Methods of using factor b inhibitors

Abstract

Described herein are methods of treating immune complex mediated membrane proliferative glomerulonephritis (IC-MPGN) with a factor B inhibitor ipropam or a pharmaceutically acceptable salt thereof, e.g., ipropam hydrochloride.

Description

Technical Field

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

[0002] Immune complex membranoproliferative glomerulonephritis (IC-MPGN) is an ultrarare, rapidly progressive renal disease that may be idiopathic (primary IC-MPGN) or may be secondary to chronic infection or other immune systemic 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 separate entity according to current classification, it shares key similarities with C3 glomerulopathy (C3G), which is also typically characterized by membranoproliferative histopathology. IC-MPGN stains predominantly with immunoglobulin complexes, whereas C3G stains predominantly with complement-3.

[0003] Both IC-MPGN and C3G are ultrarare (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 often diagnosed during childhood and adolescence, with the median age at diagnosis of IC-MPGN being around 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. [Cluster analysis identifies distinct pathogenic patterns in C3 glomerulopathy / immune complex-mediated membranoproliferative glomerulonephritis] J Am Soc Nephrol; 29(1):283-94; and Garam N, Prohászka Z, Szilágyi Á et al (2020) Validation of distinct pathogenic patterns in a cohort of membranoproliferative glomerulonephritis patients by cluster analysis. [Validation of distinct pathogenic patterns in a cohort of membranoproliferative glomerulonephritis patients by cluster analysis] Clin Kidney J; 13(2):225-34), and both are characterized by a high risk of progression to renal failure (Iatropoulos et al 2018; and Wong et al 2021). Dysregulation of the alternative pathway (AP) of the complement system has been implicated in the pathogenesis of IC-MPGN as well as C3G (Wong et al 2021).

[0004] Membranoproliferative glomerulonephritis (MPGN) is a rare histological pattern of glomerular injury characterized by hypercellularity, endocapillary proliferation, and capillary wall thickening with double contouring on light microscopic observation in renal biopsy. It has multiple etiologies, and its detection should prompt the clinician to search for possible underlying causes. Recent advances in the understanding of the pathogenesis have recognized the key role of the alternative complement pathway (AP), leading to the description of complement-mediated forms (C3 glomerulopathy, C3G) and immune complex-mediated forms (IC-MPGN) (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 observations of immunofluorescence staining of renal biopsies, C3G is diagnosed when there is predominant glomerular C3 deposition with minimal or absent Ig deposition (C3 greater than or equal to two orders of magnitude greater than any other immunoreactant), whereas IC-MPGN is diagnosed when there is predominant glomerular Ig deposition (Sethi, Fervenza 2011; Cook HT, Pickering MC (2015) Histopathology of MPGN and C3glomerulopathies. Nat Rev Nephrol; 11(1):14-22). There is evidence that the histologic diagnosis can change over time; among patients who underwent repeat biopsies, 40% had different immunofluorescence (IF) staining patterns on the initial and follow-up biopsies, and 17% demonstrated conversion from C3G to IC-MPGN or 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 has been further classified as C3 glomerulonephritis (C3GN) and dense deposit disease (DDD) based on additional findings observed only 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 such as schistosomiasis, hepatic echinococcosis, and malaria), systemic autoimmune diseases (including but not limited to SLE, Sjögren's syndrome, and rheumatoid arthritis), and last but not least, monoclonal gammopathy. Therefore, careful evaluation for the underlying cause is crucial. Treatment of such secondary cases is generally directed at the underlying condition. In the absence of such an underlying cause, IC-MPGN is classified as idiopathic (primary IC-MPGN). In such cases, a complete complement panel should be performed, as data support a key role for complement dysregulation in IC-MPGN. This panel should include functional complement assays, quantification of complement components and regulators, measurement of complement activation, complement autoantibodies, genetic testing, and immunofluorescence staining of renal biopsy specimens (KDIGO 2021). Several studies have shown that the number of patients with primary IC-MPGN and C3G is roughly equal (Servais A, Noël LH, Roumenina LT et al. (2012) Acquired and genetic complement abnormalities play a critical role indense deposit disease and other C3 glomerulopathies. Kidney Int; 82(4):454-64; Iatropoulos et al. 2016, Wong et al. 2021), with an annual incidence of 1-2 per million people (Medjeral-Thomas et al. 2014).

[0006] The clinical presentation of IC-MPGN is heterogeneous and ranges 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, whereas C3 deposits persist. Nephrotic syndrome is more frequent in patients with IC-MPGN (43%-70%) compared with patients with C3G (26%-52%). Glomerular C4d staining is positive in the majority (80%) of primary (a limited number of cases studied) and secondary Ig-MPGN cases, whereas it is positive (and weakly so) in only a minority (13%) of C3G cases. IC-MPGN is a rapidly progressive disease, with an estimated 50% of patients developing renal failure within 10 years (Servais et al. 2012). This is similar to the findings observed in patients with C3G in this study, although some recent data suggest that IC-MPGN may progress to renal failure slightly more slowly than 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] For patients with idiopathic IC-MPGN and proteinuria < 3.5 g / day and a normal estimated glomerular filtration rate (eGFR), supportive therapy with renin-angiotensin system inhibition alone is recommended. Similar therapy is recommended for patients who present late and have resolved active disease but have advanced tubulointerstitial fibrosis on renal biopsy.

[0008] The clinical practice guideline for glomerulonephritis (KDIGO 2021) recognizes that there is currently no evidence to support the use of immunosuppressive therapy in adults or children with primary IC-MPGN. However, for patients with nephrotic syndrome and a normal or near-normal GFR, a limited course of corticosteroids is recommended, or a calcineurin inhibitor can be used if corticosteroids are contraindicated. The guideline states that in children, immunosuppressive therapy can be initiated when proteinuria levels are low, and children may be more likely to receive MMF as a corticosteroid sparing agent. For 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 both innate and adaptive immunity. However, excessive AP activity is known to cause and exacerbate a variety of diseases with autoimmune components.

[0010] Ipracopan is a first-in-class, oral, low-molecular-weight (LMW) reversible, 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, p. 262). FB inhibition prevents the enhancement of all pathways and AP-induced assembly of the C3 and C5 convertases. Meanwhile, ipracopan has only a limited effect on terminal pathway activation induced by the classical pathway. Ipracopan inhibits FB in the context of the C3 convertase, thereby blocking AP-dependent C3 activation and the enhancement of CP- and LP-dependent C5 activation. However, ipracopan does not block MAC generation initiated by CP and LP. This is important because it means that in immune individuals, MAC-dependent killing of Neisseria species through activation of CP will be maintained. However, there are no available clinical data on the use of ipracopan in patients with IC-MPGN.

[0011] In summary, the mechanism and underlying causes of glomerular immune complex formation in IC-MPGN are unknown. Furthermore, although the clinical presentation and course of IC-MPGN, including the rate of progression to renal failure, are similar to those in C3G, nephrotic syndrome occurs more frequently in patients with IC-MPGN (43%–70%) compared with patients with C3G (26%–52%). No clinical data are available on the use of complement inhibitors in patients with IC-MPGN. Summary of the Invention

[0012] The present disclosure relates to methods for treating complement-mediated diseases, particularly immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), using ipracopam (Formula I, shown below) or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride). Ipracopam is also known as LNP023. The terms "ipracopam" and "LNP023" are used interchangeably herein. Ipracopam (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 enhancement of the complement system caused by C3 activation, regardless of the initial activation mechanism. The chemical name of ipracopam hydrochloride is 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride, as shown in Formula I.

[0013] Formula I

[0014] Iprazolam hydrochloride and its preparation method are disclosed in WO 2015 / 009616 (see Example 26d), which is incorporated herein by reference in its entirety. The form of Iprazolam hydrochloride used as the investigational study drug for this study was the monohydrate (Form H). B ), as shown below:

[0015]

[0016] (2S,4S)-2-(4-Carboxyphenyl)-4-ethoxy-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-1-ium chloride-water (1 / 1)

[0017] Iprazosin hydrochloride monohydrate form H B and methods for their preparation are disclosed in USSN 63 / 026,637 and USSN 63 / 052,699, disclosed in WO 2021 / 234544, each of which is incorporated herein by reference in its entirety.

[0018] 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 ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride) to the subject (e.g., patient), e.g., orally, 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, thereby treating the subject (e.g., patient), with each dose administered twice daily (bid), e.g., once about every 12 hours, thereby treating the subject (e.g., patient) (wherein the amount administered refers to the anhydrous free base of ipracopam hydrochloride).

[0019] In one aspect, the present invention provides a method of treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject in need thereof, the method comprising administering ipracopan or a pharmaceutically acceptable salt thereof to the subject, thereby treating the subject.

[0020] In another aspect, the present invention provides ipracopam 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 ipracopam or a pharmaceutically acceptable salt thereof to the subject.

[0021] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of ipracopan 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 to be administered to treat the subject.

