, at least about
a 200%, at least about a 250%, at least about a 300%, at least about a 350% or at least about a
400% increase (change in EPA level from baseline divided by baseline EPA level) in plasma,
serum and/or RBC EPA levels compared to baseline or placebo control. In a related
embodiment, the subject has a baseline EPA plasma, serum and/or RBC level not greater than
about 50 μg/g. In another embodiment, the subject is provided with about 2 g to about 4 g
per day of said composition. In another embodiment, upon administering the composition to
the subject as per above, the subject exhibits a decrease in DHA, AA and/or DGLA plasma,
serum and/or RBC levels. In another embodiment, upon administering the composition to the
subject as per above, the subject exhibits an increase in DPA plasma, serum and/or RBC
levels. In still another embodiment, upon administering the composition to the subject as per
above, DHA plasma, serum and/or RBC levels decrease by at least 16%, DGLA plasma,
serum and/or RBC levels decrease by at least 31%, AA plasma, serum and/or RBC levels
decrease by at least 20%, and/or DPA plasma, serum and/or RBC levels increase by greater
than 130%.
In a related embodiment, upon orally administering about 2 to about 4 g per day of
a composition as set forth herein to a subject for a period of at least about 5, about 10, about
, about 20, about 25, about 30, about 35, about 40, about 45 or about 50 days, the subject
exhibits at least about a 10 μg/g increase, at least about a 15 μg/g increase, at least about a 20
μg/g increase, at least about a 25 μg/g increase, at least about a 30 μg/g increase, at least
about a 35 μg/g increase, at least about a 40 μg/g increase, at least about a 45 μg/g increase,
at least about a 50 μg/g increase, at least about a 75 μg/g increase, at least about a 100 μg/g
increase, or at least about a 150 μg/g increase in serum, plasma and/or RBC EPA compared
to baseline or placebo control. In another embodiment, upon administering the composition to
the subject as per above, the subject exhibits a decrease in DHA, AA and/or DGLA plasma,
serum and/or RBC levels. In another embodiment, upon administering the composition to the
subject as per above, the subject exhibits an increase in DPA plasma, serum and/or RBC
levels. In still another embodiment, upon administering the composition to the subject as per
above, DHA plasma, serum and/or RBC levels decrease by at least 16%, DGLA plasma,
serum and/or RBC levels decrease by at least 31%, AA plasma, serum and/or RBC levels
decrease by at least 20%, and/or DPA plasma, serum and/or RBC levels increase by greater
than 130%.
In another embodiment, the subject has not been on an omega-3 fatty acid therapy
or supplement for at least 2 weeks, 3 weeks, 4 weeks, 6 weeks or 12 weeks prior to initiating
therapy as described herein.
In one embodiment, described is a composition for use in the treatment of, or a
method for treatment and/or prevention of cardiovascular-related diseases comprising
administering to a subject in need of such treatment or prevention a composition as set forth
herein. The term “cardiovascular-related disease” herein refers to any disease or disorder of
the heart or blood vessels (i.e. arteries and veins) or any symptom thereof. Non-limiting
examples of cardiovascular-related disease and disorders include hypertriglyceridemia,
hypercholesterolemia, mixed dyslipidemia, coronary heart disease, vascular disease, stroke,
atherosclerosis, arrhythmia, hypertension, myocardial infarction, and other cardiovascular
events.
The term “treatment” in relation a given disease or disorder, includes, but is not
limited to, inhibiting the disease or disorder, for example, arresting the development of the
disease or disorder; relieving the disease or disorder, for example, causing regression of the
disease or disorder; or relieving a condition caused by or resulting from the disease or
disorder, for example, relieving, preventing or treating symptoms of the disease or disorder.
The term “prevention” in relation to a given disease or disorder means: preventing the onset
of disease development if none had occurred, preventing the disease or disorder from
occurring in a subject that may be predisposed to the disorder or disease but has not yet been
diagnosed as having the disorder or disease, and/or preventing further disease/disorder
development if already present.
In one embodiment, described is a method of blood lipid therapy comprising
administering to a subject or subject group in need thereof a pharmaceutical composition as
described herein. In another embodiment, the subject or subject group has
hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia and/or very high
triglycerides.
In another embodiment, the subject or subject group being treated has a baseline
triglyceride level (or mean or median baseline triglyceride level in the case of a subject
group), fed or fasting, of about 200 mg/dl to about 500 mg/dl. In another embodiment, the
subject or subject group has a baseline LDL-C level (or mean or median baseline LDL-C
level), despite statin therapy, of about 40 mg/dl to about 100 mg/dl.
In one embodiment, the subject or subject group being treated in accordance with
methods described herein is on concomitant statin therapy, for example atorvastatin,
rosuvastatin or simvastatin therapy (with or without ezetimibe). In another embodiment, the
subject is on concomitant stable statin therapy at time of initiation of ultra-pure EPA therapy.
In another embodiment, the subject or subject group being treated in accordance
with methods described herein has a body mass index (BMI or mean BMI) of not more than
about 45 kg/m .
In one embodiment, described is a method of lowering triglycerides in a subject on
stable statin therapy having baseline fasting triglycerides of about 200 mg/dl to about 500
mg/dl, the method comprising administering to the subject a pharmaceutical composition
comprising about 1 g to about 4 g of EPA (e.g. ultra-pure EPA), wherein upon administering
the composition to the subject daily for a period of about 12 weeks the subject exhibits at
least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at
least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least
75% lower fasting triglycerides than a control subject maintained on stable statin therapy
without concomitant ultra-pure EPA for a period of about 12 weeks, wherein the control
subject also has baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl. The
term “stable statin therapy” herein means that the subject, subject group, control subject or
control subject group in question has been taking a stable daily dose of a statin (e.g.
atorvastatin, rosuvastatin or simvastatin) for at least 4 weeks prior to the baseline fasting
triglyceride measurement (the “qualifying period”). For example, a subject or control subject
on stable statin therapy would receive a constant daily (i.e. the same dose each day) statin
dose for at least 4 weeks immediately prior to baseline fasting triglyceride measurement. In
one embodiment, the subject’s and control subject’s LDL-C is maintained between about 40
mg/dl and about 100 mg/dl during the qualifying period. The subject and control subject are
then continued on their stable statin dose for the 12 week period post baseline.
In one embodiment, the statin is administered to the subject and the control subject
in an amount of about 1 mg to about 500 mg, about 5 mg to about 200 mg, or about 10 mg to
about 100 mg, for example about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg,
about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg; about 15 mg, about 20 mg,
about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55
mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about
100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250
mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg,
about 425 mg, about 450 mg, about 475 mg, or about 500 mg. In another embodiment, the
subject (and optionally the control subject) has a baseline LDL-C level, despite stable statin
therapy, of about 40 mg/dl to about 100 mg/dl. In another embodiment, the subject and/or
control subject has a body mass index (BMI; or mean BMI) of not more than about 45 kg/m .
In another embodiment, described is a method of lowering triglycerides in a
subject group on stable statin therapy having mean baseline fasting triglycerides of about 200
mg/dl to about 500 mg/dl, the method comprising administering to members of the subject
group a pharmaceutical composition comprising about 1 g to about 4 g of ultra-pure EPA per
day, wherein upon administering the composition to the members of the subject group daily
for a period of about 12 weeks the subject group exhibits at least 10%, at least 15%, at least
%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least
55%, at least 60%, at least 65%, at least 70%, at least 75% lower mean fasting
triglycerides than a control subject group maintained on stable statin therapy without
concomitant ultra-pure EPA for a period of about 12 weeks, wherein the control
subject group also has mean baseline fasting triglycerides of about 200 mg/dl to about 500
mg/dl. In a related embodiment, the stable statin therapy will be sufficient such that the
subject group has a mean LDL-C level about at least about 40 mg/dl and not more than about
100 mg/dl for the 4 weeks immediately prior to the baseline fasting triglyceride measurement.
In another embodiment, described is a method of lowering triglycerides in subject
group on stable statin therapy and having mean baseline fasting triglyceride level of about
200 mg/dl to about 500 mg/dl, the method comprising administering to members of the
subject group a pharmaceutical composition comprising about 1 g to about 4 g of ultra-pure
EPA, wherein upon administering the composition to members of the subject group daily for
a period of about 12 weeks the subject group exhibits (a) at least 10%, at least 15%, at least
%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least
55%, at least 60%, at least 65%, at least 70%, at least 75% lower mean fasting
triglycerides by comparison with a control subject group maintained on stable statin therapy
without concomitant ultra-pure EPA for a period of about 12 weeks, and (b) no increase in
mean serum LDL-C levels compared to baseline or placebo control, wherein the control
subject also has mean baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl.
In another embodiment, described is a method of lowering triglycerides in subject
on stable statin therapy and having mean baseline fasting triglyceride level of about 200
mg/dl to about 500 mg/dl, the method comprising administering to the subject a
pharmaceutical composition comprising about 1 g to about 4 g of ultra-pure EPA, wherein
upon administering the composition to the subject daily for a period of about 12 weeks the
subject exhibits (a) at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least
%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least
70%, or at least 75% lower fasting triglycerides by comparison with a control subject
maintained on stable statin therapy without concomitant ultra-pure EPA for a period of about
12 weeks and (b) no increase in serum LDL-C levels compared to baseline or placebo
control, wherein the control subject also has baseline fasting triglycerides of about 200 mg/dl
to about 500 mg/dl.
In another embodiment, described is a method of lowering triglycerides in subject
group on stable statin therapy and having mean baseline fasting triglyceride level of about
200 mg/dl to about 500 mg/dl, the method comprising administering to members of the
subject group a pharmaceutical composition comprising about 1 g to about 4 g of ultra-pure
EPA, wherein upon administering the composition to the members of the subject group daily
for a period of about 12 weeks the subject group exhibits (a) at least 10%, at least 15%, at
least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at
least 55%, at least 60%, at least 65%, at least 70%, at least 75% lower mean fasting
triglycerides and (b) at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least
%, at least 35%, at least 40%, at least 45% or at least 50% lower mean plasma or serum
LDL-C levels by comparison with a control subject group maintained on stable statin therapy
without concomitant ultra-pure EPA for a period of about 12 weeks, wherein the control
subject also has mean baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl.
In another embodiment, described is a method of lowering triglycerides in subject
group on stable statin therapy and having mean baseline fasting triglyceride level of about
200 mg/dl to about 500 mg/dl, the method comprising administering to members of the
subject group a pharmaceutical composition comprising about 1 g to about 4 g of ultra-pure
EPA, wherein upon administering the composition to the members of the subject group daily
for a period of about 12 weeks the subject group exhibits (a) at least 10%, at least 15%, at
least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at
least 55%, at least 60%, at least 65%, at least 70%, at least 75% lower mean fasting
triglycerides and (b) at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least
%, at least 35%, at least 40%, at least 45% or at least 50% lower mean plasma or serum
LDL-C levels by comparison with a control subject group maintained on stable statin therapy
without concomitant ultra-pure EPA for a period of about 12 weeks, wherein the control
subject group also has mean baseline fasting triglycerides of about 200 mg/dl to about 500
mg/dl.
In another embodiment, the subject or subject group being treated in accordance
with methods described herein exhibits a fasting baseline absolute plasma level of free total
fatty acid (or mean thereof) not greater than about 300 nmol/ml, not greater than about 250
nmol/ml, not greater than about 200 nmol/ml, not greater than about 150 nmol/ml, not greater
than about 100 nmol/ml, or not greater than about 50 nmol/ml.
In another embodiment, the subject or subject group being treated in accordance
with methods described herein 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 described herein exhibits a baseline fasting plasma
level (or mean thereof) of free EPA, expressed as a percentage of total free fatty acid, of not
more than about 3%, not more than about 2.5%, not more than about 2%, not more than about
1.5%, not more than about 1%, not more than about 0.75%, not more than about 0.5%, not
more than about 0.25%, not more than about 0.2% or not more than about 0.15%. In one
such embodiment, free plasma EPA and/or total fatty acid levels are determined prior to
initiating therapy.
