Auxora, a Selective CRAC Channel Inhibitor
COVID-19 is a disease caused by infection with SARS-CoV-2, a pandemic strain of coronavirus. Respiratory illness is the most common symptom associated with COVID-19 with a severity ranging from mild disease to life-threatening acute respiratory distress syndrome, or ARDS.
Most cases of COVID-19 occur approximately four to five days after infection by the virus and present with symptoms such as fever, dry cough, body ache, sore throat and diarrhea. As the disease progresses, many patients develop shortness of breath due to reduced lung capacity and are hospitalized. In the majority of patients, this condition resolves over time, often with the help of supplemental oxygen, but in up to 20% of patients, it progresses to moderate to severe ARDS requiring mechanical ventilation1.
Disease progression in COVID-19 has similarities to that of severe community-acquired pneumonia caused by other viruses besides SARS-CoV-2 or by bacteria. The immune response to COVID-19 infection results in overproduction of early response proinflammatory cytokines, such as tumor necrosis factor alpha, or TNFα, interleukin 6, or IL-6, and interleukin 1 beta, or IL-1β, resulting in what has been described as a cytokine storm. It is often accompanied by complement and coagulation dysfunction, leading to an increased risk of vascular hyperpermeability where fluid and proteins leak from blood vessels to the interstitial space, causing respiratory failure, multi-organ failure and sometimes to death.
Clinical data from a Phase 2 randomized, open-label trial in severe COVID-19 pneumonia patients with varying degrees of respiratory failure, showed patients receiving Auxora in addition to the standard of care were less likely to be intubated or to die, and they recovered faster than those treated with the standard of care alone. The preliminary results of this trial prompted the U.S. Food and Drug Administration to strongly recommend CalciMedica transition from the open-label study to a blinded pivotal trial. CalciMedica is now enrolling up to 400 patients with severe COVID-19 pneumonia in this registrational trial.
For more details on the clinical trial of Auxora in patients with severe COVID-19 pneumonia, please visit: clinicaltrials.gov.
Acute pancreatitis (AP) is an acute inflammatory disease of the pancreas that presents as severe upper abdominal pain, often accompanied by nausea and vomiting. In acute pancreatitis, which has numerous causes, inflammation of the pancreas occurs, which can lead to pancreatic cell death or necrosis and systemic inflammation, a precursor to organ failure. Normal pancreatic functions, such as the secretion of digestive enzymes required to break down food in the gut, are disabled. There are no approved therapies for AP, but most cases resolve after several days of supportive care in the hospital where patients are given intravenous fluids and monitored for the development of more severe symptoms. Severe acute pancreatitis can result in significant morbidity, long hospital and/or ICU stays and death.
Severe complications arise due to the acute inflammatory response that takes place in the pancreas. These complications can lead to systemic inflammatory response syndrome, or SIRS, in which the function of other tissues including the lung are compromised. Approximately one third of patients with severe acute pancreatitis develop acute lung injury or ARDS. Lung failure accounts for 60% of deaths associated with acute pancreatitis in developed countries4
Excessive signaling through calcium-dependent pathways has been linked to multiple pathologies associated with acute pancreatitis:
- Necrosis of pancreatic acinar cells. A primary function of the pancreas is to produce digestive enzymes that are required to digest food. The secretion of these enzymes from the pancreas is dependent on periodic release of calcium from internal stores in the cells called the pancreatic acinar cells. In acute pancreatitis, excess stimulation of these cells results in elevated, toxic levels of calcium in these cells and, as a consequence of inappropriate activation of digestive enzymes inside the cells, the acinar cells self-digest.
- Systemic inflammatory response syndrome or SIRS. Acute pancreatitis is also associated with a high level of inflammation, which is exacerbated by cell death caused by autodigestion. In some patients, this inflammation causes release of inflammatory cytokines and triggers a life-threatening systemic inflammatory response syndrome, or SIRS, which can lead to organ failure. Previous studies have established a strong link between calcium signaling and release of inflammatory cytokines.
- Pulmonary complications. The most frequent systemic complications in severe cases of acute pancreatitis are respiratory dysfunctions ranging from hypoxemia to ARDS. Acute pancreatitis-associated ARDS is the result of both increased vascular permeability and an increase in inflammation, which are believed to be calcium-dependent processes.
Findings from a Phase 2 trial of Auxora in predicted severe acute pancreatitis patients showed patients treated with Auxora were associated with reduced lung and kidney organ failure, less frequent requirement for ventilator use, reduced pancreatic necrosis, improved ability to tolerate solid foods and shorter hospital stays. A Phase 2b trial in acute pancreatitis is anticipated in the first half of 2021.
- Sudden Death Due to Acute Pancreatitis Acad Forensic Pathol 2018 Jun; 8(2): 239–255.
- Mortality in Acute Pancreatitis: Is It an Early or a Late Event? JOP 2005 Sep 10;6(5):438-44.
- Chronic Pancreatitis Associated Acute Respiratory Failure MOJ Immunol 2017; 5(2): 00149.
Current therapies for acute lymphocytic leukemia (ALL) result in long term survival for over 90% of pediatric ALL patients. One of the mainstays of therapy in these patients is asparaginase, an enzyme that degrades the amino acid asparagine, which is essential for the leukemic cells to survive. However, the administration of asparaginase triggers the development of acute pancreatitis in up to 7% of patients.
An investigator-initiated Phase 1/2 trial is ongoing at St. Jude Children’s Research Hospital investigating Auxora as a potential therapy for acute pancreatitis as a result of asparaginase treatment for pediatric patients with ALL. Patients enrolled in this trial are treated with a daily dose of Auxora for four days with the primary endpoints of safety, tolerability and the reduction in development of complications of acute pancreatitis including necrotizing pancreatitis and SIRS. For more details on the clinical trial, please visit: clinicaltrials.gov.