Methods of using factor B inhibitors

1. A method of treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject in need thereof, the method comprising orally administering to the subject 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof, at a dose of about 200 mg twice daily (b.i.d.), to thereby treat the subject, wherein the dose refers to an amount of anhydrous free base of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid.

2. The method of claim 1 , wherein the subject has been previously treated with an anti-C5 therapy prior to administration of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof.

3. The method of claim 2 , wherein the anti-C5 therapy is an anti-C5 monoclonal antibody therapy.

4. The method of claim 1 , wherein the subject has residual anemia.

5. The method of claim 1 , wherein hemoglobin levels, haptoglobin levels, reticulocyte levels, and/or bilirubin levels of the subject, are evaluated prior to administration of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof.

6. The method of claim 5 , wherein the hemoglobin levels of the subject are less than or equal to about 10 g/dL, prior to administration of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein treating PNH comprises increasing hemoglobin levels in the subject as compared to hemoglobin levels in the subject prior to administration of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein treating PNH comprises normalizing intravascular hemolysis (IVH) and/or extravascular hemolysis (EVH) in the subject.

9. The method of claim 8 , wherein normalizing IVH and/or EVH hemolysis comprises increasing the haptoglobin level, decreasing reticulocytes level, or decreasing bilirubin level, in the subject as compared to baseline.

10. The method of claim 1 , wherein treating PNH comprises treating PNH associated hemolysis.

11. The method of claim 1 , wherein treating PNH comprises reducing C3 deposition in the subject.

12. The method of claim 1 , wherein treating PNH comprises increasing red blood cell (RBC) survival in the subject.

13. The method of claim 1 , wherein treating PNH comprises reducing Fragment Bb level in the subject.

14. The method of claim 1 , wherein treating PNH comprises increasing hemoglobin levels in the subject by about 2 g/dL or more as compared to baseline.

15. The method of claim 1 , wherein treating PNH comprises achieving a sustained increase in hemoglobin level.

16. The method of claim 1 , wherein treating PNH comprises achieving a sustained increase in hemoglobin level to greater than or equal to about 12 g/dL.

17. The method of claim 1 , wherein treating PNH comprises increasing hemoglobin levels in the subject in the absence of receiving one or more red blood cell (RBC) transfusion(s).

18. The method of claim 1 , wherein the subject has received RBC transfusions.

19. The method of claim 1 , wherein the subject has been vaccinated prior to administration of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof, and the prior vaccination is against Neisseria meningitidis (types A, C, Y and W-135).

20. The method of claim 1 , wherein efficacy of treatment is determined by measuring the hemoglobin levels in the subject as compared to baseline.

21. The method of claim 1 , wherein treating PNH comprises achieving a sustained increase in hemoglobin level after about 4 weeks of administering to the subject 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof.

22. The method of claim 1 , comprising orally administering to the subject 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride.

23. The method of claim 8 , comprising orally administering to the subject 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride.

24. The method of claim 14 , comprising orally administering to the subject 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol -4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride.

25. The method of claim 16 , comprising orally administering to the subject 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride.

26. The method of claim 17 , comprising orally administering to the subject 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride.

27. The method of claim 19 , comprising orally administering to the subject 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol -4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride.

28. The method of claim 6 , comprising orally administering to the subject 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride.

29. The method of claim 6 , wherein treating PNH comprises increasing hemoglobin levels in the subject by about 2 g/dL or more as compared to baseline.

30. The method of claim 6 , wherein the subject has been vaccinated prior to administration of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol -4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof, and the prior vaccination is against Neisseria meningitidis (types A, C, Y and W-135).

31. The method of claim 6 , wherein treating PNH comprises increasing hemoglobin levels in the subject in the absence of receiving one or more RBC transfusion(s).

32. The method of claim 14 , wherein the subject has been vaccinated prior to administration of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof, and the prior vaccination is against Neisseria meningitidis (types A, C, Y and W-135).

33. The method of claim 14 , wherein treating PNH comprises increasing hemoglobin levels in the subject in the absence of receiving one or more RBC transfusion(s).

34. The method of claim 17 , wherein the subject has been vaccinated prior to administration of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof, and the prior vaccination is against Neisseria meningitidis (types A, C, Y and W-135).

35. The method of claim 32 , comprising orally administering to the subject 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride.

36. The method of claim 33 , comprising orally administering to the subject 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride.

37. The method of claim 34 , comprising orally administering to the subject 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride.

38. The method of claim 37 , wherein treating PNH further comprises increasing hemoglobin levels in the subject by about 2 g/dL or more as compared to baseline.