U.S. patent application number 16/029198 was filed with the patent office on 2019-02-07 for methods of treating hypertriglyceridemia.
The applicant listed for this patent is Amarin Pharmaceuticals Ireland Limited. Invention is credited to Rene Braeckman, Mehar Manku, Ian Osterloh, Paresh Soni, Pierre Wicker.
Application Number | 20190038590 16/029198 |
Document ID | / |
Family ID | 42102041 |
Filed Date | 2019-02-07 |
United States Patent
Application |
20190038590 |
Kind Code |
A1 |
Manku; Mehar ; et
al. |
February 7, 2019 |
METHODS OF TREATING HYPERTRIGLYCERIDEMIA
Abstract
In various embodiments, the present invention provides methods
of treating and/or preventing cardiovascular-related disease and,
in particular, a method of blood lipid therapy comprising
administering to a subject in need thereof a pharmaceutical
composition comprising eicosapentaenoic acid or a derivative
thereof.
Inventors: |
Manku; Mehar; (Birmingham,
GB) ; Osterloh; Ian; (Kent, GB) ; Wicker;
Pierre; (Mystic, CT) ; Braeckman; Rene;
(Richboro, PA) ; Soni; Paresh; (Mystic,
CT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Amarin Pharmaceuticals Ireland Limited |
Dublin |
|
IE |
|
|
Family ID: |
42102041 |
Appl. No.: |
16/029198 |
Filed: |
July 6, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15408077 |
Jan 17, 2017 |
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16029198 |
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13903742 |
May 28, 2013 |
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15408077 |
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13198221 |
Aug 4, 2011 |
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13903742 |
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12702889 |
Feb 9, 2010 |
8293727 |
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13198221 |
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61173755 |
Apr 29, 2009 |
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61151291 |
Feb 10, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G16Z 99/00 20190201;
A61K 31/232 20130101; A61K 31/202 20130101; A61P 3/06 20180101;
G06F 19/00 20130101; A61K 45/06 20130101 |
International
Class: |
A61K 31/232 20060101
A61K031/232; G06F 19/00 20060101 G06F019/00; A61K 45/06 20060101
A61K045/06; A61K 31/202 20060101 A61K031/202 |
Claims
1. A method of lowering high-sensitivity C-reactive protein in a
subject in need thereof, the method comprising: determining a
baseline high-sensitivity C-reactive protein level in the subject,
the subject having a triglyceride level of at least 500 mg/dl; and
administering to the subject daily (a) about 4 g of a
pharmaceutical composition comprising at least 96% pure ethyl-EPA
and (b) a statin for a period of at least 12 weeks to effect a
reduction in high-sensitivity C-reactive protein of at least about
20% compared to the baseline.
2. The method of claim 1 wherein the pharmaceutical composition
contains substantially no DHA or derivative thereof.
3. The method of claim 1 wherein the subject has a triglyceride
level of 500 mg/dl to about 2000 mg/dl.
4. The method of claim 1 wherein the subject has a triglyceride
level of 750 mg/dl to about 2000 mg/dl.
5. The method of claim 1 wherein the subject is a diabetic.
6. The method of claim 1 wherein said administration is continued
for a period greater than 12 weeks.
7. The method of claim 1 wherein the step of administering effects
a reduction in high-sensitivity C-reactive protein of at least
about 40% compared to the baseline.
8. The method of claim 1 wherein the step of administering effects
a reduction in high sensitivity C-reactive protein of at least
about 20% compared to a subject having baseline triglycerides of at
least 500 mg/dl who receives statin therapy but not the
pharmaceutical composition.
9. The method of claim 1, further comprising determining a baseline
fasting triglycerides in the subject, and administering to the
subject about 4 g of the pharmaceutical composition and the statin
daily for the period of at least 12 weeks to effect a reduction in
fasting triglycerides of at least about 35% compared to baseline
and no statistically significant increase in LDL.
10. A pharmaceutical composition comprising an effective amount of
at least 96% pure E-EPA and an HMG-CoA inhibitor for use in
reducing hsCRP in patients with TGs above 500 mg/dl.
Description
CROSS-REFERENCE TO RELATED APPLICATION(S)
[0001] This application is a continuation of U.S. application Ser.
No. 15/408,077 filed on Jan. 17, 2017, which is a continuation of
U.S. application Ser. No. 13/903,742 filed on May 28, 2013, which
is a continuation of U.S. application Ser. No. 13/198,221 filed
Aug. 4, 2011, which is a continuation of U.S. application Ser. No.
12/702,889 filed Feb. 9, 2010 (now U.S. Pat. No. 8,293,727), which
claims priority to U.S. provisional application Ser. No. 61/151,291
filed Feb. 10, 2009, and U.S. provisional application Ser. No.
61/173,755 filed Apr. 29, 2009, each of which are incorporated by
reference herein in their entireties.
BACKGROUND
[0002] Cardiovascular disease is one of the leading causes of death
in the United States and most European countries. It is estimated
that over 70 million people in the United States alone suffer from
a cardiovascular disease or disorder including but not limited to
high blood pressure, coronary heart disease, dislipidemia,
congestive heart failure and stroke. A need exists for improved
treatments for cardiovascular diseases and disorders.
