Promising triglyceride lowering with first-in-class structurally enhanced fatty acid
Icosabutate for the treatment of very high triglycerides: A placebo-controlled, randomized, double-blind, 12-week proof-of-concept studyPresented by: Harold Bays (Louisville, KY, USA)
Positive results from a Phase 2a study evaluating the safety and efficacy of icosabutate, a first-in-class structurally enhanced fatty acid (SEFA), compared with placebo in patients with very high levels of triglycerides (≥500 mg/dL) were presented today at ISA2015. Contrary to conventional prescription omega-3 therapies on the market, icosabutate is designed to provide superior triglyceride-lowering at a much lower dose (600 mg) with a convenient once daily oral dosing with or without food.
The CTN 4016 13201 trial was a randomized, double-blind, placebo-controlled, multicenter, Phase 2a proof-of-concept study to evaluate the efficacy and safety of icosabutate in patients with severe hypertriglyceridemia (TG 500 – 1500 mg/dL) with or without background statin therapy. The primary objective was to assess the effect on fasting triglycerides with patients receiving either icosabutate 600 mg once daily or placebo for 12 weeks. Secondary objectives were to assess the effect of icosabutate on other lipids and lipoproteins, markers of inflammation and glucose metabolism, and safety and tolerability. Eighty seven patients with severe hypertriglyceridemia were washed out of any non-statin lipid lowering therapies (ezetimibe therapy was allowed). Forty-three of these patients were randomized to receive 600mg once daily icosabutate and 44 patients received placebo.
Dr. Harold Bays, President of the Louisville Metabolic and Atherosclerosis Research Center (Louisville, Kentucky), showed during ISA2015 that the study met its primary endpoint of greater triglyceride lowering from baseline with icosabutate 600 mg once daily compared with placebo. Treatment with icosabutate resulted in a 51% reduction in triglycerides at 12 weeks, compared with 17% percent in the placebo group (p < 0.001). The reduction in triglycerides was attained at the first post-randomization visit at 2 weeks and was sustained throughout the treatment period. Eighty nine percent of patients receiving icosabutate achieved a triglyceride level below 500 mg/ dL at the end of the study. Levels of apolipoprotein C3 (Apo C3), an important risk marker of atherosclerotic cardiovascular disease, were also significantly reduced in those patients who received icosabutate (41% reduction) versus placebo (5% reduction) (p < 0.001). Non-HDL-C, reflecting the totality of the atherogenic cholesterol, was numerically reduced and accompanied by a partial reversal of the skewed lipid profile often seen in patients with severe hypertriglyceridemia with large and significant reductions in VLDL-C and remnant-C and smaller increases in LDL-C and HDL-C. Importantly, icosabutate also significantly reduced insulin resistance and the markers Lp-PLA2 and CRP numerically reduced.
Adverse events (AEs) were balanced between the two groups and generally mild or moderate in severity. No serious AEs were observed in the icosabutate group (one patient in the placebo group had an SAE). One patient in the icosabutate group withdrew from the study due to AEs (mild jittery feeling that resolved).
"The top-line data look very positive and encouraging," says Hilde H. Steineger, Head of Strategic Innovation Management. “For BASF, this Phase II clinical study marks an important milestone and can be considered as the first proof-of-principle that both the potency and efficacy can be substantial increased by structurally enhancing natural fatty acids.”
Dr. Harold Bays says "Icosabutate is a synthetic EPA derivative that in this study of patients with very high triglycerides produced clinically relevant reductions in triglycerides, remnant-like lipoproteins, and apolipoprotein C3. Especially intriguing is the once a day dosing of 600 mg, which is 15% of the 4 gram dosing typical of other omega-3 fatty acid agents."