How to Use Factor B Inhibitors

Abstract

Disclosed herein is a method for treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) with the factor B inhibitor iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride).

Description

[Technical Field]

[0001] The present disclosure relates to methods of treating complement-mediated diseases, particularly immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), using the factor B inhibitor iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride). [Background technology]

[0002] Immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) is an ultrarare, rapidly progressive renal disease that can be idiopathic (primary IC-MPGN) or secondary to chronic infection or other immunosystemic diseases (Sethi S, Fervenza FC (2011) Membranoproliferative glomerulonephritis: Pathogenetic heterogeneity and proposal for a new classification. Semin Nephrol; 31(4):341-8). Although IC-MPGN is a distinct disease according to the current classification, it shares important similarities with C3 glomerulopathy (C3G), which is typically characterized by membranoproliferative histopathology. IC-MPGN has predominant immunoglobulin complex staining, whereas C3G has predominant complement 3 staining.

[0003] Both IC-MPGN and C3G are extremely rare (Wong EKS, Marchbank KJ, Lomax-Browne H, et al (2021) C3 Glomerulopathy and Related Disorders in Children: Etiology-Phenotype Correlation and Outcomes. Clin J Am Soc Nephrol;16(11):1639-51) and are frequently diagnosed in childhood and adolescence, with the median age at diagnosis for IC-MPGN being approximately 21 years (Iatropoulos P, Daina E, Curreri M, et al (2018) Cluster Analysis Identifies Distinct Pathogenetic Patterns in C3 Glomerulopathies / Immune Complex-Mediated Membranoproliferative GN. J Am Soc Nephrol;29(1):283-94; and Garam N, Prohaszka Z, Szilagyi A, et al (2020) Validation of distinct Pathogenic patterns in a cohort of membranoproliferative glomerulonephritis patients by cluster analysis. Clin Kidney J; 13(2):225-34), both of which are characterized by a high risk of progression to renal failure (Iatropoulos et al., 2018; and Wong et al., 2021). Dysregulation of the alternative complement pathway (AP) is strongly implicated in the pathogenesis of IC-MpGN and C3G (Wong et al., 2021).

[0004] Membranoproliferative glomerulonephritis (MPGN) is a rare histologic pattern of glomerular injury characterized by cellular hyperplasia, endovascular proliferation, and capillary wall thickening with double contouring at the light microscopic level on renal biopsy. It has many causes, and its detection should prompt clinicians to investigate potential underlying causes. Recent improvements in understanding its pathogenesis, along with the recognition of the critical role of the alternative complement pathway (AP), have led to the description of complement-mediated (C3 glomerulopathy, C3G) and immune complex-mediated (IC-MPGN) forms (Schena FP, Esposito P, Rossini M (2020) A Narrative Review on C3 Glomerulopathy: A Rare Renal Disease. Int J Mol Sci;21(2):525). Based on immunofluorescence staining findings in renal biopsies, the diagnosis of C3G is made in cases of predominant glomerular C3 deposition with little or no Ig deposition (C3 >2 orders of magnitude greater than any other immunoreactive substance), whereas IC-MPGN is diagnosed in cases of predominantly glomerular Ig deposition (Sethi, Fervenza 2011; Cook HT, Pickering MC (2015) Histopathology of MPGN and C3 glomerulopathies. Nat Rev Nephrol; 11(1):14-22). There is evidence that histologic diagnoses can change over time; among patients who underwent repeat biopsies, 40% had variable immunofluorescence (IF) staining patterns in the initial and follow-up biopsies, and 17% showed a shift from C3G to IC-MPGN and vice versa (Hou J, Markowitz GS, Bomback AS, et al (2014) Toward a working definition of C3 glomerulopathy by immunofluorescence. Kidney Int;85(2):450-6). C3G is further classified into C3 glomerulonephritis (C3GN) and dense deposit disease (DDD) based on additional findings only seen at the electron microscopic level.

[0005] IC-MPGN may be secondary to chronic infections, including hepatitis B or C virus infection, endocarditis, shunt nephritis, abscesses, fungal infections, parasitic infections (e.g., schistosomiasis, echinococcus, malaria, etc.), or systemic autoimmune disorders, including but not limited to systemic lupus erythematosus (SLE), Sjögren's syndrome, and rheumatoid arthritis. Finally, it may be secondary to monoclonal gammopathy. Therefore, careful evaluation of the underlying cause is essential. Treatment of such secondary cases is generally directed toward the underlying condition. If no underlying cause is detected, IC-MPGN is classified as idiopathic (primary IC-MPGN). Given the current evidence supporting the critical role of complement dysregulation in IC-MPGN, a complete complement workup should be performed. This workup should include functional complement assays, quantification of complement components and regulatory factors, measurement of complement activation, complement autoantibodies, genetic testing, and immunofluorescence staining of renal biopsy samples (KDIGO 2021). Some studies indicate an incidence of 1-2 cases per million per year (Medjeral-Thomas et al., 2014) with approximately equal numbers of patients with primary IC-MPGN and C3G (Servais A, Noael LH, Roumenina LT, et al., (2012) Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int; 82(4):454-64; Iatropoulos et al., 2016, Wong et al., 2021).

[0006] The clinical manifestations of IC-MPGN are heterogeneous, ranging from asymptomatic hematuria and proteinuria, nephritis or nephrotic syndrome, or rapidly progressive glomerulonephritis with acute kidney injury (Iatropoulos et al., 2016; Holle J, Berenberg-Goßler L, Wu K, et al. (2018) Outcome of membranoproliferative glomerulonephritis and C3-glomerulopathy in children and adolescents. Pediatr Nephrol;33(12):2289-98). The MPGN pattern can be present in the absence of Ig deposits but not in the absence of C3 deposits. In serial renal biopsies within each patient, Ig deposits are variable and may disappear, while C3 deposits are always present. Nephrotic syndrome is more frequent in IC-MPGN (43%-70%) compared with C3G patients (26%-52%). Glomerular C4d staining is positive in the majority (80%) of primary Ig-MPGN (limited number of cases tested) and secondary Ig-MPGN, and only (and only marginally) in a minority (13%) of C3G cases. IC-MPGN is a rapidly progressive disease, with an estimated 50% of patients progressing to renal failure within 10 years (Servais et al., 2012). This is similar to what was found in C3G patients in this study, although some recent data suggest that progression to renal failure in IC-MPGN may be somewhat less rapid than in C3G (Lomax-Browne HJ, Medjeral-Thomas NR, Barbour SJ, et al (2022) Association of Histologic Parameters with Outcome in C3 Glomerulopathy and Idiopathic Immunoglobulin-Associated Membranoproliferative Glomerulonephritis. Clin J Am Soc Nephrol;17(7):994-1007).

[0007] Supportive therapy with renin-angiotensin system inhibition alone is recommended for patients with idiopathic IC-MPGN, proteinuria less than 3.5 g / d, and a normal estimated glomerular filtration rate (eGFR). Similar therapy is also recommended for patients who present after active disease has subsided and whose renal biopsy shows advanced tubulointerstitial fibrosis.

[0008] The Clinical Practice Guideline for Glomerulonephritis (KDIGO 2021) recognizes that there is currently no evidence supporting the use of immunosuppressive therapy in adults or children with primary IC-MPGN. However, in patients with nephrotic syndrome and a normal or near-normal glomerular filtration rate (GFR), a limited course of corticosteroids is recommended, or calcineurin inhibitors may be used if corticosteroid contraindications exist. The guideline notes that immunosuppressive therapy may be initiated in children with low levels of proteinuria, who may also be more likely to receive MMF as a corticosteroid-sparing agent. In patients with abnormal renal function, glucocorticoids and immunosuppressive therapy should be added to supportive care (KDIGO 2021).

[0009] The alternative complement pathway (AP) is important for innate and adaptive immunity, but hyperactivity of the AP is known to cause or exacerbate numerous diseases with autoimmune components.

[0010] Iptacopan is a first-in-class, oral, low-molecular-weight (LMW), reversible, and selective inhibitor of factor B (FB) (Schubart et al., 2019, Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proc Natl Acad Sci USA, pp. 7926–7931), a key protease in the AP (Merle et al., 2015, Complement System Part I—Molecular Mechanisms of Activation and Regulation. Front Immunol, pp. 262). Inhibition of FB prevents all pathway amplification and AP-induced assembly of C3 and C5 convertases. At the same time, iptacopan has limited effect on classical pathway-induced terminal pathway activation. Iptacopan inhibits FB in association with C3 convertase, thereby blocking AP-dependent C3 activation and CP- and LP-dependent C5 activation amplification. However, iptacopan does not block MAC production initiated by CP and LP. This is important because it means that MAC-dependent killing of Neisseria species through CP activation is maintained in immunized individuals. Nevertheless, no clinical data are available on the use of iptacopan in patients with IC-MPGN.

[0011] In summary, the mechanism and underlying cause of glomerular immune complex formation in IC-MPGN are unknown. In addition, the clinical symptoms and disease course (including the rate of progression to renal failure) in IC-MPGN are similar to those in C3G, but the occurrence of nephrotic syndrome is more frequent in IC-MPGN patients (43%-70%) compared with C3G patients (26%-52%). Clinical data on the use of complement inhibitors in IC-MPGN patients are still unavailable. Summary of the Invention

[0012] The present disclosure relates to methods of treating complement-mediated diseases, particularly immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), with iptacopan (Formula I shown below) or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride). Iptacopan is also known as LNP023. The terms "iptacopan" and "LNP023" are used interchangeably herein. Iptacopan (4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid) belongs to the class of factor B inhibitors of the complement pathway and acts by inhibiting or suppressing the amplification of the complement system caused by C3 activation, regardless of the initial activation mechanism.

[0013] Iptacopane hydrochloride is chemically represented as 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride, shown in formula I below. [ka]

[0014] Iptacopane hydrochloride and methods for its preparation are disclosed in WO 2015 / 009616 (see Example 26d), which is incorporated herein by reference in its entirety. The form of iptacopane hydrochloride used as the investigational study drug for this study was the monohydrate (Form H), shown in the formula: B ) [ka] (2S,4S)-2-(4-carboxyphenyl)-4-ethoxy-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-1-ium chloride-water (1 / 1)

[0015] Iptacopane hydrochloride monohydrate Form H B and methods for preparing same are disclosed in U.S. Patent Application Nos. 63 / 026,637 and 63 / 052,699, published in WO 2021 / 234544, each of which is incorporated herein by reference in its entirety.

[0016] The present disclosure provides a method of treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject (e.g., a patient) in need thereof, comprising administering (e.g., orally administering) iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride) to the subject (e.g., the patient) at a dose of, for example, about 50 mg to about 200 mg, e.g., about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose administered twice daily (bid), e.g., about every 12 hours, thereby treating the subject (e.g., the patient), wherein the dose refers to the anhydrous free base of iptacopan hydrochloride.

