Auxora (zegocractin) / CalciMedica - LARVOL DELTA

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

Contemporary Approach to Acute Pancreatitis in Emergency Medicine. (PubMed, J Am Coll Emerg Physicians Open) - "We discussed diagnostic, intervention, and disposition considerations relevant to emergency clinicians and considered risk assessment using available clinical decision tools. We also discussed changes to traditional treatments and ongoing investigational therapies, including steroids, monoclonal antibodies, and calcium release-activated calcium channel inhibitors."

Journal • Review • Pancreatitis

CalciMedica Secures Credit Facility for Up to $32.5 Million (PRNewswire) - "CalciMedica Inc...today announced that the Company has entered into a credit facility with Avenue Venture Opportunities Fund II, L.P., a fund of Avenue Capital Group, providing up to $32.5 million. Proceeds from the facility are intended to support the continued development of the Company's product pipeline. The credit agreement, which has a term of 3.5 years, includes an initial tranche of $10 million fully funded at close and additional tranches of up to $22.5 million available to the Company subject to certain milestones...'This credit agreement provides CalciMedica with additional flexibility as we prepare for multiple critical milestones throughout 2025, including anticipated data from our Phase 2 KOURAGE trial of Auxora in patients with acute kidney injury and hypoxemia'..."

Financing • P2 data • Acute Kidney Injury • Renal Disease

Enhanced STIM1 expression drives platelet hyperactivity in diabetes. (PubMed, Biochem Biophys Res Commun) - "Furthermore, the store-operated calcium entry channel inhibitor CM4620 demonstrated superior antiplatelet and antithrombotic efficacy compared to aspirin in both db/db mice and patients with T2DM. Our results suggest that elevated STIM1 expression contributes to enhanced platelet reactivity in diabetes, and targeting STIM1 may offer a promising novel therapeutic approach for thrombosis prevention in this patient population."

Journal • Cardiovascular • Diabetes • Hematological Disorders • Metabolic Disorders • Thrombosis • Type 2 Diabetes Mellitus • STIM1

Auxora Decreases the Development of Severe Organ Failure in Patients with Acute Pancreatitis and SIRS (APA-JPS-CAP-IAP 2024) - No abstract available

Clinical • Pancreatitis

A Randomized, Double-Blind, Placebo Controlled Dose Ranging Study of Auxora in Patients with Acute Pancreatitis (AP) and Accompanying Systemic Inflammatory Response Syndrome (SIRS) - CARPO (NCT04681066) (Late-Breaking Abstract) (ACG 2024) - P2 | "Auxora decreases the time solid food tolerance, as well as the rates of respiratory failure and necrotizing pancreatitis in patients with AP presenting with > 2 SIRS criteria."

Clinical • Late-breaking abstract • Immunology • Inflammation • Pain • Pancreatitis • Respiratory Diseases • Systemic Inflammatory Response Syndrome

CARPO: A Study of Auxora in Patients With Acute Pancreatitis and Accompanying SIRS (clinicaltrials.gov) - P2 | N=216 | Completed | Sponsor: CalciMedica, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Sep 2024 ➔ May 2024 | Trial primary completion date: Sep 2024 ➔ May 2024

Trial completion • Trial completion date • Trial primary completion date • Immunology • Inflammation • Pancreatitis • Systemic Inflammatory Response Syndrome • IL6

Combination of The CRAC Channel Inhibitor CM4620 And Galactose as A Potential Therapy for Acute Pancreatitis. (PubMed, Function (Oxf)) - "Our data show that CM4620 can be used at much lower concentrations than reported previously, reducing potential side effects. The novel combination of CM4620 with galactose synergistically targets complementary pathological mechanisms of AP."

Journal • Inflammation • Pancreatitis

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 2025 ➔ Dec 2027

Trial completion date • Acute Lymphocytic Leukemia • Pancreatitis

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

Enrollment open • Acute Kidney Injury • Nephrology • Renal Disease

SERUM PROTEOMICS REVEALS THAT THE ORAI1 INHIBITOR AUXORA MAY PROVIDE BENEFITS IN SEVERE ACUTE PANCREATITIS SIMILAR TO THOSE SEEN IN COVID-19 PNEUMONIA (DDW 2024) - P2 | "In COVID-19 pneumonia patients Auxora significantly increased proteins reflecting improved liver function and lipid metabolism and decreased proteins that mediate coagulopathy which were previously found increased in cohorts of patients with severe AP and systemic inflammation. The results suggest that treatment with Auxora in patients with AP may offer beneficial clinical outcomes like those seen in patients with severe COVID-19 pneumonia."

