Sebuparin for the treatment of chronic kidney disease

Abstract

The present invention relates to the substance sebparin or a pharmaceutically acceptable salt thereof for use in the treatment of subjects with chronic kidney disease (CKD), which may also include anemia. This therapy may also be useful as a combination therapy with standard of care (SOC) therapies, such as erythropoiesis-stimulating agents (ESAs) or HIF prolyl hydroxylase inhibitors.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to the substance sebumparin or a pharmaceutically acceptable salt thereof for use in the treatment of chronic kidney disease (CKD), which may also include anemia, and to the use of sebumparin in combination therapy with erythropoiesis-stimulating agents (ESAs) or HIF prolyl hydroxylase inhibitors. [Background technology]

[0002] Background of the Invention Chronic kidney disease (CKD) is associated with several complications that worsen as the disease progresses. Anemia, impaired iron metabolism, and inflammation are common features. The inflammatory response begins early in the disease, releasing proinflammatory cytokines, acute-phase reactants, and hepcidin. Hepcidin production is regulated by several factors that are altered in CKD, including hypoxia / anemia, erythropoietin and erythropoietic products, transferrin saturation (TSAT), and liver iron levels.

[0003] Chronic kidney disease (CKD) can cause anemia. Erythropoiesis-stimulating agents (ESAs), including recombinant erythropoietin (EPO) analogs, have been used to treat anemia associated with CKD by compensating for the loss of EPO (Thavarajah, S et al. al: Am.J.Kidney Dis.2019, 74, pp. 667-674: The Use of Erythropoiesis-Stimulating Agents in Patients With CKD and Cancer: A Clinical Approach). However, it has been shown that resistance and tolerance to these drugs can develop. High doses of erythropoietin-stimulating agents (ESAs) may also cause side effects such as cardiovascular disease.

[0004] Anemia is a condition in which blood cannot adequately deliver oxygen to tissues due to an insufficient number of red blood cells (RBCs) and insufficient hemoglobin within them. Red blood cells are the oxygen carriers in blood, and hemoglobin is responsible for holding oxygen molecules within the RBCs. Symptoms of anemia include fatigue, shortness of breath, weakness, and dizziness. Iron deficiency is considered the most common cause of anemia worldwide, but other factors, such as folate, vitamin B12, and vitamin A deficiencies, chronic inflammation, parasitic infections, and genetic disorders, can also contribute to anemia.

[0005] Secondary anemia, also known as anemia of chronic disease (ACD) or anemia of inflammation, is the most common anemia in hospitalized patients and the second most common anemia worldwide after iron deficiency. It is characterized by impaired iron uptake during erythropoiesis, impaired erythropoietin response, dysregulated erythropoietin production, and cytokine-mediated shortening of red blood cell survival. While the cause is clear in many patients with ACD, identifying the underlying disease is necessary in many others, and these patients are often referred to a hematologist for investigation. In patients with chronic kidney disease (CKD), a significant decrease in erythropoietin production is the most important factor causing anemia, and these patients also share features of ACD (Sarah L. Davis et al.; Blood Reviews; Volume 26, Issue 2, March 2012, Pages 65-71).

[0006] Erythropoietin-stimulating agents (ESAs) are drugs that stimulate the bone marrow to make red blood cells and increase the blood's oxygen-carrying capacity. These drugs are given by injection and work by stimulating the production of more red blood cells. Erythropoietin (EPO) is a hormone produced in the kidneys that encourages the bone marrow to form more red blood cells. The kidney cells that make erythropoietin are sensitive to low oxygen levels in the blood passing through the kidneys. If the oxygen level is too low, these cells will produce erythropoietin. Low oxygen levels may indicate a reduced number of red blood cells (anemia) or a reduction in the hemoglobin molecule that carries oxygen throughout the body. As the primary regulator of red blood cell production, erythropoietin's primary function is to promote the development of red blood cells and initiate the synthesis of hemoglobin, which carries oxygen within red blood cells. Two ESAs commercially available in the United States are epoetin alfa (Procrit®, Epogen®) and darbepoetin alfa (Aranesp®).

[0007] Red blood cell (RBC) production is a coordinated process that requires both the growth factor erythropoietin (EPO) and an adequate iron supply. EPO, produced in the kidney during hypoxia, stimulates erythroid cell proliferation and differentiation (Franke K et al; Blood 2013; 122(7) pp. 1122-1128).

[0008] To acquire iron, which is essential for hemoglobin (Hb) synthesis, erythroid precursors release soluble factors that suppress the expression of the hepatic iron-regulating hormone hepcidin to increase iron absorption and recycling. Hepcidin is an iron-regulating hepatic peptide hormone that controls iron absorption at the intestinal level and iron release from macrophages and hepatocytes. Hepcidin binds to the plasma membrane iron-efflux factor ferroportin, inducing its endocytosis and degradation, preventing iron release into the plasma (Nai et al.; Blood 2016 May 12; Vol. 127; No. 19; pp. 2327-2336). However, Therefore, elevated hepcidin levels result in iron retention in macrophages and enterocytes, reducing iron availability for erythropoiesis and leading to impaired heme synthesis. Hepcidin also limits the availability of exogenous iron administered chronically or acutely through other mechanisms (Ramos E et al: Hepatology.2011 Apr;53(4):pp.1333-41). Therefore, high hepcidin concentrations decrease the ability to take up iron.

[0009] Hepcidin plays an important role in the development of ACD, and elevated hepcidin levels have been observed in various chronic diseases, including inflammatory bowel disease (IBD), infections, myeloma, and non-Hodgkin's lymphoma (Cullis J; Diagnosis and management of anemia of chronic disease: Current status; Br. J. Haematol 2011:154: pp. 289-300).

[0010] Elevated hepcidin levels, as seen in both clinical and experimental studies, are thought to contribute to the inadequate response to EPO in these cases (Nai A et al. Blood. 2016 May 12;127(19): pp. 2327-2336; Steensma DP et al: Blood. 2015 Jun 4;125(23): pp. 3669-3671; Petruliene K et al: Medicina Kaunas; 2017;53(2): pp. 90-100). Summary of the Invention

[0011] Description of the Invention The present invention relates to the compound sebumparin or a pharmaceutically acceptable salt thereof for use in the treatment of chronic kidney disease (CKD).

[0012] In a further embodiment of the present invention, the chronic kidney disease (CKD) may include kidney damage such as fibrosis. In a further embodiment of the present invention, the subject suffering from chronic kidney disease (CKD) may also have anemia.

