Use of Iptakopan for the Treatment of Lupus Nephritis

Abstract

Described herein are methods for treating lupus nephritis with the factor B inhibitor iptacopan, or a pharma- ceutically acceptable salt thereof, such as iptacopan hydrochloride.

Description

[Technical field]

[0001] The present disclosure relates to methods of treating complement-driven diseases, particularly lupus nephritis (LN), with the factor B inhibitor iptacopan or a pharma- ceutically acceptable salt thereof, such as iptacopan hydrochloride. [Background technology]

[0002] Systemic lupus erythematosus (SLE) is a group of autoimmune diseases of various etiologies that share in common the loss of immune tolerance of endogenous nuclear material, resulting in systemic autoimmunity that can result in damage to various tissues and organs. Lupus nephritis (LN) is a form of glomerulonephritis and constitutes one of the most severe organ manifestations of SLE. 60% of adult patients with SLE develop renal disease (Anders et al 2020, Lupus nephritis. Nat Rev Dis Primers p. 7), which is the main cause of morbidity and mortality (Fanouriakis et al 2020, 2019 Update of the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR / ERA-EDTA) recommendations for the management of lupus nephritis. Ann Rheum Dis p. 713-723).

[0003] Lupus nephritis is caused by loss of tolerance to self-antigens, production of autoantibodies and deposition of complement-binding immune complexes (ICs). IC-mediated activation of complement in affected tissues is evident in both experimental and human SLE, with pathological features that are the logical consequence of complement activation (Bao et al 2015, Complement in Lupus Nephritis: New Perspectives. Kidney Dis (Basel) p. 91-9). Activation of the alternative complement pathway of the innate immune system plays a key role in the pathogenesis of LN (Song et al 2017, Complement Alternative Pathway's Activation in Patients With Lupus Nephritis. Am J Med Sci p. 247-257). The formation of immune complexes in LNs is associated with an excess of autoantibodies, particularly anti-dsDNA and anti-nucleosome antibodies (ANA), and is a consequence of systemic autoimmunity and a hallmark of the disease (Waldman and Madaio 2005, Pathogenic autoantibodies in lupus nephritis. Lupus p. 19-24; Nowling and Gilkeson 2011, Mechanisms of tissue injury in lupus nephritis. Arthritis Res Ther p. 250).

[0004] The pathophysiology of LN is heterogeneous. Genetic and environmental factors likely contribute to this heterogeneity. Despite improved understanding of LN pathogenesis, there have been few advances in treatment and the risk of renal failure remains unacceptably high (Parikh et al 2020, Update on Lupus Nephritis: Core Curriculum 2020. Am J Kidney Dis p. 265-281). As a bridge between the innate and adaptive immune systems, the complement system is likely involved in multiple pathogenesis processes in LN. LNs are histologically classified into six classes by the International Society of Nephrology / Renal Pathology Society (ISN / RPS) classification system (Markowitz and D'Agati 2007, The ISN / RPS 2003 classification of lupus nephritis: an assessment at 3 years. Kidney Int p. 491-5). Moderate to severe (classes III and IV) LNs are detected in approximately 39-71.9% of patients and have IC deposits in the subendothelial space of glomerular capillaries (Wang et al 2018, A Systematic Review and Meta-analysis of Prevalence of Biopsy-Proven Lupus Nephritis. Arch Rheumatol p.17-25). Both of these classes of LNs are considered to have similar lesions that differ in severity and distribution. Class IV diffuse LNs can be differentiated from class III based on the involvement of more than 50% of glomeruli in intracapillary lesions. The prognosis of LNs depends on the histological classification, the degree of active inflammation and chronic interstitial damage. Patients with ISN / RPS class III-IV LNs are at higher risk of loss of renal function and development of renal failure.

[0005] Treatment of LN depends on disease severity based on histopathology and / or clinical symptoms and patient variables (Flanc et al 2004, Treatment for lupus nephritis. Cochrane Database Syst Rev p. CD002922). Treatment usually consists of an intensive immunosuppressive induction therapy over a period of 3-6 months to induce complete or at least partial remission, followed by a long-term passive maintenance therapy to maintain disease remission and prevent disease relapse. Definitions of complete response can vary considerably from trial to trial (Boumpas and Balow 1998, Outcome criteria for lupus nephritis trials: a critical overview. Lupus p. 622-9). Complete remission was defined as normalization of proteinuria and serum creatinine, and patients who achieved complete remission with aggressive immunosuppressive treatment had significantly better patient and renal survival than non-responders (Korbet et al 2000, Factors predictive of outcome in severe lupus nephritis. Lupus Nephritis Collaborative Study Group. Am J Kidney Dis p. 904-14).

[0006] The American College of Rheumatology (ACR) guidelines (Hahn et al 2012, American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken) p. 797-808) as well as the joint European League Against Rheumatism (EULAR) / European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and KDIGO (Shlipak et al 2021, The case for early identification and intervention of chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int p. 34-47) guidelines are uniform in their recommendations for the treatment of class III and IV LNs and include a series of induction and maintenance phases. The goals of treatment include patient survival, long-term preservation of renal function, prevention of disease relapse, prevention of organ damage, management of comorbidities, and improvement of disease-related quality of life. LN patients with active class III / IV±V LN or pure class V LN with severe proteinuria should begin treatment in combination with high-dose corticosteroids and immunosuppression including cyclophosphamide (CYC), mycophenolate mofetil (MMF) or mycophenolate sodium (MPS) (Yap and Chan 2015, Lupus Nephritis in Asia: Clinical Features and Management. Kidney Dis (Basel) p. 100-9).The main adjunctive therapies in the treatment of LN include hydroxychloroquine (HCQ) (if not contraindicated), ACEi / ARB, strict BP control (<130 / 80 mmHg), statins (ACR recommendations 2012), dietary sodium restriction, vitamin D supplementation, weight loss and correction of metabolic abnormalities (acidosis, hyperuricemia).

[0007] LN treatment requires an initial intensive treatment period followed by a long-term maintenance treatment period to stabilize the disease and ultimately reach renal remission (Moroni et al 2018,Changing patterns in clinical-histological presentation and renal outcome over the last five decades in a cohort of 499 patients with lupus nephritis.Ann Rheum Dis p.1318-1325). A key challenge in the management of LN is the continued use of corticosteroids over a long period of time (Little J,Parker B,Lunt M,et al(2018)Glucocorticoid use and factors associated with variability in this use in the Systemic Lupus International Collaborating Clinics Inception Cohort.Rheumatology(Oxford)p.677-687). Chronic corticosteroid therapy is associated with short-term and long-term adverse events (Anders, HJ., Saxena, R., Zhao, Mh. et al. Lupus nephritis. Nature Review Disease Primers 6, 7 (2020)). Despite improved outcomes with available treatments, optimal treatment of LN remains a challenge.

[0008] The alternative complement pathway (AP) is important for innate and adaptive immunity. However, hyperactivity of the AP is known to cause and exacerbate numerous diseases with autoimmune components. Iptakopan is a novel oral low molecular weight compound with the potential to be first-in-class to inhibit factor B (FB) of the AP. The AP amplifies complement activation induced by any complement pathway, resulting in a significant decrease in C3 and increases in Bb, C3a, C5a and MAC in activated LNs (Ekdahl et al 2018,Interpretation of Serological Complement Biomarkers in Disease.Front Immunol p.2237).