[0017] In one aspect, the present invention provides a method of treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject in need thereof, comprising administering iptacopan or a pharmaceutically acceptable salt thereof to the subject, thereby treating the subject.

[0018] In a further aspect, the present invention provides iptacopan or a pharmaceutically acceptable salt thereof for use in the treatment of immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject in need thereof, which treatment comprises administering iptacopan or a pharmaceutically acceptable salt thereof to the subject.

[0019] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of iptacopan or a pharmaceutically acceptable salt thereof for use in treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject in need thereof, wherein the pharmaceutical composition is administered to thereby treat the subject.

[0020] In another aspect, the present invention provides a use of iptacopan or a pharmaceutically acceptable salt thereof for a product for treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject in need thereof.

[0021] In one embodiment, the methods and uses of the present invention comprise administering iptacopan or a pharmaceutically acceptable salt thereof to a subject at a dose of about 50 mg to about 200 mg administered twice daily (bid), e.g., about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, where this dosage refers to the anhydrous free base of iptacopan. In one embodiment, the methods and uses of the present invention comprise administering iptacopan or a pharmaceutically acceptable salt thereof to a subject at a dose of 200 mg administered twice daily (bid), where this dosage refers to the anhydrous free base of iptacopan.

[0022] Non-limiting embodiments of the present disclosure are described in the following embodiments: Embodiment 1: A method of treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject in need thereof, comprising administering iptacopan or a pharmaceutically acceptable salt thereof to the subject, thereby treating the subject.

[0023] Embodiment 2: The method of embodiment 1, wherein iptacopan or a pharmaceutically acceptable salt thereof is administered orally.

[0024] Embodiment 3: The method of embodiment 1 or 2, wherein iptacopan or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg to about 200 mg, e.g., about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, administered twice daily (bid), where the dose refers to the anhydrous free base of iptacopan.

[0025] Embodiment 4: The method of embodiment 3, wherein the dose is about 200 mg twice daily.

[0026] Embodiment 5: The method of any one of embodiments 1-4, wherein the pharmaceutically acceptable salt of iptacopan is iptacopan hydrochloride.

[0027] Embodiment 6: The method of any one of embodiments 1-5, wherein the subject is receiving supportive care including an ACEi, an ARB, mycophenolic acid (e.g., mycophenolate mofetil (MMF) and mycophenolate sodium (MPS)), a corticosteroid, an SGLT2 inhibitor, a mineralocorticoid receptor antagonist, cyclophosphamide (CYC), or a calcineurin inhibitor prior to administration of iptacopan or a pharmaceutically acceptable salt thereof.

[0028] Embodiment 7: The method of embodiment 6, wherein the ACEi or ARB is administered at the maximum recommended dose or maximum tolerated dose.

[0029] Embodiment 8: The method of embodiment 7, wherein the subject is further administered a stable dose of supportive care.

[0030] Embodiment 9: The method of any one of embodiments 1 to 8, wherein the subject is an adult or an adolescent.

[0031] Embodiment 10: The method of any one of embodiments 1 to 9, wherein the urinary protein / creatinine ratio (UPCR) in the subject is reduced compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof.

[0032] Embodiment 11: The method of embodiment 10, wherein the urinary protein / creatinine ratio (UPCR) in the subject is reduced by 50% or more compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof, particularly, the urinary protein / creatinine ratio (UPCR) in the subject is reduced by 50% or more 6 months after treatment.

[0033] Embodiment 12: The method of any one of embodiments 1 to 11, wherein the estimated glomerular filtration rate (eGFR) in the subject is stable or improved compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof.

[0034] Embodiment 13: The method of embodiment 12, wherein the estimated glomerular filtration rate (eGFR) in the subject is reduced by no more than 15% compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof, particularly, the estimated glomerular filtration rate (eGFR) in the subject is reduced by no more than 15% 6 months after treatment.

[0035] Embodiment 14: Iptacopan or a pharmaceutically acceptable salt thereof for use in treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject in need thereof, wherein the treatment comprises administering iptacopan or a pharmaceutically acceptable salt thereof to the subject.

[0036] Embodiment 15: Iptacopan or a pharmaceutically acceptable salt thereof for use according to embodiment 14, wherein the iptacopan or a pharmaceutically acceptable salt thereof is administered orally.

[0037] Embodiment 16: Iptacopan or a pharmaceutically acceptable salt thereof for use according to embodiment 14 or 15, wherein iptacopan or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg to about 200 mg, e.g., about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose administered twice daily (bid), and the doses refer to the anhydrous free base of iptacopan.

[0038] Embodiment 17: Iptacopan or a pharmaceutically acceptable salt thereof for use according to embodiment 16, wherein the dose is about 200 mg twice daily.

[0039] Embodiment 18: Iptacopan or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 14 to 17, wherein the pharmaceutically acceptable salt of iptacopan is iptacopan hydrochloride.

[0040] Embodiment 19: Iptacopan or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 14 to 18, wherein the subject is receiving supportive care including an ACEi, an ARB, mycophenolic acid (e.g., mycophenolate mofetil (MMF) and mycophenolate sodium (MPS)), a corticosteroid, an SGLT2 inhibitor, a mineralocorticoid receptor antagonist, cyclophosphamide (CYC), or a calcineurin inhibitor prior to administration of iptacopan or a pharmaceutically acceptable salt thereof.

[0041] Embodiment 20: Iptacopan or a pharmaceutically acceptable salt thereof for use according to embodiment 19, wherein the ACEi or ARB is administered at the maximum recommended dose or maximum tolerated dose.

[0042] Embodiment 21: Iptacopan or a pharmaceutically acceptable salt thereof for use according to embodiment 20, wherein the subject is further administered a stable dose of supportive care.

[0043] Embodiment 22: Iptacopan or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 14 to 21, wherein the subject is an adult or an adolescent.

[0044] Embodiment 23: Iptacopan or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 14 to 22, wherein the urinary protein / creatinine ratio (UPCR) in the subject is reduced compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof.

[0045] Embodiment 24: Iptacopan or a pharmaceutically acceptable salt thereof for use according to embodiment 23, wherein the urinary protein / creatinine ratio (UPCR) in the subject is reduced by 50% or more compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof, in particular, the urinary protein / creatinine ratio (UPCR) in the subject is reduced by 50% or more 6 months after treatment.

[0046] Embodiment 25: Iptacopan or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 14 to 24, wherein the estimated glomerular filtration rate (eGFR) in the subject is stable or improved compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof.

[0047] Embodiment 26: Iptacopan or a pharmaceutically acceptable salt thereof for use according to embodiment 25, wherein the estimated glomerular filtration rate (eGFR) in the subject is reduced by no more than 15% compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof, in particular, the estimated glomerular filtration rate (eGFR) in the subject is reduced by no more than 15% 6 months after treatment.

[0048] Embodiment 27: A pharmaceutical composition comprising a therapeutically effective amount of iptacopan or a pharmaceutically acceptable salt thereof for use in treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject in need thereof, wherein the pharmaceutical composition is administered, thereby treating the subject.

[0049] Embodiment 28: The pharmaceutical composition of embodiment 27, wherein iptacopan or a pharmaceutically acceptable salt thereof is administered orally.

[0050] Embodiment 29: The pharmaceutical composition of embodiment 27 or 28, wherein iptacopan or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg to about 200 mg, e.g., about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose administered twice daily (bid), and the doses refer to the anhydrous free base of iptacopan.

[0051] Embodiment 30: The pharmaceutical composition of embodiment 29, wherein the dose is about 200 mg twice daily.

[0052] Embodiment 31: The pharmaceutical composition of any one of embodiments 27 to 30, wherein the pharmaceutically acceptable salt of iptacopan is iptacopan hydrochloride.

[0053] Embodiment 32: The pharmaceutical composition of any one of embodiments 27 to 31, wherein the subject is receiving supportive care including an ACEi, an ARB, mycophenolic acid (e.g., mycophenolate mofetil (MMF) and mycophenolate sodium (MPS)), a corticosteroid, an SGLT2 inhibitor, a mineralocorticoid receptor antagonist, cyclophosphamide (CYC), or a calcineurin inhibitor prior to administration of iptacopan or a pharmaceutically acceptable salt thereof.

[0054] Embodiment 33: The pharmaceutical composition of embodiment 32, wherein the ACEi or ARB is administered at the maximum recommended dose or maximum tolerated dose.

[0055] Embodiment 34: The pharmaceutical composition of embodiment 33, wherein the subject is further administered a stable dose of supportive care.

[0056] Embodiment 35: The pharmaceutical composition of any one of embodiments 27 to 34, wherein the subject is an adult or an adolescent.

[0057] Embodiment 36: The pharmaceutical composition of any one of embodiments 27 to 35, wherein the urinary protein / creatinine ratio (UPCR) in the subject is reduced compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof.

[0058] Embodiment 37: The pharmaceutical composition of embodiment 35, wherein the urinary protein / creatinine ratio (UPCR) in the subject is reduced by 50% or more compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof, particularly, the urinary protein / creatinine ratio (UPCR) in the subject is reduced by 50% or more 6 months after treatment.

[0059] Embodiment 38: The pharmaceutical composition of any one of embodiments 27 to 37, wherein the estimated glomerular filtration rate (eGFR) in the subject is stable or improved compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof.

[0060] Embodiment 39: The pharmaceutical composition of embodiment 38, wherein the estimated glomerular filtration rate (eGFR) in the subject is reduced by 15% or less compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof, particularly, the estimated glomerular filtration rate (eGFR) in the subject is reduced by 15% or less 6 months after treatment.

[0061] Embodiment 40: Use of iptacopan or a pharmaceutically acceptable salt thereof for the manufacture of a method for treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject in need thereof.

[0062] Embodiment 41: The use of embodiment 40, wherein iptacopan or a pharmaceutically acceptable salt thereof is administered orally.

[0063] Embodiment 42: The use of embodiment 40 or 41, wherein the use comprises administering iptacopan or a pharmaceutically acceptable salt thereof to a subject at a dose of about 50 mg to about 200 mg, e.g., about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, wherein each dose is administered twice daily (bid), and the dose refers to the anhydrous free base of iptacopan.

[0064] Embodiment 43: The use of embodiment 42, wherein the dose is about 200 mg twice a day.

[0065] Embodiment 44: The use of any one of embodiments 40 to 43, wherein the pharmaceutically acceptable salt of iptacopan is iptacopan hydrochloride.

