CRAC inhibitors for treatment of asparaginase-induced pancreatitis in pediatric patients

Abstract

Provided herein are methods of treating asparaginase-induced pancreatitis with an intracellular calcium signaling inhibitor in pediatric patients. The intracellular calcium signaling inhibitor can be administered alone or in combination with an additional therapeutic agent. In some aspects, the additional therapeutic agent is an asparaginase-containing agent. The methods of the present disclosure show effective treatment that, among other benefits, significantly reduced the time pediatric patients spent in the hospital, an important benefit in a patient population that frequently suffers from severe disease.

Description

PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)CRAC INHIBITORS FOR TREATMENT OF ASPARAGINASE-INDUCED PANCREATITIS IN PEDIATRIC PATIENTSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 698,983, filed September 25, 2024. The disclosure of the prior applications is considered part of and is herein incorporated by reference in the disclosure of this application in its entirety.SUMMARY

[0002] Disclosed herein is a method for treating acute pancreatitis in a subject comprising administering to the subject an intracellular Calcium signaling inhibitor, wherein the intracellular calcium signaling inhibitor is N-(5-(6-chloro-2,2- difluorobenzo[d][l,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, wherein the subject is receiving an asparaginase-containing pharmaceutical composition, wherein the subject is being treated for a different disease or disorder.In some embodiments, the different disease or disorder is acute lymphoblastic leukemia. In some embodiments, the method reduces an average amount of days the subject spends in the hospital. In some embodiments, the average amount of days the subject spends in the hospital is less than 9 days. In some embodiments, the average amount of days the subject spends in the hospital is less than 8 days. In some embodiments, the average amount of days the subject spends in the hospital is less than 7 days. In some embodiments, the average amount of days the subject spends in the hospital is less than 6 days. In some embodiments, the average amount of days the subject spends in the hospital is less than 5 days.

[0003] In some embodiments, further comprising reducing the average amount of time the subject spent in an intensive care unit (ICU). In some embodiments, the average amount of time the subject spent in the ICU is from 5 days to 3 days. In some embodiments, the average amount of time the subject spent in the ICU is 3 days or less.

[0004] In some embodiments, the percentage of subjects in need of the ICU is reduced from 18.8% to 12.5%. In some embodiments, the intracellular Calcium signaling inhibitor is between 1.0 mg / kg and 3.0 mg / kg on days 1-2. In some embodiments, the intracellular Calcium signaling inhibitor is between 1.0 mg / kg and 2.5 mg / kg on days 3-4. In some embodiments, the intracellular Calcium signaling11624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) inhibitor is administered in about 2 mg / kg on day 1 and 2. In some embodiments, the intracellular Calcium signaling inhibitor is administered in about 1.6 mg / kg on days 3 and 4. In some embodiments, the intracellular Calcium signaling inhibitor is administered in between about 20 mg / m2 and 40 mg / m2 on day 1. In some embodiments, the intracellular Calcium signaling inhibitor is administered in between about 20 mg / m2 and 50 mg / m2 on days 2-4. In some embodiments, the intracellular Calcium signaling inhibitor is administered in about 30 mg / m2 on day 1. In some embodiments, the intracellular Calcium signaling inhibitor is administered in about 42 mg / m2 on days 2-4.

[0005] In some embodiments, the intracellular Calcium signaling inhibitor is administered via IV infusion. In some embodiments, the intracellular Calcium signaling inhibitor is administered via IV infusion as a 4-hour infusion.In some embodiments, the age of the subject is between 1 -20. In some embodiments, the subject is seeking pediatric care.

[0006] In some embodiments, the subject does not require total parenteral nutrition (TPN).

[0007] In some embodiments, the percentage of subjects with pancreatic necrosis greater than or equal to about 30% is severely reduced. In some embodiments, the subject does not have pancreatic necrosis greater than or equal to about 30%.

[0008] In some embodiments, a computed tomography severity’ index (CTSI) score is used to evaluate the severity of pancreatic necrosis. In some embodiments, the CTSI score of 0-3 indicates mild acute pancreatitis, the CTSI score of 4-6 indicates moderately severe acute pancreatitis, and the CTSI score greater than 7 indicates severe acute pancreatitis. In some embodiments, the subjects mean CTSI score is from 5.4 to 2.4. In some embodiments, the CTSI score range of the subject is from 0 to 10 to 0 to 4. In some embodiments, the subjects with a CTSI score of greater than or equal to about 7 is severely reduced. In some embodiments, no subjects have a CTSI score of greater than or equal to about 7.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIG. 1A is a graph showing 3-year cumulative incidence of pancreatitis in a study for patients receiving different therapies.21624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)

[0010] FIG. IB is a graph show ing the 3-year cumulative incidence of pancreatitis in the study for patients of different ancestry groups.

[0011] FIG. 2 is a schematic diagram of patient events.

[0012] FIG. 3A is a graph showing event-free survival for patients with no AAP or AAP.

[0013] FIG. 3B is a graph showing event-free survival for patients with LR with no AAP. LR with AAP, SHR with no AAP, or SHR with AAP.

[0014] FIG. 4 is a chart showing 5-year cumulative incidence of extramedullary relapse.DETAILED DESCRIPTIONCompound

[0015] In some embodiments, the methods comprise the steps of identifying a person in need of amelioration of symptoms of pancreatitis, and administering an intracellular Calcium signaling inhibitor to said person at a dose sufficient to ameliorate said symptoms. In some aspects the intracellular Calcium signaling inhibitor is a SOC channel inhibitor. In some aspects the intracellular Calcium signaling inhibitor is a CRAC channel inhibitor. In some aspects the intracellular Calcium signaling inhibitor inhibits a channel comprising a STIM1 protein. In some aspects the intracellular Calcium signaling inhibitor inhibits a channel compnsing Orail protein. In some aspects the intracellular Calcium signaling inhibits a channel comprising Orai2 protein. In some aspects the intracellular Calcium signaling inhibitor is a compound having a (collectively, "Compound A"), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some embodiments the intracellular Calcium signaling inhibitor is a compound having a structure from the group of Compound A or a nanoparticle formulation thereof, including a nanoparticle suspension or emulsion.

[0016] In some aspects the intracellular Calcium signaling inhibitor is a compound of N-(5-(6-chloro-2,2-difluorobenzo[d][l,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6- methylbenzamide. In some aspects the intracellular Calcium signaling inhibitor is a compound of N-(5-(6-chloro-2,2-difluorobenzo[d][l,3]dioxol-5-yl)pyrazin-2-yl)-2- fluoro-6-methylbenzamide or a pharmaceutically acceptable salt, pharmaceutically31624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some aspects the intracellular Calcium signaling inhibitor is chosen from among the compounds, N-(5- (6-ethoxy-4-methylpyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6- methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisonicotinamide, N-(4-(l-ethyl-3-(thiazol-2-yl)-lH-pyrazol-5-yI)phenyl)-2-fluorobenzamide, N-(5-(l-ethyl-3- (triflouromethyl)-lH-pyrazol-5-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide. 4-chloro-l- methyl-N-(4-(l -methy 1 -3-(trifluoromethyl)- lH-pyrazol-5-y 1 )pheny 1 )- lH-pyrazole-5- carboxamide, N-(4-(3-(difluoromethyl)-5-methyl-lH-pyrazol-l-yl)-3-fluorophenyl)-2.6-difluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-lH-pyrazol-l-yl)-3- fluorophenyl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-l -methy 1 -1H- pyrazol-5-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, 4-chloro-N-(3-fluoro-4-(l- methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)phenyl)-l-methyl-lH-pyrazole-5- carboxamide, 3-fluoro-4-(l -methy l -3-(trifluoromethyl)-lH — pyrazol-5-yl )-N-((3- methylisothiazol-4-yl)methyl)aniline, N-(5-(7-chloro-2,3-dihydro-[l,4]dioxino[2,3- b]pyridin-6-yl)pyridin-2-y l)-2,6-difluorobenzamide, N- (2,6-difluorobenzy l)-5-(l- ethyl-3-(thiazol-2-yl)-lH-pyrazol-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-l-(thiazol-2-yl)-lH-pyrazol-4-yl)phenyl)isonicotinamide, 5-(l -methy 1-3- (trifluoromethyl)-lH-p yrazol-5-yl)-N- (2,4,6-trifluorobenzyl)pyridin-2-amine, N-(5- (l-ethyl-3-(trifluoromethyl)-lH-pyrazol-5-yT)pyridin-2-yT)-2, 4, 6-tri fluorobenzamide, N-(5-(5-chloro-2-methylbenzo[d]oxazol-6-yl)pyrazin-2-y l)-2,6-difluorobenzamide, N- (5-(6-ethoxy-4-methylpyridin-3-yl)thiazol-2-yl)-2,3,6-trifluorobenzamide. N-(5-(l- ethyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)pyridin-2-yl)-2,3,6-trifluorobenzamide,2.3.6-trifluoro-N-(3-fluoro-4-(l-methyl-3-(trifluoromethyl)-lH-pyrazol-5- yl)phenyl)benzamide, 2,6-difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazol-4- yl)phenyl)benzamide, or N-(5-(6-chloro-2,2 difluorobenzo[d][l,3]dioxol-5-yl)pyrazin- 2-yl)-2-fluoro-6-methylbenzamide, (collectively, "Compound A"), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some aspects the symptoms are acute pancreatitis symptoms. In some aspects the symptoms comprise at least one of inflammation and edema of the pancreas, upper abdominal pain radiating to the back, left upper quadrant pain radiating to the back, nausea, vomiting, vomiting that is worsened with eating, elevated heart rate, tachycardia, elevated respiratory rate, elevated blood pressure, decreased blood pressure, dehydration, abdominal tenderness,41624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) fever, chills, peritonitis, hemodynamic instability, and reflex bowel paralysis. In some aspects the symptoms are severe acute pancreatitis symptoms. In some aspects, the symptoms comprise at least one of pancreatic necrosis and injury to extra-pancreatic organs. In some aspects the symptoms are chronic pancreatitis symptoms. In some aspects the symptoms comprise at least one of persistent abdominal pain, digestive defects, malabsorption of fats, pain during food uptake, weight loss, elevation of serum amylase activity, elevation of serum lipase activity’, elevation of a CRP inflammatory marker, impairment of bicarbonate production, elevated fecal elastase levels, elevated serum try psinogen levels, pancreatic calcification, elevated serum bilirubin levels, and elevated alkaline phosphatase levels. In some aspects the symptoms comprise at least one of elevated ESR levels, elevated IgG4 levels, elevated rheumatoid factor, presence of ANA antibody, presence of antismooth muscle antibody, assay of any of which may indicate chronic pancreatitis in a person In some aspects the symptoms comprise at least one of steatorrhea, Sudan chemical staining of feces or fecal fat excretion of 7 grams or more over a 24hr period on a 100g fat diet, and fecal elastase in a stool sample at a value of less than 200 p g / g. In some aspects the symptoms comprise at least one of abdominal pain, increased blood amylase levels, increased blood lipase levels, enlarged pancreas, nausea, vomiting, internal bleeding, bowel paralysis, fever, jaundice, weight loss, and elevated heart rate. In some aspects the symptoms comprise elevated serum levels of amylase. In some aspects the symptoms comprise elevated serum levels of lipase. In some aspects the symptoms comprise findings of necrosis by computed tomography (CT) scan. In some aspects the symptoms comprise premature digestive enzyme activation. In some aspects the premature digestive enzyme activation occurs in a pancreas of said person. In some aspects the enzyme comprises try psin.

[0017] Some embodiments relate to methods of preventing or ameliorating a symptom associated with a pancreatic disorder in a person at risk of a pancreatic disorder. In some embodiments the method comprises the steps of: identifying a person having a risk factor associated with a pancreatic disorder; and administering an intracellular Calcium signaling inhibitor at a dose sufficient to prevent or ameliorate said side effect. In some aspects the intracellular Calcium inhibiter is a SOC channel inhibitor. In some aspects the intracellular Calcium inhibiter is a CRAC channel inhibitor. In some aspects the intracellular Calcium signaling inhibitor is a compound having the structure from the group of Compound A, or a pharmaceutically acceptable51624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some aspects the intracellular Calcium signaling inhibitor is a compound of, N-(5-(6-chloro-2,2-difluorobenzo [d][l,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6- methylbenzamide. In some aspects the pancreatic disorder comprises an acute pancreatitis symptom. In some aspects the pancreatic disorder comprises a chronic pancreatitis symptom. In some aspects the person has pancreatitis as a result of being subjected to a drug regimen comprising administration of at least one of a steroid such as a corticosteroid, prednisolone, an HIV drug, didanosine, pentamidine, a diuretic, valproic acid, L-asparaginase, azathioprine, estrogen, a statin such as a cholesterol- lowering statin, an antihyperglycemic agent, metformin, a glipin such as vildagliptin and sitagliptin, an atypical antipsychotic, clozapine, risperidone, and olanzapine. In some aspects the person is identified as harboring an inherited form of pancreatitis. In some aspects the person harbors a mutant allele of at least one of trypsinl, encoding trypsinogen, SPINK1, encoding a trypsin inhibitor, and cystic fibrosis transmembrane conductance regulator. In some aspects the person has pancreatitis as a result of suffering at least one of high blood calcium, hypothermia, endoscopic retrograde cholangiopancreatography (ERCP), pancreas divisum, a congenital malformation of the pancreas, diabetes mellitus type 2, pancreatic cancer, pancreatic duct stones, vasculitis, inflammation of the small blood vessels in the pancreas, coxsackievirus infection, and porphyra. such as acute intermittent porphyria and erythropoietic protoporphyria. In some aspects the bodily health condition of said person has been impacted at least one of a gall stone, ethanol poisoning, alcoholism, trauma, mumps, an autoimmune disorder, a scorpion sting, hyperlipidaemia, hypothermia, hyperparathyroidism, and endoscopic retrograde cholangiopancreatography, azathioprine, and valproic acid. In some aspects the bodily health condition of said person has been impacted by at least one of a Coxsackie virus, a Cytomegalovirus, a Hepatitis B virus, a Herpes simplex virus, Mumps, a Varicella-zoster virus, a Legionella bacterium, a Leptospira bacterium, a Mycoplasma bacterium, a Salmonella bacterium, an Aspergillus fungus, an Ascaris parasite, a Cryptosporidium cell and a Toxoplasma cell.

[0018] Some embodiments relate to a composition comprising an intracellular Calcium signaling inhibitor and at least one drug associated with a negative impact on pancreatic activity. In some aspects the drug is selected from the list consisting of: a steroid such as a corticosteroid, prednisolone, an HIV drug, didanosine. pentamidine, a61624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) diuretic, valproic acid, L-asparaginase, azathioprine, estrogen, a statin such as a cholesterol-lowering statin, an antihyperglycemic agent, metformin, a glipin such as vildagliptin and sitagliptin. an atypical antipsychotic, clozapine, risperidone, and olanzapine, azathioprine, and valproic acid. In some aspects the intracellular Calcium signaling inhibitor is an SOC inhibitor. In some aspects the intracellular Calcium signaling inhibitor is a CRAC inhibitor. In some aspects the intracellular Calcium signaling inhibitor is a compound having the structure from the group of Compound A, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some aspects the intracellular Calcium signaling inhibitor is a compound of, N-(5-(6-chloro-2, 2-difluorobenzo [d][l,3]dioxol- 5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In some aspects the intracellular Calcium signaling inhibitor is a compound of N-(5-(6-chloro-2.2-difluorobenzo [d][l,3]dioxol -5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.

