Ferroportin-inhibitors for the use in the treatment of lupus nephritis

Abstract

The invention relates to the use of the compound of the formula (I) and pharmaceutically acceptable salts thereof, which acts as ferroportin inhibitor, for the use in the treatment of lupus nephritis and of pathophysiological symptoms and conditions associated therewith or deriving therefrom or being associated with systemic lupus erythematosus.

Description

[0001] Vifor (International) AG

[0002] FERROPORTIN-INHIBITORS FOR THE USE IN THE TREATMENT OF LUPUS NEPHRITIS

[0003] DESCRIPTION

[0004] INTRODUCTION

[0005] The invention relates to the use of the compound of the formula (I) and pharmaceutically acceptable salts thereof, which acts as ferroportin inhibitor, for the use in the treatment of lupus nephritis and of pathophysiological symptoms and conditions associated therewith or deriving therefrom or being associated with systemic lupus erythematosus.

[0006] BACKGROUND AND PRIOR ART

[0007] Systemic lupus erythematosus (also abbreviated as “SLE”) is a complex, chronic inflammatory, mostly relapsing autoimmune disorder associated with multi-organ dysfunction that can be initiated in genetically susceptible healthy individuals and damages multiple organs. The causes of the disease are multifactorial (e.g. genetic predisposition, hormonal and environmental triggers). The pathomechanisms are complex, practically all types of immune cells are involved, and various autoantibodies and immune complex deposits are formed. The adaptive immune cells of SLE patients have limited ability to discern between self and non-self- antigens, which results in the generation of autoantibodies, circulating and in-situ immune complexes (IC) that induce multi-organ pathology.

[0008] Lupus nephritis manifests as an inflammation of the kidneys and is the most severe endorgan complication of SLE that (untreated) leads to end-stage kidney disease (ESKD). Circulating and in situ IC disproportionately affect the vascular bed of the kidneys, resulting in kidney involvement ("lupus nephritis", also abbreviated as “LN”), which is observed in around half of patients and is one of the most severe forms of SLE, often with a life-threatening course. The pathogenesis of LN involves production of local cytokines that promotes influx of immune cells and in-situ autoantibody production. Progressive renal failure from LN occurs in up to 50% of SLE patients and is associated with considerable morbidity and mortality.

[0009] Drug therapy of SLE consists of basic therapy (hydroxychloroquine plus ACE inhibitor / AT1 antagonist) as well as anti-inflammatory and immunosuppressive induction and maintenance therapy. Various substances are combined for this purpose (e.g. prednisolone, azathioprine / mycophenolate mofetil, cyclosporine A / tacrolimus). Nevertheless, proliferative lupus nephritis often responds poorly to immunosuppressive therapy and up to 30 % of those affected require dialysis.

[0010] Due to persistent proteinuria and progressive renal failure lupus nephritis (LN) is further the most frequent cause of mortality in systemic lupus erythematosus (SLE) patients. Most of the therapeutics for SLE / LN target the immune system and in recent years, various immunosuppressive / immunomodulatory substances and biologicals have been tested in clinical trials for SLE therapy. However, there are only a few established immunosuppressive therapy options, compared to other SLE manifestations, available for the treatment of lupus nephritis.

[0011] The monoclonal, recombinant, humanized lgG-1A antibody belimumab has been approved as an alternative to SLE standard therapy and was also included in the 2019 update of the EULAR recommendations. The substance inhibits the activity of long-lived B cells or antibody-producing plasma cells. In 2020 a phase III study on the treatment of lupus nephritis with belimumab was published and in 2021 the approval of belimumab was extended to the treatment of lupus nephritis.

[0012] However, the current treatments for LN, in particular those based on aggressive immunosuppression, are associated with serious side effects. Further, even after immunosuppressive therapies with the best available therapies, the rate of complete remission for proliferative disease remains less than 50% and frequently culminates in ESKD for which dialysis is the only available remedy.

[0013] This indicates that non-immune mechanisms are involved in SLE / LN pathogenesis. Therefore, a significant unmet clinical need exists to understand better and treat LN.

[0014] During the evolution of LN, progressive glomerular leakiness acts as a constant source of excess iron and serves as a mechanism to iron overload the kidney. While iron is essential for physiology, the bioactive or labile Fe (Fe2+) participates in the Fenton reaction and catalyzes the generation of reactive oxygen species (ROS), which induce oxidative stress and lipid oxidation and can induce cell death via free radicle formation, lipid peroxidation and mitochondrial dysfunction. Iron carrier proteins like ferritin and neutrophil gelatinase-associated lipocalin (NGAL) have been investigated as urinary bio-markers of LN. Renal biopsies of LN patients show abundant iron deposits in tubular epithelial cells of patients with primary glomerulonephritis. Further, renal iron accumulation was observed in nephritic NZBW / F1 mice and Deferiprone, a FDA approved iron chelator, has been shown to delay the onset of albuminuria. Occurrence of ferroptosis, an iron dependent form of inflammatory cell death is also documented in human and murine LN. Thus, iron metabolism became a novel therapeutic target for intervention to ameliorate outcomes of LN.

[0015] Systemic and cellular iron metabolism is tightly regulated, with evolutionarily conserved pathways and it is well-known that the hepcidin-ferroportin axis primarily regulates systemic iron metabolism. Hepcidin production is stimulated by inflammation, resulting in anemia of inflammation (previously known as anemia of chronic disease). In context of lupus, human studies have shown that urinary Hepcidin decrease during renal flares and normalizes 4 months later. Furthermore, during remission of LN, IL-6 correlates with Hepcidin, but hemoglobin does not, thus suggesting an iron-independent regulation of Hepcidin.

[0016] Cellular iron metabolism is regulated by multiple iron importers, chaperons, storage molecules, and iron export. The pathological consequences of abnormal iron metabolism and consequent cellular dysfunctions have been documented in SLE, and the details of renal iron metabolism in the context of LN have been reviewed [E. Wlazlo, B. Mehrad, L. Morel, Y. Scindia, Iron Metabolism: An Under Investigated Driver of Renal Pathology in Lupus Nephritis, Front Med (Lausanne), 8 (2021) 643686].

[0017] The review article of Mok Chi Chiu et al: "Treatment of lupus nephritis: consensus, evidence and perspectives"; Nature Reviews Rheumatology, 2023, pages 227-238, DOI: 10.1038 / s41584-023-00925-5 describes treatment options for LN.

[0018] Recently, the occurrence of ferroptosis in LN has been demonstrated, and it was highlighted that improper iron sequestration exacerbates immune complex-mediated glomerulonephritis [AA Alli, D. Desai, A. Elshika, M. Conrad, B. Proneth, HZ Clapp, C. Atkinson, M. Segal, L.A. Searcy, N.D. Denslow, S. Bolisetty, B. Mehrad, L. Morel, Y. Scindia, Kidney tubular epithelial cell ferroptosis links glomerular injury to tubulointerstitial pathology in lupus nephritis, Clin Immunol, 248 (2023) 109213].

[0019] Further, beneficial effects of modulating iron metabolism in SLE / LN have been reported, derived from treating (New Zealand Black X New Zealand White) F1 (NZB / W) mice, a spontaneous model of SLE / LN, with deferiprone which delayed the onset of albuminuria even though anti-dsDNA IgG levels were comparable to the vehicle-treated group [E.S. Marks, M.L. Bonnemaison, S.K. Brusnahan, W. Zhang, W. Fan, J.C. Garrison, E.i. Boesen, Renal iron accumulation occurs in lupus nephritis and iron chelation delays the onset of albuminuria, Sci Rep, 7 (2017) 12821].

[0020] It has further previously been shown that exogenous hepcidin exhibits a beneficial effect in ameliorating spontaneous LN in MRL / lpr mice [Y. Scindia, E. Wlazlo, E. Ghias, S. Cechova, . Loi, J. Leeds, J. Ledesma, C. Helen, S. Swaminathan, Modulation of iron homeostasis with hepcidin ameliorates spontaneous murine lupus nephritis, Kidney international, 98 (2020) 100- 115].

[0021] Both, the experiments with the NZB / W and MRL / lpr mice treated with the iron chelator deferiprone or hepcidin did not reduce renal IC deposits and serum autoantibodies in MRL / lpr mice, but mitigated intrarenal cytokine production, immune cell infiltration, and tubular injury without worsening lupus-associated anemia. These data support the concept that modulation of iron metabolism may improve LN outcomes and may reduce dosage and dependency on toxic, nonspecific immunosuppressants.

[0022] The ferroportin inhibitor compound vamifeport (developed by the Vifor CSL group; also known as VIT-2763) is a first in-class clinical-stage oral ferroportin inhibitor acting via the same mechanism of action as hepcidin. Vamifeport and its general activity as ferroportin inhibitor has been described in the international applications WO2017 / 068089 and WO2017 / 068090. Further, international application WO2018 / 192973 relates to specific salts of selected ferroportin inhibitors described in WO2017 / 068089 and WO2017 / 068090. The international application W02021 / 191202 further describes manufacturing routes for preparing selected ferroportin inhibitors and specific salt forms and polymorphs thereof.

