Inhibition of the early asthmatic response to inhaled allergen by the 5-lipoxygenase activating protein inhibitor GSK2190915: a dose–response study

Abstract

Dave Singh,1 Malcolm Boyce,2 Virginia Norris,3 Sandra E Kent,3 Jane H Bentley31University of Manchester, Medicines Evaluation Unit, University Hospital of South Manchester, Manchester, UK; 2Hammersmith Medicines Research, London, UK; 3GlaxoSmithKline, Middlesex, UKBackground: GSK2190915, a 5-lipoxygenase activating protein inhibitor, inhibits the production of cysteinyl leukotrienes and leukotriene B4 and 5-oxo-6,8,11,14-eicosatetraenoic acid. We have previously reported that GSK2190915 100 mg daily inhibits early and late asthmatic responses to inhaled allergen; the effects of lower doses have not been reported. This study assessed the dose–response effects of GSK2190915 10 mg and 50 mg on the early asthmatic response (EAR) to inhaled allergen.Methods: Nineteen subjects with mild asthma and an EAR were enrolled in a randomized, double-blind, three-way crossover study of GSK2190915 10 mg, 50 mg, and placebo orally once-daily for 3 days. Allergen challenge was performed 2 hours after the third dose.Results: Compared with placebo, GSK2190915 10 mg and 50 mg caused significant, dose-dependent attenuation of the minimum forced expiratory volume at 1 second (FEV1) absolute change from baseline; mean treatment differences were 0.21 L (95% confidence interval [CI] 0.04 L, 0.38 L) and 0.41 L (95% CI 0.24 L, 0.58 L), respectively. GSK2190915 50 mg was more effective than 10 mg; mean difference between treatments was 0.20 L, (95% CI 0.03 L, 0.36 L). Compared with placebo, GSK2190915 50 mg, but not 10 mg, significantly inhibited the weighted mean FEV1 absolute change from baseline.Conclusion: GSK2190915 50 mg attenuated the EAR similarly to GSK2190915 100 mg in our previous study, suggesting 50 mg is at the top of the dose–response curve. GSK2190915 10 mg is a suboptimal dose. The EAR can be used to assess the therapeutic dose of a new treatment for asthma.Keywords: GSK2190915, FLAP inhibitor, early asthmatic response