Landmark Cardiovascular Risk Reduction
Benefits Demonstrated in REDUCE-IT Are Largest of Any Major
Cardiovascular Outcomes Study of a Drug Intended to Address
Residual Cardiovascular Risk Remaining After Cholesterol
Management
Amarin Corporation plc (NASDAQ:AMRN) announced today the
primary results from the Vascepa® (icosapent ethyl) cardiovascular
(CV) outcomes trial, REDUCE-IT™, following presentation of the
late-breaking clinical trial results at the 2018 Scientific
Sessions of the American Heart Association (AHA) in Chicago,
Illinois. REDUCE-IT primary results confirmed 25% relative
risk reduction (RRR) for the topline primary endpoint result with
multiple robust demonstrations of efficacy, including 20% reduction
in cardiovascular death.
Cardiovascular benefits appeared not to be
influenced significantly by triglyceride (TG) levels at baseline
(135 mg/dL to 499 mg/dL baseline range) or as achieved at one year,
suggesting mechanisms at work with use of Vascepa that are
independent of triglyceride reduction. Results were robust across
multiple subgroups, including in patients with and without diabetes
at baseline. REDUCE-IT study results were simultaneously published
in The New England Journal of Medicine and are available at
nejm.org/doi/full/10.1056/NEJMoa1812792.
REDUCE-IT was a global study of 8,179
statin-treated adults with elevated CV risk. Many patients with
well-managed LDL-C remain at high risk for cardiovascular events.
No therapy is currently approved to treat the residual risk in
REDUCE-IT patients and no other therapy has demonstrated a 25% risk
reduction on top of statin therapy in a major cardiovascular
outcomes trial. REDUCE-IT studied Vascepa 4 grams/day as compared
to placebo over a median follow-up time of 4.9 years.
Efficacy results for Vascepa as presented today
from REDUCE-IT are as follows:
Primary endpoint achieved: 25%
relative risk reduction (RRR) (hazard ratio (HR), 0.75; 95%
confidence interval CI, 0.68-0.83; p<0.001) in first occurrence
of major adverse CV events (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.
- Number needed to treat (NNT) was 21 for the
first occurrence of MACE in the 5-point primary composite endpoint.
- For perspective, NNTs for cholesterol-managing drugs
atorvastatin (Lipitor®)1 and evolocumab (Repatha®)2 were reported
to be 45 and 67, respectively. These drugs are not competitors with
Vascepa as Vascepa is not a therapy for cholesterol (LDL-C)
management nor has Vascepa been evaluated in a head-to-head study
with these drugs.
Key secondary endpoint achieved:
26% RRR (HR, 0.74; 95% CI, 0.65-0.83; p<0.001)
in 3-point MACE in the intent-to-treat population consisting of a
composite of cardiovascular death, nonfatal heart attack and
nonfatal stroke.
Additional secondary endpoints achieved: Seven
secondary endpoints were achieved below the key secondary endpoint,
as follows (in order of sequential statistical testing within the
prespecified hierarchy):
- Cardiovascular death or nonfatal heart attack:
25% RRR (HR, 0.75; 95% CI, 0.66-0.86;
p<0.001)
- Fatal or nonfatal heart attack: 31% RRR (HR,
0.69; 95% CI, 0.58-0.81; p<0.001)
- Urgent or emergent revascularization: 35% RRR
(HR, 0.65; 95% CI, 0.55-0.78; p<0.001)
- Cardiovascular death: 20% RRR (HR, 0.80; 95%
CI, 0.66-0.98; p=0.03)
- Hospitalization for unstable angina: 32% RRR
(HR, 0.68; 95% CI, 0.53-0.87; p=0.002)
- Fatal or nonfatal stroke: 28% RRR (HR, 0.72;
95% CI, 0.55-0.93; p=0.01)
- Total mortality, nonfatal heart attack or nonfatal stroke:
23% RRR (HR, 0.77; 95% CI, 0.69-0.86;
p<0.001)
The next prespecified secondary endpoint in the
hierarchy, and the only such endpoint that did not achieve
statistical significance, is as follows:
- Total mortality, which includes mortality from
non-cardiovascular and cardiovascular events: 13% RRR (HR, 0.87;
95% CI, 0.74-1.02; p=0.09)
Baseline demographics: Patients qualified to
enroll in REDUCE-IT had LDL-C between 41-100 mg/dL (median baseline
LDL-C 75 mg/dL) controlled by statin therapy and various
cardiovascular risk factors including persistent elevated
triglycerides (TGs) between 135-499 mg/dL (median baseline 216
mg/dL) and either established cardiovascular disease (secondary
prevention cohort) or age 50 or more with diabetes mellitus and at
least one other CV risk factor (primary prevention cohort).
