USE OF COMPLEMENT FACTOR D INHIBITOR FOR TREATMENT OF LUPUS NEPHRITIS AND IMMUNOGLOBULIN A NEPHROPATHY

20250090528

18/700270

October 13, 2022

Disclosed herein are methods for treating lupus nephritis (LN) and/or immunoglobulin A (IgA) nephropathy in a subject. The methods include administering to the subject a therapeutically effective amount of a small molecule complement factor D inhibitor.

Alexion Pharmaceuticals, Inc. (Boston, MA, US)

1. A method of treatment, wherein the method comprises treating lupus nephritis (LN) and/or immunoglobulin A nephropathy (IgAN) in a subject, said treating comprising administering to the subject a therapeutically effective amount of Compound 1: [chemical expression included] or a pharmaceutically acceptable salt thereof and reducing proteinuria in the subject from baseline.

2. The method of claim 1, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered at a dose of about 60 mg to about 300 mg twice daily (BID).

3. The method of claim 2, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered at a dose of about 120 mg BID.

4. The method of claim 3, wherein Compound 1 or the pharmaceutically acceptable salt thereof is administered at a dose of about 180 mg BID.

5. The method of any one of claims 1-4, wherein said treating comprises reducing proteinuria in the subject from baseline following a 50-week treatment period.

6. The method of claim 5, wherein said treating comprises reducing proteinuria in the subject by greater than about 30% from baseline following a 50-week treatment period.

7. The method of claim 6, wherein said treating comprises reducing proteinuria in the subject by greater than about 50% from baseline following a 50-week treatment period.

8. The method of any one of claims 1-7, wherein said treating comprises reducing proteinuria in the subject from baseline following a 26-week treatment period.

9. The method of claim 8, wherein said treating comprises reducing proteinuria in the subject by greater than about 30% from baseline following a 26-week treatment period.

10. The method of claim 8, wherein said treating comprises reducing proteinuria in the subject by greater than about 50% from baseline following a 26-week treatment period.

11. The method of any one of claims 1-10, wherein said treating further comprises improving renal function in the subject.

12. The method of claim 11, wherein said improving renal function comprises increasing an estimated glomerular filtration rate (eGFR) from baseline in the subject after a 50-week treatment period as calculated using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).

13. The method of claim 11 or 12, wherein said improving renal function comprises increasing an eGFR from baseline in the subject after a 26-week treatment period as calculated using CKD-EPI.

14. The method of claim 11, wherein said improving renal function comprises reducing an increase in an eGFR from baseline in the subject relative to a control after a 50-week treatment period, as calculated using CKD-EPI.

15. The method of claim 11 or 14, wherein said improving renal function comprises reducing an increase in an eGFR from baseline in the subject relative to a control after a 26-week treatment period, as calculated using CKD-EPI.

16. The method of any one of claims 11-15, wherein said improving renal function comprises improving creatinine clearance in the subject.

17. The method of any one of claims 1-16, wherein the subject has LN.

18. The method of claim 17, wherein the subject has been diagnosed with active focal or diffuse proliferative LN class II or IV confirmed by a kidney biopsy obtained <6 months prior to treatment.

19. The method of claim 18, wherein the subject is exhibiting Class V disease.

20. The method of any one of claims 17-19, wherein the LN is de novo LN.

21. The method of any one of claims 17-19, wherein the LN is relapsing LN.

22. The method of any one of claims 17-21, wherein the LN is clinically active LN which requires immunosuppression induction treatment.

23. The method of any one of claims 17-22, wherein the subject has proteinuria with urine protein:creatinine ratio (UPCR)≥1 g/g based on a 24-hour urine collection prior to treatment.

24. The method of claim 23, wherein the time to first occurrence of UPCR≤0.5 g/g as measured by spot urine sample is reduced as compared to a control.

25. The method of any one of claims 17-24, wherein the subject experiences partial renal response (PRR) following a 50-week treatment period.

26. The method of any one of claims 17-25, wherein the subject experiences complete renal response (CRR) following a 50-week treatment period.

27. The method of any one of claims 17-26, wherein the subject experiences PRR following a 26-week treatment period.

28. The method of any one of claims 17-27, wherein the subject experiences CRR following a 26-week treatment period.

29. The method of any one of claims 17-28, wherein said treating comprises reducing a time to first occurrence of UPCR≤0.5 g/g from baseline as measured by spot urine sample, as compared to a control.

