An Open-label, Crossover Study Comparing EPA+DPA-Free Fatty Acids and EPA-Ethyl Esters in Adults with Elevated Triglycerides: ENHANCE-IT

Abstract

<h3>Lead Author's Financial Disclosures</h3> K.C.M. has received consulting fees from Matinas BioPharma, Inc., Acasti Pharma, Inc., New Amsterdam Pharma, Pharmavite, and 89Bio. He has received research grant support from Matinas BioPharma, Inc, and Pharmavite. <h3>Study Funding</h3> Matinas BioPharma, Inc. <h3>Background/Synopsis</h3> Few head-to-head studies have directly compared the efficacy of prescription omega-3 fatty acid (OM-3) products. Both the degree of triglyceride (TG) lowering and the achieved blood levels of individual OM-3 fatty acids are important predictors of clinical efficacy. MAT9001 is a unique OM-3 free-fatty-acid (FFA) formulation, containing mainly eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA). A prior crossover study comparing EPA+DPA-FFA and icosapent ethyl (EPA-EE - an ethyl ester EPA formulation) showed enhanced TG lowering and higher EPA levels with EPA+DPA-FFA when both agents were administered with a very-low fat diet and once daily dosing. <h3>Objective/Purpose</h3> To compare pharmacodynamic responses and plasma OM-3 levels following 28-day twice daily treatment with EPA+DPA-FFA and EPA-EE in hypertriglyceridemic subjects consuming a Therapeutic Lifestyle Changes diet. <h3>Methods</h3> This open-label, 2-way crossover trial was conducted at 8 centers in the US and included 100 subjects with fasting TG 150-499 mg/dL (median 204 mg/dL; 57% female, average age 60.3 years). Participants were randomized to EPA+DPA-FFA or EPA-EE for 28 days, washed out for at least 28 days, and then crossed over to the other therapy. Both drugs were given as 2 g twice daily, with meals. The primary endpoint was least squares geometric mean (LSGM) % change from baseline in plasma TG. Additional measurements included other lipoprotein-related markers, high-sensitivity C-reactive protein (hs-CRP) and plasma levels of individual OM-3 fatty acids. <h3>Results</h3> Ninety-four subjects had analyzable data for both treatment periods. EPA+DPA-FFA and EPA-EE reduced TG from baseline: 20.9% and 18.3%, respectively (p=NS). EPA+DPA-FFA reduced hs-CRP by 5.8% compared with an increase of 8.5% with EPA-EE (p = 0.034). EPA+DPA-FFA increased LSGM plasma EPA, DPA, and total OM-3 concentrations by 848%, 692%, and 177% respectively, which were greater than corresponding changes with EPA-EE of 140%, 205%, and 165%, respectively (all p < 0.001). EPA+DPA-FFA increased docosahexaenoic acid (DHA) by 1.7%; EPA-EE decreased DHA by 3.3% (p = 0.011). Responses for lipoprotein cholesterol levels (total, VLDL, LDL, HDL) and apolipoprotein (A-1, B and C-3) did not differ between treatments. <h3>Conclusions</h3> These results demonstrate that a FFA formulation of EPA+DPA produced significantly higher plasma EPA, DPA and total OM-3 levels compared with an EE formulation of EPA, and support the