Amarin Corporation plc (NASDAQ:AMRN) today announced the
presentation of further insights into various potential mechanisms
of action of icosapent ethyl and differences in biological actions
of the unique form of eicosapentaenoic acid (EPA) in icosapent
ethyl from other mediators in a number of experimental systems that
mimic various aspects of arterial atherosclerotic plaque initiation
and progression. These data were presented at European
Atherosclerosis Society (EAS) Congress 2021, held virtually from
May 30 – June 2, 2021, and are based on research and analyses
supported by Amarin. These data and analyses build on previously
presented clinical, epidemiological and genetic findings, including
cardiovascular outcomes study results.
“The story of the unique multifactorial
mechanism of action of icosapent ethyl continues to unfold as we
elucidate further insights into how this agent, a unique form of
eicosapentaenoic acid, impacts cellular processes and protein
expression,” said Craig Granowitz, M.D., Ph.D., Amarin’s senior
vice president and chief medical officer. “The consistency of
results from basic science seen in these and previous presentations
to translational studies to clinical outcomes is incredibly
powerful. It is an elegant articulation of the broad elements that
support the unique cardiovascular risk reduction impact of
icosapent ethyl.”
EAS Congress 2021 presentations were as
follows:
- “EICOSAPENTAENOIC ACID MODULATES
ENDOTHELIAL FUNCTION AND INFLAMMATORY PROTEIN EXPRESSION FROM
PULMONARY AND VASCULAR TISSUES FOLLOWING CYTOKINE CHALLENGE” –
presented on behalf of all authors by R. Preston Mason, Ph.D.,
Brigham and Women’s Hospital, Boston, MA
Highlights: EPA significantly
modulated >50 proteins coordinately in pulmonary or vascular
endothelial cells (ECs) following interleukin-6 (IL-6) exposure.
These included seven proteins related to neutrophil degranulation
and cytokine signaling, and five proteins linked to EC function and
inflammation. In human umbilical vein ECs (HUVECs), treatment with
eicosapentaenoic acid (EPA) also significantly increased nitric
oxide (NO) release by 13% relative to IL-6 alone. EPA favorably
modulated expression of EC proteins associated with inflammation
and improved NO bioavailability during IL-6 exposure. These studies
support favorable anti-inflammatory effects of EPA on ECs in
multiple vascular beds that may contribute to reduced CV risk.
- “EICOSAPENTAENOIC ACID REDUCES
CYTOKINE-INDUCED EXPRESSION OF MULTIPLE PROTEINS RELATED TO
PLATELET ACTIVATION AND AGGREGATION IN PULMONARY AND VASCULAR
ENDOTHELIUM” – presented on behalf of all authors by R. Preston
Mason, Ph.D., Brigham and Women’s Hospital, Boston, MA
Highlights: EPA significantly
downregulated a total of 36 proteins involved in platelet
activation, signaling, aggregation, in EC following IL-6 exposure.
Platelet endothelial cell adhesion molecule (PECAM) was the only
common protein that EPA significantly downregulated in both HUVECs
and PECs. In PECs, EPA significantly modulated 26 other proteins
related to platelet activation, including amyloid-beta precursor
protein and thrombin receptor, while in HUVECs there were 9 other
proteins modulated related to platelet activation, including
superoxide dismutase. EPA significantly reduced expression of PECAM
in ECs from different tissues, as well as other proteins associated
with platelet activity. These findings suggest potential novel
antithrombotic mechanisms for EPA that may contribute to reduced
ischemic events.
