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

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• IL-13 can recapitulate the key pathological and clinical features of asthma.• Exhaled NO (FeNO) concentrations are elevated under conditions of pulmonary inflammation, including asthma.• Therapies that inhibit signalling by both IL-13 and the functionally redundant cytokine IL-4 have demonstrated reductions in FeNO, although relationship to dose was not reported. WHAT THIS STUDY ADDS• This study provides the first report of the safety and pharmacokinetics of GSK679586, a novel humanized monoclonal antibody that prevents IL-13 from binding its two known receptors.• This is the first report of the effects on FeNO of a therapy targeting IL-13 alone. Inhibition of IL-13 signalling by GSK679586 produces dose-and time-dependent reductions in FeNO in mild intermittent asthmatics. Thus, FeNO appears to be a dose-and time-responsive clinical biomarker of IL-13 inhibition in mild asthma. AIMSIL-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. METHODSIn this randomized, double-blind study, healthy subjects received single intravenous infusions of GSK679586 (0.005, 0.05, 0.5, 2.5, 10 mg kg) or placebo and mild intermittent asthmatics received two once monthly intravenous infusions of GSK679586 (2.5, 10, 20 mg kg -1 ) or placebo. RESULTSGSK679586 displayed approximately linear pharmacokinetics (based on AUC and Cmax) 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. CONCLUSIONSGSK679586 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.

Strategies targeting the IL-4/IL-13 axes in disease

“…GSK679586 increased serum total IL-13 and reduced FeNO in 28 mild intermittent asthmatics versus placebo [170]. In a subsequent 12 week trial in 198 severe asthmatics who remained uncontrolled (ACQ7 P 1.5) despite being up-titrated to maximal doses of ICS (P1000 lg fluticasone per day), plus or minus LABA and OCS, GSK679586 was dosed intravenously at 10 mg/kg monthly.…”

“…GSK's mAb GSK679586 (M1) is a humanized IgG1 with an affinity (K D ) for IL-13 of 300-400 pM [170]. GSK679586 increased serum total IL-13 and reduced FeNO in 28 mild intermittent asthmatics versus placebo [170].…”

Novel Therapies for Eosinophilic Disorders

“…Although eosinophils express the IL-13 receptor, 85 the clinically beneficial effects of antagonizing IL-13 in vivo are more likely to be due to its effects on other cells, thereby secondarily improving eosinophilic inflammation. Several monoclonal antibodies that specifically block IL-13 biology are in clinical trials for either asthma, ulcerative colitis or EoE and include lebrikizumab, 86–88 anrukinzumab, 89 tralokinumab, 90–92 GSK679586 93, 94 and RPC4046 (https://clinicaltrials.gov/ct2/show/NCT02098473). However, by targeting IL-4Rα1 instead, blockade of both IL-4 and IL-13 biology can be achieved, as was explored with monoclonal antibody AMG 317 in asthma 95 and so far, more successfully in atopic dermatitis and asthma with dupilumab.…”

Non‐Clinical Pharmacokinetics, Prediction of Human Pharmacokinetics and First‐in‐Human Dose Selection for CNTO 5825, an Anti‐Interleukin‐13 Monoclonal Antibody

“…The selected maximum dose (10.0 mg/kg, IV) for FIH study of CNTO 5825 provided predicted systemic exposures that were below observed systemic exposures at NO-AEL in rats and cynomolgus monkeys. In addition, the selected doses (0.1, 0.3, 1.0, 3.0 and 10.0 mg/kg) of CNTO 5825 for FIH study were within the range of doses that have been evaluated in clinical studies of related anti-IL-13 mAbs [33][34][35][36].…”