Dose-escalating enzyme replacement therapy for the treatment of acid sphingomyelinase deficiency

Claims

1. A method of treating a human subject having acid sphingomyelinase deficiency, comprising (a) a regimen for reducing the mass of accumulated sphingomyelin substrate in a human subject, comprising: (i) administering an initial low, non-toxic dose of acid sphingomyelinase (ASM) to a human subject; (ii) administering successively higher doses of ASM to a human subject and monitoring the subject for one or more undesirable adverse events after each subsequent dose as indicated by increased bilirubin or a related adverse event; and (b) a maintenance regimen comprising administering a dose equal to or less than the highest dose tolerated by the subject as a maintenance dose to the subject.

2. Acid sphingomyelinase (ASM) for use in the treatment of acid sphingomyelinase deficiency in a human subject, prepared for administration: (a) in a scheme for reducing the mass of accumulated sphingomyelin substrate, including (i) administration of an initial low, non-toxic dose of acid sphingomyelinase (ASM); (ii) administering successively higher doses of ASM and monitoring the subject for one or more undesirable side effects after each subsequent dose indicated by increased bilirubin or a related adverse event; (b) in a maintenance regimen comprising administering a dose equal to or less than the highest dose tolerated by the subject as a maintenance dose for the subject.

3. The method of claim 1, wherein the ASM is recombinant human ASM (rhASM).

4. The method of claim 3, wherein the initial dose ranges from 0.1 mg / kg to 1 mg / kg rhASM.

5. The method of claim 3, wherein the initial dose is from 0.1 mg / kg to 0.5 mg / kg rhASM.

6. The method of claim 3, wherein the initial dose is 0.1 mg / kg rhASM.

7. The method according to any one of claims 1 or 3-6, wherein successively higher doses are administered one, two, three or four weeks after the previous dose.

8. The method of claim 7, wherein a successively higher dose is administered one week after the previous dose.

9. The method of claim 7, wherein a successively higher dose is administered two weeks after the previous dose.

10. The method of any one of claims 7-9, wherein the successively higher dose is about 0.1-1.0 mg / kg higher than the previous dose.

11. The method of any one of claims 7-9, wherein the successively higher dose is about 0.1-0.5 mg / kg higher than the previous dose.

12. The method according to any one of claims 1 and 3-10, wherein the highest dose tolerated by a human subject is from 1 mg / kg to 3 mg / kg.

13. The method according to any one of claims 1-11, wherein the highest tolerated dose is administered to the human subject as a maintenance dose.

14. The method according to any one of claims 1-11, wherein the maintenance dose is a therapeutically effective dose that is less than the highest tolerated dose.

15. The method of any one of claims 1-13, further comprising monitoring the subject during the maintenance regimen for one or more undesirable side effects indicated by elevated bilirubin or a related adverse event; and adjusting the maintenance dose.

16. The method according to any one of paragraphs 13-15, wherein the maintenance dose is administered to the subject every two to four weeks.

17. ASM according to claim 2, which is rhASM.

18. rhASM according to claim 17, wherein the initial dose ranges from 0.1 mg / kg to 1 mg / kg rhASM.

19. rhASM according to claim 17, wherein the initial dose is from 0.1 mg / kg to 0.5 mg / kg rhASM.

20. rhASM according to claim 17, wherein the initial dose is 0.1 mg / kg rhASM.

21. ASM according to any one of claims 2 and 17-20, wherein successively higher doses are administered one, two, three or four weeks after the previous dose.

22. ASM according to claim 21, wherein the successively higher dose is administered one week after the previous dose.

23. ASM according to claim 21, wherein a successively higher dose is administered two weeks after the previous dose.

24. The ASM of any one of claims 21-23, wherein the successively higher dose is about 0.1-1.0 mg / kg higher than the previous dose.

25. The ASM of any one of claims 21-23, wherein the successively higher dose is about 0.1-0.5 mg / kg higher than the previous dose.

