A phase 2 study to evaluate the safety, efficacy and pharmacokinetics of DP2 antagonist GB001 and to explore biomarkers of airway inflammation in mild‐to‐moderate asthma

Abstract

Background: GB001 is an oral antagonist of the prostaglandin D2 receptor that may inhibit recruitment and activation of airway eosinophils, reducing airway inflammation.Objective: To assess GB001 safety, efficacy and pharmacokinetics from a Phase 2 study and explore the association between type 2 biomarkers (fractional exhaled nitric oxide and blood eosinophils) and asthma control markers following GB001 administration. Methods:A randomized, placebo-controlled, double-blind study evaluating 36 patients with mild-to-moderate atopic asthma. Patients receiving fluticasone propionate ≤500 mcg/day or equivalent were randomized (2:1) to GB001 (30 mg) or placebo once daily for 28 days. Safety, pharmacokinetics, forced expiratory volume in 1 second, asthma control questionnaire and rescue medication use were assessed. Clinical outcomes were analysed post hoc by baseline fractional exhaled nitric oxide (<35 and ≥35 ppb) and blood eosinophil (<250 and ≥250 cells/µL) subgroups. Results: GB001 was well tolerated and rapidly absorbed with a 14.5-hour terminal half-life. Overall, GB001 demonstrated greater improvement relative to placebo in forced expiratory volume in 1 second at Day 28 (102 mL [95% CI: −110, 314]). Greater effects on forced expiratory volume in 1 second were observed in the high baseline fractional exhaled nitric oxide and blood eosinophil subgroups (207 mL [95% CI: −283, 698];133 mL [95% CI: −422, 687], respectively). These effects were observed as early as Day 2 (229 mL [95% CI: −170, 628]; 163 mL [95% CI: −223, 550] for the high baseline fractional exhaled nitric oxide and blood eosinophil subgroups, respectively) and were sustained through treatment completion. Conclusion and clinical relevance: GB001 was well tolerated, with the estimated half-life supporting once-daily (QD) dosing. GB001 may have a rapid and sustainedThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

The Biology of Prostaglandins and Their Role as a Target for Allergic Airway Disease Therapy

“…Reduced grass-pollen induced nasal and ocular symptoms [138] GB001, oral administration, 30 mg daily for 28 days, with use of low dose inhaled fluticasone propionate Mild to moderate atopic asthma (n = 36) Improved FEV 1 (prominent in patients with high FeNO or high blood eosinophil) [139] BI671800, oral administration, 50/200/400 mg twice daily for six weeks Mild to moderate asthma (n = 389)…”

“…OC000459 was also found to be safe and effective in inhibiting the DP2 receptor, showing significant improvements in pulmonary function in patients with eosinophil-dominant allergic asthma [137]. Other DP2 selective antagonists that were effective from phase II trials include GB001, BI671800, and setipiprant (ACT-129968) [139][140][141]165].…”

Mucins and Asthma: Are We Headed to the Revolutionary Road?

“…The activation of this pathway has potent downstream effects including mucus hypersecretion and airway remodeling [10,11]. Fevipiprant is an oral competitive antagonist of CRTH2 and, together with the GB001 compound [12], is the most promising oral drug currently under investigation for patients with moderate to severe asthma and a T2 inflammatory profile [10,12].…”

RhoA/Rho‐kinases in asthma: from pathogenesis to therapeutic targets

“…Prostaglandin D 2 (PGD 2 ), one of the major lipid mediators of airway inflammation, could augment contraction of isolated BSM from naïve mice when the tissues were pre‐contracted partially with K + . One of the PGD2 receptor antagonists GB001 has been shown to have a rapid and sustained effect on lung function 15 . However, the PGD 2 ‐induced enhancement of contraction was suppressed by using Rho‐kinase inhibitor Y‐27632.…”

“…omalizumab, mepolizumab, benralizumab and dupilumab), 8 prostaglandin D2 receptor 2 antagonists (e.g. DP2 antagonist GB001) and RhoA/Rho‐kinase 14,15 . Of these, omalizumab is the first biological acknowledged by Global Initiative for Asthma (GINA) as add‐on therapy against IgE‐mediated allergic asthma 16 .…”