Management of iron deficiency in patients at risk of cardiovascular adverse events

Abstract

To provide medicaments for treating iron deficiency in subjects at risk for adverse cardiovascular events.SOLUTION: Provided is a medicament for treating iron deficiency to reduce the incidence or risk of cardiovascular death and / or hospitalization due to worsening congestive heart failure (CHF) in a subject with a history of CHF, the medicament comprising an effective amount of iron isomaltoside.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the field of treatment of iron deficiency by intravenous administration of iron-carbohydrate complexes in subjects at risk of cardiovascular adverse events. [Background technology]

[0002] Iron deficiency (ID) impairs the body's ability to produce hemoglobin, a vital oxygen carrier, and also impairs the function of essential energy-producing enzymes (ATP). As a result, symptoms include fatigue and other signs of energy deficiency, such as rapid heartbeat, shortness of breath, and chest pain.

[0003] Iron deficiency anemia (IDA) develops when iron stores are depleted. IDA is widespread; according to the WHO, approximately one billion people worldwide suffer from IDA. Daily oral iron supplementation is the most important treatment for the majority of IDA patients, but it often fails due to poor adherence, insufficient effectiveness, and side effects.

[0004] High-dose intravenous (IV) iron administration is an attractive treatment option. Patients typically require 1–3 grams of iron per year, and high-dose IV iron administration effectively and rapidly improves symptoms and increases hemoglobin levels. High-dose IV iron administration can be administered in one or a few visits, and it is the only option for patients who fail oral iron administration.

[0005] Isomaltoside 1000 (INN: ferric deluisomaltose) belongs to the new generation of high-dose intravenous iron administration products. While conventional low-dose products (ferric gluconate and sucrose iron) require 5 to 20 hospital visits, these new generation products allow for iron correction in just one or two hospital visits through rapid intravenous infusion.

[0006] Iron isomaltoside is a commonly used iron-carbohydrate complex for patients with intradialysis-dependent nephropathy (IDA) who (i) are intolerant to oral iron administration, or have had an unsatisfactory response to oral iron administration, or have a clinical need for rapid replenishment of iron stores; or (ii) to treat patients with non-dialysis-dependent chronic kidney disease (NDD-CKD); or to treat dialysis-related ID in patients with chronic kidney disease. It is marketed in the European Union and many other countries under the trade names Monofer®, Monoferric®, and Diafer®. Typical treatment regimens for iron isomaltoside consist of either a single intravenous infusion of 1000 mg of iron, an elemental iron dose of up to 20 mg iron / kg body weight given as an intravenous infusion, or a dose of up to 500 mg as an intravenous bolus injection up to three times per week, and cumulative iron should be determined using the Ganzoni formula or one of the following tables. TIFF0007897915000001.tif27170

[0007] Intravascular disease (ID) has serious consequences. In patients with chronic heart failure (CHF), those with ID have been reported to have an increased risk of death or hospitalization compared to patients with normal iron levels. Quality of life (QoL) is significantly affected and improves rapidly when iron stores are restored. For example, in an open-label, uncontrolled design with a fairly small sample size of 20 frail elderly CHF patients, a single rapid intravenous infusion of 1000 mg of iron isomaltoside was administered at a relatively high dose, without an initial test dose, and showed very good tolerability and improved QoL. Hildebrandt et al., 2010.

[0008] The collected experimental and clinical evidence provides evidence to support the idea that iron maltose (ID) is a potential therapeutic target in patients with chronic heart failure (chronic HF). In fact, several studies in recent years, including the FAIR-HF trial (Assessment of carboxymaltose ferric in patients with iron deficiency and chronic heart failure, see also Anker et al., 2009) and the CONFIRM-HF trial (Performance evaluation of carboxymaltose ferric in patients with a combination of iron deficiency and chronic heart failure, see also Ponikowski et al., 2015), which involved more than 450 and more than 300 patients, respectively, have investigated the efficacy of intravenous iron administration in iron-deficient patients with chronic HF. Based on aggregated data, Jankowska et al. (2016) conducted a meta-analysis of five randomized controlled trials evaluating the effects of intravenous iron therapy (using sucrose or ferric carboxymaltose) in iron-deficient patients with systolic HF (HFrEF). They stated that there is evidence that intravenous iron therapy in iron-deficient patients with systolic HF improves outcomes, alleviates HF symptoms, improves exercise capacity and quality of life, and reduces the risk of hospitalization due to HF. However, the mortality rate and incidence of adverse events (AEs) were similar across the five studies included in the meta-analysis.

[0009] Attempts have also been made to explore, from a mechanistic perspective, how iron supplementation provides benefits to CHF, particularly where Hb changes are minimized. For example, in a randomized, double-blind, placebo-controlled trial, a single full-dose infusion of 1000mg of iron isomaltoside was shown to replenish iron stores and increase skeletal muscle energetics two weeks after infusion. Charles-Edwards et al., 2019. Based on data from the same randomized, double-blind trial, in iron-deficient CHF patients with left ventricular ejection fraction (LVEF) ≤ 45%, a single full-dose infusion of 1000mg of iron isomaltoside was observed to replenish iron and reduce P-wave variability. Jaumdally et al., 2019.

[0010] However, none of the intravenous iron administration trials facilitated further research on the effects on key cardiovascular outcomes. Therefore, the 2016 ESC guidelines for the diagnosis and management of acute and chronic heart failure concluded that the benefits of treating iron deficiency in HFpEF / HFmrEF are unknown. Based on findings from FAIR-HF and CONFIRM-HF, the European Society of Cardiology (ESC) guidelines recommend considering intravenous ferric carboxymaltose administration in patients with iron deficiency (serum ferritin <100 μg / L, or ferritin between 100 and 299 μg / L and transferrin saturation <20%) to alleviate HF symptoms and improve exercise capacity and quality of life. Ponikowski et al., 2016. Similarly, the American College of Cardiology (ACC), the American Heart Association (AHA) Task Force on Clinical Practice Guidelines, and the Heart Failure Society of America (HSFA) recommend that intravenous iron replacement may be appropriate to improve functional status and quality of life in patients with New York Heart Association (NYHA) class II and III HF and iron deficiency (ferritin <100 ng / mL, or 100-300 nm / mL if transferrin saturation is less than 20%). Yancy et al., 2017.

[0011] Based on this understanding, it is clearly necessary to provide methods for treating iron deficiency that not only replenish iron stores but also offer benefits to patients regarding the management of chronic heart failure. [Overview of the project]

[0012] In one aspect of this invention, iron deficiency is treated in subjects at risk of cardiovascular adverse events. Accordingly, subjects are selected for treatment with iron isomaltoside not only based on the criteria commonly used to define eligibility for parenteral iron administration, namely, a diagnosis of ID or IDA, and / or a potential lack of ability to tolerate or absorb oral iron, but also on the risk of experiencing cardiovascular adverse events.

[0013] In a second aspect of this invention, treatment of iron deficiency reduces the incidence or risk of cardiovascular adverse events in subjects. Accordingly, subjects selected for treatment with iron isomaltoside based on the criteria commonly used to define eligibility for parenteral iron administration, namely a diagnosis of ID or IDA, and / or a potential lack of ability to tolerate or absorb oral iron, and on the risk of experiencing cardiovascular adverse events, benefit from the reduction in the incidence or risk of cardiovascular adverse events in the subjects.

[0014] A third aspect of the present invention relates to treatments for specific groups of subjects as defined herein that reduce the incidence or risk of cardiovascular adverse events as defined herein.

[0015] In accordance with these embodiments, the present invention particularly relates to a therapeutic method for treating iron deficiency, comprising administering to a selected subgroup of subjects a combination of iron isomaltoside and iron isomaltoside 1000 and other drugs which are used to treat subjects at risk of cardiovascular adverse events or increase the risk of such cardiovascular adverse events.

[0016] In the first embodiment described above, the present invention relates to a method for treating iron deficiency in a person at risk of cardiovascular adverse events, comprising administering an effective amount of iron isomaltoside.

[0017] In a plurality of embodiments of the first aspect, the subject at risk of cardiovascular adverse events is a subject having one or more of the following risk factors: (i) Subjects having a history of myocardial infarction (MI), particularly STEMI or non-STEMI; (ii) Subjects having a history of stroke; (iii) Subjects having a history of atrial fibrillation (AF), particularly newly diagnosed AF, paroxysmal AF, or persistent AF; (iv) Subjects having a history of congestive heart failure, particularly heart failure with reduced ejection fraction (HFrEF); (v) Subjects having a history of heart valve disorder; (vi) Subjects having a history of hypertension; (vii) Subjects having diabetes; (viii) Subjects having a history of obesity; (ix) Elderly subjects, particularly subjects 60 years or older, 65 years or older, 70 years or older, 75 years or older, or 80 years or older; (x) Smokers; (xi) Drinkers; (xii) Subjects having hyperthyroidism and / or related thyrotoxicosis; (xiii) Subjects having chronic obstructive pulmonary disease (COPD); (xiv) Subjects having cardiomyopathy, particularly genetic cardiomyopathy or acquired cardiomyopathy; (xv) Subjects having systemic inflammation without infection, wherein the systemic inflammation is particularly related to an increase in C-reactive protein (CRP) exceeding a range of about 2-3 mg / L; (xvi) Subjects undergoing dialysis, particularly hemodialysis or peritoneal dialysis; (xvii) Subjects treated with one or more of the following: a) Modulators of the hypoxia-inducible factor (HIF) signaling pathway, including prolyl hydroxylase inhibitors such as daprodustat, vadadustat, roxadustat, molidustat, and desidusta; b) Erythropoiesis-stimulating agents (ESAs), such as erythropoietin (Epo), epoetin alfa (Procrit / Epogen), epoetin beta (NeoRecormon), darbepoetin alfa (Aranesp), and methoxypolyethylene glycol-epoetin beta (Mircera); and c) Hepcidin modulators, e.g., hepcidin agonists or hepcidin antagonists; (xviii) Subjects treated with anticoagulants and / or NSAIDs; (xix) Subjects with hereditary hemorrhagic capillary dilation; or (xx) Subjects with hereditary iron-refractory iron deficiency anemia.

[0018] In a particular embodiment of the first aspect described above, the present invention relates to a method for treating iron deficiency in a subject having a history of congestive heart failure (CHF), comprising administering an effective amount of iron isomaltoside. According to one embodiment, the subject also has a history of myocardial infarction (MI) and / or stroke. According to a preferred embodiment, the CHF is heart failure with reduced ejection fraction (HFrEF).

[0019] In a further specific embodiment of the first embodiment, subjects at risk of cardiovascular adverse events or with a history of congestive heart failure have chronic kidney disease (CKD). In another specific embodiment of the first embodiment, subjects at risk of cardiovascular adverse events or with a history of congestive heart failure do not have chronic kidney disease (CKD). In another specific embodiment of the first embodiment, subjects at risk of cardiovascular adverse events have chronic kidney disease (CKD) and have a history of congestive heart failure (CHF).

[0020] According to one embodiment, a subject with a history of congestive heart failure has HFrEF. According to another embodiment, a subject with a history of congestive heart failure has congestive heart failure in New York Heart Association (NYHA) class II to IV, and in particular, HFrEF type congestive heart failure in New York Heart Association (NYHA) class II to IV.

[0021] In the embodiment of the second aspect described above, the present invention relates to a method for treating iron deficiency in a subject at risk of cardiovascular adverse events, wherein the treatment of iron deficiency reduces the incidence or risk of cardiovascular adverse events in the subject, and the method comprises administering an effective amount of iron isomaltoside.

[0022] In one embodiment of the second aspect described above, the cardiovascular adverse events whose incidence or risk is reduced are selected from the group consisting of events affecting the heart (cardiac adverse events); events affecting the peripheral vascular system (peripheral vascular adverse events); events affecting the cerebrovascular system (cerebrovascular adverse events); respiratory, thoracic, and mediastinal adverse events; general adverse events; and infections and invasiveness. According to one embodiment, cardiac adverse events are selected from the group consisting of congestive heart failure, atrial fibrillation, cardiac arrest, atrial block, heart failure, sinoatrial node dysfunction, acute myocardial infarction, bradycardia, angina pectoris, myocardial ischemia, and ventricular premature contractions; peripheral vascular adverse events are selected from the group consisting of hypertension, elevated systolic blood pressure, elevated blood pressure, elevated troponin, and hypotension; cerebrovascular adverse events are selected from the group consisting of cerebrovascular incidental symptoms, cerebral infarction, and transient ischemic attack; respiratory, thoracic, and mediastinal adverse events are selected from the group consisting of dyspnea and pulmonary edema; general adverse events are selected from the group consisting of chest pain and death; and infection and invasiveness are septic shock.

[0023] In a preferred embodiment of this second aspect of the present invention, the cardiovascular adverse events whose incidence or risk is reduced are selected from the group consisting of events affecting the heart (cardiac adverse events); events affecting the peripheral vascular system (peripheral vascular adverse events); events affecting the cerebrovascular system (cerebrovascular adverse events); and death. According to the preferred embodiment, events affecting the heart (cardiac adverse events) are congestive heart failure, myocardial infarction, unstable angina, and arrhythmias; events affecting the peripheral vascular system (peripheral vascular adverse events) are hypertension; and events affecting the cerebrovascular system (cerebrovascular adverse events) are stroke.

[0024] In a particularly preferred embodiment of this second aspect of the present invention, the cardiovascular adverse events whose incidence or risk is reduced are selected from the group consisting of congestive heart failure, myocardial infarction, unstable angina, arrhythmia, hypertension, hypotension, stroke, and death.

[0025] In a further particularly preferred embodiment of this second aspect of the present invention, the cardiovascular adverse events whose incidence or risk is reduced are congestive heart failure, atrial fibrillation, hypertension, and / or cardiac arrest.

