Claims for Patent: 10,857,212
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Summary for Patent: 10,857,212
Title: | 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. |
Inventor(s): | Do Hung V., Khanna Richie, Gotschall Russell |
Assignee: | Amicus Therapeutics, Inc. |
Application Number: | US15950347 |
Patent Claims: | 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 composition comprising recombinant human acid α-glucosidase (rhGAA) molecules produced in Chinese hamster ovary (CHO) cells;wherein the rhGAA molecules comprise first, second, third, fourth, fifth, sixth, and seventh potential N-glycosylation sites at amino acid positions corresponding to N84, N177, N334, N414, N596, N826, and N869 of SEQ ID NO: 5, respectively;wherein 40%-60% of the N-glycans on the rhGAA molecules are complex type N-glycans;wherein the rhGAA molecules comprise, per mol of rhGAA, an average of at least about 0.5 mol bis-mannose-6-phosphate (bis-M6P) at the first potential N-glycosylation site, andwherein the rhGAA molecules comprise a sequence at least 95% identical to SEQ ID NO: 1 or SEQ ID NO: 5.2. The method according to claim 1 , wherein the rhGAA molecules further comprise claim 1 , per mole of rhGAA claim 1 , an average of about 0.4 to about 0.6 mol mono-mannose-6-phosphate (mono-M6P) at the second potential N-glycosylation site.3. The method according to claim 1 , wherein the rhGAA molecules further comprise claim 1 , per mol of rhGAA claim 1 , an average of about 0.4 to about 0.6 mol bis-M6P at the fourth potential N-glycosylation site.4. The method according to claim 1 , wherein the rhGAA molecules further comprise claim 1 , per mol of rhGAA claim 1 , an average of about 0.3 to about 0.4 mol mono-M6P at the fourth potential N-glycosylation site.5. The method according to claim 1 , wherein the rhGAA molecules further comprise claim 1 , per mol of rhGAA claim 1 , about 4 to about 5.4 mol sialic acid.6. The method according to claim 1 , wherein the rhGAA molecules further comprise claim 1 , per mol of rhGAA claim 1 , at least about 4 mol sialic acid.7. The method according to claim 6 , wherein the rhGAA molecules further comprise claim 6 , per mol of rhGAA claim 6 , an average of about 0.9 to about 1.2 mol sialic acid at the third potential N-glycosylation site.8. The method according to claim 6 , wherein the rhGAA molecules further comprise claim 6 , per mol of rhGAA claim 6 , an average of about 0.8 to about 0.9 mol sialic acid at the fifth potential N-glycosylation site.9. The method according to claim 6 , wherein the rhGAA molecules further comprise claim 6 , per mol of rhGAA claim 6 , an average of about 1.5 to about 1.8 mol sialic acid at the sixth potential N-glycosylation site.10. The method according to claim 1 , wherein the rhGAA molecules further comprise claim 1 , per mol of rhGAA:(a) an average of about 0.4 to about 0.6 mol mono-M6P at the second potential N-glycosylation site;(b) an average of about 0.9 to about 1.2 mol sialic acid at the third potential N-glycosylation site;(c) an average of about 0.4 to about 0.6 mol bis-M6P at the fourth potential N-glycosylation site;(d) an average of about 0.3 to about 0.4 mol mono-M6P at the fourth potential N-glycosylation site; and(e) an average of about 0.8 to about 0.9 mol sialic acid at the fifth potential N-glycosylation site.11. The method according to claim 1 , wherein the composition 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 260 mg or about 130 mg.12. The method according to claim 11 , wherein the composition is administered for approximately four hours claim 11 , starting about one hour after the oral administration of miglustat.13. The method according to claim 12 , wherein the patient fasts for at least two hours before and at least two hours after the oral administration of miglustat.14. A composition comprising recombinant human acid α-plucosidase (rhGAA) molecules produced in Chinese hamster ovary (CHO) cells claim 12 , wherein the rhGAA molecules comprise first claim 12 , second claim 12 , third claim 12 , fourth claim 12 , fifth claim 12 , sixth claim 12 , and seventh potential N-glycosylation sites at amino acid positions corresponding to N84 claim 12 , N177 claim 12 , N334 claim 12 , N414 claim 12 , N596 claim 12 , N826 claim 12 , and N869 of SEQ ID NO: 5 claim 12 , respectively;wherein 40%-60% of the N-glycans on