Abstract and Introduction
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.
The COVID-19 pandemic has caused nearly 5.5 million deaths worldwide and more than 820,000 deaths in the US. Although most cases are asymptomatic or mild, up to 20% of patients progress to develop severe pneumonia, requiring hospitalization and intensive care, with mortality rates near 30% in high-risk groups.[2–6] In the US alone, more than 2.6 million patients with COVID-19 have been hospitalized. To address this global health crisis, antiviral treatments have been utilized to decrease the time to recovery and immunomodulatory therapies have been administered as they have demonstrated some efficacy at reducing mortality among hospitalized patients but additional novel therapeutics are urgently needed.[8–10]
In patients with severe COVID-19 pneumonia, broad dysregulated immune responses have been identified with patients showing elevations in a range of proinflammatory cytokines.[11–18] These pathophysiologic events suggest that treatments with broad-based immunomodulatory effects may be more effective in treating COVID-19 pneumonia than those targeting specific immune pathways to prevent disease progression.[11–19] One such potential treatment is Auxora, a calcium release-activated calcium (CRAC) channel inhibitor. CRAC channel inhibition by the active ingredient in Auxora, CM4620, has been shown to block the release of multiple pro-inflammatory cytokines, including interleukin (IL)-6. Further, in a Phase 2 open-label study in patients with acute pancreatitis with accompanying systemic inflammatory response syndrome (SIRS) and hypoxemia, it was noted that Auxora rapidly lowered IL-6 levels in those patients presenting with levels > 150 pg/mL. The reduction in IL-6 supported the start of an open-label study of Auxora in patients with severe COVID-19 pneumonia in the spring of 2020. The initial open-label trial showed Auxora was safe and reduced the occurrence of a composite of death and need for invasive mechanical ventilation. Given these initial results, a randomized, placebo-controlled trial was initiated to test the hypothesis that the inhibition of CRAC channels by Auxora may effectively treat patients with severe COVID-19 pneumonia.