[0022] In another aspect, the present invention provides a use of ipracopan or a pharmaceutically acceptable salt thereof for the manufacture of a preparation for treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject in need thereof.

[0023] In one embodiment, the methods and uses of the present invention comprise administering ipracopam or a pharmaceutically acceptable salt thereof to a subject at a dose of about 50 mg to about 200 mg, such as 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, twice daily (bid), wherein the amount administered is the anhydrous free base of ipracopam. In one embodiment, the methods and uses of the present invention comprise administering ipracopam or a pharmaceutically acceptable salt thereof to a subject at a dose of 200 mg, twice daily (bid), wherein the amount administered is the anhydrous free base of ipracopam.

[0024] Non-limiting embodiments of the present disclosure are described in the following examples:

[0025] Example 1: A method of treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject in need thereof, the method comprising administering ipracopan or a pharmaceutically acceptable salt thereof to the subject, thereby treating the subject.

[0026] Example 2: The method of Example 1, wherein ipracopam or a pharmaceutically acceptable salt thereof is administered orally.

[0027] Example 3: The method of Example 1 or 2, wherein ipracopan or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg to about 200 mg, for example, 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, twice daily (bid), wherein the amount administered refers to the anhydrous free base of ipracopan.

[0028] Example 4: The method of Example 3, wherein the dosage is about 200 mg twice daily.

[0029] Embodiment 5: The method of any one of embodiments 1 to 4, wherein the pharmaceutically acceptable salt of ipracopam is ipracopam hydrochloride.

[0030] Embodiment 6: The method of any one of embodiments 1 to 5, wherein the subject has been administered supportive care comprising ACEi, ARB, mycophenolic acid (e.g., mycophenolate mofetil (MMF) and mycophenolate sodium (MPS)), corticosteroids, SGLT2 inhibitors, mineralocorticoid receptor antagonists, cyclophosphamide (CYC), or a calcineurin inhibitor prior to the administration of ipracopam or the administration of ipracopam or a pharmaceutically acceptable salt thereof.

[0031] Example 7: The method of Example 6, wherein the ACEi or ARB has been administered at the maximum recommended or tolerated dose.

[0032] Example 8: The method of Example 7, wherein the subject is further administered supportive care at a stable dose.

[0033] Embodiment 9: The method of any one of embodiments 1 to 8, wherein the subject is an adult or a teenager.

[0034] Embodiment 10: The method of any one of embodiments 1 to 9, wherein the subject's urine protein to creatinine ratio (UPCR) is reduced compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof.

[0035] Example 11: The method of Example 10, wherein the urine protein / creatinine ratio (UPCR) of the subject is reduced by not less than 50% compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof, particularly wherein the urine protein / creatinine ratio (UPCR) of the subject is reduced by not less than 50% after 6 months of treatment.

[0036] Embodiment 12: The method of any one of embodiments 1 to 11, wherein the subject's estimated glomerular filtration rate (eGFR) is stabilized or improved compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof.

[0037] Example 13: The method of Example 12, wherein the subject's estimated glomerular filtration rate (eGFR) is reduced by no more than 15% compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof, particularly wherein the subject's estimated glomerular filtration rate (eGFR) is reduced by no more than 15% after 6 months of treatment.

[0038] Example 14: Ipracopam 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 ipracopam or a pharmaceutically acceptable salt thereof to the subject.

[0039] Example 15: Ipracopam or a pharmaceutically acceptable salt thereof for use as described in Example 14, wherein the ipracopam or a pharmaceutically acceptable salt thereof is administered orally.

[0040] Example 16: Ipracopam or a pharmaceutically acceptable salt thereof for use as described in Example 14 or 15, wherein ipracopam or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg to about 200 mg, for example, 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, with each dose administered twice a day (bid), wherein the amount administered refers to the anhydrous free base of ipracopam.

[0041] Example 17: Ipracopan or a pharmaceutically acceptable salt thereof for use as described in Example 16, wherein the dose is about 200 mg twice daily.

[0042] Embodiment 18: Ipracopam or a pharmaceutically acceptable salt thereof for use as described in any one of embodiments 14 to 17, wherein the pharmaceutically acceptable salt of ipracopam is ipracopam hydrochloride.

[0043] Example 19: Ipracopam or a pharmaceutically acceptable salt thereof for use as described in any one of Examples 14 to 18, wherein before the administration of ipracopam or the administration of ipracopam or a pharmaceutically acceptable salt thereof, the subject has been administered supportive care comprising ACEi, ARB, mycophenolic acid (e.g., mycophenolate mofetil (MMF) and mycophenolate sodium (MPS)), corticosteroids, SGLT2 inhibitors, mineralocorticoid receptor antagonists, cyclophosphamide (CYC) or a calcineurin inhibitor.

[0044] Example 20: Ipracopam or a pharmaceutically acceptable salt thereof for use as described in Example 19, wherein the ACEi or ARB has been administered at the maximum recommended or tolerated dose.

[0045] Example 21: Ipracopan or a pharmaceutically acceptable salt thereof for use as described in Example 20, wherein the subject is further administered supportive care at a stable dose.

[0046] Example 22: Ipracopan or a pharmaceutically acceptable salt thereof for use as described in any one of Examples 14 to 21, wherein the subject is an adult or a teenager.

[0047] Embodiment 23: Ipracopam or a pharmaceutically acceptable salt thereof for use as described in any one of embodiments 14 to 22, wherein the urine protein / creatinine ratio (UPCR) of the subject is reduced compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof.

[0048] Example 24: Ipracopam or a pharmaceutically acceptable salt thereof for use as described in Example 23, wherein the urine protein / creatinine ratio (UPCR) of the subject is reduced by not less than 50% compared to before administration of Ipracopam or a pharmaceutically acceptable salt thereof, in particular, wherein the urine protein / creatinine ratio (UPCR) of the subject is reduced by not less than 50% after 6 months of treatment.

[0049] Example 25: Ipracopam or a pharmaceutically acceptable salt thereof for use as described in Examples 14 to 24, wherein the subject's estimated glomerular filtration rate (eGFR) is stabilized or improved compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof.

[0050] Example 26: Ipracopam or a pharmaceutically acceptable salt thereof for use as described in Example 25, wherein the estimated glomerular filtration rate (eGFR) of the subject is reduced by no more than 15% compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof, in particular, wherein the estimated glomerular filtration rate (eGFR) of the subject is reduced by no more than 15% after 6 months of treatment.

[0051] Example 27: A pharmaceutical composition comprising a therapeutically effective amount of ipracopan 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 to be administered to treat the subject.

[0052] Example 28: The pharmaceutical composition according to Example 27, wherein ipracopam or a pharmaceutically acceptable salt thereof is administered orally.

[0053] Example 29: A pharmaceutical composition as described in Example 27 or 28, wherein ipracopan or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg to about 200 mg, for example, 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, with each dose administered twice a day (bid), wherein the administered amount refers to the anhydrous free base of ipracopan.

[0054] Example 30: The pharmaceutical composition of Example 29, wherein the dosage is about 200 mg twice daily.

[0055] Embodiment 31: The pharmaceutical composition of any one of Embodiments 27 to 30, wherein the pharmaceutically acceptable salt of ipracopam is ipracopam hydrochloride.

[0056] Embodiment 32: The pharmaceutical composition of any one of Embodiments 27 to 31, wherein the subject has been administered supportive care comprising ACEi, ARB, mycophenolic acid (e.g., mycophenolate mofetil (MMF) and mycophenolate sodium (MPS)), corticosteroids, SGLT2 inhibitors, mineralocorticoid receptor antagonists, cyclophosphamide (CYC), or a calcineurin inhibitor prior to the administration of ipracopam or the administration of ipracopam or a pharmaceutically acceptable salt thereof.

[0057] Embodiment 33: The pharmaceutical composition of embodiment 32, wherein the ACEi or ARB has been administered at the maximum recommended or tolerated dose.

[0058] Embodiment 34: The pharmaceutical composition of embodiment 33, wherein the subject is further administered supportive care at a stable dose.

[0059] Embodiment 35: The pharmaceutical composition of any one of Embodiments 27 to 34, wherein the subject is an adult or a teenager.

[0060] Embodiment 36: The pharmaceutical composition of any one of Embodiments 27 to 35, wherein the subject's urine protein / creatinine ratio (UPCR) is reduced compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof.

[0061] Example 37: The pharmaceutical composition of Example 35, wherein the urine protein / creatinine ratio (UPCR) of the subject is reduced by not less than 50% compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof, particularly, wherein the urine protein / creatinine ratio (UPCR) of the subject is reduced by not less than 50% after 6 months of treatment.

[0062] Embodiment 38: The pharmaceutical composition of any one of Embodiments 27 to 37, wherein the subject's estimated glomerular filtration rate (eGFR) is stabilized or improved compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof.