[0019] Some aspects relate to a dosing regimen comprising administration to an individual of a drug associated with a negative impact on pancreatic activity, and administration of an intracellular Calcium signaling inhibitor. In some aspects the drug is selected from the list consisting of: a steroid such as a corticosteroid, prednisolone, an HIV drug, didanosine, pentamidine, a diuretic, valproic acid, L-asparaginase, azathioprine. estrogen, a statin such as a cholesterol-lowering statin, an antihyperglycemic agent, metformin, a glipin such as vildagliptin and sitagliptin, an atypical antipsychotic, clozapine, risperidone, and olanzapine, azathioprine, and valproic acid. In some aspects the intracellular Calcium signaling inhibitor is an SOC inhibitor. In some aspects the intracellular Calcium signaling inhibitor is a CRAC inhibitor. In some aspects the intracellular Calcium signaling inhibitor is a compound having the structure from the group of Compound A, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some aspects the intracellular Calcium signaling inhibitor is a compound of, N-(5-(6-chloro-2,2-difluorobenzo[dJ[l,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6- methylbenzamide. In some aspects the intracellular Calcium signaling inhibitor is a compound of N-(5-(6-chloro-2,2-difluorobenzo[d][l,3]dioxol-5-yl)pyrazin-2-yl)-2-71624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) fluoro-6-methylbenzamide or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.

[0020] Some embodiments relate to a composition for use of ameliorating the symptoms of pancreatitis in a person comprising the steps of identifying a person in need of amelioration of symptoms of pancreatitis, and administering an intracellular Calcium signaling inhibitor to said person at a dose sufficient to ameliorate said symptoms. In some aspects the intracellular Calcium signaling inhibitor is a SOC channel inhibitor. In some aspects the intracellular Calcium signaling inhibitor is a CRAC channel inhibitor. In some aspects the intracellular Calcium signaling inhibitor inhibits a channel comprising a STIM1 protein. In some aspects the intracellular Calcium signaling inhibitor inhibits a channel comprising Orail protein. In some aspects the intracellular Calcium signaling inhibits a channel comprising Orai2 protein. In some aspects the intracellular Calcium signaling inhibitor is a compound having the structure from the group of Compound A, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some aspects the intracellular Calcium signaling inhibitor is a compound of, N-(5-(6- chloro-2,2-difluorobenzo[d][l,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6- methylbenzamide. In some aspects the intracellular Calcium signaling inhibitor is a compound of N-(5-(6-chloro-2,2-difluorobenzo[d][l,3]dioxol-5-yl)pyrazin-2-yT)-2- fluoro-6-methylbenzamide or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some aspects the composition further comprises a painkiller medication. In some aspects the painkiller medication comprises an opiate. In some aspects the painkiller medication comprises morphine. In some aspects the symptoms are acute pancreatitis symptoms. In some aspects the symptoms comprise at least one of inflammation and edema of the pancreas, upper abdominal pain radiating to the back, left upper quadrant pain radiating to the back, nausea, vomiting, vomiting that is worsened with eating, elevated heart rate, tachycardia, elevated respiratory rate, elevated blood pressure, decreased blood pressure, dehydration, abdominal tenderness, fever, chills, peritonitis, hemodynamic instability, and reflex bowel paralysis. In some aspects the symptoms are severe pancreatitis symptoms. In some aspects the symptoms comprise at least one of pancreatic necrosis and injury to extra-pancreatic organs. In some aspects the symptoms are chronic pancreatitis symptoms. In some aspects the symptoms comprise at least one81624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) of persistent abdominal pain, digestive defects, malabsorption of fats, pain during food uptake, weight loss, elevation of serum amylase activity, elevation of serum lipase activity, elevation of a CRP inflammatory marker, impairment of bicarbonate production, elevated fecal elastase levels, elevated semm trypsinogen levels, pancreatic calcification, elevated serum bilirubin levels, and elevated alkaline phosphatase levels. In some aspects the symptoms comprise at least one of elevated ESR levels, elevated IgG4 levels, elevated rheumatoid factor, presence of ANA antibody, presence of antismooth muscle antibody, assay of any of which may indicate chronic pancreatitis in a person. In some aspects the symptoms comprise at least one of steatorrhea, Sudan chemical staining of feces or fecal fat excretion of 7 grams or more over a 24hr period on a 100g fat diet, and fecal elastase in a stool sample at a value of less than 200 p g / g. In some aspects the symptoms comprise at least one of abdominal pain, increased blood amylase levels, increased blood lipase levels, enlarged pancreas, nausea, vomiting, internal bleeding, bowel paralysis, fever, jaundice, weight loss, and elevated heart rate. In some aspects the symptoms comprise premature digestive enzyme activation. In some aspects the premature digestive enzyme activation occurs in a pancreas of said person. In some aspects the enzyme comprises trypsin.

[0021] Some aspects relate to a composition for use of preventing or ameliorating a symptom associated with a pancreatic disorder in a person at risk of a pancreatic disorder, comprising the steps of: identifying a person having a risk factor associated with a pancreatic disorder; and administering an intracellular Calcium signaling inhibitor at a dose sufficient to prevent or ameliorate said side effect. In some aspects the intracellular Calcium inhibiter is a SOC channel inhibitor. In some aspects the intracellular Calcium inhibiter is a CRAC channel inhibitor. In some aspects the intracellular Calcium signaling inhibitor is a compound having the structure from the group of Compound A, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some aspects the intracellular Calcium signaling inhibitor is a compound of, N-(5-(6-chloro-2,2- difluorobenzo[d] [l,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. In some aspects the intracellular Calcium signaling inhibitor is a compound of N-(5-(6-chloro- 2,2-difluorobenzo [d][l,3]dioxol-5-yl)pyrazin-2-y l)-2-fluoro-6-methylbenzamide or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some aspects the pancreatic disorder91624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) comprises an acute pancreatitis symptom. In some aspects the pancreatic disorder comprises a chronic pancreatitis symptom. In some aspects the person is subjected to a drug regimen comprising administration of at least one of a steroid such as a corticosteroid, prednisolone, an HIV drug, didanosine, pentamidine, a diuretic, valproic acid, L-asparaginase, azathioprine, estrogen, a statin such as a cholesterol-lowering statin, an antihyperglycemic agent, metformin, a glipin such as vildagliptin and sitagliptin, an atypical antipsychotic, clozapine, risperidone, and olanzapine. In some aspects the person is identified as harboring an inherited form of pancreatitis. In some aspects the person harbors a mutant allele of at least one of trypsinl, encoding trypsinogen, SPINK1, encoding a trypsin inhibitor, and cystic fibrosis transmembrane conductance regulator. In some aspects the person has suffered at least one of high blood calcium, hypothermia, endoscopic retrograde cholangiopancreatography (ERCP), pancreas divisum, a congenital malformation of the pancreas, diabetes mellitus type 2, pancreatic cancer, pancreatic duct stones, vasculitis, inflammation of the small blood vessels in the pancreas, coxsackie virus infection, and porphyra, such as acute intermittent porphyria and erythropoietic protoporphyria. In some aspects the bodily health condition of said person has been impacted at least one of a gall stone, ethanol poisoning, alcoholism, trauma, mumps, an autoimmune disorder, a scorpion sting, hyperlipidaemia, hypothermia, hyperparathyroidism, and endoscopic retrograde cholangiopancreatography, azathioprine, and valproic acid. In some aspects the bodily health condition of said person has been impacted by at least one of a Cytomegalovirus, a Hepatitis B virus, a Herpes simplex virus, Mumps, a Varicella-zoster virus, a Legionella bacterium, a Leptospira bacterium, a Mycoplasma bacterium, a Salmonella bacterium, an Aspergillus fungus, an Ascaris parasite, a Cryptosporidium cell and a Toxoplasma cell.

[0022] Methods and compositions disclosed herein are used for modulating intracellular calcium to ameliorate or prevent symptoms of pancreatitis. In some aspects, the pancreatitis is acute pancreatitis. In some aspects the pancreatitis is chronic pancreatitis. In some aspects, compounds provided herein modulate SOC channel activity. In some aspects, methods and compounds provided herein modulate CRAC channel activity. In another aspect, compounds provided herein modulate STIM protein activity. In another aspect, methods and compounds provided herein modulate Orai protein activity. In another aspect, methods and compounds provided herein modulate101624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) the functional interactions of STIM proteins with Orai proteins. In another aspect, methods and compounds provided herein reduce the number of functional SOC channels. In another aspect, methods and compounds provided herein reduce the number of functional CRAC channels. In some aspects, methods and compounds described herein are SOC channel blockers. In some aspects, methods and compounds described herein are CRAC channel blockers or CRAC channel modulators.

[0023] Calcium plays a vital role in cell function and survival. For example, calcium is a key element in the transduction of signals into and within cells. Cellular responses to growth factors, neurotransmitters, hormones and a variety of other signal molecules are initiated through calcium-dependent processes.

[0024] Virtually all cell types depend in some manner upon the generation of cytoplasmic Ca2+ signals to regulate cell function, or to trigger specific responses. Cytosolic Ca2+ signals control a wide array of cellular functions ranging from shortterm responses such as contraction and secretion to longer-term regulation of cell growth and proliferation. Usually, these signals involve some combination of release of Ca2+ from intracellular stores, such as the endoplasmic reticulum (ER), and influx of Ca2+ across the plasma membrane. In one example, cell activation begins with an agonist binding to a surface membrane receptor, which is coupled to phospholipase C (PLC) through a G-protein mechanism. PLC activation leads to the production of inositol 1,4,5-triphosphate (IP3). which in turn activates the IP3 receptor causing release of Ca2+ from the ER. The fall in ER Ca2+ then signals to activate plasma membrane store-operated calcium (SOC) channels.

[0025] Store-operated calcium (SOC) influx is a process in cellular physiology that controls such diverse functions such as, but not limited to, refilling of intracellular Ca2+ stores (Putney et al. Cell, 75. 199-201. 1993), activation of enzymatic activity (Fagan et al., J. Biol. Chem. 275:26530-26537, 2000), gene transcription (Lewis, Annu. Rev. Immunol. 19:497-521, 2001), cell proliferation (Nunez et al., J. Physiol. 571.1, 57-73, 2006), and release of cytokines (Winslow et al., Curr. Opin. Immunol. 15:299-307, 2003). In some nonexcitable cells, e.g., blood cells, immune cells, hematopoietic cells, T lymphocytes and mast cells, pancreatic acinar cells (PACs). epithelial and ductal cells of other glands (e g., salivary glands), endothelial and endothelial progenitor cells, SOC influx occurs through calcium release-activated calcium (CRAC) channels, a type of SOC channel.111624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)

[0026] The calcium influx mechanism has been referred to as store-operated calcium entry (SOCE). Stromal interaction molecule (STIM) proteins are an essential component of SOC channel function, serving as the sensors for detecting the depletion of calcium from intracellular stores and for activating SOC channels.Calcium homeostasis

[0027] Cellular calcium homeostasis is a result of the summation of regulatory’ systems involved in the control of intracellular calcium levels and movements. Cellular calcium homeostasis is achieved, at least in part, by calcium binding and by movement of calcium into and out of the cell across the plasma membrane and within the cell by movement of calcium across membranes of intracellular organelles including, for example, the endoplasmic reticulum, sarcoplasmic reticulum, mitochondria and endocytic organelles including endosomes and lysosomes.

[0028] Movement of calcium across cellular membranes is carried out by specialized proteins. For example, calcium from the extracellular space can enter the cell through various calcium channels and a sodium / calcium exchanger and is actively extruded from the cell by calcium pumps and sodium / calcium exchangers. Calcium can also be released from internal stores through inositol trisphosphate or ryanodine receptors and can be taken up by these organelles by means of calcium pumps.

[0029] Calcium can enter cells by any of several general classes of channels, including but not limited to, voltage-operated calcium (VOC) channels, store-operated calcium (SOC) channels, and sodium / calcium exchangers operating in reverse mode. VOC channels are activated by membrane depolarization and are found in excitable cells like nerve and muscle and are for the most part not found in nonexcitable cells. Under some conditions, Ca2+ can enter cells viaNa+-Ca2+ exchangers operating in reverse mode. Endocytosis provides another process by which cells can take up calcium from the extracellular medium through endosomes. In addition, some cells, e.g., exocrine cells, can release calcium via exocytosis.

[0030] Cytosolic calcium concentration is tightly regulated with resting levels usually estimated at approximately 0. 1 pM in mammalian cells, whereas the extracellular calcium concentration is typically about 2 rnM. This tight regulation facilitates transduction of signals into and within cells through transient calcium flux across the plasma membrane and membranes of intracellular organelles. There is a121624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) multiplicity of intracellular calcium transport and buffer systems in cells that sen e to shape intracellular calcium signals and maintain the low resting cytoplasmic calcium concentration. In cells at rest, the principal components involved in maintaining basal calcium levels are calcium pumps and leak pathways in both the endoplasmic reticulum and plasma membrane. Disturbance of resting cytosolic calcium levels can affect transmission of calcium-dependent signals and give rise to defects in a number of cellular processes. For example, cell proliferation involves a prolonged calcium signaling sequence. Other cellular processes that involve calcium signaling include, but are not limited to, secretion, transcription factor signaling, and fertilization.

[0031] Cel 1 -surface receptors that activate phospholipase C (PLC) create cytosolic Ca2+ signals from intra- and extra-cellular sources. An initial transient rise of [Ca2+]i (intracellular calcium concentration) results from the release of Ca2+ from the endoplasmic reticulum (ER), which is triggered by the PLC product, inositol -1,4,5- trisphosphate (IP3), opening IP3 receptors in the ER (Streb et al. Nature, 306, 67-69, 1983). A subsequent phase of sustained Ca2+ entry across the plasma membrane then ensues, through specialized store operated calcium (SOC) channels (in the case of non- excitable cells like immune PAC cells, the SOC channels are calcium release-activated calcium (CRAC) channels) in the plasma membrane. Store-operated Ca2+ entry (SOCE) is the process in which the emptying of Ca2+ stores itself activates Ca2+ channels in the plasma membrane to help refill the stores (Putney, Cell Calcium, 7. 1- 12. 1986; Parekh et al.. Physiol. Rev. 757-810; 2005). SOCE does more than simply provide Ca2+ for refilling stores, but can itself generate sustained Ca2+ signals that control such essential functions as gene expression, cell metabolism and exocytosis (Parekh and Putney, Physiol. Rev. 85, 757-810 (2005)).

[0032] In lymphocytes and mast cells, activation of antigen or Fc receptors, respectively causes the release of Ca2+ from intracellular stores, which in turn leads to Ca2+ influx through CRAC channels in the plasma membrane. The subsequent rise in intracellular Ca2+ activates calcineurin, a phosphatase that regulates the transcription factor NF AT. In resting cells, NF AT is phosphorylated and resides in the cytoplasm, but when dephosphorylated by calcineurin, NF AT translocates to the nucleus and activates different genetic programs depending on stimulation conditions and cell type. In response to infections and during transplant rejection, NF AT partners with the transcription factor AP-1 (Fos-Jun) in the nucleus of "effector" T cells, thereby trans-131624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) activating cytokine genes, genes that regulate T cell proliferation and other genes that orchestrate an active immune response (Rao et al.. Annu Rev Immunol., 1997;15:707- 47). In contrast, in T cells recognizing self-antigens. NF AT is activated in the absence of AP-1, and activates a transcriptional program known as "anergy" that suppresses autoimmune responses (Macian et al., Transcriptional mechanisms underlying lymphocyte tolerance. Cell. 2002 Jun 14;109(6):719-31). In a subclass of T cells known as regulatory T cells which suppress autoimmunity mediated by self-reactive effector T cells, NF AT partners with the transcription factor FOXP3 to activate genes responsible for suppressor function (Wu et al., Cell, 2006 Jul 28;126(2):375-87; Rudensky AY, Gavin M, Zheng Y. Cell. 2006 Jul 28;126(2):253-256).

[0033] The endoplasmic reticulum (ER) carries out a variety processes. The ER has a role as both a Ca2+ sink and an agonist-sensitive Ca2+ store, and protein folding / processing takes place within its lumen. In the latter case, numerous Ca2±- dependent chaperone proteins ensure that newly synthesized proteins are folded correctly and sent off to their appropriate destination. The ER is also involved in vesicle trafficking, release of stress signals, regulation of cholesterol metabolism, and apoptosis. Many of these processes require intraluminal Ca2+ and protein misfolding, ER stress responses, and apoptosis can all be induced by depleting the ER of Ca2+ for prolonged periods of time. Because it contains a finite amount of Ca2+, it is clear that ER Ca2+ content must fall after release of that Ca2+ during stimulation. However, to preserve the functional integrity of the ER, it is vital that the Ca2+ content does not fall too low- or is maintained at least at a low' level. Replenishment of the ER with Ca2+ is therefore a central process to all eukaryotic cells. Because a fall in ER Ca2+ content activates store-operated Ca2+ channels in the plasma membrane, a major function of this Ca2+ entry pathway is believed to be maintenance of ER Ca2+ levels that are necessary for proper protein synthesis and folding. How ever, store-operated Ca2+ channels have other important roles.

