Abstract 23251: Safety, Lipid, and Lipoprotein Effects of REGN727/SAR236553, a Fully-Human Proprotein Convertase Subtilisin Kexin 9 (PCSK9) Monoclonal Antibody Administered Intravenously to Healthy Volunteers
Background: PCSK9 plays a critical role in determining circulating LDL-C levels by regulating hepatocyte cell surface LDLR. Gain-of-function mutations in PCSK9 cause autosomal dominant hypercholesterolemia, while loss-of-function mutations are associated with reduced LDL-C levels and protection from cardiovascular disease. REGN727/SAR236553, a fully human monoclonal antibody directed against PCSK9, is being evaluated as a new therapeutic modality for hypercholesterolemia. We report the safety and pharmacodynamic effects of REGN727 from a phase 1 clinical trial.
Methods: We randomized healthy men and women ages 18–65 years with LDL-C > 100 mg/dL and fasting triglycerides ≤ 200 mg/dL who were not indicated for statin therapy. Forty subjects were randomized to receive a single intravenous dose of one of five escalating doses of REGN727 (n=6 per cohort) or placebo (n=2 per cohort). Study visits were conducted up to day 106 after administration. Safety measures included treatment-emergent adverse experiences, serum chemistry (including liver transaminases, CPK, and troponin I), ECG, and hematology. Pharmacodynamic measures included LDL-C, HDL-C, non-HDL-C, ApoB, ApoA1, and triglycerides.
Results: Administration of all doses of REGN727 to healthy volunteers in this study was generally safe and well tolerated. There were no clinically meaningful elevations of liver transaminases. One subject experienced a creatine phosphokinase > 10X ULN that was associated with strenuous physical exercise. Both the degree and duration of LDL-C reduction from baseline were dose-dependant. Mean LDL-C reduction from baseline exceeded 60% and lasted for at least 30 days in the higher dose cohorts. There was no apparent change in HDL-C from baseline. Effects on apolipoprotein concentrations (≥ 50% in the higher dose cohorts) were commensurate with the effects on cholesterol levels.
Conclusions: Inhibition of PCSK9 activity by the single-dose administration of REGN727 to healthy volunteers resulted in dose-dependant reductions in LDL-C and ApoB. No dose-limiting toxicities were observed. REGN727 is being investigated in further studies for the treatment of hypercholesterolemia.
- © 2010 by American Heart Association, Inc.