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Whether the REDUCE-IT data are enough to give icosapent ethyl (Vascepa) an expanded indication will be on the table during a meeting Thursday of the FDA Endocrinologic and Metabolic Drugs Advisory Committee.

A supplemental New Drug Application proposes a new indication for icosapent ethyl: cardiovascular disease (CVD) risk reduction as an adjunct to statin therapy in adults with elevated triglyceride levels (≥135 mg/dL) and other risk factors. This indication would be a first for any lipid-lowering drug.

First approved by the FDA in 2012 as an adjunct therapy to reduce triglycerides in adults with severe hypertriglyceridemia (≥500 mg/dL), icosapent ethyl is a proprietary fish oil containing purified eicosapentaenoic acid (EPA) from Amarin of Dublin.

The discussion about the efficacy and safety of the compound will rest mainly on REDUCE-IT, the double-blind trial of more than 8,000 patients in which major adverse CV events over 4.9 years were reduced with fish oil over a mineral oil placebo (17.2% vs 22.0%, HR 0.75, 95% CI 0.68-0.83).

The REDUCE-IT cohort had been split between two groups: primary prevention (ages ≥50 with type 2 diabetes mellitus, and at least one additional risk factor for CVD) and secondary prevention (ages ≥45 with established CVD). Both appeared to benefit from the fish oil product.

The icosapent ethyl arm had a significantly reduced risk of each individual component of the primary endpoint, the composite of CV death, non-fatal MI, non-fatal stroke, coronary revascularization, and unstable angina. Secondary endpoints also favored the experimental treatment (with the exception of all-cause mortality).

Yet the initial excitement over these positive findings was tempered when it was discovered that the placebo arm showed unexpected increases in lipid and inflammatory biomarkers from baseline. One hypothesis is that there is a significant drug interaction between statins and the mineral oil placebo resulting in reduced absorption of the former.

"FDA analyses attempting to differentiate whether increases in LDL-C and other biomarkers were due to the mineral oil placebo are inconclusive. Due to lack of certain key measurements, we could neither rule out the possibility that mineral oil -- at least to some extent -- interfered with statin absorption nor estimate the magnitude of LDL-C or other biomarker increase that could be attributed to such an interaction," according to the for the meeting.

"From the scientific perspective, therefore, it remains necessary to consider what impact the increase in LDL-C and other biomarkers had on CV outcomes," agency investigators continued. "FDA's exploratory analyses to assess the effect of these markers suggested that the difference in LDL-C between the study groups could not account for the positive CV outcomes."

Also to be weighed against the efficacy of Amarin's fish oil are its safety signals: icosapent ethyl recipients in REDUCE-IT were more likely to get hospitalized for atrial fibrillation or flutter (3.1% vs 2.1%, P=0.004) and trended toward more serious bleeding treatment-emergent adverse events (2.7% vs 2.1%, P=0.06).

In 2013, a previous group of FDA advisors voted against an expanded indication for the EPA-only fish oil. They concluded that the ANCHOR trial was not enough for the expanded indication, and that they wanted to see the results of REDUCE-IT, which was ongoing at the time.

Amarin nevertheless started off-label promotion of icosapent ethyl, even suing the FDA to do so.

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