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 a human subject having an acid sphingomyelinase deficiency (ASMD), comprising administering to the human subject 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, and   (c) 0.6 mg/kg;   wherein each dose of rhASM is administered two weeks after the previous dose, wherein each dose is administered at least once before elevating the dose to the next level, and wherein the weight of the subject is calculated using the subject's height if the subject has a BMI >30.   
     
     
         21 . The method of  claim 20 , further comprising the following dose: (d) 1 mg/kg. 
     
     
         22 . The method of  claim 21 , further comprising the following dose: (e) 2 mg/kg. 
     
     
         23 . The method of  claim 22 , further comprising the following dose: (f) 3 mg/kg. 
     
     
         24 . The method of  claim 20 , wherein the ASMD is Niemann Pick Disease (NPD) type B. 
     
     
         25 . The method of  claim 20 , wherein the human subject is a human adult. 
     
     
         26 . The method of  claim 20 , wherein the doses are administered intravenously. 
     
     
         27 . The method of  claim 20 , further comprising a maintenance dose regimen comprising administering a dose equal to or less than the highest dose tolerated by the subject as the maintenance dose for the subject. 
     
     
         28 . The method of  claim 20 , wherein the maintenance dose is administered to the subject every one to four weeks. 
     
     
         29 . A method for treating a human subject having an acid sphingomyelinase deficiency (ASMD), comprising:
 (a) administering a dose of 0.1 mg/kg of recombinant human acid sphingomyelinase (rhASM) to the human subject; and   (b) administering successively higher doses of rhASM to the human subject if the human subject does not manifest a severe related adverse event, wherein each successively higher dose is from 0.1 mg/kg to 1 mg/kg higher than the previous dose,   wherein each dose of rhASM is administered two weeks after the previous dose, wherein each dose is administered at least once before elevating the dose to the next level, and wherein the weight of the subject is calculated using the subject's height if the subject has a BMI >30.   
     
     
         30 . The method of  claim 29 , wherein the doses are administered intravenously. 
     
     
         31 . The method of  claim 29 , wherein the ASMD is Niemann Pick Disease (NPD) type B. 
     
     
         32 . The method of  claim 29 , wherein the human subject is a human adult. 
     
     
         33 . The method of  claim 29 , wherein the successively higher doses comprise the following sequential doses: (i) 0.3 mg/kg, (ii) 0.6 mg/kg, (iii) 1 mg/kg, (iv) 2 mg/kg, and (v) 3 mg/kg. 
     
     
         34 . The method of  claim 29 , further comprising a maintenance dose regimen comprising administering a dose equal to or less than the highest dose tolerated by the subject as the maintenance dose for the subject. 
     
     
         35 . The method of  claim 29 , wherein the maintenance dose is administered to the subject every one to four weeks. 
     
     
         36 . A method for treating a human subject having an acid sphingomyelinase deficiency (ASMD), comprising:
 (a) administering a dose 0.025 mg/kg to 0.05 mg/kg of recombinant human acid sphingomyelinase (rhASM) to the human subject; and   (b) subsequently, administering escalating doses of (i) 0.1 mg/kg, (ii) 0.3 mg/kg, and (iii) 0.6 mg/kg of rhASM to the human subject;   wherein each dose of rhASM is administered two weeks after the previous dose, wherein each dose is administered at least once before elevating the dose to the next level, and wherein the weight of the subject is calculated using the subject's height if the subject has a BMI >30.   
     
     
         37 . The method of  claim 36 , further comprising the following escalating dose: (iv) 1 mg/kg. 
     
     
         38 . The method of  claim 37 , further comprising the following escalating dose: (e) 2 mg/kg. 
     
     
         39 . The method of  claim 38 , further comprising the following escalating dose: (f) 3 mg/kg. 
     
     
         40 . The method of  claim 36 , wherein the doses are administered intravenously. 
     
     
         41 . The method of  claim 36 , wherein the ASMD is Niemann Pick Disease (NPD) type B. 
     
     
         42 . The method of  claim 36 , wherein the human subject is less than 18 years old. 
     
     
         43 . The method of  claim 36 , further comprising a maintenance dose regimen comprising administering a dose equal to or less than the highest dose tolerated by the subject as the maintenance dose for the subject. 
     
     
         44 . The method of  claim 43 , wherein the maintenance dose is administered to the subject every one to four weeks.