30. The method of any one of claims 17-29, wherein the subject has not started corticosteroid induction treatment prior to the treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

31. The method of claim 30, wherein the subject is administered a cumulative dose of about 1 g of methylprednisolone IV in one or multiple divided doses prior to the start of treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

32. The method of claim 30 or 31, wherein the subject is administered an oral corticosteroid at a dose of 0.5 mg/kg/day with a minimum dose of about 30 mg/day and a maximum dose of about 60 mg/day prior to the start of treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

33. The method of claim 30 or 31, wherein the subject said treating comprises co-administering an oral corticosteroid at a dose of about 30 mg/day to about 60 mg/day.

34. The method of claim 33, wherein the dose of the oral corticosteroid is tapered to 7.5 mg/day after a 50-week treatment period.

35. The method of claim 33 or 34, wherein the dose of the oral corticosteroid is tapered to 7.5 mg/day after a 26-week treatment period.

36. The method of any one of claims 33-35, wherein the dose of the oral corticosteroid is tapered to 7.5 mg/day after a 12-week treatment period.

37. The method of any one of claims 31-36, wherein the subject is administered a first dose of mycophenolate mofetil (MMF) about 1-1.5 g/day in one or more doses after administration of the cumulative dose of about 1 g of methylprednisolone IV prior to treatment with Compound 1 or the pharmaceutically acceptable salt thereof, and is administered a second dose of MMF in one or more doses until 50 weeks after the start of treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

38. The method of claim 37, wherein the second dose is about 1-1.5 g/day.

39. The method of claim 37, wherein the second dose is about 1-1.5 g/day until 1 week after the start of treatment with Compound 1 or the pharmaceutically acceptable salt thereof, after which the second dose is increased to about 2-3 g/day.

40. The method of any one of claims 17-29, wherein the subject has initiated corticosteroid induction treatment prior to the start of treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

41. The method of claim 40, wherein the subject has received a cumulative dose of methylprednisolone IV of about 1 g or an equivalent oral corticosteroid and is receiving a first dose of MMF of about 2 g/day in one or more doses prior to the start of treatment with Compound 1 or the pharmaceutically acceptable salt thereof, the subject is not administered an additional dose of methylprednisolone IV or equivalent oral corticosteroid, and the subject is administered a second dose of MMF in one or more doses until 50 weeks after the start of treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

42. The method of claim 41, wherein the second dose of MMF is ≥about 2 g/day.

43. The method of claim 41, wherein the second dose of MMF is ≥about 2 g/day, and is adjusted to about 2-3 g/day before 4 weeks after the start of treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

44. The method of claim 40, wherein the subject has received a cumulative dose of methylprednisolone IV of ≥about 1 g or an equivalent oral corticosteroid and is receiving a first dose of MMF of

45. The method of claim 44, wherein the second dose of MMF is about 1-1.5 g/day at the start of treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

46. The method of claim 45, wherein the second dose of MMF is about 1-1.5 g/day for a one-week period following the start of treatment with Compound 1 or the pharmaceutically acceptable salt thereof, after which the second dose of MMF is increased to about 2-3 g/day before 4 weeks after the start of treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

47. The method of any one of claims 40-46, wherein the subject has been receiving prednisone or a prednisone equivalent at a first dose prior to the start of treatment with Compound 1 or the pharmaceutically acceptable salt thereof, the first dose is maintained through the second day of treatment with Compound 1 or the pharmaceutically acceptable salt thereof, after which the subject is administered an oral corticosteroid at a dose of 0.5 mg/kg/day with a minimum dose of about 30 mg/day and a maximum dose of about 60 mg/day.

48. The method of claim 47, wherein the dose of the oral corticosteroid is tapered to 7.5 mg/day after a 50-week treatment period.

49. The method of claim 47 or 48, wherein the dose of the oral corticosteroid is tapered to 7.5 mg/day after a 26-week treatment period.

50. The method of any one of claims 47-49, wherein the dose of the oral corticosteroid is tapered to 7.5 mg/day after a 12-week treatment period.

51. The method of any one of claims 17-50, wherein said treating comprises reducing a risk of experiencing a renal flare in the subject within a 50-week treatment period.

52. The method of any one of claims 17-51, wherein said treating comprises reducing a risk of experiencing an extrarenal systemic lupus erythematosus (SLE) flare in the subject within a 50-week treatment period.

