Auxora vs. placebo for the treatment of patients with severe COVID-19 pneumonia: a randomized-controlled clinical trial

Abstract

Background Calcium release-activated calcium (CRAC) channel inhibitors block proinflammatory cytokine release, preserve endothelial integrity and may effectively treat patients with severe COVID-19 pneumonia. Methods CARDEA was a phase 2, randomized, double-blind, placebo-controlled trial evaluating the addition of Auxora, a CRAC channel inhibitor, to corticosteroids and standard of care in adults with severe COVID-19 pneumonia. Eligible patients were adults with ≥ 1 symptom consistent with COVID-19 infection, a diagnosis of COVID-19 confirmed by laboratory testing using polymerase chain reaction or other assay, and pneumonia documented by chest imaging. Patients were also required to be receiving oxygen therapy using either a high flow or low flow nasal cannula at the time of enrolment and have at the time of enrollment a baseline imputed PaO2/FiO2 ratio > 75 and ≤ 300. The PaO2/FiO2 was imputed from a SpO2/FiO2 determine by pulse oximetry using a non-linear equation. Patients could not be receiving either non-invasive or invasive mechanical ventilation at the time of enrolment. The primary endpoint was time to recovery through Day 60, with secondary endpoints of all-cause mortality at Day 60 and Day 30. Due to declining rates of COVID-19 hospitalizations and utilization of standard of care medications prohibited by regulatory guidance, the trial was stopped early. Results The pre-specified efficacy set consisted of the 261 patients with a baseline imputed PaO2/FiO2≤ 200 with 130 and 131 in the Auxora and placebo groups, respectively. Time to recovery was 7 vs. 10 days (P = 0.0979) for patients who received Auxora vs. placebo, respectively. The all-cause mortality rate at Day 60 was 13.8% with Auxora vs. 20.6% with placebo (P = 0.1449); Day 30 all-cause mortality was 7.7% and 17.6%, respectively (P = 0.0165). Similar trends were noted in all randomized patients, patients on high flow nasal cannula at baseline or those with a baseline imputed PaO2/FiO2 ≤ 100. Serious adverse events (SAEs) were less frequent in patients treated with Auxora vs. placebo and occurred in 34 patients (24.1%) receiving Auxora and 49 (35.0%) receiving placebo (P = 0.0616). The most common SAEs were respiratory failure, acute respiratory distress syndrome, and pneumonia. Conclusions Auxora was safe and well tolerated with strong signals in both time to recovery and all-cause mortality through Day 60 in patients with severe COVID-19 pneumonia. Further studies of Auxora in patients with severe COVID-19 pneumonia are warranted. Trial registration NCT04345614.

Multi-ancestry Mendelian randomization of omics traits revealing drug targets of COVID-19 severity

“…Currently, some clinical trials have shown beneficial effects of some approved drugs on COVID-19, including IL6R antagonist 3 ACE inhibitor, 4 Peginterferon Lambda-1a, 5 fluvoxamine, 6 Calcium release-activated calcium (CRAC) channel inhibitors, 7 Janus kinase 1/2 inhibitor, 8 vitamin D. 9 In parallel, some experimental studies have identified a set of human proteins that interact with SARS-CoV-2, 10 and may provide drug targets for general coronavirus interventions. Some genetic and epidemiology studies suggested that drug response of COVID-19 differs among ethnic groups.…”

Store‐operated calcium entry controls innate and adaptive immune cell function in inflammatory bowel disease

“…For these experiments we used the CRAC channel blocker CM4620 that, like BTP2, selectively inhibits CRAC channels (I CRAC ) (Zitt et al , 2004; Waldron et al , 2019). CM4620 has been used in a phase 2 clinical trial for COVID‐19 pneumonia (NCT04345614), in which it was reported to be safe and well‐tolerated with strong signals in both time to recovery and all‐cause mortality (Bruen et al , 2022) and in an ongoing phase 1/2 clinical trial for acute pancreatitis (NCT04195347). To confirm inhibition of CRAC channels by CM4620, we overexpressed STIM1 and ORAI1 in HEK293 cells to enhance I CRAC as reported (Peinelt et al , 2006).…”

“…The intravenous formulation of CM4620, Auxora, has been administered in a Phase 2 trial of patients with severe COVID‐19 pneumonia (NCT04345614) where is was reported to be safe and well tolerated with strong signals in both time to recovery and all cause mortality (Bruen et al , 2022). Auxora was also reported to be safe and well tolerated in a Phase 2 trial (NCT03401190) of patients with acute pancreatitis and systemic inflammatory response syndrome (SIRS) (Bruen et al , 2021.…”

Potential of targeting host cell calcium dynamics to curtail SARS-CoV-2 infection and COVID-19 pathogenesis

“…The third clinical trial study of Auxora is for the extended treatment of high-risk patients with critical COVID-19 pneumonia (CARDEA-Plus) ( https://www.clinicaltrials.gov/ct2/show/NCT05171920 ). Although this particular trial was withdrawn due to the declining COVID-19 cases, the data clearly suggest a promising effect of Auxora in treatment and management COVID-19 [53] .…”

“…The inclusion of patients was done based on the baseline ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2 expressed as a fraction), PaO2/FiO2 ≤ 200. The study reported that the recovery time was reduced to 7 days from 10 days for patients who received Auxora vs placebo [53] . The all-cause mortality rate with Auxora vs placebo on day 30 was 7.6% and 17.6% while on day 60 was 13.8% and 20.6% respectively [52] .…”