SUMMARY
[0003] In various embodiments, the present invention provides
methods of treating and/or preventing cardiovascular-related
diseases and, in particular, a method of blood lipid therapy
comprising administering to a subject in need thereof a
pharmaceutical composition comprising eicosapentaenoic acid or a
derivative thereof. In one embodiment, the composition contains not
more than 10%, by weight, docosahexaenoic acid or derivative
thereof, substantially no docosahexaenoic acid or derivative
thereof, or no docosahexaenoic acid or derivative thereof. In
another embodiment, eicosapentaenoic acid ethyl ester comprises at
least 96%, by weight, of all fatty acids present in the
composition; the composition contains not more than 4%, by weight,
of total fatty acids other than eicosapentaenoic acid ethyl ester;
and/or the composition contains about 0.1% to about 0.6% of at
least one fatty acid other than eicosapentaenoic acid ethyl ester
and docosahexaenoic acid (or derivative thereof).
[0004] In one embodiment, a pharmaceutical composition useful in
accordance with the invention comprises, consists of or consists
essentially of at least 95% by weight ethyl eicosapentaenoate
(EPA-E), about 0.2% to about 0.5% by weight ethyl
octadecatetraenoate (ODTA-E), about 0.05% to about 0.25% by weight
ethyl nonaecapentaenoate (NDPA-E), about 0.2% to about 0.45% by
weight ethyl arachidonate (AA-E), about 0.3% to about 0.5% by
weight ethyl eicosatetraenoate (ETA-E), and about 0.05% to about
0.32% ethyl heneicosapentaenoate (HPA-E). In another embodiment,
the composition is present in a capsule shell. In another
embodiment, the composition contains substantially no or no amount
of docosahexaenoic acid (DHA) or derivative thereof such as
ethyl-DHA (DHA-E).
[0005] In another embodiment, the invention provides a method of
treating moderate to severe hypertriglyceridemia comprising
administering a composition as described herein to a subject in
need thereof one to about four times per day.
[0006] These and other embodiments of the present invention will be
disclosed in further detail herein below.
DETAILED DESCRIPTION
[0007] 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.
[0008] 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.
[0009] In one embodiment, the invention provides a method for
treatment and/or prevention of a cardiovascular-related disease.
The term "cardiovascular-related disease" herein refers to any
disease or disorder of the heart or blood vessels (i.e. arteries
and veins) or any symptom thereof. Non-limiting examples of
cardiovascular-related disease and disorders include
hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia,
coronary heart disease, vascular disease, stroke, atherosclerosis,
arrhythmia, hypertension, myocardial infarction, and other
cardiovascular events.
[0010] 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.
[0011] In one embodiment, the present invention provides a method
of blood lipid therapy comprising administering to a subject or
subject group in need thereof a pharmaceutical composition as
described herein. In another embodiment, the subject or subject
group has hypertriglyceridemia, hypercholesterolemia, mixed
dyslipidemia and/or very high triglycerides.
[0012] 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.
[0013] In one embodiment, the subject or subject group being
treated in accordance with methods of the invention has previously
been treated with Lovaza.RTM. and has experienced an increase in,
or no decrease in, LDL-C levels and/or non-HDL-C levels. In one
such embodiment, Lovaza.RTM. therapy is discontinued and replaced
by a method of the present invention.
[0014] In another embodiment, the subject or subject group being
treated in accordance with methods of the invention exhibits a
fasting baseline absolute plasma level of free EPA (or mean thereof
in the case of a subject group) not greater than about 0.70
nmol/ml, not greater than about 0.65 nmol/ml, not greater than
about 0.60 nmol/ml, not greater than about 0.55 nmol/ml, not
greater than about 0.50 nmol/ml, not greater than about 0.45
nmol/ml, or not greater than about 0.40 nmol/ml. In another
embodiment, the subject or subject group being treated in
accordance with methods of the invention exhibits a baseline
fasting plasma level (or mean thereof) of free EPA, expressed as a
percentage of total free fatty acid, of not more than about 3%, not
more than about 2.5%, not more than about 2%, not more than about
1.5%, not more than about 1%, not more than about 0.75%, not more
than about 0.5%, not more than about 0.25%, not more than about
0.2% or not more than about 0.15%. In one such embodiment, free
plasma EPA and/or total fatty acid levels are determined prior to
initiating therapy.
[0015] In another embodiment, the subject or subject group being
treated in accordance with methods of the invention exhibits a
fasting baseline absolute plasma level of 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.
[0016] In another embodiment, the subject or subject group being
treated in accordance with methods of the invention exhibits a
fasting baseline plasma, serum or red blood cell membrane EPA level
not greater than about 70 .mu.g/ml, not greater than about 60
pg/ml, not greater than about 50 .mu.g/ml, not greater than about
40 .mu.g/ml, not greater than about 30 .mu.g/ml, or not greater
than about 25 .mu.g/ml.