[0023] An evaluation of conformational rearrangements of ferroportin and its potential relevance for the interaction with the ferroportin inhibitor vamifeport have been investigated and described [E.F. Lehmann, M. Liziczai, K. Drozdzyk, P. Altermatt, C. Langini, . Manolova, H. Sundstrom, F. Durrenberger, R. Dutzler, C. Manatschal, Structures of ferroportin in complex with its specific inhibitor Vamifeport, Elife, 12 (2023)]. Further, vamifeport is currently in clinical development for beta-thalassemia and sickle cell disease and it has been shown that vamifeport generally has a favorable safety and tolerability profile [ Richard, J. J. van Lier, B. Roubert, T. Haboubi, U.M. Gohring, F. Durrenberger, Oral ferroportin inhibitor VIT-2763: First-in-human, phase 1 study in healthy volunteers, Am J Hematol, 95 (2020) 68-77].

[0024] The results of investigations relating to its efficacy in the treatment of beta-thalassemia and sickle cell disease have been described in several scientific papers [ ( Nyffenegger N, Flace A, et al. Oral ferroportin inhibitor ameliorates ineffective erythropoiesis in a model of / 3- thalassemia. J Clin Invest. 2019;130:491-506; Porter J, Taher A, Viprakasit V, et al. Oral ferroportin inhibitor vamifeport for improving iron homeostasis and erythropoiesis in / 3- thalassemia: current evidence and future clinical development. Expert Rev Hematol. 2021;14:633-644; Nyffenegger N, Flace A, Doucerain C, Durrenberger F, Manolova V. The oral ferroportin inhibitor VIT-2763 improves erythropoiesis without interfering with iron chelation therapy in a mouse model of ^-thalassemia. Int J Mol Sci. 2021;22:873; Kalleda N, Flace A, Altermatt P, et al. The ferroportin inhibitor vamifeport ameliorates ineffective erythropoiesis in a mouse model of beta-thalassemia with blood transfusions. Haematologica. 2023; 108 2703- 2714; Nyffenegger N, Zennadi R, Kalleda N, et al. The oral ferroportin inhibitor vamifeport improves hemodynamics in a mouse model of sickle cell disease. Blood. 2022;140:769-781]. Results on a promising target engagement and pharmacodynamic effects in patients with non- transfusion-dependent beta thalassemia have been shown [A Taher, A. Kourakli-Symeonidis, A. Tantiworawit, P. Wong, P. Szecsody, S272: Safety and preliminary pharmacodynamic effects of the ferroportin inhibitor vamifeport (vit-2763) in patients with non-transfusion-dependent beta thalassemia (NTDT): results from a phase 2a study, HemaSphere, 6 (2022) 173-174].

[0025] Further, the evaluation of a combination therapy of vamifeport with Luspatercept and the effects on anemia and myeloid skewing in MDS are described by Antypiuk Ada et al. "Combination Therapy with Luspatercept and the Ferroportin Inhibitor Vamifeport Is Superior to Either Drug Alone in Improving Anemia and Reducing Myeloid Skewing in MDS"; BLOOD, vol. 142, no. Supplement 1, 2023, pages 3836-3837, XP093242601.

[0026] Further, the use of vamifeport in methods of treating transfusion dependent thalassemia (TDT) is described in the international application WO2021 / 013771.

[0027] The use of vamifeport in methods of treating renal ischemia-reperfusion injury (IRI) or ischemic injury and acute kidney injuries (AKI) is described in the international application WO2021 / 013772.

[0028] The use of vamifeport in methods of treating sickle cell diseases (SCD) is described in the international application WO2021 / 078889.

[0029] The use of vamifeport in methods of treating myelodysplastic syndromes (MDS) is described in the international application WO2022 / 157185.

[0030] And the use of vamifeport in methods of treating hereditary hemochromatosis (HH) is described in the unpublished European application EP23181443.5.

[0031] The treatment of lupus nephritis with this novel class of ferroportin inhibitors, including vamifeport, has not been mentioned so far. The inventors of the present invention have now demonstrated that vamifeport, first in line clinical-stage, oral ferroportin inhibitor, has the capacity to reduce LN severity. Particularly, the inventors showed that vamifeport treatment attenuated renal injury, intrarenal chemokines, and infiltration of immune cells, independently of glomerular immune complex deposits and circulating autoantibodies. Therewith, the inventors offer a new treatment option for SLE patients by identifying vamifeport as a promising non-immune adjunct therapeutic for preventing the development of lupus nephritis in SLE patients, for attenuating, slowing down or stopping the deterioration of lupus nephritis in SLE patients or to reduce the associated symptoms and improve the course of the disease. In a further aspect, the novel treatment option offers to reduce dose and dependency of toxic immunosuppressants in LN. Due to its high safety and tolerability it offers a treatment option with increased tolerability and less undesired side-effects, which significantly improves patient’s treatment burden and therewith treatment compliance. For example, the orally bioavailable vamifeport has been shown to have a moderate bioavailability and half-life in the body and is thus relatively quickly washed out, which leads to less adverse effects and a faster reversibility of the drug, which is of particular importance in the treatment of elderly and chronically impaired patients. Therewith, vamifeport provides a remarkable advantage over existing lupus nephritis treatments.

[0032] OBJECT OF THE INVENTION

[0033] The object of the present invention is to provide a new method for treating lupus nephritis in SLE patients. In a particular aspect, the object of the invention is to provide a new adjunct therapeutic method for treating lupus nephritis in SLE patients and reduce dose and dependency on toxic immunosuppressants. A further aspect of the invention relates to providing a new treatment method allowing to prevent, slow down or attenuate the development of or the deterioration of lupus nephritis in SLE patients. A further aspect of the invention relates to providing new treatment options for SLE patients allowing to attenuate or reduce the symptoms and / or pathological conditions of SLE-associated lupus nephritis. A further aspect relates to providing a new treatment option allowing to generally improve the course of the disease, to increase the patients’ prospects and quality of life, to ameliorate the burden connected with the conventional treatment options, to offer a treatment with less risks and toxic side-effects and / or to avoid or at least delay development of kidney damage leading to end-stage kidney disease (ESKD).

[0034] The novel treatment should offer therapeutics which can be administered via advantageous administration routes, such as in particular orally administrable therapeutics should be provided to simplify administration, reduce side-effects resulting from parenteral administration, enhance patient compliance, safe treatment costs and reduce the treatment burden for the patients. In a further aspect an object of the invention can be seen in providing compounds for treating lupus nephritis and the symptoms and pathological conditions associated therewith, which are easier and cheaper to prepare than drugs based on recombinant engineered proteins or genetically engineered drug compounds, like antibodies. DESCRIPTION OF THE INVENTION

[0035] The inventors of the present invention surprisingly found that the ferroportin inhibitor compound Vamifeport with the general formula can be used for effectively treating lupus nephritis and the symptoms and pathological conditions associated therewith in SLE patients.

[0036] In contrast to the treatment of acute kidney injuries (AKI), which has been described in the international application WO2021 / 013772 and which aims on ameliorating or reducing inflammatory factors, like reducing ROS formation and non-transferrin bound iron (NTBI) levels, the treatment of lupus nephritis acts via a different specific pathomechanism and lupus nephritis specific parameters are affected, such as iron carrier proteins like ferritin and neutrophil gelatinase-associated lipocalin (NGAL). Vamifeport acts as hepcidin, which has been shown to increase renal H-ferritin (a ferroxidase), reduce expression of free iron dependent DNA synthesis enzymes, Ribonucleotide Reductase 1 and 2, and intra-renal macrophage proliferation [Y. Scindia, E. Wlazlo, E. Ghias, S. Cechova, V. Loi, J. Leeds, J. Ledesma, C. Helen, S. Swaminathan, Modulation of iron homeostasis with hepcidin ameliorates spontaneous murine lupus nephritis, Kidney international, 98 (2020) 100-115', https: / / doi.Org / 10.1016 / j.kint.2020.01.025.] LN and AKI have different underlying pathomechanisms and the mode of action of vamifeport differs in these disease indications. In AKI, restriction of iron export prevents the acute iron-mediated toxicity, such as formation of ROS and recruitment of innate immune system effectors, such as neutrophils in kidney. In LN, vamifeport prevents the pro-inflammatory proliferative action of excessive iron to promote T and B lymphocytes and macrophages recruitment to kidneys, proliferation and thereby limits the immune system-mediated kidney damage.

[0037] Drug Compound - Vamifeport

[0038] In accordance with the first aspect of the invention vamifeport, or a pharmaceutically acceptable salt thereof, is administered to a patient in need thereof, i.e. to an SLE patient, to treat lupus nephritis.

[0039] The novel treatment described herein includes the use of vamifeport in the form of its pharmaceutically acceptable salts, or solvates, hydrates and polymorphs thereof.

[0040] With respect to suitable pharmaceutically acceptable salts of vamifeport reference is made to the international applications WO2017 / 068089, WO2017 / 068090 and in particular WO2018 / 192973. The definition of pharmaceutically acceptable salts as disclosed therein is herein enclosed by reference. Specific salts of vamifeport, as well as a variety of polymorphs of vamifeport are described in WO2018 / 192973, hereby incorporated by reference. The use of the specific salts disclosed therein in treating lupus nephritis is not mentioned.

[0041] Particularly, among the suitable salts are: benzoic acid salt, HCI salt, citric acid salt, fumaric acid salt, lactic acid salt, malic acid salt, maleic salt, methanesulfonic acid salt, phosphoric acid salt, succinic acid salt, sulfuric acid salts, tartaric acid salts and toluenensufonic acid salts.

[0042] Vamifeport according to the formula (I), as the active part of a potential salt, can also be referred to as "base" or "free base". Vamifeport in the form of the free base has basic groups, such as amino groups, to which acidic groups can bind.

