BioWorld Today Contributing Writer

Omthera Pharmaceuticals Inc. enrolled its first patient in a new Phase III trial designed to expand the label of its investigational therapy for high triglycerides, Epanova. Epanova is a purified mixture of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that Omthera previously tested in two large, Phase III trials in Crohn's disease patients.

In spite of the availability and widespread use of statin drugs, there remains a need for additional therapies to address unbalanced blood lipids.

"Statins have been a very valuable treatment regiment for patients with cardiovascular (CV) disease or at high risk for CV disease. However, they have only shown to reduce CV risk by 30 percent to 45 percent. Therefore, there is an unmet medical need for add-on therapy that would further reduce CV events on top of statin therapy," Michael Davidson, chief medical officer of Omthera, told BioWorld Today.

The six-week, randomized, double-blind, placebo-controlled trial will evaluate safety and efficacy of Epanova in combination with statin therapy for patients with hypertriglyceridemia who do not respond adequately to statin therapy alone, and is being carried out under a special protocol assessment (SPA) with the FDA. The move comes less than a week after competitor Amarin reached a SPA agreement of its own with the FDA to run a cardiovascular outcomes study on its fish oil product, AMR101. (See BioWorld Today, Nov. 23, 2010, and Aug. 11, 2011.)

The ESPRIT trial will enroll 642 patients with hypertriglyceridemia to receive 2 gm or 4 gm daily of Epanova in addition to statin therapy with the objective of observing a decrease in non-HDL cholesterol. As secondary objectives, the trial will assess the safety of Epanova/statin combinations and the effects of the therapy on other lipids and lipoproteins.

Earlier this year, Omthera reported results from its Phase I/II ECLIPSE trial of Epanova compared to Lovaza (omega-3-acid ethyl ester, GlaxoSmithKline plc) for very high triglycerides (500 mg/dL or higher). The data showed that Epanova had superior bioavailability to Lovaza, with plasma levels of EPA plus DHA four times higher in subjects on a low-fat diet who received Epanova vs. Lovaza.

Omthera and Amarin are matching each other move for move in clinical development plans. As with Amarin's AMR101, Omthera has built a case for Epanova on studies of patients with very high triglycerides that do not respond to statin therapy, and is laying a foundation for future label expansion.

Some observers, however, are less than thrilled with Amarin's plans. Moness, Crespi, Hardt analyst Avik Roy pointed out, "Outcomes studies are big jobs for small companies," adding that "It's unusual for a company of Amarin's size to conduct a large, expensive outcomes study without a partner. While we believe the study is very likely to read out positively, the lack of a partnership at this stage strongly suggests that potential partners are uncomfortable with the company's patents."

Those results would come for Amarin just two years before its patent exclusivity on the product runs out.

Additionally, Pronova BioPharma ASA is reporting flattening demand for Lovaza. Its revenue growth was down 14 percent year-on-year in the second quarter of 2011 due to partner GSK's destocking of the drug in the U.S. There was also flat-to-declining sequential growth in Lovaza prescriptions in Pronova's second quarter report, raising questions about the true market size and demand for the fish oil class of lipid-lowering drugs.

Fish oil drugs like Epanova and AMR101 all contain EPA, which is naturally abundant in fish oil. The presence of DHA, however, is the subject of some controversy.

According to Amarin, DHA is associated with undesirable increases in LDL cholesterol in the blood, and its product, AMR101, will have an edge in the marketplace because it does not contain DHA and so far in clinical trials has not shown any increases in LDL cholesterol as a side effect.

Omthera, however, said that both EPA and DHA lower triglycerides, with DHA as the more efficacious component.

"DHA is more potent than EPA in lowering triglycerides and raising HDL-C. Also DHA appears to be more readily taken up by the brain and retinal tissues to provide potential benefits for neuronal function. DHA is given to women during pregnancy to potentially improve fetal brain development. In my opinion there are no negatives to DHA since pure DHA appears to only increase the size of LDL not the LDL particle number."

Omthera believes that Epanova will provide greater EPA blood levels than AMR101 in patients on a low fat diet and that DHA will enhance Epanova's efficacy to lower triglycerides and raise HDL-C.

Epanova may have a dosing advantage as well. AMR101 is dosed at two capsules twice a day with meals, while Epanova is dosed at two to four capsules per day regardless of meals.