[0017] In another embodiment, methods of the present invention
comprise a step of measuring the subject's (or subject group's
mean) baseline lipid profile prior to initiating therapy. In
another embodiment, methods of the invention comprise the step of
identifying a subject or subject group having one or more of the
following: baseline non-HDL-C value of about 200 mg/dl to about 400
mg/dl, for example at least about 210 mg/dl, at least about 220
mg/dl, at least about 230 mg/dl, at least about 240 mg/dl, at least
about 250 mg/dl, at least about 260 mg/dl, at least about 270
mg/dl, at least about 280 mg/dl, at least about 290 mg/dl, or at
least about 300 mg/dl; baseline total cholesterol value of about
250 mg/dl to about 400 mg/dl, for example at least about 260 mg/dl,
at least about 270 mg/dl, at least about 280 mg/dl or at least
about 290 mg/dl; baseline vLDL-C value of about 140 mg/dl to about
200 mg/dl, for example at least about 150 mg/dl, at least about 160
mg/dl, at least about 170 mg/dl, at least about 180 mg/dl or at
least about 190 mg/dl; baseline HDL-C value of about 10 to about 60
mg/dl, for example not more than about 40 mg/ dl, not more than
about 35 mg/dl, not more than about 30 mg/dl, not more than about
25 mg/dl, not more than about 20 mg/dl, or not more than about 15
mg/dl; and/or baseline LDL-C value of about 50 to about 300 mg/dl,
for example not less than about 100 mg/dl, not less than about 90
mg/dl, not less than about 80 mg/dl, not less than about 70 mg/dl,
not less than about 60 mg/dl or not less than about 50 mg/dl.
[0018] In a related embodiment, upon treatment in accordance with
the present invention, for example over a period of about 1 to
about 200 weeks, about 1 to about 100 weeks, about 1 to about 80
weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about
1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12
weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1
to about 2 weeks or about 1 week, the subject or subject group
exhibits one or more of the following outcomes:
[0019] (a) reduced triglyceride levels compared to baseline;
[0020] (b) reduced Apo B levels compared to baseline;
[0021] (c) increased HDL-C levels compared to baseline;
[0022] (d) no increase in LDL-C levels compared to baseline;
[0023] (e) a reduction in LDL-C levels compared to baseline;
[0024] (f) a reduction in non-HDL-C levels compared to
baseline;
[0025] (g) a reduction in vLDL levels compared to baseline;
[0026] (h) an increase in apo A-I levels compared to baseline;
[0027] (i) an increase in apo A-I/apo B ratio compared to
baseline;
[0028] (j) a reduction in lipoprotein A levels compared to
baseline;
[0029] (k) a reduction in LDL particle number compared to
baseline;
[0030] (l) an increase in LDL size compared to baseline;
[0031] (m) a reduction in remnant-like particle cholesterol
compared to baseline;
[0032] (n) a reduction in oxidized LDL compared to baseline;
[0033] (o) no change or a reduction in fasting plasma glucose (FPG)
compared to baseline;
[0034] (p) a reduction in hemoglobin A.sub.1c (HbA.sub.1c) compared
to baseline;
[0035] (q) a reduction in homeostasis model insulin resistance
compared to baseline;
[0036] (r) a reduction in lipoprotein associated phospholipase A2
compared to baseline;
[0037] (s) a reduction in intracellular adhesion molecule-1
compared to baseline;
[0038] (t) a reduction in interleukin-6 compared to baseline;
[0039] (u) a reduction in plasminogen activator inhibitor-1
compared to baseline;
[0040] (v) a reduction in high sensitivity C-reactive protein
(hsCRP) compared to baseline;
[0041] (w) an increase in serum or plasma EPA compared to
baseline;
[0042] (x) an increase in red blood cell (RBC) membrane EPA
compared to baseline; and/or
[0043] (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.
[0044] In one embodiment, upon administering a composition of the
invention to a subject, the subject exhibits a decrease in
triglyceride levels, an increase in the concentrations of EPA and
DPA (n-3) in red blood cells, and an increase of the ratio of
EPA:arachidonic acid in red blood cells. In a related embodiment
the subject exhibits substantially no or no increase in RBC
DHA.
[0045] In one embodiment, methods of the present invention comprise
measuring baseline levels of one or more markers set forth in
(a)-(y) above prior to dosing the subject or subject group. In
another embodiment, the methods comprise administering a
composition as disclosed herein to the subject after baseline
levels of one or more markers set forth in (a)-(y) are determined,
and subsequently taking an additional measurement of said one or
more markers.
[0046] In another embodiment, upon treatment with a composition of
the present invention, for example over a period of about 1 to
about 200 weeks, about 1 to about 100 weeks, about 1 to about 80
weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about
1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12
weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1
to about 2 weeks or about 1 week, the subject or subject group
exhibits any 2 or more of, any 3 or more of, any 4 or more of, any
5 or more of, any 6 or more of, any 7 or more of, any 8 or more of,
any 9 or more of, any 10 or more of, any 11 or more of, any 12 or
more of, any 13 or more of, any 14 or more of, any 15 or more of,
any 16 or more of, any 17 or more of, any 18 or more of, any 19 or
more of, any 20 or more of, any 21 or more of, any 22 or more of,
any 23 or more, any 24 or more, or all 25 of outcomes (a)-(y)
described immediately above.