[0043] Preferably, salts of vamifeport can be selected from salts having a ratio of base (vamifeport (I)) : acid of 1 to 2 (mol base) : 1 to 3 (mol acid), wherein with respect to the salt forming acids reference is made to the selection defined above.

[0044] Vamifeport can also form mixed salts of the base (vamifeport (I)) with more than one of the acids indicated above and which may have the same or different ratios base : acid. The acids provide the counter anion for the cationic form of vamifeport (I).

[0045] Therein, a salt having a ratio of base : acid of 1 : 1 is also called “mono-salt(s)” or “1 : 1 salt(s)”. For example, a mono-HCI salt is also designated as 1 HCI or 1 HCI salt.

[0046] Therein, a salt having a ratio of base : acid of 1 : 2 is also called “di-salt(s)” or “1 : 2 salt(s)”. For example, a di-HCI salt is also designated as 2HCI or 2HCI salt.

[0047] Therein, a salt having a ratio of base : acid of 1 : 3 is also called “tri-salt(s)”, “triple salts(s)” or “1 : 3 salt(s)”. For example, a tri-HCI salt is also designated as 3HCI or 3HCI salt.

[0048] The salts of vamifeport according to the present invention may be present in amorphous, polymorphous, crystalline and / or semi-crystalline (partly crystalline) form as well as in the form of a solvate of the salt. Preferably salts of vamifeport according to the present invention are present in crystalline and / or semi-crystalline (partly crystalline) form and / or in the form of solvates thereof.

[0049] The preferable crystallinity of the salts or salt solvates can be determined by using conventional analytical methods, such as especially by using the various X-ray methods, which permit a clear and simple analysis of the salt. In particular, the grade of crystallinity can be determined or confirmed by using Powder X-ray diffraction (reflection) methods or by using Powder X-ray diffraction (transmission) methods (PXRD). For crystalline solids having identical chemical composition, the different resulting crystal gratings are summarized by the term polymorphism. Regarding solvates, hydrates and polymorphs and salts with particular crystallinity reference is made to the international application WO2018 / 192973, which is included herein by reference.

[0050] In various embodiments, the ratio of vamifeport (I) to acid is 1 :1 , 2:1 , 1 :2 or 1 :3. As used herein, a salt of a compound refers to any ratio of compound to salt unless a specific ratio is indicated.

[0051] Particularly preferred are HCI salts of vamifeport, more preferred are 3HCI salts of vamifeport according to the formula (I-3HCI):

[0052] In a further aspect of the invention vamifeport may be used in the form of one of the following salts: a 1 :1 sulfate salt having the formula a 1 :1 phosphate salt having the formula a 2 : 1 phosphate salt (hemiphosphate)

[0053] Indication - Lupus Nephritis

[0054] The present invention relates to the new medical use of vamifeport, including its pharmaceutically acceptable salts, solvates, hydrates and polymorphs, as described herein, for the treatment of lupus nephritis. As explained above, lupus nephritis may develop and occur in patients suffering from SLE.

[0055] Generally, the term “treatment” is not limited to the treatment of SLE patients with clinically confirmed lupus nephritis. Rather, the term “treatment” is meant to include prophylaxis or prevention, attenuation of its degree or of clinical signs or symptoms, delay of the outbreak or onset of the disease, of clinical signs or symptoms, freezing or stabilizing the degree of severity to a certain steady stable degree, improving, ameliorating, reducing and returning one or more (ideally all) clinical signs and / or symptoms, and in particular cure lupus nephritis, e.g. by achieving a rate of complete remission for proliferative LN.

[0056] In accordance with the invention, particular aspects of the treatment of lupus nephritis as comprised from the present invention relate to preventing, reducing or attenuating intrarenal chemokines and / or infiltration of immune cells, e.g. by reducing renal IC deposits and serum autoantibodies, which have been identified as pathological markers in lupus nephritis.

[0057] More particularly, this aspect of preventing, reducing or attenuating intrarenal chemokines and / or infiltration of immune cells relates to one or more of the following: suppressing or decreasing gene expression of Cc / 2, CxcHO, and / or Cxcl11, suppressing or reducing the infiltration of the renal interstitium with CD45+ cells, suppressing or attenuating the reduction of CD31+ cells in the glomeruli, suppressing or attenuating the infiltration with F4 / 80 macrophages and CD4+ T cells.

[0058] In a further aspect the treatment according to the present invention allows to attenuate and improve improper iron sequestration, which in consequence allows to reduce immune complex-mediated glomerulonephritis.

[0059] A further common pathological condition deriving from or being associated with LN is the development of splenomegaly, which is an enlargement of the spleen. Splenomegaly is usually associated with increased workload (such as in hemolytic anemias), which suggests that it is a response to hyperfunction and is often associated with any disease process that involves abnormal red blood cells being destroyed in the spleen. The standard system for classifying splenomegaly on radiography is: normal (not splenomegaly): the largest dimension is less than 11 cm, moderate splenomegaly: the largest dimension is between 11 and 20 cm, severe splenomegaly: the largest dimension is greater than 20 cm, also, a cutoff of a craniocaudal height of 13 cm is also used to define splenomegaly.

[0060] In addition, individual intervals have been established, based on gender- or age-related differences.

[0061] The inventors of the present invention surprisingly observed positive effects on splenomegaly in the evaluation of the efficacy of vamifeport in the treatment of lupus nephritis. Accordingly, a further aspect of the invention relates to attenuating splenomegaly in SLE patients, in particular SLE patients suffering from LN.

[0062] SLE patients, in particular SLE patients suffering from LN, often develop dermatitis, which is accordingly designated as SLE-associated dermatitis. The inventors of the present invention surprisingly observed that vamifeport allows to attenuate SLE-associated dermatitis. Accordingly, a further aspect of the invention relates to preventing, attenuating and / or declining dermatitis associated with systemic lupus erythematosus (SLE; SLE-associated dermatitis). More particularly, this aspect of treating SLE-associated dermatitis relates to preventing, attenuating and / or reducing one or more of the following aspects: development, propagation and / or excabation of skin lesions with or without scar development, hair loss and its more severe form alopecia, scab formation, and / or inflammatory dermatitis.

[0063] In the evaluation of the potential efficacy of vamifeport in the treatment of lupus nephritis the inventors additionally surprisingly observed positive effects on lymph nodes, which are often enlarged in patients developing or suffering from lupus nephritis. Therefore, a particular aspect of the invention relates to attenuating and / or reducing the development or excabation of enlarged lymph nodes.

[0064] Generally, positive effects have been observed on renal pathology when treating lupus nephritis by administering vamifeport and accordingly a further aspect relates to attenuating LN- associated renal pathology. More particularly, this aspect of improving or reducing renal pathology in patients suffering from lupus nephritis comprises preventing, attenuating and / or ameliorating one or more of the following aspects: attenuating or reducing microalbuminuria, attenuating or reducing the urinary albumin to creatinine ratio (ACR), attenuating or reducing proteinuria, reducing NGAL gene expression, reducing tubular injury, reducing damage to the glomeruli, reducing tubular necrosis in the outer medulla extending to the deep cortex renal tubules, reducing glomerular sclerosis with crescents, reducing interstitial fibrosis, reducing hypercellularity in the interstitial and periglomerular regions, reducing glomeruli diameter, reducing glomeruli hypertrophy.

[0065] The symptoms, conditions or parameters described herein can generally be determined by conventional determination methods, e.g. those as described in the Examples. Microalbuminuria as referred to herein is preferably represented as urinary albumin to creatinine ratio: ACR).

[0066] In accordance with the prophylactic aspect of the treatment of the present invention, a further aspect relates to generally protect protection LN patients from the development, manifestation and / or excabation of one or more of the aforesaid symptoms or pathological conditions.

[0067] The World Health Organization has divided lupus nephritis into five stages based on the biopsy. This classification was defined in 1982 and revised in 1995 (see https: / / en.wikipedia.org / wiki / Lupus_nephritis): Class IV disease (Diffuse proliferative nephritis) is both the most severe, and the most common subtype. Class VI (advanced sclerosing lupus nephritis) is a final class which is included by most practitioners. It is thought to be due to the chronic interferon exposure.

[0068] In principle, patients suffering from any of the aforementioned degrees can be treated according to the present invention. When patients with milder forms of LN, e.g. class I and II or also class III, are treated the treatment aims more on stopping the process or the development of more severe forms, which may also be considered as a kind of prevention as defined herein.

[0069] However, also the treatment of more severe forms, e.g. class IV to VI may benefit from the treatment, either by an attenuation of the clinical symptoms, a reduction and amelioration and / or by reversing the course of the disease, at least to a certain extent. In a further aspect of the invention the treatment aims at improving the pathological condition of an LN patient by at least one class or at least by maintaining a patient steadily stable in a class as defined above, i.e. avoiding the progression of the disease. A classical preventive treatment may further aim on avoiding the development and onset of lupus nephritis in SLE patients at all. Accordingly, under the aspect of a prophylactic treatment, SLE patients without clinical confirmation of LN can also be treated with vamifeport.

[0070] Consequently, in a further aspect of the invention the patients to be treated with vamifeport in accordance with the invention are selected from SLE patients without clinically diagnosed LN and from SLE patients suffering from LN in a degree of any of the above classes I to VI.

[0071] In a further aspect, the treatment of LN according to the present invention may result in an improvement in the quality of life in the SLE patients as compared to the quality of life in the patients treated with conventional therapies.

