BioWorld Today Contributing Writer

Amarin Corp. plc and the FDA have reached an agreement on a special protocol assessment (SPA) for the design of a cardiovascular outcomes study (REDUCE-IT) of AMR101. The drug, a prescription-grade fish oil, has already turned in impressive results for dyslipidemia in two previous Phase III trials.

A successful outcome in REDUCE-IT may allow Amarin, of Dublin, Ireland, to market the drug for prevention of cardiac events in an at-risk population. The trial will enroll approximately 8,000 patients and will take around six years to complete. Patients with cardiovascular risk factors will receive an optimized statin regimen plus AMR101 or statins alone, with the goal of measuring outcomes.

Leerink Swann analyst Joseph Schwartz commented, "We are impressed with AMRN's ability to obtain a third SPA so rapidly, for a CV outcomes study, which is rare."

AMR101 performed better than expected in Amarin's Phase III (ANCHOR) trial by hitting both primary and secondary endpoints at all of the doses tested. The drug lowered triglyceride levels by 21.5 percent at a dose of 4 g per day, and 10.1 percent at the 2 g per day dose. (See BioWorld Today, April 19, 2011.)

Even better, AMR101 did not show elevation in low-density lipoprotein-cholesterol (LDL-C). In fact, patients in both dose groups showed a decrease in LDL-C. At 4 mg per day, the reduction of 6.2 percent was statistically significant.

The LDL cholesterol data is a key differentiator from the Japanese drug Epadel (Mochida Pharmaceutical Co. Ltd.), which has been marketed there for more than 20 years. AMR101 and Epadel share the same active ingredient eicosapentaenoic acid (EPA)-rich fish oil. AMR101 , however, does not contain docosahexaenoic acid (DHA), which is associated with undesirable increases in LDL-cholesterol.

AMR101 had already done well in the earlier MARINE study, which enrolled patients with triglyceride levels higher than 500 mg/dL. ANCHOR enrolled patients with triglycerides higher than 200 mg/dL. (See BioWorld Today, Nov. 30, 2010.)

Because about 1 in 50 adults in the U.S. have triglyceride levels above 500 mg/dL, and 1 in 5 have levels above 200 mg/dL, the market opportunity for AMR101 is easily in the 10-figure range. Adding prevention of cardiac events to the label via the REDUCE-IT trial could multiply that many-fold.

AMR101 will go toe to toe with Lovaza (omega-3-ethyl esters; GlaxoSmithKline plc). The advantage is expected to go to AMR101 in that match, because Lovaza lacks AMR101's LDL-C-lowering activity. In fact, Lovaza raises LDL-C.

Schwartz wrote, "Based on our prior analysis and positive Epadel outcomes data, we believe AMR101 will be able to demonstrate an outcomes benefit and thus be on track to become the only non-statin lipid-lowering agent to demonstrate an outcomes benefit."

Schwartz also noted that "usually no SPAs are granted for outcomes studies."

The six-year, 8,000-patient study is expected to cost between $100 million and $125 million total, with about $25 million incurred by the end of 2012, at which time Amarin expects to have achieved 50 percent enrollment, and plans to file for approval in the mixed dyslipidemia (ANCHOR) indication.

Joseph Pantginis, of Roth Capital Partners, also liked Amarin's prospects under the REDUCE-IT SPA: "We also believe the SPA helps to incrementally further de-risk the story in the company's ongoing discussions with potential partners. . . . The goal of this study is to pursue a broad label expansion of AMR101 encompassing cardiovascular event reduction. Based on current enrollment projections for this study, we remain comfortable with our 2013 projection for sNDA approval based on the ANCHOR study."

Thomas Wei, an equity analyst with Jefferies and Co., wrote, "We are encouraged that AMRN has completed SPA negotiations with the FDA in a timely fashion to enable a 4Q11 start to REDUCE-IT. Although we still need to see the specifics of the trial design, the details shared to date do not raise concerns about enrollment or the ability to demonstrate a positive outcomes benefit."

With all of the pieces falling into place for approval of AMR101 with a later expanded label, the next logical step for Amarin is partnership or acquisition. The company has been in partnership discussions, with ANCHOR results conferring a most-eligible status. Stakeholders are hoping to hear wedding bells in the near future.