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 prn) with demonstrable LAR (fall of FEV1 3-8h 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 8h after allergen inhalation on active treatment vs. placebo. Secondary endpoints included early asthmatic response, exhaled nitric oxide, and airway hyperresponsiveness to methacholine 24h 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.
Beeh
Kai M
KM
Pulmonary Department, Internal Medicine, University Hospital, Mainz, Germany. k.beeh@insaf-wi.de
Beier
Jutta
J
Meyer
Michael
M
Buhl
Roland
R
Zahlten
Rainer
R
Wolff
Gerhard
G
D000280:Administration, Inhalation; D000328:Adult; D000485:Allergens / Q000276:immunology*; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001944:Breath Tests; D001985:Bronchial Provocation Tests; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005541:Forced Expiratory Volume / Q000187:drug effects; D006586:Hexanes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007958:Leukocyte Count; D018655:Lymphocyte Count; D008297:Male; D008358:Mannose / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016210:Methacholine Chloride / Q000008:administration & dosage; D009569:Nitric Oxide / Q000378:metabolism; D016896:Treatment Outcome
D000485:Allergens; D018927:Anti-Asthmatic Agents; D006586:Hexanes; D016210:Methacholine Chloride; D009569:Nitric Oxide; C496819:bimosiamose; D008358:Mannose