- “EICOSAPENTAENOIC ACID INCREASES
OMEGA-3 FATTY ACID CONTENT AND REDUCES INFLAMMATORY PROTEIN LEVELS
IN PULMONARY ENDOTHELIAL CELLS DURING IL-6 EXPOSURE” – presented on
behalf of all authors by R. Preston Mason, Ph.D., Brigham and
Women’s Hospital, Boston, MA
Highlights: Pretreatment of
pulmonary ECs (PECs) with EPA decreased production of more than 60
proteins after IL-6 stimulation including angiotensin converting
enzyme (ACE) and ICAM-1. These changes correlated with increases in
cellular content of EPA, docosapentaenoic acid (DPA) and
docosahexaenoic acid (DHA) levels after EPA pretreatment. EPA also
significantly reduced levels of palmitic acid (PA), while levels of
linoleic acid (LA) and arachidonic acid (AA) did not change. EPA
significantly reduced expression of proteins associated with
vasoconstriction and inflammation that correlated with increased
omega-3 fatty acids and lower PA. These findings indicate a novel
effect of EPA with implications for vascular and pulmonary
function.
- “EICOSAPENTAENOIC ACID REDUCED
LEVELS OF ANGIOTENSIN CONVERTING ENZYME AND CAVEOLIN-1 IN PULMONARY
ENDOTHELIAL CELLS FOLLOWING CYTOKINE TREATMENT” – presented on
behalf of all authors by R. Preston Mason, Ph.D., Brigham and
Women’s Hospital, Boston, MA
Highlights: Pulmonary ECs
treated with EPA following IL-6 exposure showed significant changes
in expression of >400 proteins including those that mediate
inflammation and vasodilation. EPA significantly downregulated
caveolin-1, an inhibitor on NOS, and increased levels of heat shock
protein-90 (Hsp90) compared to IL-6. EPA significantly reduced
expression of additional proteins linked to NOS inhibition and as
well as ACE and endothelin-converting enzyme-1 (ECE-1) levels. EPA
favorably modulated expression of proteins associated with NOS
activation and vasoconstriction following IL-6 exposure, including
ACE and ECE-1. These studies support a novel effect of EPA on
pulmonary ECs that may contribute to reduced CV disease
progression.
- “EICOSAPENTAENOIC ACID INHIBITS
LIPOPOLYSACCHARIDE (LPS)-INDUCED MACROPHAGE ACTIVATION IN A MANNER
THAT IS ENHANCED WITH COLCHICINE” – presented on behalf of all
authors by R. Preston Mason, Ph.D., Brigham and Women’s Hospital,
Boston, MA
Highlights: Treatment with LPS
increased nitrite production by 465%. EPA treatment reduced nitrite
production in a significant, dose-dependent manner by 40-77% at
10-40 µM, respectively, compared to LPS-alone. EPA at the lowest
concentration tested produced an effect similar to diclofenac,
which reduced nitrite levels by 40%. Colchicine treatment reduced
nitrite production significantly only at the highest concentration
at 35%. The combination of EPA and colchicine (each at 10µM)
reduced nitrite release, and therefore macrophage activation, in an
additive manner by 70%, that significantly exceeded their separate
effects. The ability of EPA and colchicine to reduce macrophage
activity may contribute to limiting inflammation that participates
in cardiovascular diseases.
All analyses highlighted above were funded by
Amarin.
Additional REDUCE-IT® and icosapent
ethyl-related topics presented at EAS Congress 2021 can be found
here. For investors, additional scientific data regarding icosapent
ethyl, including data pertaining to clinical results and mechanisms
of action, can be found in the publications section of the
company’s website.
About Amarin
Amarin is an innovative pharmaceutical company
leading a new paradigm in cardiovascular disease management. From
our scientific research foundation to our focus on clinical trials,
and now our commercial expansion, we are evolving and growing
rapidly. Amarin has offices in Bridgewater, New Jersey in the
United States, Dublin in Ireland, and Zug in Switzerland as well as
commercial partners and suppliers around the world. We are
committed to rethinking cardiovascular risk through the advancement
of scientific understanding of the impact on society of significant
residual risk that exists beyond traditional therapies, such as
statins for cholesterol management.
About Cardiovascular Risk
Cardiovascular disease is the number one cause
of death in the world. In the United States alone, cardiovascular
disease results in 859,000 deaths per year.1 And the number of
deaths in the United States attributed to cardiovascular disease
continues to rise. In addition, in the United States there are
605,000 new and 200,000 recurrent heart attacks per year
(approximately 1 every 40 seconds). Stroke rates are 795,000 per
year (approximately 1 every 40 seconds), accounting for 1 of every
19 U.S. deaths. In aggregate, in the United States alone, there are
more than 2.4 million major adverse cardiovascular events per year
from cardiovascular disease or, on average, 1 every 13 seconds.
