An Inhaled Galectin-3 Inhibitor in COVID-19 Pneumonitis: A Phase Ib/IIa Randomized Controlled Clinical Trial (DEFINE)

Abstract

Rationale: High circulating galectin-3 is associated with poor outcomes in patients with coronavirus disease (COVID-19). 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 treatment-related serious adverse events. Incidences of adverse events were similar between treatment arms (40 with GB0139 + 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).

Keywords: COVID-19; GB0139; galectin-3.

Figure 1.

Consort diagram of patient disposition.

Figure 2.

Individual patient serum galectin-3 concentrations from all patients receiving GB0139 + SoC (standard of care) (red) or SoC (blue). Linear regression analysis showing the line of best fit with a 95% confidence interval (shaded area). Of note, overall treatment effect, using all available data to Day 16 was also significant for GB0139 + SoC versus SoC (post hoc analysis of covariance [ANCOVA] over days 2–16: P = 0.0001); however, the last day for data availability in the SoC arm was Day 14.

Figure 3.

Absolute change from baseline in markers of inflammation in the overall population: (A) C-reactive protein, (B) lactate dehydrogenase, (C) neutrophil/lymphocyte ratio, and (D) CXCL10. Individual patient-degree data from all those who received GB0139 + SoC (standard of care) (red) or SoC (blue): linear regression analysis showing the line of best fit with 95% confidence interval (shaded area). CXCL10 = C-X-C motif chemokine ligand 10.

Figure 4.

Effect of GB0139 + SoC (standard of care) (blue) and SoC (red) on coagulopathy: individual patient-degree data for (A) D-dimer concentrations, (B) fibrinogen/platelet ratio, (C) platelets, and (D) activated partial thromboplastin time. (A) and (B) display linear regression analysis showing the line of best fit with a 95% confidence interval (shaded area).