Data provides further evidence of the broad potential for CRAC channel inhibitors to benefit patients across multiple disease areas involving the lungs
LA JOLLA, Calif., September 9, 2021 – CalciMedica Inc. (“CalciMedica” or the “Company”), the CRAC channel company, today announced the publication of preclinical data validating calcium release-activated calcium (CRAC) channels, P2Y2 receptors, and P2X receptors as potential drug targets for diseases of the airways in the peer-reviewed Journal of Immunology. The study highlighted in the publication, Differential Regulation of ATP- and UTP-Evoked Prostaglandin E2 and IL-6 Production from Human Airway Epithelial Cells, was conducted at Northwestern University Feinberg School of Medicine in Professor Murali Prakriya’s laboratory, and the manuscript was co-authored by CalciMedica co-founder and chief scientific officer Kenneth A. Stauderman, Ph.D. and researchers from Northwestern University Feinberg School of Medicine.
“These are exciting results that build on the work that CalciMedica is already doing to enhance our understanding of CRAC channels and their important role in controlling normal function of many cell types,” said Dr. Stauderman. “In this study, we saw further evidence that activation of CRAC channels plays a key role in controlling the synthesis and release of inflammatory modulators from pulmonary epithelial cells, which has therapeutic implications. CRAC channel inhibitors have previously shown efficacy in preclinical models of asthma. In addition, CalciMedica is currently conducting a Phase 2 clinical trial with clinical investigators at Northwestern to test our CRAC channel inhibitor AuxoraTM in patients with COVID-19 pneumonia who are mechanically ventilated and suffering from acute respiratory distress syndrome (ARDS). The preclinical results published last week present further evidence that this approach could potentially benefit patients with diseases affecting the airways including ARDS and asthma, by dampening chronic inflammation in the lungs.”
The published results show that CRAC channels serve as a signaling nexus to the airway epithelial cells (AECs), which employ unique, receptor-specific signaling mechanisms to regulate the release of opposing immunomodulatory mediators. AECs lining the conducting passageways of the lung secrete a variety of factors that modulate inflammation, including prostaglandin E2 (PGE2), which limits lung inflammation and promotes the dilation of the airways, and IL-6, which drives intense airway inflammation, leading to damage and scarring of the lung tissue. In this study, scientists demonstrated that extracellular adenosine triphosphate (ATP), a damage-associated molecule pattern, stimulates the production of PGE2 and IL-6 by AECs, but at different levels of ATP. ATP-mediated synthesis of PGE2, was achieved by activating cell surface metabotropic P2Y2 receptors and CRAC channel-mediated cPLA2 signaling. In contrast, ATP-evoked synthesis of IL-6 occurred when the scientists activated P2X receptors and CRAC channel-mediated calcineurin/nuclear factor of activated T cell (NFAT) signaling. These results demonstrate that CRAC channels are essential for both PGE2 synthesis and IL-6 secretion, making CRAC channels potential drug targets for diseases affecting the lungs.
“These study results are significant both from a scientific and a therapeutic perspective,” said Dr. Prakriya. “By elucidating the mechanistic link between CRAC channels and the inflammatory modulators PGE2 and IL-6, which has historically not been well understood, we can better understand how targeting the CRAC channels can potentially treat diseases of the lungs.”
“This study builds on our growing body of research indicating that CRAC channel inhibitors can potentially improve patient outcomes in both acute critical illnesses and in certain chronic diseases,” said Rachel Leheny, Ph.D., chief executive officer of CalciMedica. “We continue to study the role that CRAC channel inhibitors play in modulating the adaptive immune response, as well as in mediating toxicity due to calcium overload in certain pathologies, while advancing multiple clinical trials evaluating Auxora in several indications including acute pancreatitis and acute hypoxemic respiratory failure associated with COVID-19.”