Auxora Vs. Placebo for the Treatment of Patients with Severe COVID-19 Pneumonia: A Randomized Clinical Trial

Bruen, Charles; Al-Saadi, Mukhtar; Michelson, Edward A.; Tanios, Maged; Mendoza-Ayala, Raul; Miller, Joseph; Zhang, Jeffrey; Stauderman, Kenneth A.; Hebbar, Sudarshan; Hou, Peter C.

doi:10.21203/rs.3.rs-1239555/v1

Cited by 3 publications

(5 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A correlation analysis of D-dimer, imputed P/F, and status on the ordinal scale at 168 hours showed that the decrease in Ddimer levels noted in the rst 72 hours after treatment with Auxora correlated with an increase in the imputed P/F over the same time period (r: -0.193, P<0.05) which in turn correlated with improvement on the ordinal scale at 168 hours (r: 0.218, P<0.01). As reported previously, the median time to recovery for patients in the e cacy group treated with Auxora was 7 days (168 hours) [14].…”

Section: Resultssupporting

confidence: 75%

“…In addition, the potential mechanism of action of Auxora in decreasing D-dimer levels would be assessed by testing the endothelial biomarkers Angiopoietin-1, Angiopoietin-2, and renin, as well as the in ammatory biomarker soluble CD25 (sCD25). The improved clinical outcomes noted in CARDEA from the treatment of severe COVID-19 with Auxora, including reductions in mortality at Days 30 and 60, have been previously published [14]. We now report the results from the testing of samples for D-dimer and biomarker levels and analyzing the correlation of the changes to outcomes.…”

Section: Introductionmentioning

confidence: 78%

See 1 more Smart Citation

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

Hou,

Miller,

Bruen

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultssupporting

confidence: 75%

Section: Introductionmentioning

confidence: 78%

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

Hou,

Miller,

Bruen

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…As reported previously, the median time to recovery for patients in the e cacy group treated with Auxora was 7 days (168 hours). 14 The ANCOVA model includes Baseline value of the endpoint as a covariate and treatment as xed effect.…”

Section: Resultsmentioning

confidence: 99%

“…The improved clinical outcomes noted in CARDEA from the treatment of severe COVID-19 with Auxora, including reductions in mortality at Days 30 and 60, have been previously published. 14 We now report the results from the testing of samples for D-dimer and biomarker levels and analyzing the correlation of the changes to outcomes.…”

Section: Introductionmentioning

confidence: 99%

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

Hou,

Miller,

Bruen

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…7F). In a complementary approach, the tool SOCE inhibitor SKF96365 and a recently identified inhibitor CM4620, which (as Auxora TM , CalciMedica) has progressed to phase 3 clinical trials in acute inflammatory disease conditions (40), impaired the SOCE in wildtype TNBC cells and further reduced the residual SOCE in EHD2-KO cells (Fig. 6C).…”

Section: Ehd2 Promotes Pro-metastatic Traits In Tnbc Cells By Upregul...mentioning

confidence: 99%

EHD2 overexpression promotes tumorigenesis and metastasis in triple-negative breast cancer by regulating store-operated calcium entry

Luan

Bielecki

Mohapatra

et al. 2022

Preprint

View full text Add to dashboard Cite

With nearly all cancer deaths a result of metastasis, elucidating novel pro-metastatic cellular adaptations could provide new therapeutic targets. Here, we show that overexpression of the EPS15-Homology Domain-containing 2 (EHD2) protein in a large subset of BCs, especially the triple-negative (TNBC) and HER2+ subtypes, correlates with shorter patient survival. The mRNAs for EHD2 and Caveolin-1/2, structural components of caveolae, show co-overexpression across breast tumors, predicting shorter survival in basal-like BC. ShRNA knockdown and CRISPR-Cas9 knockout of EHD2, together with mouse EHD2 rescue, in TNBC cell line models demonstrate a major positive role of EHD2 in promoting tumorigenesis and metastasis. Mechanistically, we link these roles of EHD2 to store-operated calcium entry (SOCE), with EHD2-dependent stabilization of plasma membrane caveolae ensuring high cell surface expression of the SOCE-linked calcium channel Orai1. The novel EHD2-SOCE oncogenic axis represents a potential therapeutic target in EHD2 and CAV1/2-overexpressing BC.

show abstract

Auxora Vs. Placebo for the Treatment of Patients with Severe COVID-19 Pneumonia: A Randomized Clinical Trial

Cited by 3 publications

References 21 publications

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

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

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

EHD2 overexpression promotes tumorigenesis and metastasis in triple-negative breast cancer by regulating store-operated calcium entry

Contact Info

Product

Resources

About