Claims for Patent: 10,512,657

Summary for Patent: 10,512,657

Title:	Bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases
Abstract:	Provided herein are methods of treating or ameliorating a pediatric cholestatic liver disease by non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric formulation comprising an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. Also provided are methods for treating or ameliorating a pediatric liver disease, decreasing the levels of serum bile acids or hepatic bile acids, treating or ameliorating pruritis, reducing liver enzymes, or reducing bilirubin comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric formulation comprising an ASBTI or a pharmaceutically acceptable salt thereof.
Inventor(s):	Bronislava Gedulin, Michael Grey, Niall O'Donnell
Assignee:	Lumena Pharmaceutials LLC , Shire Human Genetics Therapies Inc
Application Number:	US15/137,323
Patent Claims:	1. A method for treating or ameliorating pediatric progressive familial intrahepatic cholestasis type 2 (PFIC2) in a pediatric subject comprising administering to the pediatric subject an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI), the ASBTI is or a pharmaceutically acceptable salt thereof; wherein the ASBTI is effective for decreasing at least 20% of serum and/or hepatic bile acid levels in the pediatric subject as compared to bile acid levels prior to administration of the ASBTI. 2. A method for treating or ameliorating pruritis in a pediatric subject suffering from progressive familial intrahepatic cholestasis type 2 (PFIC2) comprising administering to the pediatric subject an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI), the ASBTI is or a pharmaceutically acceptable salt thereof; wherein the ASBTI is effective for decreasing at least 20% of serum and/or hepatic bile acid levels in the pediatric subject as compared to bile acid levels prior to administration of the ASBTI. 3. A method for treating or ameliorating pediatric progressive familial intrahepatic cholestasis type 2 (PFIC2) in a pediatric subject comprising administering to the pediatric subject a pharmaceutical composition comprising an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI), the ASBTI is or a pharmaceutically acceptable salt thereof; wherein the ASBTI is effective for decreasing at least 20% of serum and/or hepatic bile acid levels in the pediatric subject as compared to bile acid levels prior to administration of the ASBTI. 4. The method of claim 1, wherein the method comprises reducing xanthoma, serum lipoprotein X, liver enzymes, bilirubin, intraenterocyte bile acids/salts, or necrosis and/or damage to hepatocellular architecture. 5. The method of claim 3, wherein the composition is a pediatric dosage form. 6. The method of claim 5, wherein the pediatric dosage form is selected from a solution, syrup, suspension, elixir, powder for reconstitution as suspension or solution, dispersible/effervescent tablet, chewable tablet, gummy candy, lollipop, freezer pops, troches, oral thin strips, orally disintegrating tablet, sachet, soft gelatin capsule, and sprinkle oral powder or granules. 7. The method of claim 1, wherein the ASBTI is administered in an amount between about 10 μg/kg/day and about 300 μg/kg/day. 8. The method of claim 1, wherein the ASBTI is administered in an amount between about 14 μg/kg/day to about 280 μg/kg/day. 9. The method of claim 1, wherein the ASBTI is administered in an amount between about 14 μg/kg/day to about 140 μg/kg/day. 10. The method of claim 5, wherein the pediatric dosage form comprises between 0.1 to 20 mg of the ASBTI. 11. The method of claim 1, wherein the progressive familial intrahepatic cholestasis type 2 (PFIC2) is characterized by one or more symptoms selected from jaundice, pruritis, cirrhosis, hypercholemia, neonatal respiratory distress syndrome, lung pneumonia, increased serum concentration of bile acids, increased hepatic concentration of bile acids, increased serum concentration of bilirubin, hepatocellular injury, liver scarring, liver failure, hepatomegaly, xanthomas, malabsorption, splenomegaly, diarrhea, pancreatitis, hepatocellular necrosis, giant cell formation, hepatocellular carcinoma, gastrointestinal bleeding, portal hypertension, hearing loss, fatigue, loss of appetite, anorexia, peculiar smell, dark urine, light stools, steatorrhea, failure to thrive, and renal failure. 12. The method of claim 1, wherein the pediatric patient is between 6 months to 12 years old. 13. The method of claim 1, wherein less than 10% of the ASBTI is systemically absorbed. 14. The method of claim 3, wherein the composition further comprises a bile acid sequestrant or binder. 15. The method of claim 1, wherein the ASBTI is effective for decreasing at least 30% of serum and/or hepatic bile acid levels in the pediatric subject as compared to bile acid levels prior to administration of the ASBTI. 16. The method of claim 1, wherein the ASBTI is effective for decreasing at least 40% of serum and/or hepatic bile acid levels in the pediatric subject as compared to bile acid levels prior to administration of the ASBTI. 17. The method of claim 1, wherein the ASBTI is effective for decreasing at least 50% of serum and/or hepatic bile acid levels in the pediatric subject as compared to bile acid levels prior to administration of the ASBTI.