The EPA
Drug Initiative

Media Guide

On October 16th 2013, the FDA hosted an advisory committee meeting (ADCOM) for what most everyone expected to be nothing less than a coronation event for Vascepa, a new drug to treat high triglycerides and dyslipidemia, both considered significant risk factors for cardiovascular disease (CVD). In Japan, a large outcomes study of the same compound as Vascepa showed a 53% reduction in CVD events in 18,000 subjects over 5 years. The U.S. spends $300 billion a year treating CVD and 800,000 U.S. citizens die each year from CVD. A 25% reduction in CVD events would shrink treatment costs by $50 - $75 billion, not to mention the 100,000 and 200,000 lives that would be saved each year.

The FDA had previously made an agreement with Amarin, the drug's sponsor, called a special protocol assessment (SPA), which outlined the steps Vascepa would have to achieve to win approval. These milestones included: (1) successful clinical trials and (2) the creation of a large outcomes study - similar to what was conducted in Japan, but to FDA specifications - with at least 50% enrollment. Both of these requirements were exceeded by Amarin.

For these reasons, Vascepa was among the most anticipated new preventive therapies for cardiovascular disease in over 20 years. What made Vascepa unique was that it lowered every key lipid marker for CVD, including Triglycerides, LDLs, and inflammation. It did so without any side effects and a safety profile equal to placebo. With such a remarkable safety profile and proven efficacy, the FDA would surely grant Vascepa approval, or least that's what everyone anticipated.

In an unprecedented move, the FDA systematically disparaged Vascepa to the ADCOM panel, first casting doubt on its efficacy by pointing to the 4 grams mineral oil used in the trials as "possibly" affecting the statin potency. No such effect has been observed anywhere in the world and the mere fact the FDA approved the use of mineral oil as placebo in the clinical trials is inherently contradictory.

After its attempt to diminish the drug's efficacy, the FDA pulled out studies of Fibrate and Niacin drugs that had failed to reduce CVD events, arguing if these drugs had failed, so too would Vascepa. For a Government agency founded on scientific principle, it's unconscionable to rely on such "pseudo-science" when so much is at stake. Putting the fact that these are entirely different compounds aside, consider the subjects studied in these failed trials had normal triglyceride levels. If Statin drugs were evaluated in the same manner, they would not have reached the market for 15 years - it only takes common sense to understand CVD risk is difficult to lower if your LDL-C levels are already in the normal range.

The use of surrogate markers such as LDL-C levels in clinical trials, and not 5 year outcomes studies, has long been the basis used by the FDA as a means to approve current CVD drugs - all of which have serious side effects. But it appears the FDA is now saying a different standard of approval is needed for a drug that is as safe as a placebo.

The EPA Drug Initiative was formed in reaction to what was seen as a smear campaign and an arbitrary "moving of the goal posts", designed to prevent Vascepa from reaching the market at all costs. Thirteen days following the ADCOM, the FDA rescinded their agreement with Amarin for approving Vascepa, on the grounds that lowering high triglycerides was not considered to be associated with lowering CVD risk; this, despite lowering triglycerides and dyslipidemia being considered the standard of care throughout the United States.

What is Vascepa?

Vascepa is composed of 96% purified EPA (eicosapentaenoic acid), produced to the FDA's strict pharmaceutical standards.

After completing clinical trials in 2011, the FDA approved Vascepa in 2012 for what is called the "Marine" indication, the treatment of very high triglycerides (TG) (> 500 mg/dL). It is estimated that 4 million Americans suffer from very high TGs. Amarin has been marketing Vascepa for the Marine indication since February of this year and since then over 100,000 prescriptions have been written.

In addition to the Marine indication, Amarin had also applied for the "Anchor" indication, the treatment of high TGs in a lower range (between 200 mg/dL and 500 mg/dL) and patients with mixed dyslipidemia who were already on Statin drugs. Mixed dyslipidemia is the condition when two or more lipid markers are out of normal range. This indication addresses a larger population, estimated to be present in 40 million Americans.