[0066] Embodiment 45: The use of any one of embodiments 40 to 44, wherein the subject is receiving supportive care including an ACEi, an ARB, mycophenolic acid (e.g., mycophenolate mofetil (MMF) and mycophenolate sodium (MPS)), a corticosteroid, an SGLT2 inhibitor, a mineralocorticoid receptor antagonist, cyclophosphamide (CYC), or a calcineurin inhibitor prior to administration of iptacopan or a pharmaceutically acceptable salt thereof.

[0067] Embodiment 46: The use of embodiment 45, wherein the ACEi or ARB is administered at the maximum recommended dose or maximum tolerated dose.

[0068] Embodiment 47: The use of embodiment 46, wherein the subject is further administered a stable dose of supportive care.

[0069] Embodiment 48: The use of any one of embodiments 40 to 47, wherein the subject is an adult or an adolescent.

[0070] Embodiment 49: The use of any one of embodiments 40 to 48, wherein the urinary protein / creatinine ratio (UPCR) in the subject is reduced compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof.

[0071] Embodiment 50: The use of embodiment 49, wherein the urinary protein / creatinine ratio (UPCR) in the subject is reduced by 50% or more compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof, particularly, the urinary protein / creatinine ratio (UPCR) in the subject is reduced by 50% or more 6 months after treatment.

[0072] Embodiment 51: The use of any one of embodiments 40 to 50, wherein the estimated glomerular filtration rate (eGFR) in the subject is stable or improved compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof.

[0073] Embodiment 52: The use of embodiment 51, wherein the estimated glomerular filtration rate (eGFR) in the subject is reduced by no more than 15% compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof, particularly wherein the estimated glomerular filtration rate (eGFR) in the subject is reduced by no more than 15% 6 months after treatment. [Brief explanation of the drawings]

[0074] [Figure 1] A schematic diagram of the study design is shown. DETAILED DESCRIPTION OF THE INVENTION

[0075] Described herein is iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H). B) to treat immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a patient in need thereof. Accordingly, described herein are methods of treating IC-MPGN in a patient in need thereof, comprising administering (e.g., orally in capsule form) iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride) to the patient, wherein the iptacopan or pharmaceutically acceptable salt thereof is administered twice daily, e.g., about every 12 hours, at a dose of about 50 mg to about 200 mg, e.g., about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg (this dose refers to the anhydrous free base of iptacopan hydrochloride). Thus, described herein are methods for treating IC-MPGN in a patient in need thereof, comprising administering (e.g., orally in capsule form) iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride) to the patient, wherein the iptacopan or a pharmaceutically acceptable salt thereof is administered twice daily, e.g., about every 12 hours, at a dose of 200 mg (this dose refers to the anhydrous free base of iptacopan hydrochloride). Also described herein are methods for selecting a target patient population, monitoring treatment of the target patient population, and evaluating the safety and efficacy of treatment of the target patient population.

[0076] Details of the present disclosure are described in the accompanying specification below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, exemplary methods and materials are now described. Other features, objects, and advantages of the present disclosure will become apparent from this description and the claims. In this specification and the appended claims, the singular also includes the plural unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference in their entirety.

[0077] definition Unless specific definitions are provided, the nomenclature used in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry described herein are those well known and commonly used in the art. Standard techniques may be used for chemical syntheses and chemical analyses. Certain such techniques and procedures can be found, for example, in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa., 21st edition, 2005, incorporated herein by reference for all purposes. Where permitted, all patents, applications, published applications, and other publications and other data referenced throughout this disclosure are incorporated herein by reference in their entirety.

[0078] Unless otherwise stated, the following terms have the following meanings:

[0079] As used herein, "about" means within ±10% of a value.

[0080] As used herein, "administering" or "administration" means providing a pharmaceutical agent to an individual, including, but not limited to, administration by a medical professional and self-administration. Administration of a pharmaceutical agent to an individual can be continuous, chronic, short-term, or intermittent.

[0081] As used herein, the terms "obtain" or "obtaining," as these terms are used herein, refer to gaining possession of a physical entity (e.g., a sample, e.g., a blood sample or plasma sample) or value (e.g., a numerical value) by "directly obtaining" or "indirectly obtaining" this physical entity or value. "Directly obtaining" means performing a process (e.g., an analytical method) to obtain the physical entity or value. "Indirectly obtaining" refers to receiving the physical entity or value from another party or source (e.g., a third-party laboratory that directly obtained the physical entity or value). Directly obtaining a value includes performing a process that involves a physical change of a sample or another substance, for example, performing an analytical process that involves a physical change of a substance (e.g., a sample), performing an analytical method, e.g., a method described herein, for example, by analyzing a sample of a bodily fluid (e.g., blood), for example, by mass spectroscopy, e.g., LC-MS, e.g., LC-MS / MS methods.

[0082] As used herein, "dose" refers to a specified amount of a pharmaceutical agent provided in a single administration or within a specified period of time. In certain embodiments, the dose may be administered in a capsule. As used herein, the dose refers to the anhydrous free base of iptacopane hydrochloride.

[0083] As used herein, "individual," "patient," "participant," or "subject" refers to a human selected for treatment or therapy. As used herein, the term "adult" refers to an individual aged 18 years or older. As used herein, the term "adolescent" refers to an individual aged 12-17 years.

[0084] As used herein, "pharmaceutically acceptable salts" refers to physiologically and pharmaceutically acceptable salts of iptacopan, i.e., salts that retain the desired biological activity of iptacopan and do not impart undesired toxicological effects. The term "pharmaceutically acceptable salts" or "salts" includes salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic or organic acids and inorganic or organic bases. Pharmaceutically acceptable salts of iptacopan can be prepared by methods well known in the art. For a review of pharmaceutically acceptable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use (Wiley-VCH, Weinheim, Germany, 2002). Iptacopan hydrochloride and methods for its preparation are disclosed in WO 2015 / 009616 (see Example 26d), the entire contents of which are incorporated herein by reference.

[0085] As used herein, the terms "treat," "treating," or "treatment" refer to slowing, inhibiting, attenuating, reducing, halting, or stabilizing the onset or progression of a disorder or disease, such as lupus nephritis, immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN). Treatment does not necessarily cure the disorder, but encompasses alleviation of symptoms or underlying risk factors, or slowing of disease progression. As used herein, the terms "treat," "treatment," and "treating" refer to slowing, reducing, or ameliorating the progression or severity of IC-MPGN, or ameliorating one or more symptoms (preferably at least one or more identifiable symptoms of IC-MPGN). In specific embodiments, the terms "treat," "treatment," and "treating" refer to an improvement in at least one measurable physical parameter of IC-MPGN (e.g., achieving or at least partially achieving a desired effect (e.g., reduction in proteinuria, particularly as measured by urinary protein:creatinine ratio (UPCR), improvement in estimated glomerular filtration rate (eGFR), improvement in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score)), which physical parameter is not necessarily discernible by the patient.

[0086] Unless otherwise specified, conventional definitions of controlled terms and conventional stable atom valences are presumed and achieved in all formulas and groups.

[0087] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (e.g., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0088] How to use In one aspect, the disclosure provides a method of treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject (e.g., a patient) in need thereof, comprising administering iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H).B ) to a subject (e.g., a patient), thereby treating the subject (e.g., a patient).

[0089] In another aspect, the present disclosure provides a method for reducing proteinuria (e.g., reducing urinary protein / creatinine ratio (UPCR)) in a subject (e.g., patient) in need thereof, comprising administering (e.g., orally administering) iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride) to the subject (e.g., patient), thereby treating the subject (e.g., patient).

[0090] In another aspect, the disclosure provides a method for achieving stable or improved estimated glomerular filtration rate (eGFR) in a subject (e.g., a patient) in need thereof, comprising administering iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H). B ) to a subject (e.g., a patient), thereby treating the subject (e.g., a patient).

[0091] In another aspect, the disclosure provides iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H) for use in treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject (e.g., a patient) in need thereof. B ), wherein the treatment is performed using iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H B The present invention provides a method for treating iptacopan or a pharmaceutically acceptable salt thereof, comprising administering to the subject (e.g., patient)

[0092] In another aspect, the disclosure relates to iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H) for use in reducing proteinuria (e.g., reducing UPCR) in a subject (e.g., a patient) in need thereof. B ), wherein the treatment is performed using iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H B The present invention provides a method for treating iptacopan or a pharmaceutically acceptable salt thereof, comprising administering to the subject (e.g., patient)

[0093] In another aspect, the disclosure provides a method for the treatment of idiopathic rheumatoid arthritis (HRA) and / or rheumatoid arthritis (HRA) in a subject (e.g., a patient) in need thereof, comprising administering to the patient a therapeutically effective amount of idiopathic rheumatoid arthritis (HRA) or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H) for use in achieving stable or improved eGFR in a subject (e.g., a patient) in need thereof. B ), wherein the treatment is performed using iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H B The present invention provides a method for treating iptacopan or a pharmaceutically acceptable salt thereof, comprising administering to the subject (e.g., patient)

[0094] In another aspect, the disclosure provides a method for treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject (e.g., a patient) in need thereof, comprising administering iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form HB) to a subject (e.g., a patient) in need thereof, the method ... monohydrate Form HB) to a subject (e.g., a patient) in need thereof, the method comprising administering iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride monohydrate Form HB) to a subject (e.g., a patient) in need thereof, the method comprising administering iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride monohydrate Form HB) to a subject (e.g., a patient) in need thereof, the method comprising administering iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride monohydrate Form B ) to the subject (e.g., patient).

[0095] In another aspect, the disclosure provides a pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H) in the manufacture of a medicament for reducing proteinuria (e.g., reducing UPCR) in a subject (e.g., a patient) in need thereof. B ), wherein the treatment comprises the use of iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H B orally administering to the subject (e.g., patient)

[0096] In another aspect, the present disclosure provides a method for the use of iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H) in the manufacture of a medicament for achieving stable or improved eGFR in a subject (e.g., a patient) in need thereof. B ), wherein the treatment comprises the use of iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H B orally administering to the subject (e.g., patient)

[0097] In another aspect, the present disclosure provides iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H), for use in treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject (e.g., a patient) in need thereof. B ), wherein the pharmaceutical composition is administered to a subject (e.g., a patient) to thereby treat the subject (e.g., a patient).

[0098] In another aspect, the disclosure relates to iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H), for use in reducing proteinuria (e.g., reducing UPCR) in a subject (e.g., a patient) in need thereof. B), wherein the pharmaceutical composition is administered to a subject (e.g., a patient) to thereby treat the subject (e.g., a patient).

