Auxora, a Selective CRAC Channel Inhibitor
CalciMedica’s lead product candidate, AuxoraTM (formerly CM4620), a proprietary intravenous-formulated CRAC channel inhibitor, is being developed for several indications including acute pancreatitis (AP), Asparaginase-Associated Acute Pancreatitis (AAP), and acute kidney injury (AKI) which currently have no approved therapies.
Acute pancreatitis (AP) is an acute inflammatory process of the pancreas that presents as severe upper abdominal pain, often accompanied by nausea and vomiting. During episodes of the disease, inflammation of the pancreas occurs, which can lead to pancreatic cell death or necrosis and systemic inflammation. Normal pancreatic functions, such as the secretion of digestive enzymes required to break down carbohydrates and fats, are disabled. There are no approved therapies for AP.
There are an estimated 275,000 hospitalizations for AP annually in the United States1. Mortality in mild AP is very low at less than 5% but climbs to 20-30% in patients with severe disease2. Approximately 40% of hospitalized AP patients present with SIRS and are predicted to have moderate or severe disease, with 15% actually developing severe AP.
Severe complications arise because of the acute inflammatory response that takes place in the pancreas. These complications can lead to systemic inflammatory response syndrome (SIRS) in which the function of other tissues or organs, including the lung may be compromised. Approximately one third of patients with severe AP develop acute lung injury or ARDS. Lung failure accounts for approximately 60% of deaths associated with AP in developed countries3.
Leading causes of AP are gall stones and alcohol, together accounting for 60-80% of all cases depending on the specific population examined. Other causes include: hypertriglyceridemia, familial (genetic) types, hypercalcemia, abdominal injury or trauma (including endoscopic retrograde cholangiopancreatography), cancer, drug-induced, or autoimmune, each making up smaller slices of the total AP population. These different causes all appear to lead to a common mechanism in which calcium within pancreatic cells drives pathology.
- Burden of Gastrointestinal Disease in the United States Gastroenterology 2012;143:1179-1187.
- Acute Pancreatitis Jama. 2021;325(4):382-390.
- Chronic Pancreatitis Associated Acute Respiratory Failure MOJ Immunol 2017; 5(2): 00149.
Excessive signaling through calcium-dependent pathways has been linked to multiple pathologies associated with acute pancreatitis. A primary function of the pancreas is to produce enzymes that are required to digest food. The secretion of these enzymes from the pancreas is dependent on the periodic release of calcium from internal stores in the cells called the pancreatic acinar cells. In AP, aberrant activation of these cells results in elevated, toxic levels of intracellular calcium and as a consequence, the inappropriate activation of digestive enzymes inside the cells causes the acinar cells to self-digest.
Acute pancreatitis is also associated with a high level of inflammation. In some patients, the release of inflammatory cytokines and the triggering of SIRS can lead to life-threatening distal organ failure. Previous studies have established a strong link between calcium signaling and the release of inflammatory cytokines. The most frequent systemic complications in severe cases of AP are respiratory dysfunctions ranging from hypoxemia to ARDS. As in the case with ARDS from other underlying causes, AP-associated ARDS is the result of both increased vascular permeability and an increase in inflammation, which we believe are CRAC channel-dependent processes.
We completed a randomized, open-label Phase 2a clinical trial of Auxora in 21 patients with AP and accompanying SIRS who also had hypoxemia at presentation. Patients in this trial treated with Auxora in addition to SOC had multiple improved outcomes compared to patients treated with standard care alone. In addition, there were several patients with severe respiratory failure at enrollment and the majority of those treated with Auxora did not require mechanical ventilation.
We are currently conducting a Phase 2b clinical trial in 216 patients with AP and SIRS. We anticipate results from this trial in the second half of 2023. For more details, please visit our Clinical Trials page.
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 exposure to the virus. Patients present with symptoms that include fever, dry cough, body ache, sore throat and diarrhea. As the disease progresses, some patients develop shortness of breath resulting from lung injury and are hospitalized. In the majority of these patients, this condition resolves over time, but in up to 20% of patients, it progresses from moderate to severe ARDS requiring mechanical ventilation1.
Disease progression in severe 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 severe COVID-19 infection may result in overproduction of early response proinflammatory cytokines and may also result in complement and coagulation dysfunction, leading to an increased risk of vascular hyperpermeability, respiratory failure, multi-organ failure, and sometimes death.
- Severe Covid-19 N Engl J Med 2020 May 15. doi: 10.1056/NEJMcp2009575
For more details, please see our Clinical Trials page.
ARDS is a rapidly progressive and very serious pulmonary disorder that leads to edema, or fluid, in the lungs which compromises oxygenation of the blood, resulting in hypoxia or respiratory failure. A study found that ARDS accounted for 10% of ICU admissions and 23% of mechanical ventilations. ARDS is typically classified as mild, moderate or severe, with mortality of 40-60% in severe cases. The broader ARDS patient population includes many etiologies including sepsis, viral pneumonia, bacterial pneumonia and trauma. The incidence of ARDS in the United States is estimated to be approximately 190,000 cases per year, with sepsis being the most common cause. We believe that the Auxora clinical data in COVID-19 pneumonia suggests that Auxora can potentially be used in most ARDS settings.
In collaboration with investigators from Northwestern Memorial Hospital, we are conducting a Phase 2 dose escalation clinical trial of Auxora in patients with COVID-19 pneumonia who have ARDS and require invasive mechanical ventilation. Enrollment for this trial was recently completed. We anticipate this trial will be completed by the end of 2022. Results from this trial may inform the design of a phase 2 clinical trial for the treatment of AHRF and/or ARDS caused by a broad range of infectious agents.
For more details, please see our Clinical Trials page.
Current therapies for acute lymphoblastic 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 or asparaginase-associated pancreatitis (AAP) in 7-10%1 of patients with ALL, with more than half of those patients developing pancreatic necrosis.
- Rank C, Wolthers B, Grell K, et al. Asparaginase-associated pancreatitis in acute lymphoblastic leukemia: results from the NOPHO ALL2008 treatment of patients 1-45 years of age. J Clin Oncol. 2019 38:145-154.
For more details, please visit our Clinical Trials page.