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1. (WO2019028284) THERAPEUTIC REGIMENS FOR TREATMENT OF PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
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Claims

1. A method for treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a complement 5 (CS) inhibitor in combination with a therapeutically effective amount of a complement factor D (CFD) inhibitor;

wherein the CFD inhibitor is selected from a compound of Formula I or Formula Π:


or a pharmaceutically acceptable salt thereof;

wherein:

X is selected from N and CH;

R1 is selected from hydrogen, C1-C3 alkyl, and halogen;

R2 is selected from hydrogen and C1-C3 alkyl;

R3 is selected from hydrogen, C1-C3 alkyl, and halogen;

R4 is selected from hydrogen, C1-C3 alkyl, and halogen; and

R5 is selected from hydrogen, C1-C3 alkyl, halogen, and cyano.

2. The method of claim 1 , wherein the CFD inhibitor is selected from a compound of formula:


4. The method of claim 1, wherein the CFD inhibitor is a compound of the formula:


5. The method of any one of claims 1-4, wherein the CS inhibitor is eculizamab.

6. The method of any one of claims 1-4, wherein the CS inhibitor is selected from a recombinant human minibody, coversin, Tesidolumab/LFG316, ARC-1905, RA101348, RA101495, SOBI002, ARC 1005, a SOMAmer for CS, SSL7, MEDI7814, aurin tricarboxylic acid, an aurin tricarboxylic acid derivative, RG6107/SKYS9, ALXN1210, ALXN5500, TT30, ABP959, Anti-CS siR A, Erdigna, avacincaptad pegol/Zimura®, SOBI00S, ISU30S, and REGN3918.

7. A method for treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a complement factor D (CFD) inhibitor selected from a compound of Formula I or Formula


or a pharmaceutically acceptable salt thereof;

wherein:

X is selected from N and CH;

R1 is selected from hydrogen, C1-C3 alkyl, and halogen;

R2 is selected from hydrogen and C1-C3 alkyl;

R3 is selected from hydrogen, C1-C3 alkyl, and halogen;

R4 is selected from hydrogen, C1-C3 alkyl, and halogen;

R5 is selected from hydrogen, C1-C3 alkyl, halogen, and cyano;

wherein the subject at the time of administration of the CFD inhibitor has been or is currently receiving a therapeutic regimen comprising the administration of a complement 5 (CS) inhibitor; and

wherein the subject is experiencing extravascular hemolysis.

8. The method of claim 7, wherein the CFD inhibitor is selected from a compound of formula:

11. The method of any one of claims 7-10, wherein the C5 inhibitor is eculizamab.

12. The method of any one of claims 7-10, wherein the CS inhibitor is selected from a recombinant human minibody, coversin, Tesidolumab/LFG316, ARC- 1905, RA101348, RA101495, SOBI002, ARC 1005, a SOMAmer for C5, SSL7, MEDI7814, aurin tricarboxylic acid, an aurin tricarboxylic acid derivative, RG6107/SKY59, ALXN1210, ALXN5500, TT30, ABP959, Anti-C5 siRNA, Erdigna, avacincaptad pegol Zimura®, SOBI005, ISU305, and REGN3918.

13. The method of any one of claims 7-12, wherein the subject has a hemoglobin level of less than about 10 g/dL at the time of administration of the CFD inhibitor.

14. The method of any one of claims 7-13, wherein the subject has an LDH level within a normal range.

15. The method of any one of claims 7-14, wherein the subject has a LDH level of less than 250 U/L at the time of administration of the CFD inhibitor.

16. The method of any one of claims 7-15, wherein the subject has received one or more blood transfusions within the twelve months prior to administration of the CFD inhibitor.

17. The method of any one of claims 7-16, wherein the subject has been on a C5 therapeutic regimen for at least three months prior to administration of the CFD inhibitor.

18. The method of any one of claims 7-17, wherein upon administration of the CFD inhibitor, the C5 inhibitor also continues to be administered.

19. The method of any one of claims 7-17, wherein upon administration of the CFD inhibitor the C5 inhibitor is no longer administered.