Approximately 59% of the patients had diabetes at baseline and
approximately 71% of the patients had established cardiovascular
disease at time of enrollment.
Safety: Excluding the major adverse CV 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. The one serious adverse event occurring
at a frequency of >2% was pneumonia which occurred at a
numerically higher rate in the statin plus placebo treatment group
(2.9%) than in the statin plus Vascepa treatment group (2.6%).
Adverse events 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), constipation (5.4%
Vascepa patients versus 3.6% placebo patients), and atrial
fibrillation (5.3% Vascepa patients versus 3.9% placebo patients).
There were numerically more serious adverse events 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.
Subgroups and other REDUCE-IT information:
Positive REDUCE-IT results were consistent across various patient
subgroups, including female/male, diabetic/non-diabetic and
secondary/primary prevention. At baseline, approximately 59%
and 71% of the patients had diabetes and established cardiovascular
disease, respectively. Approximately 71% of the patients studied
were classified as Westernized with the largest cohort from the
United States. Vital status was obtained for 99.8% of the patients
randomized supporting robust trial results.
Differentiated result and mechanism of action:
The success of REDUCE-IT is distinct from past failures to show
significant benefit of other agents that lower triglyceride levels
when studied on top of statin therapy, including mixtures of
omega-3 fatty acids, fenofibrates, niacin and CETP inhibitors. In
REDUCE-IT, the median change in triglyceride levels from baseline
to year one was -18.3% (-39 mg/dL) for Vascepa and +2.2% (4.5
mg/dL) for placebo; placebo-corrected median change from baseline
of -19.7% (-44.5 mg/dL; p=<0.001). As expressed in The New
England Journal of Medicine publication, at least some of the
reduction in MACE demonstrated by Vascepa in REDUCE-IT is likely
explained by metabolic effects other than triglyceride
lowering.3
The active pharmaceutical ingredient in Vascepa
has a unique molecular structure. Vascepa has demonstrated clinical
effects that have not been shown for any other product. The
clinical effects of Vascepa demonstrated in REDUCE-IT cannot be
generalized to any other product.
Mechanisms responsible for Vascepa’s effects in
the REDUCE-IT study were not directly evaluated in the outcomes
study. Independent of REDUCE-IT, Amarin has worked to further
support the REDUCE-IT hypothesis with published scientific findings
based on various degrees of evidence that show that icosapent ethyl
may interrupt the atherosclerotic process (e.g., plaque formation
and instability) by beneficially affecting cellular functions
thought to contribute to atherosclerosis and cardiovascular events
and by beneficially affecting lipid, lipoprotein and inflammation
biomarkers.4, 5, 6, 7, 8
Scientific presentation: Presentation of the
REDUCE-IT results at AHA were made by the Global Principal
Investigator and Steering Committee Chair for the study, Deepak L.
Bhatt, MD, MPH, Professor of Medicine at Harvard Medical School,
Executive Director of Interventional Cardiovascular Programs at
Brigham and Women's Hospital Heart and Vascular Center.
Dr. Bhatt stated, “REDUCE-IT establishes a new
paradigm for the prevention of important cardiovascular events in
statin-treated patients at elevated risk with increased
triglycerides. I believe that the results of this study may
represent the most significant breakthrough in preventative
cardiovascular care since the introduction of statin therapy
decades ago.”
Amarin perspective: Commenting on these results
from Amarin:
“The robustness and consistency of these
clinical results are exciting. Extensive scientific evaluation led
to the design and conduct of this study; but the degree of benefit
shown with Vascepa nevertheless exceeded our expectation,” stated
Steven Ketchum, president of research and development and chief
scientific officer of Amarin. “We believe that these positive
results identify an important new treatment option to help lower
cardiovascular risk in appropriate patients. Cholesterol management
lowers cardiovascular risk by 25-35%. REDUCE-IT suggests that the
residual 65-75% cardiovascular risk beyond cholesterol management
can be significantly lowered with Vascepa in studied patients. We
again thank all of the patients, investigators and others involved
in this landmark study.”