[0026] According to one embodiment, a specific cardiovascular adverse event related to congestive heart failure is hospitalization or death due to congestive heart failure. According to another embodiment, a specific cardiovascular adverse event related to congestive heart failure is hospitalization due to exacerbation of congestive heart failure. The present invention particularly focuses on cardiovascular adverse events in which the cardiovascular adverse event is CHF.

[0027] In the embodiment of the third aspect described above, the present invention relates to a method for treating iron deficiency in a subject, wherein the treatment of iron deficiency reduces the incidence or risk of cardiovascular adverse events in the subject, and the method comprises administering an effective amount of iron isomaltoside. The target is, (A) Patients at risk of cardiovascular adverse events; (B) Subjects with a history of congestive heart failure (CHF); or (C) Patients with a history of congestive heart failure (CHF) and at risk of cardiovascular adverse events. And, Cardiovascular adverse events whose incidence or risk is reduced, (a) congestive heart failure, myocardial infarction, unstable angina, arrhythmia, hypertension, hypotension, stroke, and death; (b) Congestive heart failure; (c) Atrial fibrillation; (d) hypertension; or (e) cardiac arrest This relates to a method of selecting from a group consisting of the following.

[0028] In a preferred embodiment of this third aspect of the present invention, the subjects are at risk of cardiovascular adverse events, and the cardiovascular adverse event whose incidence or risk is reduced is congestive heart failure.

[0029] In a more preferred embodiment of this third aspect of the present invention, the subject is at risk of a cardiovascular adverse event, the cardiovascular adverse event whose incidence or risk is reduced is atrial fibrillation.

[0030] In a more preferred embodiment of this third aspect of the present invention, the subject is at risk of a cardiovascular adverse event, the cardiovascular adverse event whose incidence or risk is reduced is cardiac arrest.

[0031] In a more preferred embodiment of this third aspect of the present invention, the subject is a subject with a history of congestive heart failure, and the cardiovascular adverse event for which the incidence or risk is reduced is cardiac arrest, congestive heart failure, or both.

[0032] In a more preferred embodiment of this third aspect of the present invention, the subject is a subject with a history of congestive heart failure (CHF), and the cardiovascular adverse event for which the incidence or risk is reduced is atrial fibrillation.

[0033] In a more preferred embodiment of this third aspect of the present invention, the subject is a subject with a history of congestive heart failure (CHF), and the cardiovascular adverse event for which the incidence or risk is reduced is cardiac arrest.

[0034] In a particular embodiment of this third aspect of the present invention, the subjects as defined herein are subjects at risk of cardiovascular adverse events and / or have a history of congestive heart failure, and the subjects have chronic kidney disease (CKD).

[0035] In another specific embodiment of this third aspect of the present invention, the subjects as defined herein are subjects at risk of cardiovascular adverse events and / or congestive heart failure, and the subjects do not have chronic kidney disease (CKD).

[0036] In these embodiments, chronic kidney disease (CKD) is preferably non-disruptive chronic kidney disease (NDD-CKD).

[0037] In a more preferred embodiment of this third aspect of the present invention, the subject having a history of congestive heart failure has HFrEF, congestive heart failure in NYHA class II-IV, or both.

[0038] In a particularly preferred embodiment of this third aspect of the present invention, the cardiovascular adverse event whose incidence or risk is reduced is cardiovascular death and / or hospitalization resulting from the exacerbation of congestive heart failure.

[0039] According to the present invention, iron deficiency is preferably defined as TSAT < 20% and / or ferritin < 100 μg / L. In one embodiment of the present invention, iron deficiency is iron deficiency anemia.

[0040] In further embodiments of the present invention, the subject to be treated has chronic iron deficiency or malabsorption. In further embodiments of the first embodiment, the subject is one who does not tolerate or for whom oral iron administration is ineffective.

[0041] The iron-carbohydrate complex preferred for use in the present invention is iron isomaltoside, particularly ferric delisomaltose (sometimes called ferric delisomaltoside). [Brief explanation of the drawing]

[0042] [Figure 1] This table summarizes the analysis of the incidence of composite cardiovascular (CV) adverse events that occurred as a result of treatments that were judged and confirmed to have an incidence of 0.25% or higher under favorable conditions in the CKD-04 trial, the IDA-03 trial, and the CKD-04 / IDA-03 combination trial. [Figure 2] This table summarizes the analysis of congestive heart failure adverse events resulting from treatment in the CKD-04 trial, IDA-04 trial, and CKD-04 / IDA-03 combination trial in all patients, patients with or without CHF, or patients at risk of cardiovascular complications. [Figure 3] This table summarizes the analysis of congestive heart failure adverse events (logistic regression) occurring with treatment in the CKD-04 trial and the CKD-04 / IDA-03 combination trial, comparing treatment with iron isomaltoside versus iron sucrose, in patients at cardiovascular risk with or without a history of CHF. [Figure 4] This graph shows the percentage of patients who experienced a composite cardiovascular adverse event caused by a specific treatment (iron isomaltoside 1000: left bar, iron sucrose: right bar). [Figure 5] This graph shows the percentage of patients who experienced CHF adverse events as a result of the treatment (combination of CKD-04 and IDA-03; iron isomaltoside 1000: left bar, iron sucrose: right bar). [Figure 6] This is a Kaplan-Meier diagram showing the probability of a determined composite adverse cardiovascular event (CKD-04). [Figure 7] This graph shows the change from baseline in hemoglobin (g / dL) in patients with CHF in the medical history of the CKD-04 / IDA-03 combination study (iron isomaltoside 1000: dashed line, iron sucrose: solid line). [Figure 8] This graph shows the change from baseline in ferritin (ng / mL) in patients with CHF in the medical history of the CKD-04 / IDA-03 combination study (iron isomaltoside 1000: dashed line, iron sucrose: solid line). [Figure 9] This graph shows the change from baseline in TSAT (%) of patients with CHF in their medical history during the CKD-04 / IDA-03 combination study (iron isomaltoside 1000: dashed line, iron sucrose: solid line). [Figure 10] This graph shows the percentage of patients who experienced a combined cardiovascular adverse event (CV) after treatment with IIM1000, Venofer, and FCM (combination study of CKD-04 / IDA-03 against IIM1000 (Ferwon study); study using Venofer and FCM based on FDA CDER report on Injectafer). [Figure 11] This table summarizes the analysis of adverse events in the CKD-04, IDA-03, and CKD-04 / IDA-03 combination studies (Ferwon study) using IIM1000, compared with studies using Venofer and FCM (FDA CDER report on Injectafer). [Modes for carrying out the invention]

[0043] To make this description easier to understand, certain terms are defined first. Additional definitions will be explained throughout the descriptions of the modes for carrying out the invention.

[0044] "Treatment" or "treatment" of a subject means any type of treatment or process performed on the subject, or administration of an activator to the subject, with the aim of reversing, alleviating, restoring, inhibiting, slowing, or preventing the onset, progression, manifestation, severity, or recurrence of symptoms, complications, conditions, or biochemical signs related to the disease.

[0045] The “subject” may be any human or non-human animal. The term “non-human animal” includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In preferred embodiments, the subject is human. The terms “subject” and “patient” are used interchangeably herein.

[0046] The “therapeutic effective dose” or “therapeutic effective amount” of a drug or therapeutic agent is any amount of the drug, when used alone or in combination with another therapeutic agent, that is evidenced by protection against disease onset, promotion of disease regression, reduction of symptom severity, increase in frequency and duration of symptom-free periods, or prevention of disability or incapacity resulting from the distress of the disease. The ability of a therapeutic agent to promote disease regression can be evaluated by a variety of methods known to practitioners skilled in the art, such as using subjects in clinical trials in humans, predictive model systems of efficacy in humans in animals, or assays of drug activity in in vitro assays.

[0047] For the purposes of this document, when specifying doses of iron-carbohydrate complexes in mg or g, in accordance with literature convention, the values ​​refer to the amount of elemental iron provided in mg or g.

[0048] A. Iron-carbohydrate complex This invention describes a therapeutic method for treating iron deficiency, comprising administering an iron-carbohydrate complex and a combination of the iron-carbohydrate complex and an additional drug, wherein the iron-carbohydrate complex has certain properties that thereby exert a certain effect on the subject under treatment. Accordingly, the method of the present invention can be applied to complexes that share a common mechanism of action. For example, an iron-carbohydrate complex should not induce a significant increase in iFGF23 (undamaged FGF23). In particular, carboxymaltose ferric (FCM) significantly increases iFGF23 (see, e.g., WO2013 / 134273A1), but clinical trial results provide evidence that iron isomaltoside 1000 (Monofer®) increases iFGF23 and that the risk of causing an iFGF23-mediated effect is low. See, e.g., Wolf et al., 2019.

[0049] Therefore, the preferred iron-carbohydrate complex of this invention is iron isomaltoside (IIM). As used herein, the term "iron isomaltoside" refers to a colloidal complex comprising iron, for example, iron oxyhydroxylate, and iron as isomaltoside in a matrix-like structure. As used herein, the term "isomaltoside" refers to hydrogenated oligoisomaltose (oligoisomaltoside).

[0050] In certain embodiments, the isomaltoside has a weight-average molecular weight M of 500-7,000 Da, for example, 500-3,000 Da, 700-1,400 Da, and especially about 1,000 Da. W It is a mixture of hydride polysaccharides / oligosaccharides having the following characteristics: The number average molecular weight (M) of such hydride polysaccharides / oligosaccharides. nThe molecular weight of the molecules is preferably in the range of 400 to 1,400 Da, with 90% by weight of these molecules having a molecular weight of less than 3,500 Da, particularly less than 2,700 Da, and the molecular weight of the remaining 10% of the molecules being less than 4,500 Da, particularly less than 3,200 Da. For example, the hydrogenated polysaccharide / oligosaccharide is hydrogenated polyglucose, oligoglucose, or a mixture thereof, for example, hydrogenated dextran, hydrogenated dextrin, or hydrogenated oligoisomaltose (oligoisomaltoside), and hydrogenated oligoisomaltose, particularly hydrogenated oligoisomaltose in which the majority of the molecule (e.g., at least 60%, e.g., 70-80%) has 3 to 6 monosaccharide units, is preferred. Therefore, in preferred embodiments of the present invention, the iron-carbohydrate complex is iron(III) hydrogenated oligoisomaltose, in particular iron(III) hydrogenated oligoisomaltose, such as iron(III) oligoisomaltoside 1000 (INN name: ferric isomaltose), in which the majority of the oligoisomaltoside molecules (e.g., at least 60%, e.g., 70-80%) have 3-6 monosaccharide units. Iron isomaltosides are typically characterized by strong colloidal complexes of iron oxyhydroxide and hydrogenated isomaltose (isomaltoside) chains, which gradually release iron.

[0051] In the specific embodiments described above, the dimer sugar content of the hydride polysaccharide / oligosaccharide is preferably 2.9% by weight or less, 2.5% by weight or less, or 2.3% by weight or less, particularly 2.1% by weight or less, or 1.5% by weight or less, most preferably 1.0% by weight or less, based on the total weight of the hydride polysaccharide / oligosaccharide. Preferably, the hydride polysaccharide / oligosaccharide preparation used to prepare the iron carbohydrate complex of the present invention has a monomer sugar content of 0.5% by weight or less. The iron hydrogenated dextran complex prepared from such a hydride polysaccharide / oligosaccharide preparation typically has an apparent molecular weight (M) in the range of 120,000 to 180,000 Da, particularly 130,000 to 160,000 Da. p) and has. Before contacting the hydrogenated polysaccharide / oligosaccharide preparation with the iron preparation, the preparation can be purified by a membrane process to remove high molecular weight hydrogenated polysaccharides and / or low molecular weight hydrogenated polysaccharides. In certain embodiments, the hydrogenated polysaccharide / oligosaccharide preparation is purified by one or more membrane processes having a cut-off value between 340 Da and 800 Da. In even more specific embodiments, the hydrogenated polysaccharide / oligosaccharide preparation is purified by one or more membrane processes using a membrane having a cut-off value capable of blocking polysaccharides having a molecular weight greater than 2,700 Da, optionally followed by further hydrolysis, and subsequently performing one or more membrane processes using a membrane having a cut-off value between 340 Da and 800 Da. Alternatively, the purification by the membrane process is performed before hydrogenation.

[0052] In a particularly preferred embodiment, the iron isomaltoside of the present invention has the formula: Containing H2O {FeO (1-3X) (OH) (1+3X) (C6H5O7 3- ) X},(C6H 10 O6) R (-C6H 10 O5-) Z (C6H 13 O5) R ,(MeCl) Y [wherein, X is 0.0311 ± 0.0062, particularly 0.0311 ± 0.0031; R is 0.1400 ± 0.0420, particularly 0.1400 ± 0.0210; Z is 0.4900 ± 0.1470, particularly 0.4900 ± 0.0735; Y is 0.1400 ± 0.0130, particularly 0.1400 ± 0.0065; Me is a monovalent metal ion, such as a sodium ion or a potassium ion, preferably a sodium ion] and is a compound having.

[0053] In a further particularly preferred embodiment, the iron complex compound of the present invention is given by formula: {FeO (1-3X) (OH) (1+3X) (C6H5O7 3- ) X},(H2O) T ,(C6H 10 O6) R (-C6H 10 O5-) Z (C6H 13 O5) R (MeCl) Y [In the formula, X is 0.0311 ± 0.0062, and in particular 0.0311 ± 0.0031; T is 0.2500 ± 0.1250, and in particular 0.2500 ± 0.24750; R is 0.1400 ± 0.0420, and in particular 0.1400 ± 0.0210; Z is 0.4900 ± 0.1470, and in particular 0.4900 ± 0.0735; Y is 0.1400 ± 0.0130, and in particular 0.1400 ± 0.0065; Me is a monovalent metal ion, such as a sodium ion or a potassium ion, preferably a sodium ion. It is a compound that has [a certain characteristic].