[0009] Iptakopan is a first-in-class oral low molecular weight (LMW) 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 p.7926-7931), a key protease of the AP (Merle et al 2015, Complement System Part I -Molecular Mechanisms of Activation and Regulation. Front Immunol p.262). Inhibition of FB prevents the amplification of all pathways and the AP-induced assembly of C3 and C5 convertases. At the same time, iptacopan has limited effects on the activation of the terminal pathway induced by the classical pathway. Iptakopan inhibits FB in association with the C3 convertase, thereby blocking the amplification of AP-dependent C3 activation and CP- and LP-dependent C5 activation. However, iptacopan does not block the generation of MAC initiated by CP and LP. This is important as it means that MAC-dependent killing of Neisseria species through activation of the CP is maintained in immunized individuals. Summary of the Invention

[0010] The present disclosure relates to a method of treating complement-driven diseases, particularly lupus nephritis (LN), with iptacopan (Formula I, shown below) or a pharma- ceutically acceptable salt thereof, such as iptacopan hydrochloride. Iptacopane is also known as LNP023. The terms "iptacopan" and "LNP023" are used interchangeably herein. Iptacopane (4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid) belongs to the class of factor B inhibitors of the complement pathway, and acts by inhibiting or suppressing the amplification of the complement system caused by C3 activation, regardless of the initial activation mechanism. Iptacopane hydrochloride is chemically designated as 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride, having the following formula (I): [ka]

[0011] Iptacopane hydrochloride and methods for its preparation are disclosed in WO 2015 / 009616 (see Example 26d), which is incorporated herein by reference in its entirety. The form of iptacopane hydrochloride used as the investigational study drug for this study was the monohydrate (Form H), as shown in the following formula: B ). [ka] (2S,4S)-2-(4-carboxyphenyl)-4-ethoxy-1-[(5-methoxy-7-methyl-1H-indol-4-yl)methyl]piperidin-1-ium chloride-water (1 / 1)

[0012] Iptacopane hydrochloride monohydrate form H Band methods for their preparation are disclosed in U.S. Patent Application No. 63 / 026,637 and U.S. Patent Application No. 63 / 052,699, and published in WO 2021 / 234544, each of which is incorporated by reference in its entirety.

[0013] The present disclosure provides a method of treating lupus nephritis (LN) in a subject, e.g., a patient, in need thereof, comprising orally administering to the subject, e.g., patient, iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, 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, at a dose of about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose twice daily (bid), e.g., about every 12 hours, thereby treating the subject, e.g., patient (dosage amounts refer to the anhydrous free base of iptacopan hydrochloride), thereby treating the subject, e.g., patient. [Brief description of the drawings]

[0014] [Figure 1] A schematic diagram of the study design is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Described herein is a phase 2 clinical trial to determine the safety and efficacy of iptacopan or its pharmaceutically acceptable salt, such as iptacopan hydrochloride, in patients with lupus nephritis (LN), for example, in combination with and in place of tapering corticosteroid regimens, in addition to MMF, MPS or cyclophosphamide immunosuppressive treatment.Described herein is thus a method of treating LN in a patient in need of treatment, for example, comprising orally administering to the patient iptacopan or its pharmaceutically acceptable salt, such as iptacopan hydrochloride, in a dose twice a day, for example about every 12 hours, for example in capsule form (dosage refers to the anhydrous free base of iptacopan hydrochloride).Described herein is also a method of selecting a target patient population, a method of monitoring treatment of the target patient population, and a method of evaluating the safety and efficacy of treatment of the target patient population.

[0016] Details of the present disclosure are set forth in the attached specification below. Although methods and materials similar or equivalent to those described herein can be used to practice or test the present disclosure, exemplary methods and materials are described herein. Other features, objects, and advantages of the present disclosure will be apparent from the description and claims. In this specification and the appended claims, the singular forms include the plural, unless otherwise clearly indicated. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents and publications cited herein are incorporated herein by reference in their entirety.

[0017] definition Unless specific definitions are provided, the nomenclature used in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry described herein are those well known and commonly used in the art. Standard techniques may be used for chemical synthesis and chemical analysis. Certain such techniques and procedures may be found, for example, in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa., 21st edition, 2005, which is incorporated herein by reference for all purposes. Where permitted, all patent applications, published applications, and other publications and other data cited throughout this disclosure are incorporated herein by reference in their entirety.

[0018] Unless otherwise stated, the following terms have the following meanings:

[0019] As used herein, "about" means within ±10% of the value.

[0020] "Administering" or "administration" as used herein means providing a pharmaceutical agent to an individual, including, but not limited to, administration by a medical professional and self-administration. Administration of a pharmaceutical agent to an individual may be continuous, chronic, brief, or intermittent.

[0021] The term "obtain" or "obtaining" as used herein refers to gaining possession of a physical entity (e.g., a sample, e.g., a blood sample or plasma sample) or a value, e.g., a numerical 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" refers to receiving the physical entity or value from another party or source (e.g., a third party laboratory that directly obtained the physical entity or value). Directly obtaining a value includes performing a process that involves a physical change of a sample or another substance, e.g., performing an analytical process that involves a physical change of a substance, e.g., a sample, an analytical method, e.g., a method described herein, e.g., by analysis of a sample of a body fluid, e.g., blood, e.g., by mass spectroscopy, e.g., LC-MS, e.g., LC-MS / MS methods.

[0022] As used herein, "baseline" refers to the time prior to treatment with respect to a subject or patient characteristic.

[0023] As used herein, "dose" refers to a specified amount of a pharmaceutical agent provided in a single administration or within a specified time period. In certain embodiments, a dose may be administered in a capsule. As used herein, dosage refers to the anhydrous free base of iptacopane hydrochloride.

[0024] As used herein, "individual," "patient," "participant," or "subject" means a human selected for treatment or therapy.

[0025] As used herein, "pharmaceutical acceptable salt" refers to a physiologically and pharmaceutical acceptable salt of iptacopan, i.e., a salt that retains the desired biological activity of iptacopan and does not impart undesired toxic effects. The term "pharmaceutical acceptable salt" or "salt" includes salts prepared from pharmaceutical acceptable non-toxic acids or bases, including inorganic or organic acids and inorganic or organic bases. "Pharmaceutically acceptable salts" of iptacopan can be prepared by methods well known in the art. For a review of pharmaceutical acceptable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use (Wiley-VCH, Weinheim, Germany, 2002). Iptacopane hydrochloride and its preparation method are disclosed in WO 2015 / 009616 (see Example 26d), which is incorporated herein by reference in its entirety.

[0026] The term "treat" as used herein means to slow, inhibit, attenuate, reduce, arrest, or stabilize the onset or progression of a disorder or disease, such as lupus nephritis.

[0027] Unless otherwise specified, conventional definitions of control terms and conventional stable atom valences are presumed and achieved in all formulas and groups.

[0028] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (e.g., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0029] How to use Provided herein is a method of treating lupus nephritis (LN) in a subject, e.g., a patient, in need thereof, comprising administering to the subject, e.g., patient, iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, 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, at a dose of about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose twice daily (bid), e.g., about every 12 hours, e.g., orally (dosage amounts refer to the anhydrous free base of iptacopan hydrochloride), thereby treating the subject, e.g., the patient.

[0030] Provided herein is a method of achieving a complete renal response in a subject, e.g., a patient, in need thereof, comprising administering to the subject, e.g., patient, iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, 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, at a dose of about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose twice daily (bid), e.g., about every 12 hours, e.g., orally (dosage amounts refer to the anhydrous free base of iptacopan hydrochloride), thereby treating the subject, e.g., the patient.