[0047] In another embodiment, upon treatment with a composition of
the present invention, the subject or subject group exhibits one or
more of the following outcomes:
[0048] (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;
[0049] (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;
[0050] (c) substantially no change in HDL-C levels, no change in
HDL-C levels, or an increase in HDL-C levels of at least about 5%,
at least about 10%, at least about 15%, at least about 20%, at
least about 25%, at least about 30%, at least about 35%, at least
about 40%, at least about 45%, at least about 50%, at least about
55% or at least about 75% (actual % change or median % change) as
compared to baseline;
[0051] (d) a less than 60% increase, a less than 50% increase, a
less than 40% increase, a less than 30% increase, less than 20%
increase, less than 10% increase, less than 5% increase or no
increase in LDL-C levels or a reduction in LDL-C levels of at least
about 5%, at least about 10%, at least about 15%, at least about
20%, at least about 25%, at least about 30%, at least about 35%, at
least about 40%, at least about 45%, at least about 50%, at least
about 55%, at least about 55% or at least about 75% (actual %
change or median % change) as compared to baseline;
[0052] (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;
[0053] (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;
[0054] (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;
[0055] (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 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;
[0056] (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 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;
[0057] (j) a reduction in mean LDL particle number of at least
about 5%, at least about 10%, at least about 15%, at least about
20%, at least about 25%, at least about 30%, at least about 35%, at
least about 40%, at least about 45%, at least about 50%, or at
least about 100% (actual % change or median % change) compared to
baseline;
[0058] (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;
[0059] (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;
[0060] (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;
[0061] (n) substantially no change, no significant change, or a
reduction (e.g. in the case of a diabetic subject) in fasting
plasma glucose (FPG) of at least about 5%, at least about 10%, at
least about 15%, at least about 20%, at least about 25%, at least
about 30%, at least about 35%, at least about 40%, at least about
45%, at least about 50%, or at least about 100% (actual % change or
median % change) compared to baseline;
[0062] (o) substantially no change, no significant change or a
reduction in hemoglobin A.sub.1c (HbA.sub.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;
[0063] (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;
[0064] (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 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;
[0065] (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;
[0066] (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;
[0067] (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;
[0068] (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;
[0069] (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;
[0070] (w) an increase in serum phospholipid and/or red blood cell
membrane EPA of at least about 5%, at least about 10%, at least
about 15%, at least about 20%, at least about 25%, at least about
30%, at least about 35%, at least about 40%, at least about 45%, 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;
[0071] (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; and/or
[0072] (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.
[0073] In one embodiment, methods of the present invention 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.
[0074] In another embodiment, upon treatment with a composition of
the present invention, for example over a period of about 1 to
about 200 weeks, about 1 to about 100 weeks, about 1 to about 80
weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about
1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12
weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1
to about 2 weeks or about 1 week, the subject or subject group
exhibits any 2 or more of, any 3 or more of, any 4 or more of, any
5 or more of, any 6 or more of, any 7 or more of, any 8 or more of,
any 9 or more of, any 10 or more of, any 11 or more of, any 12 or
more of, any 13 or more of, any 14 or more of, any 15 or more of,
any 16 or more of, any 17 or more of, any 18 or more of, any 19 or
more of, any 20 or more of, any 21 or more of, any 22 or more of,
any 23 or more of, any 24 or more of, or all 26 or more of outcomes
(a)-(y) described immediately above.
[0075] 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-6 levels can
be determined from serum using standard enzyme immunoassay
techniques. These techniques are described in detail in standard
textbooks, for example Tietz Fundamentals of Clinical Chemistry,
6.sup.th Ed. (Burtis, Ashwood and Borter Eds.), WB Saunders
Company.
[0076] In one embodiment, subjects fast for up to 12 hours prior to
blood sample collection, for example about 10 hours.
[0077] In another embodiment, the present invention provides a
method of treating or preventing primary hypercholesterolemia
and/or mixed dyslipidemia (Fredrickson Types IIa and IIb) in a
patient in need thereof, comprising administering to the patient
one or more compositions as disclosed herein. In a related
embodiment, the present invention provides a method of reducing
triglyceride levels in a subject or subjects when treatment with a
statin or niacin extended-release monotherapy is considered
inadequate (Frederickson type IV hyperlipidemia).
[0078] In another embodiment, the present invention provides a
method of treating or preventing risk of recurrent nonfatal
myocardial infarction in a patient with a history of myocardial
infarction, comprising administering to the patient one or more
compositions as disclosed herein.
[0079] In another embodiment, the present invention provides a
method of slowing progression of or promoting regression of
atherosclerotic disease in a patient in need thereof, comprising
administering to a subject in need thereof one or more compositions
as disclosed herein.
[0080] In another embodiment, the present invention provides a
method of treating or preventing very high serum triglyceride
levels (e.g. Types IV and V hyperlipidemia) in a patient in need
thereof, comprising administering to the patient one or more
compositions as disclosed herein.
