An Inhaled Galectin-3 Inhibitor in COVID-19 Pneumonitis A Phase Ib/IIa Randomized Controlled Clinical Trial (DEFINE)
Erin E Gaughan, Tom M Quinn, Andrew Mills, Annya M Bruce, Jean Antonelli, Alison C Mackinnon, Vassilios Aslanis, Feng Li, Richard O'connor, Cecilia Boz, Ross Mills, Philip Emanuel, Matthew Burgess, Giulia Rinaldi, Asta Valanciute, Bethany Mills, Emma Scholefield, Gareth Hardisty, Emily Gwyer Findlay, Richard A Parker, John Norrie, James W Dear, Ahsan R Akram, Oliver Koch, Kate Templeton, David H Dockrell, Timothy S Walsh, Stephen Partridge, Duncan Humphries, Jie Wang-Jairaj, Robert J Slack, Hans Schambye, De Phung, Lise Gravelle, Bertil Lindmark, Manu Shankar-Hari, Nikhil Hirani, Tariq Sethi, Ph.D Kevin Dhaliwal, B.L E S T S Were, R O'
doi:10.1164/rccm.202203-0477OCon
Rationale: High circulating galectin-3 is associated with poor outcomes in patients with coronavirus disease . We hypothesized that GB0139, a potent inhaled thiodigalactoside galectin-3 inhibitor with antiinflammatory and antifibrotic actions, would be safely and effectively delivered in COVID-19 pneumonitis. Objectives: Primary outcomes were safety and tolerability of inhaled GB0139 as an add-on therapy for patients hospitalized with COVID-19 pneumonitis. Methods: We present the findings of two arms of a phase Ib/IIa randomized controlled platform trial in hospitalized patients with confirmed COVID-19 pneumonitis. Patients received standard of care (SoC) or SoC plus 10 mg inhaled GB0139 twice daily for 48 hours, then once daily for up to 14 days or discharge. Measurements and Main Results: Data are reported from 41 patients, 20 of which were assigned randomly to receive GB0139. Primary outcomes: the GB0139 group experienced no treatmentrelated serious adverse events. Incidences of adverse events were similar between treatment arms (40 with GB0139 1 SoC vs. 35 with SoC). Secondary outcomes: plasma GB0139 was measurable in all patients after inhaled exposure and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc analysis of covariance [ANCOVA] over days 2-7; P = 0.0099 vs. SoC). Plasma biomarkers associated with inflammation, fibrosis, coagulopathy, and major organ function were evaluated. Conclusions: In COVID-19 pneumonitis, inhaled GB0139 was well-tolerated and achieved clinically relevant plasma concentrations with target engagement. The data support larger clinical trials to determine clinical efficacy. Clinical trial registered with ClinicalTrials.gov (NCT04473053) and EudraCT (2020-002230-32).
Author disclosures are available with the text of this article at www.atsjournals.org .
Acknowledgment: The authors thank the participants and their families and all GB0139 study team members and investigators. The authors also thank the Clinical Research Facility staff in the Royal Infirmary of Edinburgh; the Emergency Medicine Research Group Edinburgh (EMERGE) research team; the Academic and Clinical Central Office for Research and Development (ACCORD) Facilitation; and the quality assurance and monitoring teams at the University of Edinburgh/NHS Lothian (Sponsor). Flow cytometry data were generated with support from the Queen's Medical Research Institute (QMRI) Flow Cytometry and cell sorting facility, University of Edinburgh. GB0139 is being developed by Galecto Biotech. Galecto Biotech participated in the design, study conduct, analysis, and interpretation of data, as well as the writing, review, and approval of the manuscript. The authors thank the data monitoring committee and steering committee members. Third-party medical writing assistance under the direction of the authors was provided by Sin ead Holland, Ph.D., of Ashfield MedComms, an Ashfield Health company, and was funded by Galecto Biotech.
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