[0054] In certain embodiments, the iron complex has an iron content of 23–39% by weight (determined for the dry material) and optionally exists in the form of an injectable solution having about 100 mg / ml.

[0055] Iron isomaltosides are available, for example, as described in WO2010 / 108493A1 and WO2019 / 048674A1. Preferred examples of iron isomaltosides are commercially available in many other countries under the trade names Monofer®, Monoferric®, or Diafer®.

[0056] Another specific iron-carbohydrate complex for use in this invention is ferric bepectate (FBP). As used herein, the term “ferric bepectate” refers to a colloidal complex containing an iron core, such as iron oxyhydroxyl, coated with a hydroxyethyl amylopectin derivative. Ferric bepectate is also known as polyglucoferron. Ferric bepectate and its preparation are disclosed, for example, in WO2012175608A1. Briefly, hydroxyethyl starch is dissolved in water. The pH is then adjusted to a value of 8.0–10.0. A cyanide compound is then added to the hydroxyethyl starch solution. The solution is then heated to a temperature of 80–99°C and maintained at this temperature for a first period. Finally, the pH is adjusted to a value of 2.0–4.0, and the solution is heated to a temperature of 50–90°C and maintained at this temperature for a second period. Starch produced by this method is characterized by having at least one heptonic acid residue at its terminus. Therefore, such starch may have multiple heptonic acid residues per molecule, depending on the number of terminal glucosyl residues present in the starch molecule. These heptonic acid residues increase the hydrophilicity of hydroxyethyl starch and, together with ligands such as metal ions, e.g., iron ions, increase the stability of the complexes formed by this hydroxyethyl starch. More generally, hydroxyethyl starch (HES) is a starch in which some of the hydroxyl groups of a single glucosyl residue are replaced by hydroxyethyl residues. Modification by heptonic acid residues occurs by converting the terminal glucosyl residues of hydroxyethyl starch to heptonic acid residues. Preferably, the hydroxyethyl starch used in this method has a weight-average molecular weight (Mw) of less than 200,000 g / mol, particularly less than 130,000 g / mol, particularly less than 100,000 g / mol, particularly less than 90,000 g / mol, particularly less than 80,000 g / mol, and very specifically less than 75,000 g / mol. A very well preferred molecular weight is in the range of 55,000 g / mol to 85,000 g / mol.Such hydroxyethyl starch has a considerably lower molecular weight than (unmodified) hydroxyethyl starch used in the current medical field. A preferred method for determining the molecular weight of hydroxyethyl starch is size exclusion chromatography (SEC). In preferred embodiments, hydroxyethyl starch has an average molar degree of substitution of 0.4 to 0.6, particularly 0.45 to 0.55. An average molar degree of substitution of around 0.50 is particularly preferred. The average molar degree of substitution is a measure of the amount of hydroxyl groups substituted by hydroxyethyl residues per glucosyl residue. Since each glucose unit (or glucosyl residue) has three hydroxyl groups, the average molar degree of substitution can be as high as 3. An average molar degree of substitution of 0.5 indicates that (on average or statistical basis,) one hydroxyl group for every other glucosyl residue is substituted by a hydroxyethyl residue. In preferred embodiments, the hydroxyethyl starch has a weight-average molecular weight of approximately 55,000 to 85,000 g / mol, preferably around 70,000 g / mol, and an average molar substitution degree of 0.45 to 0.55, particularly around 0.50. Such hydroxyethyl starch having a molecular weight of 70,000 g / mol ± 15,000 g / mol and an average molar substitution degree of 0.5 ± 0.05 can also be called HES 70 / 0.5. The process for producing this heptonic acid-modified hydroxyethyl starch, HES 70 / 0.5, is described in Example 1 of WO2019 / 048674A1, and the formation of the iron complex is described in Example 2, all of which are incorporated by reference.

[0057] Iron isomaltosides are preferred iron-carbohydrate complexes for use according to the present invention.

[0058] B. Treatment method This invention describes a therapeutic method for treating iron deficiency, comprising administering iron isomaltoside to a selected subgroup of subjects and / or according to a prescribed dosing regimen. Accordingly, the invention also relates to iron isomaltoside for use in the said method, the use of iron isomaltoside for treating iron deficiency, and / or the use of iron isomaltoside in the manufacture of a pharmaceutical for treating iron deficiency.

[0059] I. Subjects to Treatment The method of the present invention is typically performed on subjects who require it. Subjects who require the method of the present invention are those who have iron deficiency, have been diagnosed with iron deficiency, are suspected of having iron deficiency, or are at risk of developing iron deficiency. Iron deficiency anemia (IDA) develops when iron stores are depleted. Subjects with ID may also have IDA, but subjects with IDA inevitably have ID. Methods for diagnosing ID and IDA are well established in the art and are commonly used in clinical practice.

[0060] Subjects with iron deficiency, diagnosed with iron deficiency, suspected of having iron deficiency, or at risk of developing iron deficiency will be given parenteral, particularly intravenous, iron in the form of an iron-carbohydrate complex, i.e., iron isomaltoside according to the present invention, if oral iron administration is not tolerable or effective in the subject, i.e., if the subject is intolerant to oral iron administration or the response to oral iron administration has been unsatisfactory. Another situation in which intravenous iron administration is indicated is when there is a need for rapid iron delivery, i.e., a clinical need to rapidly replenish iron stores.

[0061] Iron deficiency and anemia Iron storage parameters Individuals with iron deficiency may exhibit low or insufficient markers of their overall iron status. This means that such individuals may not have enough iron stored in their bodies to maintain adequate iron levels. The vast majority of healthy, well-nourished people living in industrialized countries have approximately 4-5 grams of iron stored in their bodies. About 2.5 grams of this iron is contained in hemoglobin, which carries oxygen through the blood. The majority of the remaining approximately 1.5-2.5 grams of iron is contained in iron-binding complexes, which are present in all cells but are more concentrated in organs such as bone marrow, liver, and spleen. Iron stored in the liver is the primary physiological reserve of iron in a healthy body. Of the body's total iron content, about 400 mg is utilized in proteins that use iron for cellular processes such as oxygen storage (myoglobin) or the execution of redox reactions for energy production (cytochrome proteins). In addition to stored iron, a small amount of iron, typically about 3-4 mg, circulates through the blood plasma bound to a protein called transferrin.

[0062] Free soluble ferrous iron (iron(II) or Fe 2+ ) is toxic and typically exists in the body only at very low concentrations.

[0063] In individuals with iron deficiency, the iron stored in the body is depleted first. Since most of the iron the body uses is required by hemoglobin, iron deficiency anemia is the primary clinical manifestation of iron deficiency. Oxygen transport to tissues, including organs, is essential, and severe anemia is harmful, sometimes life-threatening due to systemic oxygen deficiency. Individuals with iron deficiency suffer organ damage caused by oxygen depletion well before cells deplete the iron needed for intracellular processes, and in some cases, this can be fatal.

[0064] Several systemic iron status markers exist and can be measured to determine whether a subject has sufficient iron storage to maintain proper health. These markers can be circulating iron storage, iron stored in iron-binding complexes, or both, and are typically called iron storage parameters. Examples of iron storage parameters include hematocrit, hemoglobin concentration (Hb), total iron-binding capacity (TIBC), transferrin saturation (TSAT), serum iron levels, hepatic iron levels, splenic iron levels, and serum ferritin levels. Of these, hematocrit, hemoglobin concentration (Hb), total iron-binding capacity (TIBC), transferrin saturation (TSAT), and serum iron levels are commonly known as circulating iron storage. Hepatic iron levels, splenic iron levels, and serum ferritin levels are generally referred to as storage iron or iron stored in iron-binding complexes.

[0065] Note that the blood parameters listed above are determined in serum, but can also be determined in plasma. Serum and plasma levels are correlated and can be converted to each other.

[0066] This disclosure provides a method for improving one or more iron storage parameters in subjects where this is needed. At least one iron storage parameter may be selected from serum ferritin level, transferrin saturation (TSAT), hemoglobin concentration, hematocrit, total iron-binding capacity, iron absorption level, serum iron level, liver iron level, spleen iron level, and combinations thereof.

[0067] In one embodiment, at least one iron storage parameter is hemoglobin concentration, and improvement includes an increase in the target hemoglobin concentration. In another embodiment, at least one iron storage parameter is transferrin saturation, and improvement includes an increase in the target transferrin saturation. In yet another embodiment, at least one iron storage parameter is serum ferritin level, and improvement includes an increase in the target serum ferritin level.

[0068] serum ferritin Ferritin, stored in the liver, is the primary source of iron stored in the body. Ferritin is an intracellular protein that stores iron and releases it in a controlled manner. Medically, the amount of ferritin present in blood samples and / or liver tissue samples reflects the amount of iron stored in the liver (although ferritin is ubiquitous and can be found in many other tissues in the body in addition to the liver). Ferritin plays a role in storing iron in a non-toxic form in the liver and transporting it to areas where it is needed. In healthy subjects, normal serum ferritin levels, sometimes called the reference range, are typically 30–300 ng / ml for men and 15–200 ng / ml for women. In patients at risk of cardiovascular adverse events, normal serum ferritin levels are typically greater than 100 ng / ml. However, in individuals with iron deficiency, serum ferritin levels typically decrease significantly as the amount of iron available for ferritin binding and storage in the liver decreases, which occurs because the body loses its ability to absorb and store iron.

[0069] As used herein, the term “serum ferritin” (s-ferritin) refers to the level of ferritin in blood serum, measured using a two-site immunoenzyme ("sandwich") assay. Ferritin is the body’s primary iron storage protein. Because ferritin concentration is directly proportional to the body’s total iron storage, serum ferritin levels have become a common diagnostic tool in assessing iron status. Subjects with iron deficiency anemia have serum ferritin levels approximately 1 / 10th that of normal subjects, while subjects with iron overload (hemochromatosis, hemosiderin deposition) have serum ferritin levels much higher than normal. Ferritin levels also provide a highly sensitive means of detecting iron deficiency in its early stages. In both adults and children, chronic inflammation results in elevated ferritin levels disproportionate to iron reserves. High ferritin levels are also observed in acute and chronic liver disease, chronic renal failure, and certain types of neoplastic diseases.

[0070] In some embodiments, subjects treated by the methods disclosed herein experience an increase in serum ferritin levels. In some embodiments, the disclosure provides a method for increasing serum ferritin in a subject in need thereof, the method comprising administering iron isomaltoside to the subject, wherein the iron isomaltoside results in an increase in serum ferritin.

[0071] In some embodiments, iron isomaltoside results in an average increase in serum ferritin levels of over 100 ng / ml, over 110 ng / ml, over 120 ng / ml, over 130 ng / ml, over 140 ng / ml, over 150 ng / ml, over 160 ng / ml, over 170 ng / ml, over 180 ng / ml, over 190 ng / ml, or over 200 ng / ml after 4 or 8 weeks of treatment.

[0072] In some embodiments, iron isomaltoside results in a mean increase in serum ferritin levels after 4 or 8 weeks of treatment, selected from <400 ng / mL, <390 ng / mL, <380 ng / mL, <370 ng / mL, <360 ng / mL, <350 ng / mL, <340 ng / mL, <330 ng / mL, <320 ng / mL, <310 ng / mL, <300 ng / mL, <290 ng / mL, <280 ng / mL, <270 ng / mL, <260 ng / mL, or <250 ng / mL).

[0073] In some embodiments, iron isomaltoside results in an average increase in serum ferritin levels of 100–400 ng / mL, 100–375 ng / mL, 100–350 ng / mL, 100–325 ng / mL, 100–300 ng / mL, 100–275 ng / mL, or 150–300 ng / mL after 4 or 8 weeks of treatment.

[0074] In some embodiments, iron isomaltoside results in an average increase in serum ferritin levels of over 200 ng / mL, over 230 ng / mL, over 260 ng / mL, over 290 ng / mL, over 320 ng / mL, over 350 ng / mL, over 380 ng / mL, over 410 ng / mL, or over 440 ng / mL one week after treatment.

[0075] In some embodiments, iron isomaltoside results in a mean increase in serum ferritin levels one week after treatment, selected from <600 ng / mL, <590 ng / mL, <580 ng / mL, <570 ng / mL, <560 ng / mL, <550 ng / mL, <540 ng / mL, <530 ng / mL, <520 ng / mL, <510 ng / mL, <500 ng / mL, <490 ng / mL, <480 ng / mL, <470 ng / mL, <460 ng / mL, or <450 ng / mL).

[0076] In some embodiments, iron isomaltoside results in an average increase in serum ferritin levels of 200–600 ng / mL, 250–600 ng / mL, 300–600 ng / mL, 350–600 ng / mL, or 400–600 ng / mL one week after treatment.

[0077] Transferrin saturation (TSAT) In addition to stored iron, a small amount of iron, typically about 3-4 mg, circulates through the blood plasma, bound to a protein called transferrin. Therefore, serum iron (s-iron) levels can be expressed by the amount of iron circulating in the blood bound to the protein transferrin. Transferrin is a glycoprotein produced by the liver and can bind one or two ferric (iron(III) or Fe3+) ions. Transferrin is the most common dynamic carrier of iron in the blood and is therefore an essential component of the body's ability to transport stored iron for use throughout the body. Transferrin saturation (i.e., TSAT) is measured as a percentage and calculated by multiplying the ratio of serum iron to total iron-binding capacity by 100. This value allows clinicians to know how much serum iron is actually bound relative to the total amount of transferrin available to bind iron. For example, a TSAT value of 35% means that 35% of the available iron-binding sites on transferrin in a blood sample are occupied by iron. In healthy subjects, typical TSAT values ​​are approximately 15–50% for men and 12–45% for women. In patients at risk of cardiovascular adverse events, normal TSAT values ​​are typically greater than 20%. However, in iron-deficient subjects, TSAT values ​​typically decrease significantly as the amount of iron available for transferrin binding decreases, which occurs because the body loses its ability to absorb and store iron. In some embodiments, TSAT values ​​are less than 20% and / or ferritin levels are less than 100 μg / L.

