No Expanded Vascepa Indication for High TG, Say FDA Advisors

October 16, 2013

GAITHERSBURG, MD— A Food and Drug Administration (FDA) advisory panel voted overwhelmingly against recommending approval of an expanded indication for a highly purified ethyl ester of eicosapentaenoic acid (EPA), a derivative of omega-3 fatty acids, for use in combination with a statin in the treatment of patients with mixed dyslipidemia and coronary heart disease or a coronary heart disease risk equivalent.

Specifically, the members of the Endocrinologic and Metabolic Drugs advisory committee, which was chaired by Dr Robert Smith (Brown University, Providence, RI), did not feel the reduction in lipid and lipoprotein parameters observed in the ANCHOR trial with Vascepa (Amarin, Dublin, Ireland) were sufficient to recommend to support the expanded indication, given the uncertainty about the drug's effects on hard clinical outcomes. While the panel was fairly certain Vascepa reduced triglycerides, they also felt there was insufficient evidence that reducing triglycerides lowers the risk of clinical events.

In the ANCHOR trial, treatment with Vascepa 4 g/day reduced triglyceride levels 17.5 mg/dL. Compared with placebo, the median percent change in fasting triglycerides was a 21.5% reduction favoring Vascepa. Treatment with the drug also reduced levels of non-HDL cholesterol, vLDL cholesterol, apolipoprotein B, total cholesterol, HDL cholesterol, and apolipoprotein A-1.

Despite the reductions, nine panel members said the efficacy and safety data with Vascepa from ANCHOR was insufficient to recommend approval, while just two panel members voted in favor of approval.

Dr David Cooke (Johns Hopkins University School of Medicine, Baltimore, MD), who voted against approval, said he had a high degree of confidence Vascepa lowers triglyceride levels but was less certain of the drug's effects on some of the other lipid parameters.

"I did vote no over the concern of using a surrogate end point for what really is a health benefit—that is, a decrease in cardiovascular risk," said Cooke. "I don't think this has been proven for this medication, and as has been pointed out, it hasn't yet been proven for other medications aimed at improving lipid profiles other than LDL cholesterol with statins. I feel at this point it is important to look at those hard end points and see data to support those hard end points before extending approval."

Throughout the day, many panel members had one eye on the future and one eye on the past. Regarding the past, the FDA and some panel members noted that the clinical landscape has changed somewhat since drugs were approved based on surrogate end points. The FDA stated in its presentation that no trial to date has shown that any therapy added to statins, whether it was a fibrate in ACCORD or niacin in AIM-HIGH and HPS2-THRIVE , reduced major cardiovascular outcomes.

For those more future-inclined, the REDUCE-IT study, which is sponsored by Amarin, will address the question of clinical benefit with Vascepa. The trial is enrolling more than 8000 patients, and investigators are randomizing patients with mixed dyslipidemia and at high risk for cardiovascular disease to Vascepa 4 g/day. The primary end point is an extended major adverse cardiovascular event (MACE) end point, one that includes hospitalization for angina and coronary revascularization.

Most panelists felt more comfortable waiting for those results rather than be confronted with a drug that lowers triglycerides but has no effect on hard outcomes. As was noted throughout the day, the only reason to prescribe this type of drug is to improve the patient's cardiovascular risk profile. The results from REDUCE-IT won't be available for at least three or four years.

Vascepa is already approved for the reduction of triglyceride levels in adult patients with severe hypertriglyceridemia (>500 mg/dL). Amarin submitted the supplemental new drug application to the FDA in February 2013 requesting approval of Vascepa for the reduction of triglycerides in at-risk adult patients with mixed dyslipidemia and triglyceride levels ranging from 200 to 499 mg/dL.


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