Claims for Patent: 10,792,279

Summary for Patent: 10,792,279

Title:	Methods of treating Fabry patients having renal impairment
Abstract:	Provided are methods for treatment of Fabry disease in patients having HEK assay amenable mutations in α-galactosidase A. Certain methods comprise administering migalastat or a salt thereof every other day, such as administering about 150 mg of migalastat hydrochloride every other day.
Inventor(s):	Jeff Castelli, Elfrida Benjamin
Assignee:	Bpcr LP , Amicus Therapeutics Inc
Application Number:	US16/817,927
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 10,792,279
Patent Claims:	1. A method of stabilizing renal function in enzyme replacement therapy (ERT)-experienced patients diagnosed with Fabry disease and having mild renal impairment with an eGFR of 60 to 90 mL/min/1.73 m2, the method comprising: administering, to a group of Fabry disease patients having mild renal impairment and a HEK assay amenable α-galactosidase A mutation, about 100 mg to about 150 mg free base equivalent (FBE) of migalastat at a frequency of once every other day; wherein the administration is effective to (i) reduce mean globotriaosylceramide (GL-3) accumulated in an organ of the patients, (ii) reduce mean plasma globotriaosylsphingosine (lyso-Gb3) in the patients, (iii) increase mean white blood cell (WBC) α-galactosidase A activity in the patients, (iv) reduce mean left ventricular mass index (LVMi) in the patients, and (v) stabilize mean renal function in the patients; and wherein administration of a single dose of the migalastat to the patients is effective to provide (i) a mean plasma migalastat increase in AUC0−∞of about 1.2-fold compared to healthy control subjects, and (ii) no increase in mean plasma migalastat Cmax compared to healthy control subjects. 2. The method of claim 1, wherein the administration is effective to provide a mean reduction in kidney interstitial capillary GL-3 inclusions of about 0.30. 3. The method of claim 1, wherein the administration is effective to provide a mean reduction in plasma lyso-Gb3 of about 7.7 nmol/L. 4. The method of claim 1, wherein the administration is effective to provide a mean increase in WBC α-galactosidase A activity of about 1.6 4MU/hr/mg. 5. The method of claim 1, wherein the administration is effective to provide a mean reduction in LVMi of about 9.2 g/m2. 6. The method of claim 1, wherein the administration is effective to provide a mean annualized rate of change in eGFRCKD-EPI of greater than −1.0 mL/min/1.73 m2. 7. The method of claim 1, wherein administration is effective to provide (i) a mean reduction in kidney interstitial capillary GL-3 inclusions of about 0.30, (ii) a mean reduction in plasma lyso-Gb3 of about 7.7 nmol/L, (iii) a mean increase in WBC α-galactosidase A activity of about 1.6 4MU/hr/mg, (iv) a mean reduction in LVMi of about 9.2 g/m2, and (v) a mean annualized rate of change in eGFRCKD-EPI of greater than −1.0 mL/min/1.73 m2. 8. The method of claim 7, wherein the administration is effective to reduce mean globotriaosylceramide (GL-3) accumulated in the patients' kidneys and hearts. 9. The method of claim 7, wherein the patients have a proteinuria level of less than 100 mg/24 hr prior to initiating the administration of the migalastat. 10. The method of claim 7, wherein the patients have a proteinuria level of 100 to 1,000 mg/24 hr prior to initiating the administration of the migalastat. 11. The method of claim 7, wherein the patients have a proteinuria level of greater than 1,000 mg/24 hr prior to initiating the administration of the migalastat. 12. The method of claim 7, comprising orally administering about 150 mg of migalastat hydrochloride for at least 28 days, wherein the migalastat hydrochloride is in solid dosage form. 13. The method of claim 7, herein the HEK assay amenable mutation is a mutation that, when the mutation is expressed in HEK-293 cells incubated in the presence of 10 μM migalastat compared to HEK-293 cells without migalastat, is shown to have (1) a relative increase of at least 20% α-galactosidase A activity and (2) an absolute increase of at least 3% of the wild-type α-galactosidase A activity. 14. The method of claim 1, wherein the migalastat is administered as migalastat free base. 15. The method of claim 1, wherein the migalastat is administered as a pharmaceutically acceptable salt. 16. A method of stabilizing renal function in patients diagnosed with Fabry disease and having moderate renal impairment with an eGFR of 30 to 59 mL/min/1.73 m2, the method comprising: administering, to a group of Fabry disease patients having moderate renal impairment and a HEK assay amenable α-galactosidase A mutation, about 100 mg to about 150 mg free base equivalent (FBE) of migalastat at a frequency of once every other day; wherein the administration is effective to (i) reduce mean globotriaosylceramide (GL-3) accumulated in an organ of the patients, (ii) reduce mean plasma globotriaosylsphingosine (lyso-Gb3) in the patients, (iii) increase mean white blood cell (WBC) α-galactosidase A activity in the patients, (iv) reduce mean left ventricular mass index (LVMi) in the patients, and (v) stabilize mean renal function in the patients; and wherein administration of a single dose of the migalastat to the patients is effective to provide (i) a mean plasma migalastat increase is AUC0−∞ of about 1.8-fold compared to healthy control subjects, and (ii) no increase in mean plasma migalastat Cmax compared to healthy control subjects. 