*4.3.1 Chemo attractant receptor-homologous molecule expressed on Th2 (CRTH2) inhibitors*

CRTH2 is the prostaglandin D2 (PGD2) receptor that is secreted from mast cells upon activation and degranulation. CRTH2 is normally expressed on eosinophils, basophils, and Th2 cells. The signaling pathways following PGD2-interaction\ligation to CRTH2 results in the stimulation and chemotaxis of basophils and eosinophils, Th2 response, and the increase in the amount of histamine released from basophils [52, 53]. In patients suffering from CSU, membrane CRTH2 expression on basophils and eosinophils, was found to be extremely low, which was presumably attributed to the internalization of CRTH2 upon PGD2 binding. These results suggested a role for PGD2 via CRTH2 ligation in CSU [54]. A particular CRTH2 gene polymorphism was demonstrated in several patients suffering from CSU, and these specific patients needed high doses of anti-histamines in order to control CSU [53]. These findings further establish a role for CRTH2 in CSU pathogenesis, suggesting the relevance of its targeting. Based on these considerations, a new oral CRTH2 antagonist, AZD1981, was generated and used for the treatment of CSU in a clinical trial. In a phase II, double-blind, placebo-controlled trial, twenty-six CSU patients were enrolled and completed the 4-week treatment period with either AZD1981 (40 mg three times daily) or a placebo. A clinical assessment of UAS7 and ISS7 scores revealed a significant reduction in these scores when compared with the baseline scores before treatment. However, the primary endpoint (a reduction in UAS7 ≥ 9.5 points when compared with the baseline) was not achieved in this study. No significant differences were observed in terms of anti-histamines use or the frequency of angioedema-attacks between the treatment and control groups. No serious adverse events were observed and the overall treatment was well tolerated [52], Regarding biological effects, the treatment with AZD1981 significantly

inhibited PGD2-mediated eosinophil migration to the skin. Despite failing to meet the primary endpoint, future studies evaluating the efficacy of AZD1981 with longer treatment duration and higher doses are needed.
