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

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:59

Article

McKenney, James M.^1,2  Koren, Michael J.³  Kereiakes, Dean J.⁴  Hanotin, Corinne⁵  Ferrand, Anne-Catherine⁵  Stein, Evan A.^6,7 

[1] Natl Clin Res Inc, Richmond, VA 23294 USA

[2] Virginia Commonwealth Univ, Richmond, VA USA

[3] Jacksonville Ctr Clin Res, Jacksonville, FL USA

[4] Christ Hosp, Heart & Vasc Ctr, Lindner Res Ctr, Cincinnati, OH 45219 USA

[5] Sanofi, Paris, France

[6] Metab & Atherosclerot Res Ctr, Cincinnati, OH USA

[7] Medpace Reference Labs, Cincinnati, OH USA

关键词: apolipoprotein-B;    hypercholesterolemia;    low-density lipoprotein cholesterol;    PCSK9;    safety;    SAR236553/REGN727;    statin;   

DOI  :  10.1016/j.jacc.2012.03.007

来源: Elsevier

【 摘 要 】

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 >= 100 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 >= 100 mg/dl (2.59 mmol/l) on stable-dose atorvastatin 10, 20, or 40 mg for >= 6 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; NCT01288443) (J Am Coll Cardiol 2012;59:2344-53) (C) 2012 by the American College of Cardiology Foundation

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