MARINE: Ethyl-EPA Reduces Triglyceride Levels Without Raising LDL Cholesterol

November 30, 2010

November 30, 2010 (Dublin, Ireland and Mystic, Connecticut) — Ethyl eicosapentaenoic acid (EPA), a semisynthetic derivative of omega-3 fatty acids, significantly lowers triglyceride levels in patients with very high triglyceride levels without significantly increasing LDL-cholesterol levels.

Top-line results of the MARINE trial, a randomized, placebo-controlled trial testing ethyl-EPA in 229 patients with triglyceride levels >500 mg/dL, were announced today by Amarin Corporation. During a conference call to analysts, investors, and media, the company reported that the 2-g and 4-g dose of AMR101, as the ethyl-EPA is currently known, reduced triglyceride levels 20% and 33%, respectively, all without a significant increase in LDL-cholesterol levels.

"This is the only triglyceride-lowering therapy studied in this population with very high triglycerides to show a lack of elevation in LDL cholesterol," said Dr Paresh Soni, senior vice president and head of drug development at Amarin.

Speaking with heartwire about the study, which hasn't yet been published or peer reviewed, Dr Darren McGuire (University of Texas Southwestern, Dallas) was cautious in interpreting the results, pointing out the trial was small and short in duration. He noted that researchers have not yet proven that lowering triglyceride levels reduces cardiovascular risk, and coupled with the increase in LDL-cholesterol levels, this remains a concern of all triglyceride-lowering therapies. That said, trials such as Japan EPA Lipid Intervention Study (JELIS) and GISSI-Prevenzione showed a favorable signal of reduced cardiovascular events among patients treated with fish oil.

"At the end of the day, if you can have favorable cardiovascular effects without raising LDL cholesterol, that's going to be an advantage," said McGuire. "There is a lot of enthusiasm for this compound, but this is really early in development, and I would insert a dose of caution here. The early results are intriguing."

The MARINE Trial

Briefly, the investigators enrolled 229 patients with very high triglyceride levels--the median baseline triglyceride level in the 2-g and 4-g dose arms was 681 mg/dL and 657 mg/dL, respectively--and compared the change in triglyceride levels at 12 weeks.

As noted, both doses significantly reduced triglyceride levels, but they also decreased non-HDL cholesterol, apolipoprotein B, lipoprotein-phospholipase A2, VLDL cholesterol, and total cholesterol. In a subgroup analysis evaluating patients with the highest triglyceride levels, >750 mg/dL, treatment with the 2-g and 4-g doses of ethyl-EPA resulted in 33% and 45% reductions in triglyceride levels, respectively, again without an increase in LDL-cholesterol levels.

Speaking to the results, lead MARINE investigator Dr Harold Bays (Louisville Metabolic and Atherosclerosis Research Center, KY) said the findings are good news given that increases in LDL-cholesterol levels are a problematic side effect of therapies that lower triglyceride levels, especially in patients with very high triglyceride levels. In some instances, these therapies, including fibrates and prescription omega-3 fatty acids, can increase LDL-cholesterol levels 40% to 50%.

"The findings are clinically important because elevated triglyceride levels are an important modifiable atherosclerotic coronary heart disease risk factor, and lowering triglycerides in patients with very high triglyceride levels has health benefits such as potentially reducing the risk of triglyceride-induced pancreatitis and other complications, as well as improving atherosclerotic coronary heart disease risk factors," said Bays.

To heartwire , McGuire said that he has seen LDL-cholesterol increases of 20 mg/dL, or 10% to 20%, in some patients treated with prescription fish oil, and while this might be managed with a statin, he said clinicians are reluctant to treat one drug's side effect with another drug. He said that patients with hypertriglyceridemia typically receive statins based on their background risk of cardiovascular disease, whereas lowering triglycerides is done mainly to prevent hyperviscosity complications, such as pancreatitis and other abnormalities.

Also commenting on the MARINE findings, Dr Roger Blumenthal (Johns Hopkins University Medical Institute, Baltimore, MD) said that while LDL increases can occur with prescription fish oil or fibrates, the increase is "modest" and "not that big an issue." Moreover, he said that while these drugs can raise LDL cholesterol, they do not affect levels of apolipoprotein B, a better measure of the atherogenic particles. Overall, he was skeptical of the findings, pointing out that the available prescription omega-3 fatty acid is effective in reducing triglycerides, is well tolerated, and works well with statin therapy. Most patients with high triglycerides have mixed dyslipidemia and would likely be treated with background statin therapy, he added.

Dr Steven Nissen (Cleveland Clinic, OH), on the other hand, was impressed with the MARINE data, although he expressed the same caveats about trial size, duration, and lack of peer review. The semisynthetic ethyl-EPA, which does not include docosahexaenoic acid (DHA) in the formulation and has no effect on LDL-cholesterol levels, is a real advance in the treatment of elevated triglycerides, he told heartwire .

"It gives you all the benefit without the downside," said Nissen. "It's an interesting wrinkle. There's still room for small companies to do innovative things in this field."

Nissen would like to eventually see a head-to-head comparison between Lovaza, the prescription omega-3 fatty acid made by GlaxoSmithKline, and AMR101. Although it is difficult to compare the amount of triglyceride lowering across different trials, the amount of reduction appears similar with both drugs, he said.

Background of Statin Therapy

In MARINE, approximately 25% of patients were concomitantly treated with statin therapy, and in this cohort AMR101 also significantly reduced triglyceride levels, even more so than in those who were not taking statins. During the presentation, company officials said these results are line with the JELIS, the large trial showing the benefit of adding EPA to statin therapy for primary and secondary coronary heart disease prevention. Triglyceride-lowering therapies can raise LDL-cholesterol levels even in patients treated with statins, although this is mitigated by the lipid-lowering drugs.

In contrast, an analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial recently showed that combination therapy with fenofibrate and simvastatin failed to reduce the risk of fatal cardiovascular events, nonfatal MI, or nonfatal stroke in diabetic patients. The most recent trial of prescription omega-3 fatty acids occurred in patients with symptomatic paroxysmal AF, and that study, reported by heartwire , showed that Lovaza capsules, even at the fairly high dose of 4 g/day for six months, failed to reduce the risk of atrial-fibrillation recurrence.

The company said it plans to file a new drug application with the Food and Drug Administration (FDA) in 2011, saying it believes the drug might prove to be a "first-in-class" EPA triglyceride-lowering agent. It is currently testing the drug in the ANCHOR trial, a study of approximately 650 patients with mixed dyslipidemia, including triglyceride levels between 200 mg/dL and 500 mg/dL, or <500 mg/dL on statin therapy. Like MARINE, the ANCHOR trial is 12 weeks in duration, with the primary end point being change in triglyceride levels from baseline. Results of the trial are expected in 2011.

During the conference call, the company officials, including Soni and chief executive officer Joseph Zakrzewski, were extremely excited about the findings, telling investors and analysts they believe the drug represents a potential "blockbuster." They pointed out that the first indication they are seeking with the FDA is for reducing hypertriglyceridemia, similar to Lovaza, a drug that has approximately $1 billion in revenues. ANCHOR, with its mixed-dyslipidemia population and the second sought-after indication, will represent a real-world cohort, as statin therapy currently represents the backbone of therapy for lipid disorders.

A public relations official acting on behalf of Amarin said the company plans to present the MARINE data at a meeting and publish the results in a medical journal, but final details have not yet been arranged.

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