Translational pharmacology of TD139, an inhaled small molecule galectin‐3 (Gal‐3) inhibitor for the treatment of idiopathic pulmonary fibrosis (IPF)

Abstract

Introduction Gal‐3 is a pro‐fibrotic β‐galactoside‐binding lectin highly expressed in the lungs of IPF patients 1. TD139 is an inhaled, small molecule Gal‐3 inhibitor in development for IPF[2]. In this study the translational pharmacology of TD139 from pre‐clinical to clinical studies are presented. Methods TD139 was evaluated in pre‐clinical studies investigating Gal‐3 in vitro and in vivo in naïve and bleomycin‐treated mice (male C57/Bl6 mice) 1, 2. A randomized, double‐blind, multi‐centre, placebo‐controlled, phase IIa study was completed to assess safety, tolerability, and PK/PD of TD139 in 24 patients with IPF. Inhaled TD139 was delivered at 0.3 mg, 3 mg or 10 mg QD to IPF patients (8 patients/cohort, 5:3 ratio (active:placebo)) for 14 days. Patients underwent bronchoalveolar lavage (BAL) prior to dosing and after 14 days. TD139 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. Results TD139 demonstrated high affinity (KD = 2.1 ± 0.1 nM (mean ± SD, n=4)) in vitro and reduced Gal‐3 expression ex vivo on IPF macrophages (IC50 = 361 ± 108 nM (mean ± SD, n=3 patients)). TD139 in vivo attenuated mechanistic PD (BAL Gal‐3) and fibrotic endpoints (total lung collagen/histology) in bleomycin‐treated mice with duration driven by lung retention. Clinically, inhaled TD139 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 3 mg (% change −52.52%, 95% CI −85.43% to −4.74%, P=0.023) and 10 mg (% change −78.60%, 95% CI −110.48% to −29.78%, P<0.0001) 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 pathobiology (PAI‐1, YKL‐40 and PDGF‐BB). Conclusion TD139 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 TD139 into a phase IIb IPF study 3. Support or Funding Information All studies were funded by Galecto Biotech AB. ACMacKinnonAm. J. Respir. Crit. Care Med.1855537546TDelaineChem Bio Chem171817591770NCT03832946 - A Study to Test the Efficacy and Safety of Inhaled TD139 in Subjects with Idiopathic Pulmonary Fibrosis (IPF) https://clinicaltrials.gov/

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“…Galectin-3 is implicated as a key mediator and/or biomarker of multiple fibrotic processes, including in the lung where its protein:glycoprotein interactions appear to be critical in two different models of experimental fibrosis (28). These are blocked by an experimental anti-fibrotic therapy (29, 30). Galectin-3 potentiates TGF-β1 activity at the cell surface (28), likely through stabilisation of the TGF-β receptor (TGF-βR)II protein to which it can bind directly.…”

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“…In fact, TD2 is currently undergoing clinical trials with promising results in reducing symptoms of pulmonary fibrosis [ 60 ]. With a half-maximal inhibitory concentration (IC 50 ) of 361 nM, it has been shown to be well-tolerated in humans when inhaled [ 61 ]. In the obtained pose, TD2 interacts with R32 and N48 with sidechain acceptor interactions ( Figure 7 H).…”