[0099] In another aspect, the disclosure provides a method for administering iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H) for use in achieving stable or improved eGFR in a subject (e.g., a patient) in need thereof. B ), wherein the pharmaceutical composition is administered to a subject (e.g., a patient) to thereby treat the subject (e.g., a patient).

[0100] The above-described aspects of the present invention are respectively represented by the following embodiments, and these embodiments can be combined as appropriate.

[0101] In some embodiments, iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H) is administered intravenously. B ) is administered twice daily (bid), e.g., at a dose of about 50 mg to about 200 mg administered about every 12 hours, e.g., about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg (this dosage refers to the anhydrous free base of iptacopan hydrochloride). In another embodiment, iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H) is administered. B ) is administered twice daily (bid), e.g., in a dose of 50 mg to 200 mg administered about every 12 hours, e.g., 50 mg to 100 mg, 100 mg to 200 mg, 50 mg, 75 mg, 100 mg, 150 mg, or 200 mg (this dose refers to the anhydrous free base of iptacopane hydrochloride).

[0102] In some embodiments, iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H) is administered intravenously.B ) is administered at a dose of about 100 mg twice daily (bid), and in particular at a dose of 100 mg twice daily (bid) (this dose refers to the anhydrous free base of iptacopan hydrochloride).

[0103] In some embodiments, iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H) is administered intravenously. B ) is administered twice daily (bid) at a dose of about 200 mg (this dose refers to the anhydrous free base of iptacopan hydrochloride). In a preferred embodiment, iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H) is administered. B ) is administered twice daily (bid) at a dose of 200 mg (this dose refers to the anhydrous free base of iptacopan hydrochloride).

[0104] In some embodiments, iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H) is administered intravenously. B ) is administered orally.

[0105] In one embodiment, the method comprises administering iptacopane hydrochloride monohydrate Form H B to a subject (e.g., a patient).

[0106] In one embodiment, iptacopane hydrochloride monohydrate Form H B is a crystalline form characterized by PXRD peaks identified at 2-theta angles of (4.6±0.2)°, (9.2±0.2)°, and (19.1±0.2)° when measured at temperatures ranging from 20 to 30°C using Cu-K alpha 1,2 radiation having a wavelength of 0.15419 nm.

[0107] In one embodiment, iptacopane hydrochloride monohydrate Form H Bis a crystalline form characterized by PXRD peaks identified at 2-theta angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, and (19.1±0.2)° when measured at temperatures ranging from 20 to 30°C using Cu-K alpha 1,2 radiation having a wavelength of 0.15419 nm.

[0108] In one embodiment, iptacopane hydrochloride monohydrate Form H B is a crystalline form characterized by PXRD peaks identified at 2-theta angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (19.1±0.2)°, and (24.6±0.2)° when measured at temperatures ranging from 20 to 30°C using Cu-K alpha 1,2 radiation having a wavelength of 0.15419 nm.

[0109] In one embodiment, iptacopane hydrochloride monohydrate Form H B is a crystalline form characterized by PXRD peaks identified at 2-theta angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (12.2±0.2)°, (19.1±0.2)°, and (24.6±0.2)° when measured at temperatures ranging from 20 to 30°C using Cu-K alpha 1,2 radiation having a wavelength of 0.15419 nm.

[0110] In one embodiment, iptacopane hydrochloride monohydrate Form H B is a crystalline form characterized by PXRD peaks assigned at 2-theta angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (12.2±0.2)°, (16.6±0.2)°, (19.1±0.2)°, (21.3±0.2)°, and (24.6±0.2)° when measured at temperatures ranging from 20 to 30°C using Cu-K alpha 1,2 radiation having a wavelength of 0.15419 nm.

[0111] In one embodiment, iptacopane hydrochloride monohydrate Form H B is as follows when measured at temperatures in the range of 20-30°C using Cu-K alpha 1,2 radiation with a wavelength of 0.15419 nm: (4.6±0.1)°, (9.2±0.1)°, and (19.1±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, and (19.1±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (19.1±0.1)°, and (24.6±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (12.2±0.1)°, (19.1±0.1)°, and (24.6±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (12.2±0.1)°, (19.1±0.1)°, (21.3±0.1)°, and (24.6±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (12.2±0.1)°, (12.6±0.1)°, (16.6±0.1)°, (19.1±0.1)°, (21.3±0.1)°, and (24.6±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (10.0±0.1)°, (12.2±0.1)°, (12.6±0.1)°, (16.6±0.1)°, (19.1±0.1)°, (21.3±0.1)°, and (24.6±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (10.0±0.1)°, (12.2±0.1)°, (12.6±0.1)°, (16.6±0.1)°, (19.1±0.1)°, (21.3±0.1)°, and (24.6±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (10.0±0.1)°, (12.2±0.1)°, (12.6±0.1)°, (15.3±0.1)°, (16.6±0.1)°, (19.1±0.1)°, (21.3±0.1)°, and (24.6±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (10.0±0.1)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (21.3±0.2)°, and (24.6±0.2)°; or (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21.3 0.2)°, and (24.6±0.2)°; or (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21.3±0.2)°, (24.0±0.2)°, and (24.6±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (10.0±0.1)°, (12.2±0.1)°, (12.6±0.1)°, (15.3±0.1)°, (16.6±0.1)°, (17.2±0.1)°, (19.1±0.1)°, (20.7±0.1)°, (21.3±0.1)°, (22.2±0.1)°, (24.0±0.1)°, and (24.6±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (10.0±0.1)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.1)°, (16.6±0.1)°, (17.2±0.1)°, (19.1±0.1)°, (20.7±0.1)°, (21.3±0.1)°, (22.2±0.1)°, (24.0±0.1)°, (24.6±0.1)°, and (28.0±0.1)° It is a crystalline form characterized by a PXRD peak identified at a 2-theta angle of

[0112] In one embodiment, iptacopane hydrochloride monohydrate Form H B is (3452±4) cm when measured at temperatures between 20 and 30°C using a diamond ATR cell. -1 , (2875±4)cm -1 , and (1692±4) cm -1 It is a crystalline form characterized by having a Fourier transform infrared spectrum containing a peak at a wavenumber of

[0113] In one embodiment, iptacopane hydrochloride monohydrate Form H B is (3452±4) cm when measured at temperatures between 20 and 30°C using a diamond ATR cell. -1 , (2875±4)cm -1 , (1692±4)cm -1 , and (1439±4) cm -1 It is a crystalline form characterized by having a Fourier transform infrared spectrum containing a peak at a wavenumber of

[0114] In one embodiment, iptacopane hydrochloride monohydrate Form H B is measured at temperatures between 20 and 30°C using a diamond ATR cell. (3452±2)cm -1 , (2875±2)cm -1 , and (1692±2) cm -1 , or (3452±2)cm -1 , (2875±2)cm -1 , (1692±2)cm -1 , and (1439±2) cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (1692±2)cm -1 , (1439±2)cm -1 , and (1243±2) cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (1692±2)cm -1, (1439±2)cm -1 , (1243±2)cm -1 , and (767±2) cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , (1692±2)cm -1 , (1439±2)cm -1 , (1243±2)cm -1 , and (767±2) cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , (1709±2)cm -1 , (1692±2)cm -1 , (1658±2)cm -1 , (1439±2)cm -1 , (1243±2)cm -1 , and (767±2) cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , (1709±2)cm -1 , (1692±2)cm - 1. (1658±2)cm -1 , (1615±2)cm -1 , (1439±2)cm -1 , (1243±2)cm -1 , and (767±2) cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , (1709±2)cm -1 , (1692±2)cm - 1. (1658±2)cm -1 , (1615±2)cm -1 , (1601±2)cm -1 , (1439±2)cm -1 , (1243±2)cm -1, and (767±2) cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , (1709±2)cm -1 , (1692±2)cm - 1. (1658±2)cm -1 , (1615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (1439±2)cm -1 , (1243±2)cm -1 , and (767±2) cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , (1709±2)cm -1 , (1692±2)cm - 1. (1658±2)cm -1 , (1615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (1497±2)cm -1 , (1439±2)cm -1 , (1243±2)cm -1 , and (767±2) cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , (1709±2)cm -1 , (1692±2)cm - 1. (1658±2)cm -1 , (1615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (1497±2)cm -1 , (1461±2)cm -1 , (1439±2)cm -1 , (1243±2)cm -1 , and (767±2) cm-1 or (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , (1709±2)cm -1 , (1692±2)cm - 1. (1658±2)cm -1 , (1615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (1497±2)cm -1 , (1461±2)cm -1 , (1439±2)cm -1 , (1425±2)cm -1 , (1243±2)cm -1 , and (767±2) cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , (1709±2)cm -1 , (1692±2)cm - 1. (1658±2)cm -1 , (1615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (1497±2)cm -1 , (1461±2)cm -1 , (1439±2)cm -1 , (1425±2)cm -1 , (1384±2)cm -1 , (1243±2)cm -1 , and (767±2) cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , (1709±2)cm -1 , (1692±2)cm - 1. (1658±2)cm -1 , (1615±2)cm -1 , (1601±2)cm -1, (1515±2)cm -1 , (1497±2)cm -1 , (1461±2)cm -1 , (1439±2)cm -1 , (1425±2)cm -1 , (1384±2)cm -1 , (1243±2)cm -1 , (1184±2)cm -1 , and (767±2) cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , (1709±2)cm -1 , (1692±2)cm - 1. (1658±2)cm -1 , (1615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (1497±2)cm -1 , (1461±2)cm -1 , (1439±2)cm -1 , (1425±2)cm -1 , (1384±2)cm -1 , (1243±2)cm -1 , (1184±2)cm -1 , (1069±2)cm -1 , and (767±2) cm -1 or (3452±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , (1709±2)cm -1 , (1692±2)cm - 1. (1658±2)cm -1 , (1615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (1497±2)cm -1 , (1461±2)cm -1 , (1439±2)cm -1 , (1425±2)cm -1, (1384±2)cm -1 , (1243±2)cm -1 , (1184±2)cm -1 , (1069±2)cm -1 , (767±2)cm -1 , and (739±2) cm -1 or (3452±2)cm -1 , (3274±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , (1709±2)cm -1 , (1692±2)cm - 1. (1658±2)cm -1 , (1615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (1497±2)cm -1 , (1461±2)cm -1 , (1439±2)cm -1 , (1425±2)cm -1 , (1384±2)cm -1 , (1243±2)cm -1 , (1184±2)cm -1 , (1069±2)cm -1 , (767±2)cm -1 , and (739±2) cm -1 or (3452±2)cm -1 , (3274±2)cm -1 , (2933±2)cm -1 , (2875±2)cm -1 , (2732±2)cm -1 , (1709±2)cm -1 , (1692±2)cm - 1. (1658±2)cm -1 , (1615±2)cm -1 , (1601±2)cm -1 , (1515±2)cm -1 , (1497±2)cm -1 , (1461±2)cm -1 , (1439±2)cm -1, (1425±2)cm -1 , (1384±2)cm -1 , (1243±2)cm -1 , (1184±2)cm -1 , (1069±2)cm -1 , (767±2)cm -1 , and (739±2) cm -1 It is a crystalline form characterized by having a Fourier transform infrared spectrum containing a peak at a wavenumber of

[0115] In one embodiment, iptacopane hydrochloride monohydrate Form H B is a crystalline form characterized by having a differential scanning calorimetry curve containing an endothermic event in the range of 35°C to 170°C when measured at a heating rate of 10 K / min.