[0013] The underlying problem of anemia in chronic kidney disease (CKD) is elevated plasma hepcidin levels, which result in iron retention in macrophages and enterocytes, reducing iron availability for erythropoiesis and impairing heme synthesis. Normal hepcidin levels are approximately 1-12 nmol / L. During normal erythropoiesis, in the presence of adequate nutritional iron supply and the absence of inflammation, whole-body iron homeostasis maintains plasma iron concentrations in the range of 10-30 μM, reducing whole-body iron stores to 0. Iron levels are maintained within the range of 0.3–1g. This is reflected in iron storage marker ferritin levels (27–365 μg / L in men and 13–148 μg / L in women), soluble transferrin receptor levels (0.76–1.76 mg / L), transferrin saturation levels (10 / 15–50 / 60% in men and women), and total iron binding capacity (30–80 μmol / L depending on age). The primary mechanism of iron homeostasis is the interaction between hepcidin, an iron-regulating hormone produced by hepatocytes, and ferroportin, a hepcidin receptor and cellular iron efflux factor for iron transfer to plasma. Baseline hepcidin synthesis is regulated by feedback from both iron stores and plasma iron levels. Elevated hepcidin levels result in iron retention in macrophages and enterocytes, reducing iron available for erythropoiesis and impairing heme synthesis.

[0014] Anemia associated with chronic kidney disease (CKD) often shows an inadequate response to endogenous EPO, as evidenced by elevated EPO levels and the need for increased dosage over time (normal range 2.6–18.5 IU / L) without sufficient improvement in anemia parameters such as hemoglobin, hematocrit, and reticulocyte counts, which may adversely affect EPO production in CKD and result in typically low EPO levels. In this situation, an inadequate response to EPO is indicated by insufficient improvement in anemic parameters such as hemoglobin, hematocrit, and reticulocyte counts despite administration of high doses of exogenous EPO (i.e., greater than 200 IU / kg / week EPO alpha iv or equivalent). [Brief explanation of the drawings]

[0015] [Figure 1A] FIG. 1A is a graph showing hemoglobin blood levels in mice administered sebuparin for three weeks. [Figure 1B] FIG. 1B is a graph showing hematocrit in mice administered sebuparin for 3 weeks. [Figure 1C] FIG. 1C is a graph showing the body weight of mice administered sebumparin for 3 weeks. [Figure 1D] FIG. 1D is a graph showing serum creatinine levels in mice administered sebuparin for 3 weeks. [Figure 1E] FIG. 1E is a graph showing the blood concentration of reticulocyte hemoglobin (Ret-He) in mice administered sebuparin for 3 weeks. [Figure 1F] FIG. 1F is a graph showing serum levels of hepcidin in mice treated with sebumparin for 3 weeks. [Figure 1G] FIG. 1G is a graph of histochemistry and immunostaining of paraffin-embedded kidney sections showing the physical state of mouse kidneys after 3 weeks of sebumparin administration. [Figure 2A] FIG. 2A is a photomicrograph showing the physical state of mouse kidneys after 11 weeks of treatment with sebumparin, EPO, or a combination of sebumparin and EPO. [Figure 2B] FIG. 2B shows macroscopic observations (40× magnification) of kidney organ damage after 11 weeks of treatment with sebumparin, EPO, or a combination of sebumparin and EPO. [Figure 3A] FIG. 3A is a graph showing serum levels of hepcidin upon 3 weeks of treatment with sebuparin, EPO, or a combination thereof. [Figure 3B] FIG. 3B is a graph showing serum levels of hepcidin upon 6 weeks of treatment with sebuparin, EPO, or a combination thereof. DETAILED DESCRIPTION OF THE INVENTION

[0016] Detailed Description of the Invention The object of the present invention is the compound sebumparin or a pharmaceutically acceptable salt thereof for use in the treatment of chronic kidney disease (CKD).

[0017] One aspect of the present invention is the compound sebumparin for use in the treatment of chronic kidney disease (CKD), wherein sebumparin has the following characteristics: (i) anti-factor IIa activity up to 10 IU / mg; (ii) antifactor Xa activity of up to 10 IU / mg; (iii) a weight-average molecular weight of 6.5 to 9.5 kDa; (iv) wherein the polysaccharide chains in the chemically modified heparin mainly comprise the structure of the formula:

[0018] [ka]

[0019] where n is an integer from 2 to 25, and contains 2 to 25 disaccharide units corresponding to a molecular weight of 1.2 to 15 kDa. (v) retains at least 90% of the sulfate groups compared to native heparin; (vi) a reduction in the chemically intact pentasaccharide sequence that confers the antithrombin-mediated anticoagulant effect compared to the polysaccharide chain of native heparin; and (vii) less sulfated iduronic acid units compared to native heparin; and glucuronic acid units are reduced.

[0020] In a further embodiment, sebumparin for use as described and claimed herein has no unidentified signals in the ranges of 0.10-2.00 ppm, 2.10-3.10 ppm and 5.70-8.00 ppm in the H-NMR spectrum that are greater than 4% of the height of the signal present in native heparin at 5.42 ppm.

[0021] In a further embodiment of the invention, the polysaccharide chains predominantly present in the sebparin used according to the invention have 6 to 16 disaccharide units with a molecular weight of 3.6 to 9.6 kDa.

[0022] In a further embodiment of the present invention, the sebumparin used in accordance with the present invention comprises a glycol split residue of the following chemical structure:

[0023] [ka]

[0024] Furthermore, in one aspect of the invention, in the sebparin used according to the invention, at least 30% of the polysaccharide chains have a molecular weight of at least 8 kDa. Furthermore, in one embodiment of the present invention, in the sebparin used according to the present invention, 3 to 15% of the polysaccharide chains have a molecular weight of at least 15 kDa. Furthermore, in one embodiment of the present invention, in the sebparin used according to the present invention, 25 to 47% of the polysaccharide chains have a molecular weight of at least 9 kDa. Furthermore, in one embodiment of the present invention, in the sebparin used according to the present invention, 40 to 60% of the polysaccharide chains have a molecular weight of at least 7 kDa. Furthermore, in one embodiment of the present invention, in the sebparin used according to the present invention, 60 to 80% of the polysaccharide chains have a molecular weight of at least 5 kDa. Furthermore, in one embodiment of the invention, in the sebparin used according to the invention, at least 85% of the polysaccharide chains have a molecular weight of at least 3 kDa. Furthermore, in one aspect of the invention, in the sebparin used according to the invention, at least 95% of the polysaccharide chains have a molecular weight of at least 2 kDa.

[0025] One aspect of the present invention is the compound sebparin for use in chronic kidney disease (CKD) as described herein, wherein said chronic kidney disease (CKD) comprises renal impairment.

[0026] One aspect of the present invention is the compound sebparin for use in chronic kidney disease (CKD) as described herein, wherein the kidney damage comprises inflammation.