[0072] In a further aspect, the treatment of LN according to the present invention may result in an improvement in the quality of life in the SLE patients as compared to the quality of life in the patients determined within the 1 , 2, 3, or 4 week(s) prior to the commencement of treatment of the invention.

[0073] The improvement of Quality of life is determined within 3, 6, 9, 12, 15, 18, 21 or 24 months after the commencement of the treatment. Quality of life can be determined according to an assay described in the Examples below.

[0074] With the treatment of LN according to the present invention one or more of the aforesaid improvements can be achieved.

[0075] In principle, the subjects to be treated in accordance with the invention can be any mammals such as rodents and primates, and in a preferred aspect the medical use relates to the treatment of humans. The subjects suffering from SLE and LN and to be treated with the method according to the invention are also designated as “patients” or “individuals”.

[0076] In particular, SLE patients being prone to or suffering from LN to be treated according to the present invention are characterized by the underlying pathophysiologic mechanisms explained above in detail, including suffering from impaired kidney function or renal injury, intrarenal chemokines, and infiltration of immune cells, independently of glomerular immune complex deposits, and circulating autoantibodies.

[0077] The subjects to be treated can be of any age. A preferred aspect of the invention relates to the treatment of adults. Accordingly, in a preferred aspect of the invention the subjects to be treated with the new methods described herein are more than 18 years old, preferably more than 25 years old. In a further aspect of the invention the subjects to be treated with the new methods described herein are 25-30 years old, or greater than 30 years old, such as preferably 25-30 years old, 30-35 years old, 35-40 years old, 40-45 years old, 45-50 years old, 50-55 years old, 55-60 years old, or greater than 60 years old, or 60-65 years old, 65-70 years old, 70-75 years old, 75-80 years old, or greater than 80 years old.

[0078] The patient group or population suffering from lupus nephritis and to be treated with the method according to the invention are selected from subjects (patients) being characterized as defined anywhere herein.

[0079] In a further aspect of the invention the patient group or population suffering from LN to be treated with the method according to the invention are selected from subjects (patients) showing one or more of the following characteristics: elevated anti-dsDNA IgG levels, elevated urinary albumin levels, elevated urinary albuminto creatinine ratio, increased NGAL gene expression, beginning or advanced tubular injury, beginning or advanced damage to the glomeruli, beginning or advanced tubular necrosis, beginning or advanced glomerular sclerosis, optionally with crescents, beginning or advanced interstitial fibrosis, beginning or advanced hyercellularity in the interstitial and periglomerular regions, increased glomeruli diameter, beginning or advanced glomeruli hypertrophy.

[0080] Administration Forms

[0081] In a further aspect of the invention the treatment of SLE patients with or without LN in accordance with the present invention comprises the oral administration of vamifeport, including its pharmaceutically acceptable salts, solvates, hydrates and polymorphs, to a patient in need thereof.

[0082] For this purpose, vamifeport is preferably provided in medicaments or pharmaceutical compositions in the form of oral administration forms, including e.g. pills, tablets, such as enteric-coated tablets, film tablets and layer tablets, sustained release formulations for oral administration, depot formulations, dragees, granulates, emulsions, dispersions, microcapsules, microformulations, nanoformulations, liposomal formulations, capsules, such as enteric-coated capsules, powders, microcrystalline formulations, epipastics, drops, ampoules, solutions and suspensions for oral administration.

[0083] In a preferred embodiment of the invention vamifeport is administered in the form of a tablet or capsule, as defined above. These may be present, for example, as acid resistant forms or with pH dependent coatings.

[0084] Accordingly, a further aspect of the present invention relates to vamifeport, including its pharmaceutically acceptable salts, solvates, hydrates and polymorphs, as well as medicaments, compositions and combined preparations comprising the same, for the use in the prophylaxis and treatment of lupus nephritis in SLE patients in the form of oral administration forms.

[0085] Dosina Regimen

[0086] A further aspect of the invention relates to vamifeport, including its pharmaceutically acceptable salts, solvates, hydrates and polymorphs, for the use according to the present invention, wherein the treatment is characterized by one of the following dosing regimens:

[0087] In one aspect vamifeport can be administered to a patient in need thereof in a dose of 0.001 to 500 mg, for example 1 to 4 times a day. However, the dose can be increased or reduced depending on the age, weight, condition of the patient, severity of the disease or type of administration. In a further aspect of the invention vamifeport can be administered as a dose of 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg,

[0088] 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 325 mg, 350 mg, 375 mg,

[0089] 400 mg, 425 mg, 450 mg, 475 mg, 500 mg.

[0090] Preferred is a dose of between 0.5 to 500 mg, more preferred between 1 to 300 mg or 3 to 300 mg, more preferred between 1 to 250 mg or 5 to 250 mg.

[0091] Most preferred is a dose of 5 mg, 15 mg, 60 mg, 120 mg or 240 mg.

[0092] It is possible to administer the above defined dosages as a total daily dose either in a single dose daily or divided into sub-doses for administration twice or more times daily.

[0093] In a further aspect a dose between 0.001 to 35 mg / kg body weight, between 0.01 to 35 mg / kg body weight, between 0.1 to 25 mg / kg body weight, or between 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 and up to 20 mg / kg body weight can be administered. Particularly preferred is a dose of 120 mg for patients with > 50 kg body weight and of 60 mg for patients with < 50 kg body weight, in each case once or twice daily.

[0094] In a further aspect it is possible to select one of the above defined dosages as an initial dose and subsequently administer 1 or more times the same or varying doses of those defined above in repeating intervals of 1 to 7 days, 1 to 5 days, preferably of 1 to 3 days, or every second day.

[0095] The initial dose and the subsequent doses can be selected among the above defined dosages and adjusted / varied in accordance with the need of the patient within the provided ranges.

[0096] In particular, the amount of subsequent doses can be appropriately selected depending on the individual patient, the course of disease and the treatment response. It is possible to administer 1 , 2, 3, 4, 5, 6, 7, and more subsequent doses.

[0097] It is possible that the initial dose is equal or different to the one or more subsequent doses. It is further possible, that the subsequent doses are equal or different. The repeating intervals can be of the same length or can be varied depending on the individual patient, the course of disease and the treatment response.

[0098] Preferably, the subsequent doses are of decreasing amount with increasing number of subsequent dosing.

[0099] Preferably a dose of between 3 mg and 300 mg, more preferred between 5 mg and 250 mg, most preferred of 5 mg, 15 mg, 60 mg, 120 mg or 240 mg is administered once daily over a treatment period of at least 3 days, at least 5 days, at least 7 days. In a further preferred aspect a dose of 60 mg or 120 mg is administered once daily. In a further preferred aspect a total daily dose of 120 mg is administered by administering twice daily a 60 mg dose.

[0100] In a further preferred aspect a total daily dose of 240 mg is administered by administering twice daily a 120 mg dose. Said doses turned out to be safe and well tolerated.

[0101] The preferred dosing regimen further showed fast oral absorption with detectable levels as early as 15 to 30 minutes post-dose. The absorption level can be maintained stable even upon repeated dosing and no critical accumulation is observed.

[0102] Due to its favorable tolerability, as described above, vamifeport is particularly suitable for long-term therapies, including long-term administration over months and up to life-long therapy. This is particular importance as SLE is a lifelong persisting disease, which needs longterm monitoring and observation and can result in life-long treatment requirement.

[0103] Medicaments containing Vamifeport

[0104] A further aspect of the invention relates to a medicament or a pharmaceutical composition containing vamifeport, including its pharmaceutically acceptable salts, solvates, hydrates and polymorphs, as defined anywhere herein for the new use and method of treatment of lupus nephritis as defined anywhere herein.

[0105] Such medicament may further contain one or more pharmaceutical carriers and / or one or more auxiliaries and / or one or more solvents.

[0106] Preferably, the medicament is in the form of an oral dosage form, e.g. such as defined above.

[0107] Preferably the pharmaceutical carriers and / or auxiliaries and / or solvents are selected among suitable compounds for preparing oral dosage forms.

[0108] The said pharmaceutical compositions contain, for example up to 99 weight-% or up to 90 weight-% or up to 80 weight-% or or up to 70 weight-% of vamifeport, the remainder being each formed by pharmacologically acceptable carriers and / or auxiliaries and / or solvents and / or optionally further pharmaceutically active compounds.

[0109] Therein, the pharmaceutically acceptable carriers, auxiliary substances or solvents are common pharmaceutical carriers, auxiliary substances or solvents, including various organic or inorganic carrier and / or auxiliary materials as they are customarily used for pharmaceutical purposes, in particular for solid medicament formulations. Examples include excipients, such as saccharose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talcum, calcium phosphate, calcium carbonate; binding agents, such as cellulose, methylcellulose, hydroxypropylcellulose, polypropyl pyrrolidone, gelatine, gum arabic, polyethylene glycol, saccharose, starch; disintegrating agents, such as starch, hydrolyzed starch, carboxymethylcellulose, calcium salt of carboxymethylcellulose, hydroxypropyl starch, sodium glycol starch, sodium bicarbonate, calcium phosphate, calcium citrate; lubricants, such as magnesium stearate, talcum, sodium laurylsulfate; flavorants, such as citric acid, menthol, glycin, orange powder; preserving agents, such as sodium benzoate, sodium bisulfite, paraben (for example methylparaben, ethylparaben, propylparaben, butylparaben); stabilizers, such as citric acid, sodium citrate, acetic acid and multicarboxylic acids from the titriplex series, such as, for example, diethylenetriaminepentaacetic acid (DTPA); suspending agents, such as methycellulose, polyvinyl pyrrolidone, aluminum stearate; dispersing agents; diluting agents, such as water, organic solvents; waxes, fats and oils, such as beeswax, cocoa butter; polyethylene glycol; white petrolatum; etc.

