Effects of JNJ-40929837, a leukotriene A4 hydrolase inhibitor, in a bronchial allergen challenge model of asthma

• Published in: Pulmonary pharmacology & therapeutics Vol. 29; no. 1; pp. 15 - 23
• Main Authors: Barchuk, W, Lambert, J, Fuhr, R, Jiang, J.Z, Bertelsen, K, Fourie, A, Liu, X, Silkoff, P.E, Barnathan, E.S, Thurmond, R
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2014
• Subjects: Acetates - pharmacology; Adult; Anti-Asthmatic Agents - adverse effects; Anti-Asthmatic Agents - pharmacology; Asthma; Asthma - drug therapy; Asthma - physiopathology; Bronchial Provocation Tests; Cross-Over Studies; Double-Blind Method; Epoxide Hydrolases - antagonists & inhibitors; Female; Forced Expiratory Volume; Humans; Hypersensitivity; Leukotriene antagonist; Leukotriene B4 - metabolism; Leukotriene synthesis inhibitor; Male; Medical Education; Montelukast; Pulmonary/Respiratory; Quinolines - pharmacology; Sputum - metabolism; Thiazoles - adverse effects; Thiazoles - pharmacology; Treatment Outcome; Tropanes - adverse effects; Tropanes - pharmacology; Young Adult; Montelukast; Leukotriene antagonist; Leukotriene synthesis inhibitor; Hypersensitivity; Asthma
• ISSN: 1094-5539; 1522-9629
• DOI: 10.1016/j.pupt.2014.06.003

Abstract Leukotriene B4 (LTB4 ) is a chemotactic mediator implicated in the pathogenesis of asthma. JNJ-40929837 is an oral inhibitor of LTA4 hydrolase, which catalyzes LTB4 production. We evaluated the effects of JNJ-40929837 in a human bronchial allergen challenge (BAC) model. In this double-blind, 3-period crossover study, 22 patients with mild, atopic asthma were randomized to one of three treatments per period: 100 mg/day JNJ-40929837 for 6 days followed by 50 mg/day on day 7; 10 mg/day montelukast for 6 days; and matched placebo. The BAC was performed on day 6 of each treatment period. Primary outcome was BAC-induced late asthmatic response (LAR) measured by maximal percent reduction in forced expiratory volume (FEV1 ) in one second. Secondary outcomes included early asthmatic response (EAR) by maximal percent reduction in FEV1 , EAR and LAR evaluated by area under the FEV1 /time curve (AUC0-2 , AUC3-10 , respectively), change in baseline FEV1 after 5-day treatment, safety, and correlation of JNJ-40929837 to the divalent cation ionophore A23187-stimulated whole blood LTB4 levels and sputum basal LTB4 levels. No significant differences were observed in the primary or secondary FEV1 endpoints with JNJ-40929837 versus placebo. Compared with placebo ( n  = 17, LS mean = 27.7), there was no significant attenuation of the maximal percent reduction in the LAR FEV1 with JNJ-40929837 ( n  = 16, LS mean = 28.6, P  = 0.63) but montelukast ( n  = 17, LS mean = 22.6, P  = 0.01) significantly attenuated the LAR. JNJ-40929837 substantially inhibited LTB4 production in whole blood, decreased sputum LTB4 levels and was well-tolerated. The number of adverse events leading to study withdrawal was the same in JNJ-40929837 and placebo groups. In conclusion, JNJ-40929837 demonstrated target engagement in blood and sputum. No significant impact in response to allergen inhalation was observed with JNJ-40929837 versus placebo. Registration This study is registered at ClinicalTrials.gov: NCT01241422.