[0027] One aspect of the present invention is the compound sebparin for use in chronic kidney disease (CKD) as described herein, where chronic kidney disease (CKD) includes fibrosis.

[0028] One aspect of the present invention is the compound sebumparin for use in chronic kidney disease (CKD) as described herein, wherein chronic kidney disease (CKD) includes renal dysfunction with a CKD glomerular filtration rate (GFR) that is G2, G3a, G3b, or G4, as defined by the National Kidney Foundation.

[0029] One aspect of the present invention is the compound sebparin for use in chronic kidney disease (CKD) as described herein, wherein a subject suffering from chronic kidney disease (CKD) as described herein is at risk of developing renal failure.

[0030] One aspect of the present invention is the compound sebumparin for use in chronic kidney disease (CKD) as described herein, wherein a subject suffering from chronic kidney disease (CKD) has renal failure.

[0031] One aspect of the present invention is the compound sebparin for use in chronic kidney disease (CKD) as described herein, wherein the subject suffering from chronic kidney disease (CKD) also has anemia.

[0032] One aspect of the present invention is the compound sebumparin for use in chronic kidney disease (CKD) as described herein, wherein the anemia is anemia of chronic disease (ACD).

[0033] One aspect of the present invention is the compound sebparin for use as described herein, wherein the anemia is renal anemia.

[0034] One aspect of the present invention is the compound sebumparin for use in chronic kidney disease (CKD) as described herein, wherein the sebumparin is used in combination therapy with an agent for use as standard of care (SOC) therapy in chronic kidney disease (CKD).

[0035] One aspect of the present invention is sebparin for use as monotherapy.

[0036] In one embodiment of the present invention, the compound sebparin is used in combination with an erythropoiesis-stimulating agent (ESA) as a standard of care (SOC) agent.An example of the erythropoiesis-stimulating agent (ESA) that can be used in combination with sebparin as described herein is erythropoietin (EPO).Examples of such erythropoietin (EPO) can be selected from any one of erythropoietin alpha; erythropoietin beta; erythropoietin epsilon; erythropoietin gamma; erythropoietin kappa; erythropoietin omega; erythropoietin theta; and erythropoietin zeta.

[0037] In a further embodiment of the present invention, the compound sebumparin can be used in combination therapy with a HIF prolyl hydroxylase inhibitor as a standard of care (SOC) agent. Examples of such HIF prolyl hydroxylase inhibitors can be selected from Roxadustat, Vadadustat, Daprodustat, Enarodutate, and Molidustat.

[0038] In one embodiment of the invention, sevuparin is for use as add-on therapy, wherein the sevuparin is administered to a subject suffering from chronic kidney disease (CKD) as described herein, and the subject is already being treated with a standard of care (SOC) agent indicated for the treatment of chronic kidney disease (CKD).

[0039] In one embodiment of the invention, sebumparin is administered in combination with a standard of care (SOC) indicated for the treatment of chronic kidney disease (CKD).

[0040] In one aspect of the present invention, sebumparin and standard of care (SOC) are administered simultaneously, separately, or sequentially in the treatment of chronic kidney disease (CKD).

[0041] One aspect of the present invention is the compound sebumparin for use in the treatment of chronic kidney disease (CKD) as described herein, in which monotherapy with erythropoiesis-stimulating agents (ESAs) does not provide sufficient therapeutic benefit.

[0042] One aspect of the present invention is the compound sebuparin, which is used to reduce blood hepcidin levels in subjects suffering from anemia.

[0043] One aspect of the present invention is the compound sebuparin, which is used to reduce blood hepcidin levels in subjects suffering from chronic kidney disease.

[0044] Furthermore, an aspect of the present invention is the compound sebuparin for use in reducing blood hepcidin levels in subjects with chronic kidney disease and anemia.

[0045] One aspect of the present invention is the compound sebumparin for use in the treatment of chronic kidney disease (CKD) as described herein, wherein the therapeutic effect of sebumparin is independent of the serum level of hepcidin in the treated subject.

[0046] One aspect of the present invention is the compound sebparin for use in the treatment of chronic kidney disease (CKD), as described herein, for restoring responsiveness to erythropoietin (EPO) in subjects with chronic kidney disease (CKD) accompanied by anemia. Renal anemia is a common complication in hemodialysis patients. Erythropoietin (EPO) hyporesponsiveness has been recognized as a key factor reducing the effectiveness of recombinant human erythropoietin in treating renal anemia. More importantly, an increased erythropoietic resistance index (ERI) may be associated with increased inflammation and mortality (Xiangxue Lu et al.; Hindawi Mediators of Inflammation Volume 2020, Article ID 1027230).

[0047] ESA resistance or hyporesponsiveness occurs when patients do not achieve desirable serum hemoglobin (Hb) concentrations despite using higher-than-normal doses of ESAs or when increasingly higher doses are required to maintain recommended Hb concentrations (Drueke TB et al: Summary of the KDIGO guideline on anemia and comment: reading between the (guide)line(s). Kidney Int. 2012;82(9): pp. 952-960).

[0048] Weiner et al. (J Am Soc Nephrol 18: pp. 3184-3191, 2007) reported that reducing versus discontinuing erythropoietin at high hemoglobin levels was associated with a hemoglobin concentration of 130 These findings suggest that at hemoglobin levels above 165 g / L, discontinuation of ESA therapy may be more appropriate than dose reduction. At higher hemoglobin levels, patients are at increased risk, as noted above, and are at risk of developing polycythemia, defined as a hemoglobin level of 165 g / L in men and 160 g / L in women.

[0049] One aspect of the present invention is the compound sebumparin for use in the treatment of chronic kidney disease (CKD) as described herein, wherein the subject suffering from said chronic kidney disease (CKD) is an elderly subject.

[0050] An aspect of the present invention is the compound sebumparin for use in the treatment of chronic kidney disease (CKD) as described herein, wherein said use is to increase blood levels of hemoglobin.

[0051] Additionally, an aspect of the present invention is the use of the compound sebumparin for the manufacture of a medicament for the treatment of chronic kidney disease (CKD) as described and claimed herein.

[0052] Furthermore, an aspect of the present invention is a method for treating chronic kidney disease (CKD), comprising administering a therapeutically effective amount of the compound sebumparin or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.

[0053] definition Sebuparin is a heparin derivative and its chemical code is DF02. The International Nonproprietary Name (INN) of DF02 is sebuparin sodium. The CAS Registry Number (RN) of sebuparin is RN 9041-08-1.