[0110] Liquid medicament formulations, such as solutions, suspensions and gels usually contain liquid carrier, such as water and / or pharmaceutically acceptable organic solvents. Furthermore, such liquid formulations can also contain pH-adjusting agents, emulsifiers or dispersing agents, buffering agents, preserving agents, wetting agents, gelatinizing agents (for example methylcellulose), dyes and / or flavouring agents, for example as defined above. The compositions may be isotonic, that is, they can have the same osmotic pressure as blood. The isotonicity of the composition can be adjusted by using sodium chloride and other pharmaceutically acceptable agents, such as, for example, dextrose, maltose, boric acid, sodium tartrate, propylene glycol and other inorganic or organic soluble substances. The viscosity of the liquid compositions can be adjusted by means of a pharmaceutically acceptable thickening agent, such as methylcellulose. Other suitable thickening agents include, for example, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, carbomer and the like. The preferred concentration of the thickening agent will depend on the agent selected.

[0111] Pharmaceutically acceptable preserving agents can be used in order to increase the storage life of the liquid composition. Benzyl alcohol can be suitable, even though a plurality of preserving agents including, for example, paraben, thimerosal, chlorobutanol and benzalkonium chloride can also be used.

[0112] Combination Therapy

[0113] A further object of the present invention relates to medicaments or combined preparations containing vamifeport, including its pharmaceutically acceptable salts, solvates, hydrates and polymorphs, as defined anywhere herein and at least one further pharmaceutically active compound (“combination therapy compound”), preferably an additional active compound being useful in the treatment of SLE and / or lupus nephritis or any of the associated symptoms.

[0114] Preferred combination therapy compounds are in particular compounds used in the prophylaxis and treatment of SLE patients, including the above mentioned standard treatment therapeutics, but also antibiotics as well as immunosuppressive agents. Known drugs used in the treatment of SLE and LN include prednisolone, azathioprine / mycophenolate mofetil, cyclosporine A / tacrolimus, hydroxychloroquine, methotrexate, as well as belimumab and other B-cell, plasma cell or autoantibody-targeting approaches.

[0115] Further preferred combination therapy compounds are selected from medicaments for treating iron overload and the associated symptoms. Examples of such combination therapy compounds can be selected from the group of iron-chelating compounds or compounds for the prophylaxis and treatment of any of the states, disorders or diseases accompanying or resulting from iron overload and LN. Suitable combination therapy drug compounds (co-drugs) may be selected from pharmaceutically active compounds for the prophylaxis and treatment of SLE or LN and the associated symptoms. Further examples of additional pharmaceutically active combination therapy compounds can be selected from drugs for reducing iron overload like Tmprss6-ASO, from iron chelators like curcumin, SSP-004184, Deferitrin, deferasirox, deferoxamine and deferiprone.

[0116] In a further aspect the present invention relates to the use and medical treatment of LN as defined herein, wherein vamifeport, including its pharmaceutically acceptable salts, solvates, hydrates and polymorphs, is administered to the patient in need thereof in a combination therapy with one or more of the combination therapy compounds (co-drugs) defined above in a fixed dose or free dose combination for sequential use. Such a combination therapy comprises coadministration of vamifeport with the at least one additional pharmaceutically active compound (drug / combination therapy compound).

[0117] Combination therapy in a fixed dose combination therapy comprises co-administration of vamifeport with the at least one additional pharmaceutically active compound in a fixed-dose formulation.

[0118] Combination therapy in a free dose combination therapy comprises co-administration of vamifeport and the at least one additional pharmaceutically active compound in free doses of the respective compounds, either by simultaneous administration of the individual compounds or by sequential use of the individual compounds distributed over a time period.

[0119] DESCRIPTION OF THE FIGURES

[0120] Figure 1 : Vamifeport treatment attenuates SLE / LN associated pathology

[0121] 10-week-old female MRL / lpr mice were treated with vehicle or vamifeport and outcomes of dermatitis and nephritis were followed for up to 20 weeks. Compared to vehicle, vamifeport treatment was associated with reduced dermatitis (A-B). Compared to vehicle, vamifeport treated mice presented with significantly attenuated renal disease (ACR) and renal proximal tubular epithelial cell injury (NGAL) (C-D). Hematoxylin-Eosin-stained kidney sections of vehicle treated mice at 20 weeks revealed extensive glomerular and tubular injury with necrosis and large periglomerular and interstitial immune infiltrates. A large number of anuclear tubules, tubular cast are also evident (E-F). These pathological features are attenuated in the vamifeport treated mice Scale bar = 100 pm (E) and 50 pm (F).

[0122] Figure 2: Vamifeport-mediated protection in LN is independent of anti-dsDNA antibody levels and glomerular immune complex deposits

[0123] Anti-dsDNA antibodies were detected in 10-week-old mice and increased significantly in 20- week-old vehicle treated mice and were not attenuated by vamifeport treatment (A). Glomerular and tubular immune complex deposits are evident in both vehicle and vamifeport treated mice (B-C), however glomerular hypertrophy was reduced in the vamifeport group (B-C, underlined). Scale bar = 50 pm (B-C). Compared to vehicle, the kidneys of vamifeport treated mice had lower gene expression of chemoattractants such as Cc / 2 (D), Cxcl11 (E) and Cxcl10 (F), which aligned well with the immune infiltrates shown in figures G-H. Immune cell infiltration composed of F480+ve macrophages and a few CD4+ve T cells were observed in the kidneys of MRL / lpr mice at 10 weeks (G), which increased in vehicle treated mice at 20-week of age (H) and had a periglomerular and interstitial distribution. Infiltration of both these populations was attenuated in the vamifeport treated group (I). Scale bar = 100 pm (10X) and 50 pm (20X). Nuclei are clearly visible. Monocyte derived macrophages (MDM) were pretreated for 96 hrs with 2.5 pM vamifeport and then exposed to 1.5% serum isolated from 20-week-old MRL / lpr females. Compared to vehicle and vamifeport treatment, MRL / lpr serum elicited a significant increased gene expression of I L- 1 p (J), Ccl2 (K) and Tnfa (L). All these genes were reduced by vamifeport pretreatment. Data from two experiments with 4 mice in each group was pooled for analysis. Monocytes from 5 mice were used for the experiments and the data was pooled. A 2-tailed Mann-Whitney test determined statistical significance and plotted as mean ± SEM. *P < 0.05, **P < 0.005, ***P < 0.005, ****P < 0.001.

[0124] Figure 3: Vamifeport attenuates renal pathology in MRL / lpr mice

[0125] 10-week-old female MRL / lpr mice were treated with vehicle or vamifeport (1mg / mL ad lib, through drinking water, changed twice a week) and followed for up to 20 weeks of age. Masson's Trichrome stained kidney sections of vehicle-treated mice showed severe glomerular sclerosis with crescents, large areas of interstitial fibrosis, as well as hypercellularity in the interstitial and periglomerular regions (A). All these pathological features were reduced in vamifeport-treated mice (B). Scale bar = 100 urn (10X) and 20 pm (40X) compared to 10-week-old mice, immunofluorescence staining of 20-week-old vehicle treated kidney sections revealed large infiltrates of CD45+ve cells capping the glomeruli as well as in the interstitial regions. There was a dropout of CD31+ cells (endothelial cells) in the 20-week-old vehicle-treated mice (C-D). This was especially notable in the glomeruli surrounded by CD45+ cells (D). These pathological features were attenuated in vamifeport treated mice (E). Scale bar = 100 pm (1 OX) and 50 pm (20X).

[0126] EXAMPLES

[0127] The invention is illustrated in more detail by the following examples. The examples are merely explanatory, and the person skilled in the art can extend the specific examples to further ferroportin inhibitor compounds according to the present invention.

[0128] I. Evaluation of Efficacy of Vamifeport in Treating Lupus Nephritis

[0129] Experimental Approach

[0130] All studies were carried out as described by the National Institutes of Health and Institutional Animal Care and Use Guidelines and were approved by The Institutional Animal Care and Use Committee (IACUC) of the University of Florida. Female MRL / lpr mice (Jackson Laboratories, Bar Harbor, ME, USA) were housed and maintained on a standard diet in the animal facilities of the University of Florida. They were treated with vehicle (water), vamifeport (Vifor, Batch N, 1mg / mL ad lib, through drinking water, changed twice a week). Mice (n = 7) were followed for up to 20 weeks of age or were euthanized as they approached humane endpoint parameters as described by the IACUC. Biochemical Assays and Tissue Samples

[0131] From 16 weeks of age, mice were monitored for the development of proteinuria by adding 50 pL urine on Siemens Multistix 8 SG dipsticks. Before euthanasia, animals were anesthetized with ketamine (120 mg / kg) / xylazine (12 mg / kg), and blood was drawn from the axilla. All the tissue slices were fixed with 10% neutral-buffered formalin for paraffin embedding and with periodate-lysine-paraformaldehyde fixative (PLP) to be frozen in optimal cutting temperature compound or snap frozen in liquid nitrogen for subsequent RNA extraction and immunofluorescence.