[0031] Provided herein is a method of reducing proteinuria in a subject, e.g., a patient, in need thereof, comprising administering to the subject, e.g., patient, iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, 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, at a dose of about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose twice daily (bid), e.g., about every 12 hours, e.g., orally (dosage amounts refer to the anhydrous free base of iptacopan hydrochloride), thereby treating the subject, e.g., the patient.

[0032] In another aspect, the disclosure provides iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, for use in treating lupus nephritis (LN) in a subject, e.g., a patient, in need thereof, wherein the treatment comprises administering iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, to the subject, e.g., the patient, 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, at a dose of about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose twice daily (bid), e.g., about every 12 hours, e.g., orally (dosage amounts refer to the anhydrous free base of iptacopan hydrochloride).

[0033] In another aspect, the disclosure provides iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, for use in achieving a complete renal response in a subject, e.g., a patient, in need thereof, wherein the treatment comprises administering iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, to the subject, e.g., the patient, 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, at a dose of about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose twice daily (bid), e.g., about every 12 hours, e.g., orally (dosage amounts refer to the anhydrous free base of iptacopan hydrochloride). In one embodiment, the subject, e.g., the patient, has lupus nephritis or has been diagnosed with lupus nephritis.

[0034] In another aspect, the disclosure provides iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, for use in reducing proteinuria in a subject, e.g., a patient, in need thereof, wherein the treatment comprises administering iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, to the subject, e.g., the patient, 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, at a dose of about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose twice daily (bid), e.g., about every 12 hours, e.g., orally (dosage amounts refer to the anhydrous free base of iptacopan hydrochloride). In one embodiment, the subject, e.g., the patient, has lupus nephritis or has been diagnosed with lupus nephritis.

[0035] In another aspect, the disclosure provides the use of iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, in the manufacture of a medicament for the treatment of lupus nephritis in a subject, e.g., a patient, in need of such treatment, the treatment comprising orally administering to the subject, e.g., the patient, iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, 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, at a dose of about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose twice daily (bid), e.g., about every 12 hours (dosage amounts refer to the anhydrous free base of iptacopan hydrochloride), thereby treating the subject, e.g., the patient. In one embodiment, the subject, e.g., the patient, has lupus nephritis or has been diagnosed with lupus nephritis.

[0036] In another aspect, the disclosure provides the use of iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, in the manufacture of a medicament for achieving a complete renal response in a subject, e.g., a patient, in need thereof, wherein the treatment comprises orally administering to the subject, e.g., the patient, iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, 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, at a dose of about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose twice daily (bid), e.g., about every 12 hours (dosage amounts refer to the anhydrous free base of iptacopan hydrochloride), thereby treating the subject, e.g., the patient. In one embodiment, the subject, e.g., the patient, has lupus nephritis or has been diagnosed with lupus nephritis.

[0037] In another aspect, the disclosure provides for the use of iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, in the manufacture of a medicament for reducing proteinuria in a subject, e.g., a patient, in need thereof, wherein the treatment comprises orally administering to the subject, e.g., the patient, iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, 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, at a dose of about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose twice daily (bid), e.g., about every 12 hours (dosage amounts refer to the anhydrous free base of iptacopan hydrochloride), thereby treating the subject, e.g., the patient. In one embodiment, the subject, e.g., the patient, has lupus nephritis or has been diagnosed with lupus nephritis.

[0038] In another aspect, the disclosure provides a pharmaceutical composition comprising iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, for use in treating lupus nephritis in a subject, e.g., a patient, in need thereof, comprising 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 of iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, each dose administered orally twice daily (bid), e.g., about every 12 hours (dosage amounts refer to the anhydrous free base of iptacopan hydrochloride), thereby treating the subject, e.g., the patient.

[0039] In another aspect, the disclosure provides a pharmaceutical composition comprising iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, for use in achieving a complete renal response in a subject, e.g., a patient, in need thereof, comprising administering 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 of iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, orally administered each dose twice daily (bid), e.g., about every 12 hours (dosage amounts refer to the anhydrous free base of iptacopan hydrochloride), thereby treating the subject, e.g., the patient. In one embodiment, the subject, e.g., the patient, has lupus nephritis or has been diagnosed with lupus nephritis.

[0040] In another aspect, the disclosure provides a pharmaceutical composition comprising iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, for use in reducing proteinuria in a subject, e.g., a patient, in need thereof, comprising administering 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 of iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, orally administered each dose twice daily (bid), e.g., about every 12 hours (dosage amounts refer to the anhydrous free base of iptacopan hydrochloride), thereby treating the subject, e.g., the patient. In one embodiment, the subject, e.g., the patient, has lupus nephritis or has been diagnosed with lupus nephritis.

[0041] The following embodiments apply to any of the aforementioned aspects provided herein and can be combined in any order.

[0042] In one embodiment, the method or treatment comprises administering to a subject, e.g., a patient, iptacopan hydrochloride monohydrate form H B For example, orally.

[0043] In one embodiment, the subject, e.g., patient, has active glomerulonephritis ISN / RPS class III or IV with or without coexistent class V features on a renal biopsy.

[0044] In one embodiment, the subject, e.g., patient, has active class III or IV lupus nephritis, with or without coexisting features of class V lupus nephritis on a renal biopsy.

[0045] In one embodiment, the subject, e.g., patient, has an ANA titer of 1:80 or greater.

[0046] In one embodiment, the ANA titer is based on a Hep-2 immunofluorescence assay or an equivalent positive enzyme immunoassay.

[0047] In one embodiment, the subject, eg, patient, is positive for anti-dsDNA.

[0048] In one embodiment, the subject, e.g., patient, has a urinary protein / creatinine ratio (UPCR) of 1.5 g / g or greater prior to administration of iptacopan or a pharma- ceutically acceptable salt thereof.

[0049] In one embodiment, the urinary protein / creatinine ratio is sampled from the first morning void or a 24 hour urine collection.

[0050] In one embodiment, the subject, e.g., patient, receives an airway pressure of 30 ml / min / 1.73 m prior to administration of iptacopan or a pharma- ceutical acceptable salt thereof. 2 Have an estimated glomerular filtration rate (eGFR) of ≥ 1.

[0051] In one embodiment, estimated glomerular filtration rate (eGFR) is calculated using the CKD-EPI formula or modified MDRD formula according to guidelines for specific ethnic groups and local practice.

[0052] In one embodiment, the subject, e.g., patient, is vaccinated prior to treatment with iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, prior to administration of iptacopan or a pharma- ceutically acceptable salt thereof.

[0053] In one embodiment, the subject, e.g., patient, has been vaccinated against Neisseria meningitidis (strains A, C, Y, W-135) prior to administration of iptacopan or a pharma- ceutically acceptable salt thereof.

[0054] In one embodiment, the subject, e.g., patient, has been vaccinated against Streptococcus pneumoniae (Pneumovax-23) prior to administration of iptacopan or a pharma- ceutically acceptable salt thereof.

[0055] In one embodiment, the subject, e.g., patient, has been vaccinated against Haemophilus influenzae prior to administration of iptacopan or a pharma- ceutically acceptable salt thereof.

[0056] In one embodiment, the subject, e.g., patient, is being treated, and will be further treated, with supportive care, e.g., an antimalarial (e.g., hydroxychloroquine), an ACEi, or an ARB, e.g., at a maximum daily dose or maximum tolerated dose.