[0034] The understanding of store-operated calcium entry was provided by electrophysiological studies which established that the process of emptying the stores activated a Ca2+ current in mast cells called Ca2+ release-activated Ca2+ current or ICRAC. ICRAC is non-voltage activated, inw'ardly rectifying, and remarkably selective for Ca2±. It is found in several cell types mainly of hemapoietic origin. ICRAC is not the only store-operated current, and it is now apparent that store-operated influx141624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) encompasses a family of Ca2+-permeable channels, with different properties in different cell types. ICRAC was the first store-operated Ca2+ current to be described and remains a popular model for studying store-operated influx.

[0035] Store-operated calcium channels can be activated by any procedure that empties ER Ca2+ stores; it does not seem to matter how the stores are emptied, the net effect is activation of store-operated Ca2+ entry. Physiologically, store emptying is evoked by an increase in the levels of IP3 or other Ca2± -releasing signals followed by Ca2+ release from the stores. But there are several other methods for empty ing stores. These methods include the following:1) elevation of IP3 in the cytosol (following receptor stimulation or, dialyzing the cytosol with IP3 itself or related congeners like the nonmetabolizable analog Ins(2.4.5)P3);2) application of a Ca2+ ionophore (e.g., ionomycin) to permeabilize the ER membrane;3) dialyzing the cytoplasm with high concentrations of Ca2+ chelators (e.g., EGTA or BAPTA). which chelate Ca2+ that leaks from the stores and hence prevent store refilling;4) exposure to the sarcoplasmic / endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitors like thapsigargin, cyclopiazonic acid, and di-tert-butylhydroquinone;5) sensitizing the IP3 receptors to resting levels of InsP3 with agents like thimerosal; and6) loading membrane-permeable metal Ca2+ chelators like N,N,N',N'-tetrakis(2- pyridylmethyl)ethylene diamine (TPEN) directly into the stores.

[0036] Through mass action. TPEN lowers free intraluminal Ca2+ concentration without changing total store Ca2+ such that the store depletion-dependent signal is generated.

[0037] These methods of empty ing stores are not devoid of potential problems. The key feature of store-operated Ca2+ entry is that it is the fall in Ca2+ content within the stores and not the subsequent rise in cytoplasmic Ca2+ concentration that activates the channels. However, ionomycin and SERCA pump blockers generally cause a rise in cytoplasmic Ca2+ concentration as a consequence of store depletion, and such a rise in Ca2+ could open Ca2±-activated cation channels permeable to Ca2±. One way to avoid151624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) such problems is to use agents under conditions where cytoplasmic Ca2+ has been strongly buffered with high concentrations of Ca2+ chelator such as EGTA or BAPTA.Store-Operated Calcium Entry

[0038] Reduced calcium concentration in intracellular calcium stores such as the endoplasmic reticulum resulting from release of calcium therefrom provides a signal for influx of calcium from the extracellular medium into the cell. This influx of calcium, which produces a sustained "plateau" elevation of cytosolic calcium concentration, generally does not rely on voltage-gated plasma membrane channels and does not involve activation of calcium channels by calcium. This calcium influx mechanism is referred to as capacitive calcium entry (CCE), calcium release-activated, store-operated or depletion-operated calcium entry. Store-operated calcium entry can be recorded as an ionic current with distinctive properties. This current is referred to as Isoc (store- operated current) or IcRAc (calcium release-activated current).

[0039] Electrophysiological analysis of store-operated or calcium release-activated currents reveal distinct biophysical properties (see, e.g., Parekh and Penner (1997) Physiol. Rev. 77:901-930) of these currents. For example, the current can be activated by depletion of intracellular calcium stores (e.g., by non-physiological activators such as thapsigargin, CPA, ionomycin and BAPTA, and physiological activators such as IP3) and can be selective for divalent cations, such as calcium, over monovalent ions in physiological solutions or conditions, can be influenced by changes in cytosolic calcium levels, and can show altered selectivity and conductivity in the presence of low extracellular concentrations of divalent cations. The current may also be blocked or enhanced by 2-APB (depending on concentration) and blocked by SKF96365 and Gd3+ and generally can be described as a calcium current that is not strictly voltage-gated.

[0040] Patch-clamp studies in mast cells and Jurkat leukemic T cells have established the CRAC entry mechanism as an ion channel with distinctive biophysical characteristics, including a high selectivity for Ca2+ paired with an exceedingly low conductance. Furthermore, the CRAC channel was shown to fulfill the rigorous criteria for being store-operated, which is the activation solely by the reduction of Ca2+ in the ER rather than by cytosolic Ca2+ or other messengers generated by PLC (Prakriya et al., In Molecular and Cellular Insights into Ion Channel Biology (ed. Robert Maue) 121-140 (Elsevier Science. Amsterdam, 2004)).161624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)Regulation of Store-Operated Calcium Entry by Intracellular Calcium Stores

[0041] Store-operated calcium entry is regulated by the level of calcium within an intracellular calcium store. Intracellular calcium stores can be characterized by sensitivity to agents, which can be physiological or pharmacological, which activate release of calcium from the stores or inhibit uptake of calcium into the stores. Different cells have been studied in characterization of intracellular calcium stores, and stores have been characterized as sensitive to various agents, including, but not limited to, IP3 and compounds that effect the IP3 receptor, thapsigargin, ionomycin and / or cyclic ADP -ribose (cADPR) (see, e.g., Berridge (1993) Nature 361 :315-325; Churchill and Louis (1999) Am. J. Physiol. 276 :C426-C434; Dargie et al. (1990) Cell Regul. 1 :279- 290; Gerasimenko et al. (1996) Cell 84 :473-480; Gromoda et al. (1995) FEBS Lett. 360 :303-306; Guse et al. (1999) Nature 398 : 70-73).

[0042] Accumulation of calcium within endoplasmic reticulum and sarcoplasmic reticulum (SR; a specialized version of the endoplasmic reticulum in striated muscle) storage organelles is achieved through sarcoplasmic-endoplasmic reticulum calcium ATPases (SERCAs), commonly referred to as calcium pumps. During signaling (i.e., when endoplasmic reticulum channels are activated to provide for calcium release from the endoplasmic reticulum into the cytoplasm), endoplasmic reticulum calcium is replenished by the SERCA pump with cytoplasmic calcium that has entered the cell from the extracellular medium (Yu and Hinkle (2000) J. Biol. Chem. 275:23648-23653; Hofer et al. (1998) EMBO J. 17: 1986-1995).

[0043] Calcium release channels associated with IP3 and ryanodine receptors provide for controlled release of calcium from endoplasmic and sarcoplasmic reticulum into the cytoplasm resulting in transient increases in cytoplasmic calcium concentration. IP3 receptor-mediated calcium release is triggered by IP3 formed by the breakdown of plasma membrane phosphoinositides through the action of phospholipase C, which is activated by binding of an agonist to a plasma membrane G protein-coupled receptor or tyrosine kinase. Ryanodine receptor-mediated calcium release is triggered by an increase in cytoplasmic calcium and is referred to as calcium-induced calcium release (CICR). The activity of ryanodine receptors (which have affinity for ryanodine and caffeine) may also be regulated by cyclic ADP-ribose.171624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)

[0044] Thus, the calcium levels in the stores, and in the cytoplasm, fluctuate. For example, ER free calcium concentration can decrease from a range of about 60-400 pM to about 1-50 pM when HeLa cells are treated with histamine, an agonist of PLC-linked histamine receptors (Miyawaki et al. (1997) Nature 388:882-887). Store-operated calcium entry is activated as the free calcium concentration of the intracellular stores is reduced. Depletion of store calcium, as well as a concomitant increase in cytosolic calcium concentration, can thus regulate store-operated calcium entry into cells.Cytoplasmic Calcium Buffering

[0045] Agonist activation of signaling processes in cells can involve dramatic increases in the calcium permeability of the endoplasmic reticulum, for example, through opening of IP3 receptor channels, and the plasma membrane through store- operated calcium entry. These increases in calcium permeability are associated with an increase in cytosolic calcium concentration that can be separated into two components: a "spike" of calcium release from the endoplasmic reticulum during activation of the IP3 receptor and a plateau phase which is a sustained elevation of calcium levels resulting from entry of calcium into the cytoplasm from the extracellular medium. Upon stimulation, the resting intracellular free calcium concentration of about 100 nM can rise globally to greater than 1 pM and higher in microdomains of the cell. The cell modulates these calcium signals with endogenous calcium buffers, including physiological buffering by organelles such as mitochondria, endoplasmic reticulum and Golgi. Mitochondrial uptake of calcium through a uniporter in the inner membrane is driven by the large negative mitochondrial membrane potential, and the accumulated calcium is released slowly through sodium-dependent and — independent exchangers, and, under some circumstances, the permeability transition pore (PTP). Thus, mitochondria can act as calcium buffers by taking up calcium during periods of cellular activation and can slowly release it later. Uptake of calcium into the endoplasmic reticulum is regulated by the sarcoplasmic and endoplasmic reticulum calcium ATPase (SERCA). Uptake of calcium into the Golgi is mediated by a P-type calcium transport ATPase (PMR1 / ATP2C1). Additionally, there is evidence that a significant amount of the calcium released upon IP3 receptor activation is extruded from the cell through the action of the plasma membrane calcium ATPase. For example, plasma membrane calcium ATPases provide the dominant mechanism for calcium clearance in human T181624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) cells and Jurkat cells, although sodium / calcium exchange also contributes to calcium clearance in human T cells. Within calcium-storing organelles, calcium ions can be bound to specialized calcium-buffering proteins, such as, for example, calsequestrins, calreticulins and calnexins. Additionally, there are calcium-buffering proteins in the cytosol that modulate calcium spikes and assist in redistribution of calcium ions. Thus, proteins and other molecules that participate in any of these and other mechanisms through which cytosolic calcium levels can be reduced are proteins that are involved in, participate in and / or provide for cytoplasmic calcium buffering. Thus, cytoplasmic calcium buffering helps regulate cytoplasmic Ca2+ levels during periods of sustained calcium influx through SOC channels or bursts of Ca2+ release. Large increases in cytoplasmic Ca2+ levels or store refilling deactivate SOCE.Downstream Calcium Entry-Mediated Events

[0046] In addition to intracellular changes in calcium stores, store-operated calcium entry affects a multitude of events that are consequent to or in addition to the store- operated changes. For example Ca2+ influx results in the activation of a large number of calmodulin-dependent enzymes including the serine phosphatase calcineurin. Activation of calcineurin by an increase in intracellular calcium results in acute secretory processes such as mast cell degranulation. Activated mast cells release preformed granules containing histamine, heparin, TNFa and enzymes such as f3- hexosaminidase. Some cellular events, such as B and T cell proliferation, require sustained calcineurin signaling, which requires a sustained increase in intracellular calcium. A number of transcription factors are regulated by calcineurin, including NF AT (nuclear factor of activated T cells), MEF2 and NFKB NF AT transcription factors play important roles in many cell types, including immune cells. In immune cells NFAT mediates transcription of a large number of molecules, including cytokines, chemokines and cell surface receptors. Transcriptional elements for NFAT have been found within the promoters of cytokines such as IL-2, IL-3, IL-4, IL-5, IL-8, IL-13, as well as tumor necrosis factor alpha (TNFa), granulocyte colony -stimulating factor (G- CSF), and gamma-interferon (y-IFN). The activity of NFAT proteins is regulated by their phosphorylation level, which in turn is regulated by both calcineurin and NFAT kinases. Activation of calcineurin by an increase in intracellular calcium levels results in dephosphorylation of NFAT and entry into the nucleus. Rephosphorylation of NFAT191624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) masks the nuclear localization sequence of NF AT and prevents its entry' into the nucleus. Because of its strong dependence on calcineurin-mediated dephosphorylation for localization and activity, NF AT is a sensitive indicator of intracellular free calcium levels.Calcium Channel Inhibitors

[0047] Disclosed herein are a number of Calcium channel inhibitors consistent with the methods, compositions, administration regimens and compositions for use disclosed herein. In some embodiments a Calcium channel inhibitor is a SOC inhibitor. In some embodiments the Calcium channel inhibitor is a CRAC inhibitor. In some embodiments, the Calcium channel inhibitor inhibits a channel comprising STIM1 protein. In some embodiments, the Calcium channel inhibitor inhibits a channel comprising Orail protein. In some embodiments, the Calcium channel inhibitor inhibits a channel comprising Orai2 protein.

[0048] In some embodiments the compound is a compound having the structure of: pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some embodiments the compound is selected form a list of compounds consisting: N-(5-(6-chloro-2,2- di fl uorobenzo| d | [1,3] di oxo 1 -5-yl)pyrazin-2-y 1 )-2-fluoro-6-methylbenzamide. In some aspects the intracellular Calcium signaling inhibitor is a compound of N-(5-(6-chloro- 2.2-difluorobenzo[d][l,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. In some aspects the intracellular Calcium signaling inhibitor is chosen from among the compounds, N-(5-(6-ethoxy-4- methylpyridin-3-yl)pyrazin-2-yI)-2,6-difluorobenzamide. N-(5-(2-ethyl-6- methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisonicotinamide, N-(4-(l-ethyl- 3-(thiazol-2-y 1 )-lH-pyrazol-5-y l)pheny l)-2-fluorobenzamide, N-(5-(l -ethy 1 -3- (triflouromethyl)-lH-pyrazol-5-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide. 4-chloro-l- methyl-N-(4-(l-methy 1 -3-(trifluoromethyl)- lH-pyrazol-5-y 1 )pheny 1 )- lH-pyrazole-5- carboxamide. N-(4-(3-(difluoromethyl)-5-methy 1 - IH-pyrazol-I -y l)-3-fluorophenyl)- 2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-lH-pyrazol-l-yl)-3- fluorophenyl)-2,4,6-trifluorobenzamide, N-(4-(3- (difluoromethyl)-l -methy 1-1H- pyrazol-5-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, 4-chloro-N-(3-fluoro-4-(l-201624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) methy 1 -3-(trifluoromethy 1)- 1 H-py razol-5 -y 1 )pheny 1 )- 1 -methyl- 1 H-pyrazole-5- carboxamide. 3-fluoro-4-(l-methyl-3-(trifluoromethyl)-lH — pyrazol-5-yl)-N-((3- methylisothiazol-4-yl)methyl)aniline, N-(5-(7-chloro-2,3-dihydro-[1.4]dioxino[2,3- b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide, N-(2,6-difluorobenzyl)-5-(l- ethyl-3-(thiazol-2-yl)-lH-pyrazol-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro- 4-(3-methy 1 -1 -(thiazol-2-y 1 )- IH-py razol-4-yl)phenyl)isonicotinamide, 5-( 1 -methy 1-3- (trifluoromethyl)-lH-pyrazol-5-yl)-N-(2,4,6-trifluorobenzyl)pyridin-2-amine, N-(5-(l- ethyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)pyridin-2-yl)-2,4,6-trifluorobenzamide, N- (5-(5-chloro-2-methylbenzo[d]oxazol-6-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5- (6-ethoxy-4-methylpyridin-3-yl)thiazol-2-y 1 )-2,3,6-trifluorobenzamide, N-(5-(l -ethy 1 - 3-(trifluoromethyl)-lH-pyrazol-5-yl)pyridin-2-yl)-2,3,6-trifluorobenzamide. 2,3,6- trifluoro-N-(3 -fluoro-4-(l -methy 1-3 -(trifluoromethyl)- lH-pyrazol-5- yl)phenyl)benzamide, 2,6-difluoro-N-(4-(5-methyl -2-(trifluoromethyl)oxazol-4- yl)phenyl)benzamide, or N-(5-(6-chloro-2,2-difluorobenzo[d][l,3]dioxol-5-yl)pyrazin- 2-yl)-2-fluoro-6-methylbenzamide or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.Calcium Signaling and Pancreatic Health

[0049] Calcium signaling is central to healthy pancreatic activity . Food stimulates the release of acetylcholine (ACh) and cholecyctokinin (CCK), which interact with Phospholipase C (PLC)-hnked receptors on Pancreatic Acinar Cells (PACs). In healthy PACs, ACh or CCK receptors trigger formation of IP3, 1,4,5-inositol triphosphate, which diffuses to the apical region and stimulates IP3 receptors on the Endoplasmic Reticulum (ER) to release Ca2+ in a controlled, pulsatile manner. Ca2+ oscillations stimulate release of zymogens (pro-enzymes) into the pancreatic duct. Over time, the ER Ca2+ needs to be replenished, which is accomplished by gentile activation of CRAC channels in the basolateral region of the cell.

