Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459

Abstract

CRTH2 (chemoattractant receptor expressed on T-helper (Th) type 2 cells) is a Gprotein-coupled receptor expressed by Th2 lymphocytes and eosinophils that mediates prostaglandin (PG)D 2 -driven chemotaxis. We studied the efficacy of the oral CRTH2 antagonist OC000459 in steroid-naïve asthmatic patients.A randomised, double-blind, placebo-controlled, two-way crossover study of 16 days' treatment with OC000459 (200 mg twice daily) on the late (LAR) and early (EAR) asthmatic responses to bronchial allergen challenge was conducted, with 16 subjects completing the study.There was a 25.4% (95% CI 5.1-45.6%) reduction in the LAR area under the curve (AUC) for change in forced expiratory volume in 1 s with OC000459 compared with placebo (p50.018) but no effect on the EAR. Sputum eosinophil counts at 1 day post-allergen challenge were lower after OC000459 treatment (p50.002). PGD 2 -induced blood eosinophil shape change ex vivo was assessed at day 7 (n57). The AUC of eosinophil shift for OC000459 was lower than placebo; the mean difference was -33.6% (95% CI -66.8--0.4%; p50.048).OC000459 treatment inhibited LAR and post-allergen increase in sputum eosinophils. This CRTH2 antagonist appears to inhibit allergic inflammation in asthma.

Efficacy of BI 671800, an oral CRTH2 antagonist, in poorly controlled asthma as sole controller and in the presence of inhaled corticosteroid treatment

“…In the study of OC000459 in steroid-naïve patients with asthma, the CRTH2 antagonist achieved a statistically significant improvement in the FEV 1 in the per-protocol analysis compared with placebo (7.66% predicted [95% confidence interval (CI): 0.49e14.82] or 200 mL) but not in the intention-to-treat population (2.44% predicted [95% CI: 4.42e9.31] or 80 mL) [6]. A separate study of OC000459 resulted in attenuation of the late-phase, but not the early-phase, response to allergen challenge following bronchial challenge in sensitive individuals [10]. Studies performed in patients sensitive to grass pollen [11] have also demonstrated that OC000459 can reduce nasal and ocular symptoms.…”

Discontinued drug projects in the respiratory therapeutic area during 2012

“…Oxagen has presented positive clinical data in an allergen challenge study in steroid-naïve asthmatics [21] and in a larger 4-weeks study in steroid-free moderate persistent asthmatics [22] and are currently running a Phase III asthma study in Russia and also a Phase II study in atopic dermatitis (as Atopic Therapeutics).…”

High‐ and low‐dose allergen challenges in asthmatic patients using inhaled corticosteroids

“…Phase 2 studies of the effects of novel anti-inflammatory drugs could be performed in this population, because the high-dose allergen challenge model could provide very important information on the potential effectiveness of these drugs on allergic Table 2 Sputum cell counts at baseline and after high-dose allergen challenge (n = 13) Table 3 Sputum cell counts after low-dose allergen challenge (n = 10) inflammation when administered in addition to ICS. There are a number of novel therapies in development that target Th2 inflammation, such as anticytokine monoclonal antibodies and small molecule inhibitors, such as chemoattractant receptor expressed on T-helper type 2 (CRTh2) antagonists [34][35][36][37]. The potential therapeutic effectiveness of these therapies can be tested at an early stage of clinical development in a small number of subjects using the model and end-points described here.…”