Controlling bad cholesterol, also known as
LDL-C, is one way to reduce a patient’s risk for cardiovascular
events, such as heart attack, stroke or death. However, even with
the achievement of target LDL-C levels, millions of patients still
have significant and persistent risk of cardiovascular events,
especially those patients with elevated triglycerides. Statin
therapy has been shown to control LDL-C, thereby reducing the risk
of cardiovascular events by 25-35%.2 Significant cardiovascular
risk remains after statin therapy. People with elevated
triglycerides have 35% more cardiovascular events compared to
people with normal (in range) triglycerides taking
statins.3,4,5
About REDUCE-IT®
REDUCE-IT was a global cardiovascular outcomes
study designed to evaluate the effect of VASCEPA in adult patients
with LDL-C controlled to between 41-100 mg/dL (median baseline 75
mg/dL) by statin therapy and various cardiovascular risk factors
including persistent elevated triglycerides between 135-499 mg/dL
(median baseline 216 mg/dL) and either established cardiovascular
disease (secondary prevention cohort) or diabetes mellitus and at
least one other cardiovascular risk factor (primary prevention
cohort).
REDUCE-IT, conducted over seven years and
completed in 2018, followed 8,179 patients at over 400 clinical
sites in 11 countries with the largest number of sites located
within the United States. REDUCE-IT was conducted based on a
special protocol assessment agreement with FDA. The design of the
REDUCE-IT study was published in March 2017 in Clinical
Cardiology.6 The primary results of REDUCE-IT were published in The
New England Journal of Medicine in November 2018.7 The total events
results of REDUCE-IT were published in the Journal of the American
College of Cardiology in March 2019.8 These and other publications
can be found in the R&D section on the company’s website at
www.amarincorp.com.
About VASCEPA® (icosapent ethyl)
Capsules
VASCEPA (icosapent ethyl) capsules are the
first-and-only prescription treatment approved by the U.S. Food and
Drug Administration (FDA) comprised solely of the active
ingredient, icosapent ethyl (IPE), a unique form of
eicosapentaenoic acid. VASCEPA was launched in the United States in
January 2020 as the first and only drug approved by the U.S. FDA
for treatment of the studied high-risk patients with persistent
cardiovascular risk after statin therapy. VASCEPA was initially
launched in the United States in 2013 based on the drug’s initial
FDA approved indication for use as an adjunct therapy to diet to
reduce triglyceride levels in adult patients with severe (≥500
mg/dL) hypertriglyceridemia. Since launch, VASCEPA has been
prescribed over ten million times. VASCEPA is covered by most major
medical insurance plans. In addition to the United States, VASCEPA
is approved and sold in Canada, Lebanon and the United Arab
Emirates. In Europe, in March 2021 marketing authorization was
granted to icosapent ethyl in the European Union for the reduction
of risk of cardiovascular events in patients at high cardiovascular
risk, under the brand name VAZKEPA.
Indications and Limitation of Use (in the United
States)VASCEPA is indicated:
- As an adjunct to maximally
tolerated statin therapy to reduce the risk of myocardial
infarction, stroke, coronary revascularization and unstable angina
requiring hospitalization in adult patients with elevated
triglyceride (TG) levels (≥ 150 mg/dL) and
- established cardiovascular disease
or
- diabetes mellitus and two or more
additional risk factors for cardiovascular disease.
- As an adjunct to diet to reduce TG
levels in adult patients with severe (≥ 500 mg/dL)
hypertriglyceridemia.
The effect of VASCEPA on the risk for
pancreatitis in patients with severe hypertriglyceridemia has not
been determined.
Important Safety Information
- VASCEPA is contraindicated in
patients with known hypersensitivity (e.g., anaphylactic reaction)
to VASCEPA or any of its components.
