Subcutaneous administration of an ASBT inhibitor

Claims

1. An ASBT (apical sodium-dependent bile acid transporter) inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of a liver or kidney disease or disorder, wherein the ASBT inhibitor is administered subcutaneously.

2. An ASBT inhibitor for use according to claim 1, wherein the ASBT inhibitor does not inhibit renal ASBT at clinically significant levels following oral administration of the ASBT inhibitor.

3. An ASBT inhibitor for use according to claim 1, wherein the systemic absorption of the ASBT inhibitor is less than 10% after oral administration of the ASBT inhibitor.

4. An ASBT inhibitor for use according to claim 1, wherein the ASBT inhibitor is selected from the group consisting of elobixibat, odevixibat, maralixibat, volixibat and linerixibat, or a pharmaceutically acceptable salt thereof.

5. An ASBT inhibitor for use according to claim 1, wherein the ASBT inhibitor is elobixibat or a pharmaceutically acceptable salt thereof.

6. An ASBT inhibitor for use according to claim 1, wherein the liver or kidney disease or disorder is a bile acid disease or disorder.

7. An ASBT inhibitor for use according to claim 1, wherein the liver or kidney disease or disorder includes a disruption or impairment of bile flow.

8. An ASBT inhibitor for use according to claim 1, wherein the liver or kidney disease or disorder comprises cholestasis.

9. An ASBT inhibitor for use according to claim 1, wherein the liver disease or disorder is PFIC (progressive familial intrahepatic cholestasis) type 2.

10. An ASBT inhibitor for use according to claim 1, wherein the liver disease or disorder comprises BSEP3 (bile acid export pump 3) deficiency.

11. An ASBT inhibitor for use according to claim 1, wherein the liver or kidney disease or disorder comprises biliary obstruction.

12. An ASBT inhibitor for use according to claim 1, wherein the liver disease or disorder is biliary atresia, including biliary atresia after the Kasai operation and biliary atresia after liver transplantation.

13. An ASBT inhibitor for use according to claim 1, wherein the liver disease or disorder is acute cholangitis or obstructive cholangitis.

14. An ASBT inhibitor for use according to claim 1, wherein the liver disease or disorder is a malignant biliary obstruction, such as due to cholangiocarcinoma, pancreatic cancer, gallbladder cancer or colon cancer.

15. An ASBT inhibitor for use according to claim 1, wherein the kidney disease or disorder is selected from the group consisting of cholemic nephropathy, chronic nephropathy, hyperbilirubinemia, renal dysfunction in congestive jaundice, aging-induced renal mitochondrial dysfunction, kidney inflammation, acute kidney injury (AKI), ischemia-reperfusion kidney injury (IRI), chronic kidney disease (CKD), polycystic kidney disease (PKD), arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome, hereditary lecithin-cholesterol acyltransferase (LCAT) deficiency, chronic renal failure, end-stage renal disease (ESRD), proximal tubular injury, hepatorenal syndrome type 1, hepatorenal syndrome type 2, and exacerbation of chronic liver disease.

16. An ASBT inhibitor for use according to claim 1, wherein the kidney disease or disorder is cholemic nephropathy.

17. An ASBT inhibitor for use according to claim 1, wherein the patient is also receiving treatment with an orally administered non-systemic ASBT inhibitor.

18. An ASBT inhibitor for use according to claim 1, wherein the patient does not respond to treatment with an orally administered non-systemic ASBT inhibitor.

19. An ASBT inhibitor for use according to claim 1, wherein the patient is intolerant to treatment with an orally administered non-systemic ASBT inhibitor.

20. An ASBT inhibitor for use according to claim 1, wherein the ASBT inhibitor is administered once daily.

21. An ASBT inhibitor for use according to claim 1, wherein the subject exhibits a decrease in serum bile acid concentration following subcutaneous administration of the IBAT inhibitor.

22. An ASBT inhibitor for use according to claim 21, wherein the reduction in serum bile acid concentration is at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline.

23. An ASBT inhibitor for use according to claim 1, wherein the subject exhibits an increase in the amount of bile acids in the urine following subcutaneous administration of the IBAT inhibitor.

24. An ASBT inhibitor for use according to claim 23, wherein the increase in urinary bile acids is at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline.

25. An ASBT inhibitor for use according to claim 1, wherein the subject exhibits improvement in liver parameters following subcutaneous administration of the ASBT inhibitor.

26. An ASBT inhibitor for use according to claim 25, wherein the liver parameter is selected from the group consisting of total serum bilirubin level, serum alkaline phosphatase (ALP) level, serum alanine aminotransferase (ALT) level, and serum aspartate aminotransferase (AST) level.

27. An ASBT inhibitor for use according to claim 25, wherein the improvement in liver parameters occurs after subcutaneous administration of the ASBT inhibitor for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, or at least 48 weeks.

28. An ASBT inhibitor for use according to claim 1, wherein the subject exhibits a decrease in the relative expression of kidney injury molecule-1 (KIM-1) mRNA following subcutaneous administration of the ASBT inhibitor.

29. An ASBT inhibitor for use according to claim 28, wherein the reduction in relative KIM-1 mRNA expression is at least 60%, at least 70%, at least 80%, or at least 90%.

30. An ASBT inhibitor for use according to claim 1, wherein the subject exhibits a decrease in the relative expression of lipocalin-2 (LCN2) mRNA following subcutaneous administration of the ASBT inhibitor.

31. An ASBT inhibitor for use according to claim 30, wherein the reduction in relative LCN2 mRNA expression is at least 60%, at least 70%, at least 80%, or at least 90%.