Dose escalation enzyme replacement therapy for treating acid sphingomyelinase deficiency
The invention relates to dose escalation enzyme replacement therapy using acid sphingomyelinase (ASM) for the treatment of human subjects having acid sphingomyelinase deficiency (ASMD), and, in particular, patients with non-neurological manifestations of Niemann-Pick Disease (NPD), and in certain embodiments, NPD type B.
1. A method for treating an acid sphingomyelinase deficiency (ASMD), comprising:
a. administering to a human subject in need thereof one or more initial doses of 0.1 mg/kg recombinant human acid sphingomyelinase (rhASM); and
b. administering sequentially escalating higher doses of rhASM to the human subject if the subject does not manifest one or more moderate or severe adverse events, wherein the higher doses are from 0.1 mg/kg to 1.0 mg/kg higher than the previous dose.
2. A method for treating an acid sphingomyelinase deficiency (ASMD), comprising intravenously administering to a human subject in need thereof recombinant human acid sphingomyelinase (rhASM) in an escalating dose regimen at the following sequential doses:
a. 0.1 mg/kg,
b. 0.3 mg/kg,
c. 0.6 mg/kg, and
d. 1 mg/kg,
wherein: (i) each dose may be administered two or more times, (ii) each dose is administered at two week intervals, and (iii) the subject is monitored for one or more moderate or severe adverse events before elevating the dose to the next level.
3. A method for treating an acid sphingomyelinase deficiency (ASMD), comprising:
a. a dose escalation regimen comprising:
i. administering to a human subject in need thereof a dose of 0.1 mg/kg rhASM to the human subject; and
ii. administering successively higher doses of rhASM to the human subject if the human subject does not manifest one or more moderate or severe adverse events; and
b. a maintenance regimen comprising administering a maintenance dose of 1, 2, or 3 mg/kg rhASM to the human subject.
4. A method for treating an acid sphingomyelinase deficiency (ASMD), comprising intravenously administering to a human subject in need thereof recombinant human acid sphingomyelinase (rhASM), wherein the method comprises administering:
a. a dose escalation regimen comprising:
i. administering a dose of 0.1 mg/kg rhASM to the human subject; and
ii. administering successively higher doses of rhASM to the human subject if the human subject does not manifest one or more moderate or severe adverse events; and
b. a maintenance regimen comprising administering a maintenance dose of 1, 2, or 3 mg/kg rhASM to the human subject.
5. A method for treating an acid sphingomyelinase deficiency (ASMD), comprising:
a. a dose escalation regimen comprising:
i. administering to a human subject in need thereof a dose ranging from 0.001 mg/kg to 0.05 mg/kg rhASM; and
ii. administering successively higher doses of rhASM to the human subject if the human subject does not manifest one or more moderate or severe adverse events; and
b. a maintenance regimen comprising administering a maintenance dose of 1, 2, or 3 mg/kg rhASM to the human subject.
6. The method of claim 1 , wherein each dose is administered two weeks after the previous dose.
7. The method of claim 3 , wherein each dose is administered two weeks after the previous dose.
8. The method of claim 4 , wherein each dose is administered two weeks after the previous dose.
9. The method of claim 5 , wherein each dose is administered two weeks after the previous dose.
10. The method of claim 1 , wherein the doses are administered intravenously.
11. The method of claim 3 , wherein the doses are administered intravenously.
12. The method of claim 5 , wherein the doses are administered intravenously.
13. The method of claim 1 , wherein the ASMD is Niemann Pick Disease (NPD) type B.
14. The method of claim 2 , wherein the ASMD is Niemann Pick Disease (NPD) type B.
15. The method of claim 3 , wherein the ASMD is Niemann Pick Disease (NPD) type B.
16. The method of claim 4 , wherein the ASMD is Niemann Pick Disease (NPD) type B.
17. The method of claim 5 , wherein the ASMD is Niemann Pick Disease (NPD) type B.
18. The method of claim 1 , wherein the ASMD is non-neuronopathic ASMD.
19. The method of claim 2 , wherein the ASMD is non-neuronopathic ASMD.
20. The method of claim 3 , wherein the ASMD is non-neuronopathic ASMD.
21. The method of claim 4 , wherein the ASMD is non-neuronopathic ASMD.
22. The method of claim 5 , wherein the ASMD is non-neuronopathic ASMD.
23. The method of claim 1 , wherein the human subject is a human adult.
24. The method of claim 2 , wherein the human subject is a human adult.
25. The method of claim 3 , wherein the human subject is a human adult.
26. The method of claim 4 , wherein the human subject is a human adult.
27. The method of claim 5 , wherein the human subject is a human adult.
28. The method of claim 1 , wherein the human subject is a human child.
29. The method of claim 2 , wherein the human subject is a human child.
30. The method of claim 3 , wherein the human subject is a human child.
31. The method of claim 4 , wherein the human subject is a human child.
32. The method of claim 5 , wherein the human subject is a human child.
33. The method of claim 1 , which further comprises administering a maintenance dose to the human subject.
34. The method of claim 33 , wherein the maintenance dose is 3 mg/kg.
35. The method of claim 33 , wherein the maintenance dose is administered every two weeks.
36. The method of claim 2 , which further comprises administering a maintenance dose to the human subject.
37. The method of claim 36 , wherein the maintenance dose is the highest dose tolerated the human subject.
38. The method of claim 2 , wherein the method comprises a further sequential dose of 2 mg/kg rhASM.
39. The method of claim 38 , which further comprises administering a maintenance dose to the human subject.
40. The method of claim 38 , wherein the method comprises a further sequential dose of 3 mg/kg rhASM.
41. The method of claim 40 , which further comprises administering a maintenance dose to the human subject.
42. The method of claim 41 , wherein the maintenance dose is 3 mg/kg.
43. The method of claim 37 , wherein the maintenance dose is administered every two weeks.
44. The method of claim 39 , wherein the maintenance dose is administered every two weeks.
45. The method of claim 41 , wherein the maintenance dose is administered every two weeks.
46. The method of claim 3 , wherein the maintenance dose is 3 mg/kg.
47. The method of claim 4 , wherein the maintenance dose is 3 mg/kg.
48. The method of claim 5 , wherein the maintenance dose is 3 mg/kg.