The FDA released briefing documents ahead of Wednesday’s Endocrinologic and Metabolic Drugs Advisory Committee meeting to consider approval of Amarin Corp.’s Vascepa as an add-on to statin therapy for patients with mixed dyslipidemia. The key question before the panel is whether to recommend approval now, or wait for results of the REDUCE-IT cardiovascular outcomes trial, which are due in Nov. 2016.

The primary endpoint of REDUCE-IT is time to first occurrence of a cardiovascular event for patients on statin therapy with high triglycerides receiving 4 g/day Vascepa. Amarin’s application is based on clinical data showing favorable changes in lipid profile with use of the drug, and the FDA has historically issued approval based on that.

However, recent large cardiovascular outcome trials for use of omega-3 fatty acids have failed to show a reduction in residual cardiovascular risk, in spite of improvement in HDL-C and triglyceride, raising the possibility that the panel will recommend waiting for the results of REDUCE-IT rather than immediate approval.

Jefferies analyst Tom Tarrant expects a positive panel vote in spite of the controversy around CV outcomes. “We see favorable arguments for approval centered around the fact that JELIS tests the most comparable formulation to Vascepa, subgroup analyses from failed trials still suggest benefit in high triglyceride subgroups, the strong safety profile of Vascepa and perceived safety of the fish oil class, and the favorable bias in the historical votes of the endocrine panel on similar cardiovascular outcomes debates for diabetes, obesity, and fibrates.”

Vascepa, previously AMR101, is a purified ethyl ester of eicosapentaenoic acid derived from fish oil. It was approved in July 2012 for reduction of triglycerides in adults with severe hypertriglyceridemia (more than 500 mg/dL) at a dose of 4 g per day. The product is indicated for use as an adjunct to diet. Amarin, which is based in Dublin, has now submitted a supplemental application to the FDA seeking to expand the treatment population to include patients with mixed dyslipidemia who are at high risk for heart disease and who are already receiving statin therapy.

The open-label Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico Prevenzione (GISSI-P) trial was one of the first randomized trials evaluating the effects of omega-3 fatty acids on cardiovascular outcomes. That trial enrolled more than 11 ,000 patients with a recent history of myocardial infarction to receive 1 g per day of ecosapentaenoic acid (EPA)/docosahexaenoic acid (DHA), vitamin E, or no treatment. Five percent of the participants were on statin therapy. After 3.5 years, there was a 20 percent reduction in fatal cardiovascular outcomes, but without effects on non-fatal events or lipids. A slight, statistically significant decrease in triglycerides was observed.

The 2007 JELIS trial, run on more than 18,000 Japanese men and post-menopausal women on low-dose statins, suggested that 1.8 g per day of EPA reduced adverse cardiovascular outcomes.

However, multiple other cardiovascular outcomes trials since 2007 in patients receiving omega-3 fatty acids have been published showing negligible effects on cardiovascular events. The FDA’s documents noted that GISSI-P and JELIS were open-label studies, which may have introduced bias, confounding treatment effect. Another possible difference is that only a small percentage of patients in GISSI-P and JELIS were receiving statin therapy, but that more recent trials, such as ORIGIN and the Risk and Prevention trial, include 40 to 50 percent of patients who are receiving low-dose statin therapy. Baseline consumption of dietary omega-2 fatty acid may also affect the outcome of trials designed to show a treatment effect of supplementary omega-3.

The ORIGIN trial enrolled more than 12,000 adults to receive 1 g per day of omega-3 fatty acids or olive oil placebo. After a median follow up of 6.2 years, that trial showed a mean reduction in triglycerides, but no statistically significant differences in other lipid parameters, and no statistically significant effect on cardiovascular outcomes.

The Italian Risk and Prevention study, published in May 2013, also did not show a reduction in risk of cardiovascular death or hospitalization for 1 g of omega-3 fatty acid compared with olive oil placebo in more than 12,000 adults with multiple cardiovascular risk factors after five years follow-up.

A systematic review and meta-analysis published in 2012 in JAMA of 10 trials including GISSI-P, JELIS and ORIGIN, showed no statistically significant reduction in all-cause mortality, cardiac deaths, sudden deaths, myocardial infarction and stroke. Amarin’s ANCHOR trial showed that Vascepa 2 g or 4 g was effective in reducing triglycerides compared to a mineral oil placebo in adults at high risk for cardiovascular disease who had high fasting triglycerides in spite of statin therapy.

In addition, ANCHOR showed improvement in LDL-C, non-HDL-C, VLDL-C, Lp-PLA2, Apo B and TC compared to placebo. However, Vascepa gave negative efficacy compared to placebo for HDL-C and Apo A-I.

The FDA’s reviewer noted that the placebo group experienced marked increases from baseline in lipid and lipoprotein values, resulting in larger treatment effects for Vascepa, “This reviewer could not find any statistical reasoning to explain this perplexing phenomenon of placebo. Information was not provided on the compliance of the background statin therapy during the double-blind treatment period. It is also not known whether mineral oil interferes with the absorption of statins.”

The FDA’s conclusion was that the beneficial treatment effects of Vascepa relative to placebo may be over-estimated. The advisory panel must now decide whether to recommend approval of Vascepa based on its benefit for blood lipid profile, with no real clarity about what the outcome of the REDUCE-IT trial will show two years hence.