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Effects of JNJ-40929837, a leukotriene A4 hydrolase inhibitor, in a bronchial allergen challenge model of asthma.
Pulm Pharmacol Ther. 2014 Oct; 29(1):15-23.PP

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.

Authors+Show Affiliations

Immunology, Janssen Research & Development, LLC, San Diego, CA, USA. Electronic address: wbarchuk@its.jnj.com.Early Phase Clinical Unit, PAREXEL International, Harrow, UK.Early Phase Clinical Unit, PAREXEL International, Berlin, Germany.Biostatistics, Janssen Research & Development, LLC, San Diego, CA, USA.Clinical Pharmacology, Janssen Research & Development, LLC, Titusville, NJ, USA.Immunology, Janssen Research & Development, LLC, San Diego, CA, USA.Immunology, Janssen Research & Development, LLC, San Diego, CA, USA.Immunology, Janssen Research & Development, LLC, Spring House, PA, USA.Immunology, Janssen Research & Development, LLC, Spring House, PA, USA.Immunology, Janssen Research & Development, LLC, San Diego, CA, USA.

Pub Type(s)

Comparative Study
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25018015

Citation

Barchuk, W, et al. "Effects of JNJ-40929837, a Leukotriene A4 Hydrolase Inhibitor, in a Bronchial Allergen Challenge Model of Asthma." Pulmonary Pharmacology & Therapeutics, vol. 29, no. 1, 2014, pp. 15-23.
Barchuk W, Lambert J, Fuhr R, et al. Effects of JNJ-40929837, a leukotriene A4 hydrolase inhibitor, in a bronchial allergen challenge model of asthma. Pulm Pharmacol Ther. 2014;29(1):15-23.
Barchuk, W., Lambert, J., Fuhr, R., Jiang, J. Z., Bertelsen, K., Fourie, A., Liu, X., Silkoff, P. E., Barnathan, E. S., & Thurmond, R. (2014). Effects of JNJ-40929837, a leukotriene A4 hydrolase inhibitor, in a bronchial allergen challenge model of asthma. Pulmonary Pharmacology & Therapeutics, 29(1), 15-23. https://doi.org/10.1016/j.pupt.2014.06.003
Barchuk W, et al. Effects of JNJ-40929837, a Leukotriene A4 Hydrolase Inhibitor, in a Bronchial Allergen Challenge Model of Asthma. Pulm Pharmacol Ther. 2014;29(1):15-23. PubMed PMID: 25018015.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of JNJ-40929837, a leukotriene A4 hydrolase inhibitor, in a bronchial allergen challenge model of asthma. AU - Barchuk,W, AU - Lambert,J, AU - Fuhr,R, AU - Jiang,J Z, AU - Bertelsen,K, AU - Fourie,A, AU - Liu,X, AU - Silkoff,P E, AU - Barnathan,E S, AU - Thurmond,R, Y1 - 2014/07/10/ PY - 2014/04/25/received PY - 2014/06/10/revised PY - 2014/06/25/accepted PY - 2014/7/15/entrez PY - 2014/7/16/pubmed PY - 2016/5/5/medline KW - Asthma KW - Hypersensitivity KW - Leukotriene antagonist KW - Leukotriene synthesis inhibitor KW - Montelukast SP - 15 EP - 23 JF - Pulmonary pharmacology & therapeutics JO - Pulm Pharmacol Ther VL - 29 IS - 1 N2 - UNLABELLED: 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. SN - 1522-9629 UR - https://www.unboundmedicine.com/medline/citation/25018015/Effects_of_JNJ_40929837_a_leukotriene_A4_hydrolase_inhibitor_in_a_bronchial_allergen_challenge_model_of_asthma_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1094-5539(14)00069-8 DB - PRIME DP - Unbound Medicine ER -