Amarin Corporation plc (NASDAQ: AMRN), a pharmaceutical company
focused on improving cardiovascular health, announced today that
the European Medicines Agency (EMA) has validated the marketing
authorization application (MAA) seeking approval for icosapent
ethyl (brand name Vascepa
® in the United States)
as a treatment to reduce the risk of cardiovascular events in
high-risk patients who have their cholesterol levels controlled
with statin treatment, but have elevated triglycerides,135 mg/dL or
above, and other cardiovascular risk factors. The validation
confirms the submission for Vascepa is sufficiently complete for
the EMA to begin its review procedure, which is currently expected
to be completed before the end of 2020.
“The prevalence in Europe of people with persistent
cardiovascular risk beyond standard of care statin therapy is high,
like it is in most of the world. This application moves us one step
closer to being able to potentially help millions of high-risk
patients with icosapent ethyl as studied in REDUCE-IT®,” says John
Thero, president and CEO, Amarin. “We seek to make icosapent ethyl
accessible to as many patients as possible who can benefit. If
marketing authorization is granted by the EMA, icosapent ethyl
could become the first and only EMA-approved, non-LDL lowering
agent with a cardiovascular disease risk reduction indication as an
adjunct to statin therapy in dyslipidemic patients in Europe.”
A recent survey showed that about 25 percent of a representative
sample survey of more than 7,800 patients from 27 European
countries with coronary heart disease and controlled
LDL-cholesterol levels had elevated triglycerides levels (>150
mg/dL), illustrating the potential pervasiveness of high-risk
cardiovascular disease in Europe beyond currently available
therapies.1
Icosapent ethyl is in the late stages of review in the United
States by the U.S. Food and Drug Administration (FDA) for an
indication like the one being sought through a centralized review
process in the Europe Union. In November 2019, an FDA advisory
committee voted unanimously (16 – 0) to recommend to the FDA that
icosapent ethyl be approved for an indication and label expansion
to reduce the risk of cardiovascular events in high-risk
patients. Although the FDA is not bound by the recommendation
of its advisory committee, approval of icosapent ethyl in the
United States consistent with such recommendation is anticipated on
or before the FDA’s target Prescription Drug User Fee Act (PDUFA)
date of December 28, 2019. In the United States, icosapent ethyl
has the brand name Vascepa. If approved in Europe, the brand name
may also be Vascepa, but this will be determined as part of the
regulatory review process.
The MAA for icosapent ethyl is based on the global landmark
clinical outcomes study, REDUCE-IT®.2 In the
high-risk, statin-treated patient population studied in REDUCE-IT,
as previously published, icosapent ethyl provided a highly
statistically significant 25% relative risk reduction compared to
placebo in the first occurrence of a major adverse CV event (MACE)
in the intent-to-treat population consisting of a composite of
cardiovascular death, nonfatal myocardial infarction (MI or heart
attack), nonfatal stroke, coronary revascularization (procedures
such as stents and by-pass) and unstable angina requiring
hospitalization. For total (first and subsequent) cardiovascular
events, icosapent ethyl showed a statistically significant 30%
relative risk reduction compared to placebo in published
exploratory analyses.3
In REDUCE-IT, adverse events occurring with icosapent ethyl use
at greater than 5% and greater than placebo were: peripheral edema
(6.5% Vascepa versus 5.0%); constipation (5.3% Vascepa versus
3.6%); and atrial fibrillation (5.3% Vascepa versus 3.9%). More
information on safety data associated with REDUCE-IT is provided
below.
Icosapent ethyl, which has been studied in a series of clinical
trials, including REDUCE-IT, was developed by Amarin and is
exclusively marketed by Amarin and its commercial partners in
capsule form.
In the United States, Vascepa is currently approved as an
adjunct to diet to reduce triglyceride levels in adult patients
with severe (≥500 mg/dL) hypertriglyceridemia. There have been more
than 8 million prescriptions for Vascepa since it was launched in
2013 in the United States for this important niche indication. The
drug is not currently available in Europe for any indication.
About Cardiovascular Risk and Cardiovascular
DiseaseControlling 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 high triglycerides. Statin therapy
has been shown to control LDL-C, thereby reducing the risk of
cardiovascular events by 25-35% – but that still leaves 65-75% risk
remaining.4 People with high triglycerides have 35% more
cardiovascular events compared to people with normal (in range)
triglycerides taking statins.5,6,7
Each year cardiovascular disease, including heart attacks and
stroke, causes over 1.8 million deaths in the European Union (EU).
Cardiovascular disease is the main cause of death in men in all but
12 countries of Europe and is the main cause of death in women in
all but two countries. Cardiovascular disease causes 46 times the
number of deaths and 11 times the disease burden caused by AIDS,
tuberculosis and malaria combined in Europe. Overall,
cardiovascular disease is estimated to cost the EU economy €210
billion a year. Of the total cost of cardiovascular disease in the
EU, around 53% (€111 billion) is due to health care costs, 26% (€54
billion) to productivity losses and 21% (€45 billion) to the
informal care of people with cardiovascular disease.8,9
About AmarinAmarin Corporation plc. is a
rapidly growing, innovative pharmaceutical company focused on
developing therapeutics to improve cardiovascular health. Amarin’s
product development program leverages its extensive experience in
polyunsaturated fatty acids and lipid science. Vascepa (icosapent
ethyl) is Amarin's first FDA-approved drug and is available by
prescription in the United States, Lebanon and the United Arab
Emirates. Amarin’s commercial partners are pursuing additional
regulatory approvals for Vascepa in Canada, China and the Middle
East. For more information about Amarin, visit
www.amarincorp.com.