In another embodiment, the subject or subject group being treated in accordance
with methods described herein exhibits a fasting baseline absolute plasma level of free EPA
(or mean thereof) not greater than about 1 nmol/ml, not greater than about 0.75 nmol/ml, not
greater than about 0.50 nmol/ml, not greater than about 0.4 nmol/ml, not greater than about
0.35 nmol/ml, or not greater than about 0.30 nmol/ml.
In another embodiment, the subject or subject group being treated in accordance
with methods described herein exhibits a fasting baseline plasma, serum or red blood cell
membrane EPA level not greater than about 150 μg/ml, not greater than about 125 μg/ml, not
greater than about 100 μg/ml, not greater than about 95 μg/ml, not greater than about 75
μg/ml, not greater than about 60 μg/ml, not greater than about 50 μg/ml, not greater than
about 40 μg/ml, not greater than about 30 μg/ml, or not greater than about 25 μg/ml.
In another embodiment, methods described herein comprise a step of measuring
the subject’s (or subject group’s mean) baseline lipid profile prior to initiating therapy. In
another embodiment, methods described herein 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 100 mg/dl, for
example not more than about 90 mg/ dl not, not more than about 80 mg/dl, not more than
about 70 mg/dl, not more than about 60 mg/dl, not more than about 60 mg/dl, not more than
about 50 mg/dl, not more than about 40 mg/dl, not more than about 35 mg/dl, not more than
about 30 mg/dl, not more than about 25 mg/dl, not more than about 20 mg/dl, or not more
than about 15 mg/dl; and/or baseline LDL-C value of about 30 to about 300 mg/dl, for
example not less than about 40 mg/dl, not less than about 50 mg/dl, not less than about 60
mg/dl, not less than about 70 mg/dl, not less than about 90 mg/dl or not less than about 90
mg/dl.
In a related embodiment, upon treatment in accordance with the present disclosure,
for example over a period of about 1 to about 200 weeks, about 1 to about 100 weeks, about 1
to about 80 weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about 1 to about 20
weeks, about 1 to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks,
about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, the subject or subject
group exhibits one or more of the following outcomes:
(a) reduced triglyceride levels compared to baseline or placebo control;
(b) reduced Apo B levels compared to baseline or placebo control;
(c) increased HDL-C levels compared to baseline or placebo control;
(d) no increase in LDL-C levels compared to baseline or placebo control;
(e) a reduction in LDL-C levels compared to baseline or placebo control;
(f) a reduction in non-HDL-C levels compared to baseline or placebo control;
(g) a reduction in vLDL levels compared to baseline or placebo control;
(h) an increase in apo A-I levels compared to baseline or placebo control;
(i) an increase in apo A-I/apo B ratio compared to baseline or placebo control;
(j) a reduction in lipoprotein a levels compared to baseline or placebo control;
(k) a reduction in LDL particle number compared to baseline or placebo control;
(l) a reduction in LDL size compared to baseline or placebo control;
(m) a reduction in remnant-like particle cholesterol compared to baseline or
placebo control;
(n) a reduction in oxidized LDL compared to baseline or placebo control;
(o) a reduction in fasting plasma glucose (FPG) compared to baseline or placebo
control;
(HbA ) compared to baseline or placebo
(p) a reduction in hemoglobin A1c 1c
control;
(q) a reduction in homeostasis model insulin resistance compared to baseline or
placebo control;
(r) a reduction in lipoprotein associated phospholipase A2 compared to baseline or
placebo control;
(s) a reduction in intracellular adhesion molecule-1 compared to baseline or
placebo control;
(t) a reduction in interleukin-2 compared to baseline or placebo control;
(u) a reduction in plasminogen activator inhibitor-1 compared to baseline or
placebo control;
(v) a reduction in high sensitivity C-reactive protein (hsCRP) compared to baseline
or placebo control;
(w) an increase in plasma or serum phospholipid EPA compared to baseline or
placebo control;
(x) an increase in red blood cell membrane EPA compared to baseline or placebo
control; and/or
(y) a reduction or increase in one or more of plasma, serum phospholipid and/or
red blood cell content of docosahexaenoic acid (DHA), docosapentaenoic acid (DPA),
arachidonic acid (AA), palmitic acid (PA), staeridonic acid (SA) or oleic acid (OA) compared
to baseline or placebo control.
In one embodiment, methods described herein 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.
In another embodiment, upon treatment with a composition described herein, for
example over a period of about 1 to about 200 weeks, about 1 to about 100 weeks, about 1 to
about 80 weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about 1 to about 20
weeks, about 1 to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks,
about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, the subject or subject
group exhibits any 2 or more of, any 3 or more of, any 4 or more of, any 5 or more of, any 6
or more of, any 7 or more of, any 8 or more of, any 9 or more of, any 10 or more of, any 11
or more of, any 12 or more of, any 13 or more of, any 14 or more of, any 15 or more of, any
16 or more of, any 17 or more of, any 18 or more of, any 19 or more of, any 20 or more of,
any 21 or more of, any 22 or more of, any 23 or more, any 24 or more, or all 25 of outcomes
(a) – (y) described immediately above.
In another embodiment, upon treatment with a composition described herein, the
subject or subject group exhibits one or more of the following outcomes:
(a) a reduction in triglyceride level of at least about 5%, at least about 10%, at least
about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at
least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about
75% (actual % change or median % change) as compared to baseline or placebo control;
(b) a less than 30% increase, less than 20% increase, less than 10% increase, less
than 5% increase or no increase in non-HDL-C levels or a reduction in non-HDL-C levels of
at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%,
at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about
40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual
% change or median % change) as compared to baseline or placebo control;
(c) an increase in HDL-C levels of at least about 5%, at least about 10%, at least
about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at
least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about
75% (actual % change or median % change) as compared to baseline or placebo control;
(d) a less than 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 or placebo control;
(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 or placebo control;
(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 or placebo control;
(g) 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 or placebo control;
(h) 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
%, at least about 40%, at least about 45%, at least about 50%, or at least about 100%
(actual % change or median % change) compared to baseline or placebo control;
(i) 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
%, at least about 40%, at least about 45%, at least about 50%, or at least about 100%
(actual % change or median % change) compared to baseline or placebo control;
(j) a reduction in mean LDL particle number of at least about 5%, at least about
%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least
about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100%
(actual % change or median % change) compared to baseline or placebo control;
(k) an increase in mean LDL particle size of at least about 5%, at least about 10%,
at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about
%, at least about 40%, at least about 45%, at least about 50%, or at least about 100%
(actual % change or median % change) compared to baseline or placebo control;
(l) a reduction in remnant-like particle cholesterol of at least about 5%, at least
about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at
least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about
100% (actual % change or median % change) compared to baseline or placebo control;
(m) 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%, at
least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual %
change or median % change) compared to baseline or placebo control;
(n) a reduction in fasting plasma glucose (FPG) of at least about 5%, at least about
%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least
about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100%
(actual % change or median % change) compared to baseline or placebo control;
(o) a reduction in hemoglobin A (HbA ) of at least about 5%, at least about
1c 1c
%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least
about 35%, at least about 40%, at least about 45%, or at least about 50% (actual % change or
median % change) compared to baseline or placebo control;
(p) a reduction in homeostasis model index insulin resistance of at least about 5%,
at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about
%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at
least about 100% (actual % change or median % change) compared to baseline or placebo
control;
(q) a reduction in lipoprotein associated phospholipase A2 of at least about 5%, at
least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about
%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at
least about 100% (actual % change or median % change) compared to baseline or placebo
control;
(r) 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 or placebo control;
(s) a reduction in interleukin-2 of at least about 5%, at least about 10%, at least
about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at
least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual %
change or median % change) compared to baseline or placebo control;
(t) 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 or placebo control;
(u) 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
%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at
least about 100% (actual % change or median % change) compared to baseline or placebo
control;
(v) an increase in plasma, serum phospholipids 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
%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least
about 100%, at least about 200% or at least about 400% (actual % change or median %
change) compared to baseline or placebo control;
(w) an increase in plasma, serum phospholipid and/or RBC 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 or placebo control;
(x) a reduction or increase in one or more of plasma, serum phospholipid and/or
RBC DHA, DPA, AA, PA and/or OA of at least about 5%, at least about 10%, at least
about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%,
at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least
about 75% (actual % change or median % change) compared to baseline or placebo
control; and/or
(y) a reduction in total cholesterol of at least about 5%, at least about 10%, at least
about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%,
at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least
about 75% (actual % change or median % change) compared to baseline or placebo
control.
In one embodiment, methods described herein comprise measuring baseline levels
of one or more markers set forth in (a) – (y) 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 a second measurement of the one or more markers
as measured at baseline for comparison thereto.
In another embodiment, upon treatment with a composition described herein, for
example over a period of about 1 to about 200 weeks, about 1 to about 100 weeks, about
1 to about 80 weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about 1 to
about 20 weeks, about 1 to about 15 weeks, about 1 to about 12 weeks, about 1 to about
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, or all 26 or more of outcomes (a) – (y) described immediately
above.
Parameters (a) – (y) can be measured in accordance with any clinically acceptable
methodology. For example, triglycerides, total cholesterol, HDL-C and fasting blood
sugar can be sample from serum and analyzed using standard photometry techniques.
VLDL-TG, LDL-C and VLDL-C can be calculated or determined using serum lipoprotein
fractionation by preparative ultracentrifugation and subsequent quantitative analysis by
refractometry or by analytic ultracentrifugal methodology. Apo A1, Apo B and hsCRP
can be determined from serum using standard nephelometry techniques. Lipoprotein (a)
can be determined from serum using standard turbidimetric immunoassay techniques.
LDL particle number and particle size can be determined using nuclear magnetic
resonance (NMR) spectrometry. Remnants lipoproteins and LDL-phospholipase A2 can
be determined from EDTA plasma or serum and serum, respectively, using enzymatic
immunoseparation techniques. Oxidized LDL, intercellular adhesion molecule-1 and
interleukin-2 levels can be determined from serum using standard enzyme immunoassay
techniques. These techniques are described in detail in standard textbooks, for example
Tietz Fundamentals of Clinical Chemistry, 6 Ed. (Burtis, Ashwood and Borter Eds.),
WB Saunders Company.
In one embodiment, subjects fast for up to 12 hours prior to blood sample
collection, for example about 10 hours.
In another embodiment, described is a method of treating or preventing primary
hypercholesterolemia and/or mixed dyslipidemia (Fredrickson Types IIa and IIb) in a patient
in need thereof, comprising administering to the patient one or more compositions as
disclosed herein. In a related embodiment, described is a method of reducing triglyceride
levels in a subject or subjects when treatment with a statin or niacin extended-release
monotherapy is considered inadequate (Frederickson type IV hyperlipidemia).
In another embodiment, described is a method of treating or preventing risk of
recurrent nonfatal myocardial infarction in a patient with a history of myocardial infarction,
comprising administering to the patient one or more compositions as disclosed herein.
In another embodiment, described is a method of slowing progression of or
promoting regression of atherosclerotic disease in a patient in need thereof, comprising
administering to a subject in need thereof one or more compositions as disclosed herein.
In another embodiment, described is a method of treating or preventing very high
serum triglyceride levels (e.g. Types IV and V hyperlipidemia) in a patient in need thereof,
comprising administering to the patient one or more compositions as disclosed herein.
In one embodiment, a composition described herein is administered to a subject in
an amount sufficient to provide a daily dose of ethyl eicosapentaenoic acid of about 1 mg to
about 10,000 mg, 25 about 5000 mg, about 50 to about 3000 mg, about 75 mg to about 2500
mg, or about 100 mg to about 1000 mg, for example about 75 mg, about 100 mg, about 125
mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg,
about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg,
about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg,
about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg,
about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg,
about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg,
about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075
mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about
1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg,
about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600
mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about
1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg,
about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025
mg, about 2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about
2175 mg, about 2200 mg, about 2225 mg, about 2250 mg, about 2275 mg, about 2300 mg,
about 2325 mg, about 2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450
mg, about 2475 mg or about 2500 mg.
