Effects of a FLAP inhibitor, GSK2190915, in asthmatics with high sputum neutrophils

• Published in: Pulmonary pharmacology & therapeutics Vol. 27; no. 1; pp. 62 - 69
• Main Authors: Chaudhuri, R, Norris, V, Kelly, K, Zhu, C.-Q, Ambery, C, Lafferty, J, Cameron, E, Thomson, N.C
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2014
• Subjects: 5-Lipoxygenase-activating protein (FLAP) inhibitor; 5-Lipoxygenase-Activating Protein Inhibitors - pharmacology; 5-Lipoxygenase-Activating Protein Inhibitors - therapeutic use; Adult; Aged; Asthma; Asthma - drug therapy; Asthma - physiopathology; Cross-Over Studies; Double-Blind Method; Female; GSK2190915; Humans; Indoles - pharmacology; Indoles - therapeutic use; Leukocyte Count; Male; Medical Education; Middle Aged; Neutrophils - metabolism; Pentanoic Acids - pharmacology; Pentanoic Acids - therapeutic use; Pulmonary/Respiratory; Sputum - metabolism; Sputum neutrophilia; Time Factors; Treatment Outcome; Young Adult; Sputum neutrophilia; GSK2190915; 5-Lipoxygenase-activating protein (FLAP) inhibitor; Asthma
• ISSN: 1094-5539; 1522-9629
• DOI: 10.1016/j.pupt.2013.11.007

Abstract Patients with refractory asthma frequently have neutrophilic airway inflammation and respond poorly to inhaled corticosteroids. This study evaluated the effects of an oral 5-lipoxygenase-activating protein (FLAP) inhibitor, GSK2190915, in patients with asthma and elevated sputum neutrophils. Patients received 14 (range 13–16) days treatment with GSK2190915 100 mg and placebo with a minimum 14 day washout in a double-blind, cross-over, randomised design ( N  = 14). Sputum induction was performed twice pre-dose in each treatment period to confirm sputum neutrophilia, and twice at the end of each treatment period. The primary endpoint was the percentage and absolute sputum neutrophil count, averaged for end-of-treatment visits. GSK2190915 did not significantly reduce mean percentage sputum neutrophils (GSK2190915-placebo difference [95% CI]: −0.9 [−12.0, 10.3]), or mean sputum neutrophil counts (GSK2190915/placebo ratio [95% CI]: 1.06 [0.43, 2.61]). GSK2190915 resulted in a marked suppression (>90%) of sputum LTB4 and urine LTE4 , but did not alter clinical endpoints. There were no safety issues. Despite suppressing the target mediator LTB4 , FLAP inhibitor GSK2190915 had no short-term effect on sputum cell counts or clinical endpoints in patients with asthma and sputum neutrophilia.