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The information contained in this FAQ section of Amarin's website is accurate only as of the date this page was last updated. Amarin disavows any obligation to update the information contained in this FAQ section after such date. This information is intended for communication with investors and should not be construed as marketing the use of any Amarin products or product candidates.


 

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Amarin is pleased to announce the publication of “Rationale and Design of REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl – Intervention Trial” in the March issue of Clinical Cardiology.

The article can be accessed here. Also, an Amarin press release has been issued related to this publication.

The following are key points regarding the study design for REDUCE-IT:

REDUCE-IT: Study Design

  • REDUCE-IT is a landmark global study involving approximately 8,000 patients
  • It is a randomized, multicenter, double-blind, placebo-controlled study designed to determine if treatment with VASCEPA® 4 g/day versus placebo reduces major adverse cardiovascular events (MACE) in statin-treated patients with persistent hypertriglyceridemia and high cardiovascular risk
  • The primary endpoint of the study is the time to the first occurrence of the composite endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina
  • Secondary endpoints include time to event analyses of components of the primary endpoint
  • The study is being conducted under a special protocol assessment agreement with the FDA

In September 2014, the National Lipid Association (NLA) launched a nationwide triglyceride campaign during National Cholesterol Education Month. The NLA's announced goal is to encourage patient education and drive discussions about lipid management and the consequences of high cholesterol and triglyceride levels.

According to the NLA, the mission of the campaign is to encourage physicians to inform patients about the importance of proper treatment and prevention as it relates to their entire lipid profile - not just cholesterol, but elevated triglyceride levels, too.

"We want to raise awareness around elevated triglycerides with patients and health care providers alike, as they may unsuspectingly affect patients' health, even if they look and feel healthy," said NLA President Terry A. Jacobson, MD. "Fortunately, health care providers are committed to offering their patients their best care, and we're committed to ensuring they have the tools to do so."

In a recent survey of health care providers, the NLA discovered a need for standard protocols surrounding the measure of patients' total lipid profiles, including triglycerides. To jumpstart these educational and preventive efforts, the NLA urges health care providers to compare patients' triglyceride levels to the following categories:

With this campaign, NLA hopes to provide the necessary resources for clinical practice and education, as well as generate awareness about lipid management.

Amarin is not responsible for the content of NLA's campaign.

Amarin has a co-promotion agreement with Kowa through the end of 2018 under which Kowa uses a portion of the time of their sales force to help educate physicians in the U.S. on the use of Vascepa, along with promotion of its flagship branded statin product, LIVALO® (pitavastatin).  This co-promotion arrangement increases both the number of sales targets reached and the frequency of sales calls on existing sales targets. Kowa is responsible for the cost of its sales representatives and related promotional materials.  Amarin compensates Kowa with a co-promotion fee based on a percentage of Vascepa gross margins which fee is classified by Amarin as part of selling, general and administrative expenses.

This article centers on low-dose dietary supplement products that are not designed or intended to treat cardiovascular disease. The FDA permits a dietary health claim for use with food products and applicable to dietary supplements stating that “supportive but not conclusive research shows that consumption of EPA and DHA may reduce the risk of coronary heart disease.”  This claim and other unapproved claims by dietary supplement manufacturers has led to increased use of dietary supplements in place of appropriate medical treatment for serious disease conditions.

Importantly, dietary supplements with EPA and DHA are not recommended by the FDA at doses of more than 2 grams per day and are not recommended by FDA at any dose to treat or mitigate disease. Dietary supplements are not required to meet strict FDA drug standards for safety, efficacy, and manufacturing. Many dietary supplement fish oils are low in omega-3 content, may vary in content from lot to lot, can contain harmful contaminants, are prone to oxidation that mitigates antioxidant effects, and contain DHA, which is associated with increases in bad cholesterol in patients at high risk characterized by high and very high blood levels of triglycerides. 

Amarin remains a leader in the research and development of the omega-3 acid, EPA, through clinical study of its highly pure pharmaceutical grade lead product, Vascepa® (icosapent ethyl) capsules.  Amarin received FDA approval of 4 gram daily use of Vascepa in July 2012 as an adjunct to diet to lower triglycerides in patients with very high (500 mg/dL) triglycerides (VHTG), and is pursuing FDA approval in the treatment of patients with persistent high (200-499 mg/dL) triglycerides despite statin therapy.  The effect of Vascepa on the risk for cardiovascular mortality and morbidity in patients has not been determined.  FDA approved use of Vascepa is consistent with numerous national and international treatment guidelines and position statements.

