A Dual CysLT1/2 Antagonist Attenuates Allergen-induced Airway Responses in Subjects with Mild Allergic Asthma

Abstract

Background

The cysteinyl leukotrienes (cysLTs) play a key role in the pathophysiology of asthma. In addition to functioning as potent bronchoconstrictors, cysLTs contribute to airway inflammation through eosinophil and neutrophil chemotaxis, plasma exudation and mucus secretion. We tested the activity of the dual cysLT_1/2 antagonist, ONO-6950, against allergen-induced airway responses.

Methods

Subjects with documented allergen-induced early (EAR) and late asthmatic response (LAR) were randomized in a 3-way crossover study to receive ONO-6950 (200 mg) or montelukast (10 mg) or placebo q.d. on Days 1-8 of the 3 treatment periods. Allergen was inhaled on Day 7 two hours post-dose,and forced expiratory volume in 1 second (FEV₁) was measured for 7 hours following challenge. Sputum eosinophils, and airway hyperresponsiveness were measured before and after allergen challenge. The primary outcome was the effect of ONO-6950 versus placebo on the EAR and LAR.

Results

Twenty-five non-smoking subjects with mild allergic asthma were enrolled and 20 subjects completed all 3 treatment periods per protocol. ONO-6950 was well tolerated. Compared to placebo, ONO-6950 significantly attenuated the maximum % fall in FEV₁ and area under the %FEV₁/time curve during the EAR and LAR asthmatic responses (p<0.05), and allergen-induced sputum eosinophils. There were no significant differences between ONO-6950 and montelukast.

Conclusions

Attenuation of EAR, LAR, and airway inflammation is consistent with cysLT₁ blockade. Whether dual cysLT_1/2 antagonism offers additional benefit for treatment of asthma requires further study.

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