Auxora (zegocractin) / CalciMedica - LARVOL DELTA

Targeting the Orai1 CRAC channel: translating molecular insights into therapeutic progress. (PubMed, Expert Opin Ther Targets) - "Particular attention is paid to third-generation inhibitors, especially CM4620 (zegocractin), evaluating data from recent Phase 2 clinical trials in acute pancreatitis (CARPO), severe COVID-19 pneumonia (CARDEA), and acute kidney injury (KOURAGE)...Over the coming years, the pharmacological design will diverge into acute intravenous critical care and chronic oral immunomodulation. Ultimately, the exploitation of tissue-specific Orai2 and Orai3 isoform profiles represents the next frontier to enhance therapeutic efficacy across distinct disorders."

Journal • Review • Acute Kidney Injury • Critical care • Immunology • Infectious Disease • Nephrology • Novel Coronavirus Disease • Oncology • Pancreatitis • Pneumonia • Renal Disease • Respiratory Diseases • STIM1

KOURAGE: A Study of Auxora in Patients With AKI and Injurious Lung "Crosstalk" (clinicaltrials.gov) - P2 | N=122 | Terminated | Sponsor: CalciMedica, Inc. | Active, not recruiting ➔ Terminated; The study was stopped due to imbalance in randomization stratification of severe patients.

Trial termination • Acute Kidney Injury • Nephrology • Renal Disease

Intranasal nanoparticle targeting neutrophil ORAI1 mitigates pancreatitis- and sepsis-associated acute lung injury. (PubMed, J Control Release) - "Further analyses showed that ORAI1 signaling transcriptionally promotes CD166 expression, at least in part through NFATc2. Together, these findings support intranasal neutLNP delivery as a locally directed strategy that enhances lung protection relative to intranasal free CM4620 while limiting systemic exposure compared with intraperitoneal delivery, and establish CD166 as a functionally important downstream mediator of ORAI1-dependent neutrophil adhesion in acute inflammatory lung injury."

Journal • Acute Lung Injury • Infectious Disease • Pancreatitis • Respiratory Diseases • Septic Shock

The CRAC channel inhibitor Auxora Reprograms Pathogenic Alveolar Macrophage-T Cell Circuits in Viral Pneumonia. (PubMed, J Clin Invest) - No abstract available

Journal • Infectious Disease • Pneumonia • Respiratory Diseases

KOURAGE: A Study of Auxora in Patients With AKI and Injurious Lung "Crosstalk" (clinicaltrials.gov) - P2 | N=150 | Active, not recruiting | Sponsor: CalciMedica, Inc. | Trial completion date: Apr 2026 ➔ Jul 2026 | Trial primary completion date: Apr 2026 ➔ Jul 2026

Trial completion date • Trial primary completion date • Acute Kidney Injury • Nephrology • Renal Disease

Orai1 Facilitates Angiogenesis After Myocardial Infarction Through Notch1 Signaling Pathway. (PubMed, Arterioscler Thromb Vasc Biol) - "Consistently, Orai1 inhibition with CM4620 significantly impaired subintestinal venous plexus development in zebrafish embryos...Furthermore, IL (interleukin)-17A mimicked ST-segment-elevation MI serum, inducing Orai1-mediated store-operated calcium entry and EC migration. Together, these findings reveal a novel role for the Orai1-dependent mechanism in post-MI angiogenesis, highlighting Orai1 as a potential therapeutic target for cardiac repair."

Journal • Cardiovascular • Myocardial Infarction • NOTCH1 • RAI1

Zegocractin for acute pancreatitis with systemic inflammatory response syndrome: a randomized, controlled, dose-ranging, phase 2b trial. (PubMed, EClinicalMedicine) - P2 | "These findings identified a suitable dose, a potential patient population, and endpoints for a phase 3 trial. CalciMedica."

Journal • P2b data • Immunology • Inflammation • Pancreatitis • Respiratory Diseases • Systemic Inflammatory Response Syndrome

Targeted therapeutics for pancreatitis. (PubMed, Front Physiol) - "Potential early interventions include Orai1 inhibition (CM4620/Auxora with early-phase human safety data and phase 2b signals), mitochondrial pore inhibition (NIM811) and other mitochondrial protectants...The emerging clinical pipeline includes repurposed anti-fibrotic or immunomodulatory agents (pirfenidone, paricalcitol, tocilizumab, proglumide), genotype-matched therapy (CFTR modulation in selected populations), and cell-based approaches...Therefore, progress will depend on matching treatment timing to target biology, identifying patients using practical early severity and inflammatory features, and using endpoints that reflect disease modification (organ failure, necrosis, recurrence, fibrosis progression, pancreatic function, and pain trajectories). Trial designs matching these therapeutics to their target biology will help understand the real clinical value of mechanism-based regimens across the AP-RAP-CP continuum."

