Abstract 16875: Functional Analysis of Low Density Lipoprotein Receptor Variants in Lymphocytes to Assess the Effect of Evinacumab in Homozygous Familial Hypercholesterolemia Patients With a Spectrum of Low Density Lipoprotein Receptor Activity

Background: HoFH is a rare disease characterized by markedly elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and an extremely high risk of premature atherosclerotic cardiovascular disease. In 95% of patients, HoFH is caused by mutations in LDLR that reduce receptor function. Preclinical studies suggest inhibition of angiopoietin-like 3 (ANGPTL3) protein lowers LDL-C independent of the LDL receptor. We administered 250 mg evinacumab, a fully human ANGPTL3-blocking antibody, subcutaneously at baseline and 15 mg/kg intravenously 2 weeks later to nine HoFH patients on stable background lipid-lowering therapy. Two patients additionally received four doses of 450 mg SC at weeks 12-15. In this study, we evaluated the activity of LDLR variants found in these patients. Methods: Activity of LDLR variants and classification was determined both in lymphocytes isolated from HoFH and in CHO-ldlA7 transfected cells using immunoblotting of cell extracts, FACS and confocal microscopy. Results and con...