[0132] Estimation of Urinary Albumin and Creatinine

[0133] Mice were housed individually in metabolic cages for 24 hours, and urine was collected. Microalbuminuria was estimated using a competitive enzyme-linked immunosorbent assay (ELISA) (Albuwell; Exocell, Philadelphia, PA) using the manufacturer's instructions. Briefly, albumin-coated wells were incubated with urine (1 :13 dilution) and rabbit anti-murine albumin antibody. This was followed by incubation with horseradish peroxidase-conjugated anti-rabbit antibody (Albuwell; Exocell, Philadelphia, PA). The ELISA was developed with tetramethylbenzidine substrate (Thermo Scientific, Rockford, IL), and the reaction was discontinued with 2N sulfuric acid. A standard curve was generated using different concentrations of albumin (10 to 0.156 pg / mL), and the amount of albumin in the urine samples was estimated. Urine creatinine levels were estimated using the accompanying creatinine companion kit per the manufacturer's instructions, and albumin / creatinine ratios were calculated.

[0134] Hemoglobin, Iron, and Hepcidin measurement

[0135] Mice were tail bled, and 50 uL blood was placed on a hemoglobin detection strip (AIMStrip Hb). The values were recorded immediately as mg / dL. Serum iron (Abeam) and hepcidin (Intrinsic LifeSciences) were measured by ELISA as described by the manufacturer.

[0136] Immunofluorescence

[0137] Three-micron, PLP-fixed kidney sections were used for the immunofluorescence detection of CD45+ immune cells, F4 / 80+ macrophages, CD31+ endothelial cells, and CD4+-T cells. Briefly, tissue sections were air-dried and incubated with 0.3% Triton X100 / 10% horse serum in PBS for 30 minutes. After washing the sections with PBS, an anti-CD16 / 32 antibody was added to block FCy. receptors. This was followed by 2 hr incubation with F4 / 80-PE (BM8, Invitrogen), CD4-FITC (GK1.5, Invitrogen), CD31-PE (390 Biolegend), and CD45-FITC (30-F11 , Biolegend) in 10% horse serum / PBS. The sections were washed three times in PBS and mounted with ProLong Gold antifade agent with or without DAPI (Life Technologies). In vitro Studies.

[0138] Monocytes from C57BLK mouse bone marrow and spleen were isolated using the negative selection EasySep Mouse Monocyte Isolation Kit (StemCells Technologies). Primary mouse monocyte were differentiated into macrophages (MDM) using DM EM, 10% FBS, 10ng / mL MCSF (Peprotech) and L-glutamine. Fifty % medium was changed every 3rdday for 9 days. All experiments were performed on day 9 or 10. MDM were treated for 24 and 96 hrs with 2.5 |iM vamifeport or vehicle (medium) followed by a 12 hrs treatment with 1.5% serum from 20-week-old MRL / lpr. Post treatment RNA was isolated, and gene expression was studied by real-time PCR. Vehicle or vamifeport treated MDM were used as controls.

[0139] Real-time PCR

[0140] For RNA isolation, frozen tissues were re-suspended in RLT buffer (Qiagen Inc., Valencia, CA) and homogenized using the TissueLyser system (Qiagen). Total RNA from tissue homogenates was purified using the RNeasy Plus mini kit (Qiagen) following the manufacturer's instructions. 1 ig of RNA was used to synthesize cDNA using the iScript cDNA synthesis kit (Bio-Rad Laboratories, Hercules, CA). The cDNA template was mixed with iTAQ SYBR green universal super mix (Bio-Rad), and quantitative PCR was carried out on a CFX Connect system (Bio-Rad). Predesigned primers for Cc / 2, CxcHO, Cxcl11 were purchased from Bio-Rad. Ppia (Bio-Rad) was amplified in parallel and used as the reference gene. Data are expressed as fold change over control and were calculated using the 2'AC(T)method.

[0141] Detection of Serum anti-dsDNA Antibodies.

[0142] Mouse serum anti-dsDNA IgG was measured in 1 : 100 diluted serum using plates coated with 50 pg / ml dsDNA as described in the publication [Y. Scindia, E. Wlazlo, E. Ghias, S. Cechova, V. Loi, J. Leeds, J. Ledesma, C. Helen, S. Swaminathan, Modulation of iron homeostasis with hepcidin ameliorates spontaneous murine lupus nephritis, Kidney international, 98 (2020) 100-115].

[0143] Results

[0144] Vamifeport treatment did not inhibit systemic hepcidin production or exacerbate LN- associated anemia.

[0145] 10-week-old female MRL / lpr mice were treated with vehicle or vamifeport till around 18- 20 weeks of age. The studies were terminated at this age approached humane endpoints, as few animals in both groups developed fatal glomerulonephritis. At ten weeks of age, these mice already have circulating anti-ds DNA antibodies and renal immune complexes [AA Alli, D. Desai, A. Elshika, M. Conrad, B. Proneth, W. Clapp, C. Atkinson, M. Segal, L.A. Searcy, N.D. Denslow, S. Bolisetty, B. Mehrad, L. Morel, Y. Scindia, Kidney tubular epithelial cell ferroptosis links glomerular injury to tubulointerstitial pathology in lupus nephritis, Clin Immunol, 248 (2023) 109213], Hepcidin levels increased significantly with age in vehicle-treated mice (Table 1). Vamifeport treatment did not attenuate the production of hepcidin (Table 1). At 20-weeks, increased hepcidin levels were associated with significant reduction in serum hemoglobin and iron levels in vehicle and vamifeport treated group (Table 1).

[0146] Tablel

[0147] _. . . , 20 weeks 20 weeks

[0148] Parameter 10 weeks ., .

[0149] Vehicle Vamifeport

[0150] Serum

[0151] Hepcidin 157 ± 7.3 356 ± 51.1a236 ± 21.1a16 ± 0.27 13 ± 0.28a13 ± 0.47a222 ± 7.8 161 ± 11a154 ± 8a

[0152] Spleen Weight0.17 ± 0.018 0.5 ± 0.042a0.39 ± 0.030a b

[0153] (gm)

[0154] Mouse Weight _ . . . . , . _a__ , „ „a b

[0155] (gm) 21 ± 0.41 41 ± 1.1a35 ± 1.6a’b

[0156] Data was analyzed using 1-way ANOVA with Holm-Sidak's multiple comparisons test and represented as mean ± SEM. a: significant compared to 10-week-old mice, p<0.005. b: significant compared to 20-week-old vehicle treated mice, p<0.01.

[0157] Vamifeport treatment attenuates splenomegaly and SLE-associated dermatitis

[0158] Splenomegaly is a pathological feature in MRL / lpr mice and is associated with worse outcomes of SLE [Q. Zhang, L. Xiang, M.H. Zaman, W. Dong, G. He, G.M. Deng, Predominant Role of Immunoglobulin G in the Pathogenesis of Splenomegaly in Murine Lupus, Frontiers in immunology, 10 (2019) 3020], Vehicle-treated 20-week-old mice developed splenomegaly, which was significantly attenuated by vamifeport treatment (Table 1). Spenomegaly was associated with enlarged lymph nodes and an overall increase in body weight of old vehicle- treated mice, which was significantly attenuated by vamifeport (Table 1).The MRL / lpr mice progressively develop skin lesions with scars, hair loss, and scab formation with inflammatory dermatitis [J.Q. Yang, V. Saxena, H. Xu, L. Van Kaer, C.R. Wang, R.R. Singh, Repeated alphagalactosylceramide administration results in expansion of NK T cells and alleviates inflammatory dermatitis in MRL-lpr / lpr mice, Journal of immunology, 171 (2003) 4439-4446; T. Miwa, L. Zhou, M.A. Maldonado, M.P. Madaio, R.A. Eisenberg, W.C. Song, Absence of CD59 exacerbates systemic autoimmunity in MRL / lpr mice, Journal of immunology, 189 (2012) 5434- 5441; F. Furukawa, H. Tanaka, K. Sekita, T. Nakamura, Y. Horiguchi, Y. Hamashima, Dermatopathological studies on skin lesions of MRL mice, Arch Dermatol Res, 276 (1984) 186- 194\. A blinded scorer assigned semiquantitative scores based on the size and severity of the scar tissue, scab formation, and extent of alopecia. Skin lesions with alopecia and facial scabs started developing in vehicle-treated mice at around 16 weeks. They progressively worsened but were significantly reduced in the vamifeport group (Figure 1A-B).

[0159] Vamifeport treatment attenuates LN-associated renal pathology

[0160] To examine the effect of vamifeport on renal disease in SLE, microalbuminuria (represented as urinary albumin to creatinine ratio: ACR) at 20 weeks as an indicator of renal function was measured. At ten weeks of age, the mice had negligible proteinuria, which increased significantly at 20 weeks (Figure 1C) and was significantly attenuated by vamifeport treatment (Figure 1C). Vamifeport treatment also significantly reduced renal NGAL gene expression, indicating reduced tubular injury (Figure 1 D). Hematoxylin-Eosin-stained kidney sections revealed extensive damage to the glomeruli and tubular necrosis in the outer medulla, extending to the deep cortex renal tubules (Figure 1E). These pathological features were reduced in vamifeport-treated mice (yellow dotted area shows region of injury in Figure 1 F). Furthermore, Masson's Trichrome stained kidney sections of vehicle-treated mice showed classic LN features such as severe glomerular sclerosis with crescents, large areas of interstitial fibrosis, as well as hypercellularity in the interstitial and periglomerular regions (Figure 3A). All these pathological features were reduced in vamifeport-treated mice (Figure 3B).