[0081] In another embodiment, the present invention provides a
method of treating subjects having very high serum triglyceride
levels (e.g. greater than 1000 mg/dl or greater than 2000 mg/dl)
and that are at risk of developing pancreatitis, comprising
administering to the patient one or more compositions as disclosed
herein.
[0082] In one embodiment, a composition of the invention is
administered to a subject in an amount sufficient to provide a
daily dose of eicosapentaenoic acid of about 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.
[0083] In another embodiment, any of the methods disclosed herein
are used in treatment or prevention of a subject or subjects that
consume a traditional Western diet. In one embodiment, the methods
of the invention include a step of identifying a subject as a
Western diet consumer or prudent diet consumer and then treating
the subject if the subject is deemed a Western diet consumer. The
term "Western diet" herein refers generally to a typical diet
consisting of, by percentage of total calories, about 45% to about
50% carbohydrate, about 35% to about 40% fat, and about 10% to
about 15% protein. A Western diet may alternately or additionally
be characterized by relatively high intakes of red and processed
meats, sweets, refined grains, and desserts, for example more than
50%, more than 60% or more or 70% of total calories come from these
sources.
[0084] In one embodiment, a composition for use in methods of the
invention comprises eicosapentaenoic acid, or a pharmaceutically
acceptable ester, derivative, conjugate or salt thereof, or
mixtures of any of the foregoing, collectively referred to herein
as "EPA." The term "pharmaceutically acceptable" in the present
context means that the substance in question does not produce
unacceptable toxicity to the subject or interaction with other
components of the composition.
[0085] 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.sub.1 -C.sub.5 alkyl ester of
eicosapentaenoic acid. In another embodiment, the EPA comprises
eicosapentaenoic acid ethyl ester, eicosapentaenoic acid methyl
ester, eicosapentaenoic acid propyl ester, or eicosapentaenoic acid
butyl ester. In another embodiment, the EPA comprises In one
embodiment, the EPA comprises all-cis
eicosa-5,8,11,14,17-pentaenoic acid ethyl ester.
[0086] 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.
[0087] In another embodiment, EPA is present in a composition
useful in accordance with methods of the invention in an amount of
about 50 mg to about 5000 mg, about 75 mg to about 2500 mg, or
about 100 mg to about 1000 mg, for example about 75 mg, about 100
mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about
225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg,
about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450
mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about
575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg,
about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800
mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about
925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg,
about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about
1050 mg, about 1075 mg, about 1200 mg, about 1225 mg, about 1250
mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg,
about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about
1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575
mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg,
about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about
1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900
mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg,
about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg, about
2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225
mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg,
about 2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about
2450 mg, about 2475 mg or about 2500 mg.
[0088] In another embodiment, a composition useful in accordance
with the invention contains not more than about 10%, not more than
about 9%, not more than about 8%, not more than about 7%, not more
than about 6%, not more than about 5%, not more than about 4%, not
more than about 3%, not more than about 2%, not more than about 1%,
or not more than about 0.5%, by weight, docosahexaenoic acid (DHA),
if any. In another embodiment, a composition of the invention
contains substantially no docosahexaenoic acid. In still another
embodiment, a composition useful in the present invention contains
no docosahexaenoic acid and/or derivative thereof.
[0089] In another embodiment, EPA comprises at least 70%, at least
80%, at least 90%, at least 95%, at least 96%, at least 97%, at
least 98%, at least 99%, or 100%, by weight, of all fatty acids
present in a composition that is useful in methods of the present
invention.
[0090] In one embodiment, a composition of the invention comprises
ultra-pure EPA. The term "ultra-pure" as used herein with respect
to EPA refers to a composition comprising at least 95% by weight
EPA (as the term "EPA" is defined and exemplified herein).
Ultra-pure EPA comprises at least 96% by weight EPA, at least 97%
by weight EPA, or at least 98% by weight EPA, wherein the EPA is
any form of EPA as set forth herein.
[0091] In another embodiment, a composition useful in accordance
with methods of the invention contains less than 10%, less than 9%,
less than 8%, less than 7%, less than 6%, less than 5%, less than
4%, less than 3%, less than 2%, less than 1.degree. A, less than
0.5% or less than 0.25%, by weight of the total composition or by
weight of the total fatty acid content, of any fatty acid other
than EPA. Illustrative examples of a "fatty acid other than EPA"
include linolenic acid (LA), arachidonic acid (AA), docosahexaenoic
acid (DHA), alpha-linolenic acid (ALA), stearadonic acid (STA),
eicosatrienoic acid (ETA) and/or docosapentaenoic acid (DPA). In
another embodiment, a composition useful in accordance with methods
of the invention contains about 0.1.degree. A 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.
[0092] In another embodiment, a composition useful in accordance
with the invention has one or more of the following features: (a)
eicosapentaenoic acid ethyl ester represents at least about 96%, at
least about 97%, or at least about 98%, by weight, of all fatty
acids present in the composition; (b) the composition contains not
more than about 4%, not more than about 3%, or not more than about
2%, by weight, of total fatty acids other than eicosapentaenoic
acid ethyl ester; (c) the composition contains not more than about
0.6%, not more than about 0.5%, or not more than about 0.4% of any
individual fatty acid other than eicosapentaenoic acid ethyl ester;
(d) the composition has a refractive index (20.degree. 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.degree. 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.
