THERAPEUTIC TYROSINE KINASE INHIBITORS FOR RELAPSING MULTIPLE SCLEROSIS (RMS)

Abstract

This description refers to the field of therapeutic tyrosine kinase inhibitors, in particular to Bruton's tyrosine kinase ("BTK") inhibitors for the treatment of subjects with relapsing multiple sclerosis.

Claims

1. CLAIMS A method of treating relapsing multiple sclerosis (RMS), comprising administering to a subject in need of a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin3-1)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pridin-2(3H)-one.

2. A method for reducing the number of new gadolinium (Gd)-enhancing T1 hyperintense lesions, comprising administering to a subject in need and having relapsing multiple sclerosis (RMS) a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridine-2(3H)-one.

3. A method for reducing the number of new or increasing T2 lesions, comprising administering to a subject in need and having relapsing multiple sclerosis (RMS) a BTK inhibitor comprising (R)-1-(1-acryloylpyrididin-3-1)-4-amino-3-(4-phenoxypheni)-1Himidazo[4,5-c]pyridin-2(3H)-one.

4. A method for reducing the total number of gadolinium (Gd)-enhancing T1 hyperintense lesions, comprising administering to a subject in need and having relapsing multiple sclerosis (RMS) a BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridine-2(3H)-one.

5. A method for reducing the relapse rate in a subject having multiple sclerosis (MS), comprising administering to the subject in need a BTK inhibitor comprising (R)-1 (1-acryloylpyrididin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.

6. The method according to any one of claims 1 to 5, wherein a dose of approximately 5 mg to approximately 60 mg of the BTK inhibitor is administered.

7. The method according to any one of claims 1 to 6, wherein the dose is 5 mg.

8. The method according to any one of claims 1 to 6, wherein the dose is 15 mg.

9. The method according to any one of claims 1 to 6, wherein the dose is 30 mg.

10. The method according to any one of claims 1 to 6, wherein the dose c? oonn / zznz / E / YiAi is 60 mg.

11. The method according to any one of claims 1 to 10, wherein the administration of the BTK inhibitor inhibits the formation of new active brain lesions as measured by MRI.

12. The method according to any one of claims 1 to 11, wherein the dose is once a day.

13. The method according to any one of claims 1 to 12, wherein the dose is administered once a day with food.

14. The method according to any one of claims 1 to 6, 8, 11 to 12, wherein the 15 mg dose is administered once daily with food. 119 15. The method according to any one of claims 1 to 6, 9, 11 to 12, wherein the 30 mg dose is administered once a day with food.

16. The method according to any one of claims 1 to 6 and 10 to 12, wherein the 60 mg dose is administered once a day with food.

17. The method according to any one of claims 1 to 16, wherein administration of the BTK inhibitor reduces the expression of RGS1 in a brain cell.

18. The method according to claim 17, wherein the brain cell comprises microglia.

19. The method according to any one of claims 1 to 18, wherein administration of the BTK inhibitor reduces the number of new gadolinium (Gd)-enhancing T1 hyperintense lesions as measured by MRI.

20. The method according to claim 19, wherein the number of new Gd-enhancing T1 hyperintense lesions is less than 1.

21. The method according to claim 19, wherein no new Gd-enhancing T1 hyperintense lesions are formed after 12 weeks of BTK inhibitor treatment.

22. The method according to any one of claims 1-2 or 4-21, wherein administration of the BTK inhibitor reduces the number of new or enlarging T2 lesions as measured by MRI.

23. The method according to claim 22, wherein the number of new or enlarging T2 lesions is equal to or less than 2.

24. The method according to claim 22, wherein no new or enlarging T2 lesions are formed after 12 weeks of treatment with a BTK inhibitor.

25. The method according to any one of claims 1 to 3 or 5 to 24, wherein administration of the BTK inhibitor reduces the total number of Gd-enhancing T1 hyperintense lesions after 12 weeks of BTK inhibitor treatment.

26. The method according to any one of claims 1 to 5 or 16 to 25, wherein the dose is 60 mg, and wherein one or zero new Gd-enhancing T1 hyperintense lesions are formed after 12 weeks of BTK inhibitor treatment.

27. The method according to claim 26, wherein zero new Gd-enhancing T1 hyperintense lesions are formed after 12 weeks of BTK inhibitor treatment.

28. The method according to any one of claims 1 to 5 or 16 to 27, wherein the dose is 60 mg, and wherein the number of new or enlarging T2 lesions is equal to or less than 2 after 12 weeks of BTK inhibitor treatment.

29. The method according to any one of claims 1 to 5 or 16 to 28, wherein the dose is 60 mg, and wherein administration of the BTK inhibitor reduces the total number of Gd-enhancing T1 hyperintense lesions after 12 weeks of BTK inhibitor treatment.

30. The method according to any one of claims 1 to 29, wherein the BTK inhibitor compound is administered as monotherapy. ci oonn / zznz / E / YiAi 120 31. The method according to any one of claims 1 to 30, wherein MRD is selected from clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and relapsing-progressive secondary multiple sclerosis (RPMS).

32. The method according to any one of claims 1 to 31, wherein the subject is a human being.

33. A method of treating relapsing multiple sclerosis (RMS), comprising administering to a subject in need 60 mg of a BTK inhibitor comprising (R)-1-(1acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one, wherein no new Gd-enhancing T1 hyperintense lesions are formed after 12 weeks of BTK administration.

34. A BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one for use in a method of treating relapsing multiple sclerosis (RMS) in a subject in need.

35. A BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]p!hd!n-2(3H)-one for use in a method for reducing the number of new or increasing T2 lesions in a subject having relapsing multiple sclerosis (RMS).

36. A BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one for use in a method for reducing the total number of gadolinium (Gd)-enhancing T1 hyperintense lesions in a subject having relapsing multiple sclerosis (RMS).

37. A BTK inhibitor comprising (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one for use in a method for reducing the relapse rate in a subject having multiple sclerosis (MS).