[0063] Embodiment 39: The pharmaceutical composition of embodiment 38, wherein the estimated glomerular filtration rate (eGFR) of the subject is reduced by no more than 15% compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof, particularly wherein the estimated glomerular filtration rate (eGFR) of the subject is reduced by no more than 15% after 6 months of treatment.

[0064] Example 40: Use of ipracopan or a pharmaceutically acceptable salt thereof for the manufacture of a preparation for treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject in need thereof.

[0065] Embodiment 41: The use according to embodiment 40, wherein ipracopam or a pharmaceutically acceptable salt thereof is administered orally.

[0066] Embodiment 42: The use as described in Embodiments 40 to 41, wherein the use comprises administering ipracopam or a pharmaceutically acceptable salt thereof to a subject at a dose of about 50 mg to about 200 mg, for example, 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, with each dose administered twice a day (bid), wherein the administered amount refers to the anhydrous free base of ipracopam.

[0067] Embodiment 43: The use according to embodiment 42, wherein the dosage is about 200 mg twice daily.

[0068] Embodiment 44: The use according to any one of embodiments 40 to 43, wherein the pharmaceutically acceptable salt of ipracopam is ipracopam hydrochloride.

[0069] Embodiment 45: The use of any one of embodiments 40 to 44, wherein the subject has been administered supportive care comprising ACEi, ARB, mycophenolic acid (e.g., mycophenolate mofetil (MMF) and mycophenolate sodium (MPS)), corticosteroids, SGLT2 inhibitors, mineralocorticoid receptor antagonists, cyclophosphamide (CYC) or calcineurin inhibitors prior to the administration of ipracopam or the administration of ipracopam or a pharmaceutically acceptable salt thereof.

[0070] Embodiment 46: The use according to embodiment 45, wherein the ACEi or ARB has been administered at the maximum recommended or tolerated dose.

[0071] Embodiment 47: The use according to embodiment 46, wherein supportive care is further administered to the subject at a stable dose.

[0072] Embodiment 48: The use according to any one of embodiments 40 to 47, wherein the subject is an adult or a teenager.

[0073] Embodiment 49: The use of any one of embodiments 40 to 48, wherein the subject's urine protein / creatinine ratio (UPCR) is reduced compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof.

[0074] Embodiment 50: The use according to embodiment 49, wherein the urine protein / creatinine ratio (UPCR) of the subject is reduced by not less than 50% compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof, in particular, wherein the urine protein / creatinine ratio (UPCR) of the subject is reduced by not less than 50% after 6 months of treatment.

[0075] Embodiment 51: The use of any one of embodiments 40 to 50, wherein the subject's estimated glomerular filtration rate (eGFR) is stabilized or improved compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof.

[0076] Example 52: The use according to Example 51, wherein the estimated glomerular filtration rate (eGFR) of the subject is reduced by no more than 15% compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof, particularly wherein the estimated glomerular filtration rate (eGFR) of the subject is reduced by no more than 15% after 6 months of treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0077] Figure 1 A schematic diagram depicting the study design is shown. DETAILED DESCRIPTION

[0078] Described herein is a method of using ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H) to prepare a pharmaceutical composition comprising: B ) for treating immune complex-mediated membranoproliferative glomerulonephritis, IC-MPGN, in a patient in need thereof. Accordingly, described herein are methods for treating IC-MPGN in a patient in need thereof, comprising administering to the patient, for example, orally, ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride), e.g., in capsule form, wherein ipracopam 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 twice daily (e.g., once about every 12 hours) (wherein the amount administered refers to the anhydrous free base of ipracopam hydrochloride). Thus, described herein are methods for treating IC-MPGN in a patient in need thereof, comprising administering to the patient, for example, orally, ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride), e.g., in capsule form, wherein ipracopam or a pharmaceutically acceptable salt thereof is administered at a dose of 200 mg twice daily (e.g., once about every 12 hours) (wherein the amount administered refers to the anhydrous free base of ipracopam hydrochloride). Also described herein are methods for selecting a target patient population, methods for monitoring treatment of a target patient population, and methods for assessing the safety and efficacy of treatment of a target patient population.

[0079] The details of the present disclosure are set forth in the specification sheet attached below. Although methods and materials similar or equivalent to those described herein can be used for the practice or testing of the present disclosure, illustrative methods and materials are now described. According to the specification sheet and according to the claims, other features, objects and advantages of the present disclosure will be clear. In this specification sheet and the appended claims, the singular form also includes the plural form, unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those of ordinary skill in the art to which the present disclosure belongs. All patents and public documents cited in this specification sheet are incorporated herein by reference in their entirety.

[0080] definition

[0081] Unless specific definitions are provided, the nomenclature and laboratory procedures and techniques used in conjunction with analytical chemistry, synthetic organic chemistry, and medicinal chemistry and pharmaceutical chemistry as described herein are those well-known and commonly used in the art. Standard techniques can be used for chemical syntheses and chemical analyses. Some such techniques and procedures can be found in, for example, "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa., 21st edition, 2005, which is incorporated herein by reference for any purpose. Where permitted, all patents, applications, disclosed applications, and other publications and other data cited throughout this disclosure are incorporated herein by reference in their entirety.

[0082] Unless otherwise indicated, the following terms have the following meanings:

[0083] As used herein, "about" means within ±10% of a value.

[0084] As used herein, "administering" or "administration" means providing a pharmaceutical agent to an individual and includes, but is not limited to, administration by a medical professional and self-administration. Administration of a pharmaceutical agent to an individual can be continuous, chronic, brief, or intermittent.

[0085] As used herein, the terms "acquire" or "acquiring" refer to obtaining possession of a physical entity (e.g., a sample, such as a blood sample or plasma sample) or a value (e.g., a value) by "directly obtaining" or "indirectly obtaining" the physical entity or value. "Directly obtaining" means performing a process (e.g., an analytical method) to obtain the physical entity or value. "Indirectly obtaining" means receiving the physical entity or value from another party or source (e.g., a third-party laboratory that directly obtains the physical entity or value). Directly obtaining a value includes performing a process that involves a physical change in a sample or another substance, such as performing an analytical process that involves a physical change in a substance (e.g., a sample), performing an analytical method, such as the methods described herein, for example, performing sample analysis of a bodily fluid (e.g., blood) by, for example, mass spectrometry, such as LC-MS, such as LC-MS / MS methods.

[0086] As used herein, "dose" means a specified amount of a pharmaceutical agent provided in a single administration or over a specified period of time. In certain embodiments, a dose can be administered in a capsule. As used herein, the dosage amount refers to the anhydrous free base of ipracopan hydrochloride.

[0087] As used herein, "individual," "patient," "participant," or "subject" means a human being selected for treatment or therapy. As used herein, the term "adult" means an individual who is 18 years of age or older. As used herein, the term "adolescent" means an individual between 12 and 17 years of age.

[0088] As used herein, "pharmaceutically acceptable salts" refers to physiologically and pharmaceutically acceptable salts of ipracopam, i.e., salts that retain the desired biological activity of ipracopam and do not impart undesirable toxicological effects thereto. The term "pharmaceutically acceptable salts" or "salts" includes salts prepared from pharmaceutically acceptable, non-toxic acids or bases, including inorganic or organic acids and bases. "Pharmaceutically acceptable salts" of ipracopam 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). Ipracopam hydrochloride and its preparation method are disclosed in WO 2015 / 009616 (see Example 26d), which is incorporated herein by reference in its entirety.

[0089] As used herein, the terms "treat," "treating," and "treatment" mean to reduce, inhibit, attenuate, diminish, arrest, or stabilize the development or progression of a disorder or disease (e.g., lupus nephritis, immune complex membranoproliferative glomerulonephritis (IC-MPGN)). Treatment does not require a complete cure of the disorder and encompasses alleviation of symptoms or underlying risk factors or slowing the progression of the disease. As used herein, the terms "treat," "treatment," and "treating" refer to slowing, reducing, or alleviating the progression or severity of IC-MPGN, or alleviating one or more symptoms (suitably, one or more discernible symptoms) of IC-MPGN. In specific embodiments, the terms "treat," "treatment," and "treating" refer to improving at least one measurable physical parameter of IC-MPGN (e.g., achieving or at least partially achieving a desired effect (e.g., particularly, reduction in proteinuria as measured by urine protein:creatinine ratio (UPCR), improvement in estimated glomerular filtration rate (eGFR), improvement in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue) score)), where the physical parameter is not necessarily discernible by the patient.

[0090] Unless otherwise indicated, conventional definitions of terms and conventional stable atom valencies are assumed and reflected in all formulae and groups.

[0091] As used in this disclosure, the articles “a” and “an” refer to one or more than one (eg, at least one) grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0092] How to use

[0093] In one aspect, 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, the method comprising administering ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H) to the subject (e.g., a patient), e.g., orally. B ), thereby treating a subject (e.g., a patient).

