A phase 1, randomized, placebo-controlled, dose-escalation study of an anti-IL-13 monoclonal antibody in healthy subjects and mild asthmatics

Abstract

Aims: IL-13 is implicated as an important mediator of the pathology of asthma. This first clinical study with GSK679586, a novel humanized anti-IL-13 IgG1 monoclonal antibody, evaluated the safety, pharmacokinetics and pharmacodynamics of escalating single and repeat doses of GSK679586.

Methods: In this randomized, double-blind study, healthy subjects received single intravenous infusions of GSK679586 (0.005, 0.05, 0.5, 2.5, 10 mg kg(-1)) or placebo and mild intermittent asthmatics received two once monthly intravenous infusions of GSK679586 (2.5, 10, 20 mg kg(-1)) or placebo.

Results: GSK679586 displayed approximately linear pharmacokinetics (based on AUC and C(max)) with limited accumulation upon repeat administration. In mild intermittent asthmatics, treatment with GSK679586 produced an increase in serum total IL-13 concentrations, indicative of GSK679586-IL-13 complex formation. Additionally, mean levels of exhaled nitric oxide (FeNO), a marker of pulmonary inflammation, were reduced relative to baseline at 2.5, 10 and 20 mg kg(-1) doses of GSK679586 at both 2 weeks (19%, 44% and 52% decreases) and 8 weeks (29%, 55% and 42% decreases) after the second infusion. GSK679586 was well tolerated; the incidence of AEs was comparable across all presumed biologically active doses and there were no treatment-related SAEs.

Conclusions: GSK679586 demonstrated dose-dependent pharmacological activity in the lungs of mild intermittent asthmatics. These findings, together with the favourable safety profile and advantageous PK characteristics of a monoclonal antibody (e.g. a long half-life supporting less frequent dosing), warrant further investigation of GSK679586 in a broader asthma patient population.

Trial registration: ClinicalTrials.gov NCT00411814.

Figure 1

CONSORT diagram of the sequential enrollment and treatment of (A) healthy subjects in part 1 followed by (B) mild intermittent asthmatic subjects in part 2. Dose of GSK679586 in mg kg^–1. Subjects were lost to follow-up for the final visit for PK and immunogenicity testing

Figure 2

Geometric mean (±95% CI) serum total IL-13 concentrations (log scale) by time and treatment for mild intermittent asthmatic subjects in part 2. , 20 mg kg^–1 (n = 9); , 10 mg kg^–1 (n = 6); , 2.5 mg kg^–1 (n = 6); , placebo (n = 7). LLQ lower limit of quantification (30.86 pg ml^–1). Samples with total IL-13 below LLQ were imputed as ½ of LLQ (15.43 pg ml^–1)

Figure 3

By treatment plot of mean (±SD) % change from baseline in FeNO 2 weeks and 8 weeks after the second infusion of GSK679586. , placebo; , 2.5 mg kg^–1; , 10 mg kg^–1; , 20 mg kg^–1