BACKGROUND:CRTH2 is a G-protein-coupled receptor that mediates the activation of Th2 lymphocytes, eosinophils and basophils in response to prostaglandin D(2) and may be involved in the pathogenesis of airway inflammation and dysfunction in asthma. OBJECTIVE: To evaluate the effects of a potent and selective CRTH2 antagonist, OC000459, on the lung function, symptoms and eosinophilic airway inflammation in a double-blind, parallel group trial in steroid-free subjects with moderate persistent asthma. METHODS:Adult subjects were randomized to oral OC000459 200 mg twice daily (N=65) or a placebo (N=67) for 28 days. The primary end-point was the change from baseline in pre-bronchodilator forced expiratory volume in 1 s (FEV(1) ); eosinophilic airway inflammation was assessed by induced sputum differential eosinophil count. The trial was registered on the clinicaltrials.gov database (Identifier NCT01057927). RESULTS: Data were analysed for both the Full Analysis (FA) population and the Per Protocol (PP) population (55 treated with OC000459 and 52 with placebo), which excluded non-compliant subjects. In the FA population, the mean change in FEV(1) was 7.1% on OC000459 compared with 4.3% on placebo (not significant); in the PP population, the mean changes were 9.2% and 1.8%, respectively (P=0.037). Improvement in quality of life was apparent in both FA and PP populations [difference from the placebo in AQLQ(S) total score of 0.29, P=0.0113 and 0.37, P=0.0022, respectively]. OC000459 also improved the night-time symptom scores (mean reduction of 0.36 vs. 0.11, P=0.008, FA population; 0.37 vs. 0.12, P=0.022, PP population). The geometric mean sputum eosinophil count reduced from 2.1% to 0.7% (P=0.03) after OC000459, but this effect was not significant when compared with the change on placebo (P=0.37). Adverse events on OC000459 were comparable to those on placebo; respiratory infections were notably less common during OC000459 than the placebo treatment. CONCLUSION AND CLINICAL RELEVANCE: This study provides the first clinical evidence that CRTH2 receptors contribute to airflow limitation, symptoms and eosinophilic airway inflammation in asthma. OC000459 shows promise as a novel oral treatment for asthma and related disorders.
RCT Entities:
BACKGROUND:CRTH2 is a G-protein-coupled receptor that mediates the activation of Th2 lymphocytes, eosinophils and basophils in response to prostaglandin D(2) and may be involved in the pathogenesis of airway inflammation and dysfunction in asthma. OBJECTIVE: To evaluate the effects of a potent and selective CRTH2 antagonist, OC000459, on the lung function, symptoms and eosinophilic airway inflammation in a double-blind, parallel group trial in steroid-free subjects with moderate persistent asthma. METHODS: Adult subjects were randomized to oral OC000459 200 mg twice daily (N=65) or a placebo (N=67) for 28 days. The primary end-point was the change from baseline in pre-bronchodilator forced expiratory volume in 1 s (FEV(1) ); eosinophilic airway inflammation was assessed by induced sputum differential eosinophil count. The trial was registered on the clinicaltrials.gov database (Identifier NCT01057927). RESULTS: Data were analysed for both the Full Analysis (FA) population and the Per Protocol (PP) population (55 treated with OC000459 and 52 with placebo), which excluded non-compliant subjects. In the FA population, the mean change in FEV(1) was 7.1% on OC000459 compared with 4.3% on placebo (not significant); in the PP population, the mean changes were 9.2% and 1.8%, respectively (P=0.037). Improvement in quality of life was apparent in both FA and PP populations [difference from the placebo in AQLQ(S) total score of 0.29, P=0.0113 and 0.37, P=0.0022, respectively]. OC000459 also improved the night-time symptom scores (mean reduction of 0.36 vs. 0.11, P=0.008, FA population; 0.37 vs. 0.12, P=0.022, PP population). The geometric mean sputum eosinophil count reduced from 2.1% to 0.7% (P=0.03) after OC000459, but this effect was not significant when compared with the change on placebo (P=0.37). Adverse events on OC000459 were comparable to those on placebo; respiratory infections were notably less common during OC000459 than the placebo treatment. CONCLUSION AND CLINICAL RELEVANCE: This study provides the first clinical evidence that CRTH2 receptors contribute to airflow limitation, symptoms and eosinophilic airway inflammation in asthma. OC000459 shows promise as a novel oral treatment for asthma and related disorders.
Authors: J A Schmidt; F M Bell; E Akam; C Marshall; I A Dainty; A Heinemann; I G Dougall; R V Bonnert; C A Sargent Journal: Br J Pharmacol Date: 2013-04 Impact factor: 8.739