[0094] In another aspect, the present disclosure provides a method of reducing proteinuria, e.g., reducing the urine protein / creatinine ratio (UPCR), in a subject (e.g., a patient) in need thereof, the method comprising administering ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride), e.g., orally, to the subject (e.g., the patient), thereby treating the subject (e.g., the patient).

[0095] In another aspect, the present disclosure provides a method of achieving a stable or improved estimated glomerular filtration rate (eGFR) in a subject (e.g., a patient) in need thereof, the method comprising administering ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H) to the subject (e.g., a patient), e.g., orally. B ), thereby treating a subject (e.g., a patient).

[0096] In another aspect, the present disclosure provides ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam 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 comprises administering ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H) to a subject (e.g., a patient). B ).

[0097] In another aspect, the present disclosure provides ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H) for use in reducing proteinuria in a subject (e.g., a patient) in need thereof, e.g., reducing UPCR. B ), wherein the treatment comprises administering ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H) to a subject (e.g., a patient). B ).

[0098] In another aspect, the present disclosure provides ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam 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 comprises administering ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H) to a subject (e.g., a patient). B ).

[0099] In another aspect, the present disclosure provides ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H). B ) in the manufacture of a medicament for treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject (e.g., a patient) in need thereof, wherein the treatment comprises administering ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H) to the subject (e.g., the patient). B ).

[0100] In another aspect, the present disclosure provides ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H). B ) in the manufacture of a medicament for reducing proteinuria, such as reducing UPCR, in a subject (e.g., a patient) in need thereof, wherein the treatment comprises orally administering ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, such as ipracopam hydrochloride monohydrate form H) to the subject (e.g., the patient). B ).

[0101] In another aspect, the present disclosure provides ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H). B ) in the manufacture of a medicament for achieving a stable or improved eGFR in a subject (e.g., a patient) in need thereof, wherein the treatment comprises orally administering ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H) to the subject (e.g., the patient). B ).

[0102] In another aspect, the present disclosure provides a pharmaceutical composition for use in treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject (e.g., a patient) in need thereof, the pharmaceutical composition comprising ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H). B ), wherein the pharmaceutical composition is to be administered to treat a subject (e.g., a patient).

[0103] In another aspect, the present disclosure provides a pharmaceutical composition for use in reducing proteinuria, e.g., lowering UPCR, in a subject (e.g., a patient) in need thereof, the pharmaceutical composition comprising ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H). B ), wherein the pharmaceutical composition is to be administered to treat a subject (e.g., a patient).

[0104] In another aspect, the present disclosure provides a pharmaceutical composition for use in achieving stable or improved eGFR in a subject (e.g., a patient) in need thereof, the pharmaceutical composition comprising ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H). B ), wherein the pharmaceutical composition is to be administered to treat a subject (e.g., a patient).

[0105] The above-mentioned aspects of the present invention are each represented by the following embodiments, which can be combined where applicable.

[0106] In embodiments, ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate Form H) B ) is administered at a dose of about 50 mg to about 200 mg, for example, 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, twice daily (bid) (e.g., once every 12 hours) (wherein the amount administered refers to the anhydrous free base of ipracopam hydrochloride). In another embodiment, ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, for example, ipracopam hydrochloride monohydrate form H B ) is administered at a dose of 50 mg to 200 mg, e.g., 50 mg to 100 mg, 100 mg to 200 mg, 50 mg, 75 mg, 100 mg, 150 mg or 200 mg twice daily (bid) (e.g., once every 12 hours) (wherein the administered amount refers to the anhydrous free base of ipracopan hydrochloride).

[0107] In embodiments, ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate Form H) B ) is administered at a dose of about 100 mg twice a day (bid), particularly at a dose of 100 mg twice a day (bid) (wherein the administered amount refers to the anhydrous free base of ipracopam hydrochloride).

[0108] In embodiments, ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate Form H) B ) is administered twice daily (bid) at a dose of about 200 mg (wherein the amount administered refers to the anhydrous free base of ipracopam hydrochloride). In a preferred embodiment, ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H B ) was administered at a dose of 200 mg twice daily (bid) (wherein the administered amount refers to the anhydrous free base of ipracopan hydrochloride).

[0109] In embodiments, ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate Form H) B ) are administered orally.

[0110] In an embodiment, the method comprises administering to a subject (e.g., a patient), for example, orally, ipracopam hydrochloride monohydrate Form H B .

[0111] In an embodiment, ipracolos hydrochloride monohydrate Form H B It 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 a temperature in the range of 20°C to 30°C with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm.

[0112] In an embodiment, ipracolos hydrochloride monohydrate Form H B It 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)°, and (19.1 ± 0.2)° when measured at a temperature in the range of 20°C to 30°C with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm.

[0113] In an embodiment, ipracolos hydrochloride monohydrate Form H B It 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 a temperature in the range of 20°C to 30°C with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm.

[0114] In an embodiment, ipracolos hydrochloride monohydrate Form H B It 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 a temperature in the range of 20°C to 30°C with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm.

[0115] In an embodiment, ipracolos 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)°, (16.6 ± 0.2)°, (19.1 ± 0.2)°, (21.3 ± 0.2)°, and (24.6 ± 0.2)° when measured at a temperature in the range of 20°C to 30°C with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm.

[0116] In an embodiment, ipracolos hydrochloride monohydrate Form H B is a crystalline form characterized by PXRD peaks identified at the following 2-theta angles when measured at a temperature in the range of 20°C to 30°C with Cu-Kalpha1,2 radiation having a wavelength of 0.15419 nm:

[0117] (4.6 ± 0.1)°, (9.2 ± 0.1)°, and (19.1 ± 0.1)°; or

[0118] (4.6 ± 0.1)°, (6.8 ± 0.1)°, (9.2 ± 0.1)°, and (19.1 ± 0.1)°; or

[0119] (4.6 ± 0.1)°, (6.8 ± 0.1)°, (9.2 ± 0.1)°, (19.1 ± 0.1)°, and (24.6 ± 0.1)°; or

[0120] (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

[0121] (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

[0122] (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

[0123] (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

[0124] (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

[0125] (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

[0126] (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

[0127] (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

[0128] (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

[0129] (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

[0130] (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)°.

[0131] In an embodiment, ipracolos hydrochloride monohydrate Form H B is a crystalline form characterized by having a Fourier transform infrared spectrum containing wavelengths of (3452 ± 4) cm-1 when measured with a diamond ATR unit cell at a temperature in the range of 20°C to 30°C. -1 、(2875±4)cm -1 and (1692 ± 4) cm -1 The peak at.

[0132] In an embodiment, ipracolos hydrochloride monohydrate Form H B is a crystalline form characterized by having a Fourier transform infrared spectrum containing wavelengths of (3452 ± 4) cm-1 when measured with a diamond ATR unit cell at a temperature in the range of 20°C to 30°C. -1 、(2875±4)cm -1 、(1692±4)cm -1 and (1439 ± 4) cm -1 The peak at.

[0133] In an embodiment, ipracolos hydrochloride monohydrate Form H Bis a crystalline form characterized by having a Fourier transform infrared spectrum comprising peaks at the following wavenumbers when measured with a diamond ATR unit cell at a temperature in the range of 20°C to 30°C:

[0134] (3452±2)cm -1 、(2875±2)cm -1 and (1692 ± 2) cm -1 ,or

[0135] (3452±2)cm -1 、(2875±2)cm -1 、(1692±2)cm -1 and (1439 ± 2) cm -1 ;or

[0136] (3452±2)cm -1 、(2875±2)cm -1 、(1692±2)cm -1 、(1439±2)cm -1 and (1243 ± 2) cm -1 ;or

[0137] (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

[0138] (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

[0139] (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

[0140] (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

[0141] (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

[0142] (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

[0143] (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

[0144] (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

[0145] (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

[0146] (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

[0147] (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

[0148] (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

[0149] (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

[0150] (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

[0151] (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 .

[0152] In an embodiment, ipracolos hydrochloride monohydrate Form H B is a crystalline form characterized by a differential scanning calorimetry curve comprising an endothermic event ranging from about 35°C to 170°C when measured at a heating rate of 10 K / min.

[0153] In an embodiment, ipracolos hydrochloride monohydrate Form H B is a crystalline form characterized by having a DSC curve showing a broad endothermic event ending at about 170° C., followed by an exothermic decomposition at about 200° C., when measured at a heating rate of 10 K / min. In embodiments, the broad endothermic event ending at about 170° C. is an endothermic event within the range of 35° C. to 170° C., when measured at a heating rate of 10 K / min.

[0154] In an embodiment, ipracolos hydrochloride monohydrate Form H B is a crystalline form characterized by having a thermogravimetric analysis curve showing a mass loss based on the weight of the crystalline form at a temperature of about 220°C, for example at a temperature of 200°C to 220°C, due to loss of water and residual solvents when heated from 30°C to 300°C at a rate of 20 K / min.

