Treating seizure with recombinant alkaline phosphatase

Patent metadata

Field	Value
Publication number	US-10449236-B2
Application number	US-201515532203-A
Country	US
Kind code	B2
Filing date	Dec 4, 2015
Priority date	Dec 5, 2014
Publication date	Oct 22, 2019
Grant date	Oct 22, 2019

Abstract

The present disclosure provides a method of treating seizure in a subject having aberrant alkaline phosphatase activities, comprising administering a therapeutically effective amount of at least one recombinant alkaline phosphatase to the subject.

First claim

What is claimed is:

1. A method of treating seizure in a human subject having aberrant levels of at least one alkaline phosphatase substrate selected from pyridoxal 5′-phosphate (PLP), inorganic pyrophosphate (PPi), and phosphoethanolamine (PEA), comprising administering a therapeutically effective amount of a recombinant alkaline phosphatase to the subject, wherein the subject has been determined to be nonresponsive to vitamin B6 treatment for the seizure.

2. The method of claim 1 , further comprising:
(i) identifying a population of subjects with aberrant alkaline phosphatase activities who suffer, or are at risk to suffer, from seizure; or
(ii) identifying a population of subjects with above-normal levels of at least one alkaline phosphatase substrate who suffer, or are at risk to suffer, from seizure.

3. The method of claim 1 , wherein the human subject has been diagnosed with hypophosphatasia (HPP) and wherein the human subject has minor or non-detectable bone mineralization defects.

4. The method of claim 1 , wherein the human subject has not been diagnosed with HPP.

5. The method of claim 1 , wherein the human subject has:
a) increased serum pyridoxal 5′-phosphate (PLP);
b) reduced intracellular pyridoxal 5′-phosphate (PLP);
c) at least one of reduced brain Gamma-Aminobutyric Acid (GABA) and reduced brain serine; or
d) at least one of increased brain and urinary cystathionine.

6. The method of claim 1 , wherein the recombinant alkaline phosphatase is administered to the human subject:
a) daily for at least one week, one month, three months, six months, or one year;
b) in conjunction with the at least one additional therapeutic agent; or
c) in a dosage from about 0.1 mg/kg/day to about 20 mg/kg/day, or a comparable weekly dosage.

7. The method of claim 1 , wherein administration of the recombinant alkaline phosphatase elevates brain GABA.

8. The method of claim 6 , wherein the at least one additional therapeutic agent is an anti-seizure drug or at least one of vitamin B6 (pyridoxine) and a vitamin B6 vitamer.

9. The method of claim 6 , further comprising:
i) maintaining co-administration of the at least one additional therapeutic agent with the recombinant alkaline phosphatase for a pre-determined time; and
ii) withdrawing administration of the at least one additional therapeutic agent while maintaining administration of the recombinant alkaline phosphatase to the human subject.

10. The method of claim 8 , wherein the anti-seizure drug and the recombinant alkaline phosphatase are co-administered to the human subject for at least one month, at least six months, or at least one year.

11. The method of claim 1 , wherein the recombinant alkaline phosphatase:
a) comprises at least one of a tissue nonspecific alkaline phosphatase (TNALP), a placental alkaline phosphatase (PALP), a germ cell alkaline phosphatase (GCALP), or an intestinal alkaline phosphatase (IALP);
b) comprises an amino acid sequence of SEQ ID NO: 2;
c) is a fusion protein;
d) is fused to an immunoglobulin molecule or a negatively charged peptide; or
e) comprises sALP-Fc-D10, wherein the sALP is a soluble form of the recombinant alkaline phosphatase, the Fc is a fragment crystallizable region (Fc), and the D10 comprises ten polyaspartate residues.

12. The method of claim 11 , wherein the immunoglobulin molecule is a fragment crystallizable region (Fc).

13. The method of claim 12 , wherein the Fc comprises an amino acid sequence of SEQ ID NO: 3.

14. The method of claim 11 , wherein the negatively charged peptide is at least one of D10, D16, E10, and E16.

15. The method of claim 11 , wherein the recombinant alkaline phosphatase comprises an amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 4.

16. The method of claim 6 , wherein the recombinant alkaline phosphatase is administered in a dosage from about 0.5 mg/kg/day to about 5 mg/kg/day, or a comparable weekly dosage.

17. The method of claim 6 , wherein the recombinant alkaline phosphatase is administered in a dosage from about 0.1 mg/kg/day to about 1 mg/kg/day, or a comparable weekly dosage.

18. The method of claim 1 , wherein the recombinant alkaline phosphatase is administered by at least one of intravenous, intramuscular, subcutaneous, sublingual, intrathecal, and intradermal route.

19. The method of claim 18 , wherein the recombinant alkaline phosphatase is administered intravenously.

20. The method of claim 19 , wherein the recombinant alkaline phosphatase is administered intravenously and then subcutaneously.

Assignees

• Alexion Pharma Inc

Inventors

• Marozsan Andre
• Devore Denise
• Liu-Chen Susan

Classifications

• A61P43/00

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

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title

• A61P19/08

  for bone diseases, e.g. rachitism, Paget's disease · CPC title

• A61P19/00

  Drugs for skeletal disorders · CPC title

• A61K38/465 Primary

  acting on ester bonds (3.1), e.g. lipases, ribonucleases · CPC title