Design and Rationale of the LAPLACE-TIMI 57 Trial: A Phase II, Double-Blind, Placebo-Controlled Study of the Efficacy and Tolerability of a Monoclonal Antibody Inhibitor of PCSK9 in Subjects With Hypercholesterolemia on Background Statin Therapy

Lowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone for the prevention of atherosclerotic heart disease, improving clinical outcomes and reducing vascular mortality in patients with hypercholesterolemia. The clinical benefits of LDL-C reduction appear to extend even to patients starting with LDL-C as low as 6080 mg/dL prior to initiating therapy. Statins are the first-line agents for treating hypercholesterolemia and are effective in reducing LDL-C, but many patients are unable to achieve their optimal lipid targets despite intensive statin therapy. Therefore, there has been a strong impetus for the development of novel pharmacologic agents designed to lower LDL-C further in patients already on statin therapy. Genetic mutations resulting in altered cholesterol homeostasis provide valuable information regarding novel approaches for treating hypercholesterolemia. To that end, mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) were linked to altered levels of LDL-C, illustrating this protein's role in lipid metabolism. PCSK9 promotes degradation of the LDL receptor, preventing its transport back to the cell surface and thereby increasing circulating LDL-C. Conversely, inhibition of PCSK9 can profoundly decrease circulating LDL-C, and thus is an attractive new target for LDL-Clowering therapy. AMG 145 is a fully human monoclonal immunoglobulin G2 antibody that binds specifically to human PCSK9 and inhibits its interaction with the low-density lipoprotein receptor. In this manuscript, we describe the rationale and design of LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined With Statin TherapyThrombolysis In Myocardial Infarction 57 (LAPLACE-TIMI 57; NCT01380730), a 12-week, randomized, double-blind, dose-ranging, placebo-controlled study designed to assess the safety and efficacy of AMG 145 when added to statin therapy in patients with hypercholesterolemia. Clin. Cardiol. 2012. doi: 10.1002/clc.22014 This trial was supported by Amgen. Payal Kohli, Nihar R. Desai, Robert P. Giugliano, Timothy Abrahamsen, Shannon McDonald and Marc S. Sabatine are members of the TIMI Study Group, which received research grant support from Amgen for the conduct of this trial. Payal Kohli has received honorarium for consultation from Daiichi-Sankyo. Robert P. Giugliano has received honoraria for lectures and consultation from Amgen, Merck, Regeneron, and Sanofi-Aventis, and research-grant support from Merck for work related to lipid-lowering therapies. Marc S. Sabatine has received research-grant support from AstraZeneca, Bristol-Myers Squibb/Sanofi-Aventis Joint Venture, Merck, and Pfizer and honoraria for lectures and consultation from Amgen, Bristol-Myers Squibb/Sanofi-Aventis Joint Venture, GlaxoSmithKline, Merck, and Pfizer. Jae B. Kim, Ransi Somaratne, Fannie Huang, Beat Knusel, Scott M. Wasserman, and Robert Scott are employees and stockholders of Amgen, Inc. Payal Kohli, MD, and Nihar R. Desai, MD, MPH, contributed equally to this work. The authors have no other funding, financial relationships, or conflicts of interest to disclose.