In the FDA-approved clinical trials, Vascepa exceeded both the primary and secondary endpoints of the Anchor indication (> 200 mg/dL) with statistical significance. While lowering Triglycerides was the primary endpoint, Vascepa also met and exceeded the secondary endpoints as follows:

Primary Endpoints:

  • Reduced TGs by 21.5% (p < 0.0001)
  • Reduced non‐HDL‐C by 13.6% (p < 0.0001)
  • Reduced LDL‐C by 6.2% (demonstrated superiority over statin alone) (p = 0.0067)
  • LDL‐C upper confidence boundary ‐1.7%

Vascepa achieved a statistically significantly reduction in pre‐specified Secondary Endpoints:

  • Non‐HDL‐C
  • Apo B
  • Lp‐PLA2
  • VLDL‐C

While EPA is listed on every bottle of fish oil supplements sold by the millions to unsuspecting consumers as being beneficial to cardiovascular (CV) health, it has been clinically proven that small amounts of EPA produces negligible CV benefit. In fact, clinical trials of Vascepa showed that 4 grams of EPA, taken daily, is required to produce therapeutic benefit. If you attempted to match the equivalent 4 grams of EPA using fish oil supplements, it would require, on average, over 20 fish oil capsules taken daily. In doing so, you would not only expose yourself to excessive amounts of bad cholesterol, but other harmful compounds that have been found in unregulated, non-parmaceutical grade products.

References:

http://www.amarincorp.com/products.html Author: Amarin Corp.

What is the Anchor Study?

The ANCHOR study is a Phase 3, multicenter, placebo-controlled, randomized, double-blinded, 12-week clinical trial that studied the efficacy and safety of Vascepa in high-risk, statin-treated patients with residually high triglyceride (TG) levels (≥ 200 and < 500 mg/dl) despite low-density lipoprotein (LDL) cholesterol control (≥ 40 and < 100 mg/dl).

References:

ANCHOR Study Results Overview.pdf Author: Amarin Corp.

ANCHOR Study: Outcomes of Eicosapentaenoic Acid Ethyl Ester (AMR101) Therapy in statin-treated patients with persistent high triglycerides Author: American Journal of Cardiology

http://pharmacy.hsc.wvu.edu/wvcdhi/MediaLibraries/Pharmacy-WVCDHI/Media/Documents/PDF/Monographs/2012/vascepta-(Icosapent-Ethyl).pdf Author: Keri Morgan

The FDA's Pseudo Science Revealed

Why the FDA Got It Wrong and Why the FDA Will Approve Vascepa for ANCHOR sNDA Submission Author: The EPA Drug Initiative This article provides an in-depth review and analysis of the three clinical outcome trials, cited by the FDA as the reason for rescinding the ANCHOR SPA. It is intended to educate readers as to the adequacy and fairness of FDA’s review and whether their decision was justified based on the “substantial scientific issue” argument.

Mineral oil and placebo inertness issue Author: The EPA Drug Initiative In drafting the terms of the SPA, the FDA agreed that light mineral oil was acceptable as a placebo as long as the amount per capsule did not exceed the amounts in FDA-approved products given by the same route of administration.

Triglycerides and Dyslipidemia Standards of Care

American Association of Clinical Endocrinologists' (AACE) Guidelines for the Management of Dyslipidemia and Prevention of Atherosclerosis Author: American Association of Clinical Endocrinoligists', Inc. Increasing clinical evidence suggests that elevated triglycerides may be an independent risk factor for CAD; therefore AACE recommends screening for triglycerides as a component of lipid screening. Triglyceride levels that are even moderately elevated (> 150 mg/dL) may identify individuals at risk for insulin resistance syndrome. Triglyceride levels 200 mg/dL or greater may indicate a substantial increase in CAD risk.

http://www.einstein.yu.edu/news/releases/766/high-triglyceride-levels-found-to-independently-predict-stroke-risk-in-older-women Author: Dierdre Branley, Albert Einstein College of Medicine of Yeshiva University In a surprising finding with significant implications for older women, researchers at Albert Einstein College of Medicine of Yeshiva University and NYU School of Medicine have found that high levels of triglycerides (blood fats) are the strongest risk factor for the most common type of stroke in older women – more of a risk factor than elevated levels of total cholesterol or of low-density lipoprotein (LDL) cholesterol (known as “bad” cholesterol).

Vascepa Efficacy

Effects of icosapent ethyl on lipid and inflammatory parameters in patients with diabetes mellitus-2, residual elevated triglycerides (200–500 mg/dL), and on statin therapy at LDL-C goal: the ANCHOR study Authors: Eliot A Brinton, Christie M Ballantyne, Harold E Bays, John J Kastelein, Rene A Braeckman and Paresh N Soni, Cardio Vascular Diabetology Compared with placebo, IPE 4 g/day significantly reduced TG, non-high-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol (VLDL-C), lipoprotein-associated phospholipase A2, apolipoprotein B (Apo B), total cholesterol, high-density lipoprotein cholesterol, VLDL-TG, oxidized LDL, and remnant-like particle cholesterol in all 3 diabetes groups, LDL-C in the total diabetes group, and hsCRP in the total and less-controlled diabetes groups. Decreases in hsCRP and Apo B were much greater in patients with less-controlled diabetes.

