Efficacy, safety and tolerability of GSK2190915, a 5-lipoxygenase activating protein inhibitor, in adults and adolescents with persistent asthma: a randomised dose-ranging study

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.

The novel benzimidazole derivative BRP‐7 inhibits leukotriene biosynthesis in vitro and in vivo by targeting 5‐lipoxygenase‐activating protein (FLAP)

“…BAY X-1005/DG-031) or hybrids thereof (MK591), have been developed and evaluated in clinical trials, but these compounds were not further explored (Evans et al, 2008;Sampson, 2009;Ferguson, 2012). Recent re-assessment of FLAP inhibitors of the indole series provided GSK2190915 as a promising candidate that is currently undergoing phase II trials in patients with asthma (Stock et al, 2011;Bain et al, 2013;Follows et al, 2013;Kent et al, 2013;Snowise et al, 2013). Also, the anti-inflammatory compound licofelone, which was originally developed as a dual inhibitor of the COX and 5-LOX pathways (Laufer et al, 1994a,b), targets FLAP (Fischer et al, 2007) and has reached clinical phase III for osteoarthritis (Raynauld et al, 2009).…”

Exploring the roles of UGT1A1 and UGT1A3 in oral clearance of GSK2190915, a 5-lipoxygenase-activating protein inhibitor

“…Substantial variability was seen in the pharmacokinetics (PK) of GSK2190915 on the basis of several studies investigating the PK and potential clinical benefit of therapy with GSK2190915 [3][4][5][6][7][8], in which the coefficient of variation in the area under the concentration versus time curve was greater than 50%. This high interparticipant variability was largely unaccounted for by demographic and baseline clinical variables [6,7].…”

“…For pharmacogenetic (PGx) analyses, three studies were classified as 'exploratory' (clinicaltrials.gov identifier/GSK protocol number: NCT00812773/LPA 112356 [3]; NCT00812929/LPA112025 [4]; NCT 00748306/LPA111834 [5]), and the other three were classified as 'confirmatory' (clinicaltrials.gov identifier/ GSK protocol number: NCT01147744/LPA112186 [7]; NCT01156792/LPA114255 [8]; and NCT01248975/ LPA114387 [8]). For pharmacogenetic (PGx) analyses, three studies were classified as 'exploratory' (clinicaltrials.gov identifier/GSK protocol number: NCT00812773/LPA 112356 [3]; NCT00812929/LPA112025 [4]; NCT 00748306/LPA111834 [5]), and the other three were classified as 'confirmatory' (clinicaltrials.gov identifier/ GSK protocol number: NCT01147744/LPA112186 [7]; NCT01156792/LPA114255 [8]; and NCT01248975/ LPA114387 [8]).…”

“…Animal toxicology studies suggested male risk; therefore, ongoing recruitment in the clinical studies from which the confirmatory sample was derived was restricted to female participants only [7]. If it is assumed that the associations seen in the exploratory analysis are true positive results, then several factors Exploratory sample included all racial groups: African, n = 5; Asian, n = 3; Mixed, n = 1, and White, n = 32. b Confirmatory sample included non-Hispanic white participants only.…”

Targeting 5-lipoxygenase-activating protein in asthma and chronic obstructive pulmonary disease

“…GSK 2190915 also resulted in a dose-dependent decrease in urinary excretion of LTE4. No dose-dependent differences among the adverse events were reported [33,34].…”