Shares in Amarin Corp. plc fell 61 percent Thursday following Wednesday’s surprise vote by the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) recommending against approval of the firm’s marketed fish oil-derived lipid-lowering drug Vascepa in a supplemental indication.

In doing so, the committee made a radical break with the agency’s precedent of approvals in that category based on lipid value endpoints, asking instead for results of an ongoing cardiovascular outcomes trial. The decision also set the agency up to potentially make history by rejecting an application submitted under a special protocol assessment (SPA) for the first time ever.

Amarin’s stock (NASDAQ:AMRN) lost $3.16, to close at $2.01.

In an investor conference Wednesday evening, Amarin president John Thero called the panel’s vote “disappointing” and “frustrating,” and reminded participants that the FDA is not bound to follow the panel’s decision.

In the near term, the panel’s rejection of Amarin’s application hammered its stock value and set the company up for some tough financial decisions if the FDA follows the panel’s recommendation. However, the larger implications of the FDA’s loss of faith in lipid biomarkers as surrogate endpoints for cardiovascular outcomes could shake the entire industry.

Initial approvals of a broad range of drugs for cardiovascular disease, including statins, fibrates, niacin and others, have been based on biomarkers in the blood, with cardiovascular outcomes studies following. However, the FDA’s discussion and voting questions for the committee focused on the ultimate clinical benefit of the drug for patients with mixed dyslipidemia already being treated with statin drugs, signaling a new, tougher attitude toward those blood lipid biomarkers.

Amarin’s ANCHOR trial showed a 21.5 percent median reduction in fasting triglycerides, a 6.2 percent reduction in non-HDL-C, a whopping 24.4 percent reduction in VLDL-C and other statistically significant changes in blood lipids across the board for Vascepa compared to mineral oil placebo.

The Dublin-based company began its cardiovascular outcomes trial, REDUCE-IT, in December 2011 and estimated that final results will be available in 2017. That trial, in approximately 8,000 patients with elevated triglyceride levels and coronary disease or risk factors for coronary disease, will attempt to link the lipid-lowering benefits of the drug to real-world reductions in the risk of cardiovascular events.

Vascepa currently is approved as an adjunct to diet for reduction of triglyceride levels in adults with severe hypertriglyceridemia, and that approval was based on Amarin’s MARINE trial. Expansion of Vascepa’s label to the mixed dyslipidemia indication has been a crucial part of Amarin’s strategy for Vascepa, and ANCHOR and REDUCE-IT were carefully planned and carried out under an SPA in order to enable the company to market the drug in that broader indication.

If the FDA follows the panel’s recommendation when it issues a decision on the drug, due by Dec. 20, it will be the first time the agency has “reneged” on an SPA by not approving the drug when the conditions of the SPA had been met, said Joseph T. Kennedy, Amarin’s general counsel, in the investor conference. In that event, Kennedy said the company has “legal options.”

“We will be spending a lot of time down in Washington reviewing that, and the history of SPA,” he added.

Amarin executives said the company is reviewing all of its options for dealing with the setback, in case the FDA’s final decision goes against the company in December. Those options include potential staff reductions, and Thero also would not rule out terminating the ongoing REDUCE-IT trial. “We’re going to take a look from top to bottom,” Thero said. “No decision has been made as of today.”

But the damage could be severe. Jefferies analyst Thomas Wei estimated that without the mixed dyslipidemia indication, Amarin’s stock is worth only $1. He noted that since its launch for high triglycerides, sales growth for Vascepa has been linear, projecting 2014 sales of $96 to $115 million and peak sales of $200 million by 2016. “The delay in ANCHOR approval enhances the risk and impact of generic Lovaza in 1Q15 on both Vascepa share and price,” he wrote in a research note.

Amarin reported $272 million in cash, and executives declined to give guidance at this time as to how long that cash is expected to last. Wei estimated that REDUCE-IT will cost $100 million to $130 million to complete. The company also carries $150 million in convertible debt, much of the burden taken on when it decided to launch Vascepa alone after failing to find a partner. (See BioWorld Today, Dec. 10, 2012.)

Outcomes for All?

It’s uncertain as yet whether EMDAC’s tough stance on Vascepa will translate to a generally tougher attitude toward other products in the same space. Several panel members expressed concern that the FDA’s questions about cardiovascular outcomes set the bar too high. The pipeline in cardiovascular and diabetes indications is filled with drugs whose benefits are similarly based on surrogate endpoints, and the companies sponsoring those products may be on shaky ground if the EMDAC’s decision on Vascepa becomes a precedent.

For example, Isis Pharmaceuticals Inc.’s investor-pleasing antisense drug Isis-ApoCIIIRx produced reductions of up to 70 percent in apolipoprotein C-III and up to 64 percent in triglycerides in Phase II trials. The trial also showed increases of up to 52 percent in HDL-C and reductions of up to 77 percent in apoC-III-associated VLDL particles. Isis’ stock (NASDAQ:ISIS) slid 82 cents to close Thursday at $33.35.

Regeneron Pharmaceuticals Inc. is also counting on a surrogate marker, LDL-C, from its Odyssey Mono trial to show benefit of its cholesterol candidate alirocumab, which is partnered with Sanofi SA. That trial is designed to show a benefit for the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor in patients with hyperlipidemia. Top-line results from that trial showed that the mean LDL-C reduction from baseline to week 24 with alirocumab was significantly greater in patients randomized to alirocumab. (See BioWorld Today, Oct. 17, 2013.)

The Medicines Co., and Alnylam Pharmaceuticals Inc. also are pursuing PCSK9 through the RNAi candidate ALN-PCSsc for treatment of hypercholesterolemia. Preclinical data showed cholesterol lowering of up to 68 percent in the absence of statins, and an investigational new drug application is planned for late 2014.

Amgen Inc. recently reported an efficacy analysis of pooled data from four 12-week Phase II studies testing AMG 145, a PCSK9 inhibitor, in patient populations with high cholesterol showing that treatment gave a significant reduction in LDL-C of up to 59 percent.

The list of companies affected by potentially tougher new requirements by the FDA for cardiovascular outcomes for lipid-lowering agents and a shift from the reliance on surrogate biomarkers runs to dozens and dozens, and if extended to daily therapies for chronic diseases in other indications could leave few programs untouched.