Pemafibrate

Pemafibrate is an orally bioavailable and selective agonist of peroxisome proliferator-activated receptor alpha (PPARalpha, EC50 = 1 nM for transcriptional activity), a transcription factor that is essential for regulation of lipid homeostasis. It is selective for PPARalpha over PPARdelta and PPARgamma (EC50s = 2,300 and 1,000 nM, respectively, for transcriptional activity). In human HepG2 hepatoma cells, pemafibrate is 1,000-fold more potent than the classical PPARalpha agonists fenofibrate (Cay-10005368) and Wy 14643 (Cay-70730) in activating PPARalpha transcriptional activity. Pemafibrate (0.001% w/w) reduces plasma triglyceride levels, non-esterified fatty acids, and total cholesterol in mice fed a moderate-fat diet, and, when administered at 0.00025%, it reduces liver lipid accumulation and improves prognosis in wild-type but not Ppara knockout mice in a model of diet-induced non-alcoholic fatty liver disease (NAFLD). In mouse models of non-alcoholic steatohepatitis (NASH), pemafibrate stimulates expression of PPARalpha, enhances lipid turnover, and reduces liver triglyceride levels and inflammation. It also dose-dependently reduces the area of atherosclerotic lesions in human apolipoprotein E2 (ApoE2) knock-in mice.