[0050] In certain situations (e.g., alcoholism or binge drinking, gall stones, etc.), fatty acid ethyl esters (FAEEs) formed from alcohol, or bile acids which accumulate due to gallstones diffuse into the PACs. Inside the PACs, FAEEs and bile acids cause massive release of ER Ca2+ by activating IP3 receptors. Hyperstimulation of CCK receptors can also elicit robust Ca2+ release from ER stores. Emptying of Ca2+ stores leads to hyperactivation of CRAC channels, causing excessive influx of Ca2±. The211624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) large Ca2+ influx causes release of enzy mes from zymogen granules, and inappropriate activation of intracellular trypsin, which itself then activated other pancreatic digestive enzymes and initiates autodigestion and necrosis of the pancreas that can be blocked by a CRAC channel inhibitor such as Compound I, GSK-7975A, N-(5-(2,5- dimethylbenzo[d]oxazol-6-yl)thiazol-2-yl)-2,3,6- trifluorobenzamide ("Compound II"), or 2,3,6-trifluoro-N-(3-fluoro-4-(l-methyT-3-(trifluoromethyl)-lH-pyrazol-5- yl)phenyl)benzamide ("Compound III").

[0051] If unaddressed, the inappropriate release and activation of digestive enzymes such as trypsin from zy mogen granules can lead to autodigestion of pancreatic cells, leading to pancreatitis. As mentioned above, acute or chronic pancreatitis can have a substantial negative effect on an individual's health.Symptoms and Causes of Pancreatitis

[0052] Pancreatitis, acute or chronic, is associated wi th severe upper abdominal or left upper quadrant burning pain radiating to the back, nausea, and vomiting that is worsened with eating. Depending on the severity of the condition, internal bleeding may also occur. Blood pressure, heart and respiratory rates are often elevated, although dehydration may' lead to a decrease rather than an increase in blood pressure. The abdomen is often tender but less so than the pain at the pancreas itself. Reflex bowel paralysis is commonly seen in pancreatitis cases, and fever or jaundice is not uncommon. Common symptoms and signs of pancreatitis include: severe epigastric pain (upper abdominal pain) radiating to the back, nausea, vomiting, loss of appetite, fever, chills (shivering), hemodynamic instability' (which includes shock), tachycardia (rapid heartbeat), respiratory distress, and peritonitis.

[0053] Less commonly observed symptoms, indicative of severe disease, include a number of medical 'signs' indicative of severe abdomina distress: Grey-Tumer's sign (hemorrhagic discoloration of the flanks), Cullen's sign (hemorrhagic discoloration of the umbilicus), Pleural effusions (fluid in the bases of the pleural cavity ), Grunwald sign (appearance of ecchymosis, large bruise, around the umbilicus due to local toxic lesion of the vessels), Korte's sign (pain or resistance in the zone where the head of pancreas is located (in epigastrium, 6-7 cm above the umbilicus)), Kamenchik's sign (pain with pressure under the xiphoid process), Mayo-Robson's sign (pain while pressing at the top of the angle lateral to the Erector spinae muscles and below the left221624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)12th rib (left costovertebral angle (CVA))) such as at Mayo-Robson's point (a point on border of inner 2 / 3 with the external 1 / 3 of the line that represents the bisection of the left upper abdominal quadrant, where tenderness on pressure exists in disease of the pancreas. At this point the tail of pancreas is projected on the abdominal wall).

[0054] A person suffering from pancreatitis may demonstrate some, all, or few to none of the above-mentioned symptoms. In some cases abdominal pain may be the sole symptom of the condition.

[0055] Chronic pancreatitis can lead to diabetes or pancreatic cancer. Defects in the delivery of digestive enzymes such as trypsin may lead to impaired digestion, leading to weight loss.

[0056] As many as eighty percent of cases of pancreatitis are caused by alcohol and gallstones. Gallstones are the single most common etiology of acute pancreatitis. Alcohol is the single most common etiology of chronic pancreatitis.

[0057] However, aside from alcohol and gall stones, there are a number of additional causes of pancreatitis. Some medications may be associated with pancreatitis. Examples of medications associated with pancreatitis include corticosteroids such as prednisolone, HIV drugs such as didanosine and pentamidine, diuretics, anticonvulsants such as valproic acid, chemotherapeutic agents such as L-asparaginase and azathioprine, estrogen, medications that increase blood triglycerides, statins such as cholesterol- lowering statins, antihyperglycemic agents like metformin, and gliptins such as vildagliptin, sitagliptin, saxagliptin, and linagliptin, tetracycline, sulfonamides, azathioprine, mercaptopurine, pentamidine, Grimethoprim-suilfamethoxazole, and salicylates. In some cases, drugs which are used to treat conditions associated with increased events of pancreatitis may also be incidentally linked to pancreatitis.Examples include statins in dyslipidemia and gliptins in diabetes. Additionally, some atypical antipsychotics such as clozapine, risperidone, and olanzapine may also be responsible for causing pancreatitis. This list is not exhaustive. Non-pharmaceutal causes of pancreatitis are also known. For example, inherited forms of pancreatitis are known that result in the activation of trypsinogen within the pancreas, leading to autodigestion. Genes implicated in heritable pancreatitis include Trypsinl, which codes for trypsinogen, SPINK1, which codes for a trypsin inhibitor, and cystic fibrosis transmembrane conductance regulator.231624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)

[0058] Other common nonpharmaceutical causes of pancreatitis include trauma, mumps, autoimmune disease, high blood calcium, hypothermia, and undergoing endoscopic retrograde cholangiopancreatography (ERCP). Pancreas divisum is a common congenital malformation of the pancreas that may underlie some recurrent cases. Penetrating ulcers are also associated with pancreatitis. Diabetes mellitus type 2 is associated with a 2.8-fold higher risk of developing symptoms of pancreatitis. Additional conditions associated with pancreatitis include pancreatic cancer, pancreatic duct stones, vasculitis (inflammation of the small blood vessels in the pancreas), coxsackie virus infection, and porphyria, particularly acute intermittent porphyria and ery thropoietic protoporphyria. Pregnancy is associated with pancreatitis in some cases. Repeated marathon running, anorexia and bulemia, as well as fatty necrosis, cystic fibrosis, and scorpion venom are implicated in some pancreatitis cases.

[0059] A number of infectious agents are implicated in pancreatitis. Examples include viral infection by viruses such as Cytomegalovirus, Hepatitis B, Herpes simplex virus, Mumps Rubulavirus, Varicella-zoster virus: Bacterial infection, such as by bacteria of the genera Legionella, Leptospira, Mycoplasma, or Salmonella; fungal infection such as by fungi of the genera Aspergillus; or parasitic infection by nematodes of the genus Ascaris or by apicomplexan alvelolates of the genera Cryptosporidium and Toxoplasma; among others.

[0060] The medical students’ mnemonic "‘GETS MASHED” is often used to remember some of the common causes of Pancreatitis: G - Gall stones E - Ethanol T - Trauma S - Steroids M - Mumps A - Autoimmune Pancreatitis S - Scorpion sting H - Hyperlipidaemia, Hypothermia, Hyperparathyroidism E - Endoscopic retrograde cholangiopancreatography D - Drugs commonly azathioprine, valproic acid.

[0061] Pancreatitis may also be idiopathic; in which case no cause is identified.Categorization of Pancreatitis

[0062] Pancreatitis, particularly acute pancreatitis, is often classified as either “mild”, “moderate”, or “severe” depending upon the predominant response to cell injury'. These categories are all characterized by misactivation of pancreatic zymogens such as trypsinogen inside the pancreas, often due to colocalization with the trypsinogen maturase cathepsin, which activates trypsinogen to trypsin. All three categories are characterized by inflammation and edema of the pancreas.241624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)

[0063] Moderate and severe pancreatitis are further characterized by pancreatic necrosis and secondary injury to extra-pancreatic organs, with moderate acute pancreatitis patients suffering transient (<48 hour) organ failure, while severe acute pancreatitis patients have persistent (>48 hour) organ failure. In response to the above- mentioned issues, the pancreas may directly synthesize inflammatory mediators such as TNF-a and IL-1, associated with an inflammatory response and recruitment of neutrophils to the pancreas, or due to necrosis and leakage of cellular components, otherwise activate the immune system. The inflammatory response may lead to secondary manifestations of pancreatitis, such as hypovolemia from capillary permeability, acute respiratory' distress syndrome, disseminated intravascular coagulations, renal failure, cardiovascular failure, and gastrointestinal hemorrhage.

[0064] Acute pancreatitis (acute hemorrhagic pancreatic necrosis) may further be characterized by acute inflammation and necrosis of pancreas parenchyma, focal enzymic necrosis of pancreatic fat, and vessel necrosis (hemorrhage) resulting from intrapancreatic activation of pancreatic enzymes. Lipase activation may produce necrosis of fat tissue in pancreatic interstitium and peripancreatic spaces as well as vessel damage. Digestion of vascular walls results in thrombosis and hemorrhage.Inflammatory infiltrate is rich in neutrophils. Due to the pancreas lacking a capsule, the inflammation and necrosis can extend to include fascial layers in the immediate vicinity' of the pancreas.

[0065] Chronic pancreatitis is a prolonged inflammation of the pancreas that alters the organ's normal structure and function. It may be associated with episodes of acute pancreatitis or with persistent abdominal pain or digestive defects. Chronic pancreatitis sufferers usually demonstrate persistent abdominal pain or malabsorption of the fats in foods. Pain during food uptake, particularly fatty or high-protein food uptake, is also common. Weight loss, due to malabsorption of food uptake or to a reduction in food uptake due to discomfort, is also common.

[0066] A common complication of chronic pancreatitis is diabetes.

[0067] Alcoholism, tobacco use, malnutrition, trauma, hypercalcemia, calcified stones, cystic fibrosis, and hereditary' defects in trypsinogen processing and stability are commonly associated with chronic pancreatitis.

[0068] Chronic pancreatitis is typically diagnosed based on tests on pancreatic structure and function. Serum amylase and lipase may or may not be moderately251624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) elevated in cases of chronic pancreatitis, owing to the uncertain levels of productive cell damage. Elevated lipase is the more likely found of the two. Amylase and lipase are nearly always found elevated in the acute condition along with an elevated CRP inflammatory marker that is broadly in line with the severity of the condition.

[0069] A secretin stimulation test is perhaps the most accurate functional test for diagnosis of chronic pancreatitis. Impairment of bi-carbonate production early in chronic pancreatitis is used to identify persons in early stages of disease (sensitivity of 95%). Additional tests used to determine chronic pancreatitis are fecal elastase measurement in stool, serum trypsinogen, computed tomography (CT), ultrasound, EUS, MRI, ERCP and MRCP. Pancreatic calcification may be seen on abdominal X- rays, as well as CT scans. Notably, however, ERCP and X-rays may trigger acute pancreatitis. A number of additional tests are available to assay for chronic pancreatitis. Elevated serum bilirubin and alkaline phosphatase levels may indicate chronic pancreatitis, in some cases indicating stricturing of the common bile duct due to edema, fibrosis or cancer. Autoimmune response-related chronic pancreatitis may be accompanied by elevations in ESR, IgG4, rheumatoid factor, ANA and anti-smooth muscle antibody, assay of any of which may indicate chronic pancreatitis in a person. A classic symptom of chronic pancreatitis, steatorrhea or food malabsorption, may be diagnosed by tw o different studies: Sudan chemical staining of feces or fecal fat excretion of 7 grams or more over a 24hr period on a 100g fat diet. To check for pancreatic exocrine dysfunction, an exemplary sensitive and specific test is the measurement of fecal elastase, which may be done with a single stool sample, and a value of less than 200 p g / g indicates pancreatic insufficiency.

[0070] A number of methods are known to evaluate the severity of pancreatitis in a person. Common tests include BISAP. Ranson's, APACHE-II, and CTSI. The BISAP test, for example, is based upon the following criteria assessed in the first 24 hours after admission: blood urea nitrogen > 25 mg / dL (8.92 mmol / L); Impaired Mental Status, defined as: disorientation, lethargy, somnolence, coma or stupor; >2 Systemic Inflammatory Response Syndrome Criteria; Age > 60; and Pleural Effusion Present. A positive assessment on any of these criteria results in a “poinf ’ in a total score ranging from 0 to 5. In some implementations of the test, mortality rates ranged from less than 1% in the lowest-risk group to more than 20% in the highest-risk group.261624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)

[0071] A number of references discuss tests for pancreatitis severity, each of which is hereby incorporated by reference: Wu BU, Johannes RS, Sun X, Tabak Y, Conwell DL, Banks PA. The early prediction of mortality in acute pancreatitis: a large population-based study. Gut. 2008 Dec;57(12): 1698-703. doi:10.1136 / gut.2008.152702. Epub 2008 Jun 2. PubMed PMID: 18519429; Papachristou GI, Muddana V, Yadav D, O'Connell M, Sanders MK, Slivka A, Whitcomb DC. Comparison of BISAP, Ranson's, APACHE-II, and CTSI scores in predicting organ failure, complications, and mortality in acute pancreatitis. Am J Gastroenterol. 2010 Feb;105(2):435-41 ; quiz 442. doi: 10.1038 / ajg.2009.622. Epub 2009 Oct 27. PubMed PMID: 19861954; and

[0072] Gompertz M, Fernandez L, Lara I, Miranda JP, Mancilla C, Berger Z. [Bedside index for severity in acute pancreatitis (BISAP) score as predictor of clinical outcome in acute pancreatitis: retrospective review of 128 patients]. Rev Med Chil. 2012 Aug;140(8):977-83. doi: 10. 1590 / S0034-98872012000800002. Spanish. PubMed PMID: 23282769.Therapeutic Amelioration of Pancreatitis

[0073] Disclosed herein are compositions and methods for the therapeutic amelioration of pancreatitis and symptoms thereof, such as through the administration of a calcium channel inhibitor such as a CRAC inhibitor. In some embodiments the pancreatitis is acute pancreatitis. In some embodiments the pancreatitis is chronic pancreatitis. In some embodiments a method of ameliorating the symptoms of pancreatitis in a person is disclosed. In some embodiments a method of ameliorating the symptoms of pancreatitis in a person is disclosed comprising the steps of identifying a person in need of amelioration of symptoms of pancreatitis, and administering an intracellular Calcium signaling inhibitor to said person at a dose sufficient to ameliorate said symptoms.

[0074] The person may be identified using, for example, a common test for pancreatitis symptoms, such as BISAP, Ranson's, APACHE-II, and CTSI. The test may be BISAP. The test may be Ranson's. The test may be APACHE II. The test may be CTSI. In some embodiments a person is identified as a person in need of amelioration of symptoms of pancreatitis by having a BISAP score of 5, 4, 3, 2, or 1. In some embodiments the person is identified as having a BISAP score of 2. In some271624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) embodiments the person is identified as having a BISAP score of 3. In some embodiments the person is identified as having a BISAP score of 4. In some embodiments the person is identified as having a BISAP score of 5. In some embodiments a person is identified as having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or more than 9 symptoms of pancreatitis, such as the symptoms of pancreatitis disclosed herein. In some embodiments, rather than a person, the subject is a non-human mammal.