[0054] More specifically, sebumparin is a chemically modified heparin: (i) anti-factor IIa activity is up to 10 IU / mg; (ii) antifactor Xa activity up to 10 IU / mg; (iii) the weight-average molecular weight is 6.5 to 9.5 kDa; (iv) wherein the polysaccharide chains in the chemically modified heparin mainly comprise the structure of the formula:

[0055] [ka]

[0056] wherein n is an integer between 2 and 25, and contains 2 to 25 disaccharide units corresponding to a molecular weight between 1.2 and 15 kDa; (v) retains at least 90% of the sulfate groups compared to native heparin; (vi) a reduced amount of chemically intact pentasaccharide sequence, which provides the antithrombin-mediated anticoagulant effect, compared to the polysaccharide chain of native heparin; and (vii) less sulfated iduronic acid units compared to native heparin; and glucuronic acid units are reduced.

[0057] Sebuparin may have no unidentified signals in the 1H-NMR spectrum in the ranges of 0.10-2.00 ppm, 2.10-3.10 ppm, and 5.70-8.00 ppm that are greater than 4% of the signal height present in native heparin at 5.42 ppm.

[0058] The polysaccharide chains primarily contained in sebparin have a molecular weight of 3.6 to 9.6 kDa and contain 6 to 16 disaccharide units, and may contain glycol fragment residues of the following chemical structure: [ka]

[0059] At least 30% of the polysaccharide chains of the compound sebumparin have a molecular weight of at least 8 kDa, 3-15% of the polysaccharide chains have a molecular weight of at least 15 kDa, 25-47% of the polysaccharide chains have a molecular weight of at least 9 kDa, 40-60% of the polysaccharide chains have a molecular weight of at least 7 kDa, 60-80% of the polysaccharide chains have a molecular weight of at least 5 kDa, at least 85% of the polysaccharide chains have a molecular weight of at least 3 kDa, and at least 95% of the polysaccharide chains have a molecular weight of at least 2 kDa. The average molecular weight of the major disaccharide is about 600 daltons.

[0060] The preparation of sebumparin is described in Examples 1 to 3 of published patent application WO2013 / 095276.

[0061] Chronic kidney disease (CKD) is defined as a glomerular filtration rate (GFR) of 1.73m 2 A decrease in renal function lasting at least 3 months, regardless of underlying cause, as indicated by a blood pressure of less than 60 mL / min per minute, or markers of renal damage, or both.

[0062] Glomerular filtration rate (GFR) is equal to the total amount of filtration by functioning nephrons in the kidney. Elevated blood creatinine levels are only observed after significant loss of functioning nephrons, and GFR is considered the best way to measure kidney function. Normal GFR varies with age, sex, and body size. GFR is usually estimated using a formula that combines demographic factors such as age, race, and sex with serum creatinine and / or cystatin C concentrations. The National Kidney Foundation classifies the stages and severity of chronic kidney disease (CKD) as shown in Table 1 below.

[0063] [Table 1]

[0064] In the absence of evidence of renal impairment, neither G1 nor G2 GFR categories meet the criteria for CKD. 2 If less than this, the nephrologist may need to prepare for renal replacement.

[0065] The term renal injury, as used herein, refers to the presence of subclinical and symptomatic markers of renal injury according to the classification described by the National Kidney Foundation (see Table 1 above), which includes markers present in blood analyses as well as indicators of damage present in the kidney and renal tissue.

[0066] As used herein, the term inflammation refers to the normal, maladaptive, or pathological response of the organism to a harmful stimulus, as evidenced by the measurement or observation of at least one agreed-upon inflammatory marker, in the whole body, in a tissue, or both. Maladaptive and pathological inflammation is often involved in processes that lead to more permanent damage, such as, but not limited to, fibrosis.

[0067] The term fibrosis, as used herein, refers to the pathological process in which functional tissue is replaced by connective scar-forming tissue as a result of repeated injury, chronic inflammation, and repair.

[0068] As used herein, the term renal failure refers to a medical condition in which the kidneys are no longer able to adequately filter waste products from the blood, resulting in less than 15% of normal function. Renal failure is classified as acute renal failure, which develops rapidly and may be cured, and chronic renal failure, which develops slowly and is often irreversible. Renal failure is also known as end-stage renal disease and is classified as G5 by the National Kidney Foundation.

[0069] As used herein, the term anemia refers to a condition in which the blood cannot deliver sufficient amounts of oxygen to the tissues due to an insufficient number of red blood cells (RBCs), which are oxygen carriers, and an insufficient amount of hemoglobin, which holds the oxygen molecules in the RBCs. Symptoms of anemia include fatigue, shortness of breath, weakness, and dizziness. Iron deficiency is considered the most common cause of anemia worldwide, but deficiencies of folic acid, vitamin B12, vitamin A, chronic kidney disease, and diabetes are also common. Other factors can also cause anemia, including sexual inflammation, parasitic infections, and genetic disorders.

[0070] Secondary anemia, also known as anemia of chronic disease (ACD) or anemia of inflammation, is characterized by impaired iron uptake during erythropoiesis, impaired erythropoietin response, dysregulated erythropoietin production, and cytokine-mediated shortening of red blood cell survival. In patients with chronic kidney disease (CKD), a significant decrease in erythropoietin production is the most important factor causing anemia, but these patients also share features of ACD (Sarah L. Davis et al; Blood Reviews; Volume 26, Issue 2, March 2012, Pages 65-71).

[0071] The term renal anemia refers to anemia of chronic kidney disease (CKD), ie, subjects who suffer from chronic kidney disease and also suffer from anemia suffer from renal anemia.

[0072] The terms treatment or therapy as used herein are conventional terms in the medical and pharmaceutical fields and include not only therapeutic treatment but also Prophylactic (preventive) treatment is also included.

[0073] Whenever the term therapeutic treatment is used herein, it refers to the treatment of a subject suffering from chronic kidney disease (CKD), which may also include anemia, as described herein. The treatment (treatment) can be monotherapy with sebumparin alone or in combination with standard of care (SOC) agents used to treat chronic kidney disease, such as erythropoiesis-stimulating agents (ESAs) and / or HIF prolyl hydroxylase inhibitors.

[0074] As used herein, prophylactic therapy, prophylactic treatment, Whenever the term "treatment" or "preventive treatment" is used, it means that sebum is used in subjects at risk of being diagnosed with chronic kidney disease (CKD) or at risk of developing renal failure, which may include anemia as disclosed and claimed herein. The treatment may be sebum monotherapy or combination therapy with sebum and an erythropoiesis-stimulating agent (ESA) and / or a HIF prolyl hydroxylase inhibitor.

[0075] The term monotherapy as used herein refers to the administration of the compound sebparin alone for chronic kidney disease (CKD), which may also include anemia, as described herein. Monotherapy may be therapeutic therapy (treatment) or prophylactic therapy (preventive therapy).