[0093] In another embodiment, a composition useful in accordance
with the invention comprises, consists of or consists essentially
of at least 95% by weight ethyl eicosapentaenoate (EPA-E), about
0.2% to about 0.5% by weight ethyl octadecatetraenoate (ODTA-E),
about 0.05% to about 0.25% by weight ethyl nonaecapentaenoate
(NDPA-E), about 0.2% to about 0.45% by weight ethyl arachidonate
(AA-E), about 0.3% to about 0.5% by weight ethyl eicosatetraenoate
(ETA-E), and about 0.05% to about 0.32% ethyl heneicosapentaenoate
(HPA-E). In another embodiment, the composition is present in a
capsule shell.
[0094] In another embodiment, compositions useful in accordance
with the invention comprise, consist essential of, or consist of at
least 95%, 96% or 97%, by weight, ethyl eicosapentaenoate, about
0.2% to about 0.5% by weight ethyl octadecatetraenoate, about 0.05%
to about 0.25% by weight ethyl nonaecapentaenoate, about 0.2% to
about 0.45% by weight ethyl arachidonate, about 0.3% to about 0.5%
by weight ethyl eicosatetraenoate, and about 0.05% to about 0.32%
ethyl heneicosapentaenoate. Optionally, the composition contains
not more than about 0.06%, about 0.05%, or about 0.04%, by weight,
DHA or derivative there of such as ethyl-DHA. In one embodiment the
composition contains substantially no or no amount of DHA or
derivative there of such as ethyl-DHA. The composition further
optionally comprises one or more antioxidants (e.g. tocopherol) or
other impurities in an amount of not more than about 0.5% or not
more than 0.05%. In another embodiment, the composition comprises
about 0.05% to about 0.4%, for example about 0.2% by weight
tocopherol. In another embodiment, about 500 mg to about 1 g of the
composition is provided in a capsule shell.
[0095] In another embodiment, compositions useful in accordance
with the invention comprise, consist essential of, or consist of at
least 96% by weight ethyl eicosapentaenoate, about 0.22% to about
0.4% by weight ethyl octadecatetraenoate, about 0.075% to about
0.20% by weight ethyl nonaecapentaenoate, about 0.25% to about
0.40% by weight ethyl arachidonate, about 0.3% to about 0.4% by
weight ethyl eicosatetraenoate and about 0.075% to about 0.25%
ethyl heneicosapentaenoate. Optionally, the composition contains
not more than about 0.06%, about 0.05%, or about 0.04%, by weight,
DHA or derivative there of such as ethyl-DHA. In one embodiment the
composition contains substantially no or no amount of DHA or
derivative there of such as ethyl-DHA. The composition further
optionally comprises one or more antioxidants (e.g. tocopherol) or
other impurities in an amount of not more than about 0.5% or not
more than 0.05%. In another embodiment, the composition comprises
about 0.05% to about 0.4%, for example about 0.2% by weight
tocopherol. In another embodiment, the invention provides a dosage
form comprising about 500 mg to about 1 g of the foregoing
composition in a capsule shell. In one embodiment, the dosage form
is a gel or liquid capsule and is packaged in blister packages of
about 1 to about 20 capsules per sheet.
[0096] In another embodiment, compositions useful in accordance
with the invention comprise, consist essential of, or consist of at
least 96%, 97% or 98%, by weight, ethyl eicosapentaenoate, about
0.25% to about 0.38% by weight ethyl octadecatetraenoate, about
0.10% to about 0.15% by weight ethyl nonaecapentaenoate, about
0.25% to about 0.35% by weight ethyl arachidonate, about 0.31% to
about 0.38% by weight ethyl eicosatetraenoate, and about 0.08% to
about 0.20% ethyl heneicosapentaenoate. Optionally, the composition
contains not more than about 0.06%, about 0.05%, or about 0.04%, by
weight, DHA or derivative there of such as ethyl-DHA. In one
embodiment the composition contains substantially no or no amount
of DHA or derivative there of such as ethyl-DHA. The composition
further optionally comprises one or more antioxidants (e.g.
tocopherol) or other impurities in an amount of not more than about
0.5% or not more than 0.05%. In another embodiment, the composition
comprises about 0.05% to about 0.4%, for example about 0.2% by
weight tocopherol. In another embodiment, the invention provides a
dosage form comprising about 500 mg to about 1 g of the foregoing
composition in a capsule shell.
[0097] In another embodiment, a composition as described herein is
administered to a subject once or twice per day. In another
embodiment, 1, 2, 3 or 4 capsules, each containing about 1 g of a
composition as described herein, are administered to a subject
daily. In another embodiment, 1 or 2 capsules, each containing
about 1 g of a composition as described herein, are administered to
the subject in the morning, for example between about 5 am and
about 11 am, and 1 or 2 capsules, each containing about 1 g of a
composition as described herein, are administered to the subject in
the evening, for example between about 5 pm and about 11 pm.
