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

BACKGROUND: Very late antigen-4 (VLA(4)) 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 VLA(4) receptor antagonist, HMR 1031, protects against allergen-induced airway responses and airway inflammation in humans. METHODS: Fourteen asthmatics (7F/7M), 18-49 years, PC(20) forced expiratory volume in 1 s (FEV(1)) methacholine (M) ( <8 mg/mL; FEV(1) 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 >or=2 weeks. Exhaled nitric oxide (eNO), PC(20)FEV(1)(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 FEV(1), 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 (3-9 h)+/-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 PC(20)FEV(1)(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