[0076] The term combination therapy as used herein refers to a therapy for chronic kidney disease (CKD), which may also include anemia, as described herein, in which the compound sebparin is combined with a standard of care (SOC) drug for use in treating chronic kidney disease, such as an erythropoiesis-stimulating agent (ESA) and / or a HIF prolyl hydroxylase inhibitor. Such combination therapy may be add-on therapy, co-administration, simultaneous administration, or sequential administration.

[0077] The term add-on therapy as used herein is defined as combination therapy in which the compound sebparin is administered to a subject who is already being treated with standard of care (SOC) agents, such as erythropoiesis-stimulating agents (ESAs) and / or HIF prolyl hydroxylase inhibitors, for use in the treatment of chronic kidney disease, which may also include anemia, as described herein.

[0078] The term co-administration as used herein means that sebum is administered simultaneously with standard of care (SOC) agents for use in the treatment of chronic kidney disease, which may also include anemia, as described herein, such as erythropoiesis-stimulating agents (ESAs) and / or HIF prolyl hydroxylase inhibitors.

[0079] The term co-administration as used herein means that sebumparin and a standard of care (SOC) agent for use in the treatment of chronic kidney disease, which may also include anemia, as described herein, such as an erythropoiesis-stimulating agent (ESA) and / or a HIF prolyl hydroxylase inhibitor, are administered to the subject being treated simultaneously, i.e., separately from each other but as a combination therapy.

[0080] As used herein, the term sequential administration means that the compound sebparin is administered before or after administration of a standard of care (SOC) agent for use in the treatment of chronic kidney disease, which may also include anemia, as described herein, such as an erythropoiesis stimulating agent (ESA) and / or a HIF prolyl hydroxylase inhibitor.

[0081] The term "low normal hemoglobin" (low blood count) is defined by the World Health Organization (WHO). According to the WHO, anemia is defined as a hemoglobin (Hb) concentration of less than 12.0 g / dL in women and less than 13.0 g / dL in men. However, the distribution of normal Hb levels varies not only by gender but also by ethnicity and physiological status. New lower limits of normal Hb levels have been proposed depending on ethnicity, gender, and age. When classifying and diagnosing hematological parameters, the underlying pathological mechanisms and the patient's medical history must be taken into account. With the aging of the population, anemia is increasing among the elderly, especially in Western countries. Anemia in this population is currently defined as an Hb concentration of less than 12 g / dL in both men and women, although most cases are mild (10–12 g / dL).

[0082] As used herein, the term hepcidin-associated anemia refers to anemia in which serum levels of hepcidin, ferritin, total iron-binding capacity (TIBC), transferrin saturation, and soluble transferrin receptor are abnormal according to a pattern indicative of the presence of so-called functional iron deficiency anemia, and is synonymous with the terms anemia of chronic disease and anemia of inflammation.

[0083] Hepcidin is a protein encoded by the HAMP gene in humans. Hepcidin is the primary regulator of iron entry into the circulation in mammals. In pathological conditions where hepcidin levels are abnormally high, serum iron is reduced due to iron sequestration in macrophages and hepatocytes and reduced iron absorption in the intestinal tract. This normally results in insufficient serum iron available for developing red blood cells, leading to anemia.

[0084] Erythropoiesis is defined as the process of producing red blood cells. Erythropoiesis is stimulated by a decrease in the amount of oxygen in the circulation, which the kidneys sense and secrete the hormone erythropoietin, which stimulates the proliferation and differentiation of red blood cell precursor cells, activating erythropoiesis in hematopoietic tissues and ultimately producing red blood cells (erythrocytes).

[0085] Exogenous erythropoietin, i.e., erythropoiesis-stimulating agents (ESAs) such as recombinant human erythropoietin (rhEPO), are drugs produced by recombinant DNA technology in cell culture. Epoietin alfa (Epogen®) is a 165-amino acid erythropoiesis-stimulating glycoprotein produced in cell culture using recombinant DNA technology and is used to treat patients with anemia associated with various clinical conditions. Its molecular weight is approximately 30,400 daltons and is produced by mammalian cells transfected with the human erythropoietin gene. The product contains the same amino acid sequence as isolated native erythropoietin and has biological activity similar to that of endogenous erythropoietin.

[0086] Erythropoietin (EPO) is a growth factor produced in the kidney that stimulates red blood cell production by promoting the division and differentiation of red blood cell precursor cells in the bone marrow.

[0087] Examples of erythropoiesis stimulating agents (ESAs) useful in the combination therapies described and claimed herein include epoetin alfa (Procrit®, Epogen®) and and darbepoietin alfa (Aranesp (registered trademark)); erythropoietin beta; erythropoietin epsilon; erythropoietin gamma; erythropoietin kappa; erythropoietin omega; erythropoietin theta; and erythropoietin zeta.

[0088] The term hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor refers to compounds that restore EPO production. These drugs may also optimize iron metabolism by reducing hepcidin levels.

[0089] The term ARD stands for adenine-rich diet.

[0090] The term therapeutic effect of sebparin independent of serum levels of hepcidin means that an appropriate therapeutic outcome using sebparin as described herein can be achieved without a correlated change, e.g., a decrease in measured blood levels of hepcidin.

[0091] The term use to restore, enhance or promote responsiveness to erythropoietin (EPO) in a subject with anemia means that the desired effect of treatment with EPO is improved or mitigated by the addition of treatment with another pharmaceutical compound, such as sebumparin (i.e., as a combination therapy).

[0092] Reticulocyte levels are defined as the level of hemoglobin (Hb) in reticulocytes. In subjects with hematopoiesis, reticulocyte-hemoglobin (Ret-He) is one of the most sensitive indicators of hemoglobin and the efficiency of erythropoiesis. It reflects the amount of functional iron available for erythropoiesis in the short term, with high values ​​indicating favorable conditions for efficient erythropoiesis, and low values ​​indicating the opposite. Therefore, even small increases or decreases in Ret-He can significantly affect subsequent Hb levels and the resulting success or failure of anemia treatment (Auerbach M et al. 2015 Mayo Clin Proc. 2021;96(6): pp. 1510-1519; Mast E et al. 2008: Am J of Hematol;83: pp. 307-310).

[0093] Pharmaceutical Formulations and Routes of Administration The compound sebparin used according to the present invention can be administered as a pharmaceutical formulation. Suitable routes of administration are parenteral systemic administration, such as by subcutaneous administration, intravenous injection or infusion.

[0094] A further aspect of the present invention is that the compound sebparin, when used in accordance with the present invention, is administered orally.