[0098] In one embodiment, a subject being treated in accordance
with methods of the invention is not otherwise on lipid-altering
therapy, for example statin, fibrate, niacin and/or ezetimibe
therapy.
[0099] In another embodiment, compositions useful in accordance
with methods of the invention are orally deliverable. The terms
"orally deliverable" or "oral administration" herein include any
form of delivery of a therapeutic agent or a composition thereof to
a subject wherein the agent or composition is placed in the mouth
of the subject, whether or not the agent or composition is
swallowed. Thus "oral administration" includes buccal and
sublingual as well as esophageal administration. In one embodiment,
the composition is present in a capsule, for example a soft gelatin
capsule.
[0100] A composition for use in accordance with the invention can
be formulated as one or more dosage units. The terms "dose unit"
and "dosage unit" herein refer to a portion of a pharmaceutical
composition that contains an amount of a therapeutic agent suitable
for a single administration to provide a therapeutic effect. Such
dosage units may be administered one to a plurality (i.e. 1 to
about 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 2) of times per day, or as
many times as needed to elicit a therapeutic response.
[0101] In another embodiment, the invention provides use of any
composition described herein for treating moderate to severe
hypertriglyceridemia in a subject in need thereof, comprising:
providing a subject having a fasting baseline triglyceride level of
about 500 mg/dl to about 1500 mg/dl and administering to the
subject a pharmaceutical composition as described herein. In one
embodiment, the composition comprises about 1 g to about 4 g of
eicosapentaenoic acid ethyl ester, wherein the composition contains
substantially no docosahexaenoic acid.
[0102] In one embodiment, compositions of the invention, upon
storage in a closed container maintained at room temperature,
refrigerated (e.g. about 5 to about 5-10.degree. C.) temperature,
or frozen for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
or 12 months, exhibit at least about 90%, at least about 95%, at
least about 97.5%, or at least about 99% of the active
ingredient(s) originally present therein.
[0103] In one embodiment, the invention provides use of a
composition as described herein in manufacture of a medicament for
treatment of any of a cardiovascular-related disease. In another
embodiment, the subject is diabetic.
[0104] In one embodiment, a composition as set forth herein is
packaged together with instructions for using the composition to
treat a cardiovascular disorder.
EXAMPLES
[0105] A multi-center, placebo-controlled randomized, double-blind,
12-week study with an open-label extension is performed to evaluate
the efficacy and safety of AMR101 in patients with fasting
triglyceride levels 500 mg/dL. The primary objective of the study
is 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).
[0106] The secondary objectives of this study are 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; 5. To determine the
effect of AMR101 on fasting plasma glucose (FPG) and hemoglobin
A.sub.1c (HbA.sub.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 10.
To explore the relationship between an increase in red blood cell
membrane eicosapentaenoic acid (EPA) concentrations and the
reduction in fasting TG levels.
[0107] 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 .ltoreq.45
kg/m.sup.2 who are not on lipid-altering therapy or are currently
on lipid-altering therapy. Patients currently on statin therapy
(with or without ezetimibe) will be 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) must be stable for .gtoreq.4
weeks prior to randomization. Patients taking non-statin,
lipid-altering medications (niacin >200 mg/day, fibrates, fish
oil, other products containing omega-3 fatty acids, or other herbal
products or dietary supplements with potential lipid-altering
effects), either alone or in combination with statin therapy (with
or without ezetimibe), must be able to safely discontinue
non-statin, lipid-altering therapy at screening.
[0108] Approximately 240 patients will be randomized at
approximately 50 centers in North America, South America, Central
America, Europe, India, and South Africa. The study will be a 58-
to 60-week, Phase 3, multi-center study consisting of 3 study
periods: (1) A 6- to 8-week screening period that 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.
[0109] During the screening period and double-blind treatment
period, all visits are to be within .+-.3 days of the scheduled
time. During the open-label extension period, all visits are to be
within .+-.7 days of the scheduled time. The screening period
includes a 4- or 6-week diet and lifestyle stabilization period and
washout period followed by a 2-week TG qualifying period. s) must
be stable for weeks prior to randomization.
[0110] The screening visit (Visit 1) will occur for all patients at
either 6 weeks (for patients not on lipid-altering therapy at
screening or for patients who will not need to discontinue their
current lipid-altering therapy) or 8 weeks (for patients who will
require washout of their current lipid-altering therapy at
screening) before randomization, as follows:
[0111] Patients who do not require a washout: The screening visit
will occur at Visit 1 (Week-6). Eligible patients will enter a
4-week diet and lifestyle stabilization period. At the screening
visit, all patients will receive counseling regarding the
importance of the National Cholesterol Education Program (NCEP)
Therapeutic Lifestyle Changes (TLC) diet and will receive
instructions on how to follow this diet. Patients who will require
a washout: The screening visit will occur at Visit 1 (Week-8).
