Combination of The CRAC Channel Inhibitor CM4620 And Galactose as A Potential Therapy for Acute Pancreatitis

Acute pancreatitis (AP) is a life-threatening inflammatory disease with no specific therapy. Excessive cytoplasmic Ca2+ elevation and intracellular ATP depletion are responsible for the initiation of AP. Inhibition of CRAC channels has been proposed as a potential treatment and currently, a novel selective CRAC channel inhibitor CM4620 (AuxoraTM, CalciMedica), is in Phase 2b human trials. While CM4620 is on track to become the first effective treatment for AP, it does not produce complete protection in animal models. Recently, an alternative approach has suggested reducing ATP depletion with a natural carbohydrate galactose. Here we have investigated the possibility of using the smallest effective concentration of CM4620 in combination with galactose. Protective effects of CM4620, in the range of 1-100 nM, have been studied against necrosis induced by either bile acids, palmitoleic acid or L-asparaginase. CM4620 markedly protected against necrosis induced by bile acids or asparaginase starting from 50 nM, and palmitoleic acid starting from 1 nM. Combining CM4620 and galactose (1 mM) significantly reduced the extent of necrosis to near-control levels. In the palmitoleic acids-alcohol-induced experimental mouse model of AP, CM4620 at a concentration of 0.1 mg/kg alone significantly reduced oedema, necrosis, inflammation, and the total histopathological score. A combination of 0.1 mg/kg CM4620 with galactose (100 mM) significantly reduced further necrosis, inflammation, and histopathological score. 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.