20. A method for treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a complement factor D (CFD) inhibitor selected from a compound of Formula I or Formula


or a pharmaceutically acceptable salt thereof;

wherein:

X is selected from N and CH;

R1 is selected from hydrogen, C1-C3 alkyl, and halogen;

R2 is selected from hydrogen and C1-C3 alkyl;

R3 is selected from hydrogen, C1-C3 alkyl, and halogen;

R4 is selected from hydrogen, C1-C3 alkyl, and halogen;

R5 is selected from hydrogen, C1-C3 alkyl, halogen, and cyano;

wherein the subject at the time of administration of the CFD inhibitor has been receiving a therapeutic regimen comprising the administration of a complement 5 (C5) inhibitor; and, wherein the subject is experiencing residual intravascular hemolysis.

21. The method of claim 20, wherein the CFD inhibitor is selected from a compound of formula:



23. The method of claim 20, wherein the CFD inhibitor is a compound of the formula:


24. The method of any one of claims 20-23, wherein the CS inhibitor is eculizamab.

25. The method of any one of claims 20-23, wherein the CS inhibitor is selected from a recombinant human minibody, coversin, Tesidolumab/LFG316, ARC-1905, RA101348, RA10149S, SOBI002, ARC 1005, a SOMAmer for CS, SSL7, MEDI7814, aurin tricarboxylic acid, an aurin tricarboxylic acid derivative, RG6107/SKYS9, ALXN1210, ALXN5500, TT30, ABP959, Anti-CS siK A, Erdigna, avacincaptad pegol/Zimura®, SOBI00S, ISU30S, and REGN3918.

26. The method of any one of claims 20-25, wherein the subject has a hemoglobin level of less than about 10 g/dL at the time of administration of the CFD inhibitor.

27. The method of any one of claims 20-26, wherein the subject has a LDH level greater than the upper level of normal.

28. The method of any one of claims 20-27, wherein the subject has a LDH level of greater than 250 U/L at the time of administration of the CFD inhibitor.

29. The method of any one of claims 20-28, wherein the subject has received one or more blood transfusions within the twelve months prior to administration of the CFD inhibitor.

30. The method of any one of claims 20-29, wherein the subject has been on a C5 therapeutic regimen for at least three months prior to administration of the CFD inhibitor.

31. The method of any one of claims 20-30, wherein upon administration of the CFD inhibitor, the C5 inhibitor also continues to be administered.

32. The method of any one of claims 20-30, wherein upon administration of the CFD inhibitor the C5 inhibitor is no longer administered.

33. A method for treating paroxysmal nocturnal hemoglobinuria (P H) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a complement factor D (CFD) inhibitor selected from a compound of Formula I or Formula


or a pharmaceutically acceptable salt thereof;

wherein:

X is selected from N and C¾

R1 is selected from hydrogen, C1-C3 alkyl, and halogen;

R2 is selected from hydrogen and C1-C3 alkyl;

R3 is selected from hydrogen, C1-C3 alkyl, and halogen;

R4 is selected from hydrogen, C1-C3 alkyl, and halogen;

R5 is selected from hydrogen, C1-C3 alkyl, halogen, and cyano;

wherein the subject at the time of administration of the CFD inhibitor has been or is currently receiving a therapeutic regimen comprising the administration of a complement 5 (CS) inhibitor; and wherein the subject has a hemoglobin level of less than about 10 g/dL. 34. The method of claim 33, wherein the CFD inhibitor is selected from a compound of formula:


35. The method of claim 33, wherein the CFD inhibitor is selected from a compound of formula:


36. The method of claim 33, wherein the CFD inhibitor is a compound of the formula:


37. The method of any one of claims 33-36, wherein the CS inhibitor is eculizamab.

38. The method of any one of claims 33-36, wherein the CS inhibitor is selected from a recombinant human minibody, coversin, Tesidolumab/LFG316, ARC-1905, RA101348, RA101495, SOBI002, ARC100S, a SOMAmer for CS, SSL7, MEDI7814, aurin tricarboxylic acid, an aurin tricarboxylic acid derivative, RG6107/SKYS9, ALXN1210, ALXNSS00, TT30, ABP959, Anti-CS siRNA, Erdigna, avacincaptad pegol/Zimura®, SOBI00S, ISU305, and REGN3918.

39. The method of any one of claims 33-38, wherein the subject has a hemoglobin level of less than about 8 g/dL at the time of administration of the CFD inhibitor.