“Amarin has spent over $500 million developing
Vascepa. We are intently focused on improving patient care.
Our priorities are now shifting to educate the world regarding
these results so that the pain, loss of productivity and high costs
of cardiovascular events can be reduced,” stated John F. Thero,
president and CEO of Amarin.
Regulatory Pathway
The REDUCE-IT study was designed under a special
protocol assessment agreement with the U.S. Food and Drug
Administration (FDA). Amarin intends to submit an sNDA
to the FDA in early 2019 seeking approval to expand the label for
Vascepa based on the cardioprotective effect of Vascepa
demonstrated in the REDUCE-IT study. FDA's determination of
standard or priority review will be made when the sNDA is
submitted. At this time, Amarin is planning for a
standard review with potential approval anticipated in late
2019.
Vascepa is Affordably
Priced
Vascepa is a low-cost drug. The majority of
patients covered by insurance who obtain prescriptions for Vascepa
pay a monthly co-pay charge of $9.99 or less. A patient with
commercial insurance can pay as little as $9.00 for a 90-day supply
prescription of Vascepa.
Commercial Expansion and Next
Steps
As previously described, Amarin is in the
process of increasing the number of company sales representatives
promoting Vascepa to over 400 people in the United States.
Amarin’s plans provide for greater concentration of coverage in
current sales territories and new coverage where Amarin currently
does not have sales representatives. With numerous
experienced applicants for these new positions, the company is well
on its way towards having these new sales representatives hired and
trained heading into 2019. The company is also planning to
support various medical education forums covering preventative
solutions in cardiovascular care. Amarin anticipates making
the published results of REDUCE-IT available to healthcare
professionals. Following potential label expansion,
Amarin will consider other initiatives to expand Vascepa promotion
including more extensive consumer promotion focused on
cardiovascular risk reduction.
Financial Disclosure
Funding from Amarin was provided to Brigham and
Women’s Hospital for Dr. Deepak L. Bhatt’s work as the REDUCE-IT
study chair and global principal investigator.
Conference Call and Webcast Information
Amarin will host a conference call
at 7:15 p.m. CT/ 8:15 p.m. ET, November 10, 2018 to
discuss this information. The call will be accessible through
the investor relations section of the company’s website at
www.amarincorp.com. The call can also be heard via telephone by
dialing 877-407-8033. A replay of the call will be made available
for a period of two weeks following the conference call. To hear a
replay of the call, dial 877-481-4010 (inside the United States) or
919-882-2331 (outside the United States). A replay of the call will
also be available through the company's website shortly after the
call. For both dial-in numbers please use conference ID 39894.
About Amarin
Amarin 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 lipid
science and the potential therapeutic benefits of polyunsaturated
fatty acids. 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 Cardiovascular
Disease
Worldwide, cardiovascular disease (CVD) remains
the #1 killer of men and women. In the United States CVD leads to
one in every three deaths – one death approximately every 38
seconds – with annual treatment cost in excess of $500 billion.9,
10
Multiple primary and secondary
prevention trials have shown a significant reduction of 25% to
35% in the risk of cardiovascular
events with statin therapy, leaving significant
persistent residual risk despite the achievement of target LDL-C
levels.4
Beyond the cardiovascular risk associated with
LDL-C, genetic, epidemiologic, clinical and real-world data suggest
that patients with elevated triglycerides (TG) (fats in the blood),
and TG-rich lipoproteins, are at increased risk for cardiovascular
disease. 11, 12, 13, 14
About VASCEPA® (icosapent ethyl)
Capsules
Vascepa® (icosapent ethyl) capsules are a
single-molecule prescription product consisting of the omega-3 acid
commonly known as EPA in ethyl-ester form. Vascepa is not fish oil,
but is derived from fish through a stringent and complex
FDA-regulated manufacturing process designed to effectively
eliminate impurities and isolate and protect the single molecule
active ingredient from degradation. Vascepa, known in scientific
literature as AMR101, has been designated a new chemical entity by
the FDA. Amarin has been issued multiple patents
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.
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.
Vascepa has been approved for use by the United
States Food and Drug Administration (FDA) as an adjunct to diet to
reduce triglyceride levels in adult patients with severe (≥500
mg/dL) hypertriglyceridemia. Nothing in this press release should
be construed as promoting the use of Vascepa in any indication that
has not been approved by the FDA.
