Omega-3 acid ethyl esters

Omega-3 acid ethyl esters are the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), i.e., the ester part, attached at one end to an ethanol molecule - the ethyl part. These FDA-approved prescription products are used in combination with changes in diet to lower blood triglyceride levels in adults with severe (≥ 500 mg/dL) hypertriglyceridemia. This was the first fish oil-derived product to be approved for use as a drug. The first approvals came in Europe in 2001. The first approval in the US came in 2004. These prescription products have been tested in clinical trials. In the US, omega-3 ethyl esters are also manufactured and sold as dietary supplements.

Medical use

Omega-3 acid ethyl esters are used in addition to changes in diet to reduce triglyceride levels in adults with severe (≥ 500 mg/dL) hypertriglyceridemia.[1] In the European markets and other major markets outside the US, omega-3 acid ethyl esters are indicated for hypertriglyceridemia as a monotherapy, or in combination with a statin for patients with mixed dyslipidemia and as secondary prevention after heart attack in addition to other standard therapy (e.g. statins, anticoagulants, beta-blockers, and ACE-I).[2]

Intake of large doses (2.0 to 4.0 g/day) of long-chain omega-3 fatty acids as prescription drugs or dietary supplements are generally required to achieve significant (> 15%) lowering of triglycerides, and at those doses the effects can be significant (from 20% to 35% and even up to 45% in individuals with levels greater that 500 mg/dL). It appears that both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) lower triglycerides, but DHA appears to raise LDL-C ("bad cholesterol") more than EPA, while DHA raises HDL-C ("good cholesterol") while EPA does not.[3]

Other fish-oil based drugs

There are other omega-3 fish oil based prescription drugs on the market that have similar uses and mechanisms of action.[4]

Dietary supplements

There are many fish oil dietary supplements on the market.[7] There appears to be little difference in effect between dietary supplement and prescription forms of omega-3 fatty acids as to ability to lower triglycerides, but the ethyl ester products work less well when taken on an empty stomach or with a low-fat meal.[3] The ingredients of dietary supplements are not as carefully controlled as prescription products and have not been tested in clinical trials as such drugs have.[8] Prescription omega-3 products are more concentrated, requiring fewer softgels for the same daily dose.[7]

Side effects

Special caution should be taken with people who have with fish and shellfish allergies.[1] In addition, as with other omega-3 fatty acids, taking omega-3 acid ethyl esters puts people who are on anticoagulants at risk for prolonged bleeding time.[1][3]

Side effects include stomach ache, burping, and a bad taste; some people on very high doses (8g/day) in clinical trials had atrial fibrillation.[1]

Omega-3 acid ethyl esters have not been tested in pregnant women and are rated pregnancy category C; it is excreted in breast milk and the effects on infants are not known.[1]

Pharmacology

After ingestion, omega-3 acid ethyl esters are metabolized mostly in the liver like other dietary fatty acids.[2]

Mechanism of action

Omega-3 acid ethyl esters, like other omega-3 fatty acid based drugs, appears to reduce production of triglycerides in the liver, and to enhance clearance of triglycerides from circulating very low-density lipoprotein (VLDL) particles; the way it does that is not clear, but potential mechanisms include increased breakdown of fatty acids; inhibition of diglyceride acyltransferase which is involved in biosynthesis of triglycerides in the liver; and increased activity of lipoprotein lipase in blood.[4] They may interfere with lipid production due to being poor substrates for the enzymes that create triglycerides.[2]

Physical and chemical properties

The active ingredient is concentrated omega-3-acid ethyl esters that are made from fish body oils that are purified and esterified,[9] For the Lovaza product, each 1000 mg softgel capsule contains 840 mg omega-3 fatty acids: eicosapentaenoic acid ethyl ester (460 mg) and docosahexaenoic acid ethyl ester (380 mg).[2]

History

Pronova BioPharma ASA had its roots in Norway's codfish liver oil industry; it was founded in 1991 as a spinout from the JC Martens company, which in turn was founded in 1838 in Bergen, Norway.[10] Pronova developed the concentrated omega-3 acid ethyl esters formulation that is the active pharmaceutical ingredient of Lovaza.[9]

It won approvals to market the drug, called Omacor in Europe (and initially in the US) in several European countries in 2001 after conducting a three and a half year trial in 11,000 subjects;[11] it partnered with other companies like Pierre Fabre in France.[12] In 2004 Pronova licensed the US and Puerto Rican rights to Reliant Therapeutics, the business model of which was in-licensing cardiovascular drugs.[13] In that same year, Reliant and Pronova won FDA approval for the drug[14] and it was launched in the US and Europe in 2005; global sales in 2005 were $144M and by 2008 they were $778M.[15] In 2007 GlaxoSmithKline acquired Reliant for $1.65 billion in cash.[16]

