Author + information
- Received February 6, 2012
- Revision received March 7, 2012
- Accepted March 13, 2012
- Published online June 19, 2012.
- James M. McKenney, PharmD⁎,⁎ (, )
- Michael J. Koren, MD, CPI†,
- Dean J. Kereiakes, MD‡,
- Corinne Hanotin, MD§,
- Anne-Catherine Ferrand, MSc§ and
- Evan A. Stein, MD, PhD∥
- ↵⁎Reprint requests and correspondence:
Dr. James M. McKenney, National Clinical Research, Inc., 2809 Emerywood Parkway, Suite 140, Richmond, Virginia 23294
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)
- low-density lipoprotein cholesterol
This study was financially supported by Sanofi US and Regeneron Pharmaceuticals Incorporated. Drs. McKenney and Koren are employees of a research company that has received research funding from Regeneron and Sanofi. Dr. Hanotin and Ms. Ferrand are both employees of Sanofi. Dr. Stein is affiliated with the Metabolic and Atherosclerosis Research Center, and Medpace Research Laboratories; has received research grants related to trials of SAR236553/REGN727 from Regeneron and Sanofi, as well as consultancy fees from Sanofi; and has received grants for trials of numerous lipid-modifying agents, consultancy fees, and honoraria for professional input regarding lipid-altering agents, and/or has delivered lectures for American Association of Clinical Chemistry, Abbott, Amgen, AstraZeneca, Bristol-Myers Squibb, the U.S. Food and Drug Administration, F. Hoffman La Roche, Genentech, Genzyme, GlaxoSmithKline, ISIS, Merck & Co., the National Lipid Association, Novartis, Sankyo, Schering-Plough, and Wyeth. Dr. Kereiakes has reported that he has no relationships relevant to the contents of this paper to disclose.
- Received February 6, 2012.
- Revision received March 7, 2012.
- Accepted March 13, 2012.
- American College of Cardiology Foundation