[0078] In some embodiments, subjects treated by the methods disclosed herein experience an increase in TSAT levels. In some embodiments, the disclosure provides a method for increasing TSAT in a subject in need thereof, the method comprising administering iron isomaltoside to the subject, wherein the iron isomaltoside results in an increase in TSAT in the subject.

[0079] In some embodiments, iron isomaltoside results in an average increase in TSAT of more than 1%, more than 1.5%, more than 2%, or more than 2.5% after 4 or 8 weeks of treatment.

[0080] In some embodiments, iron isomaltoside results in an average increase of less than 5%, less than 4%, or less than 3% in TSAT after 4 or 8 weeks of treatment.

[0081] In some embodiments, iron isomaltoside results in an average increase of 1–5%, 1.5–4%, or 2–3% in TSAT after 4 or 8 weeks of treatment.

[0082] In some embodiments, iron isomaltoside results in an average increase of over 5%, over 6%, or over 7% in TSAT one week after treatment.

[0083] In some embodiments, iron isomaltoside results in an average increase in TSAT of less than 20%, less than 19%, less than 18%, less than 17%, less than 16%, or less than 15% one week after treatment.

[0084] In some embodiments, iron isomaltoside results in an average increase of 5–20% or 5–15% in TSAT one week after treatment.

[0085] hematocrit Hematocrit, also known as blood volume or red blood cell volume fraction, is the percentage of blood volume of red blood cells. In healthy subjects, hematocrit is typically about 45% of blood volume in men and about 40% of blood volume in women. However, in subjects with iron deficiency, hematocrit is often significantly depleted due to poor iron absorption and / or poor iron storage capacity.

[0086] The iron isomaltosides disclosed herein may be administered to subjects to increase hematocrit. The precise timing of administration will inevitably vary depending on the subject, for example, the severity of the iron deficiency the subject is experiencing, the level of iron absorption the subject is experiencing or not experiencing, and the judgment of the healthcare professional administering the treatment. In some embodiments, the disclosure provides a method for increasing hematocrit in a subject in need thereof, the method comprising administering iron isomaltosides to the subject, wherein the iron isomaltosides result in an increase in the subject's hematocrit. In some embodiments, the increase is 1% to 30%, 1% to 15%, 1% to 12%, 1% to 10%, 1% to 9%, 1% to 8%, 1% to 7%, 1% to 6%, 1% to 5%, 1% to 4%, 1% to 3%, or 1% to 2%.

[0087] Hemoglobin concentration Hemoglobin concentration, also known as mean cellular hemoglobin concentration (MCHC), is a measure of the concentration of hemoglobin protein in a given volume of precipitated red blood cells. It is typically calculated by dividing the total amount of hemoglobin protein by the hematocrit. Hemoglobin concentration can also be measured as a fraction by mass or weight and presented as a percentage (%). However, numerically, the mass or molar measure of hemoglobin concentration and the mass or weight fraction (%) are identical, assuming a red blood cell density of 1 g / ml and negligible hemoglobin loss in blood plasma. For healthy subjects, typical mass or molar measures of hemoglobin concentration range from 32 g / dl to 36 g / dl or 4.9 mmol / L to 5.5 mmol / L, respectively. However, in iron-deficient subjects, hemoglobin concentration can be significantly reduced because the body has lost its ability to absorb and store iron.

[0088] In some embodiments, subjects treated by the methods disclosed herein experience an increase in hemoglobin concentration. In some embodiments, the disclosure provides a method for increasing hemoglobin concentration in a subject in need thereof, the method comprising administering iron isomaltoside to the subject, wherein the iron isomaltoside results in an increase in hemoglobin concentration in the subject.

[0089] In some embodiments, iron isomaltoside results in an average increase in hemoglobin concentration of 0.1–5.0 g / dL, 0.1–4.0 g / dL, 0.1–3.0 g / dL, or 0.1–2.0 g / dL one week after treatment.

[0090] In some embodiments, iron isomaltoside results in an average increase in hemoglobin concentration of more than 0.1 g / dL, more than 0.2 g / dL, more than 0.3 g / dL, more than 0.4 g / dL, more than 0.5 g / dL, more than 0.6 g / dL, more than 0.7 g / dL, more than 0.8 g / dL, or more than 0.9 g / dL one week after treatment.

[0091] In some embodiments, iron isomaltoside results in an average increase in hemoglobin concentration of less than 1.0 g / dL, less than 0.9 g / dL, or less than 0.8 g / dL. In some embodiments, one week after treatment, the levels are less than 0.7 g / dL, less than 0.6 g / dL, less than 0.5 g / dL, less than 0.4 g / dL, or 0.3 g / dL.

[0092] In some embodiments, iron isomaltoside results in an average increase in hemoglobin concentration of 0.5–5.0 g / dL, 0.5–4.0 g / dL, 0.5–3.0 g / dL, or 0.5–2.0 g / dL after 4 or 8 weeks of treatment.

[0093] In some embodiments, iron isomaltoside results in an average increase in hemoglobin concentration of more than 0.5 g / dL, more than 0.7 g / dL, more than 0.9 g / dL, more than 1.1 g / dL, more than 1.3 g / dL, or more than 1.5 g / dL after 4 or 8 weeks of treatment.

[0094] In some embodiments, iron isomaltoside results in an average increase in hemoglobin concentration of less than 2.0 g / dL, less than 1.9 g / dL, or less than 1.8 g / dL. In some embodiments, after 4 or 8 weeks of treatment, the levels are less than 1.7 g / dL, less than 1.6 g / dL, less than 1.5 g / dL, less than 1.4 g / dL, or less than 1.3 g / dL.

[0095] Total Iron-Bonding Capacity (TIBC) Total iron-binding capacity (TIBC) is a measure of the blood's ability to bind iron to the protein transferrin. TIBC is typically measured by taking a blood sample and determining the maximum amount of iron the sample can carry. Therefore, TIBC indirectly measures transferrin, the protein that transports iron in the blood. For healthy subjects, typical TIBC levels, measured in mass or molar concentration, are in the range of 250–370 μg / dL or 45–66 μmol / L, respectively. However, in iron-deficient subjects, TIBC typically rises above these levels because the body must produce more transferrin in an attempt to deliver iron to red blood cell progenitor cells and produce hemoglobin.

[0096] In some embodiments, subjects treated by the methods disclosed herein experience a reduction in TIBC. In some embodiments, the disclosure provides a method for reducing TIBC in subjects in need thereof, the method comprising administering iron isomaltoside to the subject, wherein the iron isomaltoside results in a reduction in the subject's TIBC.

[0097] In some embodiments, the reductions are 0.1% to 30%, 0.1% to 28%, 0.1% to 26%, 0.1% to 25%, 0.1% to 24%, 0.1% to 23%, 0.1% to 22%, 0.1% to 21%, 0.1% to 20%, 0.1% to 15%, 0.1% to 10%, or 0.1% to 5%.

[0098] Subjects at risk of cardiovascular adverse events are generally subject to, or at risk of, systemic inflammation, which can complicate the assessment of iron parameters. As disclosed herein, in subjects at risk of cardiovascular adverse events, normal iron parameters are generally considered to be TSAT > 20% and / or serum ferritin > 100 μg / L. According to one embodiment of the present invention, treatment is appropriate when TSAT is less than 20% and / or serum ferritin is less than 100 μg / L, or, in a related embodiment, when TSAT is less than 20% and serum ferritin is less than 300 μg / L. In a preferred embodiment, TSAT is less than 20% and / or serum ferritin is less than 100 μg / L. Treatment criteria may include upper limits for serum ferritin levels above which redosing is not recommended, such as serum ferritin levels of 300 μg / L or less, 400 μg / L or less, 500 μg / L or less, or 600 μg / L or less. Redosing criteria may also include higher limits for ferritin and TSAT than the treatment criteria. For example, in one preferred embodiment, after administration of the initial effective dose, if TSAT is less than 25% and / or serum ferritin is less than 100 μg / L, the subject would receive a further dose provided that serum ferritin is 400 μg / L or less.

[0099] Symptoms Symptoms of iron deficiency may occur before the condition progresses to iron deficiency anemia. Symptoms of iron deficiency may include, for example, fatigue, dizziness, pallor, hair loss, irritability, weakness, pica, brittle or grooved nails, Plummer-Vinson syndrome (painful atrophy of the mucous membranes covering the tongue, pharynx, and esophagus), immune dysfunction, ice eating, and restless legs syndrome.

[0100] Subjects treated by the methods disclosed herein will experience improvement in iron deficiency. In some embodiments, subjects treated by the methods disclosed herein will experience a reduction in iron deficiency. This reduction may occur because the total amount of iron in the subject's body increases through the administration of iron isomaltoside disclosed herein. In some embodiments, subjects treated by the methods disclosed herein will experience a reduction or elimination of one or more symptoms of iron deficiency, which are selected from fatigue, dizziness, pallor, hair loss, irritability, weakness, pica, brittle or grooved nails, Plummer-Vinson syndrome (distressing atrophy of the mucous membranes covering the tongue, pharynx, and esophagus), immune dysfunction, ice eating, restless legs syndrome, and combinations thereof.

[0101] In some embodiments, iron deficiency is iron deficiency anemia. Iron deficiency anemia is characterized by low levels of circulating red blood cells and can be caused by insufficient intake, absorption, and / or storage of iron from the diet. Red blood cells contain iron bound to hemoglobin protein and are typically not formed when there is insufficient iron in the body.

[0102] Iron deficiency anemia is typically characterized by pallor (a pale color in the skin and mucous membranes resulting from reduced oxyhemoglobin), fatigue, dizziness, and weakness. However, the signs of iron deficiency anemia can vary among individuals. Because iron deficiency tends to develop slowly, adaptation to the disease may occur, and it may remain unrecognized for some time. In some cases, subjects may develop symptoms such as dyspnea (difficulty breathing), pica (abnormal and compulsive cravings for food), anxiety, irritability or sadness, angina, constipation, drowsiness, tinnitus, oral ulcers, palpitations, hair loss, fainting or fainting, depression, shortness of breath on exertion, muscle spasms, pale skin, tingling or burning sensations, menstrual cycle irregularities, heavy menstrual periods, delayed social development, glossitis (inflammation or infection of the tongue), angular cheilitis (inflammatory lesions at the corners of the mouth), spoon-shaped nails, or weak or brittle nails, loss of appetite, pruritus (generalized itching), Plummer-Vinson syndrome (distressing atrophy of the mucous membranes covering the tongue, pharynx, and esophagus), and restless legs syndrome.

[0103] Anemia is typically diagnosed based on a complete blood count measured from a blood sample. Typically, an automated counter is used that reports the total number of red blood cells, hemoglobin level, and red blood cell size in the sample using flow cytometry. However, to diagnose anemia by counting the total number of red blood cells in a sample, a stained blood smear on a microscope slide can also be examined using a microscope. In many countries, the presence of anemia is determined by measuring four parameters: red blood cell count, hemoglobin concentration, mean cytological volume, and red blood cell distribution width. The World Health Organization has set certain thresholds for hemoglobin levels (Hb), in which a patient's hemoglobin level can be diagnosed as anemia if it falls below these values. These values ​​are as follows: Hb = 11.0 g / dL or 6.8 mmol / L for children aged 0.5 to 5.0 years; Hb = 11.5 g / dL or 7.1 mmol / L for children aged 5 to 12 years; Hb = 12.0 g / dL or 7.4 mmol / L for teenagers aged 12 to 15 years; Hb = 12.0 g / dL or 7.4 mmol / L for non-pregnant women aged 15 years and older; Hb = 11.0 g / dL or 6.8 mmol / L for pregnant women; and Hb = 13.0 g / dL or 8.1 mmol / L for men aged 15 years and older.

[0104] Subjects treated by the methods disclosed herein may experience improvement in anemia. Subjects treated by the methods disclosed herein may experience improvement in iron deficiency anemia. In some embodiments, subjects treated by the methods disclosed herein experience a reduction in one or more symptoms of anemia or iron deficiency anemia. In some embodiments, subjects treated by the methods disclosed herein experience resolution of one or more symptoms of anemia or iron deficiency anemia. In some embodiments, one or more symptoms of anemia or iron deficiency anemia are selected from pallor, fatigue, dizziness, weakness, shortness of breath, pica, anxiety, irritability or sadness, angina, constipation, drowsiness, tinnitus, oral ulcers, palpitations, hair loss, fainting or fainting, depression, shortness of breath on exertion, muscle spasms, pale skin, tingling (numbness) or burning sensation, irregular menstrual cycle, menorrhagia, delayed social development, glossitis, angular cheilitis, spoon-shaped nails, loss of appetite, pruritus, Plummer-Vinson syndrome, restless legs syndrome, and combinations thereof.

[0105] In some embodiments, subjects treated by the methods disclosed in the specification may experience improvement in anemia and / or iron deficiency anemia, as their hemoglobin levels rise above and / or remain above a threshold level. In some embodiments, a method for treating anemia is disclosed, which comprises administering iron isomaltoside to a subject, resulting in a hemoglobin level in the subject of a level in the range of 11.0 g / dL to 13.0 g / dL or higher, including levels selected from 11.0 g / dL, 11.5 g / dL, 12.0 g / dL, and 13.0 g / dL. In some embodiments, a method for treating anemia is disclosed, which comprises administering iron isomaltoside to a subject, resulting in a hemoglobin level in the subject of a level in the subject of a level selected from 6.8 mmol / L, 7.1 mmol / L, 7.4 mmol / L, and 8.1 mmol / L. In some embodiments, a method for treating anemia in male subjects is disclosed, which comprises administering iron isomaltoside to the male subjects, resulting in hemoglobin levels in the male subjects at or above levels selected from 13.0 g / dL and 8.1 mmol / L. In some embodiments, a method for treating anemia in female subjects is disclosed, which comprises administering iron isomaltoside to the female subjects, resulting in hemoglobin levels in the female subjects at or above levels selected from 12.0 g / dL and 7.4 mmol / L.

