Effects of JNJ-40929837, a leukotriene A 4 hydrolase inhibitor, in a bronchial allergen challenge model of asthma W. Barchuk a, * , J. Lambert b , R. Fuhr c , J.Z. Jiang d , K. Bertelsen e , A. Fourie a , X. Liu a , P.E. Silkoff f , E.S. Barnathan f , R. Thurmond a a Immunology, Janssen Research & Development, LLC, San Diego, CA, USA b Early Phase Clinical Unit, PAREXEL International, Harrow, UK c Early Phase Clinical Unit, PAREXEL International, Berlin, Germany d Biostatistics, Janssen Research & Development, LLC, San Diego, CA, USA e Clinical Pharmacology, Janssen Research & Development, LLC, Titusville, NJ, USA f Immunology, Janssen Research & Development, LLC, Spring House, PA, USA article info Article history: Received 25 April 2014 Received in revised form 10 June 2014 Accepted 25 June 2014 Available online 10 July 2014 Keywords: Leukotriene antagonist Leukotriene synthesis inhibitor Asthma Hypersensitivity Montelukast abstract Leukotriene B4 (LTB 4 ) is a chemotactic mediator implicated in the pathogenesis of asthma. JNJ-40929837 is an oral inhibitor of LTA 4 hydrolase, which catalyzes LTB 4 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 (FEV 1 ) in one second. Secondary outcomes included early asthmatic response (EAR) by maximal percent reduction in FEV 1 , EAR and LAR evaluated by area under the FEV 1 /time curve (AUC 0-2 , AUC 3-10 , respectively), change in baseline FEV 1 after 5-day treatment, safety, and correlation of JNJ-40929837 to the divalent cation ionophore A23187-stimulated whole blood LTB 4 levels and sputum basal LTB 4 levels. No significant differences were observed in the primary or secondary FEV 1 endpoints with JNJ-40929837 versus placebo. Compared with placebo (n ¼ 17, LS mean ¼ 27.7), there was no significant attenuation of the maximal percent reduction in the LAR FEV 1 with JNJ-40929837 (n ¼ 16, LS mean ¼ 28.6, P ¼ 0.63) but montelukast (n ¼ 17, LS mean ¼ 22.6, P ¼ 0.01) significantly attenuated the LAR. JNJ-40929837 sub- stantially inhibited LTB 4 production in whole blood, decreased sputum LTB 4 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. © 2014 Elsevier Ltd. All rights reserved. 1. Introduction Asthma is a chronic inflammatory disease characterized by variable airway obstruction, bronchial hyperresponsiveness, and airway inflammation [1,2]. In a pathway distinct from the cysteinyl leukotriene (LTC 4 , LTD 4 , LTE 4 ) synthetic pathway, the enzyme leukotriene A 4 hydrolase (LTA 4 H) catalyzes hydrolysis of LTA 4 to produce the pro-inflammatory mediator LTB 4 . LTB 4 is a chemo- attractant and activator of leukocytes by binding to two different G protein-coupled receptors BLT1 and BLT2 [3,4]. Studies in mice lacking BLT1 receptors have shown that LTB 4 plays a role in eosinophil and effector T-cell recruitment, interleukin-13 produc- tion, goblet cell hyperplasia and mucus secretion, immunoglobulin E (IgE) production, and airway hyperresponsiveness to methacho- line [5,6] The importance of LTB 4 in development of airway hy- perreactivity is supported by data in a primate model with the LTB 4 receptor antagonist CP-105,696, which reduced airway hyper- responsiveness (AHR) induced by multiple antigen challenges [7]. * Corresponding author. Immunology Translational Medicine Development, Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA. Tel.: þ1 858 784 3111, þ1 650 210 6437 (mobile); fax: þ1 858 320 3376. E-mail address: wbarchuk@its.jnj.com (W. Barchuk). Contents lists available at ScienceDirect Pulmonary Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/ypupt http://dx.doi.org/10.1016/j.pupt.2014.06.003 1094-5539/© 2014 Elsevier Ltd. All rights reserved. Pulmonary Pharmacology & Therapeutics 29 (2014) 15e23