LC-MS/MS analysis of plasma polyunsaturated fatty acids in type 2 diabetic patients after insulin analog initiation therapy Authors: Mutay Aslan, Filiz Özcan, Ibrahim Aslan and Gültekin Yücel, Lipids in Health and Disease The significant decrease in AA/EPA ratio indicates that insulin analog initiation therapy has anti-inflammatory properties by favoring the increase of n3 fatty acid EPA.

EPA Science

Anti-Inflammatory Medicine: Dietary Modulation of Eicosanoids Author: Inflammation Research Foundation For the past 70 years, medicine has done an excellent job treating acute infectious disease because this type of disease can often be traced to a single cause, such as bacteria, a virus, etc. However, the major problem confronting 21st-century medicine is the treatment of chronic disease. Since chronic disease is multi-factorial in nature, current medical practice tends to treat the symptoms, not the underlying cause. Treating only the symptoms is essentially micro-managing a chronic disease. Instead, the focus of health care should be on macro-managing wellness, which can be accomplished by achieving a single, broad physiological goal: Decreasing inflammation.

Eicosapentaenoic Acid (EPA) Reduces Cardiovascular Events: Relationship with the EPA/Arachidonic Acid Ratio Authors: Haruo Ohnishi and Yasushi Saito, Journal of Atherosclorosis and Thrombosis Recently, the Japan EPA Lipid Intervention Study (JELIS) of hp-EPA-E established the clinical efficacy of EPA for CVD, and higher levels of blood EPA, not DHA, were found to be associated with a lower incidence of major coronary events.

ADCOM Videos, Briefing Documents and Participant Contact Information

Annotated Video Clip of the ADCOM meeting between the FDA and Amarin:

References:

Amarin's ADCOM Briefing Document Author: Amarin Corp.

The FDA's ADCOM Briefing Document Author: U.S. Food and Drug Administration

ADCOM full videos and slides Compiled By: The EPA Drug Initiative

ADCOM Participants and Contact Information Compiled By: The EPA Drug Initiative

The JELIS Study

JELIS is a large clinical trial that evaluated whether EPA can make an additional improvement in mortality and morbidity of coronary artery disease beyond that of HMG-CoA reductase inhibitor treatment. The results of the study indicated that EPA is a promising treatment for the prevention of major coronary events, and especially non-fatal coronary events, in Japanese hypercholesterolaemic patients.

References:

JELIS Full Study Authors: MitsuhiroYokoyama, Hideki Origasa, Masunori Matsuzaki, Yuji Matsuzawa, Yasushi Saito, Yuichi Ishikawa, Shinichi Oikawa, Jun Sasaki, Hitoshi Hishida, Hiroshige Itakura, Toru Kita, Akira Kitabatake, Noriaki Nakaya, Toshiie Sakata, Kazuyuki Shimada, Kunio Shirato, for the JELIS Investigators

Design and Rationale Authors: Mitsuhiro Yokoyama and Hideki Origasa, for the JELIS Investigators

EPA Drops CV Events 53 Percent in High TG Low HDL Patients Authors: Yasushi Saitoa, Mitsuhiro Yokoyamab, Hideki Origasac, Masunori Matsuzakid, Yuji Matsuzawae, Yuichi Ishikawaf, Shinichi Oikawag, Jun Sasakih, Hitoshi Hishidai, Hiroshige Itakuraj, Toru Kitak, Akira Kitabatakel, Noriaki Nakayam, Toshiie Sakatan, Kazuyuki Shimadao, Kunio Shirato, for the JELIS Investigators

EPA Suppresses CV Events in Impaired Glucose Patients Authors: Shinichi Oikawaa, Mitsuhiro Yokoyamab, Hideki Origasac, Masunori Matsuzakid, Yuji Matsuzawae, Yasushi Saitof, Yuichi Ishikawag, Jun Sasakih, Hitoshi Hishidai, Hiroshige Itakuraj, Toru Kitak, Akira Kitabatakel, Noriaki Nakayam, Toshiie Sakatan, Kazuyuki Shimadao, Kunio Shiratop, for the JELIS Investigators

