Claims for Patent: 10,857,212

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):	Hung V. Do, Richie Khanna, Russell Gotschall
Assignee:	Amicus Therapeutics Inc
Application Number:	US15/950,347
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, and wherein 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, per mole of rhGAA, 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, per mol of rhGAA, 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, per mol of rhGAA, 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, per mol of rhGAA, about 4 to about 5.4 mol sialic acid. 6. The method according to claim 1, wherein the rhGAA molecules further comprise, per mol of rhGAA, at least about 4 mol sialic acid. 7. The method according to claim 6, wherein the rhGAA molecules further comprise, per mol of rhGAA, 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, per mol of rhGAA, 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, per mol of rhGAA, 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, 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, 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, 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-M6P at the first potential N-glycosylation site, and wherein 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, per mol of rhGAA, at least about 4 mol sialic acid. 16. The composition of claim 14, wherein the rhGAA molecules further comprise, per mol of rhGAA, 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, per mol of rhGAA, 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, per mol of rhGAA, 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, per mol of rhGAA, about 4 to about 5.4 mol sialic acid. 20. The composition of claim 15, wherein the rhGAA molecules further comprise, per mol of rhGAA, 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, per mol of rhGAA, 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, per mol of rhGAA, 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, 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, per mol of rhGAA, 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, per mol of rhGAA, 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, per mol of rhGAA, 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, per mol of rhGAA, about 4 to about 5.4 mol sialic acid. 27. The method according to claim 10, wherein the rhGAA molecules comprise, per mol of rhGAA, 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, per mol of rhGAA, 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, per mol of rhGAA, 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, per mol of rhGAA, about 4 to about 5.4 mol sialic acid. 30. The composition of claim 23, wherein the rhGAA molecules comprise, per mol of rhGAA, 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, per mol of rhGAA, an average of about 0.8 mol bis-M6P at the first potential N-glycosylation site.