Eligible patients will begin a 6-week washout period at the
screening visit. Patients will receive counseling regarding the
NCEP TLC diet and will receive instructions on how to follow this
diet. Site personnel will contact patients who do not qualify for
participation based on screening laboratory test results to
instruct them to resume their prior lipid-altering medications.
[0112] At the end of the 4-week diet and lifestyle stabilization
period or the 6-week diet and stabilization and washout period,
eligible patients will enter the 2-week TG qualifying period and
will have their fasting TG level measured at Visit 2 (Week-2) and
Visit 3 (Week-1). Eligible patients must have 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 will be 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 falls outside the
required range for entry into the study, an additional sample for
fasting TG measurement can be collected 1 week later at Visit 3.1.
If a third sample is collected at Visit 3.1, entry into the study
will be based on the average (arithmetic mean) of the values from
Visit 3 and Visit 3.1.
[0113] After confirmation of qualifying fasting TG values, eligible
patients will enter a 12-week, randomized, double-blind treatment
period. At Visit 4 (Week 0), patients will be randomly assigned to
1 of the following treatment groups: [0114] AMR101 2 g daily,
[0115] AMR101 4 g daily, or [0116] Placebo.
[0117] During the double-blind treatment period, patients will
return to the site at Visit 5 (Week 4), Visit 6 (Week 11), and
Visit 7 (Week 12) for efficacy and safety evaluations.
[0118] Patients who complete the 12-week double-blind treatment
period will be eligible to enter a 40-week, open-label, extension
period at Visit 7 (Week 12). All patients will receive open-label
AMR101 4 g daily. From Visit 8 (Week 16) until the end of the
study, changes to the lipid-altering regimen are 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 will return to the site every 12 weeks until the last
visit at Visit 11 (Week 52).
[0119] Eligible patients will be 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 is provided
in 1 g liquid-filled, oblong, gelatin capsules. The matching
placebo capsule is filled with light liquid paraffin and contains 0
g of AMR101. During the double-blind treatment period, patients
will take 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 will receive 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 will
receive 2 AMR101 1 g capsules in the morning and evening.
[0120] Patients in the placebo group will receive 2 matching
placebo capsules in the morning and evening. During the extension
period, patients will receive open-label AMR101 4 g daily. Patients
will take 2 AMR101 1 g capsules in the morning and 2 in the
evening.
[0121] The primary efficacy variable for the double-blind treatment
period is percent change in TG from baseline to Week 12 endpoint.
The secondary efficacy variables for the double-blind treatment
period include the following: [0122] 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; [0123] Percent change in very low-density lipoprotein
TG from baseline to Week 12; [0124] 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; [0125] Percent changes in
lipoprotein(a) from baseline to Week 12 (selected sites only);
[0126] Percent changes in LDL particle number and size, measured by
nuclear magnetic resonance, from baseline to Week 12 (selected
sites only); [0127] Percent change in remnant-like particle
cholesterol from baseline to Week 12 (selected sites only); [0128]
Percent change in oxidized LDL from baseline to Week 12 (selected
sites only); [0129] Changes in FPG and HbA.sub.1c from baseline to
Week 12; [0130] Change in insulin resistance, as assessed by the
homeostasis model index insulin resistance, from baseline to Week
12; [0131] Percent change in lipoprotein associated phospholipase
A2 from baseline to Week 12 (selected sites only); [0132] Change in
intracellular adhesion molecule-1 from baseline to Week 12
(selected sites only); [0133] Change in interleukin-6 from baseline
to Week 12 (selected sites only); [0134] Change in plasminogen
activator inhibitor-1 from baseline to Week 12 (selected sites
only); [0135] Change in hsCRP from baseline to Week 12 (selected
sites only); [0136] Change in serum phospholipid EPA content from
baseline to Week 12; [0137] Change in red blood cell membrane EPA
content from baseline to Week 12; and [0138] 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.
[0139] The efficacy variable for the open-label extension period is
percent change in fasting TG from extension baseline to end of
treatment. Safety assessments will include adverse events, clinical
laboratory measurements (chemistry, hematology, and urinalysis),
12-lead electrocardiograms (ECGs), vital signs, and physical
examinations
[0140] For TG, TC, HDL-C, calculated LDL-C, calculated non-HDL-C,
and VLDL-C, baseline will be 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 will be the Visit 4 (Week 0)
measurement.
[0141] For TC, HDL-C, calculated LDL-C, calculated non-HDL-C, and
VLDL-C, Week 12 endpoint will be defined as the average of Visit 6
(Week 11) and Visit 7 (Week 12) measurements. Week 12 endpoint for
all other efficacy parameters will be the Visit 7 (Week 12)
measurement.
[0142] The primary efficacy analysis will be 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 will be estimated. The same
2-way ANCOVA model will be used for the analysis of secondary
efficacy variables.
[0143] The primary analysis will be repeated for the per-protocol
population to confirm the robustness of the results for the
intent-to-treat population.
[0144] The primary efficacy variable will be the percent change in
fasting TG levels from baseline to Week 12. A sample size of 69
completed patients per treatment group will provide .gtoreq.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 is planned (80 patients per
treatment group).
* * * * *