- VASCEPA was associated with an
increased risk (3% vs 2%) of atrial fibrillation or atrial flutter
requiring hospitalization in a double-blind, placebo-controlled
trial. The incidence of atrial fibrillation was greater in patients
with a previous history of atrial fibrillation or atrial
flutter.
- It is not known whether patients
with allergies to fish and/or shellfish are at an increased risk of
an allergic reaction to VASCEPA. Patients with such allergies
should discontinue VASCEPA if any reactions occur.
- VASCEPA was associated with an
increased risk (12% vs 10%) of bleeding in a double-blind,
placebo-controlled trial. The incidence of bleeding was greater in
patients receiving concomitant antithrombotic medications, such as
aspirin, clopidogrel or warfarin.
- Common adverse reactions in the cardiovascular outcomes trial
(incidence ≥3% and ≥1% more frequent than placebo): musculoskeletal
pain (4% vs 3%), peripheral edema (7% vs 5%), constipation (5% vs
4%), gout (4% vs 3%), and atrial fibrillation (5% vs 4%).
- Common adverse reactions in the hypertriglyceridemia trials
(incidence >1% more frequent than placebo): arthralgia (2% vs
1%) and oropharyngeal pain (1% vs 0.3%).
- Adverse events may be reported by
calling 1-855-VASCEPA or the FDA at 1-800-FDA-1088.
- Patients receiving VASCEPA and
concomitant anticoagulants and/or anti-platelet agents should be
monitored for bleeding.
Key clinical effects of VASCEPA on major adverse
cardiovascular events are included in the Clinical Studies section
of the prescribing information for VASCEPA as set forth below:
Effect of VASCEPA on Time to First
Occurrence of Cardiovascular Events in Patients with
Elevated Triglyceride levels and Other Risk Factors for
Cardiovascular Disease in REDUCE-IT
|
VASCEPA |
Placebo |
VASCEPA vs Placebo |
N = 4089n (%) |
Incidence Rate (per 100 patient
years) |
N = 4090n (%) |
Incidence Rate (per 100 patient
years) |
Hazard Ratio(95% CI) |
Primary composite endpoint |
Cardiovascular death, myocardial infarction, stroke, coronary
revascularization, hospitalization for unstable angina (5-point
MACE) |
705(17.2) |
4.3 |
901(22.0) |
5.7 |
0.75(0.68, 0.83) |
Key secondary composite endpoint |
Cardiovascular death, myocardial infarction, stroke (3-point
MACE) |
459(11.2) |
2.7 |
606(14.8) |
3.7 |
0.74(0.65, 0.83) |
Other secondary endpoints |
Fatal or non-fatal myocardial infarction |
250(6.1) |
1.5 |
355(8.7) |
2.1 |
0.69(0.58, 0.81) |
Emergent or urgent coronary revascularization |
216(5.3) |
1.3 |
321(7.8) |
1.9 |
0.65(0.55, 0.78) |
Cardiovascular death [1] |
174(4.3) |
1.0 |
213(5.2) |
1.2 |
0.80(0.66, 0.98) |
Hospitalization for unstable angina [2] |
108(2.6) |
0.6 |
157(3.8) |
0.9 |
0.68(0.53, 0.87) |
Fatal or non-fatal stroke |
98(2.4) |
0.6 |
134(3.3) |
0.8 |
0.72(0.55, 0.93) |
[1] Includes adjudicated cardiovascular deaths and deaths of
undetermined causality.[2] Determined to be caused by myocardial
ischemia by invasive/non-invasive testing and requiring emergent
hospitalization. |
FULL U.S. FDA-APPROVED VASCEPA
PRESCRIBING INFORMATION CAN BE FOUND
AT WWW.VASCEPA.COM.