[0075] In some embodiments the symptoms are acute pancreatitis symptoms. In some embodiments the symptoms are chronic pancreatitis symptoms.

[0076] The symptoms may comprise at least one of abdominal pain, increased blood amylase levels, increased blood lipase levels, enlarged pancreas, nausea, vomiting, internal bleeding, bowel paralysis, fever, jaundice, weight loss, and elevated heart rate. The symptoms may comprise premature digestive enzyme activation. The premature digestive enzyme activation may, for example, occur in a pancreas of said person. In some embodiments the enzyme comprises trypsin. In some embodiments, the intracellular Calcium signaling inhibitor is an SOC channel inhibitor. In some embodiments, the intracellular Calcium signaling inhibitor is a CRAC channel inhibitor. In some embodiments, the CRAC channel inhibitor comprises Compound I. In some embodiments, the CRAC channel inhibitor comprises GSK-7975A. In some embodiments, the CRAC channel inhibitor comprises Compound II. In some embodiments, the CRAC channel inhibitor comprises Compound III. In some embodiments, ameliorating symptoms of pancreatitis further comprises administering a painkiller medication. In some embodiments, ameliorating symptoms of pancreatitis further comprises administering a painkiller medication wherein the painkiller medication comprises an opiate. In some embodiments, ameliorating symptoms of pancreatitis further comprises administering a painkiller medication wherein the painkiller medication comprises morphine. In some embodiments, ameliorating symptoms of pancreatitis further comprises administering a painkiller medication wherein the painkiller medication comprises fentanyl. In some embodiments, ameliorating symptoms of pancreatitis further comprises administering a painkiller medication wherein the painkiller medication comprises tramadol. In some embodiments, ameliorating symptoms of pancreatitis further comprises administering a painkiller medication wherein the painkiller medication comprises meperidine.281624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)

[0077] In some embodiments, the intracellular Calcium signaling inhibitor is delivered to achieve a tissue level concentration that is equal to. about, or greater than the in vitro IC50 value determined for the compound. In some embodiments, the intracellular Calcium signaling inhibitor is delivered to achieve a tissue level concentration that is equal to, about, or greater than the in vitro IC50 value determined for the compound. In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that is 1.5x. 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, lOx, 1 lx, 12x, 13x, 14x, 15x, 16x, 17x, 18x, 19x, 20x, 2 lx, 22x, 23x, 24x, 25x, 26x, 27x, 28x,29x, 30x, 3 lx, 32x, 33x, 34x, 35x, 36x, 37x, 38x, 39x, 40x, 41x, 42x, 43x, 44x, 45x,46x, 47x, 48x, 49x, 50x, 51x, 52x, 53x, 54x, 55x, 56x, 57x, 58x, 59x, 60x, 61x, 62x,63x, 64x, 65x, 66x, 67x, 68x, 69x, 70x, 71x. 72x, 73x, 74x, 75x, 76x, 77x, 78x. 79x,80x, 81x. 82x, 83x, 84x, 85x, 86x. 87x, 88x. 89x, 90x, 91x, 92x, 93x. 94x, 95x. 96x,97x, 98x, 99x, 1 OOx, or any non-integer multiple ranging from lx to 1 OOx of the in vitro IC50 value determined for the compound.

[0078] In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that ranges from lx to lOOx, 2x to 80x, 3x to 60x, 4x to 50x, 5x to 45x, 6x to 44x, 7x to 43x, 8x to 43x, 9x to 4 lx, or lOx to 40x, or any non-integer within said range, of the in vitro IC5o value determined for the compound.

[0079] In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that is IpM, 2pM, 3pM, 4pM, 5pM, 6pM, 7pM, 8pM. 9pM. lOpM. HpM, 12pM, 13pM, 14pM, 15pM. 16pM. 17pM, 18pM, 19pM, 20pM. 21pM, 22pM, 23pM, 24pM, 25pM, 26pM, 27pM, 28pM, 29pM, 30pM, 31pM,32pM, 33pM, 34pM, 35pM, 36pM, 37pM, 38pM, 39pM, 40pM, 41pM, 42pM,43pM, 44pM, 45pM, 46pM, 47pM, 48pM, 49pM, 50pM, 51pM, 52pM. 53pM,54pM, 55pM, 56pM, 57pM, 58pM. 59pM, 60pM, 61pM, 62pM, 63pM. 64pM.65pM, 66pM, 67pM, 68pM, 69pM, 70pM, 71pM, 72pM, 73pM, 74pM, 75pM,76pM, 77pM, 78pM, 79pM, 80pM, 81 pM, 82pM, 83pM, 84pM, 85pM, 86pM,87pM, 88pM, 89pM, 90pM. 91 pM, 92pM, 93pM, 94pM, 95pM, 96pM, 97pM,98pM, 99pM, lOOpM. or any non-integer multiple ranging from about IpM to about lOOpM.

[0080] In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that ranges from IpM to lOOpM, 2pM to 90pM, 3pM to291624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)80gM, 4gM to 70gM, 5gM to 60gM, 6gM to 50gM, 7gM to 40gM, 8gM to 30gM, 9gM to 20gM, or lOgM to 40gM, or any integer or non-integer within said range.

[0081] In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that ranges from 9.5 gM to 10.5 gM, 9 gM to 11 gM, 8 gM to 12 gM, 7 gM to 13 gM, 5 gM to 15 gM, 2 gM to 20 gM or 1 gM to 50 gM, or any integer or non-integer within said range.

[0082] In some embodiments amelioration of pancreatitis comprises reduction in severity of at least one pancreatitis symptom. In some embodiments amelioration of pancreatitis comprises reduction in severity of at least one pancreatitis symptom such that said symptom no longer impacts the previously affected person. In some embodiments amelioration comprises reduction of at least one symptom so that it has no effect on the person. In some embodiments amelioration comprises a 10%, 20%, 30%, 40%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% reduction in said symptom. In some embodiments, amelioration comprises reduction in severity of a plurality' of symptoms, such as 2, 3, 4, 5. 6, 7, 8, 9, or more than 9 symptoms, up to and including all symptoms, said reduction comprising a 10%, 20%, 30%, 40%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% reduction in said symptoms.

[0083] In some embodiments amelioration comprises halting the progression of pancreatitis such as acute pancreatitis or chronic pancreatitis. In some embodiments amelioration comprises halting the progression of pancreatitis such as acute pancreatitis or chronic pancreatitis such that more severe symptoms such as organ failure, pancreas necrosis or death do not occur.Prophylactic Amelioration of Acute and Chronic Pancreatitis

[0084] Disclosed herein are compositions and methods for the prophylactic amelioration of acute pancreatitis and symptoms thereof, such as through the administration of a calcium channel inhibitor such as a CRAC inhibitor. In some embodiments a method of ameliorating the symptoms of pancreatitis in a person is disclosed. In some embodiments a method of ameliorating the symptoms of pancreatitis in a person is disclosed comprising the steps of identifying a person in need of prophylactic amelioration of symptoms of pancreatitis, and administering an intracellular Calcium signaling inhibitor to said person at a dose sufficient to prophylactically ameliorate said symptoms.301624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)

[0085] In some embodiments, the intracellular Calcium signaling inhibitor is a SOC channel inhibitor. In some embodiments, the intracellular Calcium signaling inhibitor is a CRAC channel inhibitor. In some embodiments, the CRAC channel inhibitor comprises Compound I. In some embodiments, the CRAC channel inhibitor comprises GSK-7975A. In some embodiments, the CRAC channel inhibitor comprises Compound II. In some embodiments, the CRAC channel inhibitor comprises Compound III. In some embodiments, ameliorating symptoms of pancreatitis further comprises administering a painkiller medication such as an opiate. Morphine is an exemplary painkiller in some embodiments.

[0086] In some embodiments, the intracellular Calcium signaling inhibitor is delivered to achieve a tissue level concentration that is equal to. about, or greater than the in vitro IC50 value determined for the compound. In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that is 1.5x. 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, lOx, l lx, 12x, 13x, 14x, 15x, 16x, 17x, 18x, 19x, 20x, 21x, 22x, 23x, 24x, 25x, 26x, 27x, 28x, 29x, 30x, 3 lx, 32x, 33x, 34x, 35x. 36x,37x, 38x. 39x, 40x, 41x, 42x, 43x, 44x, 45x. 46x, 47x, 48x, 49x, 50x. 51x, 52x. 53x,54x, 55x, 56x, 57x, 58x, 59x, 60x, 61x, 62x, 63x, 64x, 65x, 66x, 67x, 68x, 69x, 70x,71x, 72x, 73x, 74x, 75x, 76x, 77x, 78x, 79x, 80x, 81x, 82x, 83x, 84x, 85x, 86x, 87x,88x, 89x, 90x, 91x, 92x, 93x, 94x, 95x, 96x, 97x, 98x, 99x, lOOx, or any non-integer multiple ranging from lx to lOOx of the in vitro IC50 value determined for the compound.

[0087] In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that ranges from lx to lOOx, 2x to 80x, 3x to 60x, 4x to 50x, 5x to 45x, 6x to 44x, 7x to 43x, 8x to 43x, 9x to 4 lx, or lOx to 40x, or any non-integer within said range, of the in vitro IC5o value determined for the compound.

[0088] In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that is IpM, 2pM, 3pM, 4pM, 5pM, 6pM, 7pM, 8pM, 9pM, lOpM, l lpM, 12pM, 13pM, 14pM, 15pM, 16pM, 17pM, 18pM, 19pM, 20pM, 21pM, 22pM, 23pM, 24pM, 25pM. 26pM, 27pM, 28pM, 29pM, 30pM. 31pM, 32pM. 33pM, 34pM, 35pM. 36pM. 37pM. 38pM, 39pM, 40pM, 41pM. 42pM. 43pM, 44pM, 45pM, 46pM, 47pM, 48pM, 49pM, 50pM, 51pM, 52pM, 53pM, 54pM, 55pM, 56pM, 57pM, 58pM, 59pM, 60pM, 61pM, 62pM, 63pM, 64pM, 65pM, 66pM, 67pM, 68pM, 69pM, 70pM, 71pM, 72pM, 73pM, 74pM. 75pM,311624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)76pM, 77pM, 78pM, 79pM, 80pM, 81 pM, 82pM, 83pM, 84pM, 85pM, 86pM, 87pM, 88pM, 89pM, 90pM, 91 pM, 92pM, 93pM, 94pM, 95pM, 96pM. 97pM, 98pM, 99pM, lOOpM. or any non-integer multiple ranging from about IpM to about lOOpM.

[0089] In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that ranges from IpM to lOOpM, 2pM to 90pM, 3pM to 80pM, 4pM to 70pM, 5pM to 60pM, 6pM to 50pM, 7pM to 40pM, 8pM to 30pM, 9pM to 20pM, or lOpM to 40pM, or any integer or non-integer within said range.

[0090] In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that ranges from 9.5 pM to 10.5 pM, 9 pM to 11 pM, 8 pM to 12 pM, 7 pM to 13 pM, 5 pM to 15 pM, 2 pM to 20 pM or 1 pM to 50 pM, or any integer or non-integer within said range.

[0091] In some embodiments the method comprises prophylactically ameliorating an acute pancreatitis symptom. In some embodiments the method comprises prophylactically ameliorating a chronic pancreatitis symptom.

[0092] Prophylactically ameliorating a symptom of pancreatitis may comprise reducing the severity, likelihood of occurrence, or duration of at least one symptom of pancreatitis. Prophylactically ameliorating a symptom of pancreatitis may comprise reducing the severity, likelihood of occurrence, or duration of at least one symptom of pancreatitis up to the point that said at least one symptom does not occur in the person. In some embodiments, prophylactically ameliorating a symptom of pancreatitis may comprise reducing the severity, likelihood of occurrence, or duration of 2, 3, 4, 5, 6, 7, 8, 9, or more than 9 symptoms of pancreatitis, up to and including reducing the severity, likelihood of occurrence, or duration of all symptoms of pancreatitis in a person, such as the symptoms of pancreatitis disclosed herein. In some embodiments, rather than a person, the subject is anon-human mammal.

[0093] In some embodiments the person is diagnosed as having a gall stone. In some embodiments the person exhibits symptoms of having a gall stone, such as pain, for example intense pain, in the upper-right side of the abdomen, and / or nausea and vomiting, which may steadily increase for from approximately 30 minutes to several hours. A patient may also experience referred pain between the shoulder blades or below the right shoulder.321624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)

[0094] In some embodiments the person suffers from alcoholism. In some embodiments the person suffers from chronic alcohol use. In some embodiments the person has suffered from at least one instance of acute alcohol poisoning.

[0095] In some embodiments the person is subjected to a drug regimen comprising administration of at least one of a steroid such as a corticosteroid, prednisolone, an HIV drug, didanosine, pentamidine, a diuretic, valproic acid, L-asparaginase, azathioprine, estrogen, a statin such as a cholesterol-lowering statin, an antihyperglycemic agent, metformin, a glipin such as vildagliptin and sitagliptin, an atypical antipsychotic, clozapine, risperidone, and olanzapine.

[0096] In some embodiments the person is identified as harboring an inherited form of pancreatitis. In some embodiments the person harbors a mutant allele of Trypsinl associated with inherited pancreatitis. In some embodiments the person harbors a trypsinogen enzyme variant associated with pancreatitis. In some embodiments the person harbors a mutant allele of SPINK1 associated with inherited pancreatitis. In some embodiments the person harbors a mutant allele of a cystic fibrosis transmembrane conductance regulator associated with inherited pancreatitis.

[0097] In some embodiments the person has suffered at least one of high blood calcium, hypothermia, endoscopic retrograde cholangiopancreatography (ERCP), pancreas divisum, a congenital malformation of the pancreas, diabetes mellitus ty pe 2, pancreatic cancer, pancreatic duct stones, vasculitis, inflammation of the small blood vessels in the pancreas, coxsackie virus infection, and porphyra, such as acute intermittent porphyria and erythropoietic protoporphyria.

[0098] In some embodiments a bodily health condition of said person has been impacted at least one of a gall stone, ethanol poisoning, alcoholism, trauma, mumps, an autoimmune disorder, a scorpion sting, hyperlipidaemia, hypothermia, hyperparathyroidism, and endoscopic retrograde cholangiopancreatography, azathioprine, and valproic acid.

[0099] In some embodiments a bodily health condition of said person has been impacted by at least one of a Coxsackie virus, a Cytomegalovirus, a Hepatitis B vims, a Herpes simplex vims, Mumps, a Varicella-zoster virus, a Legionella bacterium, a Leptospira bacterium, a Mycoplasma bacterium, a Salmonella bacterium, an Aspergillus fungus, an Ascaris parasite, a Cryptosporidium cell and a Toxoplasma cell. Combination administration with a drug or drugs associated with pancreatitis.331624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)

[0100] Disclosed herein are compositions and administration regimens for the combinatorial administration of a Calcium channel inhibitor and a drug associated with pancreatitis. In some embodiments an administration regimen comprises administration to an individual of a dmg associated with a negative impact on pancreatic activity, and administration of an intracellular Calcium signaling inhibitor.

[0101] In some embodiments the drug associated with a negative impact on pancreatic activity is a drug is selected from the list consisting of: a steroid such as a corticosteroid, prednisolone, an HIV drug, didanosine, pentamidine, a diuretic, valproic acid, L-asparaginase, azathioprine, estrogen, a statin such as a cholesterol-lowering statin, an antihyperglycemic agent, metformin, a glipin such as vildagliptin and sitagliptin, an atypical antipsychotic, clozapine, risperidone, and olanzapine, azathioprine. and valproic acid.

[0102] In some embodiments the intracellular Calcium signaling inhibitor is an SOC inhibitor. In some embodiments the intracellular Calcium signaling inhibitor is a CRAC inhibitor. An exemplary CRAC inhibitor comprises Compound I. An exemplary' CRAC inhibitor comprises GSK-7975A. An exemplary CRAC inhibitor comprises Compound II. An exemplary CRAC inhibitor comprises Compound III.