[0116] In one embodiment, iptacopane hydrochloride monohydrate Form H B is a crystalline form characterized by a DSC curve that shows a broad endothermic event ending at about 170° C., followed by exothermic decomposition at about 200° C., when measured at a heating rate of 10 K / min. In one embodiment, the broad endothermic event ending at about 170° C. is an endothermic event in the range of 35° C. to 170° C., when measured at a heating rate of 10 K / min.

[0117] In one embodiment, iptacopane hydrochloride monohydrate Form H B is a crystalline form characterized by having a thermogravimetric analysis curve that exhibits a mass loss at about 220°C (e.g., at a temperature of 200-220°C) due to a loss of water and residual solvent of 4.5 wt% or less (e.g., 4.3 wt% or less, e.g., 4.0 wt% or less, e.g., 3.8 wt% or less, e.g., 3.4 wt% or less), based on the weight of the crystalline form, when heated from 30 to 300°C at a rate of 20 K / min.

[0118] In one embodiment, iptacopane hydrochloride monohydrate Form HB is a crystalline form characterized by having a dynamic vapor sorption curve exhibiting a mass change of 4.5 wt % or less (e.g., 4.0 wt % or less, e.g., 3.0 wt % or less, e.g., 2.0 wt % or less, e.g., 1.8 wt %, 1.6 wt %, 1.5 wt %, or 1.4 wt % or less), based on the weight of the crystalline form, when measured using dynamic vapor sorption at a relative humidity ranging from 0 to 95°C and a temperature of (25±1.0)°C.

[0119] In certain embodiments, the subject (e.g., patient) is an adult. In one embodiment, the subject (e.g., patient) is an adolescent.

[0120] In one embodiment, the subject (e.g., patient) has been diagnosed with IC-MPGN (e.g., primary IC-MPGN), e.g., in a native kidney, as confirmed, e.g., by renal biopsy, e.g., within 12 months in adults or within 3 years in adolescents prior to administration.

[0121] In some embodiments, a subject (e.g., a patient) receives, for example, iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H B A urine protein / creatinine ratio (UPCR) of 1.0 g / g or greater sampled from the first morning void or 24-hour urine collection prior to administration of ACE inhibitors.

[0122] In some embodiments, the subject (e.g., patient) receives iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H B ) should be administered, for example, with an estimated glomerular filtration rate (eGFR) of 30 ml / min / 1.73 m, calculated using the CKD-EPI formula or the modified Schwartz formula according to the guidelines for the specific ethnic group and local practice. 2 That's all.

[0123] In some embodiments, the subject (e.g., patient) receives iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H B Before administration of ), the glomerular filtration rate (GFR) was measured to be 30 ml / min / 1.73 m 2 That's all.

[0124] In some embodiments, the subject (e.g., patient) receives iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H B ) have been vaccinated before administration.

[0125] In some embodiments, the subject (e.g., patient) receives iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H B ) have been vaccinated against encapsulated bacteria.

[0126] In some embodiments, the subject (e.g., patient) is receiving an antibiotic (e.g., an antibiotic against encapsulated bacteria) or the subject (e.g., patient) will be administered an antibiotic (e.g., an antibiotic against encapsulated bacteria).

[0127] In certain embodiments, the encapsulated bacterium is Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae, or Haemophilus influenzae.

[0128] In some embodiments, the subject (e.g., patient) receives iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H BPrior to receiving the vaccine, the patient had been vaccinated against Neisseria meningitidis (types A, C, Y, and W-135).

[0129] In some embodiments, the subject (e.g., patient) receives iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H B ) and received vaccination against Streptococcus pneumoniae (Pneumovax-23) before administration.

[0130] In some embodiments, the subject (e.g., patient) receives iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H B ) have been vaccinated against Haemophilus influenzae prior to administration.

[0131] In one embodiment, the subject (e.g., patient) has been receiving supportive care, e.g., at a maximum daily dose or maximum tolerated dose (e.g., a stable dose), for at least 90 days prior to administration of, e.g., iptacopan or a pharmaceutically acceptable salt thereof.

[0132] In one embodiment, this supportive care is the maximum daily dose or maximum tolerated dose.

[0133] In some embodiments, the supportive care is a stable dose.

[0134] In one embodiment, the supportive care has been administered for at least 90 days prior to treatment.

[0135] In certain embodiments, the subject (eg, patient) is further administered supportive care, eg, at a stable dose.

[0136] In certain embodiments, the subject (eg, patient) is receiving an anti-proteinuric drug, and the subject (eg, patient) is further administered an anti-proteinuric drug.

[0137] In certain embodiments, the subject (eg, patient) is receiving an immunosuppressant, and the subject (eg, patient) is further administered an immunosuppressant.

[0138] In certain embodiments, this supportive care includes an ACEi, an ARB, a mycophenolate (e.g., mycophenolate mofetil (MMF) and mycophenolate sodium (MPS)), a corticosteroid, an SGLT2 inhibitor, a mineralocorticoid receptor antagonist, cyclophosphamide (CYC), or a calcineurin inhibitor (e.g., voclosporin).

[0139] In one embodiment, a subject (e.g., a patient) is currently receiving an ACEi, an ARB, mycophenolic acid, a corticosteroid, an SGLT2 inhibitor, a mineralocorticoid receptor antagonist, cyclophosphamide (CYC), or a calcineurin inhibitor (e.g., voclosporin), and the subject (e.g., a patient) is further administered an ACEi, an ARB, mycophenolic acid, a corticosteroid, an SGLT2 inhibitor, a mineralocorticoid receptor antagonist, cyclophosphamide (CYC), or a calcineurin inhibitor (e.g., voclosporin).

[0140] In one embodiment, a subject (e.g., a patient) is being administered an ACEi or an ARB, e.g., at a stable maximum tolerated dose, and the subject (e.g., a patient) is further administered an ACEi or ARB, e.g., at a stable maximum tolerated dose.

[0141] In one embodiment, the subject (e.g., patient) is receiving mycophenolate mofetil (MMF) or mycophenolate sodium (MPS), and the subject (e.g., patient) is further administered mycophenolate mofetil (MMF) or mycophenolate sodium (MPS).

[0142] In one embodiment, a subject (e.g., a patient) is receiving a stable dose of an immunosuppressant or antiproteinuric agent (e.g., MMF, MPS, corticosteroids, and SGLT2i), and the subject (e.g., a patient) is receiving an additional stable dose of an immunosuppressant or antiproteinuric agent (e.g., MMF, MPS, corticosteroids, and SGLT2i).

[0143] In one embodiment, the subject (e.g., patient) is receiving a corticosteroid (e.g., prednisone), e.g., at 7.5 mg per day or less, and the subject (e.g., patient) is further administered a corticosteroid (e.g., prednisone), e.g., at 7.5 mg per day or less.

[0144] In certain embodiments, the present disclosure provides iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H) for use in reducing proteinuria (e.g., reducing UPCR) in a subject (e.g., a patient). B ), wherein the UPCR in the subject (e.g., patient) is determined by administering iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H B In some embodiments, the UPCR in a subject (e.g., a patient) is reduced by, for example, 25% or more, 30% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, or 65% or more compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H). B In a specific embodiment, the urinary tract infection (UU) is reduced by at least 25%, at least 30%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, or at least 65% six months after treatment compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H). B) is administered twice daily (bid) at a dose of 200 mg (this dose refers to the anhydrous free base of iptacopan hydrochloride).

[0145] In certain embodiments, the present disclosure provides a method of achieving stable or improved estimated glomerular filtration rate (eGFR) in a subject (e.g., a patient) in need thereof, comprising administering iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H). B ) to the subject (e.g., patient), and the eGFR or measured GFR in the subject (e.g., patient) is stable and is maintained at a constant level, e.g., by administering iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H B In some embodiments, the eGFR or measured GFR in a subject (e.g., patient) is stable and maintained for at least 20 days, at least 15%, at least 10%, or at least 5% compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H). B ) is reduced by no more than 20%, no more than 15%, no more than 10%, or no more than 5% at 6 months after treatment compared to before administration.

[0146] In certain embodiments, the present disclosure provides a method of achieving stable or improved estimated glomerular filtration rate (eGFR) in a subject (e.g., a patient) in need thereof, comprising administering iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H). B ) to the subject (e.g., patient), and the eGFR or measured GFR in the subject (e.g., patient) can be measured using, for example, iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H BIn some embodiments, the eGFR or measured GFR in a subject (e.g., patient) is improved 6 months after treatment compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride).

[0147] In certain embodiments, the disclosure provides iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride) for use in reducing proteinuria (e.g., reducing UPCR) in a subject (e.g., patient) in need thereof, wherein the treatment comprises administering iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride) to the subject (e.g., patient), for example, iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H B Compared to before administration of the compound, the UPCR in the subject (e.g., patient) is reduced by 25% or more, 30% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, or 65% or more, and the eGFR or measured GFR in the subject (e.g., patient) is stable, for example, reduced by 20% or less, reduced by 15% or less, reduced by 10% or less, or reduced by 5% or less. In some embodiments, after 6 months of treatment, compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride), the UPCR in the subject (e.g., patient) is reduced, e.g., by 25% or more, 30% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, or 65% or more, and the eGFR or measured GFR in the subject (e.g., patient) is stable, e.g., reduced by 20% or less, reduced by 15% or less, reduced by 10% or less, or reduced by 5% or less.

[0148] In some embodiments, the subject's (e.g., patient's) FACIT-Fatigue score is reduced compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride).

[0149] In certain embodiments, the present disclosure provides a method of treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject (e.g., patient) in need thereof, comprising administering (e.g., orally administering) iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride) to the subject (e.g., patient), thereby treating the subject (or patient), wherein the FACIT-Fatigue score of the subject (e.g., patient) is greater than or equal to 100 mg / kg / day of iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H). B In some embodiments, the subject's (e.g., patient's) FACIT-Fatigue score is reduced by 2 or more, reduced by 3 or more, or reduced by 4 or more compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H). B ) is reduced by 2 or more, or by 3 or more, or by 4 or more at 6 or 12 months after treatment compared to before administration.