[0095] For parenteral administration, the compound sebparin can be formulated into a solution or suspension, which may also contain one or more adjuvants, such as water for injection, saline, fixed oils, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents, antibacterial agents, antioxidants, chelating agents, buffers, and osmolality adjusters. Parenteral formulations can be provided as ampoules, vials, pre-filled or disposable syringes for self-administration, or infusion preparations for intravenous or subcutaneous infusion.

[0096] Pharmaceutical compositions useful for treating anemia according to the present invention may comprise sebumparin and at least one conventional pharmaceutically and pharmacologically acceptable excipient and / or carrier, which may be a solid, semi-solid, or liquid material that can act as a vehicle for the active ingredient. [Example]

[0097] Manufacture of Sebuparin The sebumparin used in accordance with the present invention can be prepared according to the synthetic procedures described in Examples 1-3 of published patent application WO2013 / 095276. In the following studies, cevparin was purchased from Modus Therapeutics, Sweden. Provided by AB as a 150 mg / mL solution.

[0098] Biological evaluation Kidney disease and anemia in kidney disease (KD) model mice All experimental procedures were approved by the Animal Care and Use Committee of the University of Brescia. All animals were maintained on a normal diet (Chow or standard diet, 4RF21, obtained from Mucedola srl) unless otherwise specified, as part of the "Anemia in a Mouse Model of Chronic Kidney Disease (CKD)" experiment described below. I raised it. Animals: C57BL / 6J male mice were purchased from Envigo RMS Srl. Renal impairment, kidney disease, and anemia were treated with an adenine-rich, phosphorus-rich diet (0.2% adenine, 0.9% phosphorus, 0.6% calcium, 20% casein, Cod. S1102-E750, purchased from Charles River, manufacturer: Ssniff) designated as the "adenine-rich diet" (ARD). The product was derived from Spezialdiaten GmbH.

[0099] ARD was administered to C57BL / 6J male mice at 5 weeks of age. Treatment, as described below, began at 5, 5, and 9 weeks after the initiation of ARD, at which point animals developed moderate and severe signs of renal injury, as evidenced by weight loss, anemia (defined as a decrease in hemoglobin concentration to approximately 12.5 g / dL or less), and elevated serum creatinine levels, as well as renal tissue damage assessed by macroscopic and microscopic examination. All animals were maintained on either ARD or a normal diet (standard diet, 4RF21, Mucedola srl) at the timing and extent described in the details of each experiment below. For each experiment, As a healthy control group, a group of mice was fed a normal diet (standard diet). All mice were allowed to eat freely.

[0100] Treatment Overview Adenine-rich diet (ARD) (0.2% adenine; 0.9% phosphorus; 0.6% calcium; 20% (Ssniff Spezialdiaten GmbH)), sebuparin 10 mg / kg (Opocrin SpA, Apotek Produktion & Labo) Inratorier AB, subcutaneous administration (sc), erythropoietin (EPO, darbepoetin alfa, Aranesp, AMGEN INC.) intraperitoneal administration (ip)

[0101] Blood and serum analysis Hematological parameters, hemoglobin (Hb) and hematocrit (Ht), were analyzed using a HemoVet device (Infratech) by drawing a drop of blood from the dorsalis pedis vein. Animal weights were monitored weekly in the morning at the start of treatment (P0), after 1 week of treatment (T1), 2 weeks of treatment (T2), 3 weeks of treatment (T3), 4 weeks of treatment (T4), 5 weeks of treatment (T5), 6 weeks of treatment (T6), 7 weeks of treatment (T7), 8 weeks of treatment (T8), and 9 weeks of treatment (T9).

[0102] Reticulocyte hemoglobin (Ret-He), serum hepcidin, and serum creatinine (analyzed by the Izler Institute) were analyzed at the end of each experiment.

[0103] Mice were sacrificed at predetermined time points, and blood and kidneys were collected for analysis at the endpoint of each experiment. At the endpoint, serum hepcidin in the mice was quantified using an ELISA kit (Cod. SKU# HMC-001; Intrinsic LifeScience).

[0104] Serum creatinine and blood reticulocyte-hemoglobin (Ret-He) were analyzed by the IZLER Institute (Istituto Zooprofilattico Sperimentale della Lombardia e Dell'Emilia Romagna) using standard procedures.

[0105] Histochemistry and immunostaining of paraffin-embedded kidney sections Kidney samples were formalin-fixed and paraffin-embedded, and representative sections were selected based on the quality of tissue preservation, as assessed by hematoxylin and eosin (H&E) staining.

[0106] Renal fibrosis was assessed using Sirius Red staining for collagen deposition using standard procedures and ImageJ software (Schneider, CA, Rasband, WS, & Eliceiri, KW). (2012), NIH Image to ImageJ: 25 years of image analysis. Nature Methods, 9(7), 671-675. doi:10.1038 / nmeth.2089), and also used the methodology of Ruifrok AC. et al. 2001 (Quantification of histochemical staining by color deconvolution; Anal Quant Cytol Histol. 2001;23(4): pp.291-299) and Landini G. et al. 2021 (Color deconvolution: stain unmixing in histological imaging. Bioinformatics. 2021;37(10): pp.1485-1487).

[0107] Sections were dewaxed, rehydrated, and washed in distilled water. Slides were then immersed in Sirius Red solution (picric acid solution and Sirius Red F33A-CROMA 1A 280) for 50 minutes, washed in tap water, and counterstained with Mayer's hematoxylin. Sections were then washed in tap water, dehydrated, and mounted.

[0108] Images were acquired at 20x or 40x magnification using a Nikon Eclipse 50i microscope equipped with a Nikon Plan lens mounted on a Nikon DS-Ri2 camera (4908 × 3264 full pixels) and NIS-Elements imaging software 4.3 (Nikon Corporation).

[0109] Kidneys (1 kidney / mouse) were stained with hematoxylin and eosin for routine examination and Sirius Red stained for collagen analysis. Four representative images and quantification of Sirius Red staining were performed using ImageJ software.

[0110] Four images (four separate fields) were acquired from each kidney at 20x magnification. Quantitation of each field was performed using ImageJ software, and the average of four fields per mouse was calculated. Data were analyzed and reported as two averages (one for each kidney analyzed) using GraphPad. Data were expressed as the percentage of positive area for staining. The test results (data) are presented as mean ± SD as dot plots, block charts, and data tables.

[0111] Treatment regimen for ARD-exposed mice Example 1 9 weeks of ARD pretreatment followed by 3 weeks of treatment with control or sebuparin C57BL / 6J male mice were exposed to 9 weeks of ARD pretreatment and then randomly assigned to treatment groups defined below for 3 weeks with continued ARD exposure: One group served as a healthy control group and was fed a normal diet (without ARD) throughout the experiment. a) Control treatment: Mice received PBS subcutaneously (sc) daily for 3 weeks. b) Sebuparin treatment: Mice received 10 mg / kg of sebuparin subcutaneously (sc) daily for 3 weeks.