In another embodiment, any of the methods disclosed herein are used in treatment
of a subject or subjects that consume a traditional Western diet. In one embodiment, the
methods described herein include a step of identifying a subject as a Western diet consumer
or prudent diet consumer and then treating the subject if the subject is deemed a Western diet
consumer. The term “Western diet” herein refers generally to a typical diet consisting of, by
percentage of total calories, about 45% to about 50% carbohydrate, about 35% to about 40%
fat, and about 10% to about 15% protein. A Western diet may alternately or additionally be
characterized by relatively high intakes of red and processed meats, sweets, refined grains,
and desserts, for example more than 50%, more than 60% or more or 70% of total calories
come from these sources.
In another embodiment, any of the methods disclosed herein are used in treatment
of a subject or subjects that consume less than (actual or average) about 150 g, less than about
125 g, less than about 100 g, less than about 75 g, less than about 50 g, less than about 45 g,
less than about 40 g, less than about 35 g, less than about 30 g, less than about 25 g, less than
about 20 g or less than about 15 g of fish per day.
In another embodiment, any of the methods disclosed herein are used in treatment
of a subject or subjects that consume less than (actual or average) about 10 g, less than about
9 g, less than about 8 g, less than about 7 g, less than about 6 g, less than about 5 g, less than
about 4 g, less than about 3 g, less than about 2 g per day of omega-3 fatty acids from dietary
sources.
In another embodiment, any of the methods disclosed herein are used in treatment
of a subject or subjects that consume less than (actual or average) about 2.5 g, less than about
2 g, less than about 1.5 g, less than about 1 g, less than about 0.5 g, less than about 0.25 g, or
less than about 0.2 g per day of EPA and DHA (combined) from dietary sources.
Seafood/fish allergies often manifest as hives, itching, and eczema (rash). These
reactions among those with fish allergies prevent patients from benefiting from the
cardiovascular, anti-inflammatory, neurological, endocrine and other benefits of
pharmaceutical grade fish oil derivatives by decreasing compliance. In various embodiments,
described are compositions and methods as described herein wherein the subject does not
exhibit skin rash, or exhibits reduced skin rash incidence compared to placebo.
Another shortcoming of fish oil derived therapies and medicines are the incidence
of eructation, or “fishy burp”. In various embodiments, described are compositions and
methods as described herein wherein the subject does not experience eructation or
experiences reduced eructation compared to Lovaza therapy.
In one 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
500 mg to about 1 g of a composition as described herein, are administered to a subject daily.
In another embodiment, 1 or 2 capsules, each containing about 1 g of a composition as
described herein, are administered to the subject in the morning, for example between about 5
am and about 11 am, and 1 or 2 capsules, each containing about 1 g of a composition as
described herein, are administered to the subject in the evening, for example between about 5
pm and about 11 pm.
In one embodiment, a subject being treated in accordance with methods described
herein is not on fibrate or nitrate therapy.
In another embodiment, compositions useful in accordance with methods described
herein are orally deliverable. The terms “orally deliverable” or “oral administration” herein
include any form of delivery of a therapeutic agent or a composition thereof to a subject
wherein the agent or composition is placed in the mouth of the subject, whether or not the
agent or composition is swallowed. Thus “oral administration” includes buccal and
sublingual as well as esophageal administration. In one embodiment, the composition is
present in a capsule, for example a soft gelatin capsule.
A composition for use in accordance with the treatments described herein can be
formulated as one or more dosage units. The terms “dose unit” and “dosage unit” herein
refer to a portion of a pharmaceutical composition that contains an amount of a therapeutic
agent suitable for a single administration to provide a therapeutic effect. Such dosage units
may be administered one to a plurality (i.e. 1 to about 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 2) of
times per day, or as many times as needed to elicit a therapeutic response.
In another embodiment, described is a 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.
In one embodiment, described is a method of blood lipid therapy comprising
administering to a subject or subject group in need thereof a pharmaceutical composition
as described herein. In another embodiment, the subject or subject group has
hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia and/or very high
triglycerides.
In another embodiment, the subject or subject group being treated has a baseline
triglyceride level (or 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.
In another embodiment, the subject or subject group being treated in accordance
with methods described herein 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
described herein.
In another embodiment, the subject or subject group being treated in accordance
with methods described herein 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 described herein exhibits a
baseline fasting plasma level (or mean thereof) of free EPA, expressed as a percentage of
total free fatty acid, of not more than about 3%, not more than about 2.5%, not more than
about 2%, not more than about 1.5%, not more than about 1%, not more than about
0.75%, not more than about 0.5%, not more than about 0.25%, not more than about 0.2%
or not more than about 0.15%. In one such embodiment, free plasma EPA and/or total
fatty acid levels are determined prior to initiating therapy.
In another embodiment, the subject or subject group being treated in accordance
with methods described herein 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.
In another embodiment, the subject or subject group being treated in accordance
with methods described herein 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
μg/ml, or not greater than about 25 μg/ml.
In another embodiment, methods described herein comprise a step of measuring
the subject’s (or subject group’s mean) baseline lipid profile prior to initiating therapy. In
another embodiment, methods described herein 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.
In one embodiment, compositions described herein are packaged in blister packs.
In another embodiment, the blister packs comprise PCTFE (for example 50μ) laminated
with water based adhesive to clear PVC (for example 190μ) which are heat sealed to
aluminum foil).
In a related embodiment, upon treatment in accordance with the present disclosure,
for example over a period of about 1 to about 200 weeks, about 1 to about 100 weeks,
about 1 to about 80 weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about 1
to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12 weeks, about 1 to
about 10 weeks, about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, the
subject or subject group exhibits one or more of the following outcomes:
(a) reduced triglyceride levels compared to baseline or a placebo arm;
(b) reduced Apo B levels compared to baseline or a placebo arm;
(c) increased HDL-C levels compared to baseline or a placebo arm;
(d) no increase in LDL-C levels compared to baseline or a placebo arm;
(e) a reduction in LDL-C levels compared to baseline or a placebo arm;
(f) a reduction in non-HDL-C levels compared to baseline or a placebo arm;
(g) a reduction in vLDL levels compared to baseline or a placebo arm;
(h) an increase in apo A-I levels compared to baseline or a placebo arm;
(i) an increase in apo A-I/apo B ratio compared to baseline or a placebo arm;
(j) a reduction in lipoprotein A levels compared to baseline or a placebo arm;
(k) a reduction in LDL particle number compared to baseline or a placebo arm;
(l) an increase in mean LDL size compared to baseline or a placebo arm;
(m) a reduction in remnant-like particle cholesterol compared to baseline or a
placebo arm;
(n) a reduction in oxidized LDL compared to baseline or a placebo arm;
(o) no change or a reduction in fasting plasma glucose (FPG) compared to
baseline or a placebo arm;
(p) a reduction in hemoglobin A (HbA ) compared to baseline or a placebo
1c 1c
arm;
(q) a reduction in homeostasis model insulin resistance compared to baseline or a
placebo arm;
(r) a reduction in lipoprotein associated phospholipase A2 compared to baseline or
a placebo arm;
(s) a reduction in intracellular adhesion molecule-1 compared to baseline or a
placebo arm;
(t) a reduction in interleukin-6 compared to baseline or a placebo arm;
(u) a reduction in plasminogen activator inhibitor-1 compared to baseline or a
placebo arm;
(v) a reduction in high sensitivity C-reactive protein (hsCRP) compared to
baseline or a placebo arm;
(w) an increase in serum phospholipid EPA compared to baseline or a placebo
arm;
(x) an increase in red blood cell membrane EPA compared to baseline or a
placebo arm; and/or
(y) a reduction or increase in one or more of serum phospholipid and/or red blood
cell content of docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), arachidonic
acid (AA), palmitic acid (PA), staeridonic acid (SA) or oleic acid (OA) compared to
baseline or a placebo arm.
In one embodiment, methods described herein 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.
In another embodiment, upon treatment with a composition described herein, for
example over a period of about 1 to about 200 weeks, about 1 to about 100 weeks, about
1 to about 80 weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about 1 to
about 20 weeks, about 1 to about 15 weeks, about 1 to about 12 weeks, about 1 to about
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.
In another embodiment, upon treatment with a composition described herein, the
subject or subject group exhibits one or more of the following outcomes:
(a) a reduction in triglyceride level of at least about 5%, at least about 10%, at
least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about
%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at
least about 75% (actual % change or median % change) as compared to baseline or a
placebo arm;
(b) a less than 30% increase, less than 20% increase, less than 10% increase, less
than 5% increase or no increase in non-HDL-C levels or a reduction in non-HDL-C levels
of at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least
about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%,
at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least
about 75% (actual % change or median % change) as compared to baseline or a placebo
arm;
(c) substantially no change, no change or an increase in HDL-C levels of at least
about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%,
at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least
about 50%, at least about 55% or at least about 75% (actual % change or median %
change) as compared to baseline or a placebo arm;
(d) a less than 60% increase, less than 50% increase, less than 40% increase, 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
%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at
least about 55%, at least about 55% or at least about 75% (actual % change or median %
change) as compared to baseline or a placebo arm;
(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 or a placebo
arm;
(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 or a placebo arm;
(g) 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 or a placebo arm;
(h) 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
%, at least about 40%, at least about 45%, at least about 50%, or at least about 100%
(actual % change or median % change) compared to baseline or a placebo arm;
(i) 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
%, at least about 40%, at least about 45%, at least about 50%, or at least about 100%
(actual % change or median % change) compared to baseline or a placebo arm;
(j) a reduction in mean LDL particle number of at least about 5%, at least about
%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at
least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least
about 100% (actual % change or median % change) compared to baseline or a placebo
arm;
(k) 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 or a placebo arm;
(l) 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 or a placebo
arm;
(m) 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%,
at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual
% change or median % change) compared to baseline or a placebo arm;
(n) substantially no change, no change or a reduction in fasting plasma glucose
(FPG) of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at
least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about
45%, at least about 50%, or at least about 100% (actual % change or median % change)
compared to baseline or a placebo arm;
(o) substantially no change, no change or a reduction in hemoglobin A (HbA )
1c 1c
of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least
about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%,
or at least about 50% (actual % change or median % change) compared to baseline or a
placebo arm;
(p) a reduction in homeostasis model index insulin resistance of at least about 5%,
at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least
about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%,
or at least about 100% (actual % change or median % change) compared to baseline or a
placebo arm;
(q) 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
%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at
least about 100% (actual % change or median % change) compared to baseline or a
placebo arm;
(r) 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 or a placebo
arm;
(s) a reduction in interleukin-6 of at least about 5%, at least about 10%, at least
about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%,
at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual
% change or median % change) compared to baseline or a placebo arm;
(t) 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;
(u) 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 or a
placebo arm;
(v) an increase in serum, plasma and/or RBC EPA of at least about 5%, at least
about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%,
at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least
about 100%, at least about 200% or at least about 400% (actual % change or median %
change) compared to baseline or a placebo arm;
(w) an increase in serum phospholipid and/or red blood cell membrane EPA of at
least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about
%, 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 or a placebo arm;
(x) a reduction or increase in one or more of serum phospholipid and/or red blood
cell DHA, DPA, AA, PA and/or OA of at least about 5%, at least about 10%, at least
about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%,
at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least
about 75% (actual % change or median % change) compared to baseline or a placebo
arm; and/or
(y) a reduction in total cholesterol of at least about 5%, at least about 10%, at least
about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%,
at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least
about 75% (actual % change or median % change) compared to baseline or a placebo
arm.
In one embodiment, methods described herein comprise measuring baseline levels
of one or more markers set forth in (a) – (y) 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 a second measurement of the one or more markers
as measured at baseline for comparison thereto.
In another embodiment, upon treatment with a composition described herein, for
example over a period of about 1 to about 200 weeks, about 1 to about 100 weeks, about
1 to about 80 weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about 1 to
about 20 weeks, about 1 to about 15 weeks, about 1 to about 12 weeks, about 1 to about
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, or all 25 of outcomes (a) – (y) described immediately above.