53. The method of any one of claims 17-52, wherein said treating comprises reducing a risk of treatment failure in the subject within a 50-week treatment period.

54. The method of any one of claims 17-53, wherein said treating comprises reducing a level of serum albumin in the subject from baseline.

55. The method of any one of claims 17-54, wherein said treating comprises reducing the time to first CRR or PRR as compared to a control.

56. The method of any one of claims 17-54, wherein said treating comprises reducing a time to first occurrence of UPCR>50% decrease from baseline as compared to a control.

57. The method of any one of claims 17-56, wherein the subject exhibits an increase in FACIT-Fatigue total score from baseline following a 50-week treatment period.

58. The method of any one of claims 17-57, wherein the subject exhibits an increase in FACIT-Fatigue total score from baseline following a 26-week treatment period.

59. The method of any one of claims 17-58, wherein a level of antibodies against double-stranded DNA (anti-dsDNA) and/or antibodies against C1q complement component (anti-C1q) in the subject is reduced from baseline following a 50-week treatment period.

60. The method of any one of claims 17-59, wherein a level of anti-dsDNA and/or anti-C1q in the subject is reduced from baseline following a 26-week treatment period.

61. The method of any one of claims 17-59, wherein the subject has not received treatment with cyclophosphamide ≤6 months prior to treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

62. The method of any one of claims 17-61, wherein the subject has not received treatment with a calcineurin inhibitor ≤3 months prior to treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

63. The method of any one of claims 17-62, wherein the subject has not received treatment with a cumulative dose of intravenous (IV) methylprednisolone >about 3 g for active renal flare.

64. The method of any one of claims 17-63, wherein the subject has not received treatment with MMF >about 2 g/day or an equivalent thereof for 4 consecutive weeks for active renal flare prior to treatment of Compound 1 or the pharmaceutically acceptable salt thereof.

65. The method of any one of claims 17-64, wherein the subject has not received treatment with prednisone ≥about 0.5 mg/kg/day or an equivalent thereof for 4 consecutive weeks for active renal flare prior to treatment of Compound 1 or the pharmaceutically acceptable salt thereof.

66. The method of any one of claims 17-65, wherein the subject does not have uncontrolled hypertension on 2 or more measurements within a 6-week period prior to treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

67. The method of any one of claims 17-66, wherein the subject does not have a history of or has clinically active SLE-related cerebritis, seizures, pericarditis, stroke, or stroke syndrome requiring treatment.

68. The method of any one of claims 17-67, wherein the subject does not have an inability to take or tolerate treatment with a corticosteroid, MMF, or MPS.

69. The method of any one of claims 17-68, wherein the subject is restricted from receiving treatment with a calcineurin inhibitor.

70. The method of any one of claims 1-69, wherein the subject has IgAN.

71. The method of claim 70, wherein the subject has been diagnosed with primary IgAN confirmed by a kidney biopsy obtained prior to treatment.

72. The method of claim 71, wherein the kidney biopsy is obtained more than 2 years prior to treatment, and the subject has hematuria as defined by 1+ blood based on urine dipstick or ≤10 red blood cells (RBCs)/high-power field (hp) microscopy on urine sediment.

73. The method of any one of claims 70-72, wherein the subject has been receiving treatment with a stable and optimal dose of a RAS inhibitor prior to treatment with Compound 1 or the pharmaceutically acceptable salt thereof and continues to receive treatment with the RAS inhibitor during treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

74. The method of claim 73, wherein the subject is restricted from receiving treatment with a second RAS inhibitor within a 50-week period following the start of treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

75. The method of any one of claims 70-74, wherein the subject has been receiving treatment with a stable and optimal dose of a direct renin antagonist prior to treatment with Compound 1 or the pharmaceutically acceptable salt thereof and continues to receive treatment with the direct renin antagonist during treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

76. The method of any one of claims 70-74, wherein the subject is restricted from receiving treatment with a second direct renin antagonist within a 50-week period following the start of treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

77. The method of any one of claims 70-76, wherein the subject has controlled and stable blood pressure over a 3-month period prior to treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

78. The method of any one of claims 70-77, wherein the subject experiences partial remission following a 50-week treatment period.

79. The method of any one of claims 70-78, wherein the subject experiences partial remission following a 26-week treatment period.

80. The method of any one of claims 70-79, wherein said treating comprises attenuating or flattening a slope of eGFR computed from baseline to week 26 of a treatment period as compared to a control.