[0112] result The hematological parameters hemoglobin (Hb), hematocrit (Ht), body weight, creatinine, reticulocyte hemoglobin, and hepcidin were analyzed and are summarized in Table 1A below.

[0113] [Table 2]

[0114] As shown in Table 1A, the following can be concluded: (i) Mice treated with sevparin for 3 weeks had increased blood hemoglobin levels compared with mice not treated with sevparin. These results are also shown in Figure 1A. (ii) Mice treated with sevparin for 3 weeks had increased hematocrit levels compared with mice not treated with sevparin. These results are also shown in Figure 1B. (iii) Mice treated with sebum for 3 weeks gained weight compared with mice not treated with sebum. These results are also shown in Figure 1C. (iv) Serum creatinine concentrations were elevated in mice treated with sevparin for 3 weeks compared with mice not treated with sevparin. These results are also shown in Figure 1D. (v) Mice treated with sevparin for 3 weeks had elevated blood reticulocyte hemoglobin (Ret-He) levels compared with mice not treated with sevparin. These results are also shown in Figure 1E. (vi) Serum hepcidin levels were reduced in mice treated with sebum for 3 weeks compared with mice not treated with sebum. These results are also shown in Figure 1F.

[0115] In addition, histochemistry and immunostaining of paraffin-embedded kidney sections were analyzed as described above. The physical condition of the rat kidney is shown in Figure 1G (magnification 20x). As can be seen from this figure, sebumparin significantly increased the amount of sebumparin in the photomicrographs of mouse kidneys compared to kidneys of mice not administered sebumparin. It had a positive impact.

[0116] Example 2 Nine weeks of ARD pretreatment followed by two weeks of treatment with control, sevparin, erythropoietin (EPO), or a combination of EPO and sevparin, followed by seven weeks of recovery with continued treatment without ARD. Male C57BL / 6J mice were pretreated with ARD for 9 weeks and then randomly assigned to treatment groups defined below for 2 weeks with continued ARD exposure. The ARD was then discontinued, and treatment continued for a 7-week recovery period. One group served as a healthy control and was fed a normal diet (without ARD) throughout the experiment. a) Control treatment: Mice received PBS subcutaneously (sc) daily for 2+7 weeks. b) Treatment with sebparin: Mice received 10 mg / kg sebparin subcutaneously (sc) daily for 2+7 weeks. c) Treatment with sebparin: Mice received 50 IU of EPO intraperitoneally (ip) twice a week for 2+7 weeks. d) Treatment with EPO+sebparin: Mice received 50 IU of EPO intraperitoneally (ip) twice a week and 10 mg / kg sebparin subcutaneously (sc) daily for 2+7 weeks.

[0117] The hemoglobin (Hb), hematocrit (Ht), body weight (wt), serum creatinine (S-crea), reticulocyte hemoglobin (Ret-He) content, and serum hepcidin (nM) of the mice were measured, and the results are shown in Table 2A below.

[0118] [Table 3]

[0119] As shown in Table 2A, the following can be concluded: (i) Blood hemoglobin (Hb) levels were elevated in mice treated with the combination of EPO and sevparin compared with untreated mice and mice treated with EPO alone. The EPO+sevparin combination therapy was superior to EPO monotherapy but slightly inferior to sevparin monotherapy. (ii) Hematocrit (Ht) was elevated in sebum-treated mice compared with untreated mice and mice treated with EPO alone. EPO + sebum-treated mice were superior to EPO alone, but slightly inferior to sebum-treated mice. (iii) Body weight (wt) increased in mice treated with sebumparin compared with untreated mice, but mice treated with EPO alone gained slightly more weight. Mice treated with EPO and sebumparin gained more weight than mice treated with sebumparin alone. (iv) Serum creatinine levels (s-Crea) were lower in mice treated with sevparin than in untreated mice. Serum creatinine levels were also reduced in mice treated with EPO alone, but the reduction was less pronounced than in mice treated with sevparin alone. Combination therapy with EPO and sevparin was even more beneficial in terms of serum creatinine levels. (v) The blood concentration of reticulocyte hemoglobin (Ret-HE) was increased in mice treated with sebumparin compared with untreated mice. However, EPO monotherapy and EPO + sebumparin combination therapy were inferior to sebumparin monotherapy. (vi) Serum hepcidin levels were significantly reduced in both sebparin and EPO monotherapy, whereas EPO+sebparin combination therapy elevated serum hepcidin levels.

[0120] The physical condition of the mouse kidneys was also examined, as shown in Figure 2A. Macroscopic photographs of kidneys from mice treated with sebumparin or sebumparin plus EPO showed significantly fewer cysts, a more normal color, and a more homogeneous appearance compared with kidneys from mice that had not received the same treatment.

[0121] Furthermore, as shown in Figure 2B, histological analysis of mouse kidneys confirmed the above macroscopic observations (40x magnification). Dietary adenine induced severe organ damage after 11 weeks of dietary adenine administration compared with the normal diet group. H&E staining revealed features of tubulointerstitial damage and adenine crystal deposition in tissues from adenine-treated animals. Administration of sebumparin and EPO reduced the damage compared with the untreated control group.

[0122] Sirius red staining (40x magnification) in Figure 2B confirmed collagen deposition after the adenine diet, shown as red fibers, indicating fibrosis. Sebuparin administration demonstrated a reduction in collagen deposition, an indicator of fibrosis, in kidney tissue compared with groups treated with PBS, sebumparin, or the combination of EPO and sebumparin (AD11 week + PBS).

[0123] This study demonstrated that sevparin monotherapy and sevparin plus EPO combination therapy protect the kidney from renal injury and fibrosis, thereby reducing the risk of renal failure.

[0124] Example 3 5.5 weeks of ARD conditioning followed by 3 or 6 weeks of control, sevparin, erythropoietin (EPO), or a combination of EPO and sevparin.

[0125] Male C57BL / 6J mice were pretreated with ARD for 5.5 weeks and then randomly assigned to treatments defined below for 3 or 6 weeks with maintenance ARD exposure. Healthy controls were fed a normal diet (no ARD) throughout the experiment.