Plasma EPA But Not DHA Levels Correlate to Reduced CV Events Authors: Shinichi Oikawaa, Mitsuhiro Yokoyamab, Hideki Origasac, Masunori Matsuzakid, Yuji Matsuzawae, Yasushi Saitof, Yuichi Ishikawag, Jun Sasakih, Hitoshi Hishidai, Hiroshige Itakuraj, Toru Kitak, Akira Kitabatakel, Noriaki Nakayam, Toshiie Sakatan, Kazuyuki Shimadao, Kunio Shiratop, for the JELIS Investigators

EPA Reduced Secondary But Not Primary Stroke Occurrence Authors: Kortaro Tanaka, Yuichi Ishikawa, Mitsuhiro Yokoyama, Hideki Origasa, Masunori Matsuzaki, Yasushi Saito, Yuji Matsuzawa, Jun Sasaki, Shinichi Oikawa, Hitoshi Hishida, Hiroshige Itakura, Toru Kita, Akira Kitabatake, Noriaki Nakaya, Toshiie Sakata, Kazuyuki Shimada and Kunio Shirato

DHA Not EPA Correlates to LDL Increases 2012 Authors: Hiroshige Itakura1, Mitsuhiro Yokoyama, Masunori Matsuzaki, Yasushi Saito, Hideki Origasa, Yuichi Ishikawa, Shinichi Oikawa, Jun Sasaki, Hitoshi Hishida, Toru Kita, Akira Kitabatake, Noriaki Nakaya, Toshiie Sakata, Kazuyuki Shimada, Kunio Shirato and Yuji Matsuzawa, for the JELIS Investigators

Correlation Between CAD and Non HDL 2012 Authors: Jun Sasaki, Mitsuhiro Yokoyama, Masunori Matsuzaki, Yasushi Saito, Hideki Origasa, Yuichi Ishikawa, Shinichi Oikawa, Hiroshige Itakura, Hitoshi Hishida, Toru Kita, Akira Kitabatake, Noriaki Nakaya, Toshiie Sakata, Kazuyuki Shimada, Kunio Shirato and Yuji Matsuzawa, for the JELIS Investigators

Incremental Effects of EPA in Secondary Prevention of CV Events Authors: Masunori Matsuzaki, Mitsuhiro Yokoyama, Yasushi Saito, Hideki Origasa, Yuichi Ishikawa, Shinichi Oikawa, Jun Sasaki, Hitoshi Hishida, Hiroshige Itakura, Toru Kita, Akira Kitabatake, Noriaki Nakaya, Toshiie Sakata, Kazuyuki Shimada, Kunio Shirato and Yuji Matsuzawa, for the JELIS Investigators

NLA Statement on Use of Niacin in Light of HPS2 Author: The National Lipid Association

Adherence a Major Determinent of CV Risk Reduction Authors: Hideki Origasa, Mitsuhiro Yokoyama, Masunori Matsuzaki, Yasushi Saito, Yuji Matsuzawa, for the JELIS Investigators

Diabetics at Risk From CVD

Highly Purified Eicosapentaenoic Acid Increases Interleukin-10 Levels of Peripheral Blood Monocytes in Obese Patients With Dyslipidemia Author: Diabetes Care In addition, another study demonstrated that in type 2 diabetic patients who are not treated with statins, 1.8 g/day of highly purified EPA significantly reduced carotid intima-media thickness and the pulse wave velocity, and that the administration of EPA was a significant and independent factor associated with an annual improvement of the mean carotid intima-media thickness.

Effects of icosapent ethyl on lipid and inflammatory parameters in patients with diabetes mellitus-2, residual elevated triglycerides (200--500 mg/dL), and on statin therapy at LDL-C goal: the ANCHOR study Author: Cardiovascular Diabetology The potentially favorable decreases in TG, non–HDL-C, VLDL-C, Apo B, hsCRP, Ox-LDL, and RLP-C levels seen with IPE compared with placebo may be of clinical importance because these parameters are more likely to be abnormal in patients with diabetes mellitus (especially when less controlled), and it is believed that increases in lipid, lipoprotein, and inflammatory end points may contribute to the excess CVD risk in this setting.

Heart Disease in the U.S.

Heart Disease Fact Sheet Author: Centers for Disease Control and Prevention Heart disease is the leading cause of death for both men and women. More than half of the deaths due to heart disease in 2009 were in men. About 600,000 Americans die from heart disease each year—that’s 1 in every 4 deaths. Coronary heart disease is the most common type of heart disease, killing more than 385,000 people annually.