About REDUCE-IT® REDUCE-IT is a global
cardiovascular outcomes study, which was designed to prospectively
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 Cardiology10 and can be found in the
R&D section on the company’s website at www.amarincorp.com. The
primary results of REDUCE-IT were published in The New England
Journal of Medicine in November 2018.11
About Vascepa® (icosapent ethyl)
CapsulesVascepa (icosapent ethyl) capsules are a
single-molecule prescription product which has been developed and
studied for more than a decade and has been prescribed more than 8
million times in the United States. Vascepa, known in scientific
literature as AMR101, has been designated a new chemical entity by
the FDA. Amarin has been issued multiple patents in the United
States and internationally based on the unique clinical profile of
Vascepa, including the drug’s ability to lower triglyceride levels
in relevant patient populations without raising LDL-cholesterol
levels.
Neither the FDA nor the EMA has completed its review of
REDUCE-IT data or determined whether to approve Vascepa for use to
reduce the risk of major adverse cardiovascular events in the
REDUCE-IT patient population.
Indication and Usage Based on Current FDA-Approved Label (not
including REDUCE-IT results)
- Vascepa (icosapent ethyl) is indicated as an adjunct to diet to
reduce triglyceride (TG) levels in adult patients with severe (≥500
mg/dL) hypertriglyceridemia.
- The effect of Vascepa on the risk for pancreatitis and
cardiovascular mortality and morbidity in patients with severe
hypertriglyceridemia has not been determined.
Important Safety Information for Vascepa Based on Current
FDA-Approved Label (not including REDUCE-IT results) (Includes Data
from Two 12-Week Studies (n=622) (MARINE and ANCHOR) of Patients
with Triglycerides Values of 200 to 2000 mg/dL)
- Vascepa is contraindicated in patients with known
hypersensitivity (e.g., anaphylactic reaction) to Vascepa or any of
its components.
- In patients with hepatic impairment, monitor ALT and AST levels
periodically during therapy.
- Use with caution in patients with known hypersensitivity to
fish and/or shellfish.
- The most common reported adverse reaction (incidence >2% and
greater than placebo) was arthralgia (2.3% for Vascepa, 1.0% for
placebo). There was no reported adverse reaction >3% and greater
than placebo.
- Adverse events and product complaints may be reported by
calling 1-855-VASCEPA or the FDA at 1-800-FDA-1088. Patients
receiving treatment with Vascepa and other drugs affecting
coagulation (e.g., anti-platelet agents) should be monitored
periodically.
- Patients should be advised to swallow Vascepa capsules whole;
not to break open, crush, dissolve, or chew Vascepa.
FULL VASCEPA PRESCRIBING INFORMATION CAN BE FOUND AT
WWW.VASCEPA.COM.
Important Safety Information for Vascepa based on REDUCE-IT, as
previously reported in The New England Journal of Medicine
publication of the primary results of the REDUCE-IT
study:
- Excluding the major adverse cardiovascular events (MACE)
results described above, overall adverse event rates in REDUCE-IT
were similar across the statin plus Vascepa and the statin plus
placebo treatment groups.
- There were no significant differences between treatments in the
overall rate of treatment emergent adverse events or serious
adverse events leading to withdrawal of study drug.
- There was no serious adverse event (SAE) occurring at a
frequency of >2% which occurred at a numerically higher rate in
the statin plus Vascepa treatment group than in the statin plus
placebo treatment group.
- Adverse events (AEs) occurring in 5% or greater of patients and
more frequently with Vascepa than placebo were:
- peripheral edema (6.5% Vascepa patients versus 5.0% placebo
patients), although there was no increase in the rate of heart
failure in Vascepa patients
- constipation (5.4% Vascepa patients versus 3.6% placebo
patients), although mineral oil, as used as placebo, is known to
lower constipation, and
- atrial fibrillation (5.3% Vascepa patients versus 3.9% placebo
patients), although there were reductions in rates of cardiac
arrest, sudden death and myocardial infarctions observed in Vascepa
patients
- There were numerically more SAEs related to bleeding in the
statin plus Vascepa treatment group although overall rates were low
with no fatal bleeding observed in either group and no significant
difference in adjudicated hemorrhagic stroke or serious central
nervous system or gastrointestinal bleeding events between
treatments.
- In summary, Vascepa was well tolerated with a safety profile
generally consistent with clinical experience associated with
omega-3 fatty acids and current FDA-approved labeling of such
products.