[0155] In an embodiment, ipracolos hydrochloride monohydrate Form H Bis a crystalline form characterized by having a dynamic vapor sorption curve when measured by dynamic vapor sorption at a relative humidity in the range of 0% to 95% and at a temperature of (25 ± 1.0) ° C, the dynamic vapor sorption curve showing a mass change of no more than 4.5 w-%, such as no more than 4.0 w-%, such as no more than 3.0 w-%, such as no more than 2.0 w-%, such as no more than 1.8 w-%, 1.6 w-%, 1.5 w-% or 1.4 w-%, based on the weight of the crystalline form.

[0156] In an embodiment, the subject (e.g., patient) is an adult. In an embodiment, the subject (e.g., patient) is a teenager.

[0157] In embodiments, the subject (e.g., patient) is diagnosed with IC-MPGN, e.g., primary IC-MPGN, e.g., in the native kidney, e.g., as confirmed by kidney biopsy, within 12 months in adults or within 3 years in adolescents prior to administration.

[0158] In embodiments, upon administration of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H B The subject (e.g., patient) has a urine protein-to-creatinine ratio (UPCR) ≥ 1.0 g / g when sampled prior to administration of the drug, such as from the first morning void or a 24-hour urine collection.

[0159] In embodiments, the administration of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H) B Subjects (e.g., patients) with an estimated glomerular filtration rate (eGFR) ≥ 30 ml / min / 1.73 m2 when calculated using the CKD-EPI formula or the modified Schwartz formula according to specific ethnic groups and local practice guidelines before 2 .

[0160] In embodiments, upon administration of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H B ) before the subject (e.g., patient) had a measured glomerular filtration rate (GFR) ≥ 30 ml / min / 1.73 m 2 .

[0161] In embodiments, upon administration of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H B ) before the subject (e.g., patient) has been vaccinated.

[0162] In embodiments, upon administration of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H B ) The subject (e.g., patient) has been previously vaccinated against encapsulated bacteria.

[0163] In embodiments, the subject (eg, patient) has been or is being administered an antibiotic, such as an antibiotic directed against encapsulated bacteria.

[0164] In embodiments, the enveloped bacterium is Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae, or Haemophilus influenzae.

[0165] In embodiments, upon administration of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H B ) The subject (e.g., patient) has been vaccinated against Neisseria meningitidis (types A, C, Y, and W-135) before.

[0166] In embodiments, upon administration of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H B ) The subject (e.g., patient) has been vaccinated against Streptococcus pneumoniae (Pneumovax-23) before.

[0167] In embodiments, upon administration of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H B ) The subject (e.g., patient) has been vaccinated against Haemophilus influenzae before.

[0168] In embodiments, the subject (eg, patient) has been administered supportive care, eg, at the maximum daily dose or maximum tolerated dose (eg, at a stable dose), for eg, at least 90 days prior to administration of ipracopan or a pharmaceutically acceptable salt thereof.

[0169] In embodiments, supportive care is at the maximum daily dose or the maximum tolerated dose.

[0170] In embodiments, supportive care is at a stable dose.

[0171] In embodiments, supportive care has been administered for at least 90 days prior to treatment.

[0172] In embodiments, the subject (eg, patient) is further administered supportive care, eg, at a stable dose.

[0173] In embodiments, the subject (eg, patient) has been administered and is further being administered an anti-proteinuric agent.

[0174] In embodiments, the subject (eg, patient) has been administered and is further being administered an immunosuppressive agent.

[0175] In embodiments, supportive care comprises 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 (e.g., voclosporin).

[0176] In embodiments, the subject (eg, patient) has been administered and is further being administered an ACEi, an ARB, mycophenolic acid, a corticosteroid, an SGLT2 inhibitor, a mineralocorticoid receptor antagonist, cyclophosphamide (CYC), or a calcineurin inhibitor (eg, cyclosporine).

[0177] In embodiments, the subject (eg, patient) has been administered, eg, at a stable maximum tolerated dose, and is further being administered an ACEi or ARB.

[0178] In embodiments, the subject (eg, patient) has been administered and is further being administered mycophenolate mofetil (MMF) or mycophenolate sodium (MPS).

[0179] In embodiments, the subject (eg, patient) has been administered a stable dose of and is further being administered an immunosuppressant or anti-proteinuric agent, such as MMF, MPS, corticosteroids, and SGLT2i.

[0180] In embodiments, the subject (eg, patient) has been administered DRUG AGAINST HER200, eg, at a dose of no greater than 7.5 mg per day and is further being administered a corticosteroid, such as prednisone.

[0181] In an embodiment, the present disclosure provides ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H) for use in reducing proteinuria (e.g., lowering UPCR) in a subject (e.g., a patient). B ), wherein the administration of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H B), the UPCR of the subject (e.g., patient) is reduced by, for example, not less than 25%, not less than 30%, not less than 40%, not less than 45%, not less than 50%, not less than 55%, not less than 60%, or not less than 65% compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H). B ), after 6 months of treatment, the subject's (e.g., patient's) UPCR is reduced by, for example, not less than 25%, not less than 30%, not less than 40%, not less than 45%, not less than 50%, not less than 55%, not less than 60%, or not less than 65% compared to before treatment. In specific embodiments, ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H B ) was administered at a dose of 200 mg twice daily (bid) (wherein the administered amount refers to the anhydrous free base of ipracopan hydrochloride).

[0182] In an embodiment, the present disclosure provides a method of achieving a stable or improved estimated glomerular filtration rate (eGFR) in a subject (e.g., a patient) in need thereof, the method comprising administering ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H) to the subject (e.g., a patient), e.g., orally. B ), wherein the administration of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H B ), the eGFR or measured GFR of the subject (e.g., patient) is stable, e.g., decreased by no more than 20%, decreased by no more than 15%, decreased by no more than 10%, or decreased by no more than 5%, compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H). B ), after 6 months of treatment, the subject's (e.g., patient's) eGFR or measured GFR is stable, e.g., decreased by no more than 20%, decreased by no more than 15%, decreased by no more than 10%, or decreased by no more than 5%, compared to before treatment.

[0183] In an embodiment, the present disclosure provides a method of achieving a stable or improved estimated glomerular filtration rate (eGFR) in a subject (e.g., a patient) in need thereof, the method comprising administering ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H) to the subject (e.g., a patient), e.g., orally. B ), wherein the administration of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H BIn some embodiments, the eGFR or measured GFR of the subject (e.g., patient) is improved after 6 months of treatment compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride).

[0184] In an embodiment, the present disclosure provides ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride) for use in reducing proteinuria (e.g., lowering UPCR) in a subject (e.g., a patient) in need thereof, wherein the treatment comprises administering ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride) to the subject (e.g., the patient), wherein the administration of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H B ), the subject's (e.g., patient's) UPCR is reduced, for example, by not less than 25%, not less than 30%, not less than 40%, not less than 45%, not less than 50%, not less than 55%, not less than 60%, or not less than 65%, compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride); and the subject's (e.g., patient's) eGFR or measured GFR is stable, for example, by no more than 20%, no more than 15%, no more than 10%, or no more than 5%. In embodiments, after 6 months of treatment, the subject's (e.g., patient's) UPCR is reduced, for example, by not less than 25%, not less than 30%, not less than 40%, not less than 45%, not less than 50%, not less than 55%, not less than 60%, or not less than 65%, compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride); and the subject's (e.g., patient's) eGFR or measured GFR is stable, for example, by no more than 20%, no more than 15%, no more than 10%, or no more than 5%.

[0185] In embodiments, the subject (eg, patient) has a reduced FACIT-Fatigue score compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof (eg, ipracopam hydrochloride).

[0186] In an embodiment, the present disclosure provides a method of treating immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) in a subject (e.g., patient) in need thereof, the method comprising administering ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride), for example, orally, to the subject (e.g., patient), thereby treating the subject (e.g., patient), wherein the administration of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H) is combined with the administration of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride monohydrate form H). B), the FACIT-Fatigue score of the subject (e.g., patient) is reduced by not less than 2 points, not less than 3 points, or not less than 4 points compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H B ), the subject's (e.g., patient's) FACIT-Fatigue score decreases by not less than 2 points, not less than 3 points, or not less than 4 points after 6 months or 12 months of treatment compared to before.

[0187] Key efficacy assessments:

[0188] Also provided herein is a method for evaluating the efficacy of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H) in a patient population with immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN). B ) comprising determining the efficacy of a treatment with ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H) compared to a treatment without ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride monohydrate form H) B ) to assess the efficacy of treatment by measuring the percentage of patients who achieve a reduction in proteinuria compared to the group of patients who receive treatment.

[0189] Also provided herein is a method for evaluating the efficacy of ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H) in a patient population with immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN). B ) comprising determining the efficacy of a treatment with ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride, e.g., ipracopam hydrochloride monohydrate form H) compared to a treatment without ipracopam or a pharmaceutically acceptable salt thereof (e.g., ipracopam hydrochloride monohydrate form H) B ) to assess treatment efficacy by measuring the percentage of patients who achieve stable or improved eGFR compared to the group of patients who receive treatment.