Important Cautionary Information About
REDUCE-IT Primary Results
Further REDUCE-IT data assessment and data
release could yield additional useful information to inform greater
understanding of the trial outcome. Further detailed data
assessment by Amarin and regulatory authorities will continue and
take several months to complete and record. The final evaluation of
the totality of the efficacy and safety data from REDUCE-IT may
include some or all of the following, as well as other
considerations: new information 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; consideration of
REDUCE-IT results in the context of other clinical studies.
Forward-Looking Statements
This press release contains forward-looking
statements, including expectations regarding planned regulatory
filings and the nature of FDA’s review and related timing thereof;
expectations that REDUCE-IT results could lead to a new treatment
paradigm in the patient population studied; and plans for sales
force, international and insurance coverage expansion. These
forward-looking statements are not promises or guarantees and
involve substantial risks and uncertainties. In addition, Amarin's
ability to effectively commercialize Vascepa will depend in part on
its ability to continue to effectively finance its business,
efforts of third parties, its ability to create market demand for
Vascepa through education, marketing and sales activities, to
achieve market acceptance of Vascepa, to receive adequate levels of
reimbursement from third-party payers, to develop and maintain a
consistent source of commercial supply at a competitive price, to
comply with legal and regulatory requirements in connection with
the sale and promotion of Vascepa and to maintain patent protection
for Vascepa. 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 approvals; the
risk that sales may not meet expectations and related cost may
increase beyond expectations; the risk that patents may not be
upheld in patent litigation and applications may not result in
issued patents sufficient to protect the Vascepa franchise. 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
Amarin
Investors and others should note that Amarin
communicates with its investors and the public using the company
website (http://www.amarincorp.com/), the investor relations
website (http://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.
References
1 LaRosa JC, Grundy SM, Waters DD, et al.
Intensive lipid lowering with atorvastatin in patients with stable
coronary disease. N Engl J Med 2005; 352: 1425–35.2 Sabatine MS,
Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in
patients with cardiovascular disease. N Engl J Med. 2017;376:1713.3
Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction
with icosapent ethyl for hypertriglyceridemia. N Engl J Med. DOI:
10.1056/NEJMoa1812792.
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 Borow KM, Nelson JR, Mason RP. Biologic
plausibility, cellular effects, and molecular mechanisms of
eicosapentaenoic acid (EPA) in atherosclerosis. Atherosclerosis.
2015;242(1):357-366.
6 Nelson JR, Wani O, May HT, et al. Potential
benefits of eicosapentaenoic acid on atherosclerotic plaques.
Vascul Pharmacol. 2017;91:1–9.
7 Mason RP, Dawoud H, Jacob RF, et al.
Eicosapentaenoic acid improves endothelial function and nitric
oxide bioavailability in a manner that is enhanced in combination
with a statin. Biomed Pharmacother. 2018;103:1231-1237.
8 Takamura M, Kurokawa K, Ootsuji H, et al.
Long-term administration of eicosapentaenoic acid improves
post-myocardial infarction cardiac remodeling in mice by regulating
macrophage polarization. J Am Heart Assoc. 2017;6(2). pii:
e004560.
9 American Heart Association. 2018.
Disease and Stroke Statistics-2018 Update.
10 American Heart Association. 2017.
Cardiovascular disease: A costly burden for America projections
through 2035.
11 Budoff M. Triglycerides and triglyceride-rich
lipoproteins in the causal pathway of cardiovascular disease. Am J
Cardiol. 2016;118:138-145.
12 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.
13 Nordestgaard BG. Triglyceride-rich
lipoproteins and atherosclerotic cardiovascular disease - New
insights from epidemiology, genetics, and biology. Circ Res.
2016;118:547-563.
14 Nordestgaard BG, Varbo A. Triglycerides and
cardiovascular disease. Lancet. 2014;384:626–635.
Amarin Contact Information
Investor Relations:
Elisabeth Schwartz
Investor Relations and Corporate Communications Amarin
Corporation plc In U.S.: +1 (908) 719-1315
investor.relations@amarincorp.com Lee M. Stern Trout Group
In U.S.: +1 (646) 378-2992lstern@troutgroup.com Media
Inquiries: Christy Maginn Burson-Marsteller In U.S.: +1 (646)
280-5210 Christy.Maginn@bm.com
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