Augmented acid alpha-glucosidase for the treatment of Pompe disease

Patent metadata

Field	Value
Publication number	US-12414985-B2
Application number	US-202217699927-A
Country	US
Kind code	B2
Filing date	Mar 21, 2022
Priority date	Dec 30, 2015
Publication date	Sep 16, 2025
Grant date	Sep 16, 2025

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 recombinant human acid α-glucosidase, wherein the recombinant human 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 and wherein the recombinant human acid α-alglucosidase comprises a sequence at least 95% identical to SEQ ID NO: 1 or SEQ ID NO: 5, wherein the recombinant human acid α-glucosidase is administered intravenously at a dose of about 5 mg/kg to about 20 mg/kg every week or every other week and the miglustat is administered orally at a dose of about 200 mg to about 600 mg every week or every other week.

2. 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.

3. 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.

4. 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.

5. 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.

6. The method according to claim 1 wherein the miglustat is administered prior to administration of the recombinant human acid α-glucosidase.

7. The method according to claim 6 wherein the miglustat is administered about one hour prior to administration of the recombinant human acid α-glucosidase.

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 every other week and the miglustat is administered orally at a dose of about 233 mg to about 500 mg every other week.

9. 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 every other week and the miglustat is administered orally at a dose of about 50 mg to about 200 mg every other week.

10. The method according to claim 1 wherein the recombinant human acid α-glucosidase is administered intravenously at a dose of about 20 mg/kg every other week and the miglustat is administered orally at a dose of about 260 mg every other week.

11. The method according to claim 10 wherein the miglustat is administered prior to administration of the recombinant human acid α-glucosidase.

12. The method according to claim 11 wherein the miglustat is administered about one hour prior to administration of the recombinant human acid α-glucosidase.

13. The method according to claim 1 wherein the recombinant human acid α-glucosidase has a shorter half-life than alglucosidase alfa in the plasma of the patient.

14. The method according to claim 13 wherein the half-life of recombinant human acid α-glucosidase is 20-30% shorter than alglucosidase alfa in the plasma of the patient.

15. The method according to claim 13 wherein the half-life of recombinant human acid α-glucosidase is about 25% shorter than alglucosidase alfa in the plasma of the patient.

16. The method according to claim 1 wherein the recombinant human acid α-glucosidase on average has at least one more mole of N-glycan units bearing two mannose-6-phosphate residues per compared to alglucosidase alfa.

17. The method according to claim 1 wherein the recombinant human acid α-glucosidase on average has about 1.2 more moles of N-glycan units bearing two mannose-6-phosphate residues per compared to alglucosidase alfa.

18. The method according to claim 1 wherein the recombinant human acid α-glucosidase induces a lower incidence of anti-drug antibodies than alglucosidase alfa in the patient.

19. The method according to claim 1 wherein the recombinant human acid α-glucosidase reduces glycogen in muscle tissues more effectively than alglucosidase alfa.

20. The method according to claim 19 wherein the recombinant human acid α-glucosidase is administered at a dose of 10-20 mg/kg every other week.

21. The method according to claim 1 wherein the recombinant human acid α-glucosidase reduces vacuoles in muscle fibers more effectively than alglucosidase alfa.

22. The method according to claim 1 wherein the recombinant human acid α-glucosidase clears lysosomal glycogen more effectively than alglucosidase alfa in the patient.

23. The method according to claim 1 wherein the recombinant human acid α-glucosidase increases muscle function more efficiently than alglucosidase alfa.

24. The method according to claim 1 wherein the recombinant human acid α-glucosidase internalizes into muscle fibroblasts more efficiently than alglucosidase alfa.

25. The method according to claim 1 wherein the recombinant human acid α-glucosidase reduces lysosomal proliferation more efficiently than alglucosidase alfa.

26. The method according to claim 1 wherein the recombinant human acid α-glucosidase binds cation-independent mannose-6-phosphate receptor to a greater degree than alglucosidase alfa.

27. The method according to claim 26 wherein at least about 43% more of the recombinant human acid α-glucosidase binds cation-independent mannose-6-phosphate receptor than alglucosidase alfa.

28. The method according to claim 1 , wherein at least 3% of the total glycans on the recombinant human acid α-glucosidase are bis-M6P glycans.

29. The method according to claim 1 wherein the recombinant human acid α-glucosidase comprises on average at least 1 mol bis-M6P per mol recombinant human acid α-glucosidase.

30. The method according to claim 1 wherein the recombinant human acid α-glucosidase comprises on average 1.3 mol bis-M6P per mol recombinant human acid α-glucosidase.

31. The method according to claim 1 wherein at least 17% of the total glycans on the recombinant human acid α-glucosidase are bis-M6P.

32. The method according to claim 1 wherein 3% to 25% of the total glycans on the recombinant human acid α-glucosidase are bis-M6P.

33. The method according to claim 1 wherein 17% to 25% of the total glycans on the recombi

Assignees

• Amicus Therapeutics Inc

Inventors

• Do Hung V
• Khanna Richie
• Gotschall Russell

Classifications

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C12Y302/0102

  Alpha-glucosidase (3.2.1.20) · 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