The first-in-human study of CNTO 7160, an anti-interleukin-33 receptor monoclonal antibody, in healthy subjects and patients with asthma or atopic dermatitis

Abstract

Aims: To assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of CNTO 7160, an anti-interleukin-33 receptor (IL-33R) monoclonal antibody, in healthy subjects and patients with asthma or atopic dermatitis (AD).

Methods: In Part 1 of this Phase I, randomized, double-blind, placebo-controlled study, healthy subjects (n = 68) received single ascending intravenous (IV) CNTO 7160 dose (0.001 to 10 mg/kg) or placebo. In Part 2, patients with mild asthma (n = 24) or mild AD (n = 15) received 3 biweekly IV CNTO 7160 doses (3 or 10 mg/kg) or placebo.

Results: CNTO 7160 was generally well tolerated, with 1 serious adverse event of severe cellulitis reported (AD, CNTO 7160, 3 mg/kg). CNTO 7160 exhibited nonlinear PK (0.01-10 mg/kg). Mean clearance decreased with increasing dose (2.43 to 18.03 mL/d/kg). CNTO 7160 PK was similar between healthy subjects and patients with asthma or AD (3 or 10 mg/kg). Free sIL-33R suppression was rapid and dose dependent. Ex vivo inhibition of p38 phosphorylation of basophils was dose-dependent (1-10 mg/kg) and sustained inhibition (≥75%) was observed at higher doses (3 or 10 mg/kg). PK/PD modelling and simulation suggests that 1 mg/kg IV every 2 weeks provides adequate systemic drug exposure for sustained inhibition of p38 phosphorylation of basophils. Despite confirmation of target engagement, no apparent CNTO 7160 clinical activity was observed in patients (asthma or AD).

Conclusion: This first-in-human study provides PK, PD and safety data, supporting further clinical investigation of CNTO 7160 in patients with asthma and AD.

Keywords: CNTO 7160; asthma; atopic dermatitis; interleukin-33 receptor; monoclonal antibody; pharmacodynamics.

Conflict of interest statement

Maarten van den Boer, Ivo Nnane, Bart Frederick, Zhenling Yao, Donald Raible, Cathye Shu, Patrick Branigan, Karen Duffy, Frédéric Baribaud, Damien Fink, Tong‐Yuan Yang and Zhenhua Xu are employees of Janssen Research & Development, LLC, a wholly owned subsidiary of Johnson & Johnson, Inc. Philipp Badorrek is an employee of Fraunhofer‐Gesellschaft zur Foerderung der angewandten Forschung e.V. Fraunhofer was paid by Janssen Research & Development, LLC to conduct this study.

© 2020 The British Pharmacological Society.

Figures

FIGURE 1

Mean (standard deviation) serum CNTO 7160 concentration–time profiles (semi‐log scale) after a single CNTO 7160 IV infusion in healthy subjects (A), or biweekly CNTO 7160 IV infusions in patients with asthma or atopic dermatitis (B)

FIGURE 2

Mean (standard deviation) percent ex‐vivo IL‐33‐induced p38 phosphorylation of basophils over time after a single CNTO 7160 intravenous infusion in healthy subjects (A), or biweekly CNTO 7160 intravenous infusions in patients with asthma or atopic dermatitis (B)

FIGURE 3

Pharmacokinetic–pharmacodynamic relationship of CNTO 7160 concentration and the percent inhibition of ex vivo interleukin‐33‐induced p38 phosphorylation of basophils (A), and the model‐predicted CNTO7160 concentrations following intravenous administration of 1 mg/kg every 2 weeks (B). The vertical blue and red dotted lines in plot a represent EC50 and EC90 estimated from the pharmacokinetic–pharmacodynamic model, respectively. The lower and upper lines of the shaded area in B, represent the 10th and 90th percentile of the model‐predicted CNTO 7160 concentrations, respectively, following intravenous administrations of 1 mg/kg every 2 weeks. CI, confidence interval

FIGURE 4

Mean (standard deviation) percent predicted forced expiratory volume in the first second (FEV1) change from baseline–time profiles after biweekly CNTO 7160 IV infusions in patients with asthma

FIGURE 5

Mean (standard deviation) change from baseline in SCORing Atopic Dermatitis (SCORAD) scores after biweekly CNTO 7160 IV infusions in patients with atopic dermatitis