Abstract

Gal-3 is a pro-fibrotic β-galactoside-binding lectin highly expressed in the lungs of idiopathic pulmonary fibrosis (IPF) patients. GB0139 is an inhaled, small molecule Gal-3 inhibitor in development for IPF. In this study the translational pharmacology of GB0139 from pre-clinical to clinical studies are presented. GB0139 was evaluated in pre-clinical studies investigating Gal-3 in vitro and in vivo studies. A randomized, double-blind, multi-centre, placebo-controlled, phase IIa study was completed to assess safety, tolerability, and PK/PD of GB0139 in 24 patients with IPF. Inhaled GB0139 was delivered at 0.3mg, 3mg or 10mg QD to IPF patients for 14 days. Patients underwent BAL prior to dosing and after 14 days. GB0139 drug concentration was measured in the BAL fluid, BAL macrophages and plasma. Gal-3 expression on BAL macrophages was measured by flow cytometry and systemic biomarkers of Gal-3 inhibition and fibrosis measured in plasma. GB0139 demonstrated high affinity in vitro and reduced Gal-3 expression ex vivo on IPF macrophages. GB0139 in vivo attenuated mechanistic PD and fibrotic endpoints in bleomycin-treated mice with duration driven by lung retention. Clinically, inhaled GB0139 was well tolerated at all doses with concentrations in BAL macrophages >567-fold higher than systemic exposure. Gal-3 expression on BAL macrophages was significantly lower in the 3mg and 10mg dose groups compared to placebo, with a concentration-dependent inhibition. Reduced Gal-3 expression on BAL macrophages was associated with lower plasma biomarkers relevant to IPF. GB0139 is safe and well tolerated in man and demonstrates low systemic exposure coupled with high lung concentrations resulting in suppression of Gal-3 on BAL macrophages and decreased plasma biomarkers associated with IPF progression. Pre-clinical in vitro and in vivo studies have shown to be clinically translatable. This study supported the progression of GB0139 into a phase IIb IPF study.