Journal • Review • Fibrosis • Immunology • Inflammation • Pain • Pancreatitis • ADAM17 • HMGB1 • NLRP3

7-Ketocholesterol promotes T cell migration through Ca2+-NFATc1 pathway-mediated F-actin polymerization and proinflammatory cytokine production in oral lichen planus. (PubMed, Front Immunol) - "Furthermore, CM4620-mediated blockade of Ca2+ -NFATc1 pathway in OLP T cells inhibited 7KC-induced NFATc1 activation, reduced the expressions of F-actin and its modulators ACTB/DIAPH1, and IL1B/CCL4/IL6 gene expressions, with migration suppressions of both primary OLP T cells and OLP plasma-pretreated Jurkat T cells. 7KC could promote T cell migration through Ca2+ -NFATc1 pathway-mediated F-actin polymerization and expression of IL1B/CCL4/IL6 in OLP."

Journal • Dermatology • Dermatopathology • Inflammation • Lichen Planus • CCL4 • IL1B • IL6 • ITGAL • NFATC1

Breaking the Calcium Overload Cycle in Acute Pancreatitis: Emerging Pharmacological Strategies. (PubMed, Dig Dis Sci) - "Pharmacological modulation of calcium homeostasis represents a promising pathogenetic approach to the treatment of acute pancreatitis. Existing evidence supports the need for further multicenter clinical studies to confirm the safety and efficacy of calcium-targeted strategies in routine clinical practice."

Journal • Review • Inflammation • Pancreatitis • MIR26A1

Single-cell transcriptomics reveals targeted modulation of inflammatory repertoire by SOCE blockers. (PubMed, Hum Immunol) - "SOCE blockade with the pyrazole derivative BTP2 has been explored as an anti-inflammatory strategy in preclinical models, and Zegocractin (CM4620) is under clinical investigation as a CRAC channel inhibitor with activity in multiple tissues, including immune cells...These findings suggest that SOCE blockade may provide a more targeted form of immune modulation, warranting future head-to-head comparisons with conventional immunosuppressants. Our results highlight the potential of SOCE blockers to reduce immune-mediated damage while maintaining tolerance, motivating further functional and translational studies in transplantation and other immune-mediated conditions."

Journal • Immune Modulation • Immunology • Transplantation • CD4 • CD8

KOURAGE: A Study of Auxora in Patients With AKI and Injurious Lung "Crosstalk" (clinicaltrials.gov) - P2 | N=150 | Active, not recruiting | Sponsor: CalciMedica, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Acute Kidney Injury • Nephrology • Renal Disease

CRSPA: Study of CM4620 to Reduce the Severity of Pancreatitis Due to Asparaginase (clinicaltrials.gov) - P1/2 | N=42 | Recruiting | Sponsor: St. Jude Children's Research Hospital | Trial completion date: Dec 2027 ➔ Jan 2029 | Trial primary completion date: Jun 2026 ➔ Jan 2027

Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Pancreatitis

A Study of Auxora in Patients With Critical COVID-19 Pneumonia (clinicaltrials.gov) - P2 | N=10 | Terminated | Sponsor: CalciMedica, Inc. | Completed ➔ Terminated; The trial was terminated early due to the limited number of new COVID-19 hospitalizations.

Trial termination • Infectious Disease • Novel Coronavirus Disease • Pneumonia

Zegocractin to Reduce the Severity of Asparaginase Associated Pancreatitis in Children with Acute Lymphoblastic Leukemia: Results of the Phase 1 Portion of the Crspa Study (ASH 2023) - "The infusion was stopped and diphenhydramine was administered with symptomatic improvement. The phase 1 portion of the study has provided promising data on zegocractin efficacy. Moving forward, the ongoing phase 2 portion of the study will further assess and validate the efficacy of zegocractin in treating AAP."

Clinical • P1 data • Acute Lymphocytic Leukemia • Hematological Malignancies • Immunology • Leukemia • Oncology • Pancreatitis • Systemic Inflammatory Response Syndrome

Store-Operated Calcium-Channel Inhibitor Auxora Improves Kidney Function Following Ischemia-Induced AKI in Rats (KIDNEY WEEK 2025) - "Conclusion These data suggest Auxora has therapeutically beneficial effects in a rat model of AKI and can hasten recovery of renal function. The basis for improved function may relate to alterations in inflammation and/or improved vascular function."

Preclinical • Acute Kidney Injury • Cardiovascular • Inflammation • Nephrology • Renal Disease • Reperfusion Injury • CD4 • IL17A

Novel drug targets for the early treatment of acute pancreatitis: Focusing on calcium signaling. (PubMed, Hepatobiliary Pancreat Dis Int) - "Progress in translation has now been made, targeting the ORAI channel with the inhibitor zegocractin (Auxora) to reduce pancreatic injury and inflammatory responses in human AP. Herein we evaluated potential drug targets for the early treatment of AP, focused on intra-acinar mechanisms of injury central to the onset and severity of AP. Our analysis highlights the opportunities and progress in translating these molecular insights into clinical therapies."