Amarin is also investing more than $100 million in a first-of-its-kind cardiovascular outcomes study called the REDUCE-IT study.  REDUCE-IT is being conducted to evaluate the efficacy of Vascepa in reducing cardiovascular risk in a high risk, elevated triglyceride-level patient population on statin therapy.  The REDUCE-IT study is expected to be completed in 2017 with results published in 2018.  The REDUCE-IT study follows the only other outcomes study of a highly pure EPA product, the JELIS study. JELIS, an open label study, showed that EPA in conjunction with statins in Japanese patients (N=18,645) reduced cardiovascular events by 19% compared to statins alone. Importantly, this result was obtained in a population in which triglycerides were in the normal range in approximately half of the patients. The JELIS study showed a 53% reduction in cardiovascular events in the EPA with statin group compared to the statin-only group within the subset of patients (N=957) who had both elevated levels of triglycerides (>150 mg/dL) and low levels of HDL-C (<40 mg/dL).  This result in patients with high triglyceride levels and low HDL-C is directionally consistent with subgroup analyses of patients treated with other triglyceride lowering agents in the ACCORD-Lipid and AIM-HIGH studies.

The REDUCE-IT study is the subject of a special protocol assessment with the FDA and was designed by Amarin to take into account many of the perceived weaknesses of some studies of omega-3s that did not show clinical benefit, including the use of low-doses of omega-3s, the study of patient populations at normal triglyceride levels and the use of omega-3 compositions that are not pharmaceutical grade and include the omega-3 acid, DHA.  Amarin clinical trials have demonstrated that Vascepa is effective in studied patients at lowering triglycerides without increasing bad cholesterol.  

The New York Times article raises important considerations.  Most important, careful analysis of the relevant studies and the latest scientific knowledge are essential for patients and physicians to make informed decisions on how best to care for their health and treat serious medical conditions. Amarin is dedicated to improved patient care and is spending more than $100 million to generate additional outcomes study and other data relevant to the potential of appropriate doses of pharmaceutical grade EPA to reduce cardiovascular risk in high risk patients.

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. Vascepa is under various stages of development for potential use in other indications that have not been approved by the FDA. Nothing in this information should be construed as marketing the use of Vascepa in any indication that has not been approved by the FDA.

About Vascepa® (icosapent ethyl) capsules

Vascepa® (icosapent ethyl) capsules, known in scientific literature as AMR101, is a highly pure-EPA omega-3 prescription product in a 1 gram capsule.

Indications and Usage

  • Vascepa (icosapent ethyl) is indicated in the United States 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

  • Vascepa is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to Vascepa or any of its components and should be used 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.

FULL VASCEPA PRESCRIBING INFORMATION CAN BE FOUND AT WWW.VASCEPA.COM.

In this case series report [DOI:10.1007/s40119-014-0032-9], Dr. Hassan and coauthors share the results of a retrospective analysis of records from a private endocrinology practice of patients with prediabetes or diabetes who received Lovaza® (4 g/day) and were subsequently switched to Vascepa® (4 g/day).  Dr. Hassan and colleagues note that their patients were switched to Vascepa, which contains only icosapent ethyl, an ethyl ester of eicosapentaenoic acid (EPA), due to the potential for Lovaza, which contains docosahexaenoic acid (DHA) as well as EPA, to raise low-density lipoprotein cholesterol (LDL-C) and/or cause gastrointestinal upset in some patients.1   Vascepa was well tolerated by all patients who switched from Lovaza to Vascepa, and LDL-C and other lipid parameters improved in most patients.

Patients with diabetes and prediabetes are at increased risk for dyslipidemia and cardiovascular disease (CVD). To reduce this risk, statins and additional therapies may be considered. The authors note that even when LDL-C and glycemic treatment goals are reached, some patients may have residual risk of cardiovascular (CV) events due to elevated triglycerides (TGs).  Prescription omega-3 fatty acids offer an option to reduce TGs and potentially improve other lipid parameters, although, in some patients, products that contain DHA may increase LDL-C levels.