[0161] Vamifeport-mediated protection in LN is independent of anti-dsDNA antibody levels and glomerular immune complex deposits

[0162] Anti-double-stranded DNA (dsDNA) antibodies are critical in the diagnosis and management of SLE [M.E. Orme, A. Voreck, R. Aksouh, R. Ramsey-Goldman, M. W.J. Schreurs, Systematic review of anti-dsDNA testing for systemic lupus erythematosus: A metaanalysis of the diagnostic test specificity of an anti-dsDNA fluorescence enzyme immunoassay, Autoimmun Rev, 20 (2021) 102943]. Anti-dsDNA antibodies perpetuate LN by directly or indirectly binding to cross-reactive antigens or chromatin materials on resident renal cells or extracellular matrix [S. Yung, T.M. Chan, Mechanisms of Kidney Injury in Lupus Nephritis - the Role of Anti-dsDNA Antibodies, Frontiers in immunology, 6 (2015) 475], Serum anti-dsDNA IgG was detected in MRL / lpr mice at ten weeks of age, which increased significantly in 20-week-old vehicle-treated mice (Figure 2A). Vamifeport treatment tended to attenuate the increase in serum anti-dsDNA antibodies, but the values were not significantly lower than vehicle-treated mice (Figure 2A, p = 0.07). Similarly, glomerular IC deposits (IgG) which are a common pathological observation in LN

[0040] were comparable in both staining intensity and pattern in both vehicle- and vamifeport-treated mice (Figure 2B-C). However, the glomeruli of vamifeport treated mice were smaller in diameter and less hypertrophic (Figure 2C). These data indicate that vamifeport-mediated protection against LN is independent of circulating anti-dsDNA antibodies and glomerular IC deposits.

[0163] Vamifeport treatment attenuates the expression of intra-renal chemoattractants and immune cell infiltrates

[0164] In LN, the expression of intrarenal chemoattractants that drive immune cell infiltration and inflammation are increased [Y. Scindia, E. Wlazlo, E. Ghias, S. Cechova, V. Loi, J. Leeds, J. Ledesma, C. Helen, S. Swaminathan, Modulation of iron homeostasis with hepcidin ameliorates spontaneous murine lupus nephritis, Kidney international, 98 (2020) 100-115], Compared to 10 weeks, the kidneys of 20-week-old vehicle-treated mice had a significant increase in the gene expression of Cc / 2, Cxcl10, and Cxcl11 (Figure 2D-F). Vamifeport treatment was associated with a significant suppression in these three chemoattractants (Figure 2D-F). A decrease in intrarenal chemoattractants in vamifeport-treated mice was associated with an attenuation in immune cell infiltrates (Figure 3C-D, Figure 2G-I) which was spatially resolved by immunofluorescence studies. Compared to 10-week-old mice, there were large infiltrates of CD45+ cells in the 20-week-old vehicle-treated mice. These CD45+ cells had a periglomerular distribution and interspersed throughout the renal interstitium (Figure 3C-D). There was a reduction in CD31+ cells (endothelial cells) in the 20-week-old vehicle-treated mice (Figure 3D). This was especially notable in the glomeruli surrounded by periglomerular CD45+ cells (Figure 3D, arrows). These pathological features were attenuated in the 20-week-old vamifeport-treated mice (Figure 3E). Some CD45+ cells were identified as F4 / 80 macrophages and CD4+ T cells. Compared to 10-week-old mice, there were large infiltrates of F4 / 80 macrophages and CD4+ T cells in the 20-week-old vehicle-treated mice (Figure 2G-H) and were attenuated in the vamifeport-treated mice (Figure 2I).

[0165] Vamifeport acts on macrophages but not renal proximal tubular epithelial cells to attenuate LN serum-induced immune response.

[0166] Ferroportin is the principal target of vamifeport. Ferroportin is expressed on monocytes [ / . Theurl, M. Theurl, M. Seifert, S. Mair, M. Nairz, H. Rumpold, H. Zoller, R. Bellmann-Weiler, H. Niederegger, H. Talasz, G. Weiss, Autocrine formation of hepcidin induces iron retention in human monocytes, Blood, 111 (2008) 2392-2399.; T. Eleftheriadis, G. Pissas, M. Remoundou, G. Filippidis, G. Antoniadi, N. Oustampasidou, V. Liakopoulos, I. Stefanidis, Ferroportin in monocytes of hemodialysis patients and its associations with hepcidin, inflammation, markers of iron status and resistance to erythropoietin, Int Urol Nephrol, 46 (2014) 161-167] and on renal proximal tubular epithelial cells (PTEC) [A Soofi, V. Li, J. A. Beamish, S. Abdrabh, M. Hamad, N.K. Das, Y.M. Shah, G.R. Dressier, Renal-specific loss of ferroportin disrupts iron homeostasis and attenuates recovery from acute kidney injury, American journal of physiology. Renal physiology, 326 (2024) F178-F188; N.A. Wolff, W. Liu, R.A. Fenton, W.K. Lee, F. Thevenod, C.P. Smith, Ferroportin 1 is expressed basolaterally in rat kidney proximal tubule cells and iron excess increases its membrane trafficking, J Cell Mol Med, 15 (2011) 209-219], No effect of vamifeport on HK-2 cells has been observed when treated with 1.5% human lupus nephritis serum. There are no documented reports of ferroportin expression on kidney resident macrophages. Since monocyte-macrophage infiltration was attenuated in vamifeport treated MRL / lpr mice (Figure 2 D and I), it has been evaluated whether the protective effects of vamifeport are mediated through action on monocyte derived macrophages (MDM). Vehicle and vamifeport treated MDM had a comparable immune profile (Figure 2J-L). Compared to vehicle and vamifeport treated cells, 1.5% serum from 20-week-old MRL / lpr mice significantly increased the gene expression of IL-1 / 3, Ccl2 and Tnfa (Figure 2J-L), which was significantly attenuated by treating the MDM for 96 hrs with vamifeport (Figure 2J-L). No protective effect of vamifeport has been observed when cells were pretreated only for 24 hrs before being exposed to LN serum. Discussion

[0167] Long-term, ad-lib vamifeport treatment reduced LN manifestations in MRL / lpr mice without worsening SLE-associated anemia. Vamifeport treatment was associated with reduced renal injury, inflammation, and immune cell infiltration, independent of renal IC deposits and anti-dsDNA IgG. These observations support that renal parenchymal cell resistance or susceptibility may determine the extent of kidney disease in SLE.

[0168] The results show that immune complex deposits and circulating anti-dsDNA IgG in the vehicle- and vamifeport-treated animals were comparable, which suggests that vamifeport does not act on B cells. Ferroportin is expressed on a limited number of cells, including macrophages [P. Sagar, S. Angmo, R. Sandhir, V. Rishi, H. Yadav, N.K. Singhal, Effect of hepcidin antagonists on anemia during inflammatory disorders, Pharmacol Ther, 226 (2021) 107877] and renal proximal tubular epithelial cells (PTEC) [S.E.G. van Raaij, S.K.S. Srai, D.W. Swinkels, R.P.L. van Swelm, Iron uptake by ZIP8 and ZIP14 in human proximal tubular epithelial cells, Biometals, 32 (2019) 211-226], Macrophage depletion ameliorated LN in MRL / lpr mice in the presence of autoantibodies and renal IC deposits [S.A Chalmers, J. Wen, J. Shum, J. Doerner, L. Herlitz, C. Putterman, CSF-1R inhibition attenuates renal and neuropsychiatric disease in murine lupus, Clin Immunol, 185 (2017) 100-108] and renal disease occurs in MRL / lpr mice lacking circulating Ig [O. T. Chan, LG. Hannum, A.M. Haberman, M.P. Madaio, M.J. Shlomchik, A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus, J Exp Med, 189 (1999) 1639-1648], This confirms autoantibody and IC- independent mechanisms of kidney disease in LN and support an immune complexindependent effect of vamifeport in protecting against LN.

[0169] Glomerular and tubular pathology are a common feature of LN. The renal proximal tubular epithelial cells (PTEC) express ferroportin, the main target of vamifeport. Vamifeport treatment was associated with decreased renal NGAL [R.D. Pawar, M. Pitashny, S. Gindea, A. T. Tieng, B. Levine, B. Goilav, S.R. Campbell, Y. Xia, X. Qing, D.B. Thomas, L. Herlitz, T. Berger, T. W. Mak, C. Putterman, Neutrophil gelatinase-associated lipocalin is instrumental in the pathogenesis of antibody-mediated nephritis in mice, Arthritis Rheum, 64 (2012) 1620-1631; R.D. Pawar, B. Goilav, Y. Xia, H. Zhuang, L. Herlitz, W.H. Reeves, C. Putterman, Serum autoantibodies in pristane induced lupus are regulated by neutrophil gelatinase associated lipocalin, Clin Immunol, 154 (2014) 49-65] indicating reduced PTEC injury. The renal histology supported this finding. The chemokines secreted by injured tubular cells promote the influx of immune cells and worsen LN [M. Lech, H.J. Anders, The pathogenesis of lupus nephritis, Journal of the American Society of Nephrology : JASN, 24 (2013) 1357-1366], Injured PTECs produce Ccl2 [B. Richter, T. Kapanadze, N. Weingartner, S. Walter, I. Vogt, A. Grund, J. Schmitz, J.H. Brasen, F.P. Limbourg, D. Haffner, M. Leifheit-Nestler, High phosphate-induced progressive proximal tubular injury is associated with the activation of Stat3 / Kim- 1 signaling pathway and macrophage recruitment, FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 36 (2022) e22407], CxcHO [D. Datta, O. Dormond, A. Basu, D.M. Briscoe, S. Pal, Heme oxygenase-1 modulates the expression of the anti- angiogenic chemokine CXCL-10 in renal tubular epithelial cells, American journal of physiology. Renal physiology, 293 (2007) F1222-1230] and Cxcll 1 [X. Wang, D. Wang, X. Wang, X. Wang, J.C. Sha, Q. Gao, Mechanisms underlying the production of chemokine CXCL11 in the reaction of renal tubular epithelial cells with CD4(+) and CD8(+) T cells, Transpl Immunol, 65 (2021) 101337] and can attract myeloid and T cells. Since vamifeport-treated mice had lower expression of these chemoattractants and reduced infiltration of immune cells in peri-tubular areas, its direct effect on PTECS cannot be ruled out. The direct effect of vamifeport on renal parenchymal cells in the settings of lupus is very likely, as they express ferroportin.

