Imperial College London
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ProfessorPhilipMolyneaux

Faculty of Medicine, National Heart & Lung Institute

Professor of Interstitial Lung Disease
 
 
 
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Contact

 

p.molyneaux

 
 
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Location

 

Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Hirani:2020:10.1183/13993003.02559-2020,
author = {Hirani, N and MacKinnon, AC and Nicol, L and Ford, P and Schambye, H and Pedersen, A and Nilsson, UJ and Leffler, H and Sethi, T and Tantawi, S and Gavelle, L and Slack, RJ and Mills, R and Karmakar, U and Humphries, D and Zetterberg, F and Keeling, L and Paul, L and Molyneaux, PL and Li, F and Funston, W and Forrest, IA and Simpson, AJ and Gibbons, MA and Maher, TM},
doi = {10.1183/13993003.02559-2020},
journal = {European Respiratory Journal},
pages = {1--13},
title = {Target-inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis.},
url = {http://dx.doi.org/10.1183/13993003.02559-2020},
volume = {57},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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 (0.15mg to 50mg) and three dose cohorts of eight patients with IPF (5:3 TD139:placebo ratio) with once daily doses of TD139 (0.3mg to 10mg) for 14days.Inhaled TD139 was well tolerated with no significant treatment-related side effects. TD139 was rapidly absorbed, with mean Tmax values ranging from 0.6h to 3h and a T½ of 8h. 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 3mg and 10mg 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.
AU  - Hirani,N
AU  - MacKinnon,AC
AU  - Nicol,L
AU  - Ford,P
AU  - Schambye,H
AU  - Pedersen,A
AU  - Nilsson,UJ
AU  - Leffler,H
AU  - Sethi,T
AU  - Tantawi,S
AU  - Gavelle,L
AU  - Slack,RJ
AU  - Mills,R
AU  - Karmakar,U
AU  - Humphries,D
AU  - Zetterberg,F
AU  - Keeling,L
AU  - Paul,L
AU  - Molyneaux,PL
AU  - Li,F
AU  - Funston,W
AU  - Forrest,IA
AU  - Simpson,AJ
AU  - Gibbons,MA
AU  - Maher,TM
DO  - 10.1183/13993003.02559-2020
EP  - 13
PY  - 2020///
SN  - 0903-1936
SP  - 1
TI  - Target-inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis.
T2  - European Respiratory Journal
UR  - http://dx.doi.org/10.1183/13993003.02559-2020
UR  - https://www.ncbi.nlm.nih.gov/pubmed/33214209
UR  - https://erj.ersjournals.com/content/57/5/2002559
UR  - http://hdl.handle.net/10044/1/85036
VL  - 57
ER  -
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