[0106] Risk factors for cardiovascular adverse events Certain groups of subjects having iron deficiency as disclosed herein to whom the treatment according to the present invention can be applied are characterized as being at risk of cardiovascular adverse events.

[0107] According to the present invention, subjects at risk of cardiovascular adverse events are subjects at risk of one or more events selected from the group consisting of: events affecting the heart (cardiac adverse events), e.g., congestive heart failure (CHF), especially CHF requiring hospitalization or medical treatment, myocardial infarction, unstable angina, especially angina requiring hospitalization, or arrhythmia; events affecting the peripheral vascular system (peripheral vascular adverse events), e.g., hypertension and hypotension; events affecting the cerebrovascular system (cerebrovascular adverse events), e.g., stroke; and / or general adverse events, e.g., death.

[0108] More specifically, subjects at risk of cardiovascular adverse events according to the present invention are subjects having one or more of the following risk factors for cardiovascular events, particularly cardiovascular events as defined herein.

[0109] Chronic kidney disease (CKD) For 3 months, glomerular filtration rate (GFR) < 60 ml / min / 1.73 m³ 2 Individuals with chronic kidney disease (CKD), regardless of whether they have kidney damage, are classified as having CKD. Those with CKD who require either dialysis or a kidney transplant are typically referred to as end-stage renal disease (ESRD) patients. Therefore, when a patient reaches the end of the early stage of CKD, the non-dialysis stage, they are traditionally classified as an ESRD patient. Before this point, these patients are called non-dialysis CKD patients. Non-dialysis CKD (NDD-CKD) patients are those diagnosed with early-stage chronic kidney disease who have not yet been medically advised to undergo dialysis. The U.S. National Kidney Foundation defines five stages of chronic kidney disease. Typically, patients with CKD progress through stages 1 through 4 before dialysis becomes medically necessary. However, patients with more advanced stages of CKD, such as stage 5, who have not yet started dialysis or have not been advised to undergo a transplant, are also typically referred to as non-dialysis CKD patients.

[0110] As used herein, NDD-CKD is intended to encompass all subjects diagnosed with chronic kidney disease but who have not undergone dialysis while receiving iron isomaltoside. Such subjects may include, for example, subjects who have never undergone dialysis, or, in some embodiments, subjects who have undergone dialysis but have not undergone dialysis while receiving iron isomaltoside.

[0111] Cardiovascular disease is a frequent cause of death in patients with chronic kidney disease (CKD). Despite the high prevalence of traditional risk factors for atherosclerosis in CKD patients, heart failure, arrhythmias, and sudden cardiac death constitute a disproportionately large burden of cardiovascular mortality in CKD patients compared to those with coronary artery disease (CAD). Left ventricular hypertrophy (LVH) and left ventricular dysfunction can be consequences of atherosclerosis, but they are also common non-atherosclerotic mechanisms of cardiovascular injury in CKD. Cardiac diseases, including coronary artery disease, LVH, and heart failure (HF), are common in patients with chronic kidney disease (CKD). LVH appears to become more prevalent as glomerular filtration rate (GFR) decreases, leading to increased use of dialysis.

[0112] LVH is a significant predictor of mortality in individuals with CKD, and anemia has been identified as a significant independent risk factor for the occurrence and progression of LVH and HF, as well as for the occurrence and progression of adverse cardiovascular outcomes, including mortality, in CKD.

[0113] The presence of left ventricular hyperplasia (LVH) is clinically significant because it is associated with an increased incidence of heart failure, ventricular arrhythmias, death following myocardial infarction, decreased LV ejection fraction, sudden cardiac death, aortic root dilation, and cerebrovascular events. Generally, the development of heart failure due to LVH arises from decreased left ventricular systolic function and / or diastolic dysfunction. The adverse effects of left ventricular remodeling can be a significant determinant of progression to overt heart failure.

[0114] While not intended to be limited by theory, possible mechanisms that could explain the relationship between anemia and LVH expression include reduced oxygen delivery to the myocardium, possibly resulting in increased myocyte necrosis and apoptosis; increased cardiac output and reduced systemic vascular resistance associated with anemia; increased oxidative stress; decreased effectiveness of oxidative phosphorylation; and activation of the sympathetic nervous system.

[0115] In CKD, increasingly severe anemia is associated with more frequent and severe LVH, LV dilation, HF, and a worse prognosis for all causes and cardiac factors in subjects with CKD and cardiac disease. If the increase in anemia in CKD is associated with the increasing severity of LVH and heart failure, then correcting deficiencies related to anemia according to the aspects of this disclosure has a beneficial effect on the clinical features of HF and LVH. These clinical features include the clinical manifestation of HF, and the subsequent onset and progression of LVH.

[0116] Several, mostly non-comparative, short-term studies have suggested that using erythropoietin to improve anemia to approximately 10–12 g / dL Hb levels in patients with HF and CKD improves the clinical manifestation of HF and reduces hospitalization rates, but does not improve hard endpoints in patients with CHF. However, given the rather unexpected adverse outcomes associated with erythropoietin use, erythropoietin treatment aimed at achieving normal or near-normal Hb levels may increase the risk of morbidity and / or mortality in patients.

[0117] While LVH is itself a powerful prognostic marker for adverse cardiovascular outcomes in patients with chronic kidney disease (CKD), in some patients it appears to regress as hemoglobin levels improve from less than 10 g / dL to over 10 g / dL. Furthermore, and not intended to be limiting, further increases in hemoglobin beyond normal levels do not appear to result in further regression of LVH or clinical improvement. The baseline characteristics of LVH may be an important factor in determining the subsequent clinical response to anemia correction in patients with LVH.

[0118] Congestive heart failure (CHF) The standardized MedDRA terms "congestive heart failure" and "congestive cardiac disorder" are used interchangeably herein.

[0119] Heart failure is a clinical syndrome characterized by typical symptoms (e.g., shortness of breath, ankle swelling, and fatigue) and may be accompanied by signs (e.g., elevated jugular venous pressure, moist rales of the lungs, and peripheral edema), resulting from structural and / or functional cardiac abnormalities, leading to reduced cardiac output and / or increased intracardiac pressure at rest or under stress. Therefore, the current definition of HF limits HF itself to the stage where clinical symptoms are evident. Until clinical symptoms become evident, subjects may be presented with asymptomatic structural or functional cardiac abnormalities, such as systolic or diastolic left ventricular (LV) dysfunction, which are precursors to HF. Recognition of these precursors is important because they are associated with poor outcomes, and initiating treatment at the precursor stage can reduce the mortality rate of subjects with asymptomatic systolic LV dysfunction.

[0120] "Congestive HF" is a term used to describe chronic heart failure, particularly when there is evidence of volume overload, which is mostly presented as peripheral edema or pulmonary edema. Congestive heart failure (CHF) can be heart failure with reduced ejection fraction, LVEF < 40% (HFrEF), heart failure with preserved ejection fraction, LVEF ≥ 50% (HFpEF), or heart failure with intermediate ejection fraction, LVEF 40-49% (HFmrEF). In certain embodiments of the present invention, congestive heart failure (CHF) is heart failure with reduced ejection fraction, LVEF < 40% (HFrEF).

[0121] Congestive heart failure (CHF) can also be classified according to the New York Heart Association (NYHA) classification, which categorizes patients into one of four categories based on the degree of limitation during physical activity. Patients who have no symptoms and do not experience limitations such as excessive fatigue, palpitations, or shortness of breath during normal physical activities such as walking or climbing stairs are assigned to NYHA Class I. Patients with mild symptoms (mild shortness of breath and / or angina) and slight limitations in physical activity are assigned to NYHA Class II. Patients who experience significant limitations in activity due to symptoms, even during sub-normal activity such as walking short distances of 20-100m, and who feel fine only at rest are assigned to NYHA Class III. Patients who experience symptoms even at rest and cannot continue any physical activity without discomfort are assigned to NYHA Class IV. In certain embodiments of the present invention, congestive heart failure (CHF) is congestive heart failure of NYHA Class II-IV.

[0122] Atrial fibrillation (AF) Atrial fibrillation (AF) can be newly diagnosed AF (AF that has never been previously diagnosed, regardless of the duration of arrhythmia or the presence and severity of AF-related symptoms), paroxysmal AF (in most cases, it resolves spontaneously within 48 hours; some AF episodes can last up to 7 days; AF episodes cardioverted within 7 days should be considered paroxysmal), persistent AF (AF that lasts longer than 7 days, including episodes that are terminated by cardioversion after 7 days, either with medication or by direct current cardioversion), long-term persistent AF (persistent AF that has lasted for more than one year at the time it is decided to employ a rhythm control strategy), or permanent AF (AF that is tolerated by the patient (and physician). In certain embodiments of the present invention, AF is newly diagnosed AF, paroxysmal AF, or persistent AF.

[0123] AF is associated with an increased risk of death, cardiovascular adverse events, and renal disease, including higher-risk ischemic heart disease, chronic kidney disease, sudden cardiac death, stroke, or incident congestive heart failure.

[0124] Hypertension Hypertension is defined as a systolic blood pressure increase of more than 20 mm Hg resulting in a value greater than 180 mm Hg, or a diastolic blood pressure increase of more than 15 mm Hg resulting in a value greater than 105 mm Hg.

[0125] Hypertension is a major risk factor for heart disease, particularly stroke. Hypertension accounts for approximately 50% of ischemic strokes and increases the risk of hemorrhagic stroke.

[0126] There are several mechanisms related to hypertension that make it a high-risk factor for cardiovascular adverse events. For example, in hypertension, blood vessels are stressed due to narrowing or blockage. This can lead to atherosclerosis, or the formation of weak points in the blood vessels that are prone to rupture or bulge of the arterial wall, resulting in aneurysms.

[0127] Myocardial infarction (MI) Myocardial infarction (MI) is defined as the death of cardiomyocytes due to prolonged ischemia. Histological cell death does not occur immediately after the onset of myocardial ischemia, but it does occur within a finite timeframe. Complete necrosis of cardiomyocytes may be observed several hours later. MI can be the first symptom of coronary artery disease (CAD).

[0128] MI is a term used to describe characteristic changes in cardiac enzyme markers or the presence of electrocardiogram (ECG) changes consistent with either ischemia or infarction in any of the temporally related symptomatic conditions of acute coronary syndrome. Cardiac troponin cTn(I or T), which has high myocardial tissue specificity and high clinical sensitivity, is used as the preferred biomarker. Alternatively, if a cTn assay is not available, the MB fraction of creatine kinase (CKMB), measured by mass assay, can be used. In both assays, elevated cTn and CKMB concentrations are defined as values ​​exceeding the 99th percentile (upper reference limit (URL)) of the normal reference population. This distinctive 99th percentile is referred to as the decisive level for the diagnosis of MI.

[0129] Myocardial infarction (MI) in patients with chest discomfort or other ischemic symptoms presenting with ST elevation in two adjacent leads is referred to as “ST-elevation MI” (STEMI). Patients without ST elevation at presentation are usually referred to as having “non-ST-elevation MI” (non-STEMI). In preferred embodiments, myocardial infarction (MI) is either ST-elevation myocardial infarction (STEMI) or non-STEMI.

[0130] Patients with a history of MI are among the highest risk groups for further cardiovascular adverse events. In particular, patients who have survived MI, i.e., those with a history of MI, have an increased risk of recurrent infarction and a six times higher annual mortality rate than people of the same age without coronary heart disease.

[0131] stroke Classically, stroke is characterized by neurological deficits resulting from acute focal injury to the central nervous system caused by blood vessels, including cerebral infarction, intracerebral hemorrhage, and subarachnoid hemorrhage.

[0132] Individuals with a history of stroke, i.e., those who have previously suffered a stroke, remain at high risk for further cardiovascular adverse events, particularly further strokes.

[0133] Heart valve disorder Aortic stenosis is the most common primary valvular disease in Europe and North America, often requiring surgical or catheter-based intervention, and its prevalence is increasing due to the aging population.

[0134] Mitral regurgitation (MR) is the second most common cause of valve surgery in Europe. Primary MR can be distinguished from secondary MR, particularly in relation to surgical and transcatheter management. In primary MR, one or more components of the mitral valve mechanism are directly affected. The most frequent etiology is degenerative (prolapse, flail leaflet). Endocarditis is one cause of primary MR. Secondary MR (also known as functional MR) is defined as MR resulting from primary left ventricular (LV) dysfunction, with normal mitral leaflets and chord. LV dysfunction can result from coronary heart disease (CHD) or (non-ischemic) cardiomyopathy.

[0135] For example, individuals with a congenital history of heart valve defects have an increased likelihood of developing valve problems. Heart valve disease can lead to many complications, including cardiovascular adverse events such as heart failure, stroke, blood clots, arrhythmias, or death.

[0136] diabetes Significant hypoglycemia is associated with symptoms including frequent urination, thirst, blurred vision, fatigue, and recurrent infections. The aim of lowering blood glucose is not just symptom relief, but to reduce the long-term complications of diabetes. Type 2 diabetes mellitus (also known as type 2 diabetes) is a long-term metabolic disorder characterized by high blood glucose, insulin resistance, and relative insulin deficiency. Common symptoms include increased thirst, frequent urination, and unexplained weight loss. Type 1 diabetes, formerly known as juvenile diabetes or insulin-dependent diabetes, is a chronic condition in which the pancreas produces little to no insulin. Various factors, including genetic predisposition and certain viruses, can contribute to type 1 diabetes. Type 1 diabetes usually manifests in childhood or adolescence, but can also occur in adulthood. Despite active research, there is no cure for type 1 diabetes. Treatment focuses on managing blood glucose levels and preventing complications through insulin, diet, and lifestyle.