[0126] a) Control treatment: Mice received PBS subcutaneously (sc) daily for 3 and 6 weeks. b) Treatment with sevparin: Mice were treated with 10 mg / kg sevparin for 3 and 6 weeks. The drug was administered subcutaneously (sc) daily for 14 days. c) EPO treatment: mice were given 50 IU EPO intraperitoneally (ip) twice a week for 3 weeks, and mice were given 50 IU EPO intraperitoneally (ip) twice a week for 3 weeks followed by 25 IU EPO intraperitoneally (ip) once a week for another 3 weeks. d) EPO + sebuparin treatment: Mice received 10 mg / kg sebuparin subcutaneously (sc) daily and 50 IU EPO intraperitoneally (ip) twice a week for 3 weeks. and 10 mg / kg sebuparin administered subcutaneously (sc) daily, and 50 IU EPO administered twice weekly. After 3 weeks of intraperitoneal (ip) administration, mice received 10 mg / kg sebuparin subcutaneously daily along with 25 IU EPO intraperitoneally once a week for 3 weeks.

[0127] Hemoglobin (Hb), hematocrit (Ht), body weight (wt), serum creatinine (S-crea), reticulocyte hemoglobin (Ret-He) content, and serum hepcidin (nM) were measured in the mice. The results are shown in Table 3A below and Figures 3A and 3B.

[0128] [Table 4]

[0129] As shown in Table 3A, the following can be concluded: (i) The blood concentration of hemoglobin (Hb) increased in mice treated with EPO and sebum, but not in mice treated with sebum alone or EPO alone. (ii) The hematocrit (Ht) increased in mice treated with EPO and sebum, but not in mice treated with sebum alone or EPO alone. (iii) Body weight (wt) increased in mice administered EPO and sebum in combination, but not in mice administered sebum alone or EPO alone. (iv) Serum creatinine levels (s-Crea) were lower in mice treated with sevparin than in untreated mice. Serum creatinine levels were also lower in mice treated with EPO and sevparin, but increased in mice treated with EPO alone. (v) In mice treated with EPO and sebparin, the reticulocyte hemoglobin (Re) The blood concentration of t-HE increased.

[0130] Hepcidin serum levels were also measured at 3 and 6 weeks of treatment, and the results are shown in Figures 3A and 3B. As can be seen in the graph at 3 weeks (Figure 3A), sebparin monotherapy, EPO monotherapy, and combination therapy all had a beneficial effect on hepcidin serum levels. However, by 6 weeks of treatment (Figure 3B), the beneficial effect on hepcidin serum levels was no longer observed compared to control, but the anemia-improving effect of EPO + sebparin combination therapy remained stable. This indicates that by this time point, combination therapy can treat anemia without directly reducing hepcidin. This is supported by the fact that Ret-He values ​​remained elevated in the EPO + sebparin combination group, whereas they decreased in the EPO monotherapy group. This suggests a decrease in functional iron availability and therefore a decrease in erythropoietic efficiency.

Claims

1. The compound sebumparin or a pharmaceutically acceptable salt thereof for use in the treatment of chronic kidney disease (CKD).

2. The compound sebparin for use according to claim 1, wherein said chronic kidney disease (CKD) comprises renal impairment.

3. The compound sebparin for use according to claim 2, wherein said renal damage comprises inflammation.

4. The compound sebparin for use according to claim 2 or 3, wherein said chronic kidney disease (CKD) comprises fibrosis.

5. The compound sebumparin for use according to any one of claims 1 to 4, wherein the chronic kidney disease (CKD) comprises renal dysfunction that is a CKD glomerular filtration rate (GFR) of G2, G3a, G3b, or G4 as defined by the National Kidney Foundation.

6. The compound sebparin for use according to any one of claims 1 to 5, wherein the subject suffering from chronic kidney disease (CKD) is at risk of developing renal failure.

7. The compound sebparin for use according to any one of claims 1 to 4, wherein said subject suffering from chronic kidney disease (CKD) has renal failure.

8. The compound sebparin for use according to any one of claims 1 to 7, wherein said chronic kidney disease (CKD) comprises anemia.

9. The compound sebparin for use according to claim 8, wherein said anemia is anemia of chronic disease (ACD).

10. The compound sebparin for use according to claim 8 or 9, wherein said anemia is renal anemia.

11. The compound sebparin for use according to any one of claims 1 to 10, wherein said sebparin is used in combination therapy with a drug used as standard of care (SOC) therapy for chronic kidney disease (CKD).

12. The compound sebparin for use according to claim 11, wherein erythropoiesis stimulating agents (ESAs) are used as standard of care (SOC) therapy.

13. The compound sebparin for use according to claim 12, wherein said erythropoiesis stimulating agent (ESA) is erythropoietin (EPO).

14. 13. The erythropoietin (EPO) of claim 13, wherein the erythropoietin is selected from any one of erythropoietin α; erythropoietin β; erythropoietin ε; erythropoietin γ; erythropoietin κ; erythropoietin ω; erythropoietin θ; and erythropoietin ζ. The compound sebparin for use as described in claim 1.

15. The compound sebparin for use according to claim 11, wherein HIF prolyl hydroxylase inhibitors are used as standard of care (SOC) therapy.

16. 2. The method of claim 1, wherein the HIF prolyl hydroxylase inhibitor is selected from roxadustat, vadadustat, daprodustat, enarodustat, and molidustat. Item 16. The compound sebparin for use according to item 15.

17. The compound sebparin for use according to any one of claims 11 to 16, wherein said combination therapy is an add-on therapy.

18. The compound sebparin for use according to any one of claims 11 to 16, wherein said compound sebparin and said agent used as standard of care (SOC) therapy are co-administered.

19. The compound sebparin for use according to any one of claims 11 to 16, wherein said compound sebparin and said agent used as standard of care (SOC) therapy are administered simultaneously, separately or sequentially.

20. The compound sebparin for use according to any one of claims 1 to 19, wherein the use is for a subject in whom a sufficient therapeutic effect is not obtained by monotherapy with an erythropoiesis stimulating agent (ESA).

21. The compound sebparin for use according to any one of claims 1 to 20, wherein the therapeutic effect of sebparin is independent of the serum level of hepcidin.

22. The compound sebparin for use according to any one of claims 1 to 21, wherein said use is for restoring responsiveness to erythropoietin (EPO) in a subject with anemia.

23. The compound sebparin for use according to any one of claims 1 to 22, wherein said chronic kidney disease (CKD) is present in elderly subjects.

24. The compound sebparin for use according to any one of claims 1 to 23, wherein anemia is present in elderly subjects.

25. The compound sebparin for use according to any one of claims 1 to 24, wherein said use is for increasing serum levels of hemoglobin.

26. Use of the compound sebumparin for the manufacture of a drug for the treatment of chronic kidney disease (CKD).

27. A method for treating chronic kidney disease (CKD) comprising administering a therapeutically effective amount of the compound sebumparin or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.

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