Important Cautionary Information About These
Data Further REDUCE-IT data assessment and data
release are expected to yield additional useful information to
inform greater understanding of the trial outcome. For example,
detailed data assessment by regulatory authorities, such as the
FDA, Health Canada, and EMA, will continue and take time to
complete and announce. The FDA advisory committee process and the
final evaluation by regulatory authorities of the totality of
efficacy and safety data from REDUCE-IT is anticipated to include
some or all of the following, as well as other considerations: new
information or analyses affecting the degree of treatment benefit
on studied endpoints; study conduct and data robustness, quality,
integrity and consistency; additional safety data considerations
and risk/benefit considerations; and consideration of REDUCE-IT
results in the context of other clinical studies. More detailed
presentation of such considerations is set forth in the risk
factors section of Amarin’s Quarterly Report on Form 10-Q filed
with the U.S. Securities and Exchange Commission. Because
regulatory reviews are typically fluid and not definitive
interactions between sponsor and agency on individual elements of
an application and related information, Amarin does not plan to
update investors further on ongoing communications with regulatory
authorities. Amarin plans to announce the final outcome of such
regulatory reviews when appropriate.
Recurrent event analyses for the total primary endpoint events
and for the total key secondary endpoint in REDUCE-IT as published
in the Journal of the American College of Cardiology were conducted
using a series of statistical models. These analyses were tertiary
or exploratory endpoints; most of the models used were prespecified
and one was post hoc. Each recurrent event statistical model has
inherent strengths and weaknesses, with no single model considered
definitive or outperforming the other models, and this is an
evolving field of science. Nonetheless, results from the total
primary and total key secondary endpoint events analyses are
consistent across the various recurrent event statistical models
and are also consistent with the original primary and secondary
endpoint results. Together, the REDUCE-IT recurrent event analyses
and the original primary and key secondary endpoint analyses
support the robustness of the clinical benefit of Vascepa therapy
in reducing cardiovascular risk.
Forward-Looking StatementsThis press release
contains forward-looking statements, including statements regarding
expected regulatory reviews and related timing and the use of
Vascepa to potentially help millions of patients. 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, clinical trials
and related regulatory reviews and approvals; the risk that data
interpretations or other information from third parties, the
regulatory review process, regulatory authorities could be made
public that are negative or may delay approval or limit Vascepa’s
marketability; the risk that special protocol assessment (SPA)
agreements with the FDA are not a guarantee that FDA will approve a
product candidate; the risk associated with the FDA's rescinding
the REDUCE-IT SPA agreement; the risk related to FDA advisory
committee meetings; and the risk that the FDA may not complete its
review of the REDUCE-IT sNDA within the timing expected. 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.
Availability of Other Information About
AmarinInvestors 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
Information
Investor Inquiries:Elisabeth SchwartzInvestor
RelationsAmarin Corporation plcIn U.S.: +1 (908) 719-1315
investor.relations@amarincorp.com
Lee M. SternSolebury TroutIn U.S.: +1 (646) 378-2992
lstern@soleburytrout.com
Media Inquiries:Gwen FisherCorporate
Communications Amarin Corporation plcIn U.S.: +1 (908) 325-0735
pr@amarincorp.com
References
1 De Backer G, Jankowski P, et al. on behalf of the EUROASPIRE V
collaborators* Management of dyslipidaemia in patients with
coronary heart disease: Results from the ESCEORP EUROASPIRE V
survey in 27 countries, Atherosclerosis (2019), doi:
https://doi.org/10.1016/ j.atherosclerosis.2019.03.014.2 Bhatt DL,
Steg PG, Miller M, et al. Cardiovascular Risk Reduction with
Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med
2019;380:11-22.3 Bhatt DL, Steg PG, Miller M, et al. Effects of
Icosapent Ethyl on Total Ischemic Events: From REDUCE-IT. J
Am Coll Cardiol 2019;73(22):2791-2802.4 Ganda OP, Bhatt DL, Mason
RP, et al. Unmet need for adjunctive dyslipidemia therapy in
hypertriglyceridemia management. J Am Coll Cardiol.
2018;72(3):330-343.5 Budoff M. Triglycerides and triglyceride-rich
lipoproteins in the causal pathway of cardiovascular disease. Am J
Cardiol. 2016;118:138-145.6 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):e008740.7 Nordestgaard BG. Triglyceride-rich
lipoproteins and atherosclerotic cardiovascular disease - New
insights from epidemiology, genetics, and biology. Circ Res.
2016;118:547-563.8
http://www.euro.who.int/en/health-topics/noncommunicable-diseases/cardiovascular-diseases/data-and-statistics.9
European Cardiovascular Disease Statistics, 2017.
http://www.ehnheart.org/cvd-statistics.html.10 Bhatt DL, Steg PG,
Brinton E, et al. Rationale and Sesign of REDUCE‐IT: Reduction of
Cardiovascular Events with Icosapent Ethyl–Intervention Trial.
Clinical Cardiology, 15 March 2017.11 Bhatt DL, Steg PG, Miller M,
et al. Cardiovascular Risk Reduction with Icosapent Ethyl for
Hypertriglyceridemia. N Engl J Med 2019;380:11-22.
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