[0137] Having diabetes increases the risk of cardiovascular adverse events by 2 to 4 times compared to people without diabetes. Cardiovascular adverse events are a leading cause of mortality in people with diabetes. This is particularly due to hypertension, dyslipidemia (abnormal blood lipids), and obesity, all of which are risk factors for cardiovascular adverse events and are widespread in people with diabetes.

[0138] For example, uncontrolled diabetes can cause damage to blood vessels, which can lead to atherosclerosis and hypertension. High glucose levels increase the likelihood of fatty deposits (atheroma), which, if they occur in the coronary arteries, can lead to coronary heart disease and heart attacks. Individuals with diabetes are more likely to have heart attacks or strokes than those without diabetes, and have an increased risk of heart failure compared to those without diabetes. Diabetes inhibits the protective effects of estrogen, which can increase the risk of cardiovascular adverse events in premenopausal women with diabetes.

[0139] Obesity Obesity is defined as a condition characterized by excessive body weight, where the Body Mass Index (BMI), calculated by dividing a person's weight by the square of their height, exceeds 30 kg / m². 2 Having a BMI greater than 25%, i.e., being obese, carries a serious risk of developing cardiovascular adverse events, including hypertension (e.g., due to visceral fat), diabetes mellitus, and atherosclerosis.

[0140] In particular, dietary salt is a significant factor that can raise blood pressure, thereby leading to hypertension and related risks. For example, being overweight increases the risk of cardiovascular adverse events due to high salt intake.

[0141] Age, smoking, and drinking Being elderly, a smoker, and / or a drinker increases the risk of cardiovascular adverse events.

[0142] According to certain embodiments of the present invention, elderly subjects are those aged 60 or older, 65 or older, 70 or older, 75 or older, or 80 or older. After age 55, the risk of stroke doubles every 10 years. Systolic blood pressure is an important predictor of the risk of cardiovascular events as we age.

[0143] A drinker is defined as someone who is still in the system (intact) of a large amount of alcohol, especially someone who drinks more than seven drinks a week.

[0144] Drinkers who consume excessive amounts of alcohol may suffer from or develop problems such as elevated blood pressure, acute myocardial infarction, or cardiomyopathy. Furthermore, alcohol abuse has been shown to damage the heart muscle and increase the risk of stroke and cardiac arrhythmias.

[0145] A smoker is defined as a person who has been a regular smoker of tobacco, and / or is currently a regular smoker of tobacco.

[0146] Since the 1940s, smoking has been known to be linked to cardiovascular disease. This is due to multiple mechanisms. For example, smoking damages the endothelium (the inner lining of blood vessels), increases fatty deposits in arteries, increases blockages, raises low-density lipoprotein cholesterol, decreases high-density lipoprotein cholesterol, and promotes coronary artery spasm. Furthermore, nicotine, an addictive component in tobacco, accelerates heart rate and raises blood pressure.

[0147] Hyperthyroidism and related thyroidopathy Hyperthyroidism is characterized by excessively high levels of thyroxine. Hyperthyroidism can accelerate the body's metabolism, leading to unintentional weight loss and rapid or irregular heartbeats.

[0148] Thyrotoxicosis is a condition characterized by an excess of thyroid hormones in the body.

[0149] Chronic obstructive pulmonary disease (COPD) Chronic obstructive pulmonary disease (COPD) is a disease characterized by persistent respiratory symptoms and restricted airflow, resulting from abnormalities in the airways and / or alveoli, usually caused by significant exposure to harmful particles or gases. The primary risk factor is tobacco smoking, but other environmental exposures can also contribute.

[0150] Cardiomyopathy Cardiomyopathy is defined as a structural and functional abnormality of the ventricular myocardium that cannot be explained by coronary artery disease or abnormal stress conditions that restrict blood flow. Historically, this group of disorders has been subdivided into primary disorders, in which the heart is the sole organ involved, and secondary forms, in which cardiomyopathy is a symptomatic manifestation of a systemic disorder. The ESC guidelines employ a classification system that defines cardiomyopathy by specific morphological and functional criteria, regardless of the presence of extracardiac disease, and then groups them into familial / hereditary and non-familial / non-hereditary subtypes.

[0151] In certain embodiments of the present invention, cardiomyopathy is either hereditary cardiomyopathy or acquired cardiomyopathy.

[0152] inflammation There is a relationship between pro-inflammatory biomarkers and incident hypertension, metabolic syndromes, coronary artery disease (CAD), acute coronary syndrome (ACS), peripheral artery disease, stroke, and recurrent coronary and cerebrovascular events. In certain embodiments, systemic inflammation is associated with elevated C-reactive protein (CRP). CRP is a nonspecific marker of inflammation. A range of approximately 2–3 mg / L is considered the limit above which systemic inflammation is likely to be present. The role of inflammation in the pathogenesis of atherosclerosis has been well elucidated over the past 20 years.

[0153] dialysis Dialysis is indicated for individuals at high risk of cardiovascular adverse events.

[0154] In certain embodiments of the present invention, dialysis is hemodialysis or peritoneal dialysis.

[0155] Drug therapy Treating the subject with one or more of the following methods increases the risk of cardiovascular adverse events: (i) Prolyl hydroxylase inhibitors, including, for example, daprodustat, vadadustat, roxadustat, moridustat, and digidusta, which are modulators of the hypoxia-inducible factor (HIF) signaling pathway; (ii) Erythropoiesis-stimulating agents (ESAs), such as erythropoietin (Epo), epoetin alfa (Procrit / Epogen), epoetin beta (NeoRecormon), darbepoetin alfa (Aranesp), and methoxypolyethylene glycol-epoetin beta (Mircera); and (iii) Hepcidin modulators, such as hepcidin agonists or hepcidin antagonists.

[0156] The subjects are taking one or more erythropoiesis-stimulating agents (ESAs) in an effort to control anemia. ESAs work by helping the body produce red blood cells. These red blood cells are then released from the bone marrow into the bloodstream and help maintain blood iron levels. Erythropoiesis-stimulating agents, commonly abbreviated as ESAs, are drugs whose structure and / or function are similar to the cytokine erythropoietin, which stimulates the body's red blood cell production (erythropoiesis). Typical ESAs are structurally and biologically similar to the naturally occurring protein erythropoietin. Examples of commercially available ESAs include erythropoietin (Epo), epoetin alfa (Procrit / Epogen), epoetin beta (NeoRecormon), darbepoetin alfa (Aranesp), and methoxypolyethylene glycol-epoetin beta (Mircera). The two ESAs currently approved for sale in the United States are epoetin alfa (Procrit, Epogen) and darbepoetin alfa (Aranesp).

[0157] ESAs are commonly given to patients with ESRD. These patients typically have low hemoglobin levels because they cannot produce enough erythropoietin. The most common side effects of ESA use include, in particular, high blood pressure; swelling; fever; dizziness; nausea; and pain at the injection site. In addition to these side effects, there are several safety concerns associated with the use of ESAs. ESAs increase the risk of venous thromboembolism (blood clots in the veins). ESAs can also cause excessively high hemoglobin levels, putting patients at higher risk of heart attack, stroke, heart failure, and death.

[0158] In further specific embodiments of the present invention, the subject is treated with an anticoagulant and / or an NSAID.

[0159] Hereditary hemorrhagic capillary dilation Hereditary hemorrhagic capillary dilation (also known as Osler-Weber-Rendu disorder) is a genetic disorder inherited from parents. Its severity can vary greatly from person to person, even within the same family. It is characterized by the development of abnormal connections between arteries and veins called arteriovenous malformations (AVMs). The most common affected locations are the nose, lungs, brain, and liver. These AVMs can enlarge over time, bleed, or rupture, sometimes leading to tragic complications.

[0160] Hereditary iron-refractory iron deficiency anemia Hereditary iron-refractory iron deficiency anemia (IRIDA) is a genetic disorder characterized by impaired absorption and utilization of iron. IRIDA is generally understood to be related to genetic mutations that result in hepcidin upregulation. Specific cases of IRIDA are understood to be related to mutations in the TMPRSS6 gene. IRIDA is generally refractory to oral iron administration but partially responsive to parenteral iron administration.

[0161] FGF23 High levels of fibroblast growth factor 23 (FGF23) are now understood to be a risk factor for cardiovascular disease.

[0162] Fibroblast growth factor 23 (FGF23) is a bone cell-derived hormone that regulates phosphate and vitamin D homeostasis. FGF23 undergoes protein cleavage, resulting in the discovery of uncleaved, or undamaged, FGF23 (iFGF23) and a mix of its cleaved fragments in vivo. The undamaged form, iFGF23, is the active form for phosphate metabolism, controlling urinary excretion of the phosphate; high levels of iFGF23 lead to urinary phosphate disposal. Two main types of antibody assays currently exist: one that captures only iFGF23, and the other that binds to the C-terminal end of the hormone, thus capturing both iFGF23 and its C-terminal fragment. Therefore, the latter metric, cFGF23, is a measure of the sum of the undamaged FGF23 fragment and the C-terminal FGF23 fragment. Therefore, there are two types of studies concerning FGF23, namely iFGF23 and cFGF23, and these have different interpretations.

[0163] High levels of both FGF23 are independently associated with common and incident LVH, cardiovascular events, and mortality in CKD and non-CKD populations. Furthermore, recent studies have demonstrated that FGF23 directly induces LVH, suggesting that FGF23 is not a simple biomarker of cardiovascular risk. Individuals with CKD tend to have very high FGF23 levels due to the body constantly attempting to offset high serum phosphate levels by producing iFGF23, which increases the urinary fraction of phosphate excretion via the kidney. For this reason, iFGF23 levels are elevated in individuals with CKD, and consequently, other downstream effects of iFGF23 may be more pronounced.

[0164] Elevated FGF23 levels help maintain serum phosphate levels within the normal range in CKD, but as estimated glomerular filtration rate (eGFR) decreases, FGF23 concentrations rise, stimulating greater phosphate excretion per nephron and lowering 1,25-dihydroxyvitamin D levels, thereby helping to maintain normal phosphate homeostasis despite reduced renal mass. Parenteral iron administration inhibits renal tubular phosphate reabsorption and 1-alpha-hydroxylation of vitamin D, leading to hypophosphatemia. Data suggest that elevated FGF23 mediates hypophosphatemia.

[0165] Prospective studies in predialysis-induced chronic kidney disease (CKD), incident and common ESRD, and kidney transplant recipient populations have demonstrated that high levels of both FGF23 are independently associated with CKD progression, the occurrence of cardiovascular events, and mortality. Initially, these observations were thought to be driven by high FGF23 levels acting as a highly sensitive biomarker for phosphate-induced toxicity. However, FGF23 itself has now been shown to mediate direct "off-target" end-organ toxicity in the heart, suggesting that high FGF23 levels may represent a novel mechanism for adverse outcomes in CKD.

[0166] In specific embodiments, subjects treated according to the methods described herein for one or more cardiovascular adverse events have high FGF23 levels. The normal level of undamaged FGF23 in the serum of healthy humans is approximately 26.1 pg / mL, and the normal level of C-terminal FGF23 fragments in the serum of healthy humans is approximately 49.0 RU / mL. In certain embodiments, the FGF23 levels of subjects (e.g., undamaged FGF23 and / or C-terminal FGF23 fragments) are high compared to the normal range in healthy humans. In some embodiments, the non-damaged FGF23 level in the serum of the subject is between 250 pg / mL and 350 pg / mL, between 200 pg / mL and 300 pg / mL, between 200 pg / mL and 350 pg / mL, between 300 pg / mL and 350 pg / mL, between 300 pg / mL and 400 pg / mL, or between 250 pg / mL and 500 pg / mL. In certain embodiments, the non-damaged FGF23 level in the serum of the subject is 200 pg / mL, 225 pg / mL, 250 pg / mL, 275 pg / mL, 300 pg / mL, 325 pg / mL, or greater than 350 pg / mL. In some embodiments, the C-terminal FGF23 fragment level in the serum of interest is between 60 RU / mL and 100 RU / mL, between 100 RU / mL and 200 RU / mL, between 200 RU / mL and 300 RU / mL, or between 250 RU / mL and 400 RU / mL. In certain embodiments, the C-terminal FGF23 fragment level in the serum of interest is 60 RU / mL, 100 RU / mL, 125 RU / mL, 150 RU / mL, 175 RU / mL, 200 RU / mL, 225 RU / mL, 250 RU / mL, 275 RU / mL, or greater than 300 RU / mL.

[0167] In some embodiments, subjects treated by the methods disclosed herein experience an increase in hemoglobin concentration and / or a decrease in FGF23. In specific embodiments, subjects treated by the methods disclosed herein experience an increase in the subject's hemoglobin concentration to levels greater than 10 g / dL, greater than 11 g / dL, greater than 12 g / dL, greater than 13 g / dL, or greater than 15 g / dL. In certain embodiments, subjects treated by the methods disclosed herein experience an increase in the subject's hemoglobin concentration to levels of 10 g / dL to 11 g / dL, 11 g / dL to 12 g / dL, 10 g / dL to 13 g / dL, 11 g / dL to 13 g / dL, 11 g / dL to 15 g / dL, or 12 g / dL to 15 g / dL. In some embodiments, subjects treated by the methods disclosed herein experience a decrease of at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% in serum or plasma non-damaged FGF23 levels. In certain embodiments, subjects treated by the methods disclosed herein experience a decrease of 15%–30%, 20%–30%, 25%–50%, 30%–60%, or 15%–60% in serum or plasma non-damaged FGF23 levels. In some embodiments, subjects treated by the methods disclosed herein experience a decrease of at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% in serum or plasma C-terminal FGF23 fragment levels. In some embodiments, subjects treated by the methods disclosed herein experience a decrease in serum or plasma C-terminal FGF23 fragment levels of 15%–30%, 20%–30%, 25%–50%, 30%–60%, or 15%–60%.

