Study Supports Development of CRAC Channel Inhibitors for Acute Pancreatitis
Study indicates that Orai1 inhibition prevents impaired ductal cell function in acute pancreatitis (AP)
Data describes underlying biological mechanisms that may explain key result in a Phase 2a trial of AuxoraTM in patients with AP with systemic inflammatory response syndrome and hypoxemia
LA JOLLA, Calif., March 10, 2022 – CalciMedica Inc. (CalciMedica or the Company), the CRAC (calcium release-activated calcium) channel company, today announced the publication of a research paper describing how bile acid- and ethanol-mediated activation of Orai1 damages pancreatic ductal cells in AP. The research paper, entitled “Bile acid- and ethanol-mediated activation of Orai1 damages pancreatic ductal secretion in acute pancreatitis,” appears in the peer-reviewed publication The Journal of Physiology, and is authored by a group led by Joszef Maleth, M.D., Ph.D., Principal Investigator, University of Szeged, Hungary. The results provide a description of the underlying biological mechanisms that may explain the rapid tolerance of solid food observed in CalciMedica’s Phase 2a trial of Auxora, its lead product, in patients with AP with systemic inflammatory response syndrome (SIRS) and hypoxemia.
“The relationship between Orai1 inhibition and bile acid-, and alcohol-induced damage to pancreatic ductal cell secretion was long overdue for attention,” said Dr. Maleth. “Our study demonstrates inhibiting Orai1 may improve outcomes for patients with acute pancreatitis by restoring this ductal cell function. We are thrilled to have a journal as respected as The Journal of Physiology recognize the significance of our conclusions and are glad that our work is accessible to both the public and the scientific community.”
Though sustained intracellular Ca2+ overload via over-activation of CRAC channels and Orai1 in pancreatic acinar cells is a known feature of experimental AP, expression and function of Orai1 in ductal cells of the pancreas are not well appreciated and warranted further research. The results of this study indicate that Orai1 inhibition prevents impaired function of both ductal cells, as well as acinar cells in AP caused by both bile acid/gallstones and alcohol, the leading causes of clinical AP, which has implications for improved disease outcomes in AP patients.
“The study led by Dr. Maleth utilizes our proprietary compound CM5480, one of our research tool CRAC channel inhibitors, which has been used in other proof-of-concept studies,” said Kenneth Stauderman, Ph.D., Co-founder and Chief Scientific Officer of CalciMedica. “Protection of pancreatic ductal cells by a CRAC channel inhibitor, as demonstrated in Dr. Maleth’s study, enables these cells to perform their normal function of transporting digestive enzymes produced in the pancreas to the gut, along with bicarbonate, and we believe helps to explain why, in our Phase 2a AP trial, patients were able to tolerate solid food more rapidly after treatment with Auxora compared to placebo. Together, these findings go a long way to advancing our understanding of the role of CRAC channels in AP and making a difference in the quality of life for these patients.”
Auxora is CalciMedica’s lead candidate and is currently being evaluated in a Phase 2b trial for acute pancreatitis with accompanying SIRS. The previous Phase 2a trial randomized 21 patients with acute pancreatitis and accompanying SIRS with hypoxemia to receive high- or low-dose Auxora plus standard of care or standard of care alone. From screening to day 5 or discharge, of the patients receiving Auxora, fewer experienced persistent SIRS and more experienced rapid restoration of gut function with better tolerability of solid foods within 72 hours of treatment. This allowed for earlier hospital discharge, resulting in reduced median hospital stay in the Auxora treatment groups compared to those patients receiving only standard of care, especially among patients with moderate or severe acute pancreatitis. Improvements in the severity of AP were observed in three of eight Auxora-treated patients with moderate to severe AP as demonstrated by contrast-enhanced computed tomography (CECT) scans, compared with none of four patients in the standard of care group. Efficacy signals were observed across both high-dose and low-dose cohorts.