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Keywords:

  • 5-lipoxygenase-activating protein inhibitor;
  • AM803;
  • bronchial allergen challenge;
  • GSK2190915;
  • leukotriene;
  • sputum eosinophils

Summary

Background

GSK2190915, a potent 5-lipoxygenase-activating protein inhibitor, prevents the synthesis of leukotrienes and 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE).

Objective

To assess the effect of GSK2190915 on the allergen-induced asthmatic responses.

Methods

Nineteen eligible male subjects with mild asthma were enrolled in and completed this four-centre, double-blind, two-way crossover study (ClinicalTrials.gov NCT00748306). Subjects took GSK2190915 100 mg and placebo orally once daily for 5 days in randomized order. On Day 1 and 4 they had a methacholine challenge, on Day 3 they had an inhaled allergen challenge, and on Days 4 and 6 they had sputum induction.

Results

GSK2190915 attenuated the early (0–2 h) and late (4–10 h) asthmatic responses to inhaled allergen compared with placebo. There was a statistically significant attenuation of the early asthmatic response (EAR) by GSK2190915; treatment difference of GSK2190915 vs. placebo for the minimum FEV1 EAR was 0.408 L (0.205, 0.611). There was a statistically significant attenuation of the late asthmatic response (LAR) by GSK2190915; the treatment difference of GSK2190915 vs. placebo for the minimum FEV1 LAR was 0.229 L (0.041, 0.417).

There was a statistically significant attenuation of allergen-induced sputum eosinophil count on Day 4 following GSK2190915: mean treatment difference (95% CI) between GSK2190915 and placebo was −9.95% (−18.15%, −1.77%). Compared with placebo, GSK2190915 100 mg reduced median sputum LTB4 by > 90% on Days 4 and 6. There was no effect on methacholine PC20 post allergen. GSK2190915 was generally well tolerated.

Conclusion and Clinical Relevance

GSK2190915 shows potential as a treatment for patients with asthma.