Abstract 10701: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Ascending Single Dose Study to Evaluate the Safety, Tolerability and Pharmacodynamics of AMG145
Introduction: The low-density lipoprotein receptor (LDL-R) plays a vital role in maintenance of cholesterol and plasma low-density lipoprotein-cholesterol (LDL-C) levels. Proprotein convertase subtilisin/kexin type 9 (PCSK9) downregulates LDLR levels, leading to increased circulating LDL-C. We assessed the hypothesis that AMG145, a fully human monoclonal antibody against PCSK9, lowers circulating LDL-C. Herein, we report the first-in-human randomized, double-blind, placebo-controlled, ascending-single-dose study of AMG145 in healthy volunteers.
Methods: 7 dose cohorts (A-G) were used in healthy adult subjects to evaluate safety, tolerability, pharmacokinetics and pharmacodynamics (LDL-C). 5 SC cohorts and 2 IV cohorts were employed in this trial. N=8 in each cohort, randomized 3:1, AMG145:placebo. Eligibility criteria included: age 18-45 years, LDL-C 100-190 mg/dL; body mass index 18-32 kg/m2 and no comedications 14 days prior. Safety and tolerability following a single dose was the primary endpoint.
Results: Single SC and IV administrations of AMG145 decreased mean LDL-C up to 64% relative to placebo subjects. The magnitude of LDL-C lowering, time to nadir, and duration of LDL-C lowering were all dose-dependent. Qualitatively, results for total cholesterol and apo-B were similar to those for LDL-C. AMG145 potently suppressed serum unbound PCSK9. The dose response for decrease in unbound PCSK9 correlated well with the dose responses for decreases in LDL-C, total cholesterol, and apo-B. AMG145 had no effects on serum triglycerides, HDL-C, or apo-A1. No serious adverse events were reported and no subjects discontinued the study due to an adverse event. The incidence of treatment-emergent adverse events was similar among subjects treated with AMG145 and subjects treated with placebo. No relationship was apparent between the subject incidence of adverse events and the dose of AMG145.
Conclusions: AMG145 decreased unbound PCSK9 levels and lowered circulating LDL-C, total cholesterol and apo-B. Single doses of administered SC and IV were well tolerated in healthy volunteers.
- © 2011 by American Heart Association, Inc.