Abstract 18390: Effects of a Proprotein Convertase Subtilisin/kexin Type 9 (PCSK9) Inhibitor, Alirocumab, on Lipid and Lipoprotein Metabolism in Healthy Subjects
Background: Alirocumab is a monoclonal antibody that inhibits binding of PCSK9 to LDL receptors, decreasing their lysosomal degradation and increasing their numbers on cell surfaces. In Phase 2/3 studies, alirocumab 150 mg lowered LDL-cholesterol (C) ~61%, apoB 53%, and fasting triglycerides (TG) 16%. The mechanisms that increased LDL removal or the effects on postprandial (PP) TG levels after alirocumab therapy have not been reported.
Method: 18 (10F, 8 M), healthy volunteers completed a Phase 1, placebo-controlled, single-blind, single-sequence study. Subjects received 2 placebo doses followed by 5 alirocumab doses, 150 mg SC every 2 wks. At the end of each treatment period, we measured fasting lipids and lipoproteins and subjects received a high fat meal with PP TG and apoB48 levels measured over 8hrs. Stable isotope studies were performed 3-5 days later to measure apoB turnover in very low density (VLDL), intermediate density (IDL) and LDL.
Results: In 18 subjects, Alirocumab significantly reduced plasma total-C by 35% (172±32 to 111±24 mg/dL), LDL-C by 60% (104±23 to 44±21 mg/dL) and, apoB by 45% (90±21 to 45±12 mg/dL). Plasma TG levels decreased by 13% (99±44 to 86±40mg/dL). LDL-C, LDL-TG, and LDL-apoB isolated from plasma by ultracentrifugation fell by 50±15%, 5±2%, and 41±16%, respectively, on alirocumab. Preliminary Kinetic results on N=10, show that the reductions in LDL-apoB were due to an 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). IDL-C, IDL-TG and IDL-apoB were also reduced significantly, with 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). Alirocumab had no effects VLDL-C, VLDL-TG, or VLDL-apoB, nor did alirocumab change VLDL FCR or PR. The area under the curve for PP TG and PP apoB48 did not change from placebo to alirocumab. No serious adverse event or treatment discontinuation occurred. Results for all 18 subjects will be available for presentation.
Summary: Alirocumab treatment significantly reduced levels of IDL and LDL-apoB by increasing the FCRs of these lipoproteins, particularly LDL. Alirocumab did not alter the metabolism of VLDL-apoB or PP TG-rich lipoproteins.
Author Disclosures: G. Reyes-Soffer: Research Grant; Modest; Merck, Inc. Honoraria; Modest; Sanofi. Research Grant; Significant; non- significant. Honoraria; Significant; non-significant. M. Pavlyha: None. C. Ngai: None. T. Thomas: None. S. Holleran: None. S. Ramakrishnan: None. W. Karmally: None. D. Donovan: None. L. Cowan: Employment; Significant; Sanofi. W. Sasiela: Employment; Significant; Regeneron. H. Surks: Employment; Significant; Sanofi. J. Rey: Employment; Significant; Sanofi. F. Poitiers: Employment; Significant; Sanofi. H. Ginsberg: Other Research Support; Modest; Amgen. Honoraria; Modest; Sanofi Regeneron, Amgen, Merck, Kowa. Consultant/Advisory Board; Modest; Sanofi Regeneron, Amgen, Merck, Reverlogix. Research Grant; Significant; Sanofi Regeneron. Other Research Support; Significant; Merck.
- © 2015 by American Heart Association, Inc.