Safety and efficacy of an oral CCR3 antagonist in patients with asthma and eosinophilic bronchitis: a randomized, placebo-controlled clinical trial
Article first published online: 25 MAR 2014
© 2013 John Wiley & Sons Ltd
Clinical & Experimental Allergy
Volume 44, Issue 4, pages 508–516, April 2014
How to Cite
Clinical & Experimental Allergy, 2014 (44) 508–516., , , , , , , , , , , .
- Issue published online: 25 MAR 2014
- Article first published online: 25 MAR 2014
- Accepted manuscript online: 28 NOV 2013 11:40PM EST
- Manuscript Accepted: 26 NOV 2013
- Manuscript Revised: 20 NOV 2013
- Manuscript Received: 2 SEP 2013
- clinical trial;
- sputum eosinophils
Several chemokines, notably eotaxin, mediate the recruitment of eosinophils into tissues via the CCR3 receptor.
In this study, we investigated the role of CCR3 agonists in asthma by observing the effect of a small molecule antagonist of the CCR3 receptor (GW766994) on sputum eosinophil counts in patients with eosinophilic asthma.
Clinical and physiological outcomes, the chemotactic activity of sputum supernatant for eosinophils and the presence of eosinophil progenitors in sputum and blood samples were also studied.
In a double-blind parallel group study, 60 patients with asthma were randomized to 300 mg of GW766994 twice daily or matching placebo for 10 days followed by prednisone 30 mg for 5 days. Of these patients, 53 had a sputum eosinophil count > 4.9% at baseline. Despite plasma concentrations of drug consistent with > 90% receptor occupancy during the dosing period, the CCR3 antagonist did not significantly reduce eosinophils or eosinophil progenitor cells (CD34+ 45+ IL-5Rα+) in sputum or in blood. The ex vivo chemotactic effect of sputum supernatants on eosinophils was attenuated by GW766944 compared to placebo. There was no improvement in FEV1; however, there was a modest but statistically significant improvement in PC20 methacholine (0.66 doubling dose) and ACQ scores, (0.43). Whilst the improvement in PC20 is statistically significant, it is not of clinical significance.
Conclusions and Clinical Relevance
In conclusion, this study calls into question the role of CCR3 in airway eosinophilia in asthma and suggests that other cellular mechanisms mediated by the CCR3 receptor may contribute to airway hyperresponsiveness.