Icosabutate, a Structurally Engineered Fatty Acid, Improves the Cardiovascular Risk Profile in Statin-Treated Patients with Residual Hypertriglyceridemia

Abstract

Objectives: To evaluate the efficacy and safety of icosabutate, an oral, once-daily, first-in-class medication, in reducing non-high-density lipoprotein cholesterol (non-HDL-C) in patients with persistent hypertriglyceridemia despite statin therapy. Methods: The study was designed to randomly assign 140 patients with fasting triglyceride levels ≥200 but <500 mg/dl on a stable dose of statin therapy to receive either masked icosabutate 600 mg once daily or a control for 12 weeks. The primary end point was a percentage change in non-HDL-C from baseline to 12 weeks. Results: With icosabutate, non-HDL-C levels were reduced (-9.2%) when compared with the control (-0.4%) for a between-group difference of -7.4% (p = 0.02). Compared with the control, icosabutate reduced triglycerides (-27.0%, p < 0.001), very- low-density lipoprotein (VLDL) cholesterol (-31.5%, p < 0.001) and apolipoprotein C-III (-22.5%, p < 0.001). LDL-C levels did not change (0.5%, p = 0.87). HDL-C (10.2%, p < 0.001) was increased. After 113 subjects had been randomized, the study was terminated due to a partial clinical hold imposed by US regulators after observing QT prolongation at supratherapeutic doses of icosabutate in a dog study. In this study, adverse events were balanced between treatment arms, and there were no discontinuations due to adverse events. Conclusions: Icosabutate was efficacious in lowering non-HDL-C and other biomarkers of cardiovascular risk and was generally well tolerated.

Nitro-fatty acids: New drug candidates for chronic inflammatory and fibrotic diseases

“…Clinical studies demonstrated a significant reduction in triglyceride and cholesterol levels. However, a prolongation of the QT interval observed in a 12-month dog study that ran in parallel to the clinical trial led the FDA to establish an exposure limit and consequently to the termination of the study by the sponsor (25). Nevertheless, both bempedoic and icosabutate (now being evaluated for non-alcoholic steatohepatitis) are still in clinical trials and share a similar pharmacological strategy with regards to the introduction of chemical modifications to prevent fatty acid metabolism and increase their potency.…”

Icosabutate Exerts Beneficial Effects Upon Insulin Sensitivity, Hepatic Inflammation, Lipotoxicity, and Fibrosis in Mice

“…To translate the dosing used in our rodent studies (112 or 135 mg/kg/d ) to human dosing, the following simplified calculation based on body surface area can be used as a guide: mouse dose/12.3 × human body weight; thus, 112 mg/kg/d in mice is approximately 730 mg/day for an 80‐kg human. This corresponds to the highly efficacious 600‐mg/day dose used previously in the clinic . This is markedly less than, for example, the 150 mg per mouse /day (versus approximately 4 to 7 mg/per mouse/day in current studies for APOE*3Leiden.CETP and ob/ob models, respectively) used in previous studies to achieve improvements in insulin resistance and inflammation with unmodified ω‐3 fatty‐acids .…”

“…). Icosabutate was initially developed as a hypolipidemic drug and demonstrated robust reductions in atherogenic lipids and apolipoproteins at a dose of 600 mg once daily in two recent clinical trials . Interestingly, icosabutate also induced a marked and significant reduction in homeostasis model assessment of insulin resistance (HOMA‐IR), an effect not typically associated with unmodified ω‐3 fatty‐acid supplementation .…”

Icosabutate, a More Potent Form of Omega 3 Fatty Acids, Shows Promise in Lowering Triglycerides

“…The study by Kastelein et al [11] in this issue of Cardiology reports data on icosabutate, showing a significant lowering of triglycerides by 27% and of VLDL by 31% (p < 0.001). LDL cholesterol did not significantly change (0.5%, p = 0.87).…”

“…After 113 subjects had been randomized, the study was terminated due to a partial clinical hold imposed by US regulators after observing QT prolongation at supratherapeutic doses of icosabutate in a dog study. However, in the study by Kastelein et al [11], adverse events were balanced between treatment arms and there were no QT prolongations and also no discontinuations due to adverse events.…”