Safety and Efficacy of a Monoclonal Antibody to Proprotein Convertase Subtilisin/Kexin Type 9 Serine Protease, SAR236553/REGN727, in Patients With Primary Hypercholesterolemia Receiving Ongoing Stable Atorvastatin Therapy

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• 作者：James M. McKenney ; PharmD^鈦?/sup> ; ^{jmckenney@ncrinc.net} ; Michael J. Koren ; MD ; CPI^&dagger ; ; Dean J. Kereiakes ; MD^&Dagger ; ; Corinne Hanotin ; MD^§ ; ; Anne-Catherine Ferrand ; MSc^§ ; ; Evan A. Stein ; MD ; PhD^鈭?/sup>
• 关键词：apolipoprotein-B ; hypercholesterolemia ; low-density lipoprotein cholesterol ; PCSK9 ; safety ; SAR236553/REGN727 ; statin
• 刊名：Journal of the American College of Cardiology
• 出版年：2012
• 期刊代码：201_07351097
• 类别：med
• 出版时间：19-26 June, 2012
• 卷：59
• 期：25
• 页码：2344-2353
• 文件大小：731 K

摘要

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Objectives

The primary objective of this study was to evaluate the low-density lipoprotein cholesterol (LDL-C)-lowering efficacy of 5 SAR236553/REGN727 (SAR236553) dosing regimens versus placebo at week 12 in patients with LDL-C 鈮?00 mg/dl on stable atorvastatin therapy. Secondary objectives included evaluation of effects on other lipid parameters and the attainment of LDL-C treatment goals of <100 mg/dl (2.59 mmol/l) and <70 mg/dl (1.81 mmol/l).

Background

Serum proprotein convertase subtilisin kexin 9 (PCSK9) binds to low-density lipoprotein receptors, increasing serum LDL-C. SAR236553 is a fully human monoclonal antibody to PCSK9.

Methods

This double-blind, parallel-group, placebo-controlled trial randomized 183 patients with LDL-C 鈮?00 mg/dl (2.59 mmol/l) on stable-dose atorvastatin 10, 20, or 40 mg for 鈮? weeks to: subcutaneous placebo every 2 weeks (Q2W); SAR236553 50, 100, or 150 mg Q2W; or SAR236553 200 or 300 mg every 4 weeks (Q4W), alternating with placebo for a total treatment period of 12 weeks.

Results

SAR236553 demonstrated a clear dose-response relationship with respect to percentage LDL-C lowering for both Q2W and Q4W administration: 40%, 64%, and 72%with 50, 100, and 150 mg Q2W, respectively, and 43%and 48%with 200 and 300 mg Q4W. LDL-C reduction with placebo at week 12 was 5%. SAR236553 also substantially reduced non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a). SAR236553 was generally well tolerated. One patient on SAR236553 experienced a serious adverse event of leukocytoclastic vasculitis.

Conclusions

When added to atorvastatin, PCSK9 inhibition with SAR236553 further reduces LDL-C by 40%to 72%. These additional reductions are both dose- and dosing frequency-dependent. (Efficacy and Safety Evaluation of SAR236553 [REGN727] in Patients With Primary Hypercholesterolemia and LDL-cholesterol on Stable Atorvastatin Therapy; )