[0057] In one embodiment, the subject, e.g., patient, is further treated with an agent.

[0058] In one embodiment, the agent is an immunosuppressant, such as mycophenolate (e.g., mycophenolate mofetil (MMF), mycophenolate sodium (MPS)), cyclophosphamide (CYC), anti-B cell agents (e.g., belimumab, rituximab), calcineurin inhibitors (e.g., voclosporin, cyclosporin A, tacrolimus).

[0059] In one embodiment, the subject, e.g., patient, is further treated with a corticosteroid.

[0060] In one embodiment, the subject, e.g., patient, is further treated with a corticosteroid according to a tapering regimen.

[0061] As used herein, "steroid tapering", "tapering", "tapering regimen" and the like refer to a steroid (e.g., corticosteroid, e.g., glucocorticoid, e.g., prednisone, prednisolone, methylprednisolone) reduction regimen administered to a patient over time. The tapering schedule (timing and dose reduction) depends on the original steroid (e.g., corticosteroid, e.g., glucocorticoid, e.g., prednisone, prednisolone, methylprednisolone) dose the patient is taking prior to treatment with iptacopan. The tapering regimen is consistent with common medical practice in SLE and is designed to minimize steroid-related toxicity. Steroid tapering is an important goal to achieve in SLE patients, given that current SoC SLE treatment regimens have substantial side effects from glucocorticoids and long-term immunosuppression (Schwartz (2014). Curr Opin Rheumatol; 26: 502-509). In some embodiments of the present disclosure, during treatment with iptacopan, the dose of steroid (e.g., a corticosteroid, e.g., a glucocorticoid, e.g., prednisone, prednisolone, methylprednisolone) administered to the patient is reduced using a tapering regimen, and the patient does not experience a flare as a result of said reduction.

[0062] In some embodiments of the present disclosure, when the method is used to treat a population of LN patients, during treatment with iptacopan, at least 50% of the patients achieve a daily steroid dose of less than 10 mg / day following a steroid tapering regimen.

[0063] In some embodiments of the present disclosure, when the method is used to treat a population of LN patients, during treatment with iptacopan, at least 50% of the patients achieve a daily steroid dose of less than 5 mg / day following a steroid tapering regimen.

[0064] In some embodiments of the present disclosure, when the method is used to treat a population of LN patients, during treatment with iptacopan, at least 50% of the patients achieve a daily steroid dose of less than 2.5 mg / day following a steroid tapering regimen.

[0065] In some embodiments of the present disclosure, when the method is used to treat a population of LN patients, during treatment with iptacopan, at least 50% of the patients achieve a daily steroid dose of 0 mg / day following a steroid tapering regimen.

[0066] In some embodiments of the present disclosure, when the method is used to treat a patient with LN, during treatment with iptacopan, the patient achieves a daily steroid dose of less than 10 mg / day following a steroid tapering regimen.

[0067] In some embodiments of the present disclosure, when the method is used to treat a patient with LN, during treatment with iptacopan, the patient achieves a daily steroid dose of less than 5 mg / day following a steroid tapering regimen.

[0068] In some embodiments of the present disclosure, when the method is used to treat a patient with LN, during treatment with iptacopan, the patient achieves a daily steroid dose of less than 2.5 mg / day following a steroid tapering regimen.

[0069] In some embodiments of the present disclosure, when the method is used to treat a patient with LN, during treatment with iptacopan, the patient achieves a daily steroid dose of 0 mg / day following a steroid tapering regimen.

[0070] In one embodiment, the corticosteroid tapering regimen follows Table 1 below.

[0071] In one embodiment, the subject, e.g., patient, is further treated with 2.5 mg per day of a steroid (e.g., a corticosteroid, e.g., a glucocorticoid, e.g., prednisone, prednisolone, methylprednisolone, prednisolone / prednisone equivalent) from week 13 onwards.

[0072] In one embodiment, the subject, e.g., patient, is further treated with 2.5 mg prednisolone / prednisone equivalent daily from week 13 onwards.

[0073] In one embodiment, the subject, e.g., patient, is further treated with 25 mg or less, e.g., 20 mg or less, 15 mg or less, 10 mg or less, 7.5 mg or less, 5 mg or less, 2.5 mg or less, 25 mg, 20 mg, 15 mg, 10 mg, 7.5 mg, 5 mg, or 2.5 mg of a steroid (e.g., a corticosteroid, e.g., a glucocorticoid, e.g., prednisone, prednisolone, methylprednisolone, prednisolone / prednisone equivalents) per day, e.g., after a steroid tapering regimen.

[0074] [Table 1]

[0075] In one embodiment, the subject, e.g., patient, is not further treated with steroids (e.g., corticosteroids, e.g., glucocorticoids, e.g., prednisone, prednisolone, methylprednisolone, prednisolone / prednisone equivalents), e.g., after a steroid tapering regimen.

[0076] In one embodiment, the subject, e.g., patient, is further treated with at least one of an immunosuppressant and a corticosteroid.

[0077] In one embodiment, the subject, e.g., patient, is further treated with an immunosuppressant and a corticosteroid following a tapering regimen, but without the corticosteroid after the steroid tapering regimen.

[0078] In one embodiment, the subject, e.g., patient, is further treated with an immunosuppressant without a steroid (e.g., a corticosteroid, e.g., a glucocorticoid, e.g., prednisone, prednisolone, methylprednisolone, prednisolone / prednisone equivalent).

[0079] In one embodiment, the subject, e.g., patient, is further treated with an immunosuppressant and a steroid (e.g., a corticosteroid, e.g., a glucocorticoid, e.g., prednisone, prednisolone, methylprednisolone, prednisolone / prednisone equivalent), wherein the corticosteroid is administered according to a tapering regimen.

[0080] In one embodiment, the subject, e.g., patient, is further treated with immunosuppressants, e.g., mycophenolate (e.g., mycophenolate mofetil (MMF), mycophenolate sodium (MPS)), cyclophosphamide (CYC), anti-B cell agents (e.g., belimumab, rituximab), calcineurin inhibitors (e.g., voclosporin, cyclosporin A, tacrolimus), and steroids (e.g., corticosteroids, e.g., glucocorticoids, e.g., prednisone, prednisolone, methylprednisolone, prednisolone / prednisone equivalents), e.g., according to a tapering regimen.

[0081] In one embodiment, the subject, e.g., patient, is receiving treatment with immunosuppressants, such as mycophenolates (e.g., mycophenolate mofetil (MMF), mycophenolate sodium (MPS)), cyclophosphamide (CYC), anti-B cell agents (e.g., belimumab, rituximab), calcineurin inhibitors (e.g., voclosporin, cyclosporin A, tacrolimus), and steroids (e.g., corticosteroids, e.g., glucocorticoids, e.g., prednisone, prednisolone, methylprednisolone, prednisolone / prednisone equivalents), e.g. after a steroid tapering regimen, further treated with steroids (e.g. a corticosteroid, e.g. a glucocorticoid, e.g. prednisone, prednisolone, methylprednisolone, prednisolone / prednisone equivalents) at 25 mg or less per day, e.g., 20 mg or less, 15 mg or less, 10 mg or less, 7.5 mg or less, 5 mg or less, 2.5 mg or less, 25 mg, 20 mg, 15 mg, 10 mg, 7.5 mg, 5 mg, or 2.5 mg per day.

