BioWorld Insight Contributing Writer

Over the past few weeks, a flurry of activity with omega-3 drugs has pushed these triglyceride-lowering compounds to center stage.

First, GlaxoSmithKline plc's Lovaza (omega-3-acid ethyl esters), the only FDA-approved omega-3 drug, failed a Phase III trial aimed at expanding its label into atrial fibrillation. The setback didn't stop Omthera Pharmaceuticals Inc. from filing a special protocol assessment for a Phase III trial with its omega-3 drug, Epanova, nor did it dampen the enthusiasm of Neptune Technologies & Bioresources Inc., which revealed positive results of a preclinical head-to-head study comparing its omega-3 drug, CaPre, with Lovaza.

But the biggest splash came from Phase III data showing Amarin Corp. plc's omega-3 drug AMR101 (ethyl icosapentate) lowered triglycerides (TG) without raising low-density lipoprotein (LDL) cholesterol levels in patients with high and very high TG levels. (See BioWorld Today, Nov. 30, 2010.)

With AMR101's new high profile comes higher stakes for the fledgling omega-3 prescription drug sector. Unlike statins, which have saturated the market and currently offer only single-digit yearly sales growth, omega-3 drugs are the fastest growing type of lipid-lowering compounds, with 20 percent to 25 percent annual growth.

One often-raised concern about the sector, however, is that omega-3-containing nutritional supplements are widely available and could dampen interest in more expensive prescription versions. Yet unlike FDA-regulated drugs, supplements and nutraceuticals do not undergo rigorous clinical testing, and often contain less EPA and DHA than stated on their labels.

Declan Doogan, chief medical officer of Amarin, previously explained in BioWorld Insight that fish oil nutritional supplements are "fine as a general tonic," but once a patient has been diagnosed with a medical condition, like elevated triglycerides, both doctor and patient tend to want a drug. "For high cholesterol, does your doctor tell you to go buy garlic oil? No, he tells you to change your diet and exercise, and if that doesn't work, he gives you statins," Doogan said. (See BioWorld Insight, Aug. 23, 2010.)

A Large Enough Market for TGs?

GSK's Lovaza, with $750 million in U.S. revenues last year and 83 percent coverage through managed care formularies, has proven consumers will pay for prescription-grade omega-3 drugs. But it is not clear, as the omega-3 sector matures and becomes increasingly crowded, whether or not all the players will find a niche.

The market for high TG drugs is about $500 million, and for mixed dyslipidemia it is about $1.5 billion, according to Canaccord Adams analyst Ritu Baral. "So to hit true blockbuster sales, AMR101 would need to have a mixed dyslipidemia indication as well [as TG]," she said.

And if Lovaza cannot expand beyond TG, will it be able to maintain its existing success? According to Baral, the answer is an emphatic, "no." But Leerink Swann's Joseph Schwartz disagrees, noting that if Lovaza can succeed in both the very high and high TG indications, it will be able to maintain its place in the omega-3 pantheon.

"A mix of positive data, major marketing efforts, and good reimbursement could enable Lovaza to keep its spot, because after all, it is not a specialty market," said Schwartz.

The AMR101 data, Lovaza's failure in atrial fibrillation, and earlier trials with seeming contradictions leave many unanswered questions about exactly how omega-3s work, and don't work, both analysts agreed.

"There are a still a lot of unknowns in omega-3 science," Baral said.

For example: Are both EPA and DHA necessary to reduce TGs, and if so, in what ratio? What type of formulation of the omega-3s is most effective?

Amarin's data seem to indicate that EPA could be the active ingredient in omega-3s for cardiovascular indications, as AMR101 contains more than 96 percent EPA in a semi-synthetic form of ethyl ester. But earlier studies have pointed to DHA as the active cardiovascular component of omega-3s. Both Lovaza and Omthera's Epanova have much higher percentages of DHA.

Epanova is a mixture of the free fatty acid forms of eicosapanetaenoic acid (EPA) and docosahexanoic acid (DHA), which Omthera CEO Jerry Wisler maintains is more absorbable than the ethyl ester.

"Our drug has an edge over AMR 101 and Lovaza, which both must be taken with a high-fat meal for absorption, a problem for individuals with high triglycerides," Wisler said.

To add a wildcard to the mix, Neptune's drug is a long-chain omega-3 phospholipid that is produced not from fish oil, but Arctic krill, the food fish eat to produce omega-3s. The company claims that its phospholipids "functionalize" the EPAs and DHAs. It is conceivable that krill may turn out to be a superior source of omega-3s for these drugs, said Schwartz.

In addition to its preclinical comparison of CaPre and Lovaza, Neptune appears to be aiming its drug at a fairly broad cardiovascular indication and is also developing related compounds for over-the-counter use. A study published in the Alternative Medicine Review in 2004 indicated the drug lowered LDL, TGs, glucose and total cholesterol while raising HDL.