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 - PCSK9 Inhibition in Patients With Primary Hypercholesterolemia on Atorvastatin


Serum proprotein convertase subtilisin kexin 9 (PCSK9) binds to low-density lipoprotein (LDL) receptors, increasing serum LDL cholesterol (LDL-C). The current trial is a phase II trial designed to study the safety and efficacy of SAR236553, a monoclonal antibody to PCSK9, in patients with primary hypercholesterolemia.


SAR236553 would be superior to placebo in reducing LDL-C in patients with primary hypercholesterolemia.

Study Design

  • Placebo Controlled
  • Blinded
  • Randomized
  • Parallel

Patient Populations:

  • Age 18-75 years
  • LDL-C ≥100 mg/dl (2.59 mmol/L) while receiving a stable dose of atorvastatin 10, 20, or 40 mg daily for ≥6 weeks
  • Drug-naïve patients or patients either receiving a lipid-lowering therapy other than atorvastatin or not on a stable dose of atorvastatin 10, 20, or 40 mg daily for ≥6 weeks were eligible, provided that they met the inclusion criteria above after discontinuing all other lipid-lowering therapy and completing a 6-week run-in of atorvastatin 10, 20, or 40 mg daily

    Number of screened applicants: 514
    Number of enrollees: 183
    Duration of follow-up: 8 weeks
    Mean patient age: 56.7 years
    Percentage female: 52.5%


  • Females of childbearing potential not using an effective form of contraceptive
  • Pregnant or breast-feeding
  • Known sensitivities to monoclonal antibody therapies
  • Type 1 diabetes or type 2 diabetes requiring insulin, or with glycated hemoglobin ≥8.5%
  • Any clinically significant endocrine disease
  • Blood pressure >150/95 mm Hg
  • History of major coronary event within 6 months of screening
  • History of class II-IV heart failure
  • Positive test for hepatitis B or hepatitis C
  • Triglycerides >350 mg/dl
  • Abnormal sensitive thyroid stimulating hormone level
  • Serum creatinine >1.5 x upper limit of normal (ULN) in men or >1.4 x ULN in women
  • Creatine kinase >3 x ULN
  • Alanine aminotransferase or aspartate aminotransferase >2 x ULN

Primary Endpoints:

  • % change in LDL-C from baseline

Secondary Endpoints:

  • % change in HDL-C, triglycerides, apolipoprotein (Apo)-A, Apo-B, and Lp(a) from baseline
    Adverse events

Drug/Procedures Used:

Patients were randomized 1:1:1:1:1:1 to: 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 to mimic Q2W dosing. Randomization was stratified according to atorvastatin dose, to evaluate any effect of background atorvastatin dose on the LDL-C lowering efficacy of SAR236553.

Principal Findings:

A total of 183 patients were randomized, 30 to 50 mg Q2W, 31 to 100 mg Q2W, 29 to 150 mg Q2W, 28 to 200 mg Q4W, 30 to 300 mg Q4W, and 31 to placebo. Baseline characteristics were fairly similar between the six arms. About 12% had evidence of diabetes mellitus, 5% had coronary artery disease, 3% had peripheral arterial disease, 45% were hypertensive, and 86% were on lipid-lowering therapy. Baseline LDL-C was about 125-130 mg/dl in the six arms.

Efficacy: Least squares mean reductions in LDL-C from baseline were: 39.6% with 50 mg Q2W, 64.2% with 100 mg Q2W, 72.4% with 150 mg Q2W dose, 43.2% with 200 mg Q4W, and 47.7% with 300 mg Q4W, versus 5.1% with placebo (p < 0.0001 for all comparisons vs. placebo). Target LDL-C ≤100 mg/dl was significantly higher with SAR236553 than placebo (89-100% vs. 16%, p < 0.05). LDL-C reductions with SAR236553 were similar among atorvastatin doses. Changes in high-density lipoprotein cholesterol (HDL-C) were also noted: 6.7% vs. 4.1% vs. 5.5% vs. 6.3% vs. 8.5% vs. -1.0%, respectively (only 50 mg Q2W, 200 mg Q4W, and 300 mg Q4W demonstrated p < 0.05 as compared with placebo). Similarly, reductions in serum triglycerides were noted: 6.6% vs. 5.5% vs. 18.9% vs. 10.8% vs. 8.4% vs. -9.7%, respectively (only 150 mg Q2W had p < 0.05 when compared with placebo).

Safety: Mild injection site reactions such as erythema, pruritus, and rash were common in the SAR236553 arms, and more common with Q2W dosing than Q4W dosing. Adverse effects leading to drug discontinuation were noted in six patients, with three of these in the 200 mg Q4W arm. One patient developed leukocytoclastic vasculitis, which responded to prednisone. Muscle complaints were infrequent, and no elevations in liver-associated enzymes were noted.


The results of this trial indicate that SAR236553, a monoclonal antibody against the LDL-C receptor, is associated with significant reductions in LDL-C in patients with familial hypercholesterolemia who were already on atorvastatin. This appeared to be a dose-dependent effect, with the 100 mg Q2W and 150 mg Q2W doses demonstrating the highest efficacy. The incidence of side/adverse effects was low. PCSK9 inhibition thus appears to be a potent target for further LDL-C reduction. Whether this will influence cardiovascular outcomes will need to be tested in adequately powered randomized trials.


McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. 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. J Am Coll Cardiol 2012;Mar 26:[Epub ahead of print].

Presented by Dr. James McKenney at ACC.12 & ACC-i2 with TCT, Chicago, IL, March 26, 2012.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: Coronary Artery Disease, Follow-Up Studies, Prednisone, Hyperlipoproteinemia Type II, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Peripheral Arterial Disease, Heptanoic Acids, Hypercholesterolemia, Least-Squares Analysis, Proprotein Convertases, Pyrroles, Pruritus, Liver, Subtilisins, Erythema, Triglycerides, Diabetes Mellitus, Exanthema

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