[0082] In one embodiment, the subject, e.g., patient, is further treated with an immunosuppressant, e.g., mycophenolate mofetil (MMF), mycophenolate sodium (MPS), cyclophosphamide (CYC), an anti-B cell agent (e.g., belimumab, rituximab), a calcineurin inhibitor (e.g., voclosporin, cyclosporin A, tacrolimus), without a corticosteroid, e.g., after a tapering regimen.

[0083] In one embodiment, the subject, e.g., patient, is further treated with an immunosuppressant, e.g., mycophenolate mofetil (MMF), mycophenolate sodium (MPS), cyclophosphamide (CYC), an anti-B cell agent (e.g., belimumab, rituximab), a calcineurin inhibitor (e.g., voclosporin, cyclosporin A, tacrolimus), without the use of corticosteroids.

[0084] In one embodiment, the subject, e.g., patient, is initially further treated with MMF orally at 1.5-3 g / day or MPS orally at 1080 mg / day to 2160 mg / day for an initial treatment period, e.g., 6 months.

[0085] In one embodiment, the subject, e.g., patient, is initially further treated with MMF orally at 1.5 to 3 g / day or MPS orally at 1080 mg / day to 2160 mg / day for an initial treatment period, e.g., 6 months, titrated up to maximum tolerated dose.

[0086] In one embodiment, the subject, e.g., patient, is further treated with 1-2 g / day of MMF or 720-1440 mg / day of MPS orally for, e.g., 6 months, after the initial treatment period.

[0087] In one embodiment, treating lupus nephritis (LN) includes achieving a UPCR of less than 0.5 g / g, for example, sampled from the first morning void or a 24-hour urine collection.

[0088] In one embodiment, the subject, e.g., patient, has a UPCR of less than 0.5 g / g in the subject, e.g., patient, after administration of iptacopan or a pharma- ceutically acceptable salt thereof, e.g., sampled from the first morning void or a 24-hour urine collection.

[0089] In one embodiment, treating lupus nephritis (LN) includes achieving a reduction in UPCR in a subject, e.g., a patient, of, for example, 15% or more, 20% or more, 25% or more, 30% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, or 65% or more compared to before administration of iptacopan or a pharma- ceutically acceptable salt thereof.

[0090] In one embodiment, UPCR is reduced in a subject, e.g., patient, by, for example, 15% or more, 20% or more, 25% or more, 30% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, or 65% or more compared to before administration of iptacopan or a pharma- ceutically acceptable salt thereof.

[0091] In one embodiment, treating lupus nephritis (LN) is achieved by reducing blood glucose levels by 90 mL / min / 1.73 m, calculated using the CKD-EPI formula or modified MDRD formula, for example according to guidelines for specific ethnic groups and local practice. 2 This includes achieving an eGFR of ≥ 1.

[0092] In one embodiment, a subject, e.g., a patient, after administration of iptacopan or a pharmacologic acceptable salt thereof, has a blood glucose level of 90 mL / min / 1.73 m, calculated using the CKD-EPI formula or the modified MDRD formula, e.g., according to guidelines for a particular ethnic group and local practice. 2 Have an eGFR of ≥ 1.

[0093] In one embodiment, treating lupus nephritis (LN) includes achieving an eGFR that is increased, for example, by 2.5% to 5%, 5% to 7.5%, 7.5% to 10%, 10% to 15%, or greater than 15%, compared to before administration of iptacopan or a pharma- ceutical acceptable salt thereof.

[0094] In one embodiment, the eGFR of a subject, e.g., patient, is increased, e.g., by 2.5% to 5%, 5% to 7.5%, 7.5% to 10%, 10% to 15%, or more than 15%, compared to before administration of iptacopan or a pharma- ceutically acceptable salt thereof.

[0095] In one embodiment, treating lupus nephritis (LN) includes achieving a stable eGFR, e.g., 80% or more, 85% or more, 90% or more, compared to before administering iptacopan or a pharma- ceutically acceptable salt thereof.

[0096] In one embodiment, the subject's, eGFR, e.g., patient's, is stable, e.g., 80% or more, 85% or more, 90% or more, compared to before administration of iptacopan or a pharma- ceutically acceptable salt thereof.

[0097] In one embodiment, treating lupus nephritis (LN) comprises achieving a complete renal response.

[0098] As used herein, the phrase "complete renal response" is defined as meeting the following criteria: · 90mL / min / 1.73m 2 or greater than 85% of baseline, and · 24-hour urine protein-to-creatinine ratio (UPCR) of 0.5g / g or less.

[0099] In one embodiment, treating lupus nephritis (LN) comprises achieving a complete renal response without renal flare-up.

[0100] As used herein, the phrase "renal flare" is defined as follows: (Parikh et al 2014 Renal flare as a predictor of incident and progressive CKD in patients with lupus nephritis. Clin J Am Soc Nephrol p.279-84; Yap et al 2017 Longterm Data on Disease Flares in Patients with Proliferative Lupus Nephritis in Recent Years. J Rheumatol p.1375-1383; Ayoub et al 2019 Commentary on the Current Guidelines for the Diagnosis of Lupus Nephritis Flare. Curr Rheumatol Rep.12). Proteinuria relapse: An increase in UPCR (assessed from FMV) to >1g / g if the patient previously achieved CRR, or a doubling to >2g / g if the patient previously achieved PRR but not CRR. Renal relapse: A decrease in eGFR of 15% or more compared to stable levels during remission.

[0101] In one embodiment, treating lupus nephritis (LN) comprises achieving a partial renal response.

[0102] As used herein, the phrase "partial renal response" is defined as meeting the following criteria: · 90mL / min / 1.73m 2 or greater than or equal to 80% of baseline; and A 50% or greater decrease in 24-hour UPCR (compared to baseline) to <1g / g (or <3g / g if baseline was ≥3g / g).

[0103] In one embodiment, treating lupus nephritis (LN) comprises achieving a partial renal response without renal flare.

[0104] In one embodiment, the subject's, e.g., patient's, FACIT-Fatigue score is reduced compared to before administration of iptacopan or a pharma- ceutically acceptable salt thereof.

[0105] Key efficacy evaluations Also provided herein is a method of evaluating the efficacy of treatment in a lupus nephritis patient population treated with iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, 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, at a dose of about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose twice daily (bid), e.g., about every 12 hours, comprising determining the proportion of the patient population that achieves a complete renal response in the absence of renal flare compared to a patient population not treated with iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, thereby evaluating the efficacy of treatment.

[0106] Also provided herein is a method of evaluating the efficacy of treatment in a lupus nephritis patient population treated with iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, 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, at a dose of about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose twice daily (bid), e.g., about every 12 hours, comprising determining the proportion of the patient population that achieves a partial renal response in the absence of renal flare compared to a patient population not treated with iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride, thereby evaluating the efficacy of treatment. Patient population Defined by appropriate inclusion / exclusion criteria to reflect the target LN population. The proportion of patients who achieved complete renal response (CRR) in the absence of renal relapse. A CRR is defined as meeting the following criteria: · 90mL / min / 1.73m 2 or greater than 85% of baseline, and 24-hour urine protein-to-creatinine ratio (UPCR) of 0.5 g / g or less The proportion of patients who achieved a partial renal response (PRR) in the absence of renal relapse. A PRR is defined as meeting the following criteria: o 90mL / min / 1.73m 2 or greater than or equal to 80% of baseline; and o At least a 50% decrease in 24-hour UPCR (compared to baseline) to <1g / g (or <3g / g if baseline was ≥3g / g)

