Complementary low-density lipoprotein-cholesterol lowering and pharmacokinetics of adding bempedoic acid (ETC-1002) to high-dose atorvastatin background therapy in hypercholesterolemic patients: A randomized placebo-controlled trial

• Published in: Journal of clinical lipidology Vol. 13; no. 4; pp. 568 - 579
• Main Authors: Lalwani, Narendra D., Hanselman, Jeffrey C., MacDougall, Diane E., Sterling, Lulu R., Cramer, Clay T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2019
• Subjects: Atorvastatin; Bempedoic acid; Cholesterol; ETC-1002; Hypercholesterolemia; LDL; Pharmacokinetics; Hypercholesterolemia; LDL; ETC-1002; Atorvastatin; Pharmacokinetics; Bempedoic acid; Cholesterol
• ISSN: 1933-2874; 1876-4789
• DOI: 10.1016/j.jacl.2019.05.003

Bempedoic acid is an oral, once-daily, first-in-class medication being developed to treat hypercholesterolemia. The aim of the study was to assess the low-density lipoprotein cholesterol (LDL-C)–lowering efficacy of bempedoic acid added to stable high-intensity atorvastatin background therapy and multiple-dose plasma pharmacokinetics of atorvastatin alone and combined with steady-state bempedoic acid. This was a phase 2 study in patients with hypercholesterolemia (NCT02659397). Patients received once-daily open-label atorvastatin 80 mg for 4 weeks then were randomized 2:1 at baseline to receive double-blind bempedoic acid 180 mg (n = 45) or placebo (n = 23) plus open-label atorvastatin 80 mg for 4 weeks. Efficacy was assessed 4 weeks after randomization. Atorvastatin and metabolites' steady-state levels were analyzed before first dosing with bempedoic acid and after 2 weeks of treatment. The 4-week stabilization phase with 80 mg atorvastatin resulted in approximately 40% lowering of LDL-C values from screening. The placebo-adjusted least squares mean lowering of LDL-C from baseline to Day 29 with bempedoic acid was 22% (P = .003). Placebo-adjusted reductions from baseline with bempedoic acid also were significant for total cholesterol (−10%; P = .014), non–high-density lipoprotein cholesterol (−13%; P = .015), apolipoprotein B (−15%; P = .004), and high-sensitivity C-reactive protein (−44%; P = .002). Point estimates of bempedoic acid effects on steady-state atorvastatin and ortho-hydroxy atorvastatin area under the curve were <30% and not clinically meaningful. Bempedoic acid 180 mg added to stable high-dose atorvastatin therapy effectively lowers LDL-C in patients with hypercholesterolemia without causing clinically important increases in atorvastatin exposure. •Bempedoic acid added to high-dose atorvastatin significantly lowers low-density lipoprotein cholesterol.•Atherogenic lipids and high-sensitivity C-reactive protein are lowered by bempedoic acid added to atorvastatin.•Bempedoic acid does not meaningfully increase steady-state atorvastatin exposure.•The combination of bempedoic acid and high-dose atorvastatin is well tolerated.