[0103] In some embodiments the administration regimen comprises administration of a calcium channel inhibitor such as a CRAC inhibitor such as at least one of Compound I, GSK 7975A. Compound II, and Compound III in concert with a drug associated with a negative impact on pancreatic activity. In some embodiments the calcium channel inhibitor such as a CRAC inhibitor such as at least one of Compound I, GSK 7975 A, Compound II, and Compound III is administered on the same day as a drug associated with a negative impact on pancreatic activity. In some embodiments the calcium channel inhibitor such as a CRAC inhibitor such as at least one of Compound I, GSK 7975A, Compound II, and Compound III is administered on the same week as a drug associated with a negative impact on pancreatic activity. In some embodiments the calcium channel inhibitor such as a CRAC inhibitor such as at least one of Compound I, GSK 7975A, Compound II, and Compound III is administered concurrently vxi th each administration of a drug associated with a negative impact on pancreatic activity. In some embodiments the calcium channel inhibitor such as a CRAC inhibitor such as at least one of Compound I, GSK 7975A, Compound II, and Compound III is administered on an administration regimen pattern that is independent of the341624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) administration pattern for a drug associated with a negative impact on pancreatic activity. In some embodiments the calcium channel inhibitor such as a CRAC inhibitor such as at least one of Compound I, GSK 7975A, Compound II, and Compound III is administered through the same route of delivery, such as orally or intravenously, as a drug associated with a negative impact on pancreatic activity. In some embodiments the calcium channel inhibitor such as a CRAC inhibitor such as at least one of Compound I, GSK 7975A, Compound II, and Compound III is administered through a separate route of delivery compared to a drug associated with a negative impact on pancreatic activit . In some embodiments the calcium channel inhibitor such as a CRAC inhibitor such as at least one of Compound I, GSK 7975A, Compound II, and Compound III is administered to a person receiving a drug associated with a negative impact on pancreatic activity only after said person shows at least one sign of an impact of said drug on pancreatic activity, for example through an increase in blood amylase activity or blood lipase activity’, or through manifestation of at least one pancreatitis symptom as disclosed herein. In some embodiments the calcium channel inhibitor such as a CRAC inhibitor such as at least one of Compound I, GSK 7975A, Compound IE and Compound III is administered to a person receiving a drug associated with a negative impact on pancreatic activity7in the absence of any evidence in or from said person related to any sign of an impact of said drug on pancreatic activity7, for example through an increase in blood amylase activity7or blood lipase activity, or through manifestation of at least one pancreatitis symptom as disclosed herein.

[0104] In some embodiments the calcium channel inhibitor such as a CRAC inhibitor such as at least one of Compound I, GSK 7975A, Compound II, and Compound III is administered in a single composition w ith a drug associated with a negative impact on pancreatic activity. Accordingly, some embodiments disclosed herein relate to a composition comprising an intracellular Calcium signaling inhibitor and at least one drug associated with a negative impact on pancreatic activity7. In some embodiments the at least one drug selected from the list consisting of: a steroid such as a corticosteroid, prednisolone, an HIV drug, didanosine, pentamidine, a diuretic, valproic acid, L-asparaginase, azathioprine, estrogen, a statin such as a cholesterol- lowering statin, an antihyperglycemic agent, metformin, a glipin such as vildagliptin and sitagliptin, an atypical antipsychotic, clozapine, risperidone, and olanzapine, azathioprine, and valproic acid.351624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)

[0105] In some embodiments, the intracellular Calcium signaling inhibitor of said composition is an SOC inhibitor. In some embodiments, the intracellular Calcium signaling inhibitor is a CRAC inhibitor. In some embodiments, said CRAC inhibitor comprises Compound I. In some embodiments, said CRAC inhibitor comprises GSK- 7975A. In some embodiments, said CRAC inhibitor comprises Compound II. In some embodiments, said CRAC inhibitor comprises Compound III. In some embodiments, the intracellular Calcium signaling inhibitor is delivered to achieve a tissue level concentration that is equal to, about, or greater than the in vitro IC50 value determined for the compound.

[0106] In some embodiments, the intracellular Calcium signaling inhibitor is delivered to achieve a tissue level concentration that is equal to. about, or greater than the in vitro IC50 value determined for the compound. In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that is 1.5x. 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, lOx, l lx, 12x, 13x, 14x, 15x, 16x, 17x, 18x, 19x, 20x, 21x, 22x, 23x, 24x, 25x, 26x, 27x, 28x, 29x, 30x, 3 lx, 32x, 33x, 34x, 35x. 36x,37x, 38x. 39x, 40x, 41x, 42x, 43x, 44x, 45x. 46x, 47x, 48x, 49x, 50x. 51x, 52x. 53x,54x, 55x, 56x, 57x, 58x, 59x, 60x, 61x, 62x, 63x, 64x, 65x, 66x, 67x, 68x, 69x, 70x,71x, 72x, 73x, 74x, 75x, 76x, 77x, 78x, 79x, 80x, 81x, 82x, 83x, 84x, 85x, 86x, 87x,88x, 89x, 90x, 91x, 92x, 93x, 94x, 95x, 96x, 97x, 98x, 99x, lOOx, or any non-integer multiple ranging from lx to lOOx of the in vitro IC50 value determined for the compound.

[0107] In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that ranges from lx to lOOx, 2x to 80x, 3x to 60x, 4x to 50x, 5x to 45x, 6x to 44x, 7x to 43x, 8x to 43x, 9x to 4 lx, or lOx to 40x, or any non-integer within said range, of the in vitro ICso value determined for the compound.

[0108] In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that is IpM, 2pM, 3pM, 4pM, 5pM, 6pM, 7pM, 8pM, 9pM, lOpM, l lpM, 12pM, 13pM, 14pM, 15pM, 16pM, 17pM, 18pM, 19pM, 20pM, 21pM, 22pM, 23pM, 24pM, 25pM. 26pM, 27pM, 28pM, 29pM, 30pM. 31pM, 32pM, 33pM, 34pM, 35pM. 36pM. 37pM. 38pM, 39pM, 40pM, 41pM. 42pM. 43pM, 44pM, 45pM, 46pM, 47pM, 48pM, 49pM, 50pM, 51pM, 52pM, 53pM, 54pM, 55pM, 56pM, 57pM, 58pM, 59pM, 60pM, 61pM, 62pM, 63pM, 64pM, 65pM, 66pM, 67pM, 68pM, 69pM, 70pM, 71pM, 72pM, 73pM, 74pM. 75pM,361624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)76pM, 77pM, 78pM, 79pM, 80pM, 81 pM, 82pM, 83pM, 84pM, 85pM, 86pM, 87pM, 88pM, 89pM, 90pM, 91 pM, 92pM, 93pM, 94pM, 95pM, 96pM. 97pM, 98pM, 99pM, lOOpM. or any non-integer multiple ranging from about IpM to about lOOpM.

[0109] In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that ranges from IpM to lOOpM, 2pM to 90pM, 3pM to 80pM, 4pM to 70pM, 5pM to 60pM, 6pM to 50pM, 7pM to 40pM, 8pM to 30pM, 9pM to 20pM, or lOpM to 40pM, or any integer or non-integer within said range.

[0110] In some embodiments the Calcium signaling inhibitor is delivered to achieve a tissue level concentration that ranges from 9.5 pM to 10.5 pM, 9 pM to 11 pM, 8 pM to 12 pM, 7 pM to 13 pM, 5 pM to 15 pM, 2 pM to 20 pM or 1 pM to 50 pM, or any integer or non-integer within said range.[OH l] In some embodiments, the composition additionally comprises at least one of an excipient, a solubilizer, a surfactant, a disintegrant, and a buffer. In some embodiments the composition is a liquid or an emulsion. In some embodiments the composition is a liquid, a nanoparticle, a nanoparticle suspension, or a nanoparticle emulsion. In some embodiments the composition is a tablet.Certain Terminology

[0112] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood to which the claimed subject matter pertains. In the event that there are a plurality of definitions for terms herein, those in this section prevail. All patents, patent applications, publications and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) referred to herein are incorporated by reference. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information.

[0113] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents371624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting.

[0114] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0115] Definition of standard chemistry terms may be found in reference works, including but not limited to, Carey and Sundberg "Advanced Organic Chemistry 4th Ed." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology.

[0116] Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those recognized in the field. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification.

[0117] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, compositions described herein.

[0118] The terms "kit" and "article of manufacture" are used as synonyms.

[0119] The term "subject" or "patient" encompasses mammals and non-mammals. Examples of mammals include, but are not limited to. any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and381624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0120] The terms "treat," "treating" or "treatment," as used herein, include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophy tactically and / or therapeutically.

[0121] As used herein, the term "target protein" refers to a protein or a portion of a protein capable of being bound by, or interacting with a compound described herein, such as a compound with a structure from the group of Compound A. Tn certain embodiments, a target protein is a STIM protein. In certain embodiments, a target protein is an Orai protein. As used herein, "STIM protein" includes but is not limited to, mammalian STIM-1. such as human and rodent (e.g., mouse) STIM-1, Drosophila melanogaster D-STIM, C. elegans C-STIM, Anopheles gambiae STIM and mammalian STIM-2, such as human and rodent (e.g., mouse) STIM-2. (see paragraphs

[0211] through

[0270] of US 2007 / 0031814, as well as Table 3 of US 2007 / 0031814, herein incorporated by reference) As described herein, such proteins have been identified as being involved in, participating in and / or providing for store-operated calcium entry or modulation thereof, cytoplasmic calcium buffering and / or modulation of calcium levels in or movement of calcium into, within or out of intracellular calcium stores (e.g., endoplasmic reticulum).

[0122] As used herein, an "Orai protein" includes Orail (SEQ ID NO: 1 as described in WO 07 / 081804), Orai2 (SEQ ID NO: 2 as described in WO 07 / 081804), or Orai3 (SEQ ID NO: 3 as described in WO 07 / 081804). Orail nucleic acid sequence corresponds to GenBank accession number NM_032790, Orai2 nucleic acid sequence corresponds to GenBank accession number BC069270 and Orai3 nucleic acid sequence corresponds to GenBank accession number NM_152288. As used herein. Orai refers to any one of the Orai genes, e.g., Orail, Orai2, Orai3 (see Table I of WO 07 / 081804). As described herein, such proteins have been identified as being involved in, participating in and / or providing for store-operated calcium entry or modulation thereof, cytoplasmic391624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) calcium buffering and / or modulation of calcium levels in or movement of calcium into, within or out of intracellular calcium stores (e.g., endoplasmic reticulum).

[0123] The term "fragment" or "derivative" when referring to a protein (e.g. STIM, Orai) means proteins or polypeptides which retain essentially the same biological function or activity in at least one assay as the native protein(s). For example, the fragments or derivatives of the referenced protein maintains at least about 50% of the activity of the native proteins, at least 75%, at least about 95% of the activity of the native proteins, as determined e.g. by a calcium influx assay.

[0124] As used herein, amelioration of the symptoms of a particular disease, disorder or condition by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.

[0125] The term "modulate," as used herein, means to interact with a target protein either directly or indirectly so as to alter the activity of the target protein, including, by way of example only, to inhibit the activity of the target, or to limit or reduce the activity of the target.

[0126] As used herein, the term "modulator" refers to a compound that alters an activity of a target. For example, a modulator can cause an increase or decrease in the magnitude of a certain activity of a target compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor, which decreases the magnitude of one or more activities of a target. In certain embodiments, an inhibitor completely prevents one or more activities of a target.

[0127] As used herein, "modulation" with reference to intracellular calcium refers to any alteration or adjustment in intracellular calcium including but not limited to alteration of calcium concentration in the cytoplasm and / or intracellular calcium storage organelles, e.g., endoplasmic reticulum, and alteration of the kinetics of calcium fluxes into, out of and within cells. In aspect, modulation refers to reduction.

[0128] As used herein, the term "target activity" refers to a biological activity capable of being modulated by a modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity', tumor growth, inflammation or inflammation-related processes, and amelioration of one or more symptoms associated with a disease or condition.401624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)

[0129] The terms "inhibits", "inhibiting", or "inhibitor" of SOC channel activity or CRAC channel activity, as used herein, refer to inhibition of store operated calcium channel activity or calcium release activated calcium channel activity.

[0130] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0131] The term "pharmaceutically acceptable," as used herein, refers a material, such as a earner, diluent, or formulation, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0132] The term "pharmaceutical combination" as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that one active ingredient, e.g.. a compound with a structure from the group of Compound A and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0133] The term "pharmaceutical composition" refers to a mixture of a compound with a structure from the group of Compound A, described herein with other chemical components, such as carriers, stabilizers, diluents, surfactants, dispersing agents, suspending agents, thickening agents, and / or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: intravenous, oral, aerosol, parenteral, ophthalmic, subcutaneous, intramuscular, pulmonary and topical administration.

[0134] The terms "effective amount" or "therapeutically effective amount." as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs,411624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition that includes a compound with a structure from the group of Compound A, required to provide a clinically significant decrease in disease symptoms. An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study.

[0135] The terms "enhance" or "enhancing." as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system. The terms "coadministration" or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0136] The term "carrier," as used herein, refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues. The term "diluent" refers to chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffered solutions (which also can provide pH control or maintenance) are utilized as diluents in the art, including, but not limited to a phosphate buffered saline solution.

[0137] A "metabolite" of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term "metabolized," as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free421624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) sulphydryl groups. Further information on metabolism may be obtained from The Pharmacological Basis of Therapeutics, 9th Edition. McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.

[0138] "Bioavailability" refers to the percentage of the weight of the compound disclosed herein (e.g., a compound from the group of Compound A) that is delivered into the general circulation of the animal or human being studied. The total exposure (AUC(O-oc)) of a drug when administered intravenously is usually defined as 100% bioavailable (F%). "Oral bioavailability" refers to the extent to which a compound disclosed herein, is absorbed into the general circulation when the pharmaceutical composition is taken orally as compared to intravenous injection.

[0139] “Blood plasma concentration” refers to the concentration of a compound with a structure from the group of Compound A, in the plasma component of blood of a subj ect. It is understood that the plasma concentration of compounds described herein may vary significantly between subjects, due to variability’ with respect to metabolism and / or possible interactions with other therapeutic agents. In accordance with one embodiment disclosed herein, the blood plasma concentration of the compounds disclosed herein may vary from subject to subject. Likewise, values such as maximum plasma concentration (Cmax) or time to reach maximum plasma concentration (Tmax), or total area under the plasma concentration time curve (AUC(O-oc)) may vary from subject to subject. Due to this variability, the amount necessary to constitute "a therapeutically effective amount" of a compound may vary from subject to subject.

[0140] As used herein, "calcium homeostasis" refers to the maintenance of an overall balance in intracellular calcium levels and movements, including calcium signaling, within a cell.

[0141] As used herein, "intracellular calcium" refers to calcium located in a cell without specification of a particular cellular location. In contrast, "cytosolic" or "cytoplasmic" with reference to calcium refers to calcium located in the cell cytoplasm.

[0142] As used herein, an effect on intracellular calcium is any alteration of any aspect of intracellular calcium, including but not limited to, an alteration in intracellular calcium levels and location and movement of calcium into, out of or within a cell or intracellular calcium store or organelle. For example, an effect on intracellular calcium431624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) can be an alteration of the properties, such as, for example, the kinetics, sensitivities, rate, amplitude, and electrophysiological characteristics, of calcium flux or movement that occurs in a cell or portion thereof. An effect on intracellular calcium can be an alteration in any intracellular calcium-modulating process, including, store-operated calcium entry, cytosolic calcium buffering, and calcium levels in or movement of calcium into, out of or within an intracellular calcium store. Any of these aspects can be assessed in a variety of ways including, but not limited to. evaluation of calcium or other ion (particularly cation) levels, movement of calcium or other ion (particularly cation), fluctuations in calcium or other ion (particularly cation) levels, kinetics of calcium or other ion (particularly cation) fluxes and / or transport of calcium or other ion (particularly cation) through a membrane. An alteration can be any such change that is statistically significant. Thus, for example if intracellular calcium in a test cell and a control cell is said to differ, such difference can be a statistically significant difference.

