Effects of AMG 145 on Low-Density Lipoprotein Cholesterol Levels: Results From 2 Randomized, Double-Blind, Placebo-Controlled, Ascending-Dose Phase 1 Studies in Healthy Volunteers and Hypercholesterolemic Subjects on Statins

• Published in: Journal of the American College of Cardiology Vol. 60; no. 19; pp. 1888 - 1898
• Main Authors: DIAS, Clapton S, SHAYWITZ, Adam J, GIBBS, John P, RETTER, Marc W, COOKE, Blaire P, UY, Stephen T, MATSON, Mark, STEIN, Evan A, WASSERMAN, Scott M, SMITH, Brian P, BING GAO, STOLMAN, Dina S, CRISPINO, Caroline P, SMIRNAKIS, Karen V, EMERY, Maurice G, COLBERT, Alexander
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier 06.11.2012
• Subjects: Adult; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Biological and medical sciences; Cardiology. Vascular system; Cholesterol, LDL - antagonists & inhibitors; Cholesterol, LDL - blood; Cohort Studies; Disorders of blood lipids. Hyperlipoproteinemia; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Hypercholesterolemia - blood; Hypercholesterolemia - drug therapy; Male; Medical sciences; Metabolic diseases; Proprotein Convertase 9; Proprotein Convertases - antagonists & inhibitors; Proprotein Convertases - metabolism; Receptors, LDL - antagonists & inhibitors; Receptors, LDL - metabolism; Serine Endopeptidases - metabolism; Treatment Outcome; Young Adult; Human; Phase; Healthy subject; Metabolic diseases; Cholesterol LDL; Lipids; Hyperlipoproteinemia; Statin derivative; Lipoprotein; Double; Posology; Result; Randomization; Hypercholesterolemia; Placebo; Level; Circulatory system; Dyslipemia; Cardiology; Dose
• ISSN: 0735-1097; 1558-3597; 1558-3597
• DOI: 10.1016/j.jacc.2012.08.986

The aim of this study was to evaluate the safety, tolerability, and effects of AMG 145 on low-density lipoprotein cholesterol (LDL-C) in healthy and hypercholesterolemic subjects on statin therapy. Proprotein convertase subtilisin/kexin type 9 (PCSK9) down-regulates surface expression of the low-density lipoprotein receptor (LDL-R), increasing serum LDL-C. AMG 145, a fully human monoclonal antibody to PCSK9, prevents PCSK9/LDL-R interaction, restoring LDL-R recycling. Healthy adults (phase 1a) were randomized to 1 dose of AMG 145: 7, 21, 70, 210, or 420 mg SC; 21 or 420 mg IV; or matching placebo. Hypercholesterolemic adults (phase 1b) receiving low- to moderate-dose statins were randomized to multiple SC doses of AMG 145: 14 or 35 mg once weekly (QW) ×6, 140 or 280 mg every 2 weeks (Q2W) ×3, 420 mg every 4 weeks ×2, or matching placebo. Eleven subjects receiving high-dose statins and 6 subjects with heterozygous familial hypercholesterolemia were randomized to SC AMG 145 140 mg or placebo Q2W ×3. In the trials (AMG 145 n = 85, placebo n = 28), AMG 145 reduced LDL-C up to 64% (p < 0.0001) versus placebo after 1 dose ≥21 mg and up to 81% (p < 0.001) with repeated doses ≥35 mg QW. No serious adverse events (AEs) occurred. Overall incidence of treatment-emergent AEs was similar in AMG 145 versus placebo groups: 69% versus 71% (phase 1a); 65% versus 64% (phase 1b). In phase 1 studies, AMG 145 significantly reduced serum LDL-C in healthy and hypercholesterolemic statin-treated subjects, including those with heterozygous familial hypercholesterolemia or taking the highest doses of atorvastatin or rosuvastatin, with an overall AE profile similar to placebo.