Forward-Looking Statements
This press release contains forward-looking
statements, including statements regarding the potential impact of
VASCEPA in various clinical uses. These forward-looking statements
are not promises or guarantees and involve substantial risks and
uncertainties. Among the factors that could cause actual results to
differ materially from those described or projected herein include
the following: uncertainties associated generally with research and
development and clinical trials such as further clinical
evaluations failing to confirm earlier findings. A further list and
description of these risks, uncertainties and other risks
associated with an investment in Amarin can be found in Amarin's
filings with the U.S. Securities and Exchange Commission, including
its most recent Quarterly Report on Form 10-Q. Existing and
prospective investors are cautioned not to place undue reliance on
these forward-looking statements, which speak only as of the date
hereof. Amarin undertakes no obligation to update or revise the
information contained in this press release, whether as a result of
new information, future events or circumstances or otherwise.
Amarin’s forward-looking statements do not reflect the potential
impact of significant transactions the company may enter into, such
as mergers, acquisitions, dispositions, joint ventures or any
material agreements that Amarin may enter into, amend or
terminate.
Availability of Other Information About
Amarin
Investors and others should note that Amarin
communicates with its investors and the public using the company
website (www.amarincorp.com), the investor relations website
(investor.amarincorp.com), including but not limited to investor
presentations and investor FAQs, Securities and Exchange Commission
filings, press releases, public conference calls and webcasts. The
information that Amarin posts on these channels and websites could
be deemed to be material information. As a result, Amarin
encourages investors, the media, and others interested in Amarin to
review the information that is posted on these channels, including
the investor relations website, on a regular basis. This list of
channels may be updated from time to time on Amarin’s investor
relations website and may include social media channels. The
contents of Amarin’s website or these channels, or any other
website that may be accessed from its website or these channels,
shall not be deemed incorporated by reference in any filing under
the Securities Act of 1933.
Amarin Contact
InformationInvestor Inquiries:Investor RelationsAmarin
Corporation plcIn U.S.: +1 (908) 719-1315 IR@amarincorp.com
(investor inquiries)
Solebury Troutamarinir@troutgroup.com
Media Inquiries:CommunicationsAmarin Corporation
plcIn U.S.: +1 (908) 892-2028 PR@amarincorp.com (media
inquiries)
AMARIN, REDUCE-IT, VASCEPA and VAZKEPA are trademarks of Amarin
Pharmaceuticals Ireland Limited. VAZKEPA is a registered trademark
in Europe and other countries and regions and is pending
registration in the United States.
__________________________
1 American Heart Association. Heart Disease and
Stroke Statistics—2020 Update: A Report From the American Heart
Association. Circulation. 2020;141:e139-e596.2 Ganda OP, Bhatt DL,
Mason RP, et al. Unmet need for adjunctive dyslipidemia therapy in
hypertriglyceridemia management. J Am Coll Cardiol.
2018;72(3):330-343.3 Budoff M. Triglycerides and triglyceride-rich
lipoproteins in the causal pathway of cardiovascular disease. Am J
Cardiol. 2016;118:138-145. 4 Toth PP, Granowitz C, Hull M, et al.
High triglycerides are associated with increased cardiovascular
events, medical costs, and resource use: A real-world
administrative claims analysis of statin-treated patients with high
residual cardiovascular risk. J Am Heart Assoc.
2018;7(15):e008740.5 Nordestgaard BG. Triglyceride-rich
lipoproteins and atherosclerotic cardiovascular disease - New
insights from epidemiology, genetics, and biology. Circ Res.
2016;118:547-563.6 Bhatt DL, Steg PG, Brinton E, et al., on behalf
of the REDUCE-IT Investigators. Rationale and Design of REDUCE‐IT:
Reduction of Cardiovascular Events with Icosapent
Ethyl–Intervention Trial. Clin Cardiol. 2017;40:138-148.7 Bhatt DL,
Steg PG, Miller M, et al., on behalf of the REDUCE-IT
Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl
for Hypertriglyceridemia. N Engl J Med. 2019;380:11-22.8 Bhatt DL,
Steg PG, Miller M, et al., on behalf of the REDUCE-IT
Investigators. Reduction in first and total ischemic events with
icosapent ethyl across baseline triglyceride tertiles. J Am Coll
Cardiol. 2019;74:1159-1161.
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