Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Alirocumab in Healthy Chinese Subjects: A Randomized, Double-Blind, Placebo-Controlled, Ascending Single-Dose Study

Abstract

Background: The addition of alirocumab (a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 [PCSK9]) to background statin therapy provides significant incremental low-density lipoprotein cholesterol (LDL-C) lowering and cardiovascular event risk reduction.

Objectives: Our objectives were to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of alirocumab in healthy Chinese subjects.

Methods: In this double-blind, placebo-controlled, phase I study, 35 Chinese subjects (aged 21-45 years) with baseline LDL-C > 100 mg/dL (2.59 mmol/L) were randomized to receive a single 1 mL subcutaneous injection of alirocumab 75, 150, or 300 mg, or placebo, and followed up for ~ 12 weeks.

Results: Treatment-emergent adverse events, most frequently nasal congestion and dry throat, were reported in three of seven or eight subjects in each alirocumab dose group (two of seven in the placebo group). One patient receiving alirocumab 300 mg had a mild local injection-site reaction. No alirocumab recipients demonstrated antidrug antibodies. Maximum alirocumab serum concentrations (6-34 mg/dL) occurred at a median of 3-7 days across the dose groups. Maximum mean LDL-C reductions from baseline were observed on days 8, 15, and 22 with alirocumab 75 (55.3%), 150 (63.7%), and 300 mg (73.7%), respectively. Mean free PCSK9 levels were reduced to below the lower limit of quantification within 4 h of dosing. Total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B were reduced with alirocumab.

Conclusions: In Chinese subjects, alirocumab 75, 150, and 300 mg was safe and well-tolerated. Pharmacokinetic/pharmacodynamic parameters, including clinically meaningful reductions in LDL-C and other lipids/lipoproteins, were consistent with data from Japanese and Western populations. Clinicaltrials.gov identifier: NCT02979015.

Conflict of interest statement

HL, YW, ZY, SZ, and XX are employees of the Peking University Third Hospital. MS, OV, YWW, MTB-D and JL are employees of and shareholders in Sanofi. YZ is an employee of and shareholder in Regeneron Pharmaceuticals, Inc.

Figures

Fig. 1

Subject flow though the study. aA total of 35 subjects were enrolled: 31 were initially randomized, but four subjects were replaced because of non-compliance. bOne treated subject did not finish the study visits because of a serious adverse event (acute appendicitis). GCP good clinical practice

Fig. 2

Mean serum alirocumab concentration versus time profiles after single subcutaneous administration of alirocumab 75, 150, or 300 mg (linear scale). LOQ limit of quantification, SD standard deviation

Fig. 3

Mean a percentage and b absolute change from baseline in LDL-C to EOS after single-dose alirocumab or placebo administration. Baseline = day 1 pre-dose assessment. EOS end of study, LDL-C low-density lipoprotein cholesterol, SD standard deviation

Fig. 4

Mean a free and b total PCSK9 concentrations in serum over time after single subcutaneous administration of alirocumab 75, 150, or 300 mg. Baseline = day 1 pre-dose assessment. PCSK9 proprotein convertase subtilisin/kexin type 9, SD standard deviation

Fig. 5

Relationship between alirocumab, free PCSK9, and mean percentage change in LDL-C levels following single-dose subcutaneous administration of alirocumab a 75, b 150, and c 300 mg. Baseline = day 1 pre-dose assessment. LDL-C low-density lipoprotein cholesterol, PCSK9 proprotein convertase subtilisin/kexin type 9

Fig. 6

Mean change (%) from baseline (day 1) to EOS in a TC, b non-HDL-C, and c ApoB after subcutaneous single-dose alirocumab or placebo administration. Baseline = day 1 pre-dose assessment. Apo apolipoprotein, EOS end of study, non-HDL-C non-high-density lipoprotein cholesterol, SD standard deviation, TC total cholesterol