Hematological Disorders • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pancreatitis • Pneumonia • APOC1 • CTSS • F13A1 • ICAM1 • MB • SAA1

CARPO: A Study of Auxora in Patients With Acute Pancreatitis and Accompanying SIRS (clinicaltrials.gov) - P2 | N=216 | Active, not recruiting | Sponsor: CalciMedica, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Immunology • Inflammation • Pancreatitis • Systemic Inflammatory Response Syndrome • IL6

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

New P2 trial • Acute Kidney Injury • Nephrology • Renal Disease

Vulnerability of Store-Operated Calcium Entry to Inhibitors and Microenvironment in Cells of Different Breast Cancer Subtypes. (PubMed, Life (Basel)) - "We have observed that the SOCE inhibitors Leflunomide and Teriflunomide suppress SOCE in the triple-negative BC cell line MDA-MB-231, but not in the luminal A BC cell line MCF-7...In addition, the oxygen scavenger sodium dithionide also affects SOCE, stimulating it in MDA-MB-231 cells but inhibiting in MCF-7 cells. Overall, our data highlight the importance of considering the different sensitivities of various BC cell types to inhibitors and to microenvironmental factors such as hypoxia and acidification when developing targeted drugs."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

CalciMedica Announces FDA Clearance of IND Application for Phase 2 Trial of Auxora for the Treatment of Severe Acute Kidney Injury (PRNewswire) - "CalciMedica...today announced the clearance of its Investigational New Drug (IND) application by the U.S. Food and Drug Administration (FDA) for the Company's lead product candidate, Auxora...to be evaluated in a Phase 2 trial in acute kidney injury (AKI) with associated acute hypoxemic respiratory failure (AHRF). CalciMedica expects to initiate the trial, named KOURAGE, in the first half of 2024 and data expected in 2025."

IND • New P2 trial • P2 data • Acute Kidney Injury

Side-by-side comparison of published small molecule inhibitors against thapsigargin-induced store-operated Ca2+ entry in HEK293 cells. (PubMed, PLoS One) - "Calcium (Ca2+) is a key second messenger in eukaryotes, with store-operated Ca2+ entry (SOCE) being the main source of Ca2+ influx into non-excitable cells. The compounds observed to be the most potent against SOCE in our study were: 7-azaindole 14d (12), JPIII (17), Synta-66 (6), Pyr 3 (5), GSK5503A (8), CM4620 (14) and RO2959 (7). These represent the most promising candidates for future development of SOCE inhibitors for therapeutic use."

Journal • Cardiovascular • Oncology

CARPO: A Study of Auxora in Patients With Acute Pancreatitis and Accompanying SIRS (clinicaltrials.gov) - P2 | N=216 | Recruiting | Sponsor: CalciMedica, Inc.

Trial completion date • Trial primary completion date • Immunology • Inflammation • Pancreatitis • Systemic Inflammatory Response Syndrome • IL6

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 • Pain • Pancreatitis • Systemic Inflammatory Response Syndrome

CalciMedica Collaborator St. Jude Children's Research Hospital Presents Data from Initial Cohort of CRSPA Study at 65th Annual ASH Meeting & Exposition (PRNewswire) - P1/2 | N=42 | CRSPA (NCT04195347) | "CalciMedica Inc...today announced that its collaborator, St. Jude Children's Research Hospital (SJCRH), presented data from the initial cohort of the Phase 1/2 CRSPA study of Auxora™ (zegocractin injectable emulsion) in asparaginase-induced pancreatic toxicity (AIPT) at the 65th Annual American Society of Hematology (ASH) Meeting & Exposition on Sunday, December 10, 2023, in San Diego, CA...Investigators at SJCRH presented results from the first cohort of the CRSPA study, consisting of nine children (average age 8.2 years) with acute lymphoblastic leukemia (ALL) experiencing asparaginase-associated pancreatitis, also known as AIPT and referred to as AAP in the abstract...Study results showed that Auxora reduced the average number of days patients spent in the hospital from 13.4 to 6.3 days."

P1/2 data • Acute Lymphocytic Leukemia • Hematological Malignancies • Immunology • Inflammation • Leukemia • Oncology • Pancreatitis

MECHANISMS OF CRAC-NFATC1 SIGNALING IN THE PATHOGENESIS OF ACUTE PANCREATITIS (UEGW 2023) - "Moreover, inhibition of NFATc1 – either genetically or following application of CRAC channel inhibitors (CM4620/Auxora) significantly reduces expression and release of pro-inflammatory cytokines in primary acinar cells... We propose that CRAC channel - NFATc1 signaling promotes inflammation and tissue damage in acute pancreatitis through regulation of cell-stress responses, cytokine release and immune cell infiltration. Moreover, pharmacological inactivation of the CRAC-NFATc1 pathway might offer novel therapeutic option in treatment of severe acute pancreatitis."

Inflammation • Pancreatitis • NFATC1

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 2023 ➔ Dec 2025 | Trial primary completion date: Jun 2023 ➔ Jun 2025

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

Regulation of neuropathic pain by microglial Orai1 channels. (PubMed, Sci Adv) - "A small-molecule Orai1 inhibitor, CM4620, similarly mitigated allodynia in male mice. Unexpectedly, these protective effects were not seen in female mice, revealing sexual dimorphism in Orai1 regulation of microglial reactivity and hyperalgesia. Together, these findings indicate that Orai1 channels are key regulators of the sexually dimorphic role of microglia for the neuroinflammation that underlies neuropathic pain."

Journal • Immunology • Inflammation • Neuralgia • Pain