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

Abstract

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 60–80 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-C–lowering 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 Therapy–Thrombolysis 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.

The PCSK9 decade

“…In this study, there were no reports of serious adverse events or discontinuations as a result of an adverse event. The effect of AMG145 administration will be investigated in subjects with hypercholesterolemia in the LAPLACE-TIMI 57 (NCT01380730) trial ( 99 ).…”

Efficacy and Safety of Longer-Term Administration of Evolocumab (AMG 145) in Patients With Hypercholesterolemia

“…OSLER was a global study conducted at 156 study centers that participated in 1 or more of the 4 phase 2 studies (Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C 4,5,7,10,12 Patients completing any evolocumab phase 2 parent study could enroll in OSLER provided that they did not experience a treatment-related serious adverse event (AE) that led to discontinuation of investigational product in the phase 2 parent study or were anticipated to require unblinded lipid measurements and/or adjustment of background lipid-regulating therapy during the first 12 weeks of OSLER participation. An independent ethics committee or institutional review board approved the protocol, and all patients provided written informed consent before enrollment in the extension study.…”

AMG145, a Monoclonal Antibody Against Proprotein Convertase Subtilisin Kexin Type 9, Significantly Reduces Lipoprotein(a) in Hypercholesterolemic Patients Receiving Statin Therapy

“…16,17 In brief, the study was a phase 2, double-blind, placebo-controlled, dose-ranging study of AMG145 versus placebo in 631 subjects with hypercholesterolemia and LDL-C ≥85 mg/dL on a stable dose of statin therapy with or without ezetimibe. At baseline, 30% of subjects were receiving intensive statin therapy, defined as daily simvastatin 80 mg, atorvastatin ≥40 mg, rosuvastatin ≥20 mg, or any statin in combination with ezetimibe.…”