[0168] Accordingly, in a first preferred embodiment of this aspect of the present invention, certain groups of subjects to whom the treatment according to the present invention can be applied are subjects with a history of myocardial infarction (MI), stroke, atrial fibrillation (AF), congestive heart failure (CHF), chronic kidney disease (CKD), hypertension, diabetes mellitus, heart valve disorder, obesity, and / or smokers, drinkers, and / or elderly subjects. These include, in particular, subjects with a history of myocardial infarction (MI), stroke, atrial fibrillation (AF), chronic kidney disease (CKD), congestive heart failure (CHF), and / or hypertension. Subjects with a history of myocardial infarction (MI), stroke, and / or congestive heart failure (CHF), particularly subjects with a history of congestive heart failure (CHF), are a particularly preferred group of subjects at risk of cardiovascular adverse events, and therefore the treatment according to the present invention can be applied.

[0169] A subject having a specific condition, disorder, or disease, such as a history of myocardial infarction, stroke, atrial fibrillation, or congestive heart failure (CHF), refers to the subject's past and present medical history. Medical history includes all medical events and problems the subject has experienced, i.e., the subject's previous medical illnesses, diagnoses, and overall health throughout the patient's life. A subject with a history of a specific condition, disorder, or disease does not necessarily have to have that condition, disorder, or disease at a given time to be classified as at risk. A history of a specific condition, disorder, or disease is sufficient. For example, a subject who has quit smoking is still at risk because they have a history of smoking.

[0170] In a second preferred embodiment of this aspect of the present invention, a particular group of subjects to whom the treatment according to the present invention can be applied is subjects having a history of congestive heart failure (CHF). These include subjects having a history of myocardial infarction (MI) and / or stroke. In a preferred embodiment, CHF is heart failure with reduced ejection fraction (HFrEF).

[0171] In a third preferred embodiment of this aspect of the present invention, a particular group of subjects to whom the treatment according to the present invention can be applied is a subject with a history of myocardial infarction (MI). In a preferred embodiment, the MI is STEMI or non-STEMI. In a fourth preferred embodiment of this aspect of the present invention, a particular group of subjects to whom the treatment according to the present invention can be applied is a subject with a history of stroke.

[0172] Subjects as defined herein (i.e., subjects at risk of cardiovascular adverse events and / or with a history of congestive heart failure) include subjects who also have chronic kidney disease (CKD) or subjects who do not have CKD. Subjects with CKD are a specific subgroup of patients to whom the treatment according to the present invention can be applied. In particular, these include subjects with chronic kidney disease (CKD) and congestive heart failure (CHF), where chronic kidney disease (CKD) is preferably non-discharge-type chronic kidney disease (NDD-CKD). In this group (subjects with a history of chronic kidney disease (CKD) and congestive heart failure (CHF), particularly in subjects with non-discharge-type chronic kidney disease (NDD-CKD), the therapeutic benefits of administering iron isomaltoside compared to other iron-carbohydrate complexes are particularly pronounced.

[0173] In one embodiment, subjects with a history of congestive heart failure have HFrEF. In another embodiment, subjects with a history of congestive heart failure have congestive heart failure in NYHA class II-IV, and more particularly HFrEF-type congestive heart failure in NYHA class II-IV.

[0174] In some further embodiments of this aspect of the present invention, a particular group of subjects to whom the treatment according to the present invention can be applied is a subject having one or more of the following risk factors: (i) Patients with atrial fibrillation (AF), particularly those with a history of newly diagnosed AF, paroxysmal AF, or persistent AF; (ii) Subjects with a history of heart valve disorder; (iii) Subjects with a history of hypertension; (iv) Subjects with diabetes; (v) Subjects with a history of obesity; (vi) Elderly individuals, especially those aged 60 or older, 65 or older, 70 or older, 75 or older, or 80 or older; (vii) Smoker; (viii) drinker; (ix) Subjects with hyperthyroidism and / or related thyrotoxicosis; (x) Subjects with chronic obstructive pulmonary disease (COPD); (xi) Patients with cardiomyopathy, particularly hereditary cardiomyopathy or acquired cardiomyopathy; (xii) Subjects with systemic inflammation without infection, in which the systemic inflammation is particularly associated with an increase in C-reactive protein (CRP) beyond approximately 2–3 mg / L; (xiii) Patients undergoing dialysis, specifically hemodialysis or peritoneal dialysis; (xiv) Subjects treated by one or more of the following: a) Prolyl hydroxylase inhibitors, including, for example, daprodustat, vadadustat, roxadustat, moridustat, and digidusta, which are modulators of the hypoxia-inducible factor (HIF) signaling pathway; b) Erythropoiesis-stimulating agents (ESAs), such as erythropoietin (Epo), epoetin alfa (Procrit / Epogen), epoetin beta (NeoRecormon), darbepoetin alfa (Aranesp), and methoxypolyethylene glycol-epoetin beta (Mircera); and c) Hepcidin modulators, e.g., hepcidin agonists or hepcidin antagonists; (xv) Subjects treated with anticoagulants and / or NSAIDs; (xvi) Subjects with hereditary hemorrhagic capillary dilation; or (xvii) Subjects with hereditary iron-refractory iron deficiency anemia.

[0175] II. Therapeutic Benefits In addition to delivering iron to a target, this disclosure provides methods for reducing the incidence or risk of cardiovascular adverse events in a target as defined herein. References to reducing the incidence or risk of “cardiovascular adverse events” or “cardiovascular adverse events” mean reducing the incidence or risk of one or more of the listed events.

[0176] According to one embodiment of this second aspect of the present invention, the cardiovascular adverse events whose incidence or risk is reduced are selected from the group consisting of events affecting the heart (cardiac adverse events); events affecting the peripheral vascular system (peripheral vascular adverse events); events affecting the cerebrovascular system (cerebrovascular adverse events); respiratory, thoracic, and mediastinal adverse events; general adverse events; and infections and invasiveness.

[0177] In a particular embodiment of this second aspect of the present invention, cardiac adverse events with reduced incidence or risk are selected from the group consisting of congestive heart failure, atrial fibrillation, cardiac arrest, atrial block, heart failure, sinoatrial node dysfunction, acute myocardial infarction, bradycardia, angina pectoris, myocardial ischemia, and ventricular premature contractions; peripheral vascular adverse events are selected from the group consisting of hypertension, elevated systolic blood pressure, elevated blood pressure, elevated troponin, and hypotension; cerebrovascular adverse events are selected from the group consisting of cerebrovascular incidental events, cerebral infarction, and transient ischemic attack; respiratory, thoracic, and mediastinal adverse events are selected from the group consisting of dyspnea and pulmonary edema; general adverse events are selected from the group consisting of chest pain and death; and infection and invasiveness are septic shock.

[0178] According to a preferred embodiment of this second aspect of the present invention, the cardiovascular adverse events whose incidence or risk is reduced are selected from the group consisting of events affecting the heart (cardiac adverse events); events affecting the peripheral vascular system (peripheral vascular adverse events); events affecting the cerebrovascular system (cerebrovascular adverse events); and death. Preferably, events affecting the heart (cardiac adverse events) are congestive heart failure, myocardial infarction, unstable angina, and arrhythmias; events affecting the peripheral vascular system (peripheral vascular adverse events) are hypertension; and events affecting the cerebrovascular system (cerebrovascular adverse events) are stroke.

[0179] According to a particularly preferred embodiment of this second aspect of the present invention, the cardiovascular adverse events whose incidence or risk is reduced are selected from the group consisting of congestive heart failure, myocardial infarction, unstable angina, arrhythmia, hypertension, hypotension, stroke, and death.

[0180] According to a further particularly preferred embodiment of this second aspect of the present invention, the cardiovascular adverse events whose incidence or risk is reduced are congestive heart failure, atrial fibrillation, hypertension, and / or cardiac arrest.

[0181] Therefore, in a particularly preferred embodiment of this second aspect of the present invention, the cardiovascular adverse event whose incidence or risk is reduced is congestive heart failure.

[0182] Therefore, in a particularly preferred embodiment of this second aspect of the present invention, the cardiovascular adverse event whose incidence or risk is reduced is atrial fibrillation.

[0183] Therefore, in a particularly preferred embodiment of this second aspect of the present invention, the cardiovascular adverse event whose incidence or risk is reduced is hypertension.

[0184] Therefore, in a particularly preferred embodiment of this second aspect of the present invention, the cardiovascular adverse event whose incidence or risk is reduced is cardiac arrest.

[0185] Specific cardiovascular adverse events related to congestive heart failure include hospitalization, hospitalization due to exacerbation of congestive heart failure, or death due to congestive heart failure. The present invention particularly focuses on cardiovascular adverse events in which the cardiovascular adverse event is CHF (congestive heart failure).

[0186] III. Therapeutic benefits in selected subjects Considering the specific groups of subjects as defined herein, and the cardiovascular adverse events whose incidence or risk is reduced, the present invention, according to a third aspect, provides a method for treating iron deficiency in subjects, wherein the treatment of iron deficiency reduces the incidence or risk of cardiovascular adverse events in subjects, and the method comprises administering an effective amount of iron isomaltoside. The target is, (A) Subjects at risk of cardiovascular adverse events as defined herein; (B) Subjects with a history of congestive heart failure (CHF); or (C) Subjects with a history of congestive heart failure (CHF) and at risk of cardiovascular adverse events. And, Cardiovascular adverse events whose incidence or risk is reduced, (a) congestive heart failure, myocardial infarction, unstable angina, arrhythmia, hypertension, hypotension, stroke, and death; (b) Congestive heart failure; (c) Atrial fibrillation; (d) hypertension; or (e) cardiac arrest This relates to a method of selecting from a group consisting of the following.

[0187] According to a preferred embodiment of this third aspect of the present invention, the subjects are at risk of cardiovascular adverse events, and the cardiovascular adverse event whose incidence or risk is reduced is congestive heart failure.

[0188] According to a more preferred embodiment of this third aspect of the present invention, the subject is a subject at risk of a cardiovascular adverse event, the cardiovascular adverse event whose incidence or risk is reduced is atrial fibrillation.

[0189] According to a more preferred embodiment of this third aspect of the present invention, the subject is a subject at risk of a cardiovascular adverse event, the cardiovascular adverse event whose incidence or risk is reduced is cardiac arrest.

[0190] According to a more preferred embodiment of this third aspect of the present invention, the subject is a subject having a history of congestive heart failure (CHF), and the cardiovascular adverse events for which the incidence or risk is reduced are cardiac arrest, congestive heart failure, or both.

[0191] According to a more preferred embodiment of this third aspect of the present invention, the subject is a subject with a history of congestive heart failure (CHF), and the cardiovascular adverse event for which the incidence or risk is reduced is congestive heart failure.

[0192] According to a more preferred embodiment of this third aspect of the present invention, the subject is a subject having a history of congestive heart failure (CHF), and the cardiovascular adverse event for which the incidence or risk is reduced is atrial fibrillation.

[0193] According to a more preferred embodiment of this third aspect of the present invention, the subject is a subject with a history of congestive heart failure (CHF), and the cardiovascular adverse event for which the incidence or risk is reduced is cardiac arrest.

[0194] According to a more preferred embodiment of this third aspect of the present invention, the subject is a subject with a history of congestive heart failure (CHF), and the cardiovascular adverse event for which the incidence or risk is reduced is hypertension.

[0195] According to another embodiment of this third aspect of the present invention, the subjects are subjects at risk of cardiovascular harm and / or have a history of congestive heart failure, and the subjects have chronic kidney disease (CKD). According to another embodiment of this third aspect of the present invention, the subjects are subjects at risk of cardiovascular harm and / or have a history of congestive heart failure, and the subjects do not have chronic kidney disease (CKD). In particular, these include subjects having chronic kidney disease (CKD) and / or congestive heart failure (CHF), where chronic kidney disease (CKD) is preferably non-discharge-stage chronic kidney disease (NDD-CKD).

[0196] According to a further particularly preferred embodiment of this third aspect of the present invention, the subjects are those having a history of congestive heart failure (CHF) and chronic kidney disease (CKD), particularly non-disruptive chronic kidney disease (NDD-CKD), and the cardiovascular adverse event for which the incidence or risk is reduced is congestive heart failure.

[0197] According to a further particularly preferred embodiment of this third aspect of the present invention, the subjects are those having a history of congestive heart failure (CHF) and chronic kidney disease (CKD), particularly non-dialysis-dependent chronic kidney disease (NDD-CKD), and the cardiovascular adverse event for which the incidence or risk is reduced is atrial fibrillation.

[0198] According to a further particularly preferred embodiment of this third aspect of the present invention, the subjects are those having a history of congestive heart failure (CHF) and chronic kidney disease (CKD), particularly non-dialysis-dependent chronic kidney disease (NDD-CKD), and the cardiovascular adverse event for which the incidence or risk is reduced is cardiac arrest.

[0199] According to a further particularly preferred embodiment of this third aspect of the present invention, the subjects are those having a history of congestive heart failure (CHF) and chronic kidney disease (CKD), particularly non-dialysis-dependent chronic kidney disease (NDD-CKD), and the cardiovascular adverse event for which the incidence or risk is reduced is hypertension.

[0200] In some of these embodiments, subjects with a history of congestive heart failure have HFrEF. In some embodiments, subjects with a history of congestive heart failure have congestive heart failure in NYHA class II-IV, and in particular, HFrEF-type congestive heart failure in NYHA class II-IV.