Parameters (a) – (y) can be measured in accordance with any clinically acceptable
methodology. For example, triglycerides, total cholesterol, HDL-C and fasting blood
sugar can be sample from serum and analyzed using standard photometry techniques.
VLDL-TG, LDL-C and VLDL-C can be calculated or determined using serum lipoprotein
fractionation by preparative ultracentrifugation and subsequent quantitative analysis by
refractometry or by analytic ultracentrifugal methodology. Apo A1, Apo B and hsCRP
can be determined from serum using standard nephelometry techniques. Lipoprotein (a)
can be determined from serum using standard turbidimetric immunoassay techniques.
LDL particle number and particle size can be determined using nuclear magnetic
resonance (NMR) spectrometry. Remnants lipoproteins and LDL-phospholipase A2 can
be determined from EDTA plasma or serum and serum, respectively, using enzymatic
immunoseparation techniques. Oxidized LDL, intercellular adhesion molecule-1 and
interleukin-2 levels can be determined from serum using standard enzyme immunoassay
techniques. These techniques are described in detail in standard textbooks, for example
Tietz Fundamentals of Clinical Chemistry, 6 Ed. (Burtis, Ashwood and Borter Eds.),
WB Saunders Company.
In another embodiment, described is a method of treating hypertriglyceridemia in a
subject that is allergic to or hypersensitive to fish, the method comprising identifying a
subject with hypertriglyceridemia that is allergic to or hypersensitive to fish; and
administering to the subject an effective amount of a composition comprising
eicosapentaenoic acid or a derivative thereof. In another embodiment, the composition
contains substantially no fish allergen. In another embodiment, the composition contains no
proteins. In another embodiment, the composition contains substantially no fish proteins. In
another embodiment, the composition contains substantially no fish allergens. In another
embodiment, the composition contains no fish allergens. In another embodiment, the
composition contains less than about 5% by weight, if any, of any fatty acid other than
eicosapentaenoic acid or a derivative thereof. In another embodiment, the composition
contains less than about 5% by weight of DHA or a derivative thereof. In another
embodiment, the composition comprises at least 96%, 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 nonaceapentaenoate, about 0.2% to about 0.45% by weight ethyl
arachidonate, about 0.3% to about 0.5% by weight ethyl eicosatetraenoate, about 0.05% to
about 0.32% ethyl heneicosapentaenoate, and not more than 0.05% ethyl-DHA, if any. In
another embodiment, the composition comprises at least 96% 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. In another embodiment, the composition comprises at
least 98% 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. In
another embodiment, the composition further comprises tocopherol in an amount of about
0.1% to about 0.3%, by weight. In another embodiment, the eicosapentaenoic acid or
derivative thereof is ethyl eicosapentaenoate. In another embodiment, the subject is on
concomitant statin therapy. In another embodiment, the subject is not on concomitant fibrate
or nitrate therapy. In another embodiment, the composition is encapsulated in a capsule.
In another embodiment, described is a method of increasing serum, plasma, and/or
red blood cell EPA levels in a subject that is allergic to or hypersensitive to fish, the method
comprising: identifying a subject that is allergic to or hypersensitive to fish; and
administering to the subject an effective amount of a composition comprising
eicosapentaenoic acid or a derivative thereof, wherein said composition contains substantially
no proteins.
In another embodiment, described is a method of treating or preventing
cardiovascular-related diseases in a subject that is allergic to or hypersensitive to fish, the
method comprising: identifying a subject that is allergic to or hypersensitive to fish and has
or is at risk for developing a cardiovascular-related disease; and administering to the subject
an effective amount of a composition comprising eicosapentaenoic acid or a derivative
thereof, wherein said composition contains substantially no proteins.
In another embodiment, described is a method of blood lipid therapy comprising:
identifying a subject in need of blood lipid therapy that is allergic to or hypersensitive to fish;
and administering to the subject an effective amount of a composition comprising
eicosapentaenoic acid or a derivative thereof, wherein said composition contains substantially
no proteins.
In another embodiment, described is a method for reducing triglycerides in a
subject on stable statin therapy, the method comprising: identifying a subject that is allergic
to or hypersensitive to fish; and administering to the subject an effective amount of a
composition comprising eicosapentaenoic acid or a derivative thereof, wherein said
composition contains substantially no proteins.
In another embodiment, described is a method of treating or preventing primary
hypercholesterolemia and/or mixed dyslipidemia in a subject that is allergic to or
hypersensitive to fish, the method comprising: identifying a that is allergic to or
hypersensitive to fish and has or is at risk of developing primary hypercholesterolemia and/or
mixed dyslipidemia; and administering to the subject an effective amount of a composition
comprising eicosapentaenoic acid or a derivative thereof, wherein said composition contains
substantially no proteins.
In another embodiment, described is a method of reducing triglyceride levels in a
subject that is allergic to or hypersensitive to fish after statin or niacin extended-release
monotherapy is deemed inadequate, the method comprising: identifying a subject that is
allergic to or hypersensitive to fish; and administering to the subject an effective amount of a
composition comprising eicosapentaenoic acid or a derivative thereof, wherein said
composition contains substantially no proteins.
In another embodiment, described is a method of slowing progression of or
promoting regression of atherosclerotic disease in a subject that is allergic to or
hypersensitive to fish, the method comprising: identifying a subject with atherosclerotic
disease that is allergic to or hypersensitive to fish; and administering to the subject an
effective amount of a composition comprising eicosapentaenoic acid or a derivative thereof,
wherein said composition contains substantially no proteins.
In another embodiment, described is a method of treating or preventing very high
serum triglyceride levels in a subject that is allergic to or hypersensitive to fish, the method
comprising: identifying a subject that is allergic to or hypersensitive to fish and has or is at
risk of developing very high serum triglyceride levels; and administering to the subject an
effective amount of a composition comprising eicosapentaenoic acid or a derivative thereof,
wherein said composition contains substantially no proteins.
In another embodiment, described is a method for increasing plasma and/or serum
EPA levels in a subject that is allergic to or hypersensitive to fish, the method comprising:
identifying a subject that is allergic to or hypersensitive to fish; and administering to the
subject an effective amount of a composition comprising eicosapentaenoic acid or a
derivative thereof, wherein said composition contains substantially no proteins.
In another embodiment, described is a method of increasing plasma and/or serum
EPA in a subject in need thereof that is allergic to or hypersensitive to fish, the method
comprising: identifying a subject that is allergic to or hypersensitive to fish; and
administering to the subject the composition according to the present disclosure in an amount
sufficient to increase plasma and/or serum EPA levels in the subject by at least about 200%
compared to baseline.
In another embodiment, described is a method of increasing plasma and/or serum
EPA in a subject in need thereof that is allergic to or hypersensitive to fish, the method
comprising: identifying a subject that is allergic to or hypersensitive to fish; and
administering to the subject a composition comprising at least about 96%, by weight, of
eicosapentaenoic acid or a derivative thereof in an amount sufficient to increase plasma
and/or serum EPA levels in the subject by at least about 200% compared to baseline.
In another embodiment, described is a method of treating a cardiovascular-related
disease comprising administering to a subject in need thereof a composition comprising EPA
and a cardiovascular agent, wherein the composition contains substantially no proteins.
In another embodiment, described is a method of reducing the risk of arterial
plaque development in a subject at risk thereof, comprising: determining a risk of arterial
plaque development in the subject by measuring an elevated level of an oxidative stress
marker in the subject; and subsequently administering to the subject a pharmaceutical
composition comprising EPA, DPA or a derivative thereof, wherein the pharmaceutical
composition contains substantially no proteins.
In another embodiment, described is a method of reducing the number or size of
arterial plaques in a subject in need thereof comprising: determining a baseline number or
size of arterial plaques in the subject; measuring an elevated level of 8-hydroxy-2′-
deoxyguanosine in the subject; subsequently administering to the subject an arterial plaque-
reducing amount of a pharmaceutical composition comprising EPA, DPA or a derivative
thereof, wherein the pharmaceutical composition contains substantially no proteins; and
measuring a reduced number or size of arterial plaques in the subject as compared to the
baseline number or size of arterial plaques in the subject.
In another embodiment, described is a method of treating hypertriglyceridemia in a
subject that is allergic to or hypersensitive to fish, the method comprising: (a) identifying a
subject having a fasting baseline triglyceride level of about 500 mg/dl to about 1500 mg/dl
that is allergic to or hypersensitive to fish, and (b) administering to the subject a
pharmaceutical composition comprising at least 95% all-cis eicosa-5,8,11,14,17-pentaenoic
acid ethyl ester, wherein the composition is substantially free of docosahexaenoic acid ethyl
ester. In another embodiment, the pharmaceutical composition is substantially free of fish
proteins or fish allergens.
In another embodiment, described is a pharmaceutical composition comprising
eicosapentaenoic acid, or a derivative thereof, wherein the pharmaceutical composition
contains less than about 1%, by weight, of proteins, if any. In another embodiment, the
pharmaceutical composition contains less than about 0.5%, by weight, of proteins, if any. In
another embodiment, the pharmaceutical composition contains less than about 0.2%, by
weight, of proteins, if any. In another embodiment, the pharmaceutical composition contains
less than about 0.1%, by weight, of proteins, if any. In another embodiment, the
pharmaceutical composition contains less than about 0.05%, by weight, of proteins, if any. In
another embodiment, the pharmaceutical composition contains less than about 0.005%, by
weight, of proteins, if any. In another embodiment, the pharmaceutical composition contains
less than about 0.0005%, by weight, of proteins, if any. In another embodiment, the
pharmaceutical composition contains no protein. In another embodiment, the pharmaceutical
composition contains less than about 1%, by weight, of a fish allergen, if any. In another
embodiment, the pharmaceutical composition contains less than about 0.5%, by weight, of a
fish allergen, if any. In another embodiment, the pharmaceutical composition contains less
than about 0.05%, by weight, of a fish allergen, if any. In another embodiment, the
pharmaceutical composition contains less than about 0.005%, by weight, of a fish allergen, if
any. In another embodiment, the pharmaceutical composition contains less than about
0.0005%, by weight, of a fish allergen, if any. In another embodiment, the pharmaceutical
composition contains no fish allergen. In another embodiment, the pharmaceutical
composition contains less than about 5%, by weight, of any fatty acid other than
eicosapentaenoic acid or a derivative thereof, if any. In another embodiment, the
pharmaceutical composition contains less than about 4%, by weight, of any fatty acid other
than eicosapentaenoic acid or a derivative thereof, if any. In another embodiment, the
pharmaceutical composition contains less than about 3%, by weight, of any fatty acid other
than eicosapentaenoic acid or a derivative thereof, if any. In another embodiment, the
pharmaceutical composition contains less than about 2%, by weight, of any fatty acid other
than eicosapentaenoic acid or a derivative thereof, if any. In another embodiment, the
pharmaceutical composition contains less than about 1%, by weight, of any fatty acid other
than eicosapentaenoic acid or a derivative thereof, if any. In another embodiment, the
pharmaceutical composition contains less than about 0.5%, by weight, of any fatty acid other
than eicosapentaenoic acid or a derivative thereof, if any. In another embodiment, the
pharmaceutical composition contains less than about 0.05%, by weight, of any fatty acid
other than eicosapentaenoic acid or a derivative thereof, if any. In another embodiment, the
pharmaceutical composition contains less than about 0.005%, by weight, of any fatty acid
other than eicosapentaenoic acid or a derivative thereof, if any. In another embodiment, the
pharmaceutical composition contains less than about 0.0005%, by weight, of any fatty acid
other than eicosapentaenoic acid or a derivative thereof, if any. In another embodiment, the
pharmaceutical composition contains less than about 0.1%, by weight, of ethyl-DHA, if any.
