Rationale: The aim of this clinical trial (DB, PC, R crossover) was to investigate whether repeat doses of EPI-12323, a non-glucocorticosteroid (IC50 > 100 μM at the glucocorticoid receptor; GR) with an antiinflammatory profile, reduces the early (EAR; 0-2h) and late airway (LAR; 3-8h) reactions following allergen challenge in patients with mild allergic asthma. Methods: 24 prescreened patients (mean FEV1 of 96.5% predicted) were randomized to one of 2 five-day treatment sequences (EPI/pbo, pbo/EPI), with a minimum 3 week washout between sequences. 25 mg EPI or pbo were given once daily via nebulizer, with allergen challenge 30 min after day 5 treatment. Results: Following EPI-12323, there was a 33% attenuation (P<0.032) of the allergen-induced maximal fall in LAR FEV1 compared to the placebo arm; -13.5±2.4% vs -20.2±2.2%. The LAR AUC for FEV1 was also attenuated 48% (-0.91±0.32 vs.-1.73±0.32 L· h, P< 0.017). There was no significant effect on EAR or bronchial hyperresponsiveness. EPI-12323 also attenuated symptom score (82 vs. 122), rescue β-agonist use (104 vs. 122) and nocturnal awakenings (13 vs. 23). EPI was well tolerated and no drug-related AEs were reported. Conclusions: Clinically relevant attenuation of the LAR and associated symptomology can be achieved with EPI, an action not mediated by the GR. Successful antiinflammatory therapy of asthma without GR activation may translate to a superior side effect profile (HPA-axis, bone turnover) compared to conventional steroid therapy.