ACUTE PANCREATITIS

With its lead clinical compound, CM4620, CalciMedica is currently targeting acute pancreatitis. Acute Pancreatitis is a dynamic inflammatory disease with wide-ranging outcomes; it can evolve rapidly in any given patient with little predictability. In the majority of cases, acute pancreatitis is clinically mild and transitory and resolves spontaneously, although patients are typically hospitalized for several days. However, 15%–20% of patients with acute pancreatitis will develop a severe form of the disease, and in these patients pancreatic cell death (necrosis) and systemic inflammation can lead to organ dysfunction or failure, with much longer hospital stays, often in intensive care units (ICUs), and even death in for 15-30% of severe acute pancreatitis patients.

Acute pancreatitis is the leading cause of gastrointestinal hospitalizations and cost burden in the United States. Patients typically present to the Emergency Room with intense abdominal pain, nausea and vomiting, and after diagnosis are triaged to a hospital ward or the ICU; essentially all are hospitalized for some period of time.

There are currently no therapeutic agents available to treat acute pancreatitis. Supportive care, including fluids, pain medication and nutritional support as required are provided to patients regardless of the severity of their disease. Mild cases are monitored, and released when pain has subsided and they are able to return to normal eating. The same is true for severe cases, but the hospital stay is much longer, supportive care is more extensive, especially if there is organ failure, and removal of necrotic tissue and fluids may be required. Gallstone-induced acute pancreatitis is often followed by a cholecystectomy to eliminate subsequent attacks.

CAUSES OF ACUTE PANCREATITIS

In developed countries, obstruction of the common bile duct by stones and alcohol use are the most frequent causes of acute pancreatitis, accounting for 70-80% of cases. Gallstone-induced pancreatitis is caused by duct obstruction and the action of bile acids on the pancreatic acinar cells. Gallstones allow reflux of bile into the pancreatic duct system, and once in the pancreatic acinar cells bile acids activate calcium entry into these cells through CRAC channels, causing acute pancreatitis through unregulated activation of digestive enzymes, cytokine production and infiltration of the pancreas by inflammatory cells and necrosis of the pancreatic exocrine cells.

Alcohol use is the second most frequent cause of acute pancreatitis, but the correlation between alcohol and pancreatitis is not completely understood. Although alcohol use is commonly associated with both acute and chronic pancreatitis, alcohol does not itself cause pancreatitis. Instead it appears that metabolic by-products of alcohol are likely responsible for disease in certain patients. Researchers have shown that particular ethanol metabolites called fatty acid ethyl esters (FAEEs) induce the sustained release of calcium from intracellular stores in acinar cells, which activates CRAC channels, and the resulting high intracellular calcium levels cause pancreatitis in the same way as described for gallstone-induced disease.

Other less common causes of acute pancreatitis include: hypertriglyceridemia, hypercalcemia, trauma (including by Endoscopic Retrograde CholangioPancreatography, or ERCP, a relatively common diagnostic and therapeutic procedure), cancer (by blockage of the pancreatic or bile duct, analogous to a gallstone), reactions to certain drugs, viral infections, specific gene mutations (hereditary forms), etc. A specific cause cannot be determined in approximately 20% of patients, who are therefore diagnosed with idiopathic acute pancreatitis.

CALCIMEDICA'S APPROACH

CRAC channels are found on pancreatic acinar cells, where the disease starts, and immune cells (T cells, neutrophils and macrophages), which comprise the immune response that can become a systemic problem, causing damage to organs distal to the pancreas including the lungs and kidneys. Both cell types are critical in the disease process of severe acute pancreatitis. CalciMedica’s CRAC channel inhibitor, by targeting these two cell types, can potentially reduce the necrotic cell damage within the pancreas, and the systemic inflammatory response that results. This should reduce the severity of disease experienced by patients, and help speed their recovery.