[0150] Main efficacy evaluation Also provided herein is iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H). B 1. A method for assessing the efficacy of treatment in a patient population suffering from immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) treated with iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H), comprising administering to the patient a therapeutically effective amount of iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride monohydrate Form H). B determining the proportion of a patient population achieving a reduction in proteinuria compared to a patient population not treated with the compound, thereby assessing the effectiveness of the treatment.

[0151] Also provided herein is iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H). B1. A method for assessing the efficacy of treatment in a patient population suffering from immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) treated with iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride, e.g., iptacopan hydrochloride monohydrate Form H), comprising administering to the patient a therapeutically effective amount of iptacopan or a pharmaceutically acceptable salt thereof (e.g., iptacopan hydrochloride monohydrate Form H). B and determining the proportion of a patient population achieving stable or improved eGFR compared to a patient population not treated with the treatment, thereby assessing the effectiveness of the treatment.

[0152] Effectiveness assessment: Stable or improved eGRR (<15% reduction in eGRT) compared to the baseline visit, and / or A 50% or greater reduction in urinary protein / creatinine ratio (UPCR) Patient population: Participants with biopsy-confirmed idiopathic IC-MPGN who meet other inclusion and exclusion criteria. Percentage of patients achieving the following criteria compared to the baseline visit: Stable or improved eGRR (<15% reduction in eGRT) compared to the baseline visit, and / or A 50% or greater reduction in urinary protein / creatinine ratio (UPCR) [Example]

[0153] The present disclosure is further illustrated by the following examples, which should not be construed as limiting the disclosure to the scope or spirit of the specific procedures described therein. It should be understood that the examples are provided to illustrate certain embodiments and are not intended to limit the scope of the disclosure. Furthermore, it should be understood that various other embodiments, modifications, and equivalents thereof, which may suggest themselves to those skilled in the art, may be used without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0154] [Table 1]

[0155] [Table 2]

[0156] [Table 3]

[0157] [Table 4]

[0158] [Table 5]

[0159] [Table 6]

[0160] [Table 7]

[0161] Example 1. A multicenter, randomized, double-blind, parallel-group, placebo-controlled study to evaluate the efficacy and safety of iptacopan (LNP023) in idiopathic immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN). the purpose The purpose of this Phase 3 study (CLNP023B12302) is to evaluate the efficacy and safety of iptacopan (both administered in combination with standard of care) compared with placebo in participants (adults and adolescents aged 12-17 years) with idiopathic IC-MPGN. The study aims to demonstrate a reduction in proteinuria and an improvement in estimated glomerular filtration rate (eGFR) in participants treated with iptacopan compared with placebo. Changes in patient-reported fatigue will also be evaluated. Alternative complement pathway (AP) dysregulation is thought to underlie the clinical symptoms and progression of IC-MPGN.

[0162] Test Design This is a multicenter, randomized, double-blind, parallel-group, placebo-controlled study to evaluate the efficacy and safety of iptacopan in participants with idiopathic IC-MPGN. Approximately 68 participants (adults and adolescents at least 10 years old) will be randomized. Half of the participants (n=34) will receive iptacopan at 200 mg twice daily (bid) for 6 months of blinded treatment, followed by 6 months of open-label iptacopan at 200 mg bid. The other half of the participants (n=34) will receive placebo for 6 months of blinded treatment, followed by 6 months of open-label iptacopan at 200 mg bid. Upon completion of study treatment at 12 months in CLNP023B12302, participants had the option to discontinue iptacopan treatment and enter a 30-day safety follow-up period, or transition to an open-label extension study (CLNP023B12001B) to continue iptacopan treatment. The study design is depicted in Figure 1.

[0163] The study included three periods: A screening / run-in period of up to 90 days (Note: for example, if a participant is already on a stable dose of antiproteinuric therapy (e.g., but not limited to, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, SGLT2 inhibitors, mineralocorticoid receptor antagonists, mycophenolate, oral corticosteroids) and has already received all required vaccinations, it may be possible to complete the screening / run-in period in less than 90 days), A 360-day treatment period (including a 6-month blinded treatment portion and a 6-month open-label portion), and A 30-day safety follow-up period (or, optionally, transition to an extension study).

[0164] Throughout the protocol, "baseline" refers to the Day 1 visit (pre-dose) of CLNP023B12302. Approximately 68 adult and adolescent participants aged 12-60 years will be randomized (34 treated with iptacopan and 34 treated with placebo). A minimum of 10 adolescents will be randomized separately in this study. Randomization was stratified by corticosteroid and / or mycophenolate treatment at randomization in adult participants (yes vs. no), because use of these medications may affect response to iptacopan.

[0165] To evaluate the efficacy of iptacopan in adult participants with high levels of proteinuria, approximately 50% of randomized participants are expected to have proteinuria of 3.0 g / day or greater (24-hour urine collection) on Day 1. Baseline proteinuria will be monitored throughout the study, and, if necessary, randomization of adult participants may be restricted to only those with a UPCR of 3.0 g / g or greater on Days -75 and -15.

[0166] Inclusion criteria Participants eligible for enrollment in this study must meet all of the following criteria: 1. Signed informed consent must be obtained prior to participation in this study. 2. Male and female participants aged 12 years or older and 60 years or younger at the time of screening. 3. Able to communicate well with the investigator and understand and comply with the requirements of the study. 4. Diagnosis of IC-MPGN confirmed by renal biopsy within 12 months prior to enrollment in adults and within 3 years of enrollment in adolescents (biopsy report, investigator review and confirmation required). If this confirmation is not available for adults, it should be obtained by renal biopsy at screening (adults only). 5. Prior to randomization, all participants must have been receiving the maximum recommended or tolerated dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) for at least 90 days (or according to local guidelines). Doses of other antiproteinuric medications, including mycophenolate (MMF or mycophenolate sodium), corticosteroids, SGLT2 inhibitors, and mineralocorticoid receptor antagonists, should have been stable for at least 90 days prior to randomization. Doses of ACEi / ARB, mineralocorticoid receptor antagonists, mycophenolate, corticosteroids, and SGLT2 inhibitors should remain stable throughout the study treatment period unless the participant experiences an adverse event or other safety issue requiring a dose modification. 6. For adults and adolescents, a UPCR of 1.0 g / g or greater (113 mg / mmol or greater) collected from the first morning void urine sample on both day -75 and day -15. 7. 30 ml / min / 1.73 m at screening and day -15 2 or above estimated GFR (use the CKD-EPI formula for those aged 18 or over, or the modified Schwartz formula for those aged 12-17) or measured GFR. 8. Mandatory vaccinations against Neisseria meningitidis and Streptococcus pneumoniae infections are required before the start of study treatment. If the patient has not been previously vaccinated, or if a booster is required, the vaccine should be given according to local regulations at least 2 weeks before the first dose of study treatment. If study treatment is initiated more than 2 weeks after vaccination, prophylactic antibiotic treatment should be initiated according to local standard of care. 9. If not previously vaccinated or if a booster is required, vaccination against Haemophilus influenzae infection, if available, should be administered at least 2 weeks before the first study treatment dose, in accordance with local regulations. If study treatment is initiated more than 2 weeks after vaccination, prophylactic antibiotic treatment should be initiated according to local standard of care.

[0167] Main exclusion criteria Participants who meet any of the following criteria are not eligible for enrollment in this study: 1. Participants who have received any cell or organ transplant, such as a kidney transplant. 2. Patients diagnosed with secondary IC-MPGN, including but not limited to any of the following conditions: Deposition of antigen-antibody immune complexes as a result of any infection, such as: Viral hepatitis C and B, including HCV-associated mixed cryoglobulinemia; Bacterial endocarditis, infected ventriculoatrial shunts, visceral abscesses, leprosy, meningococcal meningitis; chronic bacterial infections Protozoan / other infections - malaria, schistosomiasis, mycoplasma, leishmaniasis, filariasis, histroplasmosis Immune complex deposition as a result of autoimmune diseases: SLE Sjögren's syndrome Rheumatoid arthritis Mixed connective tissue disease, etc. Monoclonal Ig involvement due to monoclonal gammopathy resulting from plasma cell or B cell dyscrasia. Monoclonal gammopathy of undetermined significance (MGUS) confirmed by serum free light chain measurement or other investigations with local standard of care. Fibrillary glomerulonephritis 3. Rapidly progressive crescentic glomerulonephritis (defined as a 50% decline in eGFR within 3 months) with renal biopsy evidence of glomerular crescent formation in at least 50% of glomeruli. 4. Participants with acute post-infectious glomerulonephritis. 5. Renal biopsy showing interstitial fibrosis / tubular atrophy (IF / TA) greater than 50%. 6. Adult participants (aged 18 to 60 years) with a systolic blood pressure (SBP) of less than 80mmHg or more than 160mmHg, or a diastolic blood pressure (DBP) of less than 50mmHg or more than 100mmHg, or a pulse rate of less than 45bpm or more than 100bpm. 7. Adolescent participants (12-17 years old) with a systolic blood pressure (SBP) less than 80mmHg or more than 150mmHg, or a diastolic blood pressure (DBP) less than 50mmHg or more than 95mmHg, or a pulse rate less than 50bpm or more than 110bpm. 8. 38 kg / m at screening and randomization 2 Body mass index (BMI) greater than 35 kg at screening and randomization. 9. Participant has an active systemic bacterial, viral, or fungal infection within 14 days prior to study treatment administration. 10. Presence of fever of 38°C (100.4°F) or greater within 7 days prior to administration of study treatment. 11. History of recurrent invasive infections caused by encapsulated organisms, e.g., N. meningitidis and S. pneumoniae. 12. Human immunodeficiency virus (HIV) infection (history of HIV or positive test for HIV at screening). 13. Liver disease, e.g., active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection defined as hepatitis B virus surface antigen (HBsAg) positivity or hepatitis C virus ribonucleic acid (HCV RNA) positivity, or liver damage indicated by abnormal liver function tests at screening as defined below: No single parameter, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), or alkaline phosphatase, should exceed 3 × the upper limit of normal (ULN). Serum bilirubin should not exceed 2 × the upper limit of normal (ULN) (except for participants with a known confirmed diagnosis of Gilbert syndrome). 14. Evidence of urinary obstruction or difficulty voiding at screening and randomization. 15. Severe concurrent comorbidities, including but not limited to, advanced cardiac disease (e.g., New York Heart Association [NYHA] class IV), severe lung disease (e.g., severe pulmonary hypertension (World Health Organization [WHO] class IV)), or other conditions that, in the investigator's judgment, would prevent the participant from participating in the study. 16. History or current diagnosis of clinically significant cardiac arrhythmias without a pacemaker, such as sustained ventricular tachycardia and clinically significant second- or third-degree atrioventricular block (AV block), or any ECG abnormalities that present a significant safety risk to participants participating in the study. 17. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical carcinoma), treated or untreated, within the past 5 years, with or without evidence of local recurrence or metastasis. 18. History of hypersensitivity to any of the study treatments or excipients or drugs of a similar chemical class, or history of allergy of moderate to high severity, as determined by the investigator. 19. History of drug or alcohol abuse within 12 months prior to administration of study treatment. 20. Any medical condition that would possibly interfere with the patient's participation in the study 21. Use of complement factor inhibitors (e.g., factor B, factor D, C3 inhibitor, anti-C5 antibody, C5a receptor antagonist) within 6 months prior to the screening visit 22. Participation in any other investigational drug trial, or use of any other investigational drug, at the time of enrollment, or within 5 elimination half-lives or 30 days of enrollment, whichever is longer; or longer if required by local regulations. 23. Female participants who are pregnant, nursing, or attempting to become pregnant during the study period. 24. Women of childbearing potential, defined as any woman who is physiologically capable of becoming pregnant, except if she is using effective contraception while taking the study drug and for 1 week after stopping the study drug.