the rhGAA molecules are complex type N-glycans;wherein the rhGAA molecules comprise, per mol of rhGAA, an average of at least about 0.5 mol bis-M6P at the first potential N-glycosylation site, andwherein the rhGAA molecules comprise a sequence at least 95% identical to SEQ ID NO: 1 or SEQ ID NO: 5.15. The composition of claim 14 , wherein the rhGAA molecules further comprise claim 14 , per mol of rhGAA claim 14 , at least about 4 mol sialic acid.16. The composition of claim 14 , wherein the rhGAA molecules further comprise claim 14 , per mol of rhGAA claim 14 , an average of about 0.4 to about 0.6 mol mono-M6P at the second potential N-glycosylation site.17. The composition of claim 14 , wherein the rhGAA molecules further comprise claim 14 , per mol of rhGAA claim 14 , an average of about 0.4 to about 0.6 mol bis-M6P at the fourth potential N-glycosylation site.18. The composition of claim 14 , wherein the rhGAA molecules further comprise claim 14 , per mol of rhGAA claim 14 , an average of about 0.3 to about 0.4 mol mono-M6P at the fourth potential N-glycosylation site.19. The composition of claim 14 , wherein the rhGAA molecules further comprise claim 14 , per mol of rhGAA claim 14 , about 4 to about 5.4 mol sialic acid.20. The composition of claim 15 , wherein the rhGAA molecules further comprise claim 15 , per mol of rhGAA claim 15 , an average of about 0.9 to about 1.2 mol sialic acid at the third potential N-glycosylation site.21. The composition of claim 15 , wherein the rhGAA molecules further comprise claim 15 , per mol of rhGAA claim 15 , an average of about 0.8 to about 0.9 mol sialic acid at the fifth potential N-glycosylation site.22. The composition of claim 15 , wherein the rhGAA molecules further comprise claim 15 , per mol of rhGAA claim 15 , an average of about 1.5 to about 1.8 mol sialic acid at the sixth potential N-glycosylation site.23. The composition of claim 14 , wherein the rhGAA molecules further comprise claim 14 , per mol of rhGAA:(a) an average of about 0.4 to about 0.6 mol mono-M6P at the second potential N-glycosylation site;(b) an average of about 0.9 to about 1.2 mol sialic acid at the third potential N-glycosylation site;(c) an average of about 0.4 to about 0.6 mol bis-M6P at the fourth potential N-glycosylation site;(d) an average of about 0.3 to about 0.4 mol mono-M6P at the fourth potential N-glycosylation site; and(e) an average of about 0.8 to about 0.9 mol sialic acid at the fifth potential N-glycosylation site.24. The method according to claim 1 , wherein the rhGAA molecules comprise claim 1 , per mol of rhGAA claim 1 , an average of about 0.8 mol bis-M6P at the first potential N-glycosylation site.25. The composition according to claim 14 , wherein the rhGAA molecules comprise claim 14 , per mol of rhGAA claim 14 , an average of about 0.8 mol bis-M6P at the first potential N-glycosylation site.26. The method according to claim 10 , wherein the rhGAA molecules further comprise claim 10 , per mol of rhGAA claim 10 , an average of about 1.5 to about 1.8 mol sialic acid at the sixth potential N-glycosylation site; and wherein the rhGAA molecules comprise claim 10 , per mol of rhGAA claim 10 , about 4 to about 5.4 mol sialic acid.27. The method according to claim 10 , wherein the rhGAA molecules comprise claim 10 , per mol of rhGAA claim 10 , an average of about 0.8 mol bis-M6P at the first potential N-glycosylation site.28. The method according to claim 26 , wherein the rhGAA molecules comprise claim 26 , per mol of rhGAA claim 26 , an average of about 0.8 mol bis-M6P at the first potential N-glycosylation site.29. The composition of claim 23 , wherein the rhGAA molecules further comprise claim 23 , per mol of rhGAA claim 23 , an average of about 1.5 to about 1.8 mol sialic acid at the sixth potential N-glycosylation site; and wherein the rhGAA molecules comprise claim 23 , per mol of rhGAA claim 23 , about 4 to about 5.4 mol sialic acid.30. The composition of claim 23 , wherein the rhGAA molecules comprise claim 23 , per mol of rhGAA claim 23 , an average of about 0.8 mol bis-M6P at the first potential N-glycosylation site.31. The composition of claim 29 , wherein the rhGAA molecules comprise claim 29 , per mol of rhGAA claim 29 , an average of about 0.8 mol bis-M6P at the first potential N-glycosylation site. |
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