In another embodiment, the pharmaceutical composition contains less than about 0.075%, by
weight, of ethyl-DHA, if any. In another embodiment, the pharmaceutical composition
contains less than about 0.05%, by weight, of ethyl-DHA, if any. In another embodiment, the
pharmaceutical composition contains less than about 0.025%, by weight, of ethyl-DHA, if
any. In another embodiment, the pharmaceutical composition contains no ethyl-DHA. In
another embodiment, the eicosapentaenoic acid or derivative thereof is an ester of
eicosapentaenoic acid. In another embodiment, the eicosapentaenoic acid or derivative
thereof is eicosapentaenoic acid, ethyl ester.
In another embodiment, described is a pharmaceutical composition comprising
eicosapentaenoic acid or a derivative thereof, wherein the pharmaceutical composition
contains less than about 1%, by weight, of proteins, if any, and less than about 5%, by
weight, of any fatty acid other than eicosapentaenoic acid or a derivative thereof. In another
embodiment, the pharmaceutical composition contains less than about 4%, by weight, of any
fatty acid other than eicosapentaenoic acid or a derivative thereof. In another embodiment,
the pharmaceutical composition contains less than about 3%, by weight, of any fatty acid
other than eicosapentaenoic acid or a derivative thereof. In another embodiment, the
pharmaceutical composition contains less than about 2%, by weight, of any fatty acid other
than eicosapentaenoic acid or a derivative thereof. In another embodiment, the
pharmaceutical composition contains less than about 1%, by weight, of any fatty acid other
than eicosapentaenoic acid or a derivative thereof. In another embodiment, the
pharmaceutical composition contains less than about 0.5%, by weight, of proteins, if any. In
another embodiment, the pharmaceutical composition contains less than about 0.05%, by
weight, of proteins, if any. In another embodiment, the pharmaceutical composition contains
less than about 0.005%, by weight, of proteins, if any. In another embodiment, the
pharmaceutical composition contains less than about 0.0005%, by weight, of proteins, if any.
In another embodiment, the pharmaceutical composition contains less than about 0.00005%,
by weight, of proteins, if any. In another embodiment, the pharmaceutical composition
contains substantially no protein. In another embodiment, the pharmaceutical composition
contains no protein. In another embodiment, the pharmaceutical composition contains
substantially no fish protein. In another embodiment, the pharmaceutical composition
contains no fish protein. In another embodiment, the pharmaceutical composition contains
substantially no fish allergen. In another embodiment, the pharmaceutical composition
contains no fish allergen.
In another embodiment, described is a pharmaceutical composition comprising
eicosapentaenoic acid or a derivative thereof, octadecatetraenoic acid or a derivative thereof,
nonaecapentaenoic acid or a derivative thereof, arachidonic acid or a derivative thereof,
eicosatetraenoic acid or a derivative thereof, heneicosapentaenoate or a derivative thereof,
and less than about 1%, by weight, of protein, if any. In another embodiment, the
pharmaceutical composition contains less than about 0.05%, by weight, of protein, if any. In
another embodiment, the pharmaceutical composition contains less than about 0.005%, by
weight, of protein, if any. In another embodiment, the pharmaceutical composition contains
less than about 0.0005%, by weight, of protein, if any. In another embodiment, the
pharmaceutical composition contains less than about 0.00005%, by weight, of protein, if any.
In another embodiment, the pharmaceutical composition contains substantially no protein. In
another embodiment, the pharmaceutical composition contains no protein. In another
embodiment, the pharmaceutical composition contains substantially no fish protein. In
another embodiment, the pharmaceutical composition contains no fish protein. In another
embodiment, the pharmaceutical composition contains substantially no fish allergen. In
another embodiment, the pharmaceutical composition contains no fish allergen. In another
embodiment, the eicosapentaenoic acid or derivative thereof has a baseline peroxide value
not greater than 5 meq/kg and upon storage of the composition at 25 °C and 60% RH for a
period of 6 months, the eicosapentaenoic acid or derivative thereof has a second peroxide
value not greater than 8 meq/kg.
In another embodiment, described is a pharmaceutical composition comprising
eicosapentaenoic acid or a derivative thereof, octadecatetraenoic acid or a derivative thereof,
nonaecapentaenoic acid or a derivative thereof, arachidonic acid or a derivative thereof,
eicosatetraenoic acid or a derivative thereof, heneicosapentaenoate or a derivative thereof,
and less than about 1%, by weight, of any fish allergens, if any. In another embodiment, the
pharmaceutical composition contains less than about 0.05%, by weight, of fish allergens, if
any. In another embodiment, the pharmaceutical composition contains less than about
0.005%, by weight, of fish allergens, if any. In another embodiment, the pharmaceutical
composition contains less than about 0.0005%, by weight, of fish allergens, if any. In another
embodiment, the pharmaceutical composition contains less than about 0.00005%, by weight,
of fish allergens, if any. In another embodiment, the pharmaceutical composition contains no
fish allergen. In another embodiment, the eicosapentaenoic acid or derivative thereof has a
baseline peroxide value not greater than 5 meq/kg and upon storage of the composition at 25
°C and 60% RH for a period of 6 months, the eicosapentaenoic acid or derivative thereof has
a second peroxide value not greater than 8 meq/kg.
In another embodiment, described is a pharmaceutical composition comprising at
least 96%, by weight, of ethyl eicosapentaenoate, from about 0.2% to about 0.5%, by weight,
of ethyl octadecatetraenoate, from about 0.05% to about 0.25%. by weight, of ethyl
nonaecapentaenoate, from about 0.2% to about 0.45%, by weight, of ethyl arachidonate, from
about 0.3% to about 0.5%, by weight, of ethyl eicosatetraenoate, from about 0.05% to about
0.32%, by weight, of ethyl heneicosapentaenoate, less than about 0.05% by weight, of ethyl-
DHA, if any, and less than about 0.05% by weight, of fish allergens, if any.
In another embodiment, described is a method of treating hypertriglyceridemia in a
subject in need thereof, comprising: (a) identifying a subject having a fasting baseline
triglyceride level of about 500 mg/dl to about 2000 mg/dl and that is allergic to fish or
seafood, and (b) administering to the subject a pharmaceutical composition comprising about
1 g to about 4 g of a pharmaceutical composition comprising at least about 96%, by weight,
ethyl eicosapentaenoate, wherein the composition contains substantially no DHA or
derivative thereof and wherein upon administration the subject does not experience skin rash
or experiences reduced incidence of skin rash compared to placebo or to an equivalent
milligram dose of a commercially available prescription omega-3 fatty acid composition (e.g.
Lovaza). In another embodiment, the subject experiences no eructation or reduced eructation
compared to placebo or to an equivalent milligram dose of a commercially available omega-3
fatty acid composition (e.g. Lovaza).
[0208a] The term “comprising” as used in this specification and claims means “consisting at
least in part of”. When interpreting statements in this specification, and claims which include
the term “comprising”, it is to be understood that other features that are additional to the
features prefaced by this term in each statement or claim may also be present. Related terms
such as “comprise” and “comprised” are to be interpreted in similar manner.
[0208b] In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose of
providing a context for discussing the features of the invention. Unless specifically stated
otherwise, reference to such external documents is not to be construed as an admission that
such documents, or such sources of information, in any jurisdiction, are prior art, or form part
of the common general knowledge in the art.
[0208c] In the description in this specification reference may be made to subject matter that is
not within the scope of the claims of the current application. That subject matter should be
readily identifiable by a person skilled in the art and may assist in putting into practice the
invention as defined in the claims of this application.
EXAMPLES
The following examples are for illustrative purposes only and are not to be
construed as limiting in an manner.
Example 1
A single center, double blind, randomized, parallel-group, placebo controlled dose-
ranging study of E-EPA in subjects with age-associated impairment (AAMI) was performed.
The primary goal was to examine the effect of ethyl-EPA versus placebo on cognitive
performance in subjects with AAMI as measure by the power of attention tasks in a
computerized test batter over a period of 6 weeks. Secondary objectives were to:
(1) examine the effect of E-EPA versus placebo over 6 weeks on the following
tests in the computerized cognitive battery: Continuity of attention tasks; Quality of working
memory tasks; Quality of episodic memory tasks; Speed of attention tasks;
(2) to assess the safety and tolerability of E-EPA versus placebo from routine
clinical laboratory tests, adverse events (AE) monitoring and vital signs; and
(3) assess the potential dose-effect relationship of E-EPA on the cognative
endpoints by measurement of essential fatty acids in plasma and red blood cell membranes.
94 subjects were randomized.
The study plan was to enroll 96 subjects who would be randomly allocated to 1 of
4 possible treatment groups for 6 weeks, in a balanced block design (24 subjects per group),
as follows:
1. 1 g ethyl-EPA daily
2. 2 g ethyl-EPA daily
3. 4 g ethyl-EPA daily
4. Placebo (paraffin oil) daily
Ethyl-EPA was provided as 500 mg soft gel capsules providing ethyl-EPA of
>96% purity, 0.25% to 0.38% by weight ethyl octadecatetraenoate, 0.075% to 0.15% by
weight ethyl nonaecapentaenoate, 0.25% to 0.35% by weight ethyl arachidonate, 0.3% to
0.4% by weight ethyl eicosatetraenoate (ETA-E), 0.075% to 0.15% ethyl
heneicosapentaenoate and 0.2% dl--tocopherol as an antioxidant. Matching placebo
capsules contained 467 g of liquid paraffin and 0.2% dl--tocopherol. The placebo group
was further randomized so that an equal number of subjects (8) was allocated 1 g, 2 g or 4 g
placebo. Study drug was taken twice daily (BID) as a divided dose (e.g. for the 1 g dose, 500
mg was given in the morning and a further 500 mg was given in the evening) with a light
snack or meal.
The study consisted of a screening visit, a training visit and 4 study visits. At the
screening visit, subjects’ eligibility was determined through cognitive tests (verbal paired
associated learning [PAL] subscale, vocabulary subtest, Memory Assessment Clinics
Questionnaire [MAC-Q], mini mental state evaluation [MMSE] and MINI [mini international
neuropsychiatirc interview; sections 1 and 2 of Diagnostic and Statistical Manual of Mental
Disorders, 4th Ed. (DSM-IV) plus dysthymia]), haematology, clinical chemistry and 12-lead
electrocardiogram (ECG). At the training visit, subjects were shown how to use the CDR
computerized system. Subjects took study drug for 6 weeks and on Days 0, 14, 28 and 42,
subjects underwent the CDR cognitive test battery.
Inclusion Criteria
1. Written informed consent.
2. Male and female volunteers between 50 and 70 years of age.
3. Self-reported complaints of memory loss reflected in such everyday problems
as difficulty remembering names of individuals following introduction,
misplacing objects, difficulty remembering multiple items to be purchased or
multiple tasks to be performed, problems remembering telephone numbers or
postal codes and difficulty recalling information quickly or following
distraction as determined by a score of 25 or higher on the MAC-Q
questionnaire. Onset of memory loss was to be described as gradual without
sudden worsening in recent months.
4. Possession of subjective and objective cognitive impairment with a score of at
least 1 standard deviation (SD) below that of the mean for age-matched elderly
population as determined by the total score of between 13 and 20 from the
PAL subset of the Wechsler Memory Scale.
. Evidence of adequate intellectual function as determined by a scaled score of
at least 9 (raw score of at least 32) on the Vocabulary subtest of the Wechsler
Adult Intelligence Scale (WAIS).
6. Absence of dementia as determined by a score of 24 or higher on the MMSE.
7. Non-smokers or ex-smokers for >3 months.
8. Was able to travel to the centre and judged by the Investigator as likely to be
able to continue to travel for the duration of the study and comply with the
logistical aspects of the study.
9. Body mass index (BMI) <29.5 kg/m .
Exclusion Criteria
1. Unlikely or unable to comply with investigational medication dosing
requirements.
2. Diagnosis of major depressive disorder, Alzheimer’s or vascular dementia as
defined according to the MINI / DSM-IV Text Revision (TR) criteria.
3. Past or current history of a neurological or psychiatric disorder that could have
affected cognitive function.
4. Past or current history of inflammatory gastrointestinal disease such as
Crohn’s Disease or ulcerative colitis.
