Abstract 18: Bempedoic Acid Lowers Low Density Lipoprotein-Cholesterol and Attenuates Aortic Atherosclerosis in LDL Receptor-Deficient ( LDLR +/- and LDLR -/- ) Yucatan Miniature Pigs

Abstract

Bempedoic acid (ETC-1002) is an oral investigational drug that targets hepatic adenosine triphosphate-citrate lyase to reduce cholesterol biosynthesis. In Phase 2 studies (up to 12 weeks in duration), bempedoic acid lowers elevated LDL-cholesterol (C) in patients with hypercholesterolemia. The objective of the present study was to test the ability of bempedoic acid to decrease plasma-C and LDL-C, and attenuate the development of atherosclerosis in a large animal model of familial hypercholesterolemia. Gene targeting has been used to generate Yucatan miniature pigs heterozygous ( LDLR +/- ) or homozygous ( LDLR -/- ) for LDL-receptor (R) deficiency (ExeGen). LDLR +/- pigs (n=12) and LDLR -/- pigs (n=12) were fed a high fat, cholesterol-containing diet (34% kcal fat; 0.2% cholesterol) and orally administered placebo or bempedoic acid at 120 mg/d and at 240 mg/d for 160 days. Bempedoic acid was well tolerated; weight gain, caloric intake, liver enzymes and clinical chemistry analyses were unaffected by treatment. In LDLR +/- pigs at 160 days, compared to placebo, bempedoic acid significantly decreased plasma-C and LDL-C up to 43% ( P <0.01) and 63% ( P <0.002), respectively. Compared to LDLR-/- placebo pigs, in which plasma-C and LDL-C were 5-fold higher than in LDLR +/- placebo pigs, bempedoic acid significantly decreased plasma-C and LDL-C up to 26% ( P <0.04) and 29% ( P <0.03), respectively. Plasma levels of triglycerides and HDL-C, fasting glucose and insulin, and liver lipids were not affected by treatment in either genotype. In the aorta of LDLR +/- pigs, bempedoic acid treatment robustly attenuated total Sudan IV-stained lesion area (-58%, P <0.02) and area of raised lesions in the abdominal aorta (-58%, P <0.03). In LDLR -/- pigs, in which total aortic lesion area (6-fold) and area of raised abdominal lesions (12-fold) were substantially larger compared to LDLR +/- pigs, bempedoic acid significantly decreased total aortic lesion area (-47%, P <0.01) and area of raised abdominal lesions (-50%, P <0.03). The present experiments demonstrate that in a large animal model of LDLR-deficiency and atherosclerosis, long term treatment with bempedoic acid reduces LDL-C and attenuates the progression of aortic atherosclerosis in both LDLR +/- and LDLR -/- miniature pigs.