El tratamiento de la esofagitis eosinofílica Con los Oc000459-CRTH2 antagonista: A Novel Principio terapéutico

BACKGROUND :

Eosinophilic esophagitis (EoE) is a Th2-type inflammatory disease of the esophagus, characterized clinically by symptoms related to esophageal dysfunction and histologically by an eosinophil-predominant inflammation. CRTH2 (chemoattractant receptor- homologous molecule expressed on Th2 cells) is a receptor expressed by Th2 cells and eosinophils, which mediates chemotaxis and activation of these cells in response to prostaglandin D2, a key prostanoid in allergic responses. OC000459 is a selective and orally bioavailable CRTH2 antagonist, which blocks the ability of PGD2 to recruit and activate Th2 cells and eosinophils with proven efficacy in asthma. OC000459 is therefore expected to suppress tissue inflammation associated with EoE. The purpose of this study was to evaluate the efficacy and safety of an OC000459 monotherapy in adult patients with active EoE.

METHODS:

In this randomized, double-blind, placebo-controlled trial 26 adult patients (m/f = 22/4; mean age 41 yrs, range 22-69 yrs) with active (≥20 eos/hpf and symptoms), corticosteroid-dependent and/or -resistant EoE were treated either with 100 mg OC000459 (n=14) or placebo (n=12) twice daily for 8 weeks. Pre- and post-treatment disease-activity was assessed clinically, endoscopically, histologically and via biomarkers. The primary endpoint was the reduction of the esophageal eosinophil infiltration.

RESULTS:

After an 8-week treatment of active EoE with OC000459, the mean eosinophil number decreased from 114.7 to 74.2 eos/hpf, whereas under placebo, no reduction was observed (from 102.8 to 99.4 eos/hpf) (p=0.159). The effect of OC000459 was more pronounced in the proximal (64% reduction, p=0.131) than in the distal esophagus (16% reduction, p=0.667). The global assessment of disease activity decreased under OC000459 from 7.1 to 5.2 pts, whereas the reduction was less in the placebo group (from 6.7 to 5.8, p=0.424). The endoscopic appearance decreased under OC000459 from 6.3 to 5.5 and increased under placebo from 5.5 to 5.8 pts (p=0.118). In spite of these differences, the symptom score decreased in both OC000459 (from to 16.5 to 8.8 pts) and placebo (from 16.7 to 9.8 pts) groups equally (p= 0.989). The treatment was well tolerated and no serious adverse events occurred.

CONCLUSIONS:

This study demonstrates that 1) treatment with the CRTH2-antagonist OC000459 may exert a moderate anti-inflammatory effect in a subgroup of adult patients with active EoE; 2) the effect is more pronounced in the proximal than in the distal esophagus and; 3) treatment with OC000459 is well tolerated.