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

Chao Liu; Hong Lu; Fei Yuan; Wei-Li Chen; Hong-Rong Xu; Hui Li; Cheng-Pang Hsu; Ogo Egbuna; Jihua Wu; Clapton Dias; Bassam Abosaleem; Jitesh Rana; Maria Laura Monsalvo; Xue-Ning Li; Zhigang Yu

doi:10.2147/CPAA.S208033

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

Clin Pharmacol. 2019 Oct 23:11:145-153. doi: 10.2147/CPAA.S208033. eCollection 2019.

Authors

Affiliations

¹ Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
² Clinical Pharmacology and Early Development, Amgen China R & D Center, Shanghai, People's Republic of China.
³ Research & Development, Amgen Inc., Thousand Oaks, CA, USA.
⁴ Clinical Development, Amgen China R & D Center, Shanghai, People's Republic of China.

Abstract

Purpose: 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 (C_max) and area under the drug concentration-time curve from time 0 to time of last quantifiable concentration (AUC_last).

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) C_max was 13.8 (3.6 μg/mL and 67.6 (15.2) μg/mL, respectively, and mean (SD) AUC_last 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: PCSK9 inhibitors; cardiovascular disease; ethnic sensitivity; homozygous familial hypercholesterolemia; monoclonal antibodies.

Publication types

Case Reports