81. The method of any one of claims 70-80, wherein the subject was not diagnosed with rapid progressive glomerulonephritis as measured by an eGFR loss ≥30% over a period of 3 months prior to treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

82. The method of any one of claims 70-81, wherein the subject does not have a secondary etiology of IgAN.

83. The method of any one of claims 70-82, wherein the subject does not have clinically active Henoch-Schonlein purpura (IgA vasculitis) requiring treatment.

84. The method of any one of claims 70-83, wherein the subject has not received treatment with prednisone >about 20 mg/day or an equivalent thereof for >14 consecutive days or any other immunosuppression prior to treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

85. The method of any one of claims 70-84, wherein the subject does not have blood pressure of ≥140/90 mmHg prior to treatment with Compound 1 or the pharmaceutically acceptable salt thereof confirmed on 2 measurements >30 minutes apart.

86. The method of any one of claims 70-85, wherein the subject does not have a body mass index ≥38 kg/m2 prior to treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

87. The method of any one of claims 70-86, wherein the subject is restricted from receiving treatment with hydroxychloroquine.

88. The method of any one of claims 70-87, wherein the subject is restricted from receiving treatment with an immunosuppressive agent.

89. The method of any one of claims 70-88, wherein the subject is restricted from receiving treatment with a systemic corticosteroid for >14 consecutive days.

90. The method of any one of claims 1-89, wherein said treating comprises decreasing plasma Bb fragment of complement factor B (Bb) concentration and serum alternative pathway (AP) activity.

91. The method of any one of claims 1-90, wherein said treating comprises reducing hematuria in the subject.

92. The method of claim 91, wherein said reducing hematuria in the subject comprises a decrease in red blood cells (RBC) in urine from baseline after a 50-week treatment period.

93. The method of claim 91 or 92, wherein said reducing hematuria in the subject comprises a decrease in red blood cells (RBC) in urine from baseline after a 26-week treatment period.

94. The method of any one of claims 91-93, wherein said reducing hematuria in the subject comprises achieving <10 RBCs/hpf.

95. The method of any one of claims 1-94, wherein said treating comprises improving a 36-Item Short Form Survey Instrument (SF-36) score in one or more of Physical Functioning, Physical, Bodily Pain, Vitality, General Health, Emotion, Mental Health, and Social Functioning from baseline.

96. The method of any one of claims 1-95, wherein said treating comprises improving a EuroQol 5-dimension 5-level questionnaire (EQ-5D-5L) score in one or more of mobility, usual activities, self-care, pain/discomfort, and anxiety/depression.

97. The method of any one of claims 1-96, wherein the subject has an eGFR<30 mL/min/1.73 m2 as calculated using CKD-EPI.

98. The method of any one of claims 1-97, wherein the subject has less than 50% tubular atrophy, glomerular sclerosis, or crescent formation in glomeruli on the most recent kidney biopsy obtained prior to treatment.

99. The method of any one of claims 1-98, wherein the subject does not have a concomitant significant renal disease other than LN or IgAN on the most recent kidney biopsy obtained prior to treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

100. The method of any one of claims 1-99, wherein the subject does not have a history of solid organ or bone marrow transplant.

101. The method of any one of claims 1-100, wherein the subject is restricted from receiving a solid organ or bone marrow transplant during a 50-week treatment period.

102. The method of any one of claims 1-101, wherein the subject has not had a splenectomy and does not have functional asplenia.

103. The method of any one of claims 1-102, wherein the subject does not have a history of seizure.

104. The method of any one of claims 1-103, wherein the subject does not have a known or suspected complement deficiency unless the complement deficiency is attributable to LN or IgAN.

105. The method of any one of claims 1-104, wherein the subject does not have a history of or have risk factors for Torsades de Pointes, a QT interval corrected using Fridericia's formula (QTcF)>450 msec when the subject is male or >470 msec when the subject is female, or is receiving medication known to significantly increase the corrected QT interval (QTc).

106. The method of any one of claims 1-104, wherein the subject does not have an alanine aminotransferase level of >2×ULN.

107. The method of any one of claims 1-106, wherein the subject does not have a direct bilirubin level of >2×ULN.

108. The method of any one of claims 1-107, wherein the subject has a hemoglobin A1C level of <7.0% prior to treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

109. The method of any one of claims 1-108, wherein the subject does not have a known or suspected history of drug or alcohol abuse or dependence within 1 year prior to treatment.