How Much Would a Heart Attack Cost You? Author: Steve Vernon, CBS News According to an article from the National Business Group on Health, the average total cost of a severe heart attack--including direct and indirect costs--is about $1 million. Direct costs include charges for hospitals, doctors and prescription drugs, while the indirect costs include lost productivity and time away from work. The average cost of a less severe heart attack is about $760,000. Amortized over 20 years, that's $50,000 per year for a severe heart attack and $38,000 per year for a less severe heart attack.

CDC: Heart Disease Author: Centers for Disease Control and Prevention In the United States, the most common type of heart disease is coronary artery disease (CAD), which can lead to heart attack. You can greatly reduce your risk for CAD through lifestyle changes and, in some cases, medication.

ATP-4 Guidelines Challenged

Don’t Give More Patients Statins Authors: John D. Abramson and Rita F. Redberg, The New York Times On Tuesday, the American Heart Association and the American College of Cardiology issued new cholesterol guidelines that essentially declared, in one fell swoop, that millions of healthy Americans should immediately start taking pills — namely statins — for undefined health “benefits.” This announcement is not a result of a sudden epidemic of heart disease, nor is it based on new data showing the benefits of lower cholesterol. Instead, it is a consequence of simply expanding the definition of who should take the drugs — a decision that will benefit the pharmaceutical industry more than anyone else.

It’s time to question the new guidelines on cholesterol drugs Author: André Picard, The Globe And Mail There is no need to routinely monitor blood cholesterol any more, according to the new guidelines. Why? Because the arbitrary cholesterol targets are not supported by scientific evidence. Let’s not forget that about three-quarters of people have normal cholesterol levels when they have heart attacks. That hasn’t changed during the great statins experiment of the past decade. Logically, that means physicians should be prescribing fewer statins, not more. But the new guidelines are being sold as a “leap of faith,” a belief that statins can prevent heart attacks and strokes, even if that benefit doesn’t seem to come from controlling cholesterol.

FDA, Big Pharma Corruption

Reports: Emails show alleged pay-to-play between drug companies, FDA Author: Rebecca Kaplan, CBS News An Ohio attorney has obtained emails that show that pharmaceutical companies have been paying tens of thousands of dollars to attend meetings of a panel of academics and health industry regulators that advise the Food and Drug Administration on its drug policies for painkillers, according to multiple news reports.

Glaxo CEO on U.K. China Trade Mission Amid Bribery Probe Authors: Makiko Kitamura and Robert Hutton, Bloomberg GlaxoSmithKline Plc (GSK) Chief Executive Officer Andrew Witty joined U.K. Prime Minister David Cameron on a trade mission to China today as his company faces a corruption investigation in the country.

FDA "Corruption" Letter Authenticated: Lawyers, Start Your Engines! Author: Jim Edwards, CBS News Lawyers who want to sue drug companies will be drooling over the news that the FDA has "certified" a 2009 letter sent anonymously by FDA staff to President Obama describing "systemic corruption and wrongdoing that permeates all levels of FDA."

GlaxoSmithKline to Plead Guilty and Pay $3 Billion to Resolve Fraud Allegations and Failure to Report Safety Data Author: Office of Public Affairs, Department of Justice GSK agreed to plead guilty to a three-count criminal information, including two counts of introducing misbranded drugs, Paxil and Wellbutrin, into interstate commerce and one count of failing to report safety data about the drug Avandia to the Food and Drug Administration (FDA).

Ron Paul condemns close ties between FDA and Big Pharma Author: Elliott Freeman, Digital Journal GOP Presidential candidate Ron Paul rebuked the relationship between the U.S. Food and Drug Administration (FDA) and the pharmaceutical industry during a press conference, stating that "the FDA and the drug companies are in bed together." ... In addition, Paul expressed his belief that collusion between the FDA and the pharmaceutical industry is intended to drive out competition. "What does the FDA do when it comes to alternative or natural products?" he asked. "The FDA and the drug industry keep them off the market."

FDA SpyGate -- New Revelations Challenge The New York Times Investigation of Agency "Enemies List," Raise More Questions About the 'Government's Most Dysfunctional Agency' Author: Jon Entine, Forbes According to Jon Entine, after a series of stumbles and scandals, the Food and Drug Administration’s ability to oversee the most cutting edge sectors of the medical industry, medical devices and genetic screening tests, is under increasing scrutiny.

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