Preventive cardiology
Eicosapentaenoic Acid Ethyl Ester (AMR101) Therapy in Patients With Very High Triglyceride Levels (from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension [MARINE] Trial)

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AMR101 is an omega-3 fatty acid agent containing ≥96% eicosapentaenoic acid ethyl ester and no docosahexaenoic acid. Previous smaller studies suggested that highly purified eicosapentaenoic acid lowered triglyceride (TG) levels without increasing low-density lipoprotein (LDL) cholesterol levels. TG-lowering therapies such as fibrates, and fish oils containing both eicosapentaenoic acid and docosahexaenoic acid, can substantially increase LDL cholesterol levels when administered to patients with very high TG levels (≥500 mg/dl). The present double-blind study randomized 229 diet-stable patients with fasting TG ≥500 mg/dl and ≤2,000 mg/dl (with or without background statin therapy) to AMR101 4 g/day, AMR101 2 g/day, or placebo. The primary end point was the placebo-corrected median percentage of change in TG from baseline to week 12. The baseline TG level was 680, 657, and 703 mg/dl for AMR101 4 g/day, AMR101 2 g/day, and placebo. AMR101 4 g/day reduced the placebo-corrected TG levels by 33.1% (n = 76, p <0.0001) and AMR101 2 g/day by 19.7% (n = 73, p = 0.0051). For a baseline TG level >750 mg/dl, AMR101 4 g/day reduced the placebo-corrected TG levels by 45.4% (n = 28, p = 0.0001) and AMR101 2 g/day by 32.9% (n = 28, p = 0.0016). AMR101 did not significantly increase the placebo-corrected median LDL cholesterol levels at 4 g/day (−2.3%) or 2 g/day (+5.2%; both p = NS). AMR101 significantly reduced non–high-density lipoprotein cholesterol, apolipoprotein B, lipoprotein-associated phospholipase A2, very low-density lipoprotein cholesterol, and total cholesterol. AMR101 was generally well tolerated, with a safety profile similar to that of the placebo. In conclusion, the present randomized, double-blind trial of patients with very high TG levels demonstrated that AMR101 significantly reduced the TG levels and improved other lipid parameters without significantly increasing the LDL cholesterol levels.

Section snippets

Methods

The Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension (MARINE) was a Phase III study conducted in the United States, South Africa, India, Russia, Ukraine, Finland, Germany, Italy, and The Netherlands. The study was conducted under guidelines set forth by Good Clinical Practice, the Declaration of Helsinki, and all local and/or national regulations and directives. The protocol was approved by the appropriate institutional review boards, and

Results

The baseline demographics of the patients are listed in Table 1 and were comparable across the treatment groups. In general, most patients were overweight (mean body mass index 30.8 kg/m2), white (88%), and male (76%), with a mean age of 52.9 years. Of the randomized patients, 24.9% received background statin therapy, 27.5% had diabetes mellitus, and 55.0% were at a high risk of coronary heart disease according to the patients' medical histories. For the randomized population, the median TG

Discussion

AMR101 is a novel lipid-altering agent that contains ≥96% EPA ethyl ester and no DHA. The MARINE study (to our knowledge, the largest reported clinical trial of its kind) was a Phase III, 12-week, multicenter, placebo-controlled, randomized, double-blind study evaluating 229 patients with fasting TGs ≥500 mg/dl and ≤2,000 mg/dl (with or without statin therapy), who were randomized to AMR101 4 g/day, AMR101 2 g/day, or placebo. AMR101 4 g/day significantly reduced the placebo-corrected median TG

Acknowledgment

The authors wish to thank the MARINE study investigators and the patients who participated in this study.

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    The MARINE study was sponsored and designed by Amarin Pharma Inc., Mystic, Connecticut, and conducted by Medpace, Inc., Cincinnati, Ohio, with funding from Amarin Pharma Inc. Editorial assistance was provided by Peloton Advantage, LLC, Parsippany, New Jersey, and funded by Amarin Pharma Inc.

    Dr. Bays has received research grants and served as an advisor to Amarin Pharma Inc., and has also received research grants and served as a consultant and speaker for numerous other pharmaceutical companies.

    A complete list of the study investigators can be found in the Appendix.

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