Omega-3 acid ethyl esters are prescription drugs that contain eicosapentaenoic acid-ethyl ester and docosahexaenoic acid-ethyl ester that are used in combination with changes in diet to lower triglyceride levels in adults with severe (≥ 500 mg/dL) hypertriglyceridemia, and outside the US, in combination with other drugs to prevent heart attacks. This was the first class of fish oil-based drug to be approved for use as a drug. The first approvals came in Europe in 2001 and the first approval in the US came in 2004. These fish oil drugs are similar to fish oil dietary supplements but the ingredients are better controlled and have been tested in clinical trials.
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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.
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).
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.
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.
Dietary supplements
There are many fish oil dietary supplements on the market. There appears to be little difference in effect between dietary supplement and prescription forms of omega-3 fatty acids but EPA and DHA ethyl esters (prescription forms) work less well when taken on an empty stomach or with a low-fat meal. The ingredients of dietary supplements are not as carefully controlled as prescription products and have not been fixed and tested in clinical trials, as prescription drugs have, and the prescription forms are more concentrated, requiring fewer capsules to be taken and increasing the likelihood of compliance.
Side effects
Special caution should be taken with people who have with fish and shellfish allergies. 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.
Side effects include stomach ache, burping, and a bad taste; some people on very high doses (8g/day) in clinical trials had atrial fibrillation.
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.
Pharmacology
After ingestion, omega-3 acid ethyl esters are metabolized mostly in the liver like other dietary fatty acids.
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. They may interfere with lipid production due to being poor substrates for the enzymes that create triglycerides.
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, and contain 840 mg eicosapentaenoic acid ethyl ester (460mg) and docosahexaenoic acid ethyl ester (380mg).
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. Pronova developed the concentrated omega-3 acid ethyl esters formulation that is the active pharmaceutical ingredient of Lovaza.
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; it partnered with other companies like Pierre Fabre in France. In 2004 Pronova licensed the US and Puerto Rican rights to Reliant Therapeutics, the business model of which was in-licensing cardiovascular drugs. In that same year, Reliant and Pronova won FDA approval for the drug and it was launched in the US and Europe in 2005; global sales in 2005 were $144M and by 2008 they were $778M. In 2007 GlaxoSmithKline acquired Reliant for $1.65 billion in cash.
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. 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. Generic versions of Lovaza were introduced in America in April 2014.
Pronovo has continued to manufacture the ingredients in Lovaza, and in 2012 BASF announced it would acquire Pronova for $844 million, and the deal closed in 2013.