[0168] Treatment group The study will include three periods (Figure 1): a screening / run-in period of up to 90 days, a 360-day treatment period (including a 6-month blinded treatment portion and a 6-month open-label portion), and a 30-day safety follow-up period (or, optionally, transition to an extension study). The treatment period with study drug will be 12 months.

[0169] During the first 6 months of the double-blind treatment period, half of the participants will receive iptacopan 200 mg bid (100 mg for adolescents and 200 mg for adults) capsules. The other half will receive placebo capsules matching the iptacopan 100 mg and 200 mg capsules in the placebo-control group. During the 6-month open-label period, all participants in both groups will receive iptacopan 200 mg bid. Iptacopan may be temporarily interrupted or discontinued due to AEs, progression of underlying disease, and / or at the discretion of the investigator or participant.

[0170] Objectives and Endpoints

[0171] [Table 8]

[0172] [Table 9]

[0173] [Table 10]

[0174] Study design rationale The study design includes a 6-month double-blind, placebo-controlled period to evaluate the potential benefit of iptacopan in improving renal function compared with placebo. The placebo-controlled period is limited to 6 months because longer periods of placebo exposure and the withholding of other experimental therapies, such as immunosuppressants or anticomplement agents, would be considered unacceptable to both study participants and their treating investigators (Bomback, A., Kavanagh D, Vivarelli M, et al. (2022) Alternative Complement Pathway Inhibition With Iptacopan for the Treatment of C3 Glomerulopathy - Study Design of the APPEAR-C3G Trial. Kidney Int Rep;7:2150-9). Therefore, extending the placebo-controlled study beyond 6 months is considered unfeasible due to the difficulty of recruiting patients with this severe, progressive disease to longer trials.

[0175] This period also balances the need to administer iptacopan for a sufficient period to determine its effect on the kidney, while also providing all study participants with the opportunity to receive potential disease-modifying therapy during the 6-month open-label iptacopan period described below.

[0176] The registry is open to patients (ages 12–60 years) with biopsy-confirmed idiopathic IC-MPGN. Adolescents are included in the study because the etiology of adolescent disease is similar to that of adults (e.g., the central role of hyperactivated APs, as well as clinical features such as edema, severity of proteinuria, prevalence of nephrotic syndrome, hematuria, and histopathology). Many patients are diagnosed during adolescence (median age at diagnosis is approximately 21 years—(Iatropoulos et al., 2018)), and given the rapidly progressive nature of the disease, there is a high unmet need for treatment of adolescents with IC-MPGN. The rationale for including participants with biopsy-confirmed IC-MPGN and significant levels of proteinuria is to enrich the population for participants with both overt clinical symptoms of IC-MPGN and an increased risk of rapid disease progression. The purpose of the run-in period is to ensure that participants have received a stable, maximum tolerated dose of an ACEi / ARB, as well as stable doses of other immunosuppressants and antiproteinuric agents (MMF / MPS, corticosteroids, and SGLT2i) for at least 90 days prior to randomization, and have received any required vaccinations at least 2 weeks prior to the first dose of study medication. Additionally, to minimize potential carryover treatment effects of prohibited medications (i.e., immunosuppressants other than mycophenolate or corticosteroids at doses greater than 7.5 mg / day), patients receiving these treatments may need to discontinue or reduce their medications in order to comply with the allowed and prohibited medication requirements of this study.

[0177] The primary endpoint of this study is the reduction in UPCR (sampled from a 24-hour urine collection) at 6 months of treatment with iptacopan compared to placebo. Key secondary endpoints include preservation of eGFR with iptacopan compared to placebo, and a composite renal endpoint requiring: 1) stabilization of eGFR, and 2) a substantial reduction in proteinuria to designate participants as having met the endpoint. The FACIT-Fatigue questionnaire will be used to assess the effect of iptacopan on important symptoms reported by patients with IC-MPGN.

[0178] Additional analyses will be conducted at the end of the open-label period comparing proteinuria, eGFR, composite renal endpoint rate, and FACIT-Fatigue scores at Day 360 with baseline (Day 1). These data will be important for assessing the durability of any effects observed at Day 180, as well as further improvement in these variables with longer treatment durations. Proteinuria reduction is a well-recognized surrogate endpoint with a significant potential for predicting treatment efficacy across a range of renal diseases (e.g., slowing the progression of several other renal diseases, including diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), and immunoglobulin A (IgA) nephropathy) (Thompson A, Carroll K, A Inker L, et al. (2019) Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy. Clin J Am Soc Nephrol;14(3):469-81).

[0179] The key secondary endpoint of this study will assess the improvement in eGFR (measured as a continuous variable) afforded by iptacopan compared with placebo. In addition to precise measurement of proteinuria reduction on a continuous scale (the primary endpoint), a categorical definition of a clinically important change in proteinuria (a 50% or greater reduction in UPCR compared with baseline) will be included as a component of the composite renal secondary endpoint. The magnitude of a 50% or greater reduction in UPCR indicates a potential conversion from nephrotic-range proteinuria (>3.5 g / day) to non-nephrotic-range proteinuria, stabilizing eGFR in patients with IC-MPGN, thereby reducing the risk of edema, thrombosis, infection, and other associated complications. To strengthen the clinical relevance of the definition, a 15% or less reduction in eGFR over 6 months will be included as part of the composite renal endpoint. The selection of these endpoints in IC-MPGN presents an opportunity to determine whether treatment with iptacopan results in improved renal function.

[0180] Reasons for dosage The proposed iptacopan dose of 200 mg bid is considered appropriate based on data from the Phase 2 study, CLNP023X2202. Data from 16 patients with natural C3G demonstrated a dose-dependent increase in C3 levels, while sC5b-9, Bb, Wieslab assay, and urinary sC5b-9 decreased. The greatest reductions in plasma Bb, plasma sC5b-9, and urinary sC5b-9 were obtained at 100 mg bid, while the greatest reduction in Wieslab assay and increase in C3 were observed at 200 mg bid. Dose-dependent, profound, and sustained inhibition of the alternative complement pathway was observed in both cohorts upon iptacopan treatment, as demonstrated by: overall normalization of serum C3 levels, complete inhibition of Wieslab activity at 200 mg bid, and reductions in plasma Bb, plasma, and urinary sC5b-9 (for Cohort A). In patients with native C3G (N=16), iptacopan at a final dose level of 200 mg bid demonstrated a 45% reduction in UPCR from baseline to week 12 (two-sided p=0.0003) and stabilization of renal function (SCR, CrCl, eGFR). Additionally, chronic iptacopan monotherapy was well tolerated without any unexpected or novel safety findings. No deaths or serious adverse events were observed during treatment in patients with native renal C3G. One patient experienced an SAE during the run-in period (i.e., before any iptacopan treatment). There were no definitive discontinuations due to adverse events, and no significant changes in hematology, biochemistry, urinalysis, vital signs, or ECG parameters. Therefore, the 200 mg bid dose of iptacopan appears to produce the greatest changes in all complement biomarkers evaluated to date in patients with C3G.

[0181] Rationale for choice of background therapy There are no approved disease-modifying or "rescue" therapies with proven benefit available for the treatment of idiopathic IC-MPGN. The KDIGO 2021 guidelines provide recommendations for the treatment of idiopathic IC-MPGN. In line with the KDIGO guidelines, all patients will be required to receive the maximum or maximum tolerated dose of an ACEi / ARB as supportive care during the clinical trial (KDIGO 2021). The use of immunosuppressive therapy (mycophenolate, corticosteroids) is also permitted as long as it is at a stable dose, reflecting the KDIGO guidelines (which recommend such treatment for more severe cases of IC-MPGN) and clinical practice, where such medications are used according to clinical judgment in select patients. Unless otherwise indicated, clinical practice guidelines are based on very low-quality evidence, clinical experience, and expert opinion. Treatment is often influenced by and determined by the severity of proteinuria and renal dysfunction (KDIGO 2021).

[0182] The use of SGLT2 inhibitors is permitted, but the dose must be stable during the screening / run-in period and throughout the study medication treatment period. The use of corticosteroids and mycophenolate (mycophenolate mofetil (MMF) or mycophenolate sodium) is permitted during the course of the study as described in Table 3. All background therapies (ACEi / ARB, MMF / MPS, corticosteroids, and SGLT2i) are considered adjunctive medications (AMPs) in this study.

[0183] As a small-molecule oral factor B (FB) inhibitor, iptacopan blocks FB and thereby AP, which plays an important role in defense against microorganisms. Although the other two complement-initiating pathways (i.e., the classical and lectin pathways) should not be attenuated by iptacopan, there is a theoretical risk that immunological responses to infection, especially against encapsulated bacteria, may be impaired in patients taking iptacopan. To adequately mitigate this risk, participants will be vaccinated against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae at least 2 weeks before the first dose, based on local vaccine availability. In addition, the use of prophylactic antibiotics to prevent infection is permitted if this is standard of care for managing IC-MPGN patients receiving anticomplement therapy at the local site. Adverse events related to infection will be closely monitored throughout the study. Participants will be required to carry a participant card that describes the symptoms of sepsis and meningitis for participant information and awareness, allowing for early notification of a physician or investigator in the event of a potential infection. The card will also notify medical professionals of a potential increased risk of bacterial infection, helping to ensure timely diagnosis and treatment.