[0143] As used herein, "involved in" with respect to the relationship between a protein and an aspect of intracellular calcium or intracellular calcium regulation means that when expression or activity of the protein in a cell is reduced, altered or eliminated, there is a concomitant or associated reduction, alteration or elimination of one or more aspects of intracellular calcium or intracellular calcium regulation. Such an alteration or reduction in expression or activity can occur by virtue of an alteration of expression of a gene encoding the protein or by altering the levels of the protein. A protein involved in an aspect of intracellular calcium, such as. for example, store-operated calcium entry, thus, can be one that provides for or participates in an aspect of intracellular calcium or intracellular calcium regulation. For example, a protein that provides for store-operated calcium entry can be a STIM protein and / or an Orai protein.

[0144] As used herein, a protein that is a component of a calcium channel is a protein that participates in multi-protein complex that forms the channel.

[0145] As used herein, "basal" or "resting" with reference to cytosolic calcium levels refers to the concentration of calcium in the cytoplasm of a cell, such as, for example, an unstimulated cell, that has not been subjected to a condition that results in movement of calcium into or out of the cell or within the cell. The basal or resting cytosolic calcium level can be the concentration of free calcium (i.e., calcium that is not bound to a cellular calcium-binding substance) in the cytoplasm of a cell, such as, for example,441624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) an unstimulated cell, that has not been subjected to a condition that results in movement of calcium into or out of the cell.

[0146] As used herein, "movement" with respect to ions, including cations, e.g.. calcium, refers to movement or relocation, such as for example flux, of ions into, out of, or within a cell. Thus, movement of ions can be, for example, movement of ions from the extracellular medium into a cell, from within a cell to the extracellular medium, from within an intracellular organelle or storage site to the cytosol, from the cytosol into an intracellular organelle or storage site, from one intracellular organelle or storage site to another intracellular organelle or storage site, from the extracellular medium into an intracellular organelle or storage site, from an intracellular organelle or storage site to the extracellular medium and from one location to another within the cell cytoplasm.

[0147] As used herein, "cation entry" or "calcium entry" into a cell refers to entry of cations, such as calcium, into an intracellular location, such as the cytoplasm of a cell or into the lumen of an intracellular organelle or storage site. Thus, cation entry can be, for example, the movement of cations into the cell cytoplasm from the extracellular medium or from an intracellular organelle or storage site, or the movement of cations into an intracellular organelle or storage site from the cytoplasm or extracellular medium. Movement of calcium into the cytoplasm from an intracellular organelle or storage site is also referred to as "calcium release" from the organelle or storage site.

[0148] As used herein, "protein that modulates intracellular calcium" refers to any cellular protein that is involved in regulating, controlling and / or altering intracellular calcium. For example, such a protein can be involved in altering or adjusting intracellular calcium in a number of ways, including, but not limited to, through the maintenance of resting or basal cytoplasmic calcium levels, or through involvement in a cellular response to a signal that is transmitted in a cell through a mechanism that includes a deviation in intracellular calcium from resting or basal states. In the context of a "protein that modulates intracellular calcium," a "cellular" protein is one that is associated with a cell, such as, for example, a cytoplasmic protein, a plasma membrane- associated protein or an intracellular membrane protein. Proteins that modulate intracellular calcium include, but are not limited to, ion transport proteins, calcium- binding proteins and regulatory proteins that regulate ion transport proteins.

[0149] As used herein, the term "ameliorate" means to reduce, prevent, alleviate, and / or lessen the impact of a disease, symptom or condition, to bring about451624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) improvement in a disease or condition or at least a partial relief of symptoms associated with a disease or condition up to and including complete reduction such that said impact is zero or effectively zero.

[0150] As used herein, "cell response" refers to any cellular response that results from ion movement into or out of a cell or within a cell. The cell response may be associated with any cellular activity that is dependent, at least in part, on ions such as, for example, calcium. Such activities may include, for example, cellular activation, gene expression, endocytosis, exocytosis, cellular trafficking and apoptotic cell death.

[0151] As used herein, "immune cells" include cells of the immune system and cells that perform a function or activity in an immune response, such as, but not limited to, T-cells. B-cells, lymphocytes, macrophages, dendritic cells, neutrophils, eosinophils, basophils, mast cells, plasma cells, white blood cells, antigen presenting cells and natural killer cells.

[0152] As used herein, "cytokine" refers to small soluble proteins secreted by cells that can alter the behavior or properties of the secreting cell or another cell. Cytokines bind to cytokine receptors and trigger a behavior or property within the cell, for example, cell proliferation, death or differentiation. Exemplary cytokines include, but are not limited to, interleukins (e.g., IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL- 10, IL-11, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18, IL-la, IL-lf3, and IL-1 RA), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), oncostatin M. erythropoietin, leukemia inhibitory factor (LIF), interferons, B7.1 (also known as CD80), B7.2 (also known as B70, CD86), TNF family members (TNF-a, TNF-(3, LT-0, CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand, 4-1 BBL, Trail), and MIF.

[0153] "Store operated calcium entry7' or "SOC'E " refers to the mechanism by which release of calcium ions from intracellular stores is coordinated with ion influx across the plasma membrane. "Selective inhibitor of SOC channel activity" means that the inhibitor is selective for SOC channels and does not substantially affect the activity of other types of ion channels. "Selective inhibitor of CRAC channel activity" means that the inhibitor is selective for CRAC channels and does not substantially affect the activity of other types of ion channels and / or other SOC channels.

[0154] As used herein, the term “calcium” may be used to refer to the element or to the divalent cation Ca2±. While preferred embodiments of the present invention have461624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.Acute lymphoblastic leukemia

[0155] Acute lymphoblastic leukemia, also know n as ALL, is a type of blood cancer that occurs when the bone marrow produces too many immature white blood cells called lymphoblasts This rapid-growing disease can effect red blood cells, white blood cells, and platelets. ALL is the most common type of leukemia in children, accounting for about 80% of childhood leukemias.

[0156] Asparaginase (e.g., ONCASPARTM and RYLAYZETM), an enzy me that degrades the amino acid asparagine, which is essential for the leukemic cells to survive, is one of the mainstays of therapy in pediatric acute lymphoblastic leukemia (ALL) patients. However, the administration of asparaginase triggers the development of asparaginase-associated pancreatitis (AAP) or asparaginase-induced pancreatic toxicity (AIPT) in 7-10% of patients, including the over 4,000 pediatric ALL patients treated per year in the United States (US), with similar numbers in Europe.

[0157] Asparaginase-associated pancreatitis (AAP) is one of the most severe and dreaded complicated during therapy of childhood ALL. AIPT is an ultra-orphan indication affecting 300-400 pediatric patients in the US each year. AAP and AIPT is often characterized by intense abdominal pain, nausea, vomiting and systemic inflammatory response syndrome (SIRS). AIPT and AAP can lead to further chronic problems such as insulin dependence, exocrine pancreatic insufficiency, and chronic pain. As a result, many patients with ALL can no longer be treated with current asparaginase therapy, which can have a negative impact on their recovery from ALL. These symptoms are more common when pancreatic necrosis or pancreatic pseudocysts develop immediately after AAP.

[0158] Treatment for AAP has historically been limited to supportive care. A Calcium release activated Calcium channel blocker, known as Compound A, may be able to reduce the severity of AAP or AIPT. The study demonstrates that treatment of471624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) compound A is effective in reducing severity7of pancreatitis in children with AAP or AIPT during ALL treatment.Method of Treatment

[0159] The method of treatment involves administering to the subject an intracellularCalcium signaling inhibitor comprising N-(5-(6-chloro-2,2- difluorobenzo[d][l,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide. wherein the subject is also receiving an asparaginase-containing pharmaceutical composition. The method of treatment wherein the different disease or disorder is acute lymphoblastic leukemia.

[0160] Clinical data may be compared between three cohorts including the historical cohort, the age and sex matched historical cohort, and the experimental cohort. The historical cohort comprises 51 patients selected from a former study comprising 589 patients receiving treatment for acute lymphoblastic leukemia (ALL). The 51 patients were selected based on whether they developed asparaginase-associated pancreatitis (AAP) within 30 days of receiving asparaginase for ALL treatment. The experimental cohort comprises 8 patients selected for treatment with compound A to reduce symptoms and disease development associated with AAP. The experimental cohort comprises 5 male patients and 3 female patients. The mean age for the experimental cohort is 8.2 years old and the age range is between 3.1 and 17.6 years old. The age and sex matched historical cohort was established to further assess preliminary efficacy in contrast to the experimental cohort. 16 patients were selected based on the parameters of the experimental cohort so that there yvas a 2:1 ratio between the age and sex matched historical cohort and the experimental cohort; limiting parameters comprised age and sex. The patients were evaluated by a blinded radiologist.

[0161] Patients underwent an initial CT (computed tomography scan) either prior to or on day 1 of the study. Compound A was then administered as a four-hour infusion on days 1-4 starting at dose level 1 (30 mg / m2 on day 1 and 42 mg / m2 on days 2-4), with dose limiting toxicities (DLT) defined as any common terminology criteria for adverse events (CTCAE) grade 3-5 toxicity not attnbutable to either pancreatitis or ALL therapy. For context, grade 1 comprises mild or asymptomatic symptoms, grade 2 comprises moderate symptoms and noninvasive interventions, grade 3 comprises severe pain, grade 4, comprise life-threatening consequences, and grade 5 comprises death.481624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)Planned dose escalation was guided by a Keyboard design. Keyboard design comprises an intuitive Bayesian design that conducts dose escalation and de-escalation based on whether the strongest key, defined as the dosing interval that most likely contains the current dose, is below or above the target dosing interval. The primary efficacy endpoint of the study focused on the occurrence of pancreatic necrosis or pseudocyst on the CT after day 28 of treatment with compound A.

[0162] The method of treatment may further comprise reducing an average amount of days the subject spends in the hospital. The average amount of days may be reduced to less than 9 days, less than 8 days, less than 7 days, less than 6 days, less than 5 days, less than 4 days, or less than 3 days.

[0163] The method of treatment may further comprise reducing the average amount of time the subject spent in an intensive care unit (ICU). The average amount of time the subject spent in the TCU may be less than 6 days, less than 5 days, less than 4 days, or less than 3 days.

[0164] The method of treatment may further reduce the percentage of subjects in need of the ICU to less than 18%, less than 17%, less than 16%, less than 15%. less than 14%, less than 13%, or less than 12%.

[0165] The method of treatment wherein the intracellular Calcium signaling inhibitor may be administered in about 1.0 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg. about 1.9 mg / kg. about 2 mg / kg. about 2.1 mg / kg. about 2.2 mg / kg. about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, or about 3.0 mg / kg on days 1 and 2.

[0166] The method of treatment wherein the intracellular Calcium signaling inhibitor may be administered in about 1.0 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, or about 2.5 mg / kg on days 3 and 4.

[0167] The method of treatment wherein the intracellular Calcium signaling inhibitor may be administered in about 20 mg / m2, about 21 mg / m2, about 22 mg / m2, about 23 mg / m2, about 24 mg / m2, about 25 mg / m2, about 26 mg / m2, about 27 mg / m2, about 28 mg / m2, about 29 mg / m2, about 30 mg / m2, about 31 mg / m2, about 32 mg / m2, about 33491624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) mg / m2. about 34 mg / m2, about 35 mg / m2, about 36 mg / m2, about 37 mg / m2, about 38 ing / in2. about 39 mg / m2, or about 40 mg / m2 on day 1.

[0168] The method of treatment wherein the intracellular Calcium signaling inhibitor may be administered in about 20 mg / m2, about 21 mg / m2, about 22 mg / m2, about 23 mg / m2. about 24 mg / m2, about 25 mg / m2, about 26 mg / m2, about 27 mg / m2, about 28 mg / m2. about 29 mg / m2, about 30 mg / m2, about 31 mg / m2, about 32 mg / m2, about 33 mg / m2. about 34 mg / m2, about 35 mg / m2, about 36 mg / m2, about 37 mg / m2, about 38 mg / m2, about 39 mg / m2, about 40 mg / m2, about 41 mg / m2, about 42 mg / m2, about 43 mg / m2. about 44 mg / m2, about 45 mg / m2, about 46 mg / m2, about 47 mg / m2, about 48 mg / m2, about 49, or about 50 mg / m2 on days 2-4.

[0169] The method of treatment wherein the intracellular Calcium signaling inhibitor may be administered via IV infusion as a 2-hour infusion. 4-hour infusion or a 6-hour infusion.

[0170] The method of treatment wherein the age of the subject may be between 1-20. The method of treatment wherein the age of the subject may be about 1, about 2, about 3. about 4, about 5. about 6, about 7. about 8, about 9. about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20.

[0171] The method of treatment wherein the mean CTSI score of the subject may be about 5, about 4, about 3, or about 2.INCORPORATION BY REFERENCE

[0172] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0173] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.501624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)

[0174] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0175] As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof.

[0176] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.EXAMPLES

[0177] The following illustrative examples are representative of embodiments of the stimulation, systems, and methods described herein and are not meant to be limiting in any way.Example 1. Method of treatment of asparaginase-induced pancreatic toxicity (AIPT)

[0178] Clinical data was compared between three groups comprising the historical cohort, the age and sex matched historical cohort, and the experimental cohort. The historical cohort comprises 51 patients with acute lymphoblastic leukemia (ALL) experiencing asparaginase-associated pancreatitis. The 51 patients were pulled from a former study comprising 589 patients being treated with ALL wherein 51 out of the 589 patients developed AAP or AIPT in conjunction with ALL treatment. The age and sex matched historical cohort comprises 16 patients that were selected to compare with the experimental cohort. The experimental cohort included 8 patients selected for treatment with Compound A disclosed herein in the current application in response to asparaginase-associated pancreatitis. In some embodiments, compound A comprises N-511624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)(5-(6-chloro-2,2-difluorobenzo[d][l,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6- methylbenzamide.

[0179] The experimental cohort included nine children diagnosed with ALL and AAP or AIPT. Eight out of nine patients in this study received a full regimen of 4 daily doses of compound A. One patient in the age and sex matched historical cohort was unable to be evaluated for pancreatic necrosis or a CT severity' index (CTSI) score. The eight patients in the experimental cohort were given a dose of 30mg / m2 on day 1 and 42mg / m2 on days 2-4 administered via IV as a four-hour infusion. These clinical results were compared to the age and sex matched historical cohort of 16 patients.

[0180] Treatment with compound A, as compared to the age and sex matched historical cohort, was shown to have the potential to reduce the severity of AAP or AIPT in pediatric patients with ALL. Study results showed that compound A reduced the average number of days patients spent in the hospital from 13.4 to 6.3 days. The need for intensive care unit (ICU) care was also reduced, with three control patients (18.8%) requiring ICU care compared to one treated patient (12.5%). The average number of days in the ICU was reduced from 5 to 3 days. Additionally, no patients in the study required TPN. In contrast, 68.8% of the historical matched control group required TPN, with a treatment of 27 days of nutritional support on average.

[0181] A method to treat acute and chronic inflammatory and immunological diseases was developed using a calcium release-activated calcium (CRAC) channel inhibition therapies. The initial cohort was provided compound A to treat asparaginase- induced pancreatic toxicity (AIPT). Treatment with the compound delivered positive results across multiple clinical endpoints, including the elimination of the need for total parenteral nutrition (also known as TPN). Moreover, the ability to tolerate solid food correlates with pancreatic health and recovery from pancreatitis. This study found that the patients treated wi th compound A were able to eat on their own while over half of the patients in the age and sex matched historical cohort group required TPN for several weeks on average to tolerate solid food.

[0182] The CT severity index, also known as CTSI, was used to score the development of pancreatic disease. A CTSI score of 0-3 constitutes a mild acute pancreatitis, 4-6 constitutes moderately severe acute pancreatitis, and > 7 constitutes severe acute pancreatitis. A blinded central reading of pancreatic imaging showed a reduction in the development of significant pancreatic necrosis (>30%) from 4 patients521624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) in the historical cohort to zero patients in the experimental cohort. The results suggests that a dose level 1 as the recommended dosage of compound A for children with ALL experiencing AIPT.

