Tolerability, Safety, Pharmacokinetics, and Immunogenicity of a Novel SARS-CoV-2 Neutralizing Antibody, Etesevimab, in Chinese Healthy Adults: a Randomized, Double-Blind, Placebo-Controlled, First-in-Human Phase 1 Study

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread rapidly worldwide. This study is the first to report the tolerability, safety, pharmacokinetics (PK), and immunogenicity of a recombinant human anti-SARS-CoV-2 monoclonal antibody, etesevimab (CB6, JS016, LY3832479, or LY-CoV016), in healthy adults. This paper describes a randomized, double-blind, placebo-controlled, phase 1 study. A total of 40 participants were enrolled to receive a single intravenous dose of either etesevimab or placebo in one of four sequential ascending intravenous dose cohorts. All 40 participants completed the study. Seventeen (42.5%) participants experienced 22 treatment emergent adverse events (TEAEs) that were drug-related, and the rates of these TEAEs among different dose cohorts were numerically comparable. No difference was observed between the combined etesevimab group and the placebo group. The exposure after etesevimab infusion increased in an approximately proportional manner as the dose increased from 2.5 to 50 mg/kg. The elimination half-life (t1/2) value did not differ among different dose cohorts and was estimated to be around 4 weeks. Etesevimab was well tolerated after administration of a single dose at a range of 2.5 mg/kg to 50 mg/kg in healthy Chinese adults. The PK profiles of etesevimab in healthy volunteers showed typical monoclonal antibody distribution and elimination characteristics. (This study has been registered at ClinicalTrials.gov under identifier NCT04441918.).

Keywords: COVID-19; JS016; LY3832479; SARS-CoV-2; anti-spike neutralizing antibodies; etesevimab; neutralizing antibodies; pharmacokinetics.

Figures

FIG 1

CONSORT flow diagram of the JS016-001-I study. Forty healthy adults were allocated to four different dose cohorts. All participants received a single dose of the one dose level. In each dose cohort, the participants were randomly allocated to receive etesevimab or placebo at a ratio of 3:1. The randomization scheme was generated using an interactive web response system (IWRS). All participants completed the study at the time of submission of the manuscript.

FIG 2

Mean (± standard deviation [SD]) of etesevimab concentration-time profiles in healthy participants following single-dose intravenous infusions. PK samples were collected on day 1 (dosing) and days 2, 3, 4, 8, 15, 22, 29, 36, 57, 71, and 85 postdose, or at early discontinuation. The left side of the figure represents a linear scale; the right side of the figure represents a semi-log scale. At each time point, the error bars represent the SD. Concentration values less than the lower limit of quantitation (LLQQ) were set as 0 on the linear scale plot and were omitted on the semi-log plot. The mean serum concentrations of etesevimab in healthy participants increased as the dose increased from 2.5 to 50 mg/kg.

FIG 3

Comparison of exposure parameters (the first row) or dose-normalized exposure parameters (the second row) of etesevimab across different dose cohorts. Cmax, maximum concentration; AUC0–last, area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration; AUC0–∞, area under the curve from time zero to infinity. Note that in each boxplot, the horizontal line at the center of the box is the median, the box represents the interquartile distance, and whiskers represent ≤1.5 times the interquartile range (75th to 25th quartile). In the first row, the value below the boxplot is the number of participants included in the analysis. Hollow circles represent outliers. The exposure parameters (Cmax and AUC) increased in an approximately proportional manner as the dose increased from 2.5 to 50 mg/kg. In the second row, the value below the boxplot is the number of participants included in the analysis. Hollow circles represent outliers. After dose normalization of exposure parameters, all boxes (cohorts) were distributed on a uniform horizontal line, indicating the exposure parameters (Cmax and AUC) increased in an approximately proportional manner as the dose increased from 2.5 to 50 mg/kg.

FIG 4

Goodness-of-fit plots for the population pharmacokinetic model of etesevimab. The black dashed line indicates the unit line. The red line indicates the locally weighted regression line (Loess).

FIG 5

Prediction-corrected visual predictive check (pcVPC) for final PPK model of etesevimab. The circles indicate the observed concentration corrected by prediction. The solid line is the median for prediction-corrected observed data, and the deep shaded area is the 95% confidence interval. The two dashed lines represent the 90% and 10% percentiles for prediction-corrected observed data, respectively, whereas the shallow shaded area corresponds to the 95% confidence interval. The inset graph shows the pcVPC results within 3 days following drug administration.

FIG 6

Simulation of a PPK model of etesevimab following a single administration. The left and right panels show the time profiles of etesevimab in the central and peripheral compartments, respectively. The doses are 700, 1,400, or 2,800 mg. The infusion time was 1 h. The solid line indicates the median of the predicted concentration and the shaded area indicates the 90% confidence interval.