[0190] •Efficacy evaluation:

[0191] o Stable or improved eGFR compared to baseline visit (eGFR decrease ≤ 15%), and / or

[0192] o Urine protein / creatinine ratio (UPCR) reduction ≥ 50%

[0193] Patient population: Participants with biopsy-proven idiopathic IC-MPGN who meet other inclusion and exclusion criteria

[0194] The proportion of patients who achieved the following criteria compared to the baseline visit:

[0195] o Stable or improved eGFR compared to baseline visit (eGFR decrease ≤ 15%), and

[0196] o Urine protein / creatinine ratio (UPCR) reduction ≥ 50%

[0197] Examples

[0198] The present disclosure is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the present disclosure to the specific procedures described herein. It should be understood that these examples are provided to illustrate certain embodiments, and the scope of the present disclosure is not intended to be limited thereto. It should be further understood that various other embodiments, modifications, and their equivalents that can be imagined by those skilled in the art can be adopted without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0199] Professional Glossary

[0200]

[0201]

[0202]

[0203] Example 1. A multicenter, randomized, double-blind, parallel-group, placebo-controlled study to evaluate the efficacy and safety of ipracopan (LNP023) in idiopathic immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN).

[0204] Purpose

[0205] This Phase III study (CLNP023B12302) is designed to evaluate the efficacy and safety of ipracopam compared with placebo (both administered in combination with standard of care) 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 ipracopam compared with placebo. Changes in patient-reported fatigue will also be assessed. Dysregulation of the alternative complement pathway (AP) is believed to underlie the clinical manifestations and progression of IC-MPGN.

[0206] Study Design

[0207] This multicenter, randomized, double-blind, parallel-group, placebo-controlled study is designed to evaluate the efficacy and safety of ipracopam in participants with idiopathic IC-MPGN. Approximately 68 participants (adults and a minimum of 10 adolescents) will be randomly assigned to the trial. Half of the participants (n = 34) will receive ipracopam at a dose of 200 mg twice daily (bis in die) / twice daily (bid) as blinded treatment for 6 months, followed by 6 months of open-label ipracopam at 200 mg bid. The other half of the participants (n = 34) will receive a blinded placebo for 6 months, followed by 6 months of open-label ipracopam at 200 mg bid. After completing 12 months of study treatment with CLNP023B12302, participants will have the option of discontinuing ipracopan treatment and entering a 30-day safety follow-up period or transitioning to an open-label extension study (CLNP023B12001B) and continuing ipracopan treatment. Figure 1 As displayed.

[0208] The study covers the following three periods:

[0209] • A screening / run-in period of up to 90 days (Note: The screening / run-in period can be completed in fewer than 90 days if, for example, the participant is already receiving a stable dose of antiproteinuric therapy (such as, but not limited to, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, SGLT2 inhibitors, mineralocorticoid receptor antagonists, mycophenolic acid, oral corticosteroids) and has received all required vaccinations.

[0210] • 360-day treatment period (consisting of a 6-month blinded treatment portion and a 6-month open-label portion), and

[0211] • 30-day safety follow-up period (or optionally, transition to the extension study).

[0212] Throughout the protocol, "baseline" refers to the Day 1 visit (pre-dose) of CLNP023B12302. Approximately 68 adult and adolescent participants aged 12 to 60 years (34 treated with ipracopan and 34 treated with placebo) will be randomized. A minimum of 10 adolescents will be individually randomized during the study. Among adult participants, randomization will be stratified by corticosteroid and / or mycophenolic acid treatment (yes or no) at the time of randomization, as use of these agents may affect responsiveness to ipracopan.

[0213] To assess the efficacy of ipracopan in adult participants with high levels of proteinuria, approximately 50% of randomized participants are expected to have proteinuria ≥ 3.0 g / day on Day 1 (24-hour urine collection). Baseline proteinuria will be monitored throughout the study, and if necessary, randomization of adult participants may be restricted to those with a UPCR ≥ 3.0 g / g on Days -75 and -15.

[0214] Inclusion criteria

[0215] Participants eligible for inclusion in this study must meet all of the following criteria:

[0216] 1. Must provide signed informed consent before participating in this study.

[0217] 2. Male and female participants must be ≥ 12 years and ≤ 60 years old at screening.

[0218] 3. Ability to communicate well with researchers to understand and comply with study requirements.

[0219] 4. A diagnosis of IC-MPGN confirmed by renal biopsy within 12 months prior to enrollment for adults and within 3 years prior to enrollment for adolescents (biopsy report, review and confirmation by the investigator is required). If such confirmation is not available for adults, it should be obtained by renal biopsy at screening (adults only).

[0220] 5. Prior to randomization, all participants must have received the maximum recommended or tolerated dose of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) for at least 90 days (or according to local guidelines). The dose of other antiproteinuric agents (including mycophenolic acid (MMF or mycophenolate sodium), corticosteroids, SGLT2 inhibitors, and mineralocorticoid receptor antagonists) should be stable for at least 90 days before randomization. The dose of ACEI / ARB, mineralocorticoid receptor antagonist, mycophenolic acid, corticosteroids, and SGLT2 inhibitor should remain stable throughout the study treatment period unless the participant experiences adverse events or other safety issues that require dose modification.

[0221] 6. For adults and adolescents, UPCR ≥ 1.0 g / g (≥ 113 mg / mmol) in the first morning urine sample on days -75 and -15.

[0222] 7. Estimated GFR (using the CKD-EPI formula for participants ≥ 18 years and the modified Schwartz formula for participants 12 to 17 years) or measured GFR ≥ 30 ml / min / 1.73m at screening and day -15 2 .

[0223] 8. Mandatory vaccination against Neisseria meningitidis and Streptococcus pneumoniae infections is required before starting study treatment. If the patient has not been previously vaccinated or requires a booster vaccination, they should be vaccinated at least 2 weeks before the first dose of study treatment in accordance with local regulations. If study treatment must be started earlier than 2 weeks after vaccination, prophylactic antibiotic therapy should be initiated according to local standards of care.

[0224] 9. If not previously vaccinated or if booster vaccination is required, vaccination against Haemophilus influenzae infection should be given at least 2 weeks before the first dose of study treatment (if available and in accordance with local regulations). If study treatment must be started earlier than 2 weeks after vaccination, prophylactic antibiotic treatment should be started according to local standards of care.

[0225] Main exclusion criteria

[0226] Participants who met any of the following criteria were not eligible for inclusion in this study.

[0227] 1. Participants who have received any cell or organ transplant (including kidney transplant).

[0228] 2. Patients diagnosed with secondary IC-MPGN including but not limited to any of the following conditions:

[0229] • Deposition of antigen-antibody immune complexes due to any infection, including

[0230] o Viral hepatitis C (including HCV-associated mixed cryoglobulinemia), hepatitis B;

[0231] o Bacterial endocarditis, infected ventriculo-atrial shunt, visceral abscess, leprosy, meningococcal meningitis; chronic bacterial infections

[0232] o Protozoal / other infections – malaria, schistosomiasis, mycoplasma, leishmaniasis, filariasis, histoplasmosis)

[0233] • Deposition of immune complexes due to autoimmune diseases:

[0234] o SLE

[0235] o Sjögren's syndrome

[0236] Rheumatoid arthritis

[0237] o Mixed connective tissue disease, etc.

[0238] • Deposition of monoclonal Ig due to a monoclonal gammopathy caused by a plasma cell or B cell disorder. Monoclonal gammopathy of undetermined significance (MGUS) confirmed by measurement of serum free light chains or other studies according to local standard of care.

[0239] • Fibrillary glomerulonephritis

[0240] 3. Rapidly progressive crescentic glomerulonephritis (defined as a 50% decrease in eGFR within 3 months), with glomerular crescents observed in at least 50% of the glomeruli on renal biopsy.

[0241] 4. Participants with acute post-infectious glomerulonephritis.

[0242] 5. Kidney biopsy shows interstitial fibrosis / tubular atrophy (IF / TA) exceeding 50%.

[0243] 6. Adult participants (≥ 18 years and ≤ 60 years old) with systolic blood pressure (SBP) < 80 mmHg or > 160 mmHg, or diastolic blood pressure (DBP) < 50 mmHg or > 100 mmHg, or pulse rate < 45 bpm or > 100 bpm.

[0244] 7. Adolescent participants (12-17 years old) with systolic blood pressure (SBP) < 80 mmHg or > 150 mmHg, or diastolic blood pressure (DBP) < 50 mmHg or > 95 mmHg, or pulse rate < 50 bpm or > 110 bpm.

[0245] 8. Body mass index (BMI) > 38 kg / m at screening and randomization 2 Body weight < 35 kg at screening and randomization.

[0246] 9. Participants with active systemic bacterial, viral, or fungal infection within 14 days prior to study treatment administration.