[0107] CRR / PRR will be derived using the average of two 24-hour UPCR values, both collected within 10 days prior to each study visit. Renal flare in patients who achieved a complete or partial renal response (CRR or PRR) is objectively defined as (Parikh et al 2014 Renal flare as a predictor of incident and progressive CKD in patients with lupus nephritis.Clin J Am Soc Nephrol p.279-84;Yap et al 2017 Longterm Data on Disease Flares in Patients with Proliferative Lupus Nephritis in Recent Years.J Rheumatol p.1375-1383;Ayoub et al 2019 Commentary on the Current Guidelines for the Diagnosis of Lupus Nephritis Flare.Curr Rheumatol Rep.12): o Proteinuria relapse: An increase in UPCR (assessed from FMV) to >1g / g if the patient previously achieved CRR, or a doubling to >2g / g if the patient previously achieved PRR but not CRR. o Renal relapse: A decrease in eGFR of 15% or more compared to stable levels during remission. EXAMPLES

[0108] The following examples and synthetic schemes further illustrate the present disclosure, but 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 the examples are provided to illustrate specific embodiments and are not intended to limit the scope of the present disclosure. In addition, it should be understood that various other embodiments, modifications, and equivalents thereof that may suggest themselves to those skilled in the art may be relied upon without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0109] [Table 2]

[0110] [Table 3]

[0111] [Table 4]

[0112] [Table 5]

[0113] [Table 6]

[0114] Example 1 An Adaptive Randomized, Double-Blind, Dose-Finder, Parallel-Group, Placebo-Controlled, Multicenter, Phase 2 Study to Evaluate the Efficacy, Safety, and Tolerability of LNP023 in Combination with Standard of Care with or without Oral Corticosteroids in Patients with Active Lupus Nephritis Class III-IV, + / -V

[0115] the purpose The overall objective of this two-part study is to evaluate the efficacy, safety, and tolerability of iptacopan (LNP023) in addition to MMF / MPS immunosuppressive treatment, both in combination with and instead of tapering corticosteroid regimens in patients with active LN (ISN / RPS class III or IV, with or without coexistent class V features).

[0116] Iptacopane will first be evaluated in the proof-of-concept portion at a dose of 200 mg bid as an add-on to SoC (corticosteroid tapering + MMF / MPS) compared to SoC for inducing a clinically meaningful increase in complete renal response (CRR) and reduction in proteinuria (Part 1). Data collected in this proof-of-concept portion will determine whether to initiate Part 2 of the study, evaluating iptacopan at a lower dose of 50 mg bid in addition to SoC, and at the previously tested dose of 200 mg bid as an alternative to corticosteroids, such that LN patients would benefit from an effective steroid-free treatment.

[0117] Primary Objectives and Endpoints The first objective is to: Four treatment schemes are envisaged: (a) Iptakopan 200 mg + corticosteroid tapering + MMF / MPS ("Iptakopan 200 mg + steroids") (b) Iptakopan 50 mg + corticosteroid taper + MMF / MPS ("Iptakopan 50 mg + steroids") (c) iptacopan 200 mg + no corticosteroid taper + MMF / MPS ("iptacopan 200 mg alone") (d) no iptacopan + corticosteroid tapering + MMF / MPS ("steroids alone") Part 1: i) To evaluate the proportion of patients who achieved complete renal response (CRR) at week 24 with treatment (a) "iptacopan 200 mg + steroids" compared to (d) "steroids alone." Part 2*: ii) To evaluate the proportion of patients who achieved complete renal response (CRR) at week 24 with treatment (b) “iptacopan 50 mg + steroids” compared with (d) “steroids alone.” iii) To evaluate the proportion of patients who achieved complete renal response (CRR) at 24 weeks with treatment (c) “iptacopan 200 mg alone” compared to (d) “steroids alone.” *Due to study suitability, comparisons (ii) and (iii) will only be performed if Part 2 is initiated.

[0118] Secondary Objectives: Parts 1 and 2: The advantages of the following are evaluated: (i) treatment “iptacopan 200 mg + steroid” compared with “steroid alone”; and (ii) treatment “iptacopan 50 mg + steroid” compared with “steroid alone”; and (iii) treatment “iptacopan 200 mg alone” compared with “steroid alone”; - Achieving CRR or PRR at 24 weeks - Achieving CRR at 52 weeks In achieving early CRR - Achievement of CRR or PRR rate at 52 weeks Achieving at least a 25% improvement in 24-hour UPCR at Week 24 - Reduction in the incidence of renal relapse between weeks 24 and 52 In reducing the frequency of courses of corticosteroids for renal and non-renal indications at doses exceeding an average of 20 mg / day (of prednisolone or equivalent) for more than 10 days at weeks 24 and 52 Change from baseline in FACIT-Fatigue score at weeks 24 and 52 Change from baseline in SLEDAI-2K score at weeks 24 and 52 Change from baseline in BILAG-2004 score at weeks 24 and 52 To evaluate the safety and tolerability of 52 weeks of treatment with iptacopan 200mg + steroids, iptacopan 50mg + steroids, and iptacopan 200mg alone compared to steroids alone To evaluate the dose-exposure response for reduction in proteinuria at 24 weeks to iptacopan added to SoC (corticosteroid tapering + MMF / MPS)

[0119] Test Design This study is a two-part, dose-finding, randomized, double-blind, parallel-group, placebo-controlled, multicenter study evaluating the efficacy, safety, and tolerability of iptacopan 50 mg bid and 200 mg bid in combination with MMF / MPS for the treatment of LN (see Figure 1): Part 1 will evaluate whether the use of iptacopan 200 mg bid is effective and safe as an add-on therapy to an MMF / MPS + tapering corticosteroid regimen. Approximately 80 patients will be randomized in a 5:3 ratio to each treatment arm to ensure sufficient power at the interim analysis. Part 1 will consist of a screening period that can last up to 6 weeks. A pre-specified interim analysis (IA) will occur when substantially all enrolled patients have completed the Week 24 visit. The objective of the IA is to evaluate the effect of iptacopan 200 mg bid + MMF / MPS + corticosteroid tapering vs. matching placebo + MMF / MPS + tapering corticosteroid regimen on complete renal response (CRR) as assessed by UPCR values ​​and reduction in proteinuria (both determined from two 24-hour urine collections). The overall efficacy and safety data up to the interim analysis cutoff point and pre-specified IA outcomes will determine the initiation of Part 2 of the study. The double-blind treatment period will continue through Week 52 for Part 1. · Upon confirmation of positive results from the IA, Part 2 will begin. Part 2 will evaluate (i) whether the use of iptacopan 50 mg bid is effective and safe as an add-on therapy to MMF / MPS + tapering corticosteroid regimen, and (ii) whether the use of iptacopan 200 mg bid is effective and safe as an add-on treatment to MMF / MPS without corticosteroids versus iptacopan matching placebo + MMF / MPS + tapering corticosteroid regimen. After confirmation of eligibility criteria, approximately 160 patients will be randomized in a 3:7:6 ratio to one of three treatment arms, respectively, to ensure sufficient power for all comparisons in the primary analysis. The active treatment of the control arm will be the same as in Part 1, and control patients from both parts will be pooled in the primary analysis to achieve greater power. Part 2 will consist of a screening period that can last up to 6 weeks. The double-blind treatment period will continue until week 52 for Part 2.

[0120] Rationale for Study Design This study is a two-part adaptive dose-finding randomized, double-blind, parallel-group, placebo-controlled, multicenter study evaluating the efficacy and safety of iptacopan in addition to mycophenolate mofetil (MMF) or mycophenolate sodium (MPS) immunosuppressive treatment, both in combination with and instead of corticosteroids, in patients with active LN (ISN / RPS class III or IV, with or without coexistent class V features).

