COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISEASES

• US 20190314382A1
• Filed: 11/09/2017
• Published: 10/17/2019
• Est. Priority Date: 11/10/2016
• Status: Abandoned Application

• Current Assignee: Galapagos NV
• Original Assignee: Galapagos NV
• Inventors: TASSET, Chantal Therese, HARRISON, Pille, GALIEN, Rene Alexandre, SUNDY, John Sargent, MCHUTCHISON, John G., O'RIORDAN, Thomas, MOZAFFARIAN, Neelufar, PATEL, Uptal Dinesh, WATKINS, Timothy R., GOSSAGE, David L.
• Application Number:
  US16/348,799
• Publication Number:
  US 20190314382A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/541 Non-condensed thiazines containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

The present invention relates to the use of compounds or pharmaceutical compositions comprising the same, and methods of treatment using the same, in the prophylaxis and/or treatment of alopecia areata, vitiligo, cutaneous lupus, lupus nephritis, giant cell arteritis, sarcoïdosis and/or sarcoïdosis-related conditions. In particular the compounds are JAK inhibitors.

Claims

1. A compound according to Formula I:

2. The compound for use according to claim 1, wherein the active metabolite is according to Formula II:

3. A compound for use according to claim 1, wherein the compound according to Formula I is a pharmaceutically acceptable salt, wherein said salt is formed with a salt forming agent selected from a hydrobromic acid, hydrochloric acid, sulfuric acid, toluenesulfonic acid, benzenesulfonic acid, oxalic acid, maleic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-2-ethane disulfonic acid, methanesulfonic acid, 2-hydroxy ethanesulfonic acid, phosphoric acid, ethane sulfonic acid, malonic acid, 2-5-dihydroxybenzoic acid, or L-Tartaric acid.

4. A compound for use according to claim 1, wherein the compound according to Formula I is a pharmaceutically acceptable salt, wherein said salt is formed with maleic acid.

5. A compound, or a pharmaceutically acceptable salt thereof for use according to any one of claims 1-4, in combination with a further therapeutic agent.

6. A pharmaceutical composition for use in the prophylaxis and/or treatment of alopecia areata, vitiligo, cutaneous lupus, lupus nephritis, giant cell arteritis, sarcoï

dosis, and/or a sarcoï

dosis-related condition comprising the compound, or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, and a pharmaceutically acceptable carrier, excipient, or diluent.

7. A pharmaceutical composition for use according to claim 6, comprising a further therapeutic agent.

8. The compound or a pharmaceutically acceptable salt thereof, according to claim 5 or the pharmaceutical composition for use according to claim 7, wherein the further therapeutic agent is an agent for the prophylaxis and/or treatment of alopecia areata.

9. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-4, or a pharmaceutical composition according to claim 6 or 7 in an individual afflicted with alopecia areata, vitiligo, cutaneous lupus, lupus nephritis, giant cell arteritis, sarcoï

dosis, and/or a sarcoï

dosis-related condition.

10. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 1-9, wherein the compound is administered at a dose of 100 mg b.i.d.

11. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 1-9, wherein the compound is administered at a dose of 200 mg qd.

12. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 1-11, wherein the compound is administered over a period of least 4, 6, 8, 10, 12, 14, 16, 20, or 24 weeks.

13. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 1-11, wherein the compound is administered over a period of least 12 weeks.

14. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-4, or a pharmaceutical composition according to claim 6 or 7 in an individual afflicted with alopecia areata, as characterized by the Severity Alopecia Tool (SALT) score.

15. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-4, or a pharmaceutical composition according to claim 6 or 7 in an individual afflicted with alopecia areata, as characterized by a SALT score of at least 25%.

16. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-4, or a pharmaceutical composition according to claim 6 or 7 in an individual afflicted with alopecia areata, as characterized by a SALT score of at least 50%.

17. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-4, or a pharmaceutical composition according to claim 6 or 7 in an individual afflicted with alopecia areata, as characterized by a SALT score of at least 75%.

18. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-4, or a pharmaceutical composition according to claim 6 or 7, wherein the regrowth improvement is at least 10% (SALT₁₀), 20% (SALT₂₀), 30% (SALT₃₀), 40% (SALT₄₀), or 50% (SALT₅₀) after treatment compared to before treatment.

20. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-4, or a pharmaceutical composition according to claim 6 or 7 in an individual afflicted with alopecia areata, said use comprising the steps of

a) assaying a blood sample,

b) measuring levels of at least one alopecia areata-associated biomarker,

c) administering a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof to the individual,

d) measuring the post-treatment level of said alopecia areata-associated biomarker and comparing with pre-treatment levels, and

e) adjusting the dosage of compound, or a pharmaceutically acceptable salt thereof to be administered to the individual, wherein said dosage is increased when a decrease of less than 2% after 12 weeks in levels of said alopecia areata-associated biomarker is detected.

21. A compound, or a pharmaceutically acceptable salt thereof, for use according to claim 20, wherein the biomarker is IFN_γ

.

22. A compound, or a pharmaceutically acceptable salt thereof, for use according to claim 20, wherein the biomarker level is decreased by at least 5%, at least 10%, or at least 15% compared to pre-treatment levels.

23. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to claim 20, wherein the IFN_γ

are decreased by at least 5% compared to pre-treatment levels after 12 weeks treatment.

24. The compound or a pharmaceutically acceptable salt thereof, according to claim 5 or the pharmaceutical composition for use according to claim 7, wherein the further therapeutic agent is an agent for the prophylaxis and/or treatment of vitiligo.

25. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according to claim 6 or 7 in an individual afflicted with vitiligo.

26. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claim 1-7, 24, or 25, wherein the compound is administered at a dose of 100 mg b.i.d.

27. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claim 1-7, 24, or 25, wherein the compound is administered at a dose of 200 mg qd.

28. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claim 1-9, 24, or 25, wherein the compound is administered over a period of least 4, 6, 8, 10, 12, 14, 16, 20, or 24 weeks.

29. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claim 1-9, 24, or 25, wherein the compound is administered over a period of least 12 weeks.

30. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according to claim 24 or 25 in an individual afflicted with vitiligo, as characterized by the Vitiligo Activity Severity Index (VAST) score.

31. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according to claim 24 or 25 in an individual afflicted with vitiligo, as characterized by a VASI score of at least 25%.

32. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according to claim 24 or 25 in an individual afflicted with vitiligo, as characterized by a VASI score of at least 50%.

33. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according to claim 24 or 25 in an individual afflicted with vitiligo, as characterized by a VASI score of at least 75%.

34. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according to claim 24 or 25, wherein the VASI improvement is at least 10%, 20%, 30%, 40%, or 50% after treatment compared to before treatment.

36. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claim 1-5, or a pharmaceutical composition according to claim 24 or 25 in an individual afflicted with vitiligo, said use comprising the steps of:

a) assaying a blood sample,

b) measuring levels of at least one vitiligo-associated biomarker,

c) administering a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof to the individual,

d) measuring the post-treatment level of said vitiligo-associated biomarker and comparing with pre-treatment levels, and

e) adjusting the dosage of the compound, or a pharmaceutically acceptable salt thereof to be administered to the individual, wherein said dosage is increased when a decrease of less than 2% after 12 weeks in levels of said vitiligo-associated biomarker is detected.

37. A compound, or a pharmaceutically acceptable salt thereof, for use according to claim 36, wherein the biomarker is IFN_γ

.

38. A compound, or a pharmaceutically acceptable salt thereof, for use according to claim 36, wherein the biomarker level is decreased by at least 5%, at least 10%, or at least 15% compared to pre-treatment levels.

39. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to claim 36, wherein the IFN_γ

are decreased by at least 5% compared to pre-treatment levels after 12 weeks of treatment.

42. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition for use according to claim 40 or 41 in an individual afflicted with cutaneous lupus.

43. A method of treating cutaneous lupus in a human, which comprises administering to an individual afflicted with cutaneous lupus, a therapeutically effective amount of compound, according to any one of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof.

44. The method according to claim 43, wherein said method comprises administering at least one further therapeutic agent.

46. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according for use according to claim 40 or 42, or the method according to claim 43, wherein said cutaneous lupus is selected from the group consisting of chronic cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, discoid lupus erythematosus, acute cutaneous lupus erythematosus, and drug-induced lupus erythematosus.

47. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according for use according to claim 40 or 41, wherein the administration of said compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition results in detectable changes of a biomarker.

48. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according to claim 40 or 41 in an individual afflicted with cutaneous lupus, said use comprising the steps of:

a) assaying a blood sample,

b) measuring levels of at least one cutaneous lupus-associated biomarker,

c) administering a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof to the individual,

d) measuring the post-treatment level of said cutaneous lupus-associated biomarker and comparing with pre-treatment levels, and

e) adjusting the dosage of the compound, or a pharmaceutically acceptable salt thereof to be administered to the individual, wherein said dosage is increased when a decrease of less than 2% after 12 weeks in levels of said cutaneous lupus-associated biomarker is detected.

49. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to claim 47 or 48, wherein the biomarker is selected from the group consisting of IL-6 and a complement component.

50. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to claim 47 or 48, wherein the biomarker is IL6.

51. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to claim 47 or 48, wherein the biomarker level is decreased by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% compared to pre-treatment levels.

52. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according for use according to claim 40 or 41, or the method according to claim 43 or 44, in an individual afflicted with cutaneous lupus as characterized by the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI).

53. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according for use according to claim 40 or 41, or the method according to claim 43 or 44, wherein the compound is administered at a dose of 100 mg b.i.d.

54. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according for use according to claim 40 or 41, or the method according to claim 43 or 44, wherein the compound is administered at a dose of 200 mg qd.

55. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according for use according to claim 40 or 41, or the method according to claim 43 or 44, wherein the compound is administered over a period of at least 6 months.

58. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition for use according to claim 56 or 57 in an individual afflicted with lupus nephritis.

59. A method of treating lupus nephritis in a human, which comprises administering to a patient having lupus nephritis a therapeutically effective amount of compound, according to any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof.

60. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according for use according to claim 56 or 57, or the method according to claim 59, wherein said lupus nephritis is membranous lupus nephritis.

61. The method according to claim 59, wherein said method comprises administering a further therapeutic agent.

62. The compound, or a pharmaceutically acceptable salt thereof for use according to claim 5, or a pharmaceutical composition for use according to claim 57, or the method according to claim 61, wherein further therapeutic agent is selected from angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), antimalarials, statins, cyclophosphamide, azathioprine, 6-mercaptopurine, abatacept, rituximab, belimumab, cyclosporine and other calcineurin inhibitors.

63. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according for use according to claim 56 or 57, wherein the administration of said compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition results in detectable changes of a biomarker.

65. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to claim 63, or the method according to claim 64, wherein the biomarker is selected from the group consisting of IL-6, IL-10, IFNγ

and TGFβ

.

66. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to claim 63, or the method according to claim 64, wherein the biomarker is IL6.

67. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to claim 63, or the method according to claim 64, wherein the biomarker level is decreased by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% compared to pre-treatment level.

68. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according for use according to claim 56 or 57, or the method of any claim 59 or 61, wherein the administration of said compound, or a pharmaceutically acceptable salt thereof, or said pharmaceutical composition reduces proteinuria in the subject.

69. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or the method of claim 68, wherein proteinuria reduction is measured by 24 hour urine protein, 24 hour protein to creatinine ratio, spot protein to creatinine ratio, 24 hour urine albumin, 24 hour albumin to creatinine ratio, spot albumin to creatinine ratio, or by a urinary dipstick.

70. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or the method of claim 68, wherein the periodic administration of said compound, or a pharmaceutically acceptable salt thereof reduces the subject'"'"'s protein to creatinine ratio.

71. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or the method of claim 70, wherein the subject'"'"'s protein to creatinine ratio is reduced by at least 50% as compared to baseline.

72. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according for use according to claim 56 or 57, or the method of any claim 59 or 61, wherein the compound is administered at a dose of 100 mg b.i.d.

73. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according for use according to claim 56 or 57, or the method of any claim 59 or 61, wherein the compound is administered at a dose of 200 mg qd.

74. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or the method according to claim 72 or 73, wherein the compound is administered over a period of at least 6 months.

77. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition for use according to claim 75 or 76 in an individual afflicted with sarcoï

dosis.

78. A method of treating sarcoï

dosis in a human, which comprises administering to a patient having sarcoï

dosis a therapeutically effective amount of compound, according to any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof.

79. The method according to claim 78, further comprising the administration of a further therapeutic agent.

80. The method according to claim 79, wherein the further therapeutic agent is selected from anti-inflammatory agent, a steroid, an immunosuppressant compound, and an antibiotic

81. The method according to claim 79, wherein the further therapeutic agent is selected from corticosteroid, prednisone, methotrexate, azathioprine, hydroxychloroquine, cyclophosphamide, minocycline, doxycycline, chloroquin, infliximab, a penicillin antibiotic, a cephalosporin antibiotic, a macrolide antibiotic, a lincomycin antibiotic, and a tetracycline antibiotic.

82. The compound, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition or the method according to any one of claim 1-5, or 75-81, wherein said sarcoï

dosis is selected from the group consisting of cardiac sarcoï

dosis, cutaneous sarcoï

dosis, hepatic sarcoï

dosis, pulmonary sarcoï

dosis, neurosarcoï

dosis, Lofgren'"'"'s syndrome, and chronic cutaneous sarcoï

dosis.

