Misleading Information in Amarin Corporation supported literature regarding omega-3 nomenclature
Eric Roehm, MD, Oct. 2020
1. Why the principal investigator of REDUCE-IT1, the Vascepa trial, incorrectly told an interviewer that his trial tested a different molecule than the JELIS2 trial.
REDUCE-IT1 (Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia)
JELIS2 (Japan Eicosapentaenoic Acid Lipid Intervention Study)
In the February 2019 American College of Cardiology Extension Learning (ACCEL) Audio Digest program, the primary investigator of the REDUCE-IT trial, Deepak Bhatt, MD, MPH, FACC was interviewed by Nanette Wenger, MD, MACC.3
When Dr. Bhatt compared JELIS (Epadel) with REDUCE-IT (Vascepa), he made the following comments:
“An older, randomized open label trial called JELIS used 1.8 grams of an EPA construct…”
“And therefore, we studied (in REDUCE-IT) a different molecule, at a higher dose,
4 grams of icosapent ethyl.”3 This is incorrect, both JELIS and REDUCE-IT studied the same molecule, EPA ethyl ester, also called icosapent ethyl4. Both Epadel (JELIS2) and Vascepa (REDUCE-IT1) consist of capsules containing ≥96% EPA ethyl ester4.
How did a respected, talented, academic physician of high integrity like Dr.Bhatt (who has no personal funding from Amarin Corp.) come to this viewpoint? It is not difficult to understand given the following plethora of misleading and incorrect information that has been put out in Amarin Corporation associated literature.
2. Amarin Corporation inaccurately suggests a uniqueness that does not exist for a generic term that is applicable to Vascepa.
Vascepa was initially called AMR1014. In the early trials, Vascepa (AMR101) was acknowledged to be eicosapentaenoic acid ethyl ester (EPA ethyl ester)5,6.
However, in 2013, in an article by three Amarin employees and two non-employee physicians, a different description is then used: “Icosapent ethyl is a high-purity prescription form of eicosapentaenoic acid ethyl ester…”.7 This is inaccurate and incorrect terminology.
Icosapent ethyl is a synonym for the identical chemical structure called eicosapentaenoic acid ethyl ester.4 The phrase “icosapent ethyl is a high purity form of EPA ethyl ester” makes no more sense, and is no more valid, than the phrase “EPA ethyl ester is a high purity form of icosapent ethyl”. A generic name does not have purity in and of itself. When has the nomenclature of stating that a generic name is of high purity (rather than the brand name product is of high purity) ever been used for any another generic chemical name?
The erroneous wording also creates a false ambiguity. (i.e. Is there more than one form of EPA ethyl ester? -There is not.) This confusing and inaccurate terminology is then carried forward into the scientific articles written with the assistance of Amarin Corporation employees.
3. Different schematic diagrams for the identical chemical structures are shown that falsely make icosapent ethyl appear unique in an Amarin assisted article.
In 2015, in the journal Pharmacy & Therapeutics, an article written by a pharmacist with two Amarin employees providing medical review and scientific references and with a third individual paid by Amarin providing writing assistance, information is presented in a very misleading fashion.8 The schematic diagrams for the chemical structures of icosapent ethyl (Vascepa) and EPA ethyl ester (a component of Lovaza) are drawn differently in Figure 1 of the article. This is very misleading. EPA ethyl ester and icosapent ethyl are in fact synonyms for the identical chemical structure4 with the same spatial arrangement of atoms. EPA ethyl ester is drawn in the schematic in a linear fashion and icosapent ethyl is drawn showing more spatial detail,8 giving the reader the incorrect impression that these are different substances.
Furthermore, in Table 1 of the article, the three other omega-3 prescription products are described as being derived from fish oil.8 Only Vascepa does not say it is derived from fish oil. This is another false difference. The omega-3 agent in Vascepa is also derived from fish oil.4
4. Different generic names are given to Epadel (JELIS) and Vascepa (REDUCE-IT) and different molecular weights are listed in an Amarin assisted article incorrectly suggesting the predominant omega-3 agent is not the same.
In 2017, in the journal Lipids in Health and Disease, there is an article written by 2 authors with the assistance of Amarin Corporation.9 (One of the 2 authors is also a REDUCE-IT trial author.) The article is titled “Prescription omega-3 fatty acid products containing highly purified eicosapentaenoic acid (EPA)”. There are only two such products, Vascepa (Amarin Corp.) used in REDUCE-IT and Epadel (Mochida Pharm.) used in JELIS. Both contain ≥96% icosapent ethyl (also known as EPA ethyl ester4). A reader of this Amarin assisted article would never learn that Epadel and Vascepa both contain ≥96% of the identical omega-3 agent.
Table 1 in the article lists Epadel as having the generic names “ethyl icosapentate” or “icosapent”, while Vascepa is listed as containing “icosapent ethyl”.9 Notice the same generic name is not used, even though any generic name of the predominant omega-3 agent applicable to Epadel is equally applicable to Vascepa.
Furthermore, the molecular weights are incorrectly listed as different: 330.50 vs. 330.51 9. The molecular weight of icosapent ethyl, icosapent, and EPA ethyl ester are the same because they are synonyms4 for the identical chemical structure.
