Augmented acid alpha-glucosidase for the treatment of Pompe disease

Patent metadata

Field	Value
Publication number	US-10857212-B2
Application number	US-201815950347-A
Country	US
Kind code	B2
Filing date	Apr 11, 2018
Priority date	Dec 30, 2015
Publication date	Dec 8, 2020
Grant date	Dec 8, 2020

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.

First claim

The invention claimed is:

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 , whe

Assignees

• Amicus Therapeutics Inc

Inventors

• Do Hung V
• Khanna Richie
• Gotschall Russell

Classifications

• C12Y302/0102

  Alpha-glucosidase (3.2.1.20) · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K38/47 Primary

  acting on glycosyl compounds (3.2), e.g. cellulases, lactases · CPC title

• A61K31/445

  Non condensed piperidines, e.g. piperocaine · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title