The effect of a single inhaled dose of a VLA‐4 antagonist on allergen‐induced airway responses and airway inflammation in patients with asthma

Abstract

Adhesion molecule very late antigen-4 (VLA-4) is implicated in the recruitment and activation of inflammatory cells in asthma, including eosinophils, T cells and mast cells. VLA-4 antagonists have been proposed as a new anti-inflammatory treatment modality for asthma. Therefore, we investigated whether a single inhaled dose of VLA-4 antagonist GW559090X could protect against allergen-induced changes in airway responses and airway inflammation in patients with asthma. We performed a randomized, double-blind, three-way crossover study with single inhaled doses of 3 mg of GW559090X, 500 microg of fluticasone propionate (FP) or placebo in 15 patients with mild intermittent asthma, controlled with short-acting beta(2)-agonists only. All patients developed a late asthmatic response (LAR) after allergen inhalation during screening. Study medication was administered 30 min prior to allergen challenge. Pre-dose and 24 h post-dose PC20 methacholine and levels of exhaled nitric oxide (eNO) were determined. At the given dose, VLA-4 antagonist GW559090X did not attenuate the early asthmatic response (EAR) when compared with placebo: mean AUC0-2 h(+/-SEM) (%fall h): 27.2+/-3.7 and 21.9+/-3.0 respectively (P=0.33); nor the LAR: mean AUC3-8 h(+/-SEM) (%fall h): 98.8+/-12.9 and 94.8+/-6.8 respectively (P=0.84). However, pretreatment with FP did attenuate both EAR and LAR when compared with placebo: mean AUC0-2 h11.6+/-3.3 (P=0.024) and mean AUC3-8 h 6.3+/-7.6 (P<0.001). None of these treatments had an effect on allergen-induced changes in airway hyper-responsiveness or eNO levels. These findings suggest that VLA-4 may not play a major role in allergen-induced airway responses and inflammation in asthma.

Roles of integrin activation in eosinophil function and the eosinophilic inflammation of asthma

“…Thus, while described above, BIO-1211, HMR 1031, IVL745, TR14035, or GW559090X α4β1 antagonists have negligible benefit in human asthma clinical trials, these compounds have had significant effects in sheep [118,121,126], mouse [121,127], rat [118,123,128], or guinea pig [123] models of asthma. The HP1/2, PS2/3, PS/2, TA-2, or Max-68P anti-α4 blocking antibodies, CS-1 peptide ligand anti-α4β1 mimic, or α4β1 small molecule inhibitors reduce either numbers of eosinophils in the airway or ameliorate inflammatory histopathology or airway allergic responses in the guinea pig [129][130][131][132][133], sheep [134][135][136][137], mouse [138][139][140], rat [141,142], or rabbit [143].…”

“…Two orally active dual α4β1/α4β7 antagonists, TR14035 and R411, were examined in clinical trials by Tanabe/GlaxoSmithKline and Roche, respectively [117]. TR14035 is no longer listed in GlaxoSmithKline's therapeutic pipeline [117], R411 was discontinued as noted on Roche's 2006 annual investor report [122], and several other α4β1 antagonists, including GW-559090 from GlaxoSmithKline [123,124] or RBx-7796 (Clafrinast) from Ranbaxy [125], are no longer listed in either company's pipeline.…”

Btk Inhibitor RN983 Delivered by Dry Powder Nose-only Aerosol Inhalation Inhibits Bronchoconstriction and Pulmonary Inflammation in the Ovalbumin Allergic Mouse Model of Asthma

“…(39) Steroids predominantly dampen inflammation in the lungs by repressing the transcription of inflammatory mediators (40) that are important in the LAR, (41) and have little effect on the EAR. (42) b-Agonists predominantly relax airway smooth muscle and can reverse bronchoconstriction present in the EAR, but chronic use can exacerbate the decrements in lung function during the LAR. (43) Btk inhibitors inhibit mast cells from generating a diverse number of mediators (13,44,45) that induce symptoms and the pathogenesis of asthma.…”

Importance of integrin receptors in the field of pharmaceutical &amp; medical science

“…Davenport et al in a review on α4-intgerin antagonism has provided a comprehensive discussion of the different small molecule antagonists that have been subject to clinical trial [16]. Bio-1211 & IVL-745 are two small molecule antagonists (urea based) of both α4β1 & α4β7 that failed phase-II clinical trial for the treatment of asthma due to poor bioavailability [16,145,146]. There are two other urea based small molecule antagonists, TBS-4746 & DW-908e, that have been subject to phase-I clinical trial for the treatment of asthma and MS [16].…”