The incorrect information in this table is referenced from the Vascepa and Epadel package inserts. Though that information may be from the product inserts, the authors of this review are misleading the readers by not indicating that Epadel and Vascepa have the same identical component for ≥96% of the product and the same generic names are applicable. (Also, the correct molecular weight for icosapent ethyl, also known as EPA ethyl ester, is 330.51 for either term.4,10 Not noting this and simply putting different molecular weights down for the identical chemical structure misleads the reader.)
5. The REDUCE-IT trial1 (NEJM 2019) authors incorrectly suggest that the REDUCE-IT and JELIS trials tested a different chemical structure. (Five of 12 authors of REDUCE-IT are Amarin employees with stock ownership and 3 of the other 12 authors are Amarin consultants1.)
Both REDUCE-IT and JELIS trials studied the identical chemical structure, EPA ethyl ester, also known as icosapent ethyl. Vascepa was used in REDUCE-IT at a dose of 4 grams3, and Epadel was used in JELIS at a dose of 1.8 grams1. Both Epadel and Vascepa contain ≥96% EPA ethyl ester2 (differing only in the other 4% of capsule contents4 and dose).
There is confusion about the omega-3 agent used in JELIS by the REDUCE-IT authors in the NEJM article. The JELIS study authors frequently referred to their study drug simply as eicosapentaenoic acid (EPA). However, in the JELIS Procedures section, the 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 ester2,10,11,12 as well as for the specific free fatty acid chemical structure eicosapentaenoic acid (EPA)13. The use of the term EPA to include eicosapentaenoic acid ethyl ester is well known to the REDUCE-IT authors. (The original name of REDUCE-IT, subsequently changed, included: “REDUCE-IT (Reduction of Cardiovascular Events With EPA – Intervention Trial)”.14
The REDUCE-IT authors in the NEJM 2019 article, when talking of the JELIS study drug, confusingly only use the terms “eicosapentaenoic acid or EPA”1. When referring to the REDUCE-IT study drug, the REDUCE-IT authors use the term “icosapent ethyl”1. The REDUCE-IT authors never clarify that the JELIS and REDUCE-IT trials use the identical omega-3 agent, EPA ethyl ester, also called icosapent ethyl.
In the REDUCE-IT article conclusions, there is the following misleading statement about the REDUCE-IT and JELIS omega-3 agents: “Both the formulation (a highly purified and stable EPA ethyl ester) and dose (total daily dose of 4 g) used in REDUCE-IT were different from those in previous outcome trials”. Contrary to what the NEJM REDUCE-IT article implies in these conclusions, both the treatment group in REDUCE-IT1 and in JELIS received a highly purified (≥96%) and stable EPA ethyl ester2,4 (also called icosapent ethyl). The chemical structure of this omega-3 agent in both trials was the same.
The NEJM article states that “Icosapent ethyl is a highly purified and stable EPA ethyl ester that …”1 This is inaccurate and incorrect terminology. Icosapent ethyl and eicosapentaenoic acid ethyl ester are generic names for the identical chemical structure. A generic name does not have purity in and of itself. Anything that can be said for icosapent ethyl can be said for EPA ethyl ester since they are synonyms for the identical chemical structure and can be used interchangeably.
REFERENCES:
1. 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.
2. 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.
3. Deepak L. Bhatt, MD (lead author of REDUCE-IT) interviewed by Nanette Wenger MD. The Primary Results of REDUCE-IT. ACCEL (American College of Cardiology Extended Learning) AudioDigest; Feb. 2019, Volume 51, Issue 02.
4. Vascepa FDA Application- Pharmacology Review 2011, Accessed May 2020.
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202057Orig1s000PharmR.pdf
5. Bays HE, Ballantyne CM, Kastelein, JJ, et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) (from the Multi-center, placebo-controlled, randomized, double-blind, 12-week study with an open-label extension [MARINE] trial). Am J Cardiol 2011;108:682–690.
6. Ballantyne CM, Bays HE, Kastelein JJ, et al. Efficacy and Safety of Eicosapentaenoic Acid Ethyl Ester (AMR101) Therapy in Statin-Treated Patients With Persistent High Triglycerides (from the ANCHOR Study). Am J Cardiol 2012;110:984–992.
7. Bays HE, Ballantyne CM, Braeckman RA, Stirtan WG, Soni PN. Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies. Am J Cardiovasc Drugs 2013; 13:37-46.
8. Ito MK. A Comparative Overview of Prescription Omega-3 Fatty Acid Products.
Pharmacy & Therapeutics 2015; 40:826-57.
9. 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.
10. Omacor prescribing information. Accessed May 2020.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/21654lbl.pdf
11. 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.
12. 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.
13. Rationale and design of the STRENGTH trial. Nicholls S, Lincoff AM, Bash D, et al. Clinical Cardiology 2018;41:1281-88
14. Clin.gov- REDUCE-IT Included in initial title under “Study Design”. Accessed Sept 2020. https://clinicaltrials.gov/ct2/show/NCT01492361
