Journal
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Volume 59, Issue 25, Pages 2344-2353Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jacc.2012.03.007
Keywords
apolipoprotein-B; hypercholesterolemia; low-density lipoprotein cholesterol; PCSK9; safety; SAR236553/REGN727; statin
Categories
Funding
- Sanofi US
- Regeneron Pharmaceuticals Incorporated
- Regeneron
- Sanofi
- American Association of Clinical Chemistry
- Abbott
- Amgen
- AstraZeneca
- Bristol-Myers Squibb
- U.S. Food and Drug Administration
- F. Hoffman La Roche
- Genentech
- Genzyme
- GlaxoSmithKline
- ISIS
- Merck Co.
- National Lipid Association
- Novartis
- Sankyo
- Schering-Plough
- Wyeth
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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 >= 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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