Dose escalation enzyme replacement therapy for treating acid sphingomyelinase deficiency

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.

1 .- 19 . (canceled) 
     
     
         20 . A method for treating an acid sphingomyelinase deficiency (ASMD), comprising:
 a. administering to a human subject in need thereof at least one initial dose of 0.025 mg/kg to 0.05 mg/kg recombinant human acid sphingomyelinase (rhASM); and   b. subsequent to the administration of the at least one initial dose, administering an escalating dose regimen to the human subject at the following sequential doses: (i) 0.1 mg/kg, (ii) 0.3 mg/kg, and (iii) 0.6 mg/kg, wherein each escalating dose is administered at least once before elevating the dose to the next level.   
     
     
         21 . The method of  claim 20 , wherein each dose is administered two weeks after the previous dose. 
     
     
         22 . The method of  claim 20 , wherein the doses are administered intravenously. 
     
     
         23 . The method of  claim 20 , wherein the human subject is a human child. 
     
     
         24 . The method of  claim 20 , wherein the ASMD is Niemann Pick Disease (NPD) type A. 
     
     
         25 . The method of  claim 20 , wherein the ASMD is Niemann Pick Disease (NPD) type B. 
     
     
         26 . The method of  claim 20  further comprising the following sequential dose: (iv) 1 mg/kg. 
     
     
         27 . The method of  claim 26  further comprising the following sequential dose: (v) 2 mg/kg. 
     
     
         28 . The method of  claim 27  further comprising the following sequential dose: (vi) 3 mg/kg. 
     
     
         29 . The method of  claim 28 , wherein each dose is administered two weeks after the previous dose. 
     
     
         30 . The method of  claim 20 , wherein the human subject has a missense mutation in the gene encoding acid sphingomyelinase. 
     
     
         31 . The method of  claim 30 , wherein the mutation is L302P, H421Y, or R496L. 
     
     
         32 . The method of  claim 20 , wherein the human subject has a mutation in the gene encoding acid sphingomyelinase and the mutation is ΔR608. 
     
     
         33 . The method of  claim 20 , wherein the dose of 0.1 mg/kg is administered once before elevating the dose to the next level. 
     
     
         34 . The method of  claim 33 , wherein the dose of 0.3 mg/kg is administered twice before elevating the dose to the next level. 
     
     
         35 . The method of  claim 34 , wherein the dose of 0.6 mg/kg is administered twice before elevating the dose to the next level. 
     
     
         36 . The method of  claim 20 , which further comprises administering a maintenance dose to the human subject. 
     
     
         37 . The method of  claim 36 , wherein the maintenance dose is administered every two weeks. 
     
     
         38 . The method of  claim 36 , wherein the maintenance dose is the highest dose tolerated. 
     
     
         39 . The method of  claim 36 , wherein the maintenance dose is 1 mg/kg to 3 mg/kg.