GB0139, an inhaled small molecule inhibitor of galectin-3, in COVID-19 pneumonitis: a randomised, controlled, open-label, phase 2a experimental medicine trial of safety, pharmacokinetics, and potential therapeutic value
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Abstract
Rationale
High galectin-3 levels predict poor outcomes in patients with COVID-19. Galectin-3 activates monocytes and macrophages which are directly implicated in COVID-19 immunopathology and the cytokine storm. GB0139 is a potent thiodigalactoside galectin-3 inhibitor and may reduce the severe effects of the disease. We report safety and pharmacokinetics and pharmacodynamics of the inhaled galectin-3 inhibitor, GB0139, and assess clinical outcomes and key systemic inflammatory biomarkers in hospitalised patients with COVID-19 (ClinicalTrials.gov/EudraCT identifier: NCT04473053 /2020-002230-32).
Methods
Adults with COVID-19 requiring oxygen, and with pneumonitis on x-ray, were randomised to receive standard of care (SOC; including dexamethasone; n=21) or SOC plus 10 mg GB0139 twice daily for 48 hours, then once daily for ≤14 days (n=20).
Results
Patients aged 27–87 years were enrolled from July 2020; the final patient completed the 90-day follow-up in April 2021. GB0139+SOC was well tolerated with no treatment-related serious adverse events reported. Incidences of adverse events were similar between treatment arms (40 with GB0139+SOC vs 35 with SOC). Plasma GB0139 was measurable in all patients after inhaled exposure, with moderate interpatient variability, and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc over days 2–7: p=0·0099 vs SOC). Rate of decline in fraction of inspired oxygen (%) requirement was significantly greater in the GB0139+SOC arm with a posterior mean difference of -1·51 (95% highest posterior density: -2·90, -0·189) versus SOC. Plasma levels of biomarkers associated with inflammation, coagulopathy, major organ function and fibrosis showed a downward trend versus SOC.
Conclusions
GB0139+SOC was well tolerated and achieved clinically relevant plasma concentrations and target engagement. This, and the reduction in markers associated with inflammatory, coagulation, fibrosis, and reduction in inspired oxygen (%) over SOC alone, indicates the therapeutic potential for inhaled GB0139 in hospitalised patients with COVID-19.
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SciScore for 10.1101/2021.12.21.21267983: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: Independent ethics committee approval (Scotland A Research Ethics Committee: 20/SS/0066) was obtained prior to initiation of the study. Sex as a biological variable not detected. Randomization Study design: DEFINE (University of Edinburgh COVID-19 DEFINE trial, 2020; ClinicalTrials.gov identifier: NCT04473053, EurdraCT number: 2020-002230-32) was a randomised, controlled, open-label, parallel-group Blinding Patients, investigators, and treating clinicians were unaware of treatment allocations before they were assigned to each individual patient. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources All statistical models were fitted using SAS software (SAS … SciScore for 10.1101/2021.12.21.21267983: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: Independent ethics committee approval (Scotland A Research Ethics Committee: 20/SS/0066) was obtained prior to initiation of the study. Sex as a biological variable not detected. Randomization Study design: DEFINE (University of Edinburgh COVID-19 DEFINE trial, 2020; ClinicalTrials.gov identifier: NCT04473053, EurdraCT number: 2020-002230-32) was a randomised, controlled, open-label, parallel-group Blinding Patients, investigators, and treating clinicians were unaware of treatment allocations before they were assigned to each individual patient. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources All statistical models were fitted using SAS software (SAS Institute Inc. SAS Institutesuggested: (Statistical Analysis System, RRID:SCR_008567)Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04473053 Active, not recruiting DEFINE - Evaluating Therapies for COVID-19 NCT03832946 Recruiting A Study to Test the Efficacy and Safety of Inhaled GB0139 in… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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