title: 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.affiliation: Merck Sharp & Dohme Corp, Rahway, NJ 07065-0900, USA.
authors.forename: Yasmine S
authors.initials: YS
authors.lastname: Wasfi
authors.forename: César
authors.initials: C
authors.lastname: Villarán
authors.forename: Celine Le Bailly
authors.initials: Cle B
authors.lastname: de Tilleghem
authors.forename: Steven S
authors.initials: SS
authors.lastname: Smugar
authors.forename: William D
authors.initials: WD
authors.lastname: Hanley
authors.forename: Theodore F
authors.initials: TF
authors.lastname: Reiss
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Knorr
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001249:Asthma / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D001557:Benzenesulfonates / Q000627:therapeutic use*; D001578:Benzopyrans / Q000627:therapeutic use*; D002908:Chronic Disease; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D007975:Leukotriene B4 / Q000819:agonists*; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010069:Oxadiazoles / Q000627:therapeutic use*; D013147:Spirometry / Q000379:methods*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001557:Benzenesulfonates; D001578:Benzopyrans; D016859:Lipoxygenase Inhibitors; C552157:MK-0633 p-toluenesulfonate; D010069:Oxadiazoles; D007975:Leukotriene B4