[0247] 10. Fever ≥ 38°C (100.4°F) within 7 days prior to study treatment administration.

[0248] 11. History of recurrent invasive infections caused by encapsulated organisms (e.g., Neisseria meningitidis and Streptococcus pneumoniae).

[0249] 12. Presence of human immunodeficiency virus (HIV) infection (known history of HIV or positive HIV antibody test at screening).

[0250] 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, defined as follows:

[0251] •Any single parameter of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), or alkaline phosphatase should not exceed 3 × upper limit of normal (ULN).

[0252] • Serum bilirubin should not exceed 2 × upper limit of normal (ULN) (except for those participants with a known diagnosis of Gilbert syndrome).

[0253] 14. Evidence of urinary tract obstruction or dysuria during screening and randomization.

[0254] 15. The presence of severe concurrent comorbidities (including but not limited to advanced heart 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 any other condition that the investigator believes will prevent the participant from participating in this study.

[0255] 16. A history of ECG abnormalities or a current diagnosis that indicates a significant safety risk to the participant's participation in this study, such as the presence of clinically significant arrhythmias, such as sustained ventricular tachycardia and clinically significant second- or third-degree atrioventricular block (AV block) in the absence of a pacemaker.

[0256] 17. History of malignant disease of any organ system (excluding localized basal cell carcinoma of the skin or in situ cervical cancer) that has been treated or untreated in the past 5 years (regardless of whether there is evidence of local recurrence or metastasis).

[0257] 18. History of hypersensitivity or moderate to severe allergy to any of the study treatments or excipients or to drugs of similar chemical classes, as judged by the investigator.

[0258] 19. History of drug or alcohol abuse within 12 months prior to study treatment.

[0259] 20. The presence of any medical condition that is considered to be potentially interfering with the patient's participation in the study.

[0260] 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.

[0261] 22. Participation in any other investigational drug trial or use of other investigational drugs at the time of enrollment, or within 5 elimination half-lives or 30 days of enrollment (whichever is longer); or use of other investigational drugs for a longer period if required by local regulations.

[0262] 23. Female participants who are pregnant, breastfeeding, or planning to become pregnant during the study.

[0263] 24. Females of childbearing potential are defined as all females who are physiologically capable of becoming pregnant, unless they use effective contraception during the administration of the study drug and within 1 week after stopping the study drug.

[0264] Treatment group

[0265] The study included the following three periods: Figure 1 ): Up to 90 days of screening / run-in period; 360 days of 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). Duration of treatment with study drug is 12 months.

[0266] During the first 6 months of the double-blind treatment phase, half of the participants will receive ipracopan 200 mg twice daily (100 mg for adolescents and 200 mg for adults) capsules. In the placebo control group, the other half will receive placebo capsules matching the 100 mg and 200 mg ipracopan capsules. During the 6-month open-label period, all participants in both groups will receive ipracopan 200 mg twice daily. Ipracopan may be temporarily interrupted or discontinued due to adverse events, progression of the underlying disease, and / or at the discretion of the investigator or participant.

[0267] Goals and End Points

[0268] Table 1 Objectives and relevant endpoints of the double-blind treatment period

[0269]

[0270] Table 2 Objectives and relevant endpoints of the open-label treatment period

[0271]

[0272] Study Design Rationale

[0273] The study design included a 6-month double-blind, placebo-controlled period to evaluate the potential beneficial effect of iptacopan compared with placebo in improving renal function. The duration of the placebo-controlled period was limited to 6 months because both the study participants and the treating investigators considered longer periods of placebo exposure and discontinuation of other experimental therapies (e.g., immunosuppressants or anti-complement agents) unacceptable (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 trial beyond 6 months was not considered feasible due to the difficulty in recruiting patients with this severe and progressive disease for longer studies with an ultra-rare disease.

[0274] This time period also allowed us to balance the need to administer ipracopam for a sufficient period of time to determine its effects on the kidneys and to provide all study participants with the opportunity to receive potential disease-modifying therapies during the subsequent 6-month open-label ipracopam period.

[0275] Patients aged 12 to 60 years with biopsy-proven idiopathic IC-MPGN were eligible. Adolescents were included in the study because their disease pathogenesis is similar to that of adults, including the central role of overactive APs, as well as clinical features of 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, adolescents with IC-MPGN present a high unmet treatment need. The rationale for enrolling participants with biopsy-proven IC-MPGN and significant proteinuria levels was to enrich the cohort for participants with clear clinical manifestations of IC-MPGN and an increased risk of rapid disease progression. The goal of the run-in period was to ensure that participants were receiving a stable maximum tolerated dose of an ACE inhibitor / ARB and other immunosuppressive and antiproteinuric agents (MMF / MPS, corticosteroids, and SGLT2 inhibitors) for at least 90 days prior to randomization and had received all required vaccinations at least 2 weeks before the first dose of study medication. In addition, to minimize potential carryover therapeutic effects of prohibited agents (i.e., immunosuppressants other than mycophenolic acid or corticosteroids at doses greater than 7.5 mg / day), patients receiving these therapies may have to have their agents discontinued or their doses reduced to comply with the study's allowed and prohibited agent requirements.

[0276] The study's primary endpoint is a reduction in UPCR (sampled from a 24-hour urine collection) with ipracopam at six months of treatment compared to placebo. Key secondary endpoints include maintenance of eGFR with ipracopam compared to placebo, as well as a composite renal endpoint requiring: 1) stabilization of eGFR and 2) a significant reduction in proteinuria for participants to be designated as having met the endpoint. The FACIT-Fatigue questionnaire will be used to assess the effect of ipracopam on important symptoms reported by patients with IC-MPGN.

[0277] Additional analyses will be conducted at the end of the open-label period comparing proteinuria, eGFR, composite renal endpoint rates, and FACIT-fatigue scores at day 360 with baseline (day 1). These data will be important to assess the durability of any effects observed at day 180 and further improvements in these variables with longer treatment durations. Proteinuria reduction is a well-established surrogate endpoint that may reasonably predict treatment efficacy in a range of renal diseases, such as slowing the progression of several other renal diseases, including diabetic nephropathy, FSGS (focal segmental glomerulosclerosis), and immunoglobulin A (IgA) nephropathy (Thompson A, Carroll K, A Inker L et al. (2019) ProteinuriaReduction as a Surrogate End Point in Trials of IgA Nephropathy. Clin J Am Soc Nephrol;14(3):469-81).

[0278] The study's key secondary endpoint will evaluate the improvement in eGFR (measured as a continuous variable) provided by ipracopan compared to placebo. In addition to precisely measured proteinuria reduction on a continuous scale (the primary endpoint), a categorical definition of a clinically important change in proteinuria (≥ 50% reduction in UPCR compared to baseline) is included as a component of the composite renal secondary endpoint. A 50% or greater reduction in UPCR would indicate a potential conversion from nephrotic-range proteinuria (>3.5 g / day) to non-nephrotic-range proteinuria, thereby reducing the risk of edema, thrombosis, infection, and other related complications while stabilizing eGFR in patients with IC-MPGN. To strengthen the clinical relevance of this definition, a decrease in eGFR of no more than 15% over a six-month period was included as part of the composite renal endpoint. The selection of these endpoints in IC-MPGN presents an opportunity to determine whether treatment with ipracopan improves renal function.

[0279] Justification of dosage

[0280] The proposed ipracopan dose of 200 mg twice daily is considered appropriate based on data from the Phase 2 study, CLNP023X2202. Data from 16 patients with primary C3G demonstrated a dose-dependent increase in C3 levels and a dose-dependent decrease in sC5b-9, Bb, the Wieslab assay, and urinary sC5b-9. The greatest reductions in plasma Bb, plasma sC5b-9, and urinary sC5b-9 were achieved with 100 mg twice daily; however, the greatest reduction in the Wieslab assay and an increase in C3 were observed with 200 mg twice daily. Following ipracopan treatment, dose-dependent, potent, and sustained inhibition of the alternative complement pathway was observed in both cohorts, as demonstrated by global normalization of serum C3 levels, complete inhibition of Wieslab activity at 200 mg twice daily, and reductions in plasma Bb, plasma, and urinary sC5b-9 (for Cohort A). In patients with primary C3G (N = 16), ipracopan, at the final dose level of 200 mg twice daily, demonstrated a 45% reduction in UPCR from baseline to week 12 (two-sided p = 0.0003) and stabilization of renal function (SCR, CrCl, eGFR). Furthermore, chronic ipracopan monotherapy was well tolerated, with no unexpected or new safety findings. No deaths or serious adverse events were observed during the treatment period in patients with primary renal C3G. During the run-in period (i.e., before any ipracopan treatment), a SAE was observed in one patient. No adverse events led to definitive discontinuation of treatment, and there were no significant changes in hematologic, biochemical, urinalysis, vital signs, or ECG parameters. Thus, the 200 mg twice daily dose of ipracopan appears to produce the greatest changes in all complement biomarkers evaluated in patients with C3G to date.

