Dose escalation enzyme replacement therapy for treating acid sphingomyelinase deficiency

Patent metadata

Field	Value
Publication number	US-2018055916-A1
Application number	US-201715485604-A
Country	US
Kind code	A1
Filing date	Apr 12, 2017
Priority date	Aug 28, 2009
Publication date	Mar 1, 2018
Grant date	—

Abstract

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.

First claim

1 .- 19 . (canceled)

20 . 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.

21 . 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.

22 . 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.

23 . 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 1, 2, or 3 mg/kg rhASM to the human subject.

24 . 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.

25 . The method of claim 20 , wherein each dose is administered two weeks after the previous dose.

26 . The method of claim 22 , wherein each dose is administered two weeks after the previous dose.

27 . The method of claim 23 , wherein each dose is administered two weeks after the previous dose.

28 . The method of claim 24 , wherein each dose is administered two weeks after the previous dose.

29 . The method of claim 20 , wherein the doses are administered intravenously.

30 . The method of claim 22 , wherein the doses are administered intravenously.

31 . The method of claim 24 , wherein the doses are administered intravenously.

32 . The method of claim 20 , wherein the ASMD is Niemann Pick Disease (NPD) type B.

33 . The method of claim 21 , wherein the ASMD is Niemann Pick Disease (NPD) type B.

34 . The method of claim 22 , wherein the ASMD is Niemann Pick Disease (NPD) type B.

35 . The method of claim 23 , wherein the ASMD is Niemann Pick Disease (NPD) type B.

36 . The method of claim 24 , wherein the ASMD is Niemann Pick Disease (NPD) type B.

37 . The method of claim 20 , wherein the ASMD is non-neuronopathic ASMD.

38 . The method of claim 21 , wherein the ASMD is non-neuronopathic ASMD.

39 . The method of claim 22 , wherein the ASMD is non-neuronopathic ASMD.

40 . The method of claim 23 , wherein the ASMD is non-neuronopathic ASMD.

41 . The method of claim 24 , wherein the ASMD is non-neuronopathic ASMD.

42 . The method of claim 20 , wherein the human subject is a human adult.

43 . The method of claim 21 , wherein the human subject is a human adult.

44 . The method of claim 22 , wherein the human subject is a human adult.

45 . The method of claim 23 , wherein the human subject is a human adult.

46 . The method of claim 24 , wherein the human subject is a human adult.

47 . The method of claim 20 , wherein the human subject is a human child.

48 . The method of claim 21 , wherein the human subject is a human child.

49 . The method of claim 22 , wherein the human subject is a human child.

50 . The method of claim 23 , wherein the human subject is a human child.

51 . The method of claim 24 , wherein the human subject is a human child.

52 . The method of claim 20 , which further comprises administering a maintenance dose to the human subject.

53 . The method of claim 52 , wherein the maintenance dose is 3 mg/kg.

54 . The method of claim 52 , wherein the maintenance dose is administered every two weeks.

55 . The method of claim 21 , which further comprises administering a maintenance dose to the human subject.

56 . The method of claim 55 , wherein the maintenance dose is the highest dose tolerated the human subject.

57 . The method of claim 21 , wherein the method comprises a further sequential dose of 2 mg/kg rhASM.

58 . The method of claim 57 , which further comprises administering a maintenance dose to the human subject.

59 . The method of claim 57 , wherein the method comprises a further sequential dose of 3 mg/kg rhASM.

60 . The method of claim 59 , which further comprises administering a maintenance dose to the human subject.

61 . The method of claim 60 , wherein the maintenance dose is 3 mg/kg.

62 . The method of claim 56 , wherein the maintenance dose is administered every two weeks.

63 . The method of claim 58 , wherein the maintenance dose is administered every two weeks.

64 . The method of claim 60 , wherein the maintenance dose is administered every two weeks.

65 . The method of claim 22 , wherein the maintenance dose is 3 mg/kg.

66 . The method of claim 23 , wherein the maintenance dose is 3 mg/kg.

67 . The method of claim 24 , wherein the maintenance dose is 3 mg/kg.

Assignees

• Icahn School Med Mount Sinai
• Genzyme Corp

Inventors

• Schuchman Edward H
• Desnick Robert J
• Cox Gerald F
• Andrews Laura P
• Murray James M

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title