Therapeutic tyrosine kinase inhibitors for relapsing multiple sclerosis (RMS)
This disclosure relates to the field of therapeutic tyrosine kinase inhibitors, in particular Bruton tyrosine kinase (“BTK”) inhibitors for treatment of subjects with relapsing multiple sclerosis.
1. A method of reducing the number of new gadolinium (Gd)-enhancing T1 hyperintense lesions, comprising administering to a human subject in need thereof that has relapsing multiple sclerosis (RMS) an effective amount of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.
2. The method of claim 1 , wherein the effective amount is a dose of about 5 mg to about 60 mg of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one.
3. The method of claim 2 , wherein the dose is 5 mg.
4. The method of claim 2 , wherein the dose is 15 mg.
5. The method of claim 2 , wherein the dose is 30 mg.
6. The method of claim 2 , wherein the dose is 60 mg.
7. The method of claim 1 , wherein administration of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one inhibits the formation of new active brain lesions as measured by MRI.
8. The method of claim 2 , wherein the dose is once daily.
9. The method of claim 2 , wherein the dose is administered once daily with food.
10. The method of claim 1 , wherein administration of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one reduces RGS1 expression in a brain cell.
11. The method of claim 1 , wherein administration of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one reduces the number of new gadolinium (Gd)-enhancing T1 hyperintense lesions as measured by MRI.
12. The method of claim 11 , wherein the number of new Gd-enhancing T1 hyperintense lesions is less than 1.
13. The method of claim 11 , wherein no new Gd-enhancing T1 hyperintense lesions are formed after 12 weeks of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one treatment.
14. The method of claim 1 , wherein administration of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one reduces the number of new or enlarging T2 lesions as measured by MRI.
15. The method of claim 14 , wherein the number of new or enlarging T2 lesions is equal to or less than 2.
16. The method of claim 1 , wherein administration of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one reduces the total number of Gd-enhancing T1-hyperintense lesions after 12 weeks of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one treatment.
17. The method of claim 2 , wherein the dose is 60 mg, and wherein one or zero new Gd-enhancing T1 hyperintense lesion is formed after 12 weeks of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one treatment.
18. The method of claim 2 , 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 (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one treatment.
19. The method of claim 2 , wherein the dose is 60 mg, and wherein the administration of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one reduces the total number of Gd-enhancing T1-hyperintense lesions after 12 weeks of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one treatment.
20. The method of claim 1 , wherein (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered as monotherapy.
21. The method of claim 1 , wherein RMS is chosen from clinically isolated syndrome (CIS), relapsing remitting multiple sclerosis (RRMS), and relapsing secondary progressive multiple sclerosis (R-SPMS).
22. The method of claim 6 , wherein administration of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one inhibits the formation of new active brain lesions as measured by MRI.
23. The method of claim 6 , wherein the dose is once daily.
24. The method of claim 6 , wherein the dose is administered once daily with food.
25. The method of claim 6 , wherein administration of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one reduces RGS1 expression in a brain cell.
26. The method of claim 6 , wherein administration of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one reduces the number of new gadolinium (Gd)-enhancing T1 hyperintense lesions as measured by MRI.
27. The method of claim 6 , wherein administration of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one reduces the total number of Gd-enhancing T1-hyperintense lesions after 12 weeks of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one treatment.
28. The method of claim 6 , wherein (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered as monotherapy.
29. The method of claim 6 , wherein RMS is chosen from clinically isolated syndrome (CIS), relapsing remitting multiple sclerosis (RRMS), and relapsing secondary progressive multiple sclerosis (R-SPMS).
30. The method of claim 22 , wherein the dose is once daily.
31. The method of claim 30 , wherein the dose is administered once daily with food.
32. The method of claim 31 , wherein administration of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one reduces RGS1 expression in a brain cell.
33. The method of claim 31 , wherein administration of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one reduces the number of new gadolinium (Gd)-enhancing T1 hyperintense lesions as measured by MRI.
34. The method of claim 33 , wherein administration of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one reduces the total number of Gd-enhancing T1-hyperintense lesions after 12 weeks of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one treatment.
35. The method of claim 33 , wherein one or zero new Gd-enhancing T1 hyperintense lesion is formed after 12 weeks of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one treatment.
36. The method of claim 31 , wherein (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one is administered as monotherapy.
37. The method of claim 31 , wherein RMS is chosen from clinically isolated syndrome (CIS), relapsing remitting multiple sclerosis (RRMS), and relapsing secondary progressive multiple sclerosis (R-SPMS).