[0121] Study population The study population will consist of 240 randomized participants, male and female patients aged 18 years or older with LNs, who have undergone a renal biopsy within 3 months prior to screening, showing ISN / RPS class III or IV LNs with or without coexistent class V features. A repeat renal biopsy is required to confirm LNs as the primary cause of relapse and to exclude other factors such as scarring, infection and drug toxicity if more than 3 months have elapsed since the last biopsy. Patients enrolled in both parts 1 and 2 of the study should have evidence of active nephritis, defined by a UPCR (based on 24-hour urine collection) of 1.5 g / g or greater (confirmed on two separate or consecutive visits) and a positive dipstick of hematuria (not menstrual or UTI related) requiring treatment with an MPA-based immunosuppressive regimen by the local SoC.

[0122] Membership criteria Participants eligible for enrollment in the study must meet all of the following criteria. All criteria listed below pertain to both Part 1 and Part 2 unless otherwise specified. 1.Adult male and female patients aged 18 years or older at the time of screening 2. Signed informed consent must be obtained prior to participation in the study. Patients must be able to communicate satisfactorily with the investigator and be able to understand and comply with the requirements of the study. 3. A clearly positive ANA test result at screening, defined as an ANA titer of 1:80 or greater (based on a HEp-2 immunofluorescence assay or equivalent positive enzyme immunoassay), and / or a positive anti-dsDNA test result. 4. Biopsy-proven active lupus nephritis within 3 months of screening demonstrating class III or IV lupus nephritis with or without coexisting features of class V lupus nephritis. If a biopsy is not performed within 3 months of screening, a repeat biopsy should be performed to confirm LNs as the primary cause of relapse. Renal biopsy should be performed during the screening period and after confirmation that the patient meets all other inclusion / exclusion criteria. 5. Documentation of active renal disease at screening requiring initiation of treatment with corticosteroids in combination with MMF / MPS. Active renal disease is defined by: Positive dipstick for hematuria (not menstrual or UTI related) Proteinuria (checked at screening and before randomization) At Screening: UPCR ≥ 1.5 g / g sampled from the first morning void or 24-hour urine collection Pre-randomization: Confirmed UPCR of ≥ 1.5 g / g sampled from 24-hour urine collections on 2 separate days within a 10-day window prior to randomization 6.30ml / min / 1.73m 2 eGFR above 18.5 (eGFR calculated using the CKD-EPI or modified MDRD formulas according to guidelines for specific ethnic groups and local practice) 7. Vaccination against Neisseria meningitidis and Streptococcus pneumoniae infections is required prior to the start of study treatment. If the patient has not been previously vaccinated or if a booster is required, the vaccine must be given according to local regulations at least 2 weeks prior to the first study drug administration. If study treatment is expected to begin more than 2 weeks after vaccination, prophylactic antibiotic treatment should be given at least 2 weeks after vaccination. 8. Vaccination against Haemophilus influenzae infection, if available, should be administered at least 2 weeks prior to the first study drug administration, in accordance with local regulations. If study treatment is expected to begin more than 2 weeks after vaccination, prophylactic antibiotic treatment should be administered at the start of study treatment and continued for at least 2 weeks after vaccination. 9. All patients must have been receiving supportive care at screening, including a stable dose regimen of antimalarials (e.g. hydroxychloroquine), ACEi or ARB unless contraindicated, either at the maximum locally approved daily dose or maximum tolerated dose (at the investigator's discretion), according to local clinical practice. Doses should remain stable throughout the study. First symptoms or flare-up of lupus nephritis. All participants with LN flare-up after previous treatment with cyclophosphamide may be included. Participants who developed LN flare-up after treatment with MMF may be included if the treating physician considers that participation in the study would be of potential benefit to the patient, taking into account the dose of MMF with or without corticosteroids used in the study protocol. 10. All participants must be vaccinated against COVID-19 before randomization in accordance with the local SoC. Participants must also undergo a COVID-19 test in accordance with the local SoC.

[0123] Main Exclusion Criteria Participants who meet any of the following criteria are not eligible for enrollment in the study. All criteria listed below pertain to both Part 1 and Part 2 unless otherwise specified. 1. Participants who, in the investigator's opinion, have not previously responded to treatment with MMF / MPS will not be included. 2. Induction treatment with cyclophosphamide within 3 months of planned treatment for this study; treatment with a calcineurin inhibitor within the past 3 months prior to screening 3. Presence of rapidly progressive glomerulonephritis (RPGN) defined by a 50% decline in eGFR within 3 months prior to screening. 4. Renal biopsy demonstrating interstitial fibrosis / tubular atrophy (IF / TA) greater than 50% or glomerulosclerosis, or which, in the investigator's opinion, precludes a response to immunosuppressive therapy. 5. Patients who have been previously treated with immunosuppressants or other immunomodulatory agents not considered standard of care for the treatment of lupus nephritis within the past year. 6. Participant being treated with systemic corticosteroids (>5 mg / day prednisone or equivalent) for indications other than SLE or LN, e.g., acute asthma, inflammatory bowel disease. 7. Participants being treated with systemic corticosteroids for SLE or LN will be excluded if they have taken an average of more than 10 mg / day of prednisone (or equivalent) in the past 4 weeks and an average of more than 20 mg / day of prednisone in the past week. 8. Having received a total dose of pulse intravenous methylprednisolone (cumulative dose) equivalent to more than 1000 mg within 2 weeks prior to (and at) enrollment 9. Prior treatment with any of the following within 1 year prior to screening: Nitrogen mustard, chlorambucil, vincristine, procarbazine, etoposide, abatacept, Treatment with any B cell targeted therapy Treatment with an investigational biological agent Treatment with Interleukin-6 targeted therapy 10. Participants with current clinical, radiological, or laboratory evidence of active or latent TB, a history of active TB (even if treated) within 2 years of screening, or a risk of TB reactivation that, in the investigator's opinion, precludes the use of conventional immunosuppression based on appropriate assessment

[0124] Test procedure In Part 1, study participants will be randomized to receive iptacopan 200 mg bid as add-on to SoC (MMF / MPS+CS).

[0125] In Part 2, study participants will be randomized to receive either (i) 50 mg bid as add-on to SoC for LN (MMF / MPS+CS) or (ii) iptacopan 200 mg bid + MMF / MPS without corticosteroids.

[0126] initial treatment The recommended doses of MMF / MPS for initial treatment are as follows: MMF 1.5-3 g / day orally, or MPS 1080 mg / day-2160 mg / day orally. Investigators should determine the appropriate starting dose for each individual participant based on consideration of possible clinical benefit and side effects. However, it is expected that the dose will be titrated to the maximum tolerated dose within the recommended dose range by week 2. At the time of study entry and confirmation of eligibility, patients should be initiated on the recommended dose of MMF or MPS+iptacopan / matching placebo and a tapering corticosteroid regimen / matching placebo should be initiated. Reductions in MMF / MPS doses are only permitted in cases of toxicity or intolerance and according to the investigator's discretion. According to the guidelines, after 6 months of initial treatment with MMF or MPS, the dose of MMF may be reduced or switched at the investigator's discretion and / or according to the local SoC.

