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.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Hirani reports grants from Galecto Biotech, during the conduct of the study;.
Conflict of interest: Dr. Mackinnon reports personal fees from Galecto Biotech, outside the submitted work; In addition, Dr. Mackinnon has a patent CA2,794,066 issued to Patent is fully owned by Galecto Biotech, a patent US13/832,672 issued to Patent is fully owned by Galecto Biotech, and a patent WO/2014/067986 pending to Patent is fully owned by Galecto Biotech.
Conflict of interest: Dr. Nicol reports grants from Galecto Biotech, during the conduct of the study; personal fees from Lecture fees received for delivering a presentation on the early detection of IPF to an audience of GPs. Training day was sponsored by Boehringer Ingelheim., outside the submitted work;.
Conflict of interest: Dr. Ford reports personal fees and non-financial support from Galecto, during the conduct of the study; In addition, Dr. Ford has a patent TD139 issued.
Conflict of interest: Dr. Schambye reports personal fees from Galecto Inc, outside the submitted work; In addition, Dr. Schambye has a patent WO/2016/180483 pending to Patent is fully owned by Galecto Biotech.
Conflict of interest: Dr. Pedersen reports personal fees from Galecto Biotech, outside the submitted work;.
Conflict of interest: Dr. Nilsson reports In addition, Dr. Nilsson has a patent CA2,794,066 issued to Patent is fully owned by Galecto Biotech, a patent US13/832,672 issued to Patent is fully owned by Galecto Biotech, a patent WO/2014/067986 pending to Patent is fully owned by Galecto Biotech, a patent WO/2005/113569 pending to Patent is fully owned by Galecto Biotech, a patent WO/2009/139719 pending to Patent is fully owned by Galecto Biotech, and a patent null pending.
Conflict of interest: Dr. Leffler reports In addition, Dr. Leffler has a patent CA2,794,066 issued to Patent is fully owned by Galecto Biotech, a patent US13/832,672 issued to Patent is fully owned by Galecto Biotech, a patent WO/2014/067986 pending to Patent is fully owned by Galecto Biotech, and a patent WO/2005/113569 pending to Patent is fully owned by Galecto Biotech.
Conflict of interest: Dr. Sethi reports personal fees from Galecto Biotech, outside the submitted work; In addition, Dr. Sethi has a patent CA2,794,066 issued to Patent is fully owned by Galecto Biotech, a patent US13/832,672 issued to Patent is fully owned by Galecto Biotech, and a patent WO/2014/067986 pending to Patent is fully owned by Galecto Biotech.
Conflict of interest: Dr. Tantawi reports personal fees from Galecto Biotech, outside the submitted work;.
Conflict of interest: Dr. Gravelle reports personal fees from Galecto Biotech, outside the submitted work; In addition, Dr. Gravelle has a patent WO/2017/103109 pending.
Conflict of interest: Dr. Slack reports personal fees from Galecto Biotech, outside the submitted work;.
Conflict of interest: Dr. Mills has nothing to disclose.
Conflict of interest: Dr. Karmakar has nothing to disclose.
Conflict of interest: Dr. Humphries has nothing to disclose.
Conflict of interest: Dr. Zetterberg reports personal fees from Galecto Biotech, outside the submitted work;.
Conflict of interest: Dr. Keeling has nothing to disclose.
Conflict of interest: Mrs Paul has nothing to disclose.
Conflict of interest: Dr. Molyneaux, via his institution received industry-academic funding from AstraZeneca and has received speaker and consultancy fees from Boehringer Ingelheim and Hoffman-La Roche outside the submitted work.Dr. Molyneaux reports personal fees from Boehringer Ingelheim, personal fees from Hoffman-La Roche, other from AstraZeneca, outside the submitted work;.
Conflict of interest: Dr. LI has nothing to disclose.
Conflict of interest: Dr. Funston has nothing to disclose.
Conflict of interest: Dr. Forrest reports personal fees from Boehringer Ingelheim, personal fees from Roche Ltd, outside the submitted work;.
Conflict of interest: Dr. Simpson has nothing to disclose.
Conflict of interest: Dr. Gibbons has nothing to disclose.
Conflict of interest: TMM has, via his institution, received industry-academic funding from Astra Zeneca and GlaxoSmithKline R&D and has received consultancy or speakers fees from Astra Zeneca, Bayer, Blade Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Galapagos, GlaxoSmithKline R&D, Indalo, Novartis, Pliant, Respivant, Roche and Samumed.
This is a PDF-only article. Please click on the PDF link above to read it.
- Received June 29, 2020.
- Accepted November 5, 2020.
- Copyright ©ERS 2020
This version is distributed under the terms of the Creative Commons Attribution Licence 4.0.