[0281] Rationale for selecting background therapy

[0282] There are currently no licensed disease-modifying or "rescue therapies" with proven beneficial effects for the treatment of idiopathic IC-MPGN. The KDIGO 2021 guidelines provide recommendations for the treatment of idiopathic IC-MPGN. According to the KDIGO guidelines, all patients will be required to receive the maximum or maximum tolerated dose of an ACE inhibitor / ARB as supportive therapy for the duration of the trial (KDIGO 2021). Immunosuppressive therapy (mycophenolic acid, corticosteroids) is also permitted, as long as it is maintained at a stable dose, reflecting both the KDIGO guidelines (which recommend such treatment for more severe cases of IC-MPGN) and clinical practice, where such agents are used in some patients based on clinical judgment. Unless otherwise noted, practice guidelines are based on very low-quality evidence, clinical experience, and expert opinion. Treatment is generally influenced and determined by the severity of proteinuria and renal dysfunction (KDIGO 2021).

[0283] SGLT2 inhibitors are permitted; however, the dose must be stable during the screening / run-in period and throughout the study drug treatment period. As described in Table 3, the use of corticosteroids and mycophenolic acid (mycophenolate mofetil (MMF) or mycophenolate sodium) is permitted during the course of the study. In this trial, all background therapies (ACEI / ARB, MMF / MPS, corticosteroids, and SGLT2i) will be considered adjunctive medicinal products (AMPs).

[0284] As a small molecule, oral factor B (FB) inhibitor, ipracopan blocks FB and, consequently, AP, which plays an important role in defense against microorganisms. Although the other two complement initiation pathways (i.e., classical and lectin pathways) should not be attenuated by ipracopan, there is a theoretical risk that the immune response to infection, particularly against encapsulated bacteria, may be impaired in patients taking ipracopan. To fully mitigate this risk, participants will be vaccinated against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae at least 2 weeks prior to the first dose, based on local availability. Additionally, prophylactic antibiotics to prevent infection are permitted, provided they are standard of care for managing patients with IC-MPGN receiving anti-complement therapy at this site. Adverse events of infection will be closely monitored throughout the study. Participants will be asked to carry a participant card describing the symptoms of sepsis and meningitis to provide information and awareness, allowing them to notify their physician or investigators early in the event of a potential infection. The card also informs medical professionals of the potential increased risk of bacterial infection and helps ensure timely diagnosis and treatment.

[0285] Table 3 Use of corticosteroids and mycophenolic acid

[0286]

[0287] Key efficacy variables to be estimated

[0288] ● Primary: Reduction in proteinuria quantified by log-transformed ratio of UPCR relative to baseline

[0289] ● Secondary: stable or improved eGFR compared to baseline visit (eGFR decrease ≤ 15%) and a decrease in UPCR ≥ 50% compared to baseline visit (based on a 24-hour urine collection)

[0290] ● Change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score

[0291] Equivalent

[0292] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed within the scope of the following claims.

Claims

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

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

3. The method of claim 1 or 2, wherein the ipracopam or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg to about 200 mg, such as 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, twice daily (bid), wherein the amount administered refers to the anhydrous free base of ipracopam.

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 ipracopam is ipracopam hydrochloride.

6. The method of any one of claims 1 to 5, wherein the subject has been administered supportive care comprising 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 the administration of ipracopam or the administration of ipracopam or a pharmaceutically acceptable salt thereof.

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

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

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

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

11. The method of claim 10, wherein the urine protein / creatinine ratio (UPCR) of the subject is reduced by not less than 50% compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof, particularly, wherein the urine protein / creatinine ratio (UPCR) of the subject is reduced by not less than 50% after 6 months of treatment.

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

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

14. Ipracopan 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 ipracopan or a pharmaceutically acceptable salt thereof to the subject.

15. Ipracopam or a pharmaceutically acceptable salt thereof for use according to claim 14, wherein the ipracopam or a pharmaceutically acceptable salt thereof is administered orally.

16. Ipracopam or a pharmaceutically acceptable salt thereof for use according to claim 14 or 15, wherein the ipracopam or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg to about 200 mg, such as 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, with each dose administered twice daily (bid), wherein the administered amount refers to the anhydrous free base of ipracopam.

17. Ipracopam or a pharmaceutically acceptable salt thereof for use according to claim 16, wherein the dosage is about 200 mg twice daily.

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

19. Ipracopam or a pharmaceutically acceptable salt thereof for use according to any one of claims 14 to 18, wherein the subject has been administered supportive care comprising ACEi, ARB, mycophenolic acid (e.g., mycophenolate mofetil (MMF) and mycophenolate sodium (MPS)), corticosteroids, SGLT2 inhibitors, mineralocorticoid receptor antagonists, cyclophosphamide (CYC) or calcineurin inhibitors prior to administration of ipracopam or administration of ipracopam or a pharmaceutically acceptable salt thereof.

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

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

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

23. Ipracopam or a pharmaceutically acceptable salt thereof for use according to any one of claims 14 to 22, wherein the subject's urine protein / creatinine ratio (UPCR) is reduced compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof.

24. Ipracopam or a pharmaceutically acceptable salt thereof for use according to claim 23, wherein the urine protein / creatinine ratio (UPCR) of the subject is reduced by not less than 50% compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof, in particular, wherein the urine protein / creatinine ratio (UPCR) of the subject is reduced by not less than 50% after 6 months of treatment.

25. Ipracopam or a pharmaceutically acceptable salt thereof for use according to claims 14 to 24, wherein the subject's estimated glomerular filtration rate (eGFR) is stabilized or improved compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof.

26. Ipracopam or a pharmaceutically acceptable salt thereof for use according to claim 25, wherein the estimated glomerular filtration rate (eGFR) of the subject is reduced by no more than 15% compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof, in particular, wherein the estimated glomerular filtration rate (eGFR) of the subject is reduced by no more than 15% after 6 months of treatment.

27. A pharmaceutical composition comprising a therapeutically effective amount of ipracopan 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 to be administered to treat the subject.

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

29. The pharmaceutical composition of claim 27 or 28, wherein the ipracopan or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg to about 200 mg, such as 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, with each dose administered twice daily (bid), wherein the administered amount refers to the anhydrous free base of ipracopan.

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

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

32. The pharmaceutical composition of any one of claims 27 to 31, wherein the subject has been administered supportive care comprising ACEi, ARB, mycophenolic acid (e.g., mycophenolate mofetil (MMF) and mycophenolate sodium (MPS)), corticosteroids, SGLT2 inhibitors, mineralocorticoid receptor antagonists, cyclophosphamide (CYC), or a calcineurin inhibitor prior to the administration of ipracopam or the administration of ipracopam or a pharmaceutically acceptable salt thereof.

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

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

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

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

37. The pharmaceutical composition of claim 35, wherein the urine protein / creatinine ratio (UPCR) of the subject is reduced by not less than 50% compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof, particularly, wherein the urine protein / creatinine ratio (UPCR) of the subject is reduced by not less than 50% after 6 months of treatment.

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

39. The pharmaceutical composition of claim 38, wherein the estimated glomerular filtration rate (eGFR) of the subject is reduced by no more than 15% compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof, particularly, wherein the estimated glomerular filtration rate (eGFR) of the subject is reduced by no more than 15% after 6 months of treatment.

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

41. The use according to claim 40, wherein the ipracopam or a pharmaceutically acceptable salt thereof is administered orally.

42. The use of claims 40 to 41, wherein the use comprises administering ipracopam or a pharmaceutically acceptable salt thereof to the subject at a dose of about 50 mg to about 200 mg, such as 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, with each dose administered twice daily (bid), wherein the amount administered refers to the anhydrous free base of ipracopam.

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

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

45. The use of any one of claims 40 to 44, wherein the subject has been administered supportive care comprising ACEi, ARB, mycophenolic acid (e.g., mycophenolate mofetil (MMF) and mycophenolate sodium (MPS)), corticosteroids, SGLT2 inhibitors, mineralocorticoid receptor antagonists, cyclophosphamide (CYC), or a calcineurin inhibitor prior to the administration of ipracopam or the administration of ipracopam or a pharmaceutically acceptable salt thereof.

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

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

48. The method of any one of claims 40 to 47, wherein the subject is an adult or a teenager.

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

50. The use according to claim 49, wherein the urine protein / creatinine ratio (UPCR) of the subject is reduced by not less than 50% compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof, in particular, wherein the urine protein / creatinine ratio (UPCR) of the subject is reduced by not less than 50% after 6 months of treatment.

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

52. The use of claim 51, wherein the estimated glomerular filtration rate (eGFR) of the subject is reduced by no more than 15% compared to before administration of ipracopam or a pharmaceutically acceptable salt thereof, in particular, wherein the estimated glomerular filtration rate (eGFR) of the subject is reduced by no more than 15% after 6 months of treatment.

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