[0183] Table 1:Example 2. Method of treatment of asparaginase-induced pancreatic toxicity (AIPT)

[0184] Approximately 90% of children with acute lymphoblastic leukemia (ALL) become long-term survivors utilizing asparaginase containing regimens. However, asparaginase associated pancreatitis (AAP) occurs in 1-7.4% of ALL patients during therapy. AAP occurs early in therapy (after a median of 3-5 doses), and most cases are severe: approximately two-thirds meet systemic inflammatory response syndrome (SIRS) criteria acutely or progress to pancreatic necrosis or pseudocyst as the AAP resolves. Pseudocysts developed in up to 60% of patients, with an overall average of531624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)26% across multiple groups in a large international study. One recent study demonstrated that 17 of 43 patients (39.5%) with AAP developed organ failure or pancreatic necrosis, including necrosis within the first week in 12 (27.9%).

[0185] Understanding AAP is critical for clinical decision-making in the context of ongoing leukemia-directed therapy. Re-exposure to asparaginase is frequently desired, as asparaginase truncation can increase the risk of relapse. Re-exposure is generally only considered in patients whose pancreatic enzymes rapidly normalize and who do not develop either a pseudocyst or pancreatic necrosis. Despite this, recurrent pancreatitis occurs in half of patients.

[0186] To understand predictors and consequences of severe AAP, patient-level data was retrospectively reviewed in patients treated for newly diagnosed ALL on Total Therapy XVI (NCT00549848). Children <19 years old at diagnosis received 1-2 doses of PEG-asparaginase during induction. Patients subsequently received four (low-risk) or 15 (standard / high-risk) post-inductions doses of PEG-asparaginase during the first 30 weeks of continuation therapy. Infants <1 year old at diagnosis received modified therapy and are excluded from the current study. All patients and / or families provided informed consent / assent in alignment with the Declaration of Helsinki. The IRB approved all studies.

[0187] The protocol adverse events database was reviewed to identify patients who experienced symptomatic pancreatitis (CTCAE v3 grade 2 or higher, equivalent to CTCAE v5 grade 3 or higher). Pancreatitis required at least 2 of 3 diagnostic criteria: imaging evidence of pancreatic inflammation, amylase and / or lipase 3 times the laboratory upper limit of normal (ULN), and pain characteristic of pancreatitis. Pancreatitis was categorized as AAP if it occurred within 35 days of asparaginase therapy. All patients with computed tomography (CT) or ultrasound (US) available after the incident pancreatitis episode had imaging reviewed by a single pediatric radiologist (MBM).

[0188] Statistical analyses were performed in R. The cumulative incidence of pancreatitis was calculated using the Kalbfleisch-Prentice method with the first episode as an event and non-pancreatitis toxic death, relapse, and second malignancy considered as competing risks. In analysis of AAP risk, other pancreatitis episodes were treated as non-events. The impact of pancreatitis on event free survival (EFS) was calculated using Cox proportional hazard regressions with survival censored at last follow-up.541624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)

[0189] Pancreatitis occurred in 57 of 586 patients (9.7%) who experienced a total of 80 discrete episodes. The first episode of pancreatitis occurred a median of 195 days into therapy (interquartile range 112-236 days) with 1-year and 3-year cumulative incidences of 9.4% and 9.7%, respectively. 47 (59%) of episodes were classified as grade 2, 27 (34%) as grade 3, 5 (6%) as grade 4, and one resulted in death (grade 5). This fatality following a prolonged hospitalization with multiorgan failure and was discovered post-mortem; pancreatitis was diagnosed >35 days from this patient’s 5th dose of asparaginase therapy. In 5 additional patients, the first episode of pancreatitis occurred >35 days after 1 to 17 doses of asparaginase treatment. Among patients with pancreatitis, 42 patients experienced a single episode, 10 had 2 episodes, 2 experienced 3 episodes, and 3 had 4 episodes. Recurrent pancreatitis occurred in 5 / 35 patients who received no asparaginase after their first AAP compared to 11 / 16 rechallenged with asparaginase after a mean of 5 additional doses (range 1 -12). Seven patients experienced a higher-grade pancreatitis after an initial grade 2 AAP episode, although the overall grade of first and subsequent pancreatitis was similar (p=0.6). All six patients with non-AAP had only a single episode without known prior AAP and none recurred. Four of these patients experienced their episode of pancreatitis during mercaptopurine therapy, one patient experienced pancreatitis following high-dose dexamethasone containing reintensification II therapy, and the final patient, noted above, was more than 35 days from reinduction 1 asparaginase.

[0190] AAP (N=51) occurred more frequently in older patients, in those receiving standard / high-risk therapy (FIG. 1A), in children of Hispanic ancestry (FIG. IB), and in children with elevated BMI (Table 1). Pancreatitis incidence in Total 16 differed by age, treatment, and patient ancestry'. The 3-year cumulative incidence of pancreatitis was 4.5% in patients <10 years old receiving low-risk (LR) therapy, 8.9% in patients <10 years old receiving standard- or high-risk (SHR) therapy, 6.7% in older patients (10+) receiving low-risk therapy, and 18.9% in older patients receiving standard- or high-risk therapy (FIG. 1A). The 3-year cumulative incidence of pancreatitis was 6.6% in European ancestry patients, 0% in Asian ancestry patients, 12.4% in African ancestry patients, 21.9% in Hispanic ancestry patients, and 13.2% in patients of other or mixed ancestry groups (FIG. IB). Note that the Y-axis of both figures runs from 0-20%. There was no significant difference in AAP by sex, leukemia immunophenotype, randomized asparaginase dose, Down syndrome, or in other ancestral groups. In multivariable551624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) analyses, standard / high-risk therapy and mixed / other ancestry7were associated with AAP (Table 1).

[0191] TABLE 1: Patient characteristics and associations with asparaginase associated pancreatitis.561624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)

[0192] AAP: asparaginase associated pancreatitis, CIN: cumulative incidence, Min: minimum, Max: maximum. ALL: acute lymphoblastic leukemia.

[0193] BMI data is NULL for patients age <2 years at diagnosis or in children with Down syndrome. P-values calculated using logistic regression.

[0194] When testing multivariable models, continuous variables for age and BMI z- score were preferred to discrete categories.

[0195] AAP was frequently severe. Patients were hospitalized for a median of 10 days and 11 required intensive care. TPN was required in 30 cases for a median duration of 23 days (range 3-153). Serial pancreatic enzymes were available for 47 patients and remained 3 times ULN 72 hours after pancreatitis onset in 22 patients.

[0196] Among 39 patients with follow-up imaging after the diagnosis of AAP, 22 (56% of patients with imaging, 43% of all patients with AAP) had imaging sequalae of severe pancreatitis after their first episode including pancreatic necrosis (N=4), pseudocyst (N=8), or both (N=10; FIG. 2). Among 48 patients with evaluable followup pancreatic imaging (n=l), enzymes (n=18), or both (n=29), 30 met published criteria for severe AAP. Severe AAP was due to imaging identification of sequalae of severe pancreatitis (n=8), prolonged pancreatic enzyme elevation (n=8), or both (n=14). The 5- year cumulative incidence of extramedullary relapse (isolated or combined) was greater571624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) in patients experiencing asparaginase associated pancreatitis (7.1%, 3 events) than in other patients (1.4%, 7 events, p=0.012, Gray's test). Adjusting for risk group, there remained a trend toward increased risk in those with AAP (p=0.08, hazard ratio 3.4, Fine and Gray’s test). Competing events in these analyses include medullary relapse without extramedullary involvement, death, and second malignancy.

[0197] To identify risks for severe pancreatitis, cases with severe AAP were compared to all other patients. Older age (odds ratio [OR] 1.16, 95%CI 1.01-1.17 per year) and standard / high-risk therapy (OR 2.74, 95%CI 1.2-7) but not other features were associated with severe AAP. There were no differences between patients with severe AAP and other patients with AAP (p>0.2 for all features).

[0198] Because AAP interrupts early leukemia therapy and thus may compromise treatment efficacy, the impact of pancreatitis on both asparaginase delivery and EFS of patients treated on this trial was assessed. Patients with AAP received 5.2 fewer doses of asparaginase after adjusting for treatment arm (p<0.001) and had inferior EFS compared to those without AAP (5-year EFS without AAP 90.4% vs. 80.7% in those with pancreatitis. FIR 2.14 [1.09-4.2], p=0.028, FIG. 3A). In multivariate analysis including treatment group, patients with AAP had a non-significant trend toward inferior EFS in both low- and standard / high-risk treatment groups (HR 1.52 [0.77— -3], p=0.22, FIG. 3B). Event free survival (EFS) was associated with the occurrence of asparaginase associated pancreatitis (AAP). In univariate analysis, the 5-year EFS was 80.7% in those with AAP and 90.4% in those without AAP (p=0.028) (FIG. 3A). While this difference was not statistically significant after adjusting for treatment arm (p=0.22), 5-year EFS was lower in patients with AAP in both treatment arms (FIG. 3B). Events for EFS analysis included death from any cause, failure to achieve remission, relapse, and second cancer. Results were similar when also adjusting for age at diagnosis and ancestry (p=0.3 for association of AAP and EFS in this model). Causes of failure differed in patients who experienced AAP with more extramedullary relapse (EM) in those w ith AAP (5-year cumulative incidence of EM 7.1% vs. 1.4%, p=0.012, FIG. 4) with a trend in multivariate analysis including treatment risk group (p=0.08). 5- year overall survival was 92% in those with vs. 95% in those without AAP (p=0.2), consistent with high salvage rates for patients experiencing EM.

[0199] Pancreatitis is among the most feared complications of ALL therapy because complications such as pseudocyst, pancreatic necrosis, abdominal pain, and endocrine581624090979.1PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761) or exocrine pancreatic insufficiency can persist after therapy with lifelong morbidity. (7. 8) Pancreatitis also interrupts therapy and often necessitates early discontinuation of asparaginase, possibly increasing the risk of relapse. (10, 12) Thus, it is critical to understand not only the frequency of pancreatitis but also the frequency of these severe complications.

[0200] This cohort validated previously identified risk factors for AAP including older age, prolonged asparaginase exposure, obesity, and Hispanic ancestry. 4 of the 6 patients who developed pancreatitis unassociated with asparaginase therapy were also Hispanic, suggesting that the risk imparted by Hispanic ancestry applies throughout therapy and not just limited to AAP, consistent with prior genomic studies.

[0201] More than 40% of patients in this study who developed AAP had radiographic severe pancreatic injury, and only 18 of 48 evaluable patients met criteria for rechallenge. Patients with AAP also trended toward more EM relapses than other patients (5-year CIR 7.1% vs. 1.4%). It has previously been shown that truncation of asparaginase therapy increases the risk of relapse in Dana Farber and Children's Oncology’ Group trials. Data from the earlier Total 15 study demonstrated that antiasparaginase antibodies which reduce asparaginase exposure increased the risk of CNS but not systemic relapse. AAP may increase the risk of extramedullary relapse by both terminating asparaginase therapy early and interrupting other leukemia therapy, compromising extramedullary control.

[0202] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now’ occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.591624090979.1

Claims

1. PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)CLAIMS1. A method for treating acute pancreatitis in a subject comprising administering to the subject an intracellular Calcium signaling inhibitor, wherein the intracellular calcium signaling inhibitor comprises N-(5-(6-chloro-2,2-difluorobenzo[d][l,3]dioxol-5-yl)pyrazin-2- yl)-2-fluoro-6-methylbenzamide, wherein the subject is receiving an asparaginase-containing pharmaceutical composition, wherein the subject is being treated for a different disease or disorder as compared to acute pancreatitis.

2. The method of claim 1, wherein the different disease or disorder is acute lymphoblastic leukemia.

3. The method of claim 1 or 2, wherein the method reduces an average amount of days the subject spends in the hospital.

4. The method of any of claims 1 to 3, wherein an average amount of days the subject spends in the hospital is less than about 9 days.

5. The method of any of claims 1 to 3, wherein an average amount of days the subject spends in the hospital is less than about 8 days.

6. The method of any of claims 1 to 3, wherein an average amount of days the subject spends in the hospital is less than about 7 days.

7. The method of any of claims 1 to 3, wherein an average amount of days the subject spends in the hospital is less than about 6 days.

8. The method of any of claims 1 to 3, wherein an average amount of days the subject spends in the hospital is less than about 5 days.

9. The method of any of claims 1 to 8, further comprising reducing an average amount of time the subj ect spent in an intensive care unit (ICU).

10. The method of claim 9. wherein the average amount of time the subject spent in the ICU is from about 5 days to about 3 days.

11. The method of claim 9, wherein the average amount of time the subject spent in the ICU is about 3 days or less.

12. The method of any of claims 1 to 11. wherein a percentage of subjects in need of the ICU is reduced from about 18.8% to about 12.5%.

13. The method of any of claims 1 to 12, further comprising administering the intracellular Calcium signaling inhibitor at about between 1.0 mg / kg and 3.0 mg / kg on daysPATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)14. The method of any of claims 1 to 13, further comprising administering the intracellular Calcium signaling inhibitor at about between 1.0 mg / kg and 2.5 mg / kg on days 3-4.

15. The method of any of claim 13, further comprising administering the intracellular Calcium signaling inhibitor at about 2 mg / kg on day 1 and 2.

16. The method of claim 14, further comprising administering the intracellular Calcium signaling inhibitor at about 1.6 mg / kg on days 3 and 4.

17. The method of any of claims 1 to 12, further comprising administering the intracellular Calcium signaling inhibitor at between about 20 mg / m2and 40 mg / m2on day 1.

18. The method of any one of claims 1 to 12, further comprising administering the intracellular Calcium signaling inhibitor at between about 20 mg / m2and 50 mg / m2on days 2- 4.

19. The method of claim 17, further comprising administering the intracellular Calcium signaling inhibitor at about 30 mg / m2on day 1.

20. The method of claim 18, further comprising administering the intracellular Calcium signaling inhibitor at about 42 mg / m2on each of days 2-4.

21. The method of any of claims 1 to 20, further comprising administering the intracellular Calcium signaling inhibitor via an IV infusion.

22. The method of any of claims 1 to 21, further comprising administering the intracellular Calcium signaling inhibitor via an intravenous (IV) infusion for a time span of about 4 hours.

23. The method of any of claims 1 to 22, wherein an age of the subject is between 1-20.

24. The method of any of claims 1 to 23, wherein the subject seeks pediatric care.

25. The method of any one of claims 1 to 24, wherein the subject does not require receiving nutrition via IV administration.

26. The method of any of claims 1 to 25, wherein a percentage of subjects with pancreatic necrosis affecting greater than or equal to about 30% of the pancreas is reduced after treatment with the intracellular Calcium signaling inhibitor.

27. The method of any of claims 1 to 26. wherein the subject does not have pancreatic necrosis affecting greater than or equal to about 30% of the pancreas after treatment w ith the intracellular Calcium signaling inhibitor.PATENTATTORNEY DOCKET NO. CM1720-1WO (449399-761)28. The method of any of claims 1 to 27, further comprising evaluating a severity of pancreatic necrosis using a computed tomography severity index (CTSI) score.

29. The method of claim 28, wherein the CTSI score of 0-3 indicates mild acute pancreatitis, the CTSI score of 4-6 indicates moderately severe acute pancreatitis, and the CTSI score greater than 7 indicates severe acute pancreatitis.

30. The method of claim 28, wherein a mean CTSI score of the subject is from 5.4 to 2.4.

31. The method of claim 28, wherein a CTSI score range of the subject is from 0 to 10 to 0 to 4.

32. The method of any of claims 1 to 31, wherein the subject with a CTSI score of greater than or equal to about 7 has a reduced score subsequent to administration of the intracellular Calcium signaling inhibitor compared to a second subject that did not receive administration of the intracellular Calcium signaling inhibitor.

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