[0127] Intravenous corticosteroids must be administered to all patients in all treatment arms within 2 weeks of randomization and prior to the initiation of an oral corticosteroid tapering regimen at a cumulative total dose of 1000 mg or less of intravenous methylprednisolone or equivalent. Oral corticosteroids are permitted at a mean prednisolone / prednisone dose of 10 mg / day or less in the preceding 4 weeks or equivalent (not including any prior intravenous corticosteroid doses) and a mean prednisolone / prednisone dose of 20 mg / day or less in the preceding week prior to enrollment. Forced tapering with oral corticosteroids begins on day 1 with a starting dose according to weight as shown in Table 1. A predefined induction corticosteroid tapering regimen must be followed (see Table 1). From week 13 onwards, the target dose of oral corticosteroids for all participants is 2.5 mg prednisolone / prednisone equivalent per day.

[0128] Maintenance therapy After completion of the initial treatment period, if determined by the investigator, the dose of MMF may be reduced to 1–2 g / day (MPS 720–1440 mg / day) according to the local standard of care.

[0129] Treatment period The planned duration of Parts 1 and 2 is 52 weeks (for each part). Participants may discontinue treatment early due to unacceptable toxicity (reported as an AE), disease progression, and / or at the discretion of the investigator or participant.

[0130] Rationale for dose and duration of treatment The study will first investigate the treatment effect of iptacopan 200 mg bid added to SoC compared to SoC alone (Part 1). This dose was selected based on the least sensitive alternative pathway biomarker (Wieslab assay) and ensures >90% target inhibition in >70% of individuals as determined from FIH study CLNP023X2101. Dose range discovery was performed with doses from 10 to 200 mg bid in phase 2 studies in IgAN, C3G and PNH. Based on an integrated evaluation of key biomarker, efficacy and safety endpoints, the 200 mg bid dose was selected as this dose shows the greatest therapeutic potential: In healthy volunteer studies (CLNP023X2101 and CLNP023X1102), iptacopan was administered in single ascending doses (SAD, 10-400 mg) and multiple ascending doses (MAD, 10-200 mg bid for 2 weeks) to 102 subjects. Results showed that iptacopan was well tolerated, highly soluble, well permeable, and rapidly absorbed. No deaths, serious adverse events (SAEs), or adverse events (AEs) leading to discontinuation of study drug were observed. Preliminary data from an ongoing Phase 2 study in PNH indicate that PNH patients treated with iptacopan 200 mg bid, both as add-on to eculizumab (CLNP023X2201) and as monotherapy (CLNP023X2204), have clinically relevant benefit. The majority of patients demonstrated reduced LDH concentrations and improved hemoglobin in the absence of red blood cell (RBC) transfusions. This was achieved with control of both intravascular and extravascular hemolysis. Furthermore, iptacopan was overall safe and well tolerated in both studies. Interim results from an ongoing Phase 2 study (CLNP023X2203) in patients with IgAN showed a statistically significant dose-response effect of iptacopan on UPCR at 90 days, which was the primary endpoint of the study. At the 200 mg bid dose, clinically meaningful reductions in UPCR and stable / improved eGFR levels were observed compared to placebo. Iptacopane had an overall well-tolerated safety profile. · Interim results from a Phase 2 study in patients with C3G (CLNP023X2202) showed that treatment with iptacopan 200 mg bid was also well tolerated in these patients, resulting in a 49% reduction in UPCR and stabilization of eGFR at 12 weeks.

[0131] If iptacopan 200 mg bid demonstrates a clinically meaningful effect in addition to SoC in Part 1 (assessed at the week 24 interim analysis or the week 52 repeat interim analysis), a lower dose of 50 mg bid in addition to SoC will be explored in Part 2. The dose-finding study above suggests that the 50 mg bid dose may be within the dynamic range of dose-exposure relationships for the key biomarkers UPCR and eGFR. Together with the 200 mg bid dose, the 50 mg bid will inform a broad range of dose-exposure relationships in lupus nephritis.

[0132] Effectiveness Complete Renal Response (CRR) Partial renal response (PRR) Proteinuria quantified by urinary protein-to-creatinine ratio (UPCR) Estimated glomerular filtration rate (eGFR) · Kidney flare-up British Isles Lupus Activity (BILAG) score (BILAG-2004) Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) · Functional Assessment of Chronic Illness Therapy Fatigue(FACIT-Fatigue) Corticosteroids

[0133] Equivalent Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments specifically described herein, which equivalents are intended to be encompassed within the scope of the following claims.

Claims

1. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt thereof for use in treating lupus nephritis (LN) in a subject in need thereof, the pharmaceutical composition being to be orally administered to the subject at doses of about 50 mg to about 200 mg of iptacopan or a pharmaceutically acceptable salt thereof twice daily (b.i.d.), each dose being in the range of about 50 mg to about 200 mg, the dosages referring to the anhydrous free base of iptacopan hydrochloride.

2. 10. The pharmaceutical composition of claim 1, wherein the dose is about 50 mg twice daily.

3. 10. The pharmaceutical composition of claim 1, wherein the dose is about 100 mg twice daily.

4. 10. The pharmaceutical composition of claim 1, wherein the dose is about 200 mg twice daily.

5. The pharmaceutical composition of claim 1 , wherein the subject is further administered an immunosuppressant.

6. 6. The pharmaceutical composition of claim 5, wherein the immunosuppressant is mycophenolate mofetil (MMF), mycophenolate sodium (MPS), cyclophosphamide (CYC), an anti-B cell agent, or a calcineurin inhibitor (CNI).

7. The pharmaceutical composition of claim 1 , wherein a corticosteroid is administered to the subject.

8. 8. The pharmaceutical composition of claim 7, wherein the corticosteroid is administered to the subject according to a tapering regimen.

9. 9. The pharmaceutical composition of claim 8, wherein the subject achieves a daily corticosteroid dose of less than 10 mg / day following a corticosteroid tapering regimen.

10. 9. The pharmaceutical composition of claim 8, wherein the subject achieves a daily corticosteroid dose of 0 mg / day following a corticosteroid tapering regimen.

11. 7. The pharmaceutical composition of claim 6, wherein the immunosuppressant is administered without a corticosteroid.

12. 10. The pharmaceutical composition of claim 1, wherein the subject has been vaccinated against Neisseria meningitidis and Streptococcus pneumoniae prior to administration of iptacopan or a pharmaceutically acceptable salt thereof.

13. 13. The pharmaceutical composition of claim 12, wherein the subject has been vaccinated against Haemophilus influenzae prior to administration of iptacopan or a pharmaceutically acceptable salt thereof.

14. 10. The pharmaceutical composition of claim 1, wherein the subject is further treated with supportive care, and the supportive care is selected from the group consisting of hydroxychloroquine, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers.

15. 2. The pharmaceutical composition of claim 1, wherein treating lupus nephritis (LN) comprises achieving a UPCR of less than 0.5 g / g in the subject.

16. 16. The pharmaceutical composition of claim 15, wherein treating lupus nephritis (LN) comprises achieving a 50% reduction in UPCR in the subject compared to before administering iptacopan or a pharmaceutically acceptable salt thereof, wherein the UPCR value is measured by sampling from the first morning void or a 24-hour urine collection.

17. Treating lupus nephritis (LN) is 90 ml / min / 1.73 m ２ The pharmaceutical composition of claim 1, which achieves an eGFR of at least 100 mg / kg / day.

18. 18. The pharmaceutical composition of claim 17, wherein treating lupus nephritis (LN) comprises achieving an eGFR value of 80% or greater compared to before administering iptacopan or a pharmaceutically acceptable salt thereof.

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