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

Leukotriene B4 (LTB4) is a potent inflammatory mediator in asthma, and is increased in more severe asthma. Targeting LTB4, 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 FEV1 >= 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 FEV1 over the last 4 weeks of the 6-week primary treatment period. Secondary endpoints included symptom scores, p-agonist use, peak expiratory flow (PEF), asthma quality of life questionnaire (AQLQ), asthma control questionnaire (ACQ), asthma attacks, exacerbations, days with asthma control, post-beta-agonist FEV1, and blood eosinophils. MK-0633 100 mg was significantly more effective than placebo for the change from baseline in FEV1 (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 p-agonist use, AQLQ, AM and PM PEER, ACQ and post-beta-agonist FEV1 (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. (C) 2011 Elsevier Ltd. All rights reserved.