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BackgroundETC-1002 is an oral, once-daily, first-in-class medication being developed to treat hypercholesterolemia.ObjectivesTo compare 2 doses of ETC-1002, alone or combined with ezetimibe 10 mg (EZE), vs EZE monotherapy for lowering low-density lipoprotein cholesterol (LDL-C).MethodsThis phase 2b, multicenter, double-blind trial-evaluated hypercholesterolemic patients (LDL-C, 130 to 220 mg/dL) with (n = 177) or without (n = 171) muscle-related intolerance to ≥2 statins; 1 at lowest approved dose. Subjects were randomized to 12-week treatment with ETC-1002 120 mg or ETC-1002 180 mg alone, EZE alone, ETC-1002 120 mg plus EZE, or ETC-1002 180 mg plus EZE.ResultsEZE alone lowered LDL-C by 21%, whereas ETC-1002 monotherapy with 120 mg or 180 mg reduced LDL-C by 27% (P = .0008 vs EZE) and 30% (P

Bempedoic acid (ETC-1002), a novel therapeutic approach for low-density lipoprotein cholesterol (LDL-C) lowering, inhibits ATP citrate lyase (ACL), an enzyme involved in fatty acid and cholesterol synthesis. Although rodent studies suggested potential effects of ACL inhibition on both fatty acid and cholesterol synthesis, studies in humans show an effect only on cholesterol synthesis. In phase 2 studies, ETC-1002 reduced LDL-C as monotherapy, combined with ezetimibe, and added to statin therapy, with LDL-C lowering most pronounced when ETC-1002 was combined with ezetimibe in patients who cannot tolerate statins. Whether clinically relevant favorable effects on other cardiometabolic risk factors such as hyperglycemia and insulin resistance occur in humans is unknown and requires further investigation. Promising phase 2 results have led to the design of a large phase 3 program to gain more information on efficacy and safety of ETC-1002 in combination with statins and when added to ezetimibe in statin-intolerant patients.