40. The method of any one of claims 33-39, wherein the subject has a LDH level greater than the upper level of normal.

41. The method of any one of claims 33-39, wherein the subject has a LDH level of greater than about 250 U/L at the time of administration of the CFD inhibitor.

42. The method of any one of claims 33-39, wherein the subject has a LDH level within a normal range.

43. The method of any one of claims 33-39, wherein the subject has a LDH level of less than about 250 U/L at the time of administration of the CFD inhibitor.

44. The method of any one of claims 33-43, wherein the subject has received one or more blood transfusions within the twelve months prior to administration of the CFD inhibitor.

45. The method of any one of claims 33-44, wherein the subject has been on a C5 therapeutic regimen for at least three months prior to administration of the CFD inhibitor.

46. The method of any one of claims 33-45, wherein upon administration of the CFD inhibitor, the C5 inhibitor also continues to be administered.

47. The method of any one of claims 33-45, wherein upon administration of the CFD inhibitor the C5 inhibitor is no longer administered.

48. A method for treating paroxysmal nocturnal hemoglobinuria (P H) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a complement 3 (C3) inhibitor in combination with a therapeutically effective amount of a complement factor D (CFD) inhibitor;

wherein the CFD inhibitor is selected from a compound of Formula I or Formula Π:


or a pharmaceutically acceptable salt thereof;

wherein:

X is selected from N and CH;

R1 is selected from hydrogen, C1-C3 alkyl, and halogen;

R2 is selected from hydrogen and C1-C3 alkyl;

R3 is selected from hydrogen, C1-C3 alkyl, and halogen;

R4 is selected from hydrogen, C1-C3 alkyl, and halogen; and

R5 is selected from hydrogen, C1-C3 alkyl, halogen, and cyano.

49. The method of claim 48, wherein the CFD inhibitor is selected from a compound of formula:


50. The method of claim 33, wherein the CFD inhibitor is selected from a compound of formula:

52. The method of any one of claims 48-51, wherein the C3 inhibitor is selected from compstatin, 4(lMeW)/APL-l, Cp40/AMY-101, PEG-Cp40, 4(lMeW)POT-4, and AMY- 201.

53. The method of any one of claims 48-51, wherein the C3 inhibitor is selected from HI 7, mirocept, sCRl, TT32, HC-1496, CB-2782, and APL-2.

54. A method for treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a complement factor B (CFB) inhibitor in combination with a therapeutically effective amount of a complement factor D (CFD) inhibitor;

wherein the CFD inhibitor is selected from a compound of Formula I or Formula II:


or a pharmaceutically acceptable salt thereof;

wherein:

X is selected from N and C¾

R1 is selected from hydrogen, C1-C3 alkyl, and halogen;

R2 is selected from hydrogen and C1-C3 alkyl;

R3 is selected from hydrogen, C1-C3 alkyl, and halogen;

R4 is selected from hydrogen, C1-C3 alkyl, and halogen; and

R5 is selected from hydrogen, C1-C3 alkyl, halogen, and cyano.

55. The method of claim 54, wherein the CFD inhibitor is selected from a compound of formula:


58. The method of any one of claims S4-S7, wherein the CFB inhibitor is selected from anti- FB siKNA, TA106, LNP106, LNP023, complin, and Ionis-FB-LRx.

59. The method of any one of claims 54-57, wherein the CFB inhibitor is a compound of the formula:


60. A method for treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pan- inhibitor of complement components in combination with a therapeutically effective amount of a complement factor D (CFD) inhibitor;

wherein the CFD inhibitor is selected from a compound of Formula I or Formula Π:


or a pharmaceutically acceptable salt thereof;

wherein:

X is selected from N and CH

R1 is selected from hydrogen, C1-C3 alkyl, and halogen;

R2 is selected from hydrogen and C1-C3 alkyl;

R3 is selected from hydrogen, C1-C3 alkyl, and halogen;

R4 is selected from hydrogen, C1-C3 alkyl, and halogen; and

R5 is selected from hydrogen, C1-C3 alkyl, halogen, and cyano.

61. The method of claim 60, wherein the CFD inhibitor is selected from a compound of formula:



63. The method of claim 60, wherein the CFD inhibitor is a compound of the formula:


64. The method of any one of claims 60-64, wherein the pan-inhibitor of complement components is FUT-175.