26. The ASM of any one of claims 2 and 17-25, wherein the highest dose tolerated by a human subject is from 1 mg / kg to 3 mg / kg.

27. The ASM of any one of claims 2 and 17-26, wherein the highest tolerated dose is administered to the human subject as a maintenance dose.

28. The ASM of claim 27, wherein the maintenance dose is a therapeutically effective dose that is less than the highest tolerated dose.

29. The ASM of claim 27, wherein the maintenance dose is administered to the subject every two to four weeks.

30. A method of treating a human subject having acid sphingomyelinase deficiency, comprising administering rhASM in a dose escalation regimen at the following sequential doses: (a) 0.1 mg / kg, (b) 0.3 mg / kg (c) 0.6 mg / kg; wherein each dose of rhASM is administered at least twice, and each dose is administered at two-week intervals, and wherein the subject is monitored for toxic side effects before increasing the dose to the next level.

31. The method of claim 30, further comprising a subsequent dose of 1 mg / kg in a dose escalation regimen.

32. The method of claim 31, further comprising a subsequent dose of 2 mg / kg in a dose escalation regimen.

33. The method of claim 32, further comprising a subsequent dose of 3 mg / kg in a dose escalation regimen.

34. rhASM for use in the treatment of acid sphingomyelinase deficiency in a human subject, prepared for administration in a dose-escalating schedule at the following sequential doses: (a) 0.1 mg / kg, (b) 0.3 mg / kg and (c) 0.6 mg / kg; where each dose is administered at least twice, and each dose is administered at two-week intervals, and where the subject is monitored for toxic side effects before increasing the dose to the next level.

35. rhASM according to claim 34, further including a subsequent dose of 1 mg / kg in a dose escalation regimen.

36. rhASM according to claim 35, further including a subsequent dose of 2 mg / kg in a dose escalation regimen.

37. rhASM according to claim 36, further including a subsequent dose of 3 mg / kg in a dose escalation regimen.

38. The method according to any one of paragraphs 1, 3-16 and 30-33, wherein the doses are administered intravenously.

39. The method according to any one of claims 1, 3-16 and 30-33, wherein the doses are administered intradermally, subcutaneously or intramuscularly.

40. The method according to any one of claims 1, 3-16 and 30-33, wherein the acid sphingomyelinase deficiency is Niemann-Pick disease (NPD) type A.

41. The method according to any one of claims 1, 3-16 and 30-33, wherein the acid sphingomyelinase deficiency is NPD type B.

42. The method according to any one of claims 1, 3-16 and 30-33, wherein the human subject has a missense mutation in the gene encoding acid sphingomyelinase.

43. The method according to any one of claims 1, 3-16 and 30-33, wherein the mutation is L302P, H421Y or R496L.

44. The method according to any one of claims 1, 3-16 and 30-33, wherein the human subject has a mutation in a gene encoding acid sphingomyelinase, and the mutation is ΔR608.

45. ASM according to any one of paragraphs 2, 17-29 and 34-37, wherein the doses are administered intravenously.

46. ​​ASM according to any one of paragraphs 2, 17-29 and 34-37, wherein the doses are administered subcutaneously or intramuscularly.

47. The ASM of any one of claims 2, 17-29, and 34-37, wherein the acid sphingomyelinase deficiency is Niemann-Pick disease (NPD) type A.

48. The ASM of any one of claims 2, 17-29, and 34-37, wherein the acid sphingomyelinase deficiency is NPD type B.

49. The ASM of any one of claims 2, 17-29, and 34-37, wherein the human subject has a missense mutation in the gene encoding acid sphingomyelinase.

50. ASM according to any one of claims 2, 17-29 and 34-37, wherein the mutation is L302P, H421Y or R496L.

51. The ASM of any one of claims 2, 17-29, and 34-37, wherein the human subject has a mutation in a gene encoding acid sphingomyelinase, and the mutation is ΔR608.