Bimosiamose, an inhaled small-molecule pan-selectin antagonist, attenuates late asthmatic reactions following allergen challenge in mild asthmatics: A randomized, double-blind, placebo controlled clinical cross-over-trial

Background: Asthma is characterized by increased recruitment of inflammatory cells from the circulation into the airways. As selectins mediate tethering and rolling of leukocytes on the vascular endothelium, they constitute a promising target for the therapeutic modulation of inflammation. We evaluated the effect of inhaled bimosiamose (TBC1269), a synthetic pan-selectin antagonist, on allergen-induced late asthmatic reactions (LAR) in mild asthmatics. Methods: Twelve male subjects with mild allergic asthma (only beta-agonists pm) with demonstrable LAR (fall of FEVI 3-8 h after allergen inhalation > 15% of baseline) at screening completed a randomized, double-blind, placebo-controlled clinical cross-over-trial. Subjects were treated with inhaled bimosiamose 70 mg bid or matching placebo on days 1-3 and 70 mg once on the morning of day 4. On day 4 following the last inhalation of study drug, an allergen challenge was performed. The primary endpoint was the maximum fall in FEV1, between 3 and 8 It after allergen inhalation on active treatment vs. placebo. Secondary endpoints included early asthmatic response, exhaled nitric oxide, and airway hyperresponsiveness to methacholine 24 h post allergen. Results: Bimosiamose significantly attenuated the maximum LAR compared to placebo by 50.2% (placebo mean SEM fall - 13.10 +/- 2.30%, bimosiamose -6.52 +/- 3.86%, treatment effect p = 0.045; linear mixed-effects model). There was no effect of active treatment on early asthmatic response, post allergen airway hyperresponsiveness or exhaled nitric oxide, and peripheral blood cells. Conclusions: Administration of the pan-selectin antagonist bimosiamose is effective in a human allergen challenge model of asthma. The result of this proof-of-concept exploratory trial is the first study that demonstrates clinical efficacy of selectin-antagonists as novel therapeutic strategy in asthma. (c) 2005 Elsevier Ltd. All rights reserved.