Augmented Acid Alpha-Glucosidase For The Treatment Of Pompe Disease

Abstract

A method for treating Pompe disease including administration of recombinant human acid α-glucosidase having optimal glycosylation with mannose-6-phosphate residues in combination with an amount of miglustat effective to maximize tissue uptake of recombinant human acid α-glucosidase while minimizing inhibition of the enzymatic activity of the recombinant human acid α-glucosidase is provided.

1 . A method of treating Pompe disease in a patient in need thereof, the method comprising administering miglustat to the patient in combination with a recombinant acid α-glucosidase, wherein the recombinant acid α-glucosidase is expressed in Chinese hamster ovary (CHO) cells and comprises an increased content of N-glycan units bearing one or two mannose-6-phosphate residues when compared to a content of N-glycan units bearing one or two mannose-6-phosphate residues of alglucosidase alfa. 
     
     
         2 . The method according to  claim 1  wherein the recombinant human acid α-glucosidase comprises a sequence at least 95% identical to SEQ ID NO: 1 or SEQ ID NO: 5. 
     
     
         3 . The method according to  claim 1  wherein at least 30% of molecules of the recombinant human acid α-glucosidase comprise one or more N-glycan units bearing one or two mannose-6-phosphate residues. 
     
     
         4 . The method according to  claim 1  wherein the recombinant human acid α-glucosidase comprises on average from 0.5 to 7.0 moles of N-glycan units bearing one or two mannose-6-phosphate residues per mole of recombinant human acid α-glucosidase. 
     
     
         5 . The method according to  claim 1  wherein the recombinant human acid α-glucosidase comprises on average at least 2.5 moles of mannose-6-phosphate residues per mole of recombinant human acid α-glucosidase and at least 4 moles of sialic acid residues per mole of recombinant human acid α-glucosidase. 
     
     
         6 . The method according to  claim 1  wherein the recombinant human acid α-glucosidase comprises seven potential N-glycosylation sites, at least 50% of molecules of the recombinant human acid α-glucosidase comprise an N-glycan unit bearing two mannose-6-phosphate residues at the first site, at least 30% of molecules of the recombinant human acid α-glucosidase comprise an N-glycan unit bearing one mannose-6-phosphate residue at the second site, at least 30% of molecules of the recombinant human acid α-glucosidase comprise an N-glycan unit bearing two mannose-6-phosphate residue at the fourth site, and at least 20% of molecules of the recombinant human acid α-glucosidase comprise an N-glycan unit bearing one mannose-6-phosphate residue at the fourth site. 
     
     
         7 . The method according to  claim 1  wherein the recombinant human acid α-glucosidase is produced by Chinese hamster ovary cell line GA-ATB-200 or ATB-200-001-X5-14 or a subculture thereof. 
     
     
         8 . The method according to  claim 1  wherein the recombinant human acid α-glucosidase is administered intravenously at a dose of about 5 mg/kg to about 20 mg/kg and the miglustat is administered orally at a dose of about 200 mg to about 600 mg. 
     
     
         9 . The method according to  claim 8  wherein the miglustat is administered prior to administration of the recombinant human acid α-glucosidase. 
     
     
         10 . The method according to  claim 9  wherein the miglustat is administered about one hour prior to administration of the recombinant human acid α-glucosidase. 
     
     
         11 . The method according to  claim 1  wherein the recombinant human acid α-glucosidase is administered intravenously at a dose of about 5 mg/kg to about 20 mg/kg and the miglustat is administered orally at a dose of about 233 mg to about 500 mg. 
     
     
         12 . The method according to  claim 1  wherein the recombinant human acid α-glucosidase is administered intravenously at a dose of about 5 mg/kg to about 20 mg/kg and the miglustat is administered orally at a dose of about 50 mg to about 200 mg. 
     
     
         13 . The method according to  claim 1  wherein the recombinant human acid α-glucosidase is administered intravenously at a dose of about 20 mg/kg and the miglustat is administered orally at a dose of about 260 mg. 
     
     
         14 . The method according to  claim 13  wherein the miglustat is administered prior to administration of the recombinant human acid α-glucosidase. 
     
     
         15 . The method according to  claim 14  wherein the miglustat is administered about one hour prior to administration of the recombinant human acid α-glucosidase. 
     
     
         16 . A kit for combination therapy of Pompe disease in a patient in need thereof, the kit including a pharmaceutically acceptable dosage form comprising miglustat, a pharmaceutically acceptable dosage form comprising a recombinant human acid α-glucosidase, and instructions for administering the pharmaceutically acceptable dosage form comprising miglustat and the pharmaceutically acceptable dosage form comprising the recombinant acid α-glucosidase to a patient in need thereof;
 wherein the recombinant acid α-glucosidase is expressed in Chinese hamster ovary (CHO) cells and comprises an increased content of N-glycan units bearing one or two mannose-6-phosphate residues when compared to a content of N-glycan units bearing one or two mannose-6-phosphate residues of alglucosidase alfa. 
 
     
     
         17 . The kit according to  claim 16  wherein the pharmaceutically acceptable dosage form comprising the recombinant human acid α-glucosidase is configured for intravenous administration at a dose of about 5 mg/kg to about 20 mg/kg and pharmaceutically acceptable dosage form comprising miglustat comprises a dose of about 200 mg to about 600 mg and is configured for oral administration. 
     
     
         18 . The kit according to  claim 17  wherein the instructions comprise instructions to administer the miglustat about one hour prior to administration of the recombinant human acid α-glucosidase. 
     
     
         19 . The kit according to  claim 16  wherein the pharmaceutically acceptable dosage form comprising the recombinant human acid α-glucosidase is configured for intravenous administration at a dose of about 5 mg/kg to about 20 mg/kg and the pharmaceutically acceptable dosage form comprising miglustat comprises a dose of about 50 mg to about 200 mg and is configured for oral administration. 
     
     
         20 . The kit according to  claim 16  wherein the pharmaceutically acceptable dosage form comprising the recombinant human acid α-glucosidase is configured for intravenous administration at a dose of about 20 mg/kg and the pharmaceutically acceptable dosage form comprising miglustat comprises a dose of about 260 mg and is configured for oral administration. 
     
     
         21 . The kit according to  claim 20  wherein the instructions comprise instructions to administer the pharmaceutically acceptable dosage form comprising miglustat about one hour prior to administration of the pharmaceutically acceptable dosage form comprising the recombinant human acid α-glucosidase.