[0184] [Table 11]

[0185] Key efficacy estimates Primary: Reduction in proteinuria as quantified by log-transformed ratio of UPCR to baseline Secondary: Stable or improved eGFR compared to the baseline visit (≤15% reduction in eGFR) and ≥50% reduction in UPCR compared to the baseline visit (based on a 24-hour urine collection) Change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score

[0186] equivalent Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments specifically described herein which equivalents are intended to be encompassed by the following claims.

Claims

1. 1. A method of treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject in need thereof, comprising administering iptacopan or a pharmaceutically acceptable salt thereof to the subject, thereby treating the subject.

2. 10. The method of claim 1, wherein the iptacopan or a pharmaceutically acceptable salt thereof is administered orally.

3. 3. The method of claim 1 or 2, wherein the iptacopan or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg to about 200 mg, e.g., about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, administered twice daily (b.i.d.), wherein the dose refers to the anhydrous free base of iptacopan.

4. 4. The method of claim 3, wherein the dose is about 200 mg twice daily.

5. The method of any one of claims 1 to 4, wherein the pharmaceutically acceptable salt of iptacopan is iptacopan hydrochloride.

6. 6. The method of any one of claims 1 to 5, wherein the subject is receiving supportive care including an ACEi, an ARB, mycophenolic acid (e.g., mycophenolate mofetil (MMF) and mycophenolate sodium (MPS)), a corticosteroid, an SGLT2 inhibitor, a mineralocorticoid receptor antagonist, cyclophosphamide (CYC), or a calcineurin inhibitor prior to administration of iptacopan or a pharmaceutically acceptable salt thereof.

7. 7. The method of claim 6, wherein the ACEi or ARB is administered at a maximum recommended dose or a maximum tolerated dose.

8. 8. The method of claim 7, wherein the subject is further administered a stable dose of said supportive care.

9. The method of any one of claims 1 to 8, wherein the subject is an adult or an adolescent.

10. The method of any one of claims 1 to 9, wherein the urinary protein / creatinine ratio (UPCR) in the subject is reduced compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof.

11. 11. The method of claim 10, wherein the urinary protein / creatinine ratio (UPCR) in the subject is reduced by 50% or more compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof, and particularly, the urinary protein / creatinine ratio (UPCR) in the subject is reduced by 50% or more 6 months after treatment.

12. 12. The method of any one of claims 1 to 11, wherein the estimated glomerular filtration rate (eGFR) in the subject is stable or improved compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof.

13. 13. The method of claim 12, wherein the estimated glomerular filtration rate (eGFR) in the subject is reduced by 15% or less compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof, and particularly, the estimated glomerular filtration rate (eGFR) in the subject is reduced by 15% or less 6 months after treatment.

14. 1. Iptacopan or a pharmaceutically acceptable salt thereof for use in the treatment of immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject in need thereof, said treatment comprising administering iptacopan or a pharmaceutically acceptable salt thereof to said subject.

15. 15. The use of iptacopan or a pharmaceutically acceptable salt thereof according to claim 14, wherein the iptacopan or a pharmaceutically acceptable salt thereof is administered orally.

16. 16. The use of iptacopan or a pharmaceutically acceptable salt thereof according to claim 14 or 15, wherein the iptacopan or a pharmaceutically acceptable salt thereof is administered in a dose of about 50 mg to about 200 mg, e.g., about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose administered twice daily (b.i.d.), and the dosages refer to the anhydrous free base of iptacopan.

17. 17. The use of iptacopan or a pharmaceutically acceptable salt thereof according to claim 16, wherein the dose is about 200 mg twice daily.

18. 18. Iptacopan or a pharmaceutically acceptable salt thereof for use according to any one of claims 14 to 17, wherein the pharmaceutically acceptable salt of iptacopan is iptacopan hydrochloride.

19. 19. Iptacopan or a pharmaceutically acceptable salt thereof for use according to any one of claims 14 to 18, wherein the subject is receiving supportive care including an ACEi, an ARB, mycophenolic acid (e.g., mycophenolate mofetil (MMF) and mycophenolate sodium (MPS)), a corticosteroid, an SGLT2 inhibitor, a mineralocorticoid receptor antagonist, cyclophosphamide (CYC), or a calcineurin inhibitor prior to administration of iptacopan or a pharmaceutically acceptable salt thereof.

20. 20. Iptacopan or a pharmaceutically acceptable salt thereof for use according to claim 19, wherein the ACEi or ARB is administered at the maximum recommended dose or maximum tolerated dose.

21. 21. The use of iptacopan or a pharmaceutically acceptable salt thereof according to claim 20, wherein the subject is further administered a stable dose of supportive care.

22. 22. Iptacopan or a pharmaceutically acceptable salt thereof for use according to any one of claims 14 to 21, wherein the subject is an adult or an adolescent.

23. 23. Iptacopan or a pharmaceutically acceptable salt thereof for use according to any one of claims 14 to 22, wherein the urinary protein / creatinine ratio (UPCR) in the subject is reduced compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof.

24. 24. The use of iptacopan or a pharmaceutically acceptable salt thereof according to claim 23, wherein the urinary protein / creatinine ratio (UPCR) in the subject is reduced by 50% or more compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof, and particularly, the urinary protein / creatinine ratio (UPCR) in the subject is reduced by 50% or more 6 months after treatment.

25. 25. The use of iptacopan or a pharmaceutically acceptable salt thereof according to any one of claims 14 to 24, wherein the estimated glomerular filtration rate (eGFR) in the subject is stable or improved compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof.

26. 26. The use of iptacopan or a pharmaceutically acceptable salt thereof according to claim 25, wherein the estimated glomerular filtration rate (eGFR) in the subject is reduced by no more than 15% compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof, and particularly wherein the estimated glomerular filtration rate (eGFR) in the subject is reduced by no more than 15% six months after treatment.

27. 1. A pharmaceutical composition comprising a therapeutically effective amount of iptacopan or a pharmaceutically acceptable salt thereof for use in treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject in need thereof, wherein the pharmaceutical composition is administered to thereby treat the subject.

28. 28. The pharmaceutical composition of claim 27, wherein the iptacopan or a pharmaceutically acceptable salt thereof is administered orally.

29. 29. The pharmaceutical composition of claim 27 or 28, wherein the iptacopan or pharmaceutically acceptable salt thereof is administered in a dose of about 50 mg to about 200 mg, e.g., about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose administered twice daily (b.i.d.), and the doses refer to the anhydrous free base of iptacopan.

30. 30. The pharmaceutical composition of claim 29, wherein the dose is about 200 mg twice daily.

31. 31. The pharmaceutical composition of any one of claims 27 to 30, wherein the pharmaceutically acceptable salt of iptacopan is iptacopan hydrochloride.

32. 32. The pharmaceutical composition of any one of claims 27 to 31, wherein the subject is receiving supportive care including an ACEi, an ARB, mycophenolic acid (e.g., mycophenolate mofetil (MMF) and mycophenolate sodium (MPS)), a corticosteroid, an SGLT2 inhibitor, a mineralocorticoid receptor antagonist, cyclophosphamide (CYC), or a calcineurin inhibitor prior to administration of iptacopan or a pharmaceutically acceptable salt thereof.

33. 33. The pharmaceutical composition of claim 32, wherein the ACEi or ARB is administered at a maximum recommended dose or a maximum tolerated dose.

34. 34. The pharmaceutical composition of claim 33, wherein the subject is further administered a stable dose of the supportive care.

35. The pharmaceutical composition according to any one of claims 27 to 34, wherein the subject is an adult or an adolescent.

36. The pharmaceutical composition of any one of claims 27 to 35, wherein the urinary protein / creatinine ratio (UPCR) in the subject is reduced compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof.

37. 36. The pharmaceutical composition of claim 35, wherein the urinary protein / creatinine ratio (UPCR) in the subject is reduced by 50% or more compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof, and particularly, the urinary protein / creatinine ratio (UPCR) in the subject is reduced by 50% or more 6 months after treatment.

38. 38. The pharmaceutical composition of any one of claims 27 to 37, wherein the estimated glomerular filtration rate (eGFR) in the subject is stable or improved compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof.

39. 39. The pharmaceutical composition of claim 38, wherein the estimated glomerular filtration rate (eGFR) in the subject is reduced by 15% or less compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof, and particularly, the estimated glomerular filtration rate (eGFR) in the subject is reduced by 15% or less 6 months after treatment.

40. Use of iptacopan or a pharmaceutically acceptable salt thereof for the manufacture of a method for treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject in need thereof.

41. 41. The use of claim 40, wherein the iptacopan or a pharmaceutically acceptable salt thereof is administered orally.

42. 42. The use of claim 40 or 41, wherein the use comprises administering iptacopan or a pharmaceutically acceptable salt thereof to the subject in a dose of about 50 mg to about 200 mg, e.g., about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose administered twice daily (b.i.d.), and the doses refer to the anhydrous free base of iptacopan.

43. 43. The use of claim 42, wherein the dose is about 200 mg twice daily.

44. The use according to any one of claims 40 to 43, wherein the pharmaceutically acceptable salt of iptacopan is iptacopan hydrochloride.

45. 45. The use of any one of claims 40 to 44, wherein the subject is receiving supportive care including an ACEi, an ARB, mycophenolic acid (e.g., mycophenolate mofetil (MMF) and mycophenolate sodium (MPS)), a corticosteroid, an SGLT2 inhibitor, a mineralocorticoid receptor antagonist, cyclophosphamide (CYC), or a calcineurin inhibitor prior to administration of iptacopan or a pharmaceutically acceptable salt thereof.

46. 46. ​​The use of claim 45, wherein the ACEi or ARB is administered at the maximum recommended dose or maximum tolerated dose.

47. 47. The use of claim 46, wherein the subject is further administered a stable dose of said supportive care.

48. The use according to any one of claims 40 to 47, wherein the subject is an adult or an adolescent.

49. The use of any one of claims 40 to 48, wherein the urinary protein / creatinine ratio (UPCR) in the subject is reduced compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof.

50. 50. The use of claim 49, wherein the urinary protein / creatinine ratio (UPCR) in the subject is reduced by 50% or more compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof, and particularly, the urinary protein / creatinine ratio (UPCR) in the subject is reduced by 50% or more 6 months after treatment.

51. The use of any one of claims 40 to 50, wherein the estimated glomerular filtration rate (eGFR) in the subject is stable or improved compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof.

52. 52. The use of claim 51, wherein the estimated glomerular filtration rate (eGFR) in the subject is reduced by no more than 15% compared to before administration of iptacopan or a pharmaceutically acceptable salt thereof, and particularly wherein the estimated glomerular filtration rate (eGFR) in the subject is reduced by no more than 15% six months after treatment.

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