Abstract 9318: The Safety, Pharmacokinetics, Pharmacodynamics and Immunogenicity of Ebronucimab in Healthy Volunteers: Result From a Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Dose-Escalation Study

Abstract

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have demonstrated to be effective therapeutic agents for lowing low-density lipoprotein cholesterol (LDL-C). Ebronucimab (AK102) is a novel fully human immunoglobulin G1 (IgG1) monoclonal antibody against PCSK9. The objective of this study is to investigate the safety and tolerability of ebronucimab in healthy subjects. Methods: A total of 32 healthy adult subjects were planned to be enrolled and treated in a dose escalation manner. In each cohort, 8 subjects were randomized in a 3:1 ratio to receive a single dose of ebronucimab (75, 150, 300 or 500 mg) or matching placebo via subcutaneous injection (Figure 1). Blood was drawn at pre-selected timepoints to evaluate the pharmacokinetic parameters, free PCSK9 concentration and anti-drug antibody (ADA). Safety assessment was carried out up to day 85 ± 3 or early termination visit. Results: Safety Among the 32 subjects recruited, 87.5% (21/24) subjects administrated ebronucimab and 75% (6/8) subjects treated with placebo reported treatment emergent adverse events (TEAEs). The majority of adverse events were mild and moderate in severity. No relationship was identified between the dose of ebronucimab and the incidence of TEAEs. No TEAEs leading to study discontinuation and death were reported. Pharmacokinetics (PK)/Pharmacodynamics (PD) Following a single subcutaneous injection of 75 mg to 500 mg ebronucimab in healthy subjects, the median of T max ranged from 2.0 to 6.0 days and t 1/2 was within 4.11 to 5.01 days across cohorts. C max, AUC 0-t , and AUC 0-∞ increased approximately in a dose-proportional manner, see Table 1 and Figure 2. Serum free PCSK9 was almost completely inhibited after ebronucimab injection. The lowest level of free PCSK9 was observed around 2 days post administration and maintained at a low level 14-22 days post injection, see Figure 3. Immunogenicity A total of 3 subjects were tested ADA positive at least once during the study (75 mg, 1 subject; 500 mg, 2 subjects). The incidence of ADAs in subjects treated with ebronucimab was 12.5 % (3/24). Conclusions: Ebronucimab was well tolerated in healthy subjects and no special safety signal was identified during the study.