[0170] The observations described in the present Example support that the severity of kidney disease in SLE can be attenuated independent of T and B cell therapies.

[0171] The in vitro studies on human PTEC cell line suggest that vamifeport may not directly act on and protects the PTECs. Additionally, immune complex deposits and circulating anti- dsDNA IgG in the vehicle- and vamifeport-treated animals were comparable suggesting that vamifeport does not act on T or B cells.

[0172] The major immune cell type that express ferroportin are splenic macrophages [P. Sagar, S. Angmo, R. Sandhir, V. Rishi, H. Yadav, N.K. Singhal, Effect of hepcidin antagonists on anemia during inflammatory disorders, Pharmacol Ther, 226 (2021) 107877] and monocytes [ / . Theurletal. Blood, 111 (2008) 2392-2399; T. Eleftheriadis etal. Int Urol Nephrol, 46 (2014) 161-167], Monocytes are macrophage precursors and are detected in LN kidney biopsies [G.S. Hill, M. Delahousse, D. Nochy, P. Remy, F. Mignon, J.P. Mery, J. Bariety, Predictive power of the second renal biopsy in lupus nephritis: significance of macrophages, Kidney international, 59 (2001) 304-316], In LN, circulating inflammatory CCR2 expressing monocytes are recruited into the inflamed kidneys by chemotaxis in a CCL2 (MCP-1) dependent manner [H. Haller, A. Bertram, F. Nadrowitz, J. Menne, Monocyte chemoattractant protein-1 and the kidney, Curr Opin Nephrol Hypertens, 25 (2016) 42-49; G.H. Tesch, S. Maifert, A. Schwarting, B.J. Rollins, V.R. Kelley, Monocyte chemoattractant protein 1- dependent leukocytic infiltrates are responsible for autoimmune disease in MRL-Fas(lpr) mice, J Exp Med, 190 (1999) 1813-1824] and the renal micro-environment leads to their differentiation into macrophages and / or dendritic cells | Cortez-Retamozo, M. Etzrodt, M.J. Pittet, Regulation of macrophage and dendritic cell responses by their lineage precursors, Journal of innate immunity, 4 (2012) 411-423], Macrophage depletion ameliorated LN in MRL / lpr mice in the presence of autoantibodies and renal IC deposits [S.A Chalmers, J. Wen, J. Shum, J. Doerner, L. Herlitz, C. Putterman, CSF-1R inhibition attenuates renal and neuropsychiatric disease in murine lupus, Clin Immunol, 185 (2017) 100-108] and renal disease occurs in MRL / lpr mice lacking circulating Ig [O.T. Chan, L.G. Hannum, A.M. Haberman, M.P. Madaio, M.J. Shlomchik, A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus, J Exp Med, 189 (1999) 1639-1648], highlighting their importance in disease progression. The consequence of attenuating ferroportin expression on monocytes-derived macrophages (MDM) in settings of lupus nephritis has not yet been reported. Chronic treatment of monocyte derived macrophages with vamifeport attenuated LN serum-induced IL-1 / 3, Ccl2 and Tnfa. Attenuating the inflammatory phenotype of this large cell population in LN kidney (Figure 2H), may indirectly reduce tissue pathology (Figure 1 E-F). The data of the present Example argue to the existence of autoantibody and IC-independent mechanisms of kidney disease in LN and support the expected benefits of ferroportin inhibition to improve the outcomes of SLE and LN.

[0173] In the present Example, no primary human or murine PTECs that express ferroportin were used. It is described in the literature that injured PTECs produce Ccl2, CxcHO and Cxcl11 and can attract myeloid and T cells to worsen LN. Since vamifeport-treated mice had lower expression of these chemoattractants and reduced infiltration of immune cells in peri-tubular regions, its direct effect on primary PTECS can be concluded.

[0174] The overarching goal in managing LN is to prevent end-stage kidney disease (ESKD). Despite several large clinical trials in LN, no second-line drug is licensed for remission induction. The data generated and presented in the present Example suggest that vamifeport, a clinical- stage, commercially available molecule with rapid pharmacodynamic effects and a well- established safety profile, carries high translational potential for efficiently treating SLE / LN patients.

[0175] II. Quality of Life

[0176] The assessment of quality of life mentioned herein can be evaluated using the Short Form (36) Health Survey (SF-26) and / or the Functional Assessment of Cancer Therapy-Anemia (FACT -An) as described e.g. in WO2016 / 183280.

Claims

CLAIMS1. A compound according to the following formula (I)or a pharmaceutically acceptable salt, solvate, hydrate or polymorph thereof, for the use in the treatment of lupus nephritis (LN).

2. The compound for the use according to claim 1 , wherein the compound is a HCI salt, preferably a 3HCI salt having the following formula (I-3HCI)(I-3HCI).

3. The compound for the use according to claim 1 or 2, wherein the treatment relates to preventing, reducing or attenuating intrarenal chemokines and / or infiltration of immune cells.

4. The compound for the use according to claim 3, wherein the prevention, reduction or attenuation of intrarenal chemokines and / or infiltration of immune cells relates to suppressing or decreasing gene expression of Cc / 2, CxcHO, and / or Cxcl11, suppressing or reducing the infiltration of the renal interstitium with CD45+ cells, suppressing or attenuating the reduction of CD31+ cells in the glomeruli, suppressing or attenuating the infiltration with F4 / 80 macrophages and CD4+ T cells.

5. The compound for the use according to any one of claims 1 to 4, wherein the treatment relates to attenuating splenomegaly.

6. The compound for the use according to any one of claims 1 to 5, wherein the treatment relates to preventing, attenuating and / or declining dermatitis associated with systemic lupus erythematosus (SLE; SLE-associated dermatitis).

7. The compound for the use according to claim 6, wherein the treatment of SLE- associated dermatitis relates to preventing, attenuating and / or reducing one or more of the following aspects selected from development of skin lesions with or without scar development, hair loss or its severe form alopecia, scab formation, and inflammatory dermatitis.

8. The compound for the use according to any one of claims 1 to 7, wherein the treatment relates to attenuating enlarged lymph nodes.

9. The compound for the use according to any one of claims 1 to 8, wherein the treatment relates to attenuating LN-associated renal pathology.

10. The compound for the use according to claim 9, wherein the treatment of LN-associated renal pathology relates to ameliorating one or more of the following aspects selected from attenuating or reducing microalbuminuria, attenuating or reducing the urinary albumin to creatinine ratio (ACR), attenuating or reducing proteinuria, reducing NGAL gene expression, reducing tubular injury, reducing damage to the glomeruli, reducing tubular necrosis in the outer medulla extending to the deep cortex renal tubules, reducing glomerular sclerosis with crescents, reducing interstitial fibrosis, reducing hypercellularity in the interstitial and periglomerular regions, reducing glomeruli diameter, reducing glomeruli hypertrophy.11 . The compound for the use according to any one of claims 1 to 10, wherein the treatment relates to a protection of LN patients from the development or manifestation of one or more of the symptoms or pathological conditions of the claims 5 to 10.

12. The compound for the use according to any one of claims 1 to 11 , which is in a form for oral administration.

13. The compound for the use according to any one of claims 1 to 12, wherein the treatment comprises administering to a patient in need thereof a daily dose of 5 mg, 15 mg, 30 mg, 60 mg, 120 mg or 240 mg; or a daily dose of 30 mg or 60 mg to patients with a body weight of > 50 kg and <100 kg.

14. The compounds for the use according to any one of claims 1 to 13, wherein the treatment comprises administering to a patient in need thereof the selected daily dose in a long-term therapy administration.

15. A combination therapy composition for the use according to any one of claims 1 to 14, wherein the compound (I) or (I-3HCI) as defined in claims 1 and 2 is present in a fixed dose or free dose combination with at least one additional pharmaceutically active compound for sequential use or for co-administration of the compounds, and wherein the at least one additional pharmaceutically active compound is preferably selected from the group comprising immunosuppressants, such as prednisolone, azathioprine / mycophenolate mofetil, cyclosporine A / tacrolimus, hydroxychloroquine, methotrexate, as well as belimumab and other B-cell, plasma cell or autoantibodytargeting approaches, iron chelators, such as deferiprone, deferoxamine or deferasirox, and antibodies, such as belimumab.

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