. Constipation which required active treatment.
6. Current or previous history of cancer, excluding diagnosis of basal cell
carcinoma.
7. Any history or evidence of clinically significant cardiac abnormality as
measured by 12-lead ECG.
8. Any other medical condition or intercurrent illness not adequately controlled,
which, in the opinion of the Investigator, may have put the subject at risk
when participating in the study or may have influenced the results of the study
or affected the subject’s ability to take part in the study.
9. Clinically significant abnormal screening laboratory results (haematology,
biochemistry) on screening or vital signs that fell outside the normal range for
this population, which in the opinion of the Investigator affected the subject’s
suitability for the study.
. Any changes to prescribed medication for a medical condition within 4 weeks
of the baseline visit.
11. Omega-3 supplementation within 4 weeks of the baseline visit or during the
study treatment period.
12. Currently taking anticoagulants or daily dose of aspirin >325 mg.
13. Cough or cold flu remedies containing opiates or antihistamines, within 2
weeks of the baseline visit or during the 6-week treatment period.
14. Known allergy to any ingredients of the study drug or placebo.
Any subject could withdraw from the study at any time at their or their legal
guardian’s request, or at the discretion of the investigator, if the subjects continued inclusion
was not in their best interest, or in the event of a serious or unexpected AE. Every reasonable
effort was made to document subject outcome and reasons for withdrawal. Any ongoing AEs
were followed-up until the event had resolved, stabilised or was otherwise explained.
Subjects who were withdrawn were not replaced. Subjects were assigned unique
identification numbers according to a pre-determined randomization list generated by
Catalent Pharma Solutions and used in the drug packaging.
Study drug was administered orally BID as a divided dose with food, for 6 weeks.
Subjects were randomized to 1 of 6 possible treatment groups (Table 1).
Tabl
e 1.
Treatment Groups
Group Dose (g) Study Drug Dosage Form (soft gel capsule)
Group Dose (g) Study Drug Dosage Form
(soft gel capsule)
Active 1 1 Ethyl-EPA 1 x 500 mg BID
Active 2 2 Ethyl-EPA 2 x 500 mg BID
Active 3 4 Ethyl-EPA 4 x 500 mg BID
Placebo 1 1 Paraffin oil 1 x 500 mg BID
Placebo 2 2 Paraffin oil 2 x 500 mg BID
Placebo 3 4 Paraffin oil 4 x 500 mg BID
BID = twice daily, ethyl-EPA = ethyl-eicosapentaenoic acid
Study drug was dispensed at Visits 3, 4 and 5; the maximum period between Visit
3 and each subsequent visit was:
• Visit 3 to Visit 4 (2 weeks ±2 days from Visit 3).
• Visit 3 to Visit 5 (4 weeks ±2 days from Visit 3).
• Visit 3 to Visit 6 (6 weeks ±2 days from Visit 3).
All treatment packs were identical in appearance, in order to maintain subject and
investigator blind throughout the study. The investigator, Sponsor/clinical research
organization personnel and subjects remained blinded throughout this study. The investigator
was permitted to un-blind individual subjects if it was considered medically imperative. The
process for breaking the blind is outlined below.
Omega-3 supplements had to be discontinued at least 4 weeks prior to the baseline
visit (Visit 3). Cough and influenza remedies containing opiates or antihistamines had to be
discontinued 2 weeks prior to the baseline visit (Visit 3) and were not permitted for the
duration of the study.
Existing medication had to have been stable for 4 weeks prior to the baseline visit
(Visit 3) and the dose maintained for the duration of the study. Where a dose change was
absolutely necessary this was recorded in the electronic case report form (eCRF).
Subjects who required anticoagulant medication during the study were to be
withdrawn. Psychological counseling or therapy was not permitted for the duration of the
study, as these could have interfered with the outcome of the study. Unused study drug was
returned to the study site. Subjects who used less than 80% of the prescribed dose were
considered non-compliant.
At screening cognitive testing and suitability for the study were assessed using the
Verbal Paired Associates 1 (Wechsler Memory Scale), Vocabulary Subtest of the WAIS,
MAC-Q, MMSE and MINI (DSM-IV Sections 1 and 2 plus Dysthymia).
A selection of tasks from the CDR computerized cognitive assessment system were
administered (Appendix 8 of protocol) at Visit 2 (training visit), Visit 3 (baseline), Visit 4
(Day 14), Visit 5 (Day 28) and Visit 6 (Day 42). Parallel forms of the tests were presented at
each testing session. All tasks were computer-controlled, the information presented on high
resolution monitors, and the responses recorded via a response model containing 2 buttons 1
marked ‘no’ the other ‘yes’. Five CDR composite scores were used as the primary/secondary
outcome variables.
The task titles were:
• Word Presentation • Numeric Working Memory
• Immediate Word Recall • Delayed Word Recall
• Picture Presentation • Word Recognition
• Simple Reaction Time • Picture Recognition
• Digit Vigilance • Bond-Lader Visual
gue Scales of Mood
• Choice Reaction Time Analo
• Spatial Working Memory and Alertness
• Screen, Using the
Computer Mouse
To ensure consistency of approach, full training on the cognitive tests and CDR
test battery was provided to study site staff and study subjects. The results of each variable
were automatically recorded using the machine interface developed by CDR.
An AE was defined as any untoward medical occurrence temporally associated
with the use of a medicinal product whether or not considered related to the medicinal
product.
The investigator was responsible for the detection and documentation of AEs. At
each visit the subject was asked about AEs by means of non-leading questions. AEs were
recorded from the time a subject provided a written informed consent and deemed eligible to
participate until completion of the treatment period. AEs ongoing at the end of the treatment
period were followed until resolution or return to baseline or normal value or if the event was
considered unrelated to study drug.
A serious adverse event (SAE) was defined as any AE at any dose that:
• resulted in death;
• was life-threatening;
• required hospitalisation or prolongation of existing hospitalisation;
• resulted in disability or incapacity, or
• resulted in a congenital anomaly/birth defect.
Other events were considered SAEs if they jeopardized the subject or required
medical or surgical intervention to prevent one of the outcomes listed above.
Regardless of the above criteria, any AE that the Sponsor or investigator
considered serious was to have been immediately reported as a SAE. Any death or SAE
experienced by the patient while receiving or within 30 days of last dose of Investigational
Medicinal Product must be promptly reported (within 24 hours of learning of the event) to
pharmacovigilance. All AEs (including SAEs) are to be accurately recorded on the adverse
event page of the subject’s eCRF, beginning from first administration of Investigational
Medicinal Product until 30 days after the last dose.
Blood samples for the laboratory assessments for haematology (a 5 mL blood
sample) and clinical chemistry (a 10 mL blood sample) listed in Table 2, were collected at the
screening visit (Visit 1). Samples were processed and analyzed by Simbec Laboratories Ltd.
Table 2. Laboratory Assessments
Clinical Chemistry Haematology
Sodium Red blood cell count
Potassium White blood cell count
Bicarbonate Mean corpuscular volume
Urea Mean corpuscular haemoglobin
Creatinine Mean corpuscular haemoglobin concentration
Total bilirubin Haemoglobin
Aspartate aminotransferase Platelet count
Alanine aminotransferase Neutrophils
Gamma glutamyl transferase Lymphocytes
Total protein Monocytes
Albumin Glucose Basophils
Pharmacodynamic: Essential Fatty Acid (EFA) Measurements
Blood samples (10 mL) were collected at Visit 1 (screening) and at Visits 4, 5 and
6. Analysis was performed by MSR Lipid Analysis, Scottish Crop Research Institute,
Dundee, UK. The screening sample acted as baseline for the EFA measurements.
Lipid was extracted from plasma, serum and RBC suspensions and converted into
fatty acid methyl esters which were analysed by gas chromatography to give fatty acid
profiles as micrograms fatty acid per gram of sample (μgFA/g) and normalised area percent.
The CDR computerized system has been used to measure the effects of pharmaceuticals on
cognitive function in a variety of clinical trials. Efficacy was assessed by a battery of
cognition tests designed by CDR. Safety data were analysed by Quanticate.
Populations analyzed included:
• Intent to Treat (ITT) Population: All randomised subjects with at least 1 visit post-
baseline were included in this population, regardless of treatment actually received.
• Per Protocol Population (PP): All randomised subjects that completed the study,
excluding significant protocol deviators, were defined as the Safety PP population.
An Efficacy PP population was based on the Efficacy completers. The intercept of
the Safety and Efficacy PP populations defined the Study PP Population.
• Safety Population: All randomised subjects that received at least 1 dose of study
medication.
Summary statistics were provided for the ITT and Study PP Populations separately
for all composite scores, major and supportive variables. Summary statistics were performed
for both the unadjusted and difference from baseline data (i.e. the difference from the time
matched predose assessments on Day 0). Summary statistics were calculated by treatment,
day and time-point. The summary statistics comprised n, mean, median, SD, standard error
of mean (SEM), minimum and maximum values.
Difference from baseline data for each major variable was evaluated by an
Analysis of Covariance (ANCOVA) using SAS PROC MIXED Version 8.2.
Fixed effects for treatment, day, time point, treatment by day, treatment by time
point, treatment by day by time-point were fitted. Subject within treatment was fitted as a
repeated effect using the repeated statement. The compound symmetry covariance structure
was used. Subjects’ time-matched predose assessments on Day 0 were used as a covariate in
the analysis. Least squares means (LS means) were calculated for treatment by day,
treatment by time-point and treatment by day by time-point interaction. This formal analysis
was conducted for the ITT and Study PP Populations separately.
Safety evaluations were based on the safety population. Safety and tolerability
were assessed in terms of AEs, vital signs, 12-lead ECG, clinical laboratory data, medical
history, and study drug compliance. Safety and tolerability data were presented by treatment
group. All safety data were listed individually by subject.
RBC and plasma EFA data were collected at baseline, Day 14, 28 and 42 and
summarized by visit for each treatment group. Change from baseline and percent change
from baseline were also summarized. ANCOVA comparison of ethyl-EPA dose groups and
ethyl-EPA versus placebo was performed.
The sample size calculation was based on Power of Attention. Ispronicline (50
mg), a neuronal nicotinic acetylcholine receptor partial agonist, in subjects with AAMI on
Day 21 of repeated dosing in an earlier study showed a benefit of 61 msec (50 mg mean=-
32.54, SD = 61.22; placebo mean=28.25, SD = 49.64) to Power of Attention. Using a pooled
SD, a sample size of 15 subjects per treatment arm was considered sufficient to detect a
difference of 61 msec, with 80% power and 5% significance level (no adjustment for multiple
testing). As there was no prior experience with the compound or mechanism of action with
these cognitive measures, a sample size of 24 subjects per treatment arm was chosen as
sufficient to allow for early withdrawals.
There were no changes to the conduct of the study. The following changes were
made to the planned analyses: The equation to calculate Speed of Memory was changed to
SPEEDMEM (speed of memory) = SPMRT (spatial working memory speed) + NWMRT
(numeric working speed) + DRECRT (word recognition speed) + DPICRT (picture
recognition speed).
• Subject’s time-matched pre-dose assessments on Day 0 were used as a covariate in
the analysis.
• Day 0 was removed from Day values in the list of ANCOVA variable values.
Covariate = Baseline was changed to Covariate = Time matched predose assessments
on Day 0 in the list of ANCOVA variable values.
• Day by Time-point was added to the list of model effects in SAS® code for
ANCOVA model.
• F Tests table and Treatment Effects table were added to list of ANCOVA summary
tables.
• ANCOVA summary tables were renumbered to follow on from ANCOVA raw
outputs.
• Figures were included for Treatment, Treatment by Day, Treatment by Time-point,
Treatment by Day by Time-point effects for ANCOVA LS means.
• Figures were added for ANCOVA LS means differences to placebo (95% confidence
interval [CI]).
• A post-hoc analysis was performed which compared the individual placebo groups (1
g, 2 g and 4 g paraffin oil) with the corresponding ethyl-EPA dose rather than to a
pooled placebo group.
