Abstract
BackgroundGSK2190915 is a high affinity 5-lipoxygenase-activating protein inhibitor being developed for the treatment of asthma. The objective of this study was to evaluate GSK2190915 efficacy, dose–response and safety in subjects with persistent asthma treated with short-acting beta2-agonists (SABAs) only.MethodsEight-week multicentre, randomised, double-blind, double-dummy, stratified (by age and smoking status), parallel-group, placebo-controlled study in subjects aged ≥12 years with a forced expiratory volume in 1 second (FEV1) of 50–85% predicted. Subjects (n = 700) were randomised to receive once-daily (QD) oral GSK2190915 (10–300 mg), twice-daily inhaled fluticasone propionate 100 μg, oral montelukast 10 mg QD or placebo. The primary endpoint was mean change from baseline (randomisation) in trough (morning pre-dose and pre-rescue bronchodilator) FEV1 at the end of the 8-week treatment period. Secondary endpoints included morning and evening peak expiratory flow, symptom-free days and nights, rescue-free days and nights, day and night-time symptom scores, day and night-time rescue medication use, withdrawals due to lack of efficacy, Asthma Control Questionnaire and Asthma Quality of Life Questionnaire scores.ResultsFor the primary endpoint, there was no statistically significant difference between any dose of GSK2190915 QD and placebo. However, repeated measures sensitivity analysis demonstrated nominal statistical significance for GSK2190915 30 mg QD compared with placebo (mean difference: 0.115 L [95% confidence interval: 0.00, 0.23], p = 0.044); no nominally statistically significant differences were observed with any of the other doses. For the secondary endpoints, decreases were observed in day-time symptom scores and day-time SABA use for GSK2190915 30 mg QD versus placebo (p ≤ 0.05). No dose–response relationship was observed for the primary and secondary endpoints across the GSK2190915 dose range studied; the 10 mg dose appeared to be sub-optimal. GSK2190915 was associated with a dose-dependent reduction in urinary leukotriene E4. The profile and incidence of adverse events were similar between treatment groups.ConclusionEfficacy was demonstrated for GSK2190915 30 mg compared with placebo in day-time symptom scores and day-time SABA use. No additional improvement on efficacy endpoints was gained by administration of GSK2190915 doses greater than 30 mg. GSK2190915 was well-tolerated. These results may support further studies with GSK2190915 30 mg.Trial registrationClinicaltrials.gov: NCT01147744.
Highlights
GSK2190915 is a high affinity 5-lipoxygenase-activating protein inhibitor being developed for the treatment of asthma
Administration of GSK2190915 for 8 weeks led to numerical increases in mean change from baseline in trough forced expiratory volume in 1 second (FEV1) at all doses, none of these achieved statistical significance compared with placebo
The results reported in this study population suggest that inhibition of FLAP may not provide further improvement on efficacy endpoints beyond those achieved with cysteinyl LTs (cysLTs) receptor antagonism
Summary
GSK2190915 is a high affinity 5-lipoxygenase-activating protein inhibitor being developed for the treatment of asthma. Leukotrienes (LTs) are produced by mast cells, eosinophils, macrophages and neutrophils in response to allergic or inflammatory stimuli [1,2,3] They are products of the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism and their synthesis is initiated by 5-LO in concert with 5-lipoxygenase-activating protein (FLAP). Concentrations of the products of the 5-LO pathway are increased in patients with asthma of all severities despite treatment with corticosteroids [8,9,10], the cornerstone anti-inflammatory therapy in asthma. Administration of the 5-LO inhibitor zileuton to patients with severe asthma led to improvements in lung function [16] These observations indicate that inhibition of the production of LTs via the two branches of the 5-LO pathway could confer beneficial effects on patients with persistent asthma
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