Efficacy of BI 671800, an oral CRTH2 antagonist, in poorly controlled asthma as sole controller and in the presence of inhaled corticosteroid treatment

Ian P Hall,Andrew V Fowler,Abhya Gupta,Kay Tetzlaff,Michael C Nivens,Maria Sarno,Helen A Finnigan,Eric D Bateman,E Rand Sutherland

doi:10.1016/j.pupt.2015.03.003

Abstract

The prostaglandin D2 (PGD2) receptor, CRTH2, plays a role in allergic airway inflammation. The efficacy of BI 671800, a CRTH2 antagonist, was assessed in 2 separate trials in patients with asthma, in either the absence or the presence of inhaled corticosteroid (ICS) therapy. In this study, BI 671800 (50, 200 or 400 mg) and fluticasone propionate (220 μg) all given twice daily (bid) were compared with bid placebo in symptomatic controller-naïve adults with asthma (Trial 1), and BI 671800 400 mg bid compared with montelukast 10 mg once daily (qd), and matching placebo bid, in patients with asthma receiving inhaled fluticasone (88 μg bid) (Trial 2). The primary endpoint in both trials was change from baseline in trough forced expiratory volume in 1 s (FEV1) percent predicted. After 6 weeks' treatment, adjusted mean treatment differences (SE) for the primary endpoint compared with placebo in Trial 1 were 3.08% (1.65%), 3.59% (1.60%) and 3.98% (1.64%) for BI 671800 50, 200 and 400 mg bid, respectively, and 8.62% (1.68%) for fluticasone 220 μg bid (p = 0.0311, p = 0.0126, p = 0.0078 and p < 0.0001, respectively). In Trial 2, adjusted mean FEV1 (SE) treatment differences compared with placebo were 3.87% (1.49%) for BI 671800 400 mg bid and 2.37% (1.57%) for montelukast (p = 0.0050 and p = 0.0657, respectively). These findings suggest that BI 671800 is associated with a small improvement in FEV1 in symptomatic controller-naïve asthma patients, and in patients on ICS.

Highlights

Asthma is a chronic inflammatory disease of the airways, marked by symptoms attributable to episodic bronchodilatorresponsive airflow limitation and airway hyperresponsiveness [1]
Many pro-inflammatory effects of prostaglandin D2 (PGD2) are mediated in the airway through interaction with the chemoattractant receptor homologous molecule on T-helper type 2 [cell] (Th2) cells (CRTH2) receptor expressed on Th2 cells, eosinophils and basophils [2e4]
We present here the results of 2 clinical trials designed to study the efficacy and safety of an oral CRTH2 antagonist, BI 671800, in patients with symptomatic asthma in the presence or absence of inhaled corticosteroid (ICS) therapy

Summary

Introduction

Asthma is a chronic inflammatory disease of the airways, marked by symptoms attributable to episodic bronchodilatorresponsive airflow limitation and airway hyperresponsiveness [1]. Airway inflammation in asthma involves a complex interaction of inflammatory mediators, often triggered by an allergen-induced immunoglobulin E (IgE)-mediated release by mast cells of mediators such as histamine, proteases, cytokines and eicosanoids, including leukotrienes and prostaglandins. The proinflammatory effects of PGD2 occur via interactions with the chemoattractant receptor homologous molecule on Th2 cells (CRTH2), a 7-transmembrane G-protein-coupled receptor selectively expressed on Th2 cells, eosinophils and basophils [2e4]. PGD2 chemotactic activity recruits circulating eosinophils and basophils from the vascular bed to the site of inflammation in a CRTH2-dependent manner. PGD2 has an important role in the early phase of CRTH2-dependent Th2-cell recruitment and activation, resulting in the production of cytokines (eg, interleukin (IL)-4, IL-5, IL-9 and IL-13), which, in turn, further stimulate mast cells and eosinophils [5]. Inhibition of CRTH2 may attenuate important inflammatory pathways in asthma, thereby reducing airway inflammation and potentially improving asthma control

Methods

Results

Conclusion