BI-671800

Asthma is characterized by a complex interaction of inflammatory mediators. The prostaglandin D2 receptor, chemoattractant receptor-homologous molecule on Th2 cells (CRTH2), plays a pivotal role in the pathogenesis of allergic airway inflammation.

To ealuate the efficacy, safety, and pharmacokinetics of BI 671800, a CRTH2 antagonist, when added to inhaled corticosteroid therapy in adult patients with symptomatic asthma.

In this phase IIa, 12-week, randomized, double-blind, three-period, four-treatment, incomplete block crossover trial, BI 671800 was administered either as a single 400-mg dose in the morning (A.M.) or evening (P.M.), or 200 mg twice daily (A.M. and P.M.) versus placebo, together with fluticasone propionate (44 μg, two inhalations twice daily). The primary end point was the change from baseline in trough forced expiratory volume in 1 second percentage predicted after 4 weeks. The secondary end point was the change in Asthma Control Questionnaire score from baseline.

A total of 108 patients were randomized and treated. After 4 weeks, the adjusted mean (± SE) treatment differences for the primary end point versus placebo were 0.08 ± 0.62%, 0.28 ± 0.61%, and 0.67 ± 0.63% for BI 671800 at 200 mg twice daily, 400 mg A.M., and 400 mg P.M., respectively (not statistically significant). No statistically significant or clinically meaningful differences in the Asthma Control Questionnaire score were observed versus placebo. Each treatment was well tolerated.

BI 671800 at a dose of 400 mg administered for 4 weeks with fluticasone propionate did not provide clinical improvement in patients with asthma; reasons for this are unclear, but it may be due to insufficient inhibition of the CRTH2 receptor at the doses used.

Extensive research into the therapeutics of asthma has yielded numerous effective interventions over the past few decades. However, adverse effects and ineffectiveness of most of these medications especially in the management of steroid resistant severe asthma necessitate the development of better medications. Numerous drug targets with inherent airway smooth muscle tone modulatory role have been identified for asthma therapy. This article reviews the latest understanding of underlying molecular aetiology of asthma towards design and development of better antiasthma drugs. New drug candidates with their putative targets that have shown promising results in the preclinical and/or clinical trials are summarised. Examples of these interventions include restoration of Th1/Th2 balance by the use of newly developed immunomodulators such as toll-like receptor-9 activators (CYT003-QbG10 and QAX-935). Clinical trials revealed the safety and effectiveness of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonists such as OC0000459, BI-671800 and ARRY-502 in the restoration of Th1/Th2 balance. Regulation of cytokine activity by the use of newly developed biologics such as benralizumab, reslizumab, mepolizumab, lebrikizumab, tralokinumab, dupilumab and brodalumab are at the stage of clinical development. Transcription factors are potential targets for asthma therapy, for example SB010, a GATA-3 DNAzyme is at its early stage of clinical trial. Other candidates such as inhibitors of Rho kinases (Fasudil and Y-27632), phosphodiesterase inhibitors (GSK256066, CHF 6001, roflumilast, RPL 554) and proteinase of activated receptor-2 (ENMD-1068) are also discussed. Preclinical results of blockade of calcium sensing receptor by the use of calcilytics such as calcitriol abrogates cardinal signs of asthma. Nevertheless, successful translation of promising preclinical data into clinically viable interventions remains a major challenge to the development of novel anti-asthmatics.