110. The method of any one of claims 1-109, wherein the subject does not have a history of malignancy within 5 years prior to treatment, wherein the malignancy is not nonmelanoma skin cancer or carcinoma in situ of the cervix that has been treated with no evidence of recurrence.

111. The method of any one of claims 1-110, wherein the subject is not exhibiting signs of a hepatitis B viral infection with negative surface antibodies.

112. The method of any one of claims 1-111, wherein the subject is not exhibiting signs of a hepatitis C viral infection; or is exhibiting signs of a hepatitis C viral infection but has been successfully treated and has a documented sustained virologic response.

113. The method of any one of claims 1-112, wherein the subject is not exhibiting signs of a human immunodeficiency virus infection.

114. The method of any one of claims 1-113, wherein the subject does not have bone marrow insufficiency or thrombocytopenia.

115. The method of any one of claims 1-114, wherein the subject did not have an active systemic bacterial, viral or fungal infection within 14 days prior to treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

116. The method of any one of claims 1-115, wherein the subject does not have a history of N meningitidis infection.

117. The method of any one of claims 1-116, wherein the subject is not receiving treatment with a biologic medication that may affect immune system functioning; or has stopped receiving treatment with the biologic medication, and 5 terminal half-lives of the biologic has elapsed prior to treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

118. The method of any one of claims 1-117, wherein the subject has not received treatment with belimumab or rituximab <6 months prior to treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

119. The method of any one of claims 1-118, wherein the subject has not received, or is not receiving treatment with a complement inhibitor other than Compound 1 or the pharmaceutically acceptable salt thereof.

120. The method of any one of claims 1-119, wherein the subject has not received treatment with a medication selected from a strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitor; a moderate CYP3A inhibitor; a strong inducer of CYP3A; a moderate inducer of CYP3A; and a sensitive substrate of CYP3A, within the longer of two weeks or five half-lives of the medication prior to the treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

121. The method of any one of claims 1-120, wherein the subject has not received treatment with a medication selected from meperidine, pethidine, a typical (1st generation) antipsychotic, clozapine, olanzapine, lithium, a tricyclic antidepressant, bupropion, aminophylline, and theophylline.

122. The method of any one of claims 1-121, wherein the subject is not pregnant or breastfeeding.

123. The method of any one of claims 1-122, wherein the subject is restricted from consuming foods and beverages that inhibit CYP3A4 enzyme activity.

124. The method of any one of claims 1-123, wherein the subject is restricted from receiving treatment with eculizumab.

125. The method of any one of claims 1-124, wherein the subject has been receiving treatment with a sodium-glucose cotransporter-2 (SGLT-2) inhibitor prior to treatment with Compound 1 or the pharmaceutically acceptable salt thereof, and the dose of the SGLT-2 inhibitor does not change during treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

126. The method of any one of claims 1-124, wherein the subject has not been receiving treatment with a SGLT-2 inhibitor prior to treatment with Compound 1 or the pharmaceutically acceptable salt thereof, and the subject is restricted from receiving treatment with a SGLT-2 inhibitor within a 50-week period following the start of treatment with Compound 1 or the pharmaceutically acceptable salt thereof.

127. The method of any one of claims 1-126, wherein the subject is restricted from using a medication selected from a strong CYP3A inhibitor, a moderate CYP3A inhibitor, a strong inducer of CYP3A, a moderate inducer of CYP3A, and a sensitive substrate of CYP3A.

128. The method of any one of claims 1-127, wherein the subject is restricted from using a medication selected from meperidine, pethidine, a typical (1st generation) antipsychotic, clozapine, olanzapine, lithium, a tricyclic antidepressant, bupropion, aminophylline, and theophylline.

129. The method of any one of claims 1-128, wherein the subject is restricted from using a medication known to significantly prolong QTc, provided that the medication is not hydroxychloroquine for use by a subject with LN.

130. Use of Compound 1: [chemical expression included] or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of treatment, wherein the method of treatment is the method of any one of claims 1-129.

131. A compound for use in a method of treatment, wherein the compound is Compound 1: [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein the method of treatment is the method of any one of claims 1-129.

132. A kit for treating LN or IgAN in a subject, comprising: (a) a dose of Compound 1: [chemical expression included] or a pharmaceutically acceptable salt thereof; and (b) instructions for using Compound 1 or the pharmaceutically acceptable salt thereof according to the method of any one of claims 1-129.

61; 61; 61

edspap.20250090528