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

Abstract

Galectin (Gal)-3 is a profibrotic 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, multicentre, placebo-controlled, phase 1/2a study was conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled TD139 in 36 healthy subjects and 24 patients with IPF. Six dose cohorts of six healthy subjects were evaluated (4:2 TD139:placebo ratio) with single doses of TD139 (0.15-50 mg) and three dose cohorts of eight patients with IPF (5:3 TD139:placebo ratio) with once-daily doses of TD139 (0.3-10 mg) for 14 days.Inhaled TD139 was well tolerated with no significant treatment-related side-effects. TD139 was rapidly absorbed, with mean time taken to reach maximum plasma concentration (C _max) values ranging from 0.6 to 3 h and a plasma half-life (T _1/2) 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 and 10 mg dose groups compared with 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 (platelet-derived growth factor-BB, plasminogen activator inhibitor-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 bronchoalveolar lavage macrophages and, in a concerted fashion, decrease plasma biomarkers associated with IPF progression.

Trial registration: ClinicalTrials.gov NCT02257177.

FIGURE 1

Schematic of the study design and CONSORT (Consolidated Standards of Reporting Trials) diagrams. PK: pharmacokinetics; BAL: bronchoalveolar lavage; PD: pharmacodynamics. a) Part 1 (healthy subjects). Each single-dose cohort consisted of six healthy subjects randomised 4:2 to active and placebo. A minimum of five patients’ data was required in each cohort prior to data review. b) CONSORT diagram for part 1. c) Part 2 (idiopathic pulmonary fibrosis patients). Each repeat-dose cohort consisted of eight subjects randomised 5:3 to active and placebo. A minimum of seven patients’ data was required in each cohort prior to data review. d) CONSORT diagram for part 2.

FIGURE 2

TD139 pharmacokinetics in healthy subjects and idiopathic pulmonary fibrosis (IPF) patients. ELF: epithelial lining fluid; AM: alveolar macrophage. a) Healthy subjects: log-linear mean plasma concentration of TD139 versus time over 48 h following a single dose of drug. b) IPF patients: log-linear mean plasma concentration of TD139 versus time over 24 h following the first dose of drug on day 1 or the last dose on day 14. c) Log-linear individual measured concentrations (median) in plasma (total), ELF and AMs at 2 h post-administration of 0.3, 3 and 10 mg TD139 on day 14. d) Correlation between concentrations of TD139 in ELF and AMs for all active cohorts on day 14 (r=0.89 (95% CI 0.70–0.96); p<0.0001). e) Correlation between concentrations of TD139 in plasma (total) and AMs for all active cohorts on day 14 (r=0.89 (95% CI 0.65–0.96); p<0.0001). Shading represents 95% CI of the linear fit.

FIGURE 3

Galectin (Gal)-3 changes in alveolar macrophages (AMs). a) Box plot of TD139 dose-dependent effect on percentage change from baseline in surface macrophage Gal-3 levels. Boxes indicate median and interquartile range; whiskers indicate minimum–maximum range. p-value from ANCOVA model adjusted for baseline. b) Concentration-dependent effect between TD139 in AMs and percentage of baseline in surface macrophage Gal-3, with maximum plasma concentration (C_max) at 10 mg dose (dotted line) shown for comparison (r= −0.63 (95% CI −0.86– −0.18); p=0.011). Shading represents 95% CI of the linear fit. Individual subject data are labelled by dose. c) Fitted maximum effect model of surface macrophage Gal-3 (percentage of baseline) versus macrophage TD139 concentration. Maximum effect (E_max, AM surface Gal-3 percentage of baseline) and median inhibitory concentration (IC₅₀) values are shown. Shading represents 95% CI of the fitted maximum effect model.

FIGURE 4

Biomarker changes in plasma. PDGF: platelet-derived growth factor; AM: alveolar macrophage; PAI: plasminogen activator inhibitor; Gal: galectin; CCL: chemokine (C-C motif) ligand. a, c, e, g, i) Percentage of baseline at day 14 for a) PDGF-BB, c) PAI-1, e) Gal-3, g) CCL18 and i) YKL-40 in the 0.3, 3 and 10 mg TD139 dose groups or placebo. Boxes indicate median and interquartile range; whiskers indicate minimum–maximum range. p-value from ANCOVA model adjusted for baseline. b, d, f, h, j) Correlation between percentage of baseline in b) PDGF-BB, d) PAI-1, f) Gal-3, h) CCL18 and j) YKL-40 versus the change in lung macrophage Gal-3 expression in the placebo and 10 mg TD139 groups. Dotted line shows no change from baseline. Fisher's exact test for percentage of baseline <100% for plasma Gal-3 and AM Gal-3 expression (yes/no) versus treatment group (placebo, 10 mg) p=0.031.