Auxora for the Treatment of Patients With Acute Pancreatitis and Accompanying Systemic Inflammatory Response Syndrome: Clinical Development of a Calcium Release-Activated Calcium Channel Inhibitor.
Acute Disease
Adult
Aged
Calcium Channel Blockers
/ administration & dosage
Calcium Release Activated Calcium Channels
/ antagonists & inhibitors
Cohort Studies
Dose-Response Relationship, Drug
Female
Humans
Interleukin-6
/ metabolism
Male
Middle Aged
Pancreatitis
/ complications
Respiratory Insufficiency
/ chemically induced
Systemic Inflammatory Response Syndrome
/ complications
Treatment Outcome
Journal
Pancreas
ISSN: 1536-4828
Titre abrégé: Pancreas
Pays: United States
ID NLM: 8608542
Informations de publication
Date de publication:
01 04 2021
01 04 2021
Historique:
entrez:
3
5
2021
pubmed:
4
5
2021
medline:
20
1
2022
Statut:
ppublish
Résumé
To assess the safety of Auxora in patients with acute pancreatitis (AP), systemic inflammatory response syndrome (SIRS), and hypoxemia, and identify efficacy endpoints to prospectively test in future studies. This phase 2, open-label, dose-response study randomized patients with AP, accompanying SIRS, and hypoxemia (n = 21) to receive low-dose or high-dose Auxora plus standard of care (SOC) or SOC alone. All patients received pancreatic contrast-enhanced computed tomography scans at screenings, day 5/discharge, and as clinically required 90 days postrandomization; scans were blinded and centrally read to determine AP severity using computed tomography severity index. Solid food tolerance was assessed at every meal and SIRS every 12 hours. The number of patients experiencing serious adverse events was not increased with Auxora versus SOC alone. Three (36.5%) patients with moderate AP receiving low-dose Auxora improved to mild AP; no computed tomography severity index improvements were observed with SOC. By study end, patients receiving Auxora better tolerated solid foods, had less persistent SIRS, and had reduced hospitalization versus SOC. The favorable safety profile and patient outcomes suggest Auxora may be an appropriate early treatment for patients with AP and SIRS. Clinical development will continue in a randomized, controlled, blinded, dose-ranging study.
Identifiants
pubmed: 33939666
doi: 10.1097/MPA.0000000000001793
pii: 00006676-202104000-00009
pmc: PMC8104014
doi:
Substances chimiques
Calcium Channel Blockers
0
Calcium Release Activated Calcium Channels
0
Interleukin-6
0
Banques de données
ClinicalTrials.gov
['NCT03401190']
Types de publication
Clinical Trial, Phase II
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
537-543Informations de copyright
Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.
Déclaration de conflit d'intérêts
J.M. reports grants from CalciMedica, Inc. during the conduct of the study; and grants from CalciMedica, Inc. and Abbott Labs outside of the present work. K.S. and S.H. are employees of, and hold stock in, CalciMedica, Inc. C.B., J.W., C.M., T.L.B. declare no conflict of interest.
Références
Banks PA, Freeman ML; Practice Parameters Committee of the American College of Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol . 2006;101:2379–2400.
Boukerrouche A. The Stepup Approach in Treating Infected Pancreatic Necrosis. Med Clin Rev . 2020;6:95.
Johnson CD, Abu-Hilal M. Persistent organ failure during the first week as a marker of fatal outcome in acute pancreatitis. Gut . 2004;53:1340–1344.
Lankisch PG, Apte M, Banks PA. Acute pancreatitis. Lancet . 2015;386:85–96.
Mounzer R, Langmead CJ, Wu BU, et al. Comparison of existing clinical scoring systems to predict persistent organ failure in patients with acute pancreatitis. Gastroenterology . 2012;142:1476–1482.
Schepers NJ, Bakker OJ, Besselink MG, et al. Impact of characteristics of organ failure and infected necrosis on mortality in necrotising pancreatitis. Gut . 2019;68:1044–1051.
Mole DJ, McClymont KL, Lau S, et al. Discrepancy between the extent of pancreatic necrosis and multiple organ failure score in severe acute pancreatitis. World J Surg . 2019;33:2427–2432.