The authors included the records of the 10 patients in this practice that met the criteria for this analysis, but were outside of Vascepa FDA-approved product labeling. Patient records were analyzed for LDL-C, TG, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and non-HDL-C measured before and after the switch to Vascepa. They found that, in most cases, patients experienced decreases in LDL-C, TG, non-HDL-C, and TC and increases in HDL-C following the switch to Vascepa.

Nine of the 10 patients were on concomitant statin therapy throughout the study period.  Reductions in LDL-C, TC, and non-HDL-C were observed in 8 patients, reductions or no changes in TG were observed in 8 patients, and increases or no changes in HDL-C were observed in 8 patients. No gastrointestinal adverse events were observed.  Two patients experienced increases in LDL-C, TG, non-HDL-C, and TC after switching to Vascepa.

The authors’ findings are similar to those of other recent reports of patients switched from EPA + DHA formulations to Vascepa.2,3  The authors note that their analysis was exploratory and may be of interest to the clinical community for potential future prospective studies.

Dr. Hassan acknowledged that the role for omega-3 fatty acids in the prevention of CV events bears further investigation, and points to the ongoing cardiovascular outcomes study REDUCE-IT as highly anticipated. REDUCE-IT is Amarin’s ongoing, large, phase III trial to assess the efficacy of Vascepa 4 g/day in preventing a first major cardiovascular event in patients with persistent hypertriglyceridemia despite statin treatment who also have established CVD or are at high risk for CVD.

Amarin provided support and funding for writing assistance as acknowledged in the publication.

______

Note:

 

  • LOVAZA® is a registered trademark of the GlaxoSmithKline group of companies
  • VASCEPA® is a registered trademark of the Amarin group of companies

 

  1. LOVAZA (omega-3-acid ethyl esters) capsules [package insert]. Research Triangle Park, NC: GlaxoSmithKline; May 2014.
  2. Hilleman DE, Malesker MA. Potential benefits of icosapent ethyl on the lipid profile: case studies. Clin Med Insights Cardiol. 2014;8:13-15.
  3. Castaldo RS. A retrospective case series of the lipid effects of switching from omega-3 fatty acid ethyl esters to icosapent ethyl in hyperlipidemic patients. Postgrad Med. 2014;126:268-273.

In this article (doi: 10.1016/j.bbamem.2014.10.016), Dr. R. Preston Mason (Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School) and his colleague Robert F. Jacob report the results of a study that tested the comparative effects of EPA and other triglyceride-lowering agents (fenofibrate, niacin, and gemfibrozil) on lipid oxidation (i.e. oxidative stress) in human low-density lipoprotein (LDL) as well as on polyunsaturated fatty acids-enriched membrane lipid vesicles.The antioxidant effects were also tested for EPA in combination with the active metabolite arising from atorvastatin (i.e. the o-hydroxy (active) metabolite (ATM)). Additionally, this study compared the effects of EPA and the other triglyceride-lowering agents on the formation of cholesterol crystalline domains that can form in membranes under oxidative stress conditions.Oxidative stress and the resultant damage leads to endothelial dysfunction, inflammation, and foam cell formation during atherogenesis.

In this study, EPA was found to inhibit LDL oxidation in a dose-dependent manner and was distinguished from the other triglyceride-lowering agents, which had no significant effect.Similar effects were observed in membrane lipid vesicles, an effect that was significantly enhanced in combination with ATM.Additionally, in this study, only EPA inhibited glucose-induced cholesterol domain formation.

These data demonstrate that EPA inhibits hyperglycemia-induced changes in membrane lipid structural organization through a potent antioxidant mechanism associated with its distinct physicochemical interactions with the membrane bilayer.

Amarin provided financial support for this study.

In this publication (https://postgradmed.org/doi/10.3810/pgm.2014.11.2828), Dr. Howard S. Weintraub, Clinical Professor of Medicine, New York University School of Medicine, Clinical Director, NYU Center for the Prevention of Cardiovascular Disease, offers a comprehensive summary of efficacy, safety, and key considerations of currently approved prescription omega-3 fatty acids (OM3FA) products in patients with elevated triglycerides, with or without concomitant elevations in other atherogenic parameters, who may be at a higher risk for cardiovascular disease.

Excluding generic formulations of Lovaza, there are four prescription OM3FA formulations approved in the United States:  omega-3-acid ethyl esters (Lovaza® and Omtryg™), omega-3-carboxylic acids (Epanova®), each of which contains both EPA and DHA, and icosapent ethyl (Vascepa®), which is an EPA-only formulation.

