Safety and efficacy of an oral CCR3 antagonist in patients with asthma and eosinophilic bronchitis: a randomized, placebo‐controlled clinical trial. Issue 4 (April 2014)

• Record Type: Journal Article
• Authors: Neighbour, H.; Boulet, L.‐P.; Lemiere, C.; Sehmi, R.; Leigh, R.; Sousa, A. R.; Martin, J.; Dallow, N.; Gilbert, J.; Allen, A.; Hall, D.; Nair, P.
• Is Part Of: Clinical & experimental allergy. Volume 44:Issue 4(2014:Apr.)
• Page Start: 508
• Page End: 516
• Publication Date: 2014-04
• Subjects: Allergy -- Periodicals; Immunology -- Periodicals; 616.97
• DOI: 10.1111/cea.12244
• Languages: English
• ISSNs: 0954-7894

Abstract

<abstract abstract-type="main" id="cea12244-abs-0001"> <title>Summary</title> <sec id="cea12244-sec-0001" sec-type="section"> <title>Background</title> <p>Several chemokines, notably eotaxin, mediate the recruitment of eosinophils into tissues via the CCR3 receptor.</p> </sec> <sec id="cea12244-sec-0002" sec-type="section"> <title>Objective</title> <p>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.</p> </sec> <sec id="cea12244-sec-0003" sec-type="section"> <title>Methods</title> <p>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.</p> </sec> <sec id="cea12244-sec-0004" sec-type="section"> <title>Results</title> <p>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<sup>+</sup> 45<sup>+</sup> IL‐5Rα<sup>+</sup>) in sputum or in blood. The <italic>ex vivo</italic> chemotactic effect of sputum supernatants on eosinophils was attenuated by GW766944 compared to placebo. There was no improvement in FEV<sub>1</sub>; however, there was a modest but statistically significant improvement in PC<sub>20</sub> methacholine (0.66 doubling dose) and ACQ scores, (0.43). Whilst the improvement in PC<sub>20</sub> is statistically significant, it is not of clinical significance.</p> </sec> <sec id="cea12244-sec-0005" sec-type="section"> <title>Conclusions and Clinical Relevance</title> <p>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.</p> </sec> </abstract>