Effect of a very late antigen-4 receptor antagonist on allergen-induced airway responses and inflammation in asthma

Background: Very late antigen-4 (VLA4) plays a key role in the recruitment of eosinophils in allergic responses in animal studies. Objective: We investigated whether pretreatment with multiple doses of a VLA4 receptor antagonist, HMR 1031, protects against allergen-induced airway responses and airway inflammation in humans. Methods: Fourteen asthmatics (7F/7M), 18-49 years, PC2o forced expiratory volume in l s (FEV 1) methacholine (M) (<8mg/mL; FEV1 82.3-116.1% predicted) with dual responses to inhaled allergen participated in a double-blind, placebo-controlled, cross-over study. Each treatment period consisted of 9 days, separated by ≥2 weeks. Exhaled nitric oxide (eNO), PC20QFEV1(M) and hypertonic saline-induced sputum was obtained on Days 1, 7 and 9. Subjects inhaled HMR 1031 (20 mg b.i.d.) or placebo (P) on Days 1-8. On Day 8, an allergen bronchoprovocation test was performed, the airway response was measured by FEV1, and expressed as %fall from baseline. Data from 12 evaluable subjects are presented here. Results: Both treatments were well tolerated. There was no significant difference between HMR 1031 and P in the early asthamatic response: mean AUC (0-3 h) ±SEM (%fall h): 26.01 ±4.26 and 17.41 ±4.26, respectively (P = 0.18), nor in the late response: mean AUC (3-9h) ±SEM (%fall h): 97.09 ±8.63 and 97.61 ±8.63, respectively, P = 0.97. This corresponded to the absence of significant allergen-induced changes in PC2QFEV1(M), eNO, sputum eosinophils and soluble inflammation markers between both treatment periods. Conclusions: Treatment with multiple inhaled doses of the VLA 4 antagonist, HMR 1031, did not result in detectable protection against allergen-induced airway responses or airway inflammation in asthma.

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