83. The compound, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition or the method according to any one of claim 1-5, or 75-81, wherein said sarcoï

dosis is cutaneous sarcoï

dosis.

84. The compound, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition or the method according to any one of claim 1-5, or 75-81, wherein said sarcoï

dosis is Lö

fgren'"'"'s syndrome

85. The compound, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition or the method according to any one of claim 1-5, or 75-81, wherein said sarcoï

dosis is neurosarcoï

dosis

86. The compound, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition or the method according to any one of claim 1-5, or 75-81, wherein said sarcoï

dosis is cardiac sarcoï

dosis

87. The compound, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition or the method according to any one of claim 1-5, or 75-81, wherein said sarcoï

dosis is pulmonary sarcoï

dosis.

88. The compound, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition or the method according to any one of claim 1-5, or 75-81, wherein said sarcoï

dosis is pulmonary fibrosis caused by pulmonary sarcoï

dosis.

89. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according for use according to claim 75 or 77, or the method according to claim 78 or 79 wherein the administration of said compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition results in detectable changes of a biomarker.

91. The compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according for use according to claim 89 or the method according to claim 90, wherein the biomarker is CXCL9 or CXCL10.

92. The compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according for use according to claim 89 or the method according to claim 90, wherein the biomarker is CXCL10.

93. The compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according for use according to claim 89 or the method according to claim 90, wherein the biomarker level is decreased by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% compared to pre-treatment levels.

94. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according for use according to claim 75 or 77, or the method according to claim 78 or 79, wherein the administration of said compound, or a pharmaceutically acceptable salt thereof, or said pharmaceutical composition results in a detectable improvement in one or more symptoms of said sarcoï

dosis.

95. A compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition or the method of claim 94, wherein said symptom is one or more of formation of granulomas, fatigue, weight loss, fever, aches, pains, arthritis, dry eyes, swelling of the knees, blurry vision, shortness of breath, cough and skin lesions.

96. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according for use according to claim 75 or 77, or the method according to claim 78 or 79, wherein the compound is administered at a dose of 100 mg b.i.d.

97. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according for use according to claim 75 or 77, or the method according to claim 78 or 79, wherein the compound is administered at a dose of 200 mg qd.

98. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or the method according to claim 97, wherein the compound is administered over a period of at least 6 months.

102. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according to claim 99 or 100 in an individual afflicted with giant cell arteritis.

103. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according to claim 99 or 100 in an individual afflicted with giant cell arteritis, as characterized by CRP level greater than 3 mg/L.

104. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1-5, or a pharmaceutical composition according to claim 99 or 100 in an individual afflicted with giant cell arteritis, as characterized by a erythrocyte sedimentation rate greater than 30 mm/h.

105. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 1-5, or a pharmaceutical composition according to claim 99 or 100, wherein the compound is administered at a dose of 100 mg b.i.d.

106. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 1-5, or a pharmaceutical composition according to claim 99 or 100, wherein the compound is administered at a dose of 200 mg qd.

107. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 1-5, or a pharmaceutical composition according to claim 99 or 100, wherein the compound is administered over a period of least 4, 6, 8, 10, 12, 14, 16, 20, or 24 weeks.

108. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 1-5, or a pharmaceutical composition according to claim 99 or 100, wherein the compound is administered over a period of least 12 weeks.

110. A compound, or a pharmaceutically acceptable salt thereof, for use according to claims 1-5, or a pharmaceutical composition according to claim 99 or 100 in an individual afflicted with giant cell arteritis, said use comprising the steps of:

a) assaying a blood sample,

b) measuring levels of at least one giant cell arteritis-associated biomarker,

c) administering a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof to the individual,

d) measuring the post-treatment level of said giant cell arteritis-associated biomarker and comparing with pre-treatment levels, and

e) adjusting the dosage of the compound, or a pharmaceutically acceptable salt thereof to be administered to the individual, wherein said dosage is increased when a decrease of less than 2% after 12 weeks in levels of said giant cell arteritis-associated biomarker is detected.

111. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to claim 110, wherein the biomarker is IL6.

112. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to claim 110, wherein the biomarker is IL1.

113. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to claim 110, wherein the biomarker is GM-CSF.

