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

Autor: Frazer Giles Morgan, Mark Jonathan Main, Peter Phillips, Pavan Vajjah, Roger Palframan, Malcolm Boyce, Foteini Strimenopoulou, Miren Zamacona, Lars Larsson, Margaret Jones, Gary Burgess, Alison Scrimgeour
Rok vydání: 2018
Předmět:
Zdroj: EBioMedicine. 35
ISSN: 2352-3964
Popis: Background 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. Methods 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). Findings 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. Interpretation 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 target in the airways of participants diagnosed with mild asthma. These data, together with the numerical improvements observed for predose FEV1, justify further clinical evaluation of VR942 in a broader population of patients with asthma, and continue to support the development of an inhaled anti-IL-13 antibody fragment as a potential future treatment that is alternative to monoclonal antibodies delivered via the parenteral route. Funding Study funding and funding for the medical writing and editorial support for preparation of the manuscript were split equally between the two study co-funders (Vectura Ltd and UCB Pharma).
Databáze: OpenAIRE
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