Target inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis

Abstract

Galectin-3 (Gal-3) is a pro-fibrotic β-galactoside-binding lectin that plays a key role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and IPF exacerbations. TD139 is a novel and potent small molecule inhibitor of Gal-3.A randomised, double-blind, multi-centre, placebo-controlled, phase I/IIa study was conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled TD139 in 36 healthy subjects and 24 patients with IPF (NCT02257177). Six dose cohorts of six healthy subjects were evaluated (4:2 TD139:placebo ratio) with single doses of TD139 (0.15 mg to 50 mg) and three dose cohorts of eight patients with IPF (5:3 TD139:placebo ratio) with once daily doses of TD139 (0.3 mg to 10 mg) for 14 days.Inhaled TD139 was well tolerated with no significant treatment-related side effects. TD139 was rapidly absorbed, with mean Tmax values ranging from 0.6 h to 3 h and a T½ of 8 h. The concentration of TD139 in the lung was >567-fold higher than in the blood, with systemic exposure predicting exposure in the target compartment. Gal-3 expression on alveolar macrophages was reduced in the 3 mg and 10 mg dose groups compared to placebo, with a concentration-dependent inhibition demonstrated. Inhibition of Gal-3 expression in the lung was associated with reductions in plasma biomarkers centrally relevant to IPF pathobiology (PDGF-BB, PAI-1, Gal-3, CCL18 and YKL-40).TD139 is safe and well tolerated in healthy subjects and IPF patients. It was shown to suppress Gal-3 expression on BAL macrophages and, in a concerted fashion, decrease plasma biomarkers associated with IPF progression.

Galectin-3 as a potential prognostic biomarker of severe COVID-19 in SARS-CoV-2 infected patients

“…Chronic pulmonary fibrosis has been observed in recovered COVID-19 patients (10, 24). Galectin-3 is known to play a role in the pathogenesis of pulmonary fibrosis, and clinical trials testing galectin-3 inhibitors are currently underway for the treatment of idiopathic pulmonary fibrosis (30). Galectin-3 could provide an important biomarker for severe COVID-19 with potential for involvement in the direct pathophysiological process of the underlying disease.…”

Chemokines modulate glycan binding and immunoregulatory activity of galectins

“…Our finding that galectin-chemokine interactions modulate glycan binding affinity and specificity could also have implications for the efficacy of glycan-based small molecule inhibitors that target galectins 38 and the growing arsenal of new drugs that unleash the immune system against tumors 39,40 .…”

Targeting Alveolar Repair in Idiopathic Pulmonary Fibrosis

“…This includes modulation of endogenous lung epithelial progenitor cells and their environment with small and large molecules, as well as exogenous delivery of stromal cells or lung epithelial progenitor cells or their secreted products to promote regeneration (136). These approaches have shown promise in vitro and in preclinical in vivo models (10,(137)(138)(139)(140) and there are clinical trials of compounds targeting proteins expressed by epithelial cells which have reached Phase II (NCT03832946, galectin-1 and -3 inhibitor GB0139) and III (NCT03711162 and NCT03733444, autotaxin antagonist GLPG1690), albeit targeting of the epithelium was not part of the initial rationale for the implementation of these compounds (141)(142)(143)(144). Autotaxin is known to convert LPC to LPA, which can then elicit pleiotropic effects on numerous cell types including fibroblasts, endothelial cells and epithelial cells (145).…”