Randomized study of the safety and pharmacodynamics of inhaled interleukin-13 monoclonal antibody fragment VR942

Interleukin-13 (IL-13) is a key mediator of T-helper-cell-type-2 (Th-2)-driven asthma, the inhibition of which may improve treatment outcomes. We examined the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of VR942, a dry-powder formulation containing CDP7766, a high-affinity anti-hu...

Full description

Saved in:
Bibliographic Details
Published in:EBioMedicine 2018-09, Vol.35, p.67-75
Main Authors: Burgess, Gary, Boyce, Malcolm, Jones, Margaret, Larsson, Lars, Main, Mark J., Morgan, Frazer, Phillips, Peter, Scrimgeour, Alison, Strimenopoulou, Foteini, Vajjah, Pavan, Zamacona, Miren, Palframan, Roger
Format: Article
Language:English
Subjects:
Administration, Inhalation
Adult
Antibodies, Monoclonal - administration & dosage
Antibodies, Monoclonal - adverse effects
Antibodies, Monoclonal - pharmacokinetics
Antibodies, Monoclonal - pharmacology
Asthma
Asthma - metabolism
Asthma - physiopathology
Exhalation
Female
Humans
Immunotherapy
Interleukin-13
Interleukin-13 - immunology
Least-Squares Analysis
Male
Nitric Oxide - metabolism
Pharmacodynamics
Research paper
Safety
Tolerability
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Interleukin-13 (IL-13) is a key mediator of T-helper-cell-type-2 (Th-2)-driven asthma, the inhibition of which may improve treatment outcomes. We examined the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of VR942, a dry-powder formulation containing CDP7766, a high-affinity anti-human-IL-13 antigen-binding antibody fragment being developed for the treatment of asthma. We conducted a phase 1, randomized, double-blind, placebo-controlled, ascending-dose study at Hammersmith Medicines Research, London, UK, which is now complete. Healthy adults aged 18–50 years (n = 40) were randomized 3:1 to a single inhaled dose of VR942 0.5, 1.0, 5.0, 10, or 20 mg, or placebo. Adults aged 18–50 years who were diagnosed with asthma for ≥6 months before screening, and had forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) values ≥70% of the predicted values at screening (n = 45), were randomized to once-daily inhaled VR942 0.5 or 10 mg, or placebo (2:2:1), or VR942 20 mg or placebo (3:2), for 10 days. All participants were randomized to receive VR942 or placebo based on a randomization list prepared by an independent HMR statistician using SAS® software (SAS Institute, Cary, NC). The primary outcome was safety and tolerability of VR942 (safety population, defined as all who received at least one dose of VR942 or placebo). This study is listed on ClinicalTrials.gov (NCT02473939). In the VR942 and placebo groups, treatment-emergent adverse events (TEAEs) were reported in 10/30 (33%) and 0/10 (0%) healthy participants, and in 16/29 (55%) and 9/16 (56%) participants with asthma, respectively. Mild intermittent wheezing occurred in 7 participants (VR942 20 mg, n = 4; corresponding placebo, n = 3), resolving spontaneously within 1 h. All TEAEs were mild or moderate; there were no deaths, serious adverse events, or clinically significant changes in vital signs, electrocardiograms, or laboratory parameters. There was no clinically significant immunogenicity, with only one participant with asthma considered positive for treatment-related immunogenicity for CDP7766. This study, considered to be the only example of a dry powder anti-IL-13 fragment antibody being administered via inhalation, demonstrated that single and repeat doses were well tolerated over a period of up to 10 days in duration. Rapid and durable inhibition of fractional exhaled nitric oxide (FeNO) (secondary outcome) provided evidence of pharmacological engagement with the IL-13 tar
ISSN:2352-3964
2352-3964
DOI:10.1016/j.ebiom.2018.07.035