17. The method of claim 16, wherein the patients are enzyme replacement therapy (ERT)-experienced patients. 18. The method of claim 16, wherein the administration is effective to provide a mean reduction in kidney interstitial capillary GL-3 inclusions of about 0.39. 19. The method of claim 16, wherein the administration is effective to provide a mean reduction in plasma lyso-Gb3 of about 29.0 nmol/L. 20. The method of claim 16, wherein the administration is effective to provide a mean increase in WBC α-galactosidase A activity of about 1.4 4MU/hr/mg. 21. The method of claim 16, wherein the administration is effective to provide a mean reduction in LVMi of about 5.5 g/m2. 22. The method of claim 16, wherein the administration is effective to provide a mean annualized rate of change in eGFRCKD-EPI of greater than −1.0 mL/min/1.73 m2. 23. The method of claim 16, wherein administration is effective to provide (i) a mean reduction in kidney interstitial capillary GL-3 inclusions of about 0.39, (ii) a mean reduction in plasma lyso-Gb3 of about 29.0 nmol/L, (iii) a mean increase in WBC α-galactosidase A activity of about 1.4 4MU/hr/mg, (iv) a mean reduction in LVMi of about 5.5 g/m2, and (v) a mean annualized rate of change in eGFRCKD-EPI of greater than −1.0 mL/min/1.73 m2. 24. The method of claim 23, wherein the administration is effective to reduce mean globotriaosylceramide (GL-3) accumulated in the patients' kidneys and hearts. 25. The method of claim 23, wherein the patients have a proteinuria level of less than 100 mg/24 hr prior to initiating the administration of the migalastat. 26. The method of claim 23, wherein the patients have a proteinuria level of 100 to 1,000 mg/24 hr prior to initiating the administration of the migalastat. 27. The method of claim 23, wherein the patients have a proteinuria level of greater than 1,000 mg/24 hr prior to initiating the administration of the migalastat. 28. The method of claim 23, comprising orally administering about 150 mg of migalastat hydrochloride for at least 28 days, wherein the migalastat hydrochloride is in solid dosage form. 29. The method of claim 23, wherein the HEK assay amenable mutation is a mutation that, when the mutation is expressed in HEK-293 cells incubated in the presence of 10 μM migalastat compared to HEK-293 cells without migalastat, is shown to have (1) a relative increase of at least 20% α-galactosidase A activity and (2) an absolute increase of at least 3% of the wild-type α-galactosidase A activity. 30. The method of claim 16, wherein the migalastat is administered as migalastat free base. 31. The method of claim 16, wherein the migalastat is administered as a pharmaceutically acceptable salt. 32. A method of stabilizing renal function in patients diagnosed with Fabry disease and having severe renal impairment with an eGFR less than 30 mL/min/1.73 m2, the method comprising: administering, to a group of Fabry disease patients having severe renal impairment and a HEK assay amenable α-galactosidase A mutation, about 100 mg to about 150 mg free base equivalent (FBE) of migalastat at a frequency of once every other day; wherein the administration is effective to (i) reduce mean globotriaosylceramide (GL-3) accumulated in an organ of the patients, (ii) reduce mean plasma globotriaosylsphingosine (lyso-Gb3) in the patients, (iii) increase mean white blood cell (WBC) α-galactosidase A activity in the patients, (iv) reduce mean left ventricular mass index (LVMi) in the patients, and (v) stabilize mean renal function in the patients; and wherein administration of a single dose of the migalastat to the patients is effective to provide (i) a mean plasma migalastat increase in AUC0−∞ of about 4.5-fold compared to healthy control subjects, and (ii) no increase in mean plasma migalastat Cmax compared to healthy control subjects. 33. The method of claim 32, wherein the patients are enzyme replacement therapy (ERT)-experienced patients. 34. The method of claim 32, wherein the administration is effective to reduce mean globotriaosylceramide (GL-3) accumulated in the patients' kidneys and hearts. 35. The method of claim 32, wherein the patients have a proteinuria level of less than 100 mg/24 hr prior to initiating the administration of the migalastat. 36. The method of claim 32, wherein the patients have a proteinuria level of 100 to 1,000 mg/24 hr prior to initiating the administration of the migalastat. 37. The method of claim 32, wherein the patients have a proteinuria level of greater than 1,000 mg/24 hr prior to initiating the administration of the migalastat. 38. The method of claim 32, comprising orally administering about 150 mg of migalastat hydrochloride for at least 28 days, wherein the migalastat hydrochloride is in solid dosage form. 39. The method of claim 32, wherein the HEK assay amenable mutation is a mutation that, when the mutation is expressed in HEK-293 cells incubated in the presence of 10 μM migalastat compared to HEK-293 cells without migalastat, is shown to have (1) a relative increase of at least 20% α-galactosidase A activity and (2) an absolute increase of at least 3% of the wild-type α-galactosidase A activity. 40. The method of claim 32, wherein the migalastat is administered as migalastat free base. 41. The method of claim 32, wherein the migalastat is administered as a pharmaceutically acceptable salt.