Claims for Patent: 11,951,101

Summary for Patent: 11,951,101

Title:	Methods of using factor B inhibitors
Abstract:	Described herein are methods of treating paroxysmal nocturnal hemoglobinuria (PNH) with the Factor B inhibitor LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride.
Inventor(s):	Irina Baltcheva, Peter End, Julie Marie-Pomme Gabrielle MILOJEVIC
Assignee:	Novartis AG , Novartis Pharma AG
Application Number:	US17/376,483
Patent Claims:	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.