The discussion includes review of both older clinical study results of Lovaza as well as more recent clinical results for Lovaza as studied as a separate arm of the phase 3 trial of Omtryg.  All prescription OM3FA products effectively lower triglycerides.  Products that contain DHA can raise levels of low-density lipoprotein cholesterol (LDL-C), which is of particular concern in patients with atherosclerosis.  The only approved prescription OM3FA that does not contain DHA is Vascepa.

The review also emphasizes that omega-3 dietary supplements should not be substituted for prescription OM3FA’s as the efficacy of such products have not been clinically demonstrated or FDA approved and the safety and tolerability of supplements are not well known, particularly at prescription OM3FA dose levels.

Amarin provided support and funding for writing assistance as acknowledged in the publication.

_____________

Note:

  • LOVAZA® is a registered trademark of the GlaxoSmithKline group of companies
  • OMTRYG is a trademark of Trygg Pharma, Inc.
  • EPANOVA® is a registered trademark of the AstraZeneca group of companies
  • VASCEPA® is a registered trademark of the Amarin group of companies

Amarin has reviewed with enthusiasm the publication on June 18th in The New England Journal of Medicine of two independent studies by leading research groups funded by the National Institutes of Health and the European Union related to reduced triglyceride (TG) levels and reduced cardiovascular (CV) risk.  One study was led by Dr. Sekar Katherisan of the Cardiovascular Research Center and Center for Human Genetic Research at Massachusetts General Hospital in Boston (DOI: 10.1056/NEJMoa1307095) and the other by Dr. Anne Tybjærg-Hansen from the Department of Clinical Biochemistry and Molecular Genetics at the Copenhagen University Hospital in Denmark( DOI: 10.1056/NEJMoa1308027).  Amarin did not provide funding or support for either study.  As the medical community eagerly searches for ways to further reduce CV risk beyond LDL-C-lowering, Amarin believes these two independent studies provide encouraging new data connecting reduced TG levels to reduced CV risk.  We encourage investors to review the publications and related press reports on the new studies for more information and consider this new information alongside our public disclosures filed with the Securities and Exchange Commission and other public comments we have made on the results of our ANCHOR study and our related pending REDUCE-IT cardiovascular outcomes study.   Of relevance to the new data, we refer investors to our May 2, 2014 press release titled, Amarin Announces Presentation of New MARINE and ANCHOR Post-Hoc Analyses at National Lipid Association Annual Scientific Sessions Showing Vascepa® Significantly Reduced Apolipoprotein C-III Levels.

The Lancet, August 16th review article, Triglycerides and cardiovascular disease, by Drs. Nordestgaard and Varbo, University of Copenhagen (doi:10.1016/S0140-6736(14)61177-6), discusses how the medical community has sought to further reduce cardiovascular risk beyond low-density lipoprotein cholesterol (LDL-C)-lowering and how the therapeutic raising of high-density lipoprotein cholesterol (HDL-C) has not demonstrated a cardiovascular benefit.  The article then offers an overview of the compelling epidemiological, clinical and genetic data connecting the treatment of elevated triglyceride levels to reduced cardiovascular risk. 

The authors summarize that “[t]he magnitude of the effect caused by triglyceride-lowering compares favourably with the reduction of… major vascular events and… all-cause mortality… [with] reduction in LDL cholesterol in statin trials, while acknowledging that the totality of evidence supporting the therapeutic lowering of LDL-C is more extensive than that for the therapeutic lowering of triglycerides.   Investors can review this publication to consider how this information may influence continued healthcare professional interest in triglyceride lowering therapies.  

The authors note that “[n]o large-scale randomized trial has examined the effect of reducing triglycerides on cardiovascular disease risk in people with raised triglycerides”, and cite REDUCE-IT as a study that is providing an “urgently needed” randomized intervention trial in patients with elevated triglycerides despite statin therapy. 

Please note, in referring to the REDUCE-IT study, the review article presents 2016 as the projected date for study completion.  As described in Amarin’s public disclosures, 2016 is the current estimated timing for an interim look at the study results.

Amarin has no connection to The Lancet article. Investors should consider this information together with Amarin public disclosures filed with the Securities and Exchange Commission, public comments on MARINE and ANCHOR studies and updates on the pending REDUCE-IT cardiovascular outcomes study.

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Updated: September 1, 2017 at 3:21 PM Eastern Time