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.
CNTO 7160
asthma
atopic dermatitis
interleukin-33 receptor
monoclonal antibody
pharmacodynamics
Journal
British journal of clinical pharmacology
ISSN: 1365-2125
Titre abrégé: Br J Clin Pharmacol
Pays: England
ID NLM: 7503323
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
09
09
2019
revised:
17
04
2020
accepted:
22
04
2020
pubmed:
18
5
2020
medline:
30
6
2021
entrez:
17
5
2020
Statut:
ppublish
Résumé
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). 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. 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). This first-in-human study provides PK, PD and safety data, supporting further clinical investigation of CNTO 7160 in patients with asthma and AD.
Identifiants
pubmed: 32415720
doi: 10.1111/bcp.14361
pmc: PMC7688540
doi:
Substances chimiques
Antibodies, Monoclonal
0
Interleukin-1 Receptor-Like 1 Protein
0
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2507-2518Subventions
Organisme : Janssen Research and Development
Informations de copyright
© 2020 The British Pharmacological Society.
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