Reduction in D-dimer Levels After Treatment with Auxora in Patients with Severe Covid-19 Pneumonia Reflects Endothelial Stabilization

Abstract

Background Auxora, a calcium release-activated channel (CRAC) inhibitor, was demonstrated to improve recovery and decrease mortality in patients with severe COVID-19 pneumonia initially in an open-label trial and then in CARDEA, a phase 2, randomized, double-blind, placebo-controlled trial. In the open-label trial, treatment with Auxora was noted to be associated with a decrease in D-Dimer levels. To confirm these findings, blood samples were collected in CARDEA and tested for D-dimer levels. In a subset of patients, additional biomarkers were assessed to elucidate a potential mechanism of action of Auxora in decreasing D-dimer levels. Methods In patients enrolled in CARDEA, blood samples were collected prior to randomization and again at 72 hours after the start of the first infusion of Auxora for testing of D-dimer levels. In patients who consented for additional biomarker testing, blood samples were collected prior to randomization and again at 96 hours for testing of Angiopoietin-1, Angiopoietin-2, renin, and sCD25 levels. Results The baseline mean D-dimer level in the Auxora group was 2.61 mg/L and in the placebo group 2.05 mg/L. Patients treated with Auxora had a significant decrease in D-dimer levels within the first 72 hours compared to those treated with placebo. The difference was − 0.92 (95% CI: -1.82, -0.02; P < 0.0460). The decrease in D-dimer levels correlated with an increase in imputed PaO2/FiO2 (P/F) at 72 hours (r: -0.193; P < 0.05) which in turn correlated with improved clinical outcomes at 168 hours (r: 0.218, P < 0.01). Additional biomarker testing demonstrated that treatment with Auxora reduced levels of Angiopoietin-2 and sCD25 and increased Angiopoietin-1 levels at 96 hours. Conclusion In patients with severe COVID-19 pneumonia, Auxora reduced D-dimer levels which correlated with improved oxygenation and clinical outcomes. In addition, Auxora appears to have decreased endothelial activation through a reduction in systemic inflammation and likely had a direct effect on endothelium stabilization. This trial is registered at ClinicalTrials.gov number, NCT04345614.