19. A method for the treatment the prophylaxis and/or treatment of alopecia areata comprising the steps of:

a) measuring the SALT score of an individual by performing a scalp hair loss analysis by assessing the hair loss on the left side, right side, top and back of the patient, wherein the left side and the right side each account for 18% of the overall head surface, the top accounts for 40% of the overall head surface and the back accounts for 24% of the overall head surface,

b) assessing the type of hair remaining on each area (pigmented/non-pigmented/indeterminant),

c) calculating a SALT score by the formula;

d) SALT score=(% left side)*0.18+(% right side)*0.18+(% top side)*0.40+(% back side)*0.24, and

e) determining a daily dose of the compound according to Formula I, or a pharmaceutically acceptable salt thereof comprised between 25 mg and 400 mg for administration to said individual.

35. A method for the treatment the prophylaxis and/or treatment of vitiligo comprising the steps of:

a) measuring the depigmentation of the hands, upper extremities (excluding hands), trunk, lower extremities (excluding the feet), and feet of an individual using the hand as a unit (palm plus the volar surface of all the digits),

b) calculating a VASI score by the formula;

VASI=Σ

_{all body site}[Hand Unit]×

[Residual Depigmentation] 

 

a.

c) determining a daily dose of the compound according to Formula I, or a pharmaceutically acceptable salt thereof comprised between 25 mg and 400 mg for administration to said individual.

40. A pharmaceutical composition for use in the prophylaxis and/or treatment of cutaneous lupus, comprising the compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

41. A pharmaceutical composition for use according to claim 40, comprising a further therapeutic agent.

45. The compound, or a pharmaceutically acceptable salt thereof, for use according to claim 5, or the pharmaceutical composition for use according to claim 41, or the method according to claim 44, wherein the further therapeutic agent is selected from angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), antimalarials, statins, cyclophosphamide, azathioprine, 6-mercaptopurine, abatacept, rituximab, belimumab, cyclosporine and other calcineurin inhibitors.

56. A pharmaceutical composition for use in the prophylaxis and/or treatment of lupus nephritis, comprising the compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

57. A pharmaceutical composition for use according to claim 56, comprising a further therapeutic agent.

64. A method of treating lupus nephritis in an individual afflicted with lupus nephritis, comprising the steps of:

a) assaying a blood sample,

b) measuring levels of at least one lupus nephritis-associated biomarker,

c) administering a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof to the individual,

d) measuring the post-treatment level of said lupus nephritis-associated biomarker and comparing with pre-treatment levels, and

e) adjusting the dosage of the compound, or a pharmaceutically acceptable salt thereof to be administered to the individual, wherein said dosage is increased when a decrease of less than 2% after 12 weeks in levels of said lupus nephritis-associated biomarker is detected.

75. A pharmaceutical composition for use in the prophylaxis and/or treatment of sarcoï

dosis, comprising the compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

76. A pharmaceutical composition for use according to claim 75, comprising a further therapeutic agent.

90. A method of treating sarcoï

dosis in an individual afflicted with sarcoï

dosis, comprising the steps of;

a) assaying a blood sample,

b) measuring levels of at least one sarcoï

dosis and/or a sarcoï

dosis-related condition-associated biomarker,

c) administering a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof to the individual,

d) measuring the post-treatment level of said sarcoï

dosis and/or a sarcoï

dosis-related condition-associated biomarker and comparing with pre-treatment levels, and

e) adjusting the dosage of compound, or a pharmaceutically acceptable salt thereof to be administered to the individual, wherein said dosage is increased when a decrease of less than 2% after 12 weeks in levels of said sarcoï

dosis and/or a sarcoï

dosis-related condition-associated biomarker is detected.

99. A pharmaceutical composition for use in the prophylaxis and/or treatment of giant cell arteritis, comprising the compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

100. A pharmaceutical composition for use according to claim 99, comprising a further therapeutic agent.

101. The compound or a pharmaceutically acceptable salt thereof, according to claim 5 or the pharmaceutical composition for use according to claim 100, wherein the further therapeutic agent is an agent for the prophylaxis and/or treatment of giant cell arteritis.

109. A method for the treatment the prophylaxis and/or treatment of giant cell arteritis comprising the steps of:

a) measuring the ESR of an individual,

b) measuring the CRP level of an individual,

c) comparing said ESR and/or CRP level with normal values,

d) determining a daily dose of the compound according to Formula I, or a pharmaceutically acceptable salt thereof comprised between 25 mg and 400 mg for administration to said individual.

114. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 109-113, wherein the biomarker level is decreased by at least 5%, at least 10%, at 15% compared to pre-treatment level.

115. A compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use according to any one of claims 109-113, wherein the biomarker levels are decreased by at least 5% after 12 weeks.