In 2009 generic companies Teva Pharmaceuticals and Par Pharmaceutical made clear their intentions to file Abbreviated New Drug Applications to bring generics to market, and in April 2009 Pronova sued them from infringing the key US patents covering Lovaza, US 5,656,667 (due to expire in April 2017) US 5,502,077 (exp March 2013) and in May 2012 a district court ruled in Pronova's favor, saying that the patents were valid.[17][18][19] The generic companies appealed and in September 2013 the Federal Circuit reversed, saying that because more than one year before Pronova's predecessor company applied for a patent, it had sent samples of the fish oil used in Lovaza to a researcher for testing, and this constituted "public use" that made the patent invalid.[20][21] Generic versions of Lovaza were introduced in America in April 2014.[22]

Pronovo has continued to manufacture the ingredients in Lovaza, and in 2012 BASF announced it would acquire Pronova for $844 million,[23] and the deal closed in 2013.[24]

Brand names

References

  1. 1 2 3 4 5 Lovaza Label Revised: March 2016. Updated labels available at FDA website here
  2. 1 2 3 4 UK electronic Medicines Compendium (eMC) Omacor. Last Updated on eMC 20-Apr-2015
  3. 1 2 3 Jacobson TA, et al, NLA Expert Panel. National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2. J Clin Lipidol. 2015 Nov-Dec;9(6 Suppl):S1-S122.e1. PMID 26699442 Free full text
  4. 1 2 Weintraub, HS (2014). "Overview of prescription omega-3 fatty acid products for hypertriglyceridemia". Postgrad Med. 126: 7–18. PMID 25387209. doi:10.3810/pgm.2014.11.2828. Retrieved 20 April 2015.
  5. ↑ CenterWatch Vascepa (icosapent ethyl) Page accessed March 31, 2016
  6. ↑ "Epanova (omega-3-carboxylic acids)". CenterWatch. Retrieved 15 December 2014.
  7. 1 2 Ito MK. A Comparative Overview of Prescription Omega-3 Fatty Acid Products. P T. 2015 Dec;40(12):826-57. PMID 26681905 Free PMC Article PMC 4671468
  8. ↑ Sweeney MET. Hypertriglyceridemia Pharmacologic Therapy for Medscape Drugs & Diseases, Ed. Khardori R. Updated: Apr 14, 2015, page accessed April 1, 2016
  9. 1 2 Adis Insight Omega-3 ethylester concentrate Page accessed March 31, 2016
  10. ↑ Epax History Page accessed March 31, 2016
  11. ↑ Pharma Times. March 22, 2001. Pronova wins Omacor approval
  12. ↑ Staff, ICIS Chemical Business. 26 March 2001 Omacor approved
  13. ↑ Amanda Ernst for Law360 November 27, 2007 German Court Invalidates Omega-3 Drug Patent
  14. ↑ VHA Pharmacy Benefits Management Strategic Healthcare Group and the Medical Advisory Panel. October 2005 National PBM Drug Monograph Omega-3-acid ethyl esters (Lovaza, formerly Omacor)
  15. ↑ Staff, Pharmaceutical Technology. Pronova Biopharma Pharmaceutical Production Facility, Denmark. Page accessed March 31, 2016
  16. ↑ Staff, Genetic Engineering News. Nov 21, 2007. GSK to Acquire Reliant Pharmaceuticals for $1.65B
  17. ↑ U.S. Patent 5,656,667
  18. ↑ U.S. Patent 5,502,077
  19. ↑ Pronova BioPharma May 29, 2012 Press Release: US District Court rules in Pronova BioPharma's favour on Lovaza(TM) patents
  20. ↑ Ryan Davis for Law360 September 12, 2013 Fed. Circ. Nixes Pronova's Patent Win Against Teva, Par
  21. ↑ United States Court of Appeals for the Federal Circuit. Pronova Biopharma Norge AS vs Teva Pharmaceuticals, Inc and Par Pharmaceutical. 2012-1498, -1499. Decided September 12, 2013 Federal Circuit Decision
  22. ↑ Tracy Staton for FiercePharmaMarketing April 9, 2014 Teva puts GSK and Amarin on notice with generic Lovaza launch
  23. ↑ Ryan McBride for FierceBiotech. November 21, 2012 BASF to snap up fish oil drugmaker Pronova BioPharma in $844M buyout
  24. ↑ Eric Palmer for FierceManufacturing. January 22, 2013 BASF lands Pronova making it a top omega-3 maker
  25. ↑ University of Utah Pharmacy Services (August 15, 2007) "Omega-3-acid Ethyl Esters Brand Name Changed from Omacor to Lovaza"
  26. ↑ Omtryg Label Revised April 2014
  27. ↑ FDA Omega-3 acid ethyl esters products Page accessed March 31, 2016
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