A Phase 1, Randomized, Double-Blind, Single-Dose, Placebo-Controlled Safety, Tolerability, And Pharmacokinetic/Pharmacodynamic Study Of Evolocumab In Healthy Chinese Subjects

Abstract

Chao Liu,1 Hong Lu,2 Fei Yuan,1 Wei-Li Chen,1 Hong-Rong Xu,1 Hui Li,1 Cheng-Pang Hsu,3 Ogo Egbuna,3 Jihua Wu,2 Clapton Dias,3 Bassam Abosaleem,3 Jitesh Rana,3 Maria Laura Monsalvo,3 Xue-Ning Li,1 Zhigang Yu4 1Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Clinical Pharmacology and Early Development, Amgen China R & D Center, Shanghai, People’s Republic of China; 3Research & Development, Amgen Inc., Thousand Oaks, CA, USA; 4Clinical Development, Amgen China R & D Center, Shanghai, People’s Republic of ChinaCorrespondence: Xue-Ning LiDepartment of Clinical Pharmacology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People’s Republic of ChinaTel [phone]Email [email protected] YuResearch & Development, Amgen Inc., Thousand Oaks, CA 91320, USATel [phone]Email [email protected]: Evolocumab is a human monoclonal antibody that reduces circulating low-density lipoprotein cholesterol (LDL-C) by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9). Data on evolocumab pharmacokinetics and pharmacodynamics are derived mostly from Caucasian populations. The objectives of this study were to characterize the single-dose pharmacokinetic and pharmacodynamic parameters, safety, and tolerability of evolocumab in healthy Chinese subjects.Subjects and methods: This was a phase 1, randomized, double-blind, placebo-controlled study (CTR20150465). Two parallel cohorts were randomized 5:1 to receive single subcutaneous injections of either evolocumab (140 mg or 420 mg) or placebo. Pharmacokinetics, pharmacodynamics, and safety were evaluated through day 85. The primary endpoints were maximum concentration (Cmax) and area under the drug concentration–time curve from time 0 to time of last quantifiable concentration (AUClast).Results: Thirty-six men (median age 26) were enrolled to receive evolocumab 140 mg (n=15), evolocumab 420 mg (n=15), or placebo (n=6). After 140 mg and 420 mg evolocumab, mean (SD) Cmax was 13.8 (3.6 μg/mL and 67.6 (15.2) μg/mL, respectively, and mean (SD) AUClast was 166 (55) day·μg/mL and 1110 (274) day·μg/mL, respectively. LDL-C declined reversibly, with reductions of 70% at 140 mg and 71% at 420 mg. Maximum effects on LDL-C and PCSK9 levels were reached by day 15 and 24 hrs, respectively, at 140 mg, and by day 22 and 4 hrs, respectively, at 420 mg. No serious adverse events occurred and the overall incidence of treatment-emergent adverse events was similar for evolocumab and placebo: 26.7% (140 mg) and 33.3% (placebo); 66.7% (420 mg) and 66.7% (placebo).Conclusion: In this population of healthy Chinese subjects, single 140 mg and 420 mg doses of evolocumab exhibited nonlinear kinetics and more than dose-proportional increases in exposure, were associated with up to 71% reduction in LDL-C, and demonstrated a safety profile similar to placebo.Keywords: cardiovascular disease, homozygous familial hypercholesterolemia, PCSK9 inhibitors, monoclonal antibodies, ethnic sensitivity

Keywords

• cardiovascular disease
• homozygous familial hypercholesterolemia
• PCSK9 inhibitors
• monoclonal antibodies
• ethnic sensitivity