Journal • Review • Inflammation • Metabolic Disorders • Pancreatitis

Single-cell transcriptomics reveals targeted modulation of inflammatory repertoire by SOCE blockers. (PubMed, bioRxiv) - "SOCE blockers BTP2 and CM4620 reduce cytotoxic gene expression in CD8□ T cells and NK cells.SOCE blockade preserves anti-inflammatory programs in CD4□ Tregs, supporting selective immune modulation."

Journal • Immune Modulation • Immunology • Transplantation • CD4 • CD8

CRSPA: Study of CM4620 to Reduce the Severity of Pancreatitis Due to Asparaginase (clinicaltrials.gov) - P1/2 | N=42 | Recruiting | Sponsor: St. Jude Children's Research Hospital | Trial primary completion date: Jun 2025 ➔ Jun 2026

Trial primary completion date • Acute Lymphocytic Leukemia • Pancreatitis

Inhibition of Calcium Release-Activated Calcium (CRAC) channels to Treat Acute Kidney Injury: Design and Rationale of the KOURAGE study. (PubMed, Am J Nephrol) - P2 | "The KOURAGE trial will investigate the safety and efficacy of Auxora in patients with severe AKI and AHRF."

Journal • Acute Kidney Injury • Nephrology • Renal Disease • Respiratory Diseases

Edaravone attenuates cerebral inflammation by inhibiting mast cells degranulation via ROS/STIM1 signaling pathway in HIE model. (PubMed, Int Immunopharmacol) - "CM4620 inhibited MCs degranulation and downregulated the expression of STIM1, tryptase, IL-6, TNF-α. In conclusion, the current investigation revealed that edaravone attenuates MCs degranulation and neuroinflammation, at least partially, via ROS/STIM1 pathway after HI injury."

Journal • CNS Disorders • Inflammation • Oncology • IL6 • STIM1 • TNFA

PANCREATIC CELL-SPECIFIC ORAI1 MEDIATES CHRONIC PANCREATITIS AND ITS ASSOCIATED PAIN IN EXPERIMENTAL CHRONIC PANCREATITIS (DDW 2025) - "PSC activation was prevented in PSC ex vivo culture with Orai1 inhibitor, CM4620 or co-culture with acinar or ductal cells. Pancreatic cell-specific deletion or inhibition of Orai1 mitigates PSC activation, pancreatic fibrosis, and CP-associated pain in two experimental chronic pancreatitis via pancreatic epithelial-stromal crosstalk. Our findings provide invaluable preclinical evidence for using Orai1 inhibitor to relieve the progression of CP and CP-associated pain in man."

Fibrosis • Gastrointestinal Disorder • Immunology • Inflammation • Neuralgia • Pain • Pancreatitis • IL6 • PDX1 • SOX9 • TNFA

NEUTROPHIL ORAI1 CALCIUM CHANNEL PROTECTS AGAINST ACUTE PANCREATITIS-ASSOCIATED ACUTE LUNG INJURY VIA NFATC2-CD166 AXIS AND LIPOSOME TARGETED THERAPY (DDW 2025) - "Anti-Ly6G-modified liposomes loaded with the Orai1 inhibitor (CM4620) were designed to target neutrophils and downregulate Orai1 in vivo...Liposomes targeting neutrophil Orai1 showed promising targeting efficiency with both intranasal and systemic administration, significantly reducing pulmonary neutrophil infiltration and ameliorating AP-ALI. Conclusion Neutrophil-specific Orai1 deletion ameliorates AP-ALI via the NFATC2-CD166 axis, highlighting liposomes targeting neutrophil Orai1 as a promising therapeutic strategy."

Acute Lung Injury • Acute Respiratory Distress Syndrome • Pancreatitis • Respiratory Diseases • NFATC1

PATIENTS WITH ACUTE PANCREATITIS (AP) AND ACCOMPANYING SYSTEMIC INFLAMMATORY RESPONSE SYNDROME (SIRS) HAVE A LARGER VOLUME OF DISTRIBUTION COMPARED TO HEALTHY VOLUNTEERS (DDW 2025) - P2 | "CARPO (NCT04681066) was a global blinded RCT that assessed the dose response and efficacy of zegocractin, a calcium release-activated calcium channel inhibitor, in 214 patients with AP and SIRS...An elevated hematocrit (≥44% in men and ≥40% in women) was associated with lower plasma concentrations at the 24 hour time point, consistent with the increase in volume of distribution. Conclusion AP and SIRS is characterized by an increased volume of distribution and higher doses of therapeutic agents may be required in treating this disease."

Clinical • Immunology • Inflammation • Pancreatitis • Systemic Inflammatory Response Syndrome

KOURAGE: A Study of Auxora in Patients With AKI and Injurious Lung "Crosstalk" (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: CalciMedica, Inc. | Trial completion date: Aug 2025 ➔ Mar 2026 | Trial primary completion date: Aug 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • Acute Kidney Injury • Nephrology • Renal Disease