CHICAGO, Nov. 11, 2018 /PRNewswire/ -- 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.
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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) 378-2992
lstern@troutgroup.com
Media Inquiries:
Christy
Maginn
Burson-Marsteller
In U.S.: +1 (646) 280-5210
Christy.Maginn@bm.com
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