METHODS TO INCREASE GROWTH IN PEDIATRIC SUBJECTS WITH CHOLESTATIC LIVER DISEASE

Abstract

This paper presents methods for increasing growth in a pediatric subject with cholestatic liver disease. The method involves administering an effective amount of an ASBTI to the subject.

Claims

CLAIMS MA / t / ZUZ I / U / 4OOU Having described the invention as above, the following claims are claimed as property:

1. A method for increasing growth in a pediatric subject having cholestatic liver disease, characterized in that it comprises administering to the subject an effective amount of an ASBTI.

2. The method according to claim 1, characterized in that the ASBTI is: (maralixibat), (volixibat), OH NS (odevixibat), - 333 MA / t / ZUZ I / U / 4OOU (elobixibat), (GSK2330672), or a pharmaceutically acceptable salt thereof.

3. The method according to claim 1, characterized in that the ASBTI is maralixibat, or a pharmaceutically acceptable alternative salt thereof.

4. The method according to claim 1, characterized in that the ASBTI is volixibat, or a pharmaceutically acceptable salt thereof.

5. The method according to claim 1, characterized in that the ASBTI is odevixibat, or a pharmaceutically acceptable salt thereof. - 334 - 6. The method according to claim 1, characterized in that the ASBTI is elobixibat, or a pharmaceutically acceptable salt thereof.

7. The method according to claim 1, characterized in that the ASBTI is GSK2330672, or a pharmaceutically acceptable salt thereof.

8. The method according to any one of claims 1 to 7, characterized in that the cholestatic liver disease is progressive familial intrahepatic cholestasis (PFIC), biliary atresia, Alagille syndrome (ALGS), intrahepatic cholestasis of pregnancy (ICP), or any pediatric cholestatic condition resulting in below-normal growth, height, or weight.

9. The method according to any of claims 1 to 8, characterized in that cholestatic liver disease is biliary atresia.

10. The method according to any of claims 1 to 8, characterized in that cholestatic liver disease is PFIC.

11. The method according to claim 10, characterized in that the PFIC is selected from PFIC type 1, PFIC type 2 and PFIC type 3.

12. The method according to claim 11, characterized in that the PFIC is a type 2 PFIC. M A / E / ZυZΊ / U 7 4OOU - 335 - 13. The method according to claim 12, characterized in that the subject has a subject ABCB11 gene with a nonsense mutation and a non-truncating mutation.

14. The method according to any of claims 1 to 8, characterized in that cholestatic liver disease is ALGS.

15. The method according to any of claims 1 to 8, characterized in that the cholestatic liver disease is TCP.

16. The method according to any of claims 1 to 15, characterized in that the ASBTI is administered once daily (QD).

17. The method according to claim 16, characterized in that ASBTI is administered in an amount of approximately 140 pg / kg / day to approximately 1400 pg / kg / day.

18. The method according to any of claims 1 to 17, characterized in that the ASBTI is administered twice 19. The daily (BID) method according to claim 18, characterized in that ASBTI is administered in an amount of approximately 70 pg / kg to approximately 700 pg / kg per dose.

20. The method in accordance with any of claims 1 to 19, characterized in that an increase in growth is measured as an increase in height or weight Z rating.

21. The method according to claim 20, characterized in that the administration results in an increase in the height or weight Z rating of at least 0.1 relative to the initial values.

22. The method according to claim 21, characterized in that the administration results in an increase in the height or weight Z rating of at least 0.25 relative to the initial values.

23. The method in accordance with any of claims 1 to 22, characterized in that the administration results in an increase in growth within one year of the first administration of the ASBTI.

24. The method according to any of claims 1 to 23, characterized in that an increase in the height or weight Z rating is maintained for a period of up to 20 weeks.

25. The method according to claim 24, characterized in that the increase in the height or weight rating Z is maintained for a period of up to 2 years.

26. The method according to any of claims 1 to 25, characterized in that the administration of ASBTI results in an increase in the height or weight Z rating in a dose-dependent manner.

27. The method according to any of claims 1 to 26, characterized in that the administration of ASBTI results in a reduction in a symptom or a change in a disease-relevant laboratory measure of cholestatic liver disease that is maintained for at least 10 weeks.

28. The method according to claim 27, characterized in that the reduction in a symptom or a change in a laboratory measure relevant to the disease comprises a reduction in the concentration of sBA, an increase in the serum concentration of 7aC4, an increase in the ratio of the serum concentration of 7aC4 to the concentration of sBA (7aC4:sBA), a reduction in pruritus, an increase in the quality of life inventory score, an increase in the fatigue-related quality of life inventory score, an increase in growth, or a combination thereof.

29. The method according to claim 28, characterized in that the reduction in the symptom or a change in the laboratory measurement relevant to the disease is determined relative to an initial MA / t / ZUZ I / U / 4OOU - 338 level.

30. The method according to any of claims 1 to 29, characterized in that the administration of ASBTI results in an increase in the excretion of fBA.

31. The method according to claim 30, characterized in that the administration of ASBTI results in a dose-dependent increase in fBA excretion.

32. The method according to claim 30 or 31, characterized in that the ASBTI is administered in a dose sufficient to result in an increase of at least 1.5 times in fBA excretion relative to initial values.

33. The method according to any of claims 1 to 32, characterized in that the administration of ASBTI results in an increase in the ratio of serum concentration of 7aC4 to sBA concentration (7aC4:sBA).

34. The method according to claim 33, characterized in that the 7aC4:sBA ratio is increased from approximately 2 times to approximately 5,000 times relative to the initial values.

35. The method according to MA / I / U / 40OU-339 claim 33 or 34, characterized in that it further comprises administering a second dose of ASBTI, wherein the second dose is greater than the first dose, if after administration of the first dose of ASBTI, the 7aC4:sBA ratio is not maintained at approximately >2 times higher than the initial ratio.

36. The method according to claim 33 or 34, characterized in that it further comprises administering a second dose of ASBTI, wherein the second dose is greater than the first dose, if the 7aC4:sBA ratio initially increases to at least > 2 times higher than the initial ratio and then begins to decrease back to the initial ratio.