The CRAC channel inhibitor Auxora interrupts inflammatory circuits between alveolar macrophages and T cells in patients with viral pneumonia

Viral pneumonia is perpetuated by inflammatory circuits between activated T cells and monocyte-derived alveolar macrophages (MoAM). T cells and macrophages express ORAI1 and STIM1, which form calcium release-activated calcium (CRAC) channels that allow extracellular calcium entry in response to endoplasmic reticulum calcium store depletion. In a randomized, placebo-controlled, multicenter phase 2 trial (CARDEA), Auxora, a CRAC channel inhibitor, reduced all-cause 30-day mortality by 56% in patients with severe SARS-CoV-2 pneumonia1. Here, we report a multi-omics analysis of serially collected alveolar samples from unvaccinated patients with severe SARS-CoV-2 pneumonia treated with Auxora versus placebo. We found reductions in plasma levels of the monocyte- and T cell-chemokines, CCL8 and CXCL10. Using PBMCs from healthy volunteers, we show Auxora directly targets T cells to inhibit the transcription of CCL8 and CXCL10 in monocyte-derived macrophages, supporting a mechanism for its effects and a potential intermediate biomarker of efficacy.