Trials and their respective Omega-3 Agents
EPA ethyl ester = icosapent ethyl
Eric Roehm, MD, Oct. 2020
The 3 very large randomized CV outcome trials using
>1 gram of omega-3 agent daily:
| Trial | Omega-3 Agent | Brand Name |
| JELIS1 (2007) | EPA ethyl ester1 (1.8g/day) Icosapent ethyl is a synonym for EPA ethyl ester2 (eicsosapentaenoic acid ethyl ester) |
Epadel |
| REDUCE-IT3 (2019) | Icosapent ethyl3(Also called EPA ethyl ester2) (4g/day) | Vascepa |
| STRENGTH4 (2020- pending) | Free fatty acids primarily composed4 of EPA (eicosapentaenoic acid) & DHA (docosahexaenoic acid) (4g/day) |
Epanova |
Two additional recent large randomized omega-3 trials:
| ASCEND5 (2018) | ≥900mg of omega-3 ethyl esters, including5: ~465 mg of EPA ethyl ester (icosapent ethyl) ~375 mg of DHA ethyl ester |
Omacor 5,6,7 (called Lovaza in USA) |
| VITAL8 (2019) | ≥900mg of omega-3 ethyl esters, including5: ~465 mg of EPA ethyl ester (icosapent ethyl) ~375 mg of DHA ethyl ester |
Omacor5,8 |
Names of Trials:
JELIS1 (Japan Eicosapentaenoic Acid Lipid Intervention Study)
REDUCE-IT3(Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia) (Initially titled: “Reduction of Cardiovascular Events with EPA– Intervention Trial”9)
STRENGTH4 (Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol)
VITAL8 (Vitamin D and Omega-3 Trial)
ASCEND6 (Effects of n−3 Fatty Acid Supplements in Diabetes Mellitus)
Omega-3 Nomenclature Confusion- Comments:
Both JELIS and REDUCE-IT studied the identical chemical structure, EPA ethyl ester (eicosapentaenoic acid ethyl ester) also known as icosapent ethyl. Epadel, used in JELIS1, and Vascepa in REDUCE-IT3, both contain ≥96% EPA ethyl ester2 (differing only in the other 4% of capsule contents2 & dose- 1.8g/day in JELIS1 and 4g/day in REDUCE-IT3). The STRENGTH trial used a mixture of free fatty acids, primarily EPA and DHA4.
There has been confusion about the omega-3 agent used in JELIS by the REDUCE-IT authors. The JELIS study authors frequently referred to their study drug simply as EPA. However, in the Procedures section, JELIS authors specifically state “We used capsules that contained 300mg of highly purified (≥ 98%) EPA ethyl ester…”1. Of note, in the literature, the term EPA is used at times for the various chemical structures derived from EPA such as EPA ethyl ester1,6,8,9, and at other times for the specific free fatty acid chemical structure eicosapentaenoic acid (EPA)4. The other cause for omega-3 naming confusion is misleading information in Amarin Corp. supported literature regarding omega-3 nomenclature.10
Evidence for assertions of fact made on this webpage-
REFERENCED STATEMENTS:
A) The JELIS trial (Japan Eicosapentaenoic Acid Lipid Intervention Study) used EPA ethyl ester as its omega-3 agent.
In the JELIS trial Procedures section, the JELIS authors specifically state “We used capsules that contained 300mg of highly purified (≥ 98%) EPA ethyl ester…”1.
JELIS trial- The Lancet p. 1091:
B) Vascepa- has multiple synonymous and equivalent generic names including:
– icosapent ethyl
– eicosapentaenoic acid ethyl ester
– ethyl-eicosapentaenoate
– ethyl-EPA
– ethyl icosapent
FDA Vascepa evaluation- Pharmacology Review 2011 p. 17 2 :
(AMR101 was an early name for Vascepa during the FDA application process. The list under “Generic Name” represents a partial list of the multiple generic synonyms for eicosapentaenoic acid ethyl ester.)
C) “The purity of ethyl-EPA” of Vascepa and Epadel in both products “are identical (≥96%)”… The ≤4% “impurities for each product (Vascepa and Epadel) are similar but not identical…”. The impurities “are intermediates in fatty acid synthesis…”
FDA Vascepa evaluation- Pharmacology Review 2011 p. 2-3 in the last 9 unnumbered pages found at the end of the document:2
(The greyed out areas are considered proprietary information and not released in the above FDA report.)
D) Amarin Corp. (Vascepa) requested the FDA to forgo some of the animal studies usually required because these animal studies had already been done with Epadel (Mochida Pharm., Japan).
FDA Vascepa evaluation- Pharmacology Review 2011 p. 46 2 :
However, because the products differed in the ≤4% impurities, the FDA required one animal bridging study before allowing Amarin Corporation to use the Epadel animal studies. “The purpose of this study (an animal study by Amarin) was to provide a bridge from AMR101 (ethyl-EPA, icosapent ethyl) to the Japanese marketed ethyl-EPA product, Epadel.”2 (AMR101-early name for Vascepa). The involved Amarin Corporation employees are obviously quite aware that both Epadel and Vascepa contain ≥96% of the identical chemical structure.
E) The REDUCE-IT3 (2019, NEJM) study authors (5 of which are Amarin employees1) confusingly always refer to the JELIS omega-3 agent as “EPA” and the REDUCE-IT omega-3 agent as “icosapent ethyl”.3 In fact, both the omega-3 agents in JELIS and in REDUCE-IT consisted of ≥96% of EPA ethyl ester.2 Amarin Corp (Vascepa- REDUCE-IT) and Mochida Pharm (Epadel-JELIS) are well known to each other, and these companies announced “collaboration on future development of EPA-base drug products” in 2018.11.
F) “The effect of Epadel (Mochida Pharm., Japan) was investigated in JELIS” 12
Addendum; “Omega-3 fatty acids” are also called “n-3 fatty acids”. For further details: fatty acid nomenclature.
REFERENCES:
1. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090-8.
2. Vascepa FDA Application- Pharmacology Review 2011, Accessed May 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202057Orig1s000PharmR.pdf
3. Bhatt DL, Steg PG, Miller M, et al. for the REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.
4. Rationale and design of the STRENGTH trial. Nicholls S, Lincoff AM, Bash D, et al. Clinical Cardiology 2018;41:1281-88.
5. Bowman L, Mafham M, Wallendszus K, et al. Effects of n−3 fatty acid supplements in diabetes mellitus. N Engl J Med 2018;379:1540-50.
6. Omacor prescribing information. Accessed May 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/21654lbl.pdf
7. ASCEND clin.gov Trial details. Accessed May 2020. https://clinicaltrials.gov/ct2/show/NCT00135226
8. Manson JE, Cook NR, Lee I, et al. for the VITAL Research Group. Marine n−3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N Engl J Med 2019;380:23-32.
9. Clin.gov- REDUCE-IT Included “EPA” in their initial title (subsequently changed) under “Study Design” section. Accessed Sept 2020. https://clinicaltrials.gov/ct2/show/NCT01492361
10. Misleading Amarin Corporation omega-3 literature.
11. Amarin Corp. and Mochida Pharm. announce collaboration. Accessed Sept. 2020 https://investor.amarincorp.com/news-releases/news-release-details/amarin-and-mochida-announce-collaboration-future-development-epa
12. Brinton E, Mason R. Prescription omega-3 fatty acid products containing highly purified eicosapentaenoic acid (EPA).Lipids Health Dis. 2017; 16:23. doi: 10.1186/s12944-017-0415-8.