Ninety-one subjects completed the study, three subjects discontinued; 2 subjects
from the ethyl-EPA 2 g treatment group (1 subject due to an SAE considered unrelated to the
study drug and 1 due to a protocol violation and 1 subject from the placebo 2 g group due to
an AE.
For Power of Attention, there was no statistically significant effect of treatment,
nor any treatment by day, treatment by time-point or treatment by day by time-point
interactions. There was no LS mean difference between active treatment and placebo at any
time-point. For Choice Reaction Time there were statistically significant benefits for ethyl-
EPA 1 g and 2g on Day 28, and some trends for benefit for 1 and 4 g ethyl-EPA on Day 42,
versus placebo; however no clear treatment-related pattern was observed.
Continuity of Attention did not show a difference between placebo and ethyl-EPA,
except for an overall decrease for 2 g ethyl-EPA that was only visible in the ITT population.
The subtask Digit Vigilance Targets Detected showed isolated decreases for active treatment
versus placebo, but there was no obvious treatment-related pattern.
Quality of Working Memory was the only composite score that showed a
statistically significant treatment by day interaction in the F-ratio. However, there were only
isolated statistically significant decreases for ethyl-EPA 1 g and 2 g versus placebo on Days
14 and 28, and these were most likely to be due to chance and not treatment related.
Quality of Episodic Secondary Memory showed statistically significant decreases
for ethyl-EPA versus placebo at various time-points. However, it seems unlikely to be an
effect of active treatment as the unadjusted data showed pre-existing differences between the
treatment groups that was most notable on Day 0 in the first assessment session. In
difference from Baseline data that were calculated prior to ANCOVA analysis, these
differences were no longer apparent. This suggests that the ANCOVA model fitted a strong
negative correlation with the baseline values. This is often the case when the variability
within subjects overlaps the variability between subjects.
Speed of Memory and the subtasks Spatial and Numeric Working Memory Speeds
and Word and Picture Recognition Speed showed no differences in performance, in the F-
ratio statistics, between Ethyl-EPA and placebo.
For Self-rated Alertness, there was no apparent difference in ratings between ethyl-
EPA and placebo. There were isolated decreases in ratings for active treatment versus
placebo that were unlikely to be compound related.
Self-rated Contentment showed statistically significant decreases in ratings for
ethyl-EPA 2 g on Day 28. However, these individual decreases were not statistically
significant. It is unlikely that this was a treatment-related effect as it was restricted to a single
day and no other dose level showed a similar pattern on any other day. For Self-rated
Calmness there was no difference in ratings between active treatment and placebo.
When the results of each ethyl-EPA dose and their corresponding placebo were
compared (post-hoc analysis), it appeared that ethyl-EPA 4 g improved the subjects’ reaction
times in the attention tasks (Power of Attention, Simple Reaction Time and Choice Reaction
Time). This was seen most clearly for Choice Reaction Time, where a pattern of gradual
improvement over the assessment day for 4 g was seen. It is possible that a longer period of
administration would clarify the effects of ethyl –EPA on these parameters.
EPA (shown in Table 3), DPAn-3 and EPA/AA ratio (data not shown) plasma and
RBC values increased substantially from baseline to Day 42 for the AMR-101 1, 2, and 4 g
treatment groups. AA, DHA and DGLA values decreased substantially from baseline (data
not shown).
Table 3. Mean (SD) EPA (Plasma and RBC (μg/g)) Change from Baseline.
Ethyl-EPA Placebo
1 g 2 g 4 g 1 g (N=7) 2 g (N=8) 4 g
(N=23) (N=24) (N=24) (N=8)
Plasma
Baseline 48.3 44.9 49.1 47.5 42.1 42.5
(31.03) (25.01) (17.23) (26.41) (16.18) (11.86)
Day 14 61.2 124.6 207.7 1.6 (24.69 -1.2 21.9
(26.61) (42.25) (57.05) (19.82) (32.91)
Day 28 60.3 142.2 215.2 6.5 1.6 1.3
(36.03) (46.23) (58.68) (15.46) (13.64) (14.03)
Day 42 62.0 133.4 204.6 11.9 0.4 4.4
(39.43) (43.34) (80.69) (26.34) (21.18) (23.32)
Baseline 19.8 18.9 19.8 20.4 19.3 17.2
(10.85) (8.91) (5.28) (5.77) (6.58) (4.94)
Day 14 12.3 26.9 39.5 -0.5 0.0 (7.17) 2.6
(7.39) (9.15) (13.16) (6.32) (6.73)
Day 28 14.5 32.9 50.2 1.5 (4.16) 0.0 (7.06 0.6
(10.47) (10.11) (15.82) (4.42)
Day 42 17.6 38.3 52.5 -0.2 1.0 (8.01) -0.2
(11.89) (12.46) (20.56) (5.90) (6.97)
As can be seen in Table 3, at the 2 g per day AMR101 dose, plasma EPA levels
increased 297% after 42 days and at the 4 g per day AMR101 dose, plasma EPA levels
increased by 417% compared to baseline or placebo control.
Grimsgaard et al. previously published an article describing serum phospholipid
levels at baseline and after 7 weeks of supplementation with 4 g per day of 90% ethyl-DHA,
4 g per day of 95% ethyl-EPA with some DHA present, or corn oil. Am. J. Clin. Nutr. 1997;
66:649-59 (1997). The complete profile of additional fatty acids and ingredients present in
these compositions is unknown. After supplementation over a period of 7 weeks, subjects
exhibited only a 297% increase in serum phospholipid EPA compared to the increase of
417% shown above with an inventive composition. A comparison of other chances in
plasma/serum fatty acids is shown in Table 4.
Table 4. Percent Fatty Acid Change from Baseline After
Administration of 4 g Dose
Fatty Acid Grimsgaard AMR101
EPA +297% +417%
AA -18.5% -21.9%
DHA -15.20% -17.5%
DPA +130% +147%
DGLA -30.5% -39.4%
Furthermore, in the Japanese Eicosapentaenoic Acid (EPA) Lipid Intervention
Study (JELIS), Yokoyama et al. reported that they followed over 18,000 patients randomly
assigned to received either 1800 mg of EPA composition (Epadel) with statin, or statin only
with a 5-year follow-up. Lancet 2007; 369: 1090-98. After 5 years of treatment, subjects
exhibited an increase in plasma EPA of only 70% (from baseline of 93 mg/L to 169 mg/L).
Figures 1 and 2 and show a comparison of the change in plasma/serum EPA levels
observed with AMR101 treatment in the current study compared to those observed with
different EPA compositions in the JELIS study and by Grimsgaard. As will be noted, at ~2 g
per day, AMR101 achieved much greater plasma EPA increase compared to baseline (~4-
fold) after just 6 weeks than the JELIS study observed (< 2-fold) after 5 years of treatment.
Moreover, at the 4 g per day dose, AMR101 treatment for 6 weeks achieved much higher
(>250 μg/g) plasma EPA levels than reported by Grimsgaard after 7 weeks of treatment
(87.66 μg/g serum). Overall, the 4 g per day dose of AMR101 resulted in a greater than 5-
fold increase in plasma EPA over baseline while the 4 g per day dose of Grimsgaard’s
composition resulted in less than a 3-fold increase in serum EPA. These results were
unexpected.
Example 2
A multi-center, randomized, double-blind, placebo-controlled trial was conducted
in North America to determine whether 1 gram twice daily of EPA for 6 months improves
motor performance in Huntington’s patients. A post-hoc analysis was performed to evaluate
the effect of EPA on non-fasting triacylglycerols.
Study of the effects of ethyl-EPA on the progression of Huntington Disease
enrolled study participants at 41 sites in Canada and the United States. Based on the results
of the earlier study, the study entry criteria were designed to enrich the participation of
individuals with Huntington disease with a CAG repeat less than 45, without requiring
genetic testing to reveal the length of expansions to research participants or investigators. To
participate in the study, individuals had to have the clinical features of HD and either a
confirmatory family history or a known CAG expansion. Eligibility criteria included a
minimum age of 35, a total functional capacity of at least 7, minimal dystonia (not exceeding
2 on the UHDRS in either the trunk or extremities), minimal bradykinesia (not exceeding 2
on the UHDRS item for bradykinesia), the use of adequate birth control, the ability to take
oral medications, and the willingness and ability to comply with study requirements.
Individuals were not eligible to participate if, within 60 days of the baseline visit, they had
used omega-3 fatty acid supplements, tetrabenazine or reserpine, high or variable doses of
oral anti-psychotic medications (e.g., haloperidol), steroids other than topical preparations,
high dose selenium supplements, lithium, high doses of benzodiazepines, anti-coagulation
medication (e.g., coumadin), high doses (greater than 325 mg per day) of aspirin, unstable
does of NMDA receptor antagonists (e.g., memantine), unstable doses of anti-epileptic
medications, or if they had participated in other investigational drug studies. Additional
exclusion criteria were the use of depot neuroleptics within 6 months of the baseline visit, a
history of tardive dyskinesia, unstable medical or psychiatric illness, major depression
(defined as a score greater than 20 on the Beck Depression Inventory II), suicidal ideation,
clinically significant substance abuse within 12 months of the baseline visit, women who
were pregnant or lactating, known allergy to ethyl-EPA or placebo, or previous participation
in an investigational study of EPA.
This was a randomized, double-blind, placebo-controlled, parallel group study of
EPA (1 gram twice/day). The institutional review board at each participating site approved
the research plan and consent documents. Eligible study participants provided written
consent. At the baseline visit, participants were randomized according to a block-balanced
computer-generated randomization plan that was stratified by site and generated by the
Biostatistics Center at the University of Rochester. Individuals were randomized in a 1:1
ratio to receive either active drug (n=158) in the form of two 500 mg capsules of AMR101
orally or placebo (n=154) in the form of two 500 mg capsules containing light paraffin oil
and 0.2% dl-alpha-tocopherol twice daily orally for 6 months. After 6 months, all TREND-
HD participants were treated with AMR101 for 6 months in an open-label fashion. Only data
from the first 6 months were used to evaluate the effects of AMR101 on lipids.
The outcome measure of this study was the change in non-fasting triacylglycerol
(TG) levels in those on AMR101 compared to those on placebo.
Safety was assessed at all study visits, including evaluation and assessment of
adverse events and serious adverse events and review of clinical laboratory tests (complete
blood count, serum chemistry, and urine pregnancy tests). The safety of research participants
was monitored in a blinded manner by a medical monitor from both the sponsor and from the
Huntington Study Group. In addition, an independent Safety Monitoring Committee that had
access to treatment assignments reviewed safety data throughout the study to determine if any
modifications were needed to the trial’s conduct.
Changes in lipid levels were compared using an analysis of covariance
(ANCOVA) with treatment group as the factor of interest, site as a stratification factor, and
baseline value as a covariate. All individuals who received study medication were included
in the safety analysis. For each type of adverse event, the treatment groups were compared
regarding the occurrence of at least one event using Fisher’s exact test. Continuous measures
of safety such as laboratory test results and vital signs were analyzed using methods similar
to those described above for the primary outcome variable (ANCOVA). No corrections were
made for multiple comparisons in evaluating safety data.
One hundred forty-five subjects on AMR101 (92% of those assigned) and 141 of
those on placebo (92% of those assigned) had red blood cell content of EPA determined at
baseline and 6 months. Baseline red blood cell content of 20:5n3 (EPA) increased
significantly after 6 months in those on AMR101 (from a mean of 0.52% to 3.07%) but
decreased in those on placebo (from a mean of 0.61% to 0.55%); p<0.0001). After 6 months,
individuals taking AMR101 had a 26 mg/dL decrease in TGs from a baseline of 171
compared to a decrease of 11 mg/dL from a baseline of 187 mg/dL in those on placebo;
p=0.007. Total cholesterol was reduced significantly more in those taking AMR101 (9.5
mg/dL) from a baseline of 204 mg/dL than in those taking placebo (2.5 mg/dL) from a
baseline of 208 mg/dL; p=0.009. Lipid and Motor Scoer data are shown in Tables 5 and 6,
respectively.
