Abstract 129: Effects of a Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor, Alirocumab, on Lipid and Lipoprotein Metabolism in Normal Subjects
Background: Proprotein convertase subtilisin/kexin type (PCSK9) inhibitors are promising new drugs for the treatment of hypercholesterolemia. They inhibit the binding of PCSK9 to the low density lipoprotein (LDL) receptor that, in turn, decreases lysosomal degradation of LDL receptors and increases their numbers on the cell surface. In Phase 2/3 studies, alirocumab significantly lowered plasma levels of LDL-cholesterol (C) and apolipoprotein B (apoB). The mechanism underlying the LDL-C lowering effects of PCSK9 inhibition has not been reported.
Method: We enrolled 10 healthy volunteers (4 male, 6 female), into a Phase 1, placebo-controlled, single-blind, single-sequence study to examine the effects of alirocumab, 150 mg administered subcutaneously every two weeks, on lipid and lipoproteins levels and the metabolism of apoB in very low density (VLDL), intermediate density (IDL) and LDL. Subjects received 2 doses of placebo followed by 5 doses of alirocumab. At the end of each treatment period, fasting lipids and lipoprotein levels were measured, and stable isotope studies of the apoB turnover in VLDL, IDL and LDL were performed.
Results: Alirocumab significantly reduced plasma levels of total-C by 37% (178.4±34 to 112.7±29 mg/dL), LDL-C by 59% (110.2±25 to 45.5±26 mg/dL), and apoB by 51% (93.6±25 to 45.5±13 mg/dL) compared to placebo. Plasma triglycerides (TG) and HDL-C did not change. Levels of LDL-C, LDL-TG, and LDL-apoB fell by 55.8±10%, 33.9±13%, and 56.0±11%, respectively (all p<0.0001), on alirocumab. The reductions in LDL apoB were explained by a dramatic increase in the fractional clearance rate (FCR) of LDL apoB from 0.50±0.18 on placebo to 1.02±0.35 pools/day on alirocumab (p<0.001) and a trend toward lower LDL apoB production rates on alirocumab (15.1±4.6 vs 12.9±3.3 mg/kg/day; p=0.10). Levels of IDL-C, IDL-TG and IDL-apoB were also reduced significantly and there was a trend toward an increase in IDL apoB FCR on alirocumab (placebo: 9.2±4 vs alirocumab: 10.8±3 pools/day; p=0.06). Additional kinetic parameters will be presented at the meeting.
Summary: Alirocumab treatment significantly reduced the levels of IDL and LDL, and these changes were due to increases in the FCRs of these lipoproteins, particularly LDL.
Author Disclosures: G. Reyes-Soffer: Research Grant; Modest; Sanofi. Honoraria; Modest; Genzyme, Inc. Consultant/Advisory Board; Modest; Genzyme, Inc. M. Pavlyha: None. C. Ngai: None. P. Ippolito: None. S. Holleran: None. R. Ramakrishnan: None. W. Karmally: None. D. Donovan: None. L. Cowan: Employment; Modest; Sanofi, Inc. W. Sasiela: Employment; Significant; Regeneron Inc. H. Surks: Employment; Significant; Sanofi, Inc. J. Rey: Employment; Significant; Sanofi, Inc. H. Ginsberg: Research Grant; Modest; Merck,Inc.. Other Research Support; Modest; Merck, Inc., Genzyme, Inc.. Honoraria; Modest; Merck, Inc. Consultant/Advisory Board; Modest; Merck, Inc, Sanofi,Inc, Amgen, Inc..
- © 2015 by American Heart Association, Inc.