Bradley EL. A clinically based classification system for acute pancreatitis. Summary of the International Symposium on Acute Pancreatitis, Atlanta, Ga, September 11 through 13, 1992. Arch Surg . 1993;128:586–590.
Larvin M, McMahon MJ. APACHE-II score for assessment and monitoring of acute pancreatitis. Lancet . 1989;2:201–205.
Wu BU, Johannes RS, Sun X, et al. The early prediction of mortality in acute pancreatitis: a large population-based study. Gut . 2008;57:1698–1703.
Miller J, Wu Y, Safa R, et al. Derivation and validation of the ED-SAS score for very early prediction of mortality and morbidity with acute pancreatitis: a retrospective observational study. BMC Emerg Med . 2021;21:16.
Browne GW, Pitchumoni CS. Pathophysiology of pulmonary complications of acute pancreatitis. World J Gastroenterol . 2006;12:7087–7096.
Singh VK, Wu BU, Bollen TL, et al. Early systemic inflammatory response syndrome is associated with severe acute pancreatitis. Clin Gastroenterol Hepatol . 2009;7:1247–1251.
Raghu MG, Wig JD, Kochhar R, et al. Lung complications in acute pancreatitis. JOP . 2007;8:177–185.
Feske S, Wulff H, Skolnik EY. Ion channels in innate and adaptive immunity. Annu Rev Immunol . 2015;33:291–353.
Waldron RT, Chen Y, Pham H, et al. The Orai Ca(2+) channel inhibitor CM4620 targets both parenchymal and immune cells to reduce inflammation in experimental acute pancreatitis. J Physiol . 2019;597:3085–3105.
Gandhirajan RK, Meng S, Chandramoorthy HC, et al. Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation. J Clin Invest . 2013;123:887–902.
Gryshchenko O, Gerasimenko JV, Gerasimenko OV, et al. Ca2+ signals mediated by bradykinin type 2 receptors in normal pancreatic stellate cells can be inhibited by specific Ca2+ channel blockade. J Physiol . 2006;594:281–293.
Gryshchenko O, Gerasimenko JV, Peng S, et al. Calcium signalling in the acinar environment of the exocrine pancreas: physiology and pathophysiology. J Physiol . 2018;596:2663–2678.
Gerasimenko JV, Gryshchenko O, Ferdek PE, et al. Ca2+ release-activated Ca2+ channel blockade as a potential tool in antipancreatitis therapy. Proc Natl Acad Sci U S A . 2013;110:13186–13191.
Petersen OH, Sutton R. Ca2+ signalling and pancreatitis: effects of alcohol, bile and coffee. Trends Pharmacol Sci . 2006;27:113–120.
Raraty M, Ward J, Erdemli G, et al. Calcium-dependent enzyme activation and vacuole formation in the apical granular region of pancreatic acinar cells. Proc Natl Acad Sci U S A . 2000;97:13126–13131.
Vadász I, Sznajder JI. Gas exchange disturbances regulate alveolar fluid clearance during acute lung injury. Front Immunol . 2017;8:757.
Wen L, Voronina S, Javed MA, et al. Inhibitors of ORAI1 prevent cytosolic calcium-associated injury of human pancreatic acinar cells and acute pancreatitis in 3 mouse models. Gastroenterology . 2015;149:481–492.e7.
Stauderman KA. CRAC channels as targets for drug discovery and development. Cell Calcium . 2018;74:147–159.
Miller J, Bruen C, Wilburn J, et al. An open-label, dose-response study of CM4620-injectable emulsion in emergency department patients with acute pancreatitis. Ann Emerg Med . 2019;74:S138–S139.
Miller J, Bruen C, Schnaus M, et al. Auxora versus standard of care for the treatment of severe or critical COVID-19 pneumonia: results from a randomized controlled trial. Crit Care . 2020;24:502.
Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA evidence-based guidelines for the management of acutepancreatitis. Pancreatology . 2013;13:e1–e15.
Shi N, Liu T, de la Iglesia-Garcia D, et al. Duration of organ failure impacts mortality in acute pancreatitis. Gut . 2020;69:604–605.
Fisic E, Poropat G, Bilic-Zulle L, et al. The role of IL-6, 8, and 10, sTNFr, CRP, and pancreatic elastase in the prediction of systemic complications in patients with acute pancreatitis. Gastroenterol Res Pract . 2013;2013:1–6.