The efficacy and tolerability of MK-0633, a 5-lipoxygenase inhibitor, in chronic asthma.

Abstract

Leukotriene B4 (LTB(4)) is a potent inflammatory mediator in asthma, and is increased in more severe asthma. Targeting LTB(4), in addition to cysteinyl leukotrienes, could be beneficial in asthma. This was a randomized, double-blind trial of once-daily MK-0633, a potent 5-lypoxygenase inhibitor, 10 mg, 50 mg, and 100 mg, and placebo in patients 18-70 years with a history of chronic asthma, and FEV(1) ≥45 and ≤85% predicted. There was a 6-week main period and optional 18-week and 34-week periods (52 weeks total), the latter two comparing only MK-0633 100 mg and placebo. The primary endpoint was the change from baseline in FEV(1) over the last 4 weeks of the 6-week primary treatment period. Secondary endpoints included symptom scores, β-agonist use, peak expiratory flow (PEF), asthma quality of life questionnaire (AQLQ), asthma control questionnaire (ACQ), asthma attacks, exacerbations, days with asthma control, post-β-agonist FEV(1), and blood eosinophils. MK-0633 100 mg was significantly more effective than placebo for the change from baseline in FEV(1) (0.20 L vs. 0.13 L; p = 0.004). The other MK-0633 doses were not significantly more effective than placebo. MK-0633 (at various doses) was also more effective than placebo for β-agonist use, AQLQ, AM and PM PEFR, ACQ, and post-β-agonist FEV(1) (p < 0.05 for all). MK-0633 was associated with a dose-dependent increase in elevated aspartate aminotransferase and alanine aminotransferase. Because of the relative benefit-risk ratio, the optional study periods were terminated after unblinding for the main study period. Overall, the benefit-risk ratio did not support the clinical utility of MK-0633 in asthma.

• Authors: Yasmine S Wasfi, César Villarán, Celine Le Bailly de Tilleghem, Steven S Smugar, William D Hanley, Theodore F Reiss, Barbara A Knorr
• Journal: Respiratory medicine (Respir Med) Vol. 106 Issue 1 Pg. 34-46 (Jan 2012) ISSN: 1532-3064 [Electronic] England
• PMID: 21945511 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Benzenesulfonates
• Benzopyrans
• Lipoxygenase Inhibitors
• MK-0633 p-toluenesulfonate
• Oxadiazoles
• Leukotriene B4

Topics

• Adolescent
• Adult
• Aged
• Asthma (blood, drug therapy, physiopathology)
• Benzenesulfonates (therapeutic use)
• Benzopyrans (therapeutic use)
• Chronic Disease
• Disease Progression
• Double-Blind Method
• Female
• Forced Expiratory Volume (drug effects)
• Humans
• Leukotriene B4 (agonists)
• Lipoxygenase Inhibitors (therapeutic use)
• Male
• Middle Aged
• Oxadiazoles (therapeutic use)
• Spirometry (methods)
• Treatment Outcome
• Young Adult