Table 5. Motor Score Results.
All Study Participants Study Participants with
n = 316 CAG < 45
n = 221
Total motor score 4 of the Ethyl- Placebo p- Ethyl- Placebo p-
Unified EPA value EPA value
Huntington’s Disease
Rating Scale
At baseline [mean (SD)] 25.2 23.9 0.16 24.9 23.4 0.18
(8.3) (8.1) (8.3) (7.7)
Change in total motor score 4 0.2 1.0 0.20 0.0 0.3 0.70
at 6 months
(mean)
Change in total motor score 4 0.0 2.0 0.02 -1.2 1.6 0.004
at 12 months (mean)
Table 6. Lipid Parameter Results.
Lipoprotein Variable Ethyl-EPA Placebo p-value
Baseline triglycerides (mean mg/dL ± SD) 171 ± 108 187 ± 139 0.27
Baseline total cholesterol (mean mg/dL ± 204 ± 41.4 208 ± 40.6 0.42
Change in triglycerides after 6 months -25.8 ± 89.1 -11.1 ± 105.2 .007
(mean mg/dL ± SD)
Change in total cholesterol after 6 months -9.5 ± 28.6 -2.5 ± 24.7 .009
(mean mg/dL ± SD)
Change in triglycerides after 12 months -17.7 ± 86.7 -40.0 ± 126.0 0.66
(mean mg/dL ± SD)
Change in total cholesterol after 12 months -5.6 ± 25.5 -6.9 ± 34.5 0.95
(mean mg/dL ± SD)
By comparison with these data for AMR101, Grimsgaard reported a decrease
(from baseline) of only 12% in serum triglycerides in the EPA group after 7 weeks of
treatment. Furthermore, addition of the Epadel EPA composition to existing statin therapy in
the JELIS study resulted in only a 9% reduction in triglycerides after 5 years of treatment.
Example 3
A study was performed to evaluate and compare the content of Epadel capsules
with AMR101 capsules. Six capsules of each composition were selected for analysis by gas
chromatography. Averages of the six capsules for each of the two compositions are shown in
Table 7.
Table 7. Measured and Identified Components of AMR101 and Epadel.
AMR101 Epadel
Component Amount (%w/w)
Ethyl-EPA 96.3 94.5
ODTA-E 0.25 0.09
Impurity 3 ND0.06
NDPA-E 0.11 0.11
Impurity 4 0.08 0.07
AA-E 0.30 0.06
ETA-E 0.38 0.11
Isomer A 0.08 0.23
Isomer D,E 0.11 0.62
HPA-E 0.11 0.06
ND = w/w% less than 0.05%
Example 4
A phase I, multiple dose pharmacokinetic study in healthy male volunteers was
carried out at a single center. Twenty four subjects were divided into two treatment groups of
12 subjects each (groups A and B). Both groups received the same total daily dose of
AMR101 but the dosing regiments were different. All subjects received a single oral dose of
2 g AMR101 on Day 1. Treatment Group A received 28 continuous once daily doses of 2 g
AMR101. Treatment Group B received 27 continuous twice daily doses of 1 g AMR101 and
a single does of 2 g of AMR101 on day 30.
Levels of EPA and other essential fatty acids were determined in plasma and red
blood cells. Blood samples for pharmacokinetic analysis were taken at the following time
points for Treatment groups A and B:
Days 1 and 30: Pre-dose, 1, 2, 3, 4, 5, 6, 8, 20, 12, 24, 36 and 48 h. post-dose;
Days 9, 16, 23: pre morning dose;
Days 37, 44, 58: post last dose.
A first Interim Report presents the following pharmacokinetic results for
Treatment Group B:
Plasma – Day 1 (Pre-dose, 1, 2, 3, 4, 5, 6, 8, 20, 12, 24, 36 and 48 h post-dose);
Red cell—Day 1 (Pre-dose and 36 h), Day 30 (1 h post-dose), Day 37, Day 44,
Day 58.
Using a corrected value obtained by subtracting the pre-administration
concentration from the concentrations at each sampling, a single oral dose of 2 g of AMR101
resulted in a rapid rise in plasma lipid EPA. Maximum values were observed at 5 hours post-
administration with EPA levels remaining above baseline at 48 hours post-administration.
The half-life of removal of EPA from plasma lipids was 87 ± 65 h (non-baseline subtracted)
and 42 ± 31 h (baseline subtracted). Summary pharmacokinetic data are shown in Table 8.
Table 8. Non-Compartmental Analysis – Arithmetic Mean and SD.
Terminal Mean Oral VoD at VoD at Max Tmax
Half-Life Residence Clearance Terminal Steady Drug (h)
Time (h) Phase State Conc.
(mg/ml)
Unadjusted 86.6 126.6 0.381 37.0 37.8 78.3 4.64
SD 65.4 93.3 0.202 13.2 13.5 33.7 0.92
Baseline 42.2 63.6 1.27 58.8 62.8 55.5 4.64
Subtracted
0.021 30.9 43.1 0.83 23.9 25.7 28.2 0.92
In the Per Protocol population oral administration of AMR101 resulted in RBC
EPA levels increasing from a mean value of 190.4 mg/g before dosing on Day 1 to 40.3 mg/g
one hour following the final dose on Day 30.
Example 5
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 AMR101 in
patients with fasting triglyceride levels ≥500 mg/dL. The primary objective of the study was
to determine the efficacy of AMR101 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).
The secondary objectives of this study was the following:
1. To determine the safety and tolerability of AMR101 2 g daily and 4 g daily;
2. To determine the effect of AMR101 on lipid and apolipoprotein profiles;
3. To determine the effect of AMR101 on low-density lipoprotein (LDL) particle number
and size;
4. To determine the effect of AMR101 on oxidized LDL;
. To determine the effect of AMR101 on fasting plasma glucose (FPG) and hemoglobin
(HbA );
A1c 1c
6. To determine the effect of AMR101 on insulin resistance;
7. To determine the effect of AMR101 on high-sensitivity C-reactive protein (hsCRP);
8. To determine the effects of AMR101 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
. To explore the relationship between an increase in red blood cell membrane
eicosapentaenoic acid (EPA) concentrations and the reduction in fasting TG levels.
The population for this study is men and women (women of childbearing potential
will need to be on contraception or practice abstinence) >18 years of age with a body mass
index ≤45 kg/m who are 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 can be safely discontinued at screening, or if it
should be continued. If statin therapy (with or without ezetimibe) is to be continued, dose(s)
were 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), were required
to safely discontinue non-statin, lipid-altering therapy at screening.
Approximately 240 patients were randomized at approximately 50 centers in North
America, South America, Central America, Europe, India, and South Africa. The Phase 3,
multi-center study consisted of 3 study periods: (1) A 6- to 8-week screening period that
includes 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.
During the screening period and double-blind treatment period, all visits were
within ±3 days of the scheduled time. During the open-label extension period, all visits were
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.
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:
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.
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 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 was collected 1 week later at Visit 3.1. If a third sample was collected at Visit
3.1, entry into the study was based on the average (arithmetic mean) of the values from Visit
3 and Visit 3.1.
After confirmation of qualifying fasting 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.
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.
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 received
open-label AMR101 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 returned to the site every 12
weeks until the last visit at Visit 11 (Week 52).
Eligible patients were randomly assigned at Visit 4 (Week 0) to receive orally
AMR101 2 g daily, AMR101 4 g daily, or placebo for the 12-week double-blind treatment
period. AMR101 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 AMR101. During
the double-blind treatment period, patients took 2 capsules (AMR101 or matching placebo) in
the morning and 2 in the evening for a total of 4 capsules per day. Patients in the AMR101
2 g/day treatment group receiveed 1 AMR101 1 g capsule and 1 matching placebo capsule in
the morning and in the evening. Patients in the AMR101 4 g/day treatment group received
2 AMR101 1 g capsules in the morning and evening.
Patients in the placebo group receiveed 2 matching placebo capsules in the
morning and evening. During the extension period, patients received open-label AMR101 4 g
daily. Patients took 2 AMR101 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:
• 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 HbA from baseline to Week 12;
• Change in insulin resistance, as assessed by the homeostasis model index insulin
resistance, from baseline to Week 12;
• Percent change in lipoprotein associated phospholipase A2 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.
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
For TG, TC, HDL-C, calculated LDL-C, calculated non-HDL-C, and VLDL-C,
baseline ws defined as the average of Visit 4 (Week 0) and the preceding lipid qualifying visit
(either Visit 3 [Week -1] or if it occurs, Visit 3.1) measurements. Baseline for all other
efficacy parameters was the Visit 4 (Week 0) measurement.
For 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.
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 will be
used for the analysis of secondary efficacy variables.
The primary analysis was repeated for the per-protocol population to confirm the
robustness of the results for the intent-to-treat population.
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 results of the study are show in Figures 3 and 4. Adverse events are
shown in Table 9 by comparison with placebo and those experienced by subjects taking
commercially available mixture of E-EPA and E-DHA (Lovaza).
LOVAZA label AMR101 Number (%) of Patients
with TEAE
Lovaza Placebo AMR101 AMR101
4 g Placebo 2 g/day 4 g/day
N=226 N= 228 N=76 N=76 N=77
Event % % n (%) n (%) n (%)
Subjects with any 35.4 27.6
29 (38.2) 27 (35.5) 28 (36.4)
TEAE
Diarrhea 5 (6.6) 4 (5.3) 1 (1.3)
Nausea 4 (5.3) 5 (6.6) 1 (1.3)
Dyspepsia 7 (3.1) 6 (2.6) 0 (0.0) 1 (1.3) 1 (1.3)
Eructation 11 (4.9) 5 (2.2) 3 (3.9) 1 (1.3) 0 (0.0)
Skin rash 4 (1.8) 1 (0.4) 1 (1.3) 1(1.3) 0 (0.0)
Infection 10 (4.4) 5 (2.2) 9 (11.8) 2 (2.6) 4 (5.2)
Hypertension 0 (0.0) 4 (5.3) 1 (1.3)
TEAE = treatment-emergent adverse event
Claims (9)
1. Use of ethyl eicosapentaenoate in the manufacture of a medicament to treat or prevent stroke, myocardial infarction, or both in a subject on statin therapy, wherein (a) the subject has been identified as having a baseline triglyceride level of at least about 150 mg/dL and as allergic or hypersensitive to fish or seafood, and (b) the medicament is formulated to provide about 4 g of ethyl eicosapentaenoate to the subject per day, is substantially free of fish protein, and is encapsulated in one or more capsules.
2. The use of claim 1, wherein the subject has or is at risk for developing a cardiovascular-related disease.
3. The use of claim 1 or 2, wherein the subject has coronary heart disease or hypertension.
4. The use of any one of claims 1 to 3, wherein the subject does not develop skin rash after administration of the medicament.
5. Use of ethyl eicosapentaenoate in the manufacture of a medicament for treating hypertriglyceridemia in a subject in need thereof, wherein (a) the subject has been identified as having fasting baseline triglyceride level of at least about 500 mg/dl and as allergic to fish or seafood, and (b) the medicament is formulated to provide about 4 g of ethyl eicosapentaenoate to the subject per day, is substantially free of fish protein, and is encapsulated in one or more capsules.
6. The use of claim 5, wherein the subject has or is at risk for developing a cardiovascular-related disease.
7. The use of claim 5 or 6, wherein the subject has coronary heart disease or hypertension.
8. The use of any one of claims 5 to 7, wherein the subject does not develop skin rash after administration of the medicament.
9. A use as claimed in any one of claims 1-8 substantially as herein described and with reference to any example thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ778131A NZ778131A (en) | 2010-11-29 | 2011-11-28 | Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US41769110P | 2010-11-29 | 2010-11-29 | |
US61/417,691 | 2010-11-29 | ||
NZ757815A NZ757815A (en) | 2010-11-29 | 2011-11-28 | Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ763702A NZ763702A (en) | 2021-10-29 |
NZ763702B2 true NZ763702B2 (en) | 2022-02-01 |
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