[0201] In other embodiments, the Disclosure provides methods for reducing the incidence or risk of hospitalization for cardiovascular adverse events in the subject matter as defined herein.

[0202] In some embodiments, this disclosure provides methods for reducing mortality and morbidity, i.e., mortality, attributable to cardiovascular adverse events, in the subject matter as defined herein.

[0203] IV. Medication and Administration Regimen A method for treating iron deficiency in a person at risk of cardiovascular adverse events according to the present invention comprises administering an effective amount of iron isomaltoside. Therefore, the method of the present invention may include, according to a preferred embodiment, determining whether the patient is iron deficient before administering the iron isomaltoside, and administering the iron isomaltoside if the patient is iron deficient. More specifically, the method of the present invention further comprises determining whether the patient is at risk of cardiovascular adverse events before administering the iron isomaltoside, and administering the iron isomaltoside if the patient is at risk of cardiovascular adverse events.

[0204] A typical treatment regimen for iron isomaltoside consists of either a single intravenous infusion of 1000 mg of iron, a maximum dose of elemental iron at a rate of 20 mg iron / kg body weight, or an intravenous bolus injection of up to 500 mg, up to three times per week. The cumulative iron requirement can be determined using the Ganzoni formula, and according to one embodiment, the calculated dose is administered. Alternatively, the cumulative dose to be administered is selected according to the table below. TIFF0007897915000002.tif27170

[0205] Alternatively, a typical treatment regimen for iron isomaltoside is selected according to the table below. TIFF0007897915000003.tif42170

[0206] Therefore, in some embodiments, the effective amount of iron isomaltoside is elemental iron in the range of about 500 mg to 2000 mg, for example, 500 mg, 1000 mg, 1500 mg, or 2000 mg, and can be administered as a single dose or in two or more doses, particularly two or three doses. Alternatively, the effective amount of iron isomaltoside is up to 50 mg iron / kg body weight, particularly up to 30 mg iron / kg body weight, or preferably up to 20 mg iron / kg body weight.

[0207] In certain embodiments, the dose is a single daily dose. For example, a typical single daily dose of iron isomaltoside is 1000 mg of elemental iron.

[0208] For repeated administration, a first dose of elemental iron of 200-700 mg, preferably 300-600 mg, most preferably up to 500 mg, is followed by a second dose of elemental iron of 200-700 mg, preferably 300-600 mg, most preferably up to 500 mg. The two doses may be administered within one month, two weeks, or preferably within one week. Preferably, they are administered within one week. A further dose of iron isomaltoside, for example, a third dose of elemental iron of 200-700 mg, preferably 300-600 mg, most preferably up to 500 mg, may follow. This further, for example, third dose, may be administered within the same time frame, i.e., within one month, two weeks, or preferably within one week. These multiple doses are preferably administered as a bolus injection. It is even more preferable if each dose is administered at least two days apart, particularly three days apart. For example, if three doses are administered within one week, it is preferable that these doses be administered on day 1, day 4, and day 7.

[0209] When using bepectate ferric as the iron-carbohydrate complex of the present invention, the effective cumulative dose as elemental iron can be similarly determined based on the Ganzoni formula or the table presented above. Alternatively, 1000 mg or 1500 mg of elemental iron can be used as the effective cumulative dose. A suitable single dose of bepectate ferric, i.e., the dose administered at one time, is, for example, 500 mg, 1000 mg, or 1500 mg, with a maximum of 15 mg / kg, or alternatively, a maximum of 20 mg / kg. Alternatively, a suitable single dose can be 15 mg / kg or 20 mg / kg body weight.

[0210] For CKD patients undergoing hemodialysis, repeated doses of iron isomaltoside or ferric bepectate, such as 100 mg to 500 mg, preferably 100 mg or 200 mg, may be administered in combination with dialysis sessions.

[0211] C. Drug combinations A combination of iron isomaltoside and one or more additional drugs for use in the treatment of iron deficiency according to the present invention, wherein the additional drugs are (1) Angiotensin-converting enzyme inhibitors (ACEIs), such as captopril, enalapril, lisinopril, ramipril, or trandolapril; (2) Beta-blockers, such as bisoprolol, carvedilol, metoprolol succinate, or nevivolol; (3) Inorganocorticoid receptor antagonists (MRAs), such as eplerenone or spironolactone; (4) Angiotensin receptor blockers, e.g., candesartan, valsartan, or losartan; (5) If channel blockers, e.g., ivabradine; (6) Angiotensin receptor neprilysin inhibitors, such as sacubitril / valsartan, and (7) Diuretics, such as furosemide, bumetanide, torasemide, bendroflumethoazide, hydrochlorothiazide, metrazone, indapamide, amiloride, or triamterene Combinations selected from the group consisting of are further described herein.

[0212] The dosage for additional medications typically refers to the amount administered to adults. Dosages for infants may be adjusted accordingly.

[0213] A particular combination of iron isomaltoside and one or more additional drugs for use in the treatment of iron deficiency according to the present invention is one in which the additional drugs increase the risk of cardiovascular adverse events in the subject. According to this embodiment, the additional drugs are (i) Prolyl hydroxylase inhibitors, including, for example, daprodustat, vadadustat, roxadustat, moridustat, and digidusta, which are modulators of the hypoxia-inducible factor (HIF) signaling pathway; (ii) Erythropoiesis-stimulating agents (ESAs), such as erythropoietin (Epo), epoetin alfa (Procrit / Epogen), epoetin beta (NeoRecormon), darbepoetin alfa (Aranesp), and methoxypolyethylene glycol-epoetin beta (Mircera); and (iii) Heptidine modulators, e.g., heptidine agonists or heptidine antagonists It is selected from the group consisting of the following.

[0214] Exemplary Embodiments 1. A method for treating iron deficiency in a person at risk of cardiovascular adverse events, comprising administering an effective amount of iron isomaltoside.

[0215] 2. The method according to Embodiment 1, wherein subjects at risk of cardiovascular adverse events include subjects with a history of myocardial infarction (MI), stroke, atrial fibrillation (AF), congestive heart failure (CHF), chronic kidney disease (CKD), hypertension, diabetes mellitus, heart valve disorder, or obesity, as well as / or smokers, drinkers, and / or elderly subjects.

[0216] 3. The method according to Embodiment 2, wherein the subjects at risk of cardiovascular adverse events are subjects with a history of myocardial infarction (MI), a history of stroke, a history of atrial fibrillation (AF), a history of chronic kidney disease (CKD), a history of congestive heart failure (CHF), and / or a history of hypertension.

[0217] 4. The method according to Embodiment 3, wherein the subjects at risk of cardiovascular adverse events are subjects with a history of myocardial infarction (MI), a history of stroke, and / or a history of congestive heart failure (CHF).

[0218] 5. A method for treating iron deficiency in a subject with a history of congestive heart failure (CHF), comprising administering an effective amount of iron isomaltoside.

[0219] 6. The method according to Embodiment 5, wherein a subject with a history of congestive heart failure (CHF) also has a history of myocardial infarction (MI) and / or stroke.

[0220] 7. The method according to any one of Embodiments 2 to 6, wherein congestive heart failure (CHF) is heart failure with reduced ejection fraction (HFrEF).

[0221] 8. The method according to Embodiments 1 to 4, wherein the subject at risk of cardiovascular adverse events is a subject with a history of myocardial infarction (MI).

[0222] 9. The method according to Embodiment 8, wherein the myocardial infarction (MI) is STEMI or non-STEMI.

[0223] 10. The method according to Embodiments 1 to 4, wherein the subject at risk of cardiovascular adverse events is a subject with a history of stroke.

[0224] 11. The method according to any one of Embodiments 1 to 7, wherein the subject is at risk of cardiovascular adverse events and / or has a history of congestive heart failure, and the subject has chronic kidney disease (CKD).

[0225] 12. The method according to any one of Embodiments 1 to 7, wherein the subject is at risk of cardiovascular adverse events and / or has congestive heart failure, and the subject does not have chronic kidney disease (CKD).

[0226] 13. The method according to any one of Embodiments 1 to 11, wherein the subject at risk of cardiovascular adverse events is a subject having chronic kidney disease (CKD) and a history of congestive heart failure (CHF).

[0227] 14. The method according to Embodiment 13, wherein the subject has a history of congestive heart failure and has HFrEF.

[0228] 15. The method according to Embodiment 13 or 14, wherein the subject has a history of congestive heart failure and has congestive heart failure in New York Heart Association (NYHA) Class II-IV.

[0229] 16. The method according to any one of embodiments 11 to 15, wherein the chronic kidney disease (CKD) is non-disruptive chronic kidney disease (NDD-CKD).

[0230] 17. The method according to Embodiments 1 to 3, wherein the subject at risk of cardiovascular adverse events is a subject with a history of atrial fibrillation (AF).

[0231] 18. The method according to Embodiment 17, wherein the atrial fibrillation (AF) is first diagnosed AF, proximal AF, or persistent AF.

[0232] 19. The method according to embodiment 1 or 2, wherein the subject at risk of cardiovascular adverse events is a subject with a history of heart valve disorder.

[0233] 20. The method according to any one of embodiments 1 to 3, wherein the subject at risk of cardiovascular adverse events is a subject with a history of hypertension.

[0234] 21. The method according to embodiment 1 or 2, wherein the subject at risk of cardiovascular adverse events is a subject with diabetes.

[0235] 22. The method according to embodiment 1 or 2, wherein the subject at risk of cardiovascular adverse events is a subject with a history of obesity.

[0236] 23. The method according to embodiment 1 or 2, wherein the subject at risk of cardiovascular adverse events is an elderly subject, a smoker, or a drinker.

[0237] 24. The method according to embodiment 23, wherein the elderly subject is 60 years old or older, 65 years old or older, 70 years old or older, 75 years old or older, or 80 years old or older.

[0238] 25. The method according to embodiment 1, wherein the subject at risk of cardiovascular adverse events is a subject with hyperthyroidism and / or related thyrotoxicosis.

[0239] 26. The method according to embodiment 1, wherein the subject at risk of cardiovascular adverse events is a subject with chronic obstructive pulmonary disease (COPD).

[0240] 27. The method according to embodiment 1, wherein the subject at risk of cardiovascular adverse events is a subject with cardiomyopathy.

[0241] 28. The method according to embodiment 27, wherein the cardiomyopathy is hereditary cardiomyopathy or acquired cardiomyopathy. <e000925> 29. The method according to embodiment 1, wherein the subject at risk of cardiovascular adverse events is a subject with systemic inflammation without infection.

[0243] 30. The method according to Embodiment 29, wherein systemic inflammation is associated with an increase in C-reactive protein (CRP) beyond approximately 2-3 mg / L.

[0244] 31. The method according to Embodiment 1, wherein the subject at risk of cardiovascular adverse events is a subject undergoing dialysis.

[0245] 32. The method according to embodiment 31, wherein dialysis is hemodialysis or peritoneal dialysis.

[0246] 33. The patient is at risk of one or more of the following cardiovascular adverse events: a) Prolyl hydroxylase inhibitors, including, for example, daprodustat, vadadustat, roxadustat, moridustat, and digidusta, which are modulators of the hypoxia-inducible factor (HIF) signaling pathway; b) Erythropoiesis-stimulating agents (ESAs), such as erythropoietin (Epo), epoetin alfa (Procrit / Epogen), epoetin beta (NeoRecormon), darbepoetin alfa (Aranesp), and methoxypolyethylene glycol-epoetin beta (Mircera); and c) Heptidine modulators, e.g., heptidine agonists or heptidine antagonists The method according to Embodiment 1, wherein the subject is treated by [the method].

[0247] 34. The method according to Embodiment 1, wherein the subject at risk of cardiovascular adverse events is a subject treated with an anticoagulant and / or an NSAID.

[0248] 35. The method according to Embodiment 1, wherein the subject at risk of cardiovascular adverse events is a subject with hereditary hemorrhagic capillary dilation.

[0249] 36. The method according to Embodiment 1, wherein the subject at risk of cardiovascular adverse events is a subject with hereditary iron-refractory iron deficiency anemia.

[0250] 37. The method according to any one of embodiments 1 to 36, wherein the iron deficiency is iron deficiency anemia.

[0251] 38. The method according to any one of embodiments 1 to 37, wherein the subject has chronic iron depletion or malabsorption.

[0252] 39. The method according to any one of embodiments 1 to 38, wherein the subject is intolerant to oral iron administration or oral iron administration is ineffective.

[0253] 40. The method according to any one of embodiments 1 to 39, wherein the iron deficiency is defined as TSAT < 20% and / or ferritin < 100 μg / L.

[0254] 41. The method according to any one of embodiments 1 to 40, wherein treatment of iron deficiency reduces the incidence or risk of cardiovascular adverse events in the subject.

[0255] 42. The method according to embodiment 41, wherein the cardiovascular adverse event is an event affecting the heart (cardiac adverse event); an event affecting the peripheral vascular system (peripheral vascular adverse event); an event affecting the cerebrovascular system (cerebrovascular adverse event); a respiratory, thoracic and mediastinal adverse event; a general adverse event; and an event selected from the group consisting of an infection and an invasion.

[0256] 43. The cardiac adverse event is selected from the group consisting of congestive heart failure, atrial fibrillation, cardiac arrest, atrial block, heart failure, sinoatrial node dysfunction, acute myocardial infarction, bradycardia, angina pectoris, myocardial ischemia, and ventricular premature beats; the peripheral vascular adverse event is selected from the group consisting of hypertension, increased systolic blood pressure, increased blood pressure, increased troponin, and hypotension; the cerebrovascular adverse event is selected from the group consisting of cerebrovascular accidental symptoms, cerebral infarction, and transient ischemic attack; the respiratory, thoracic and mediastinal adverse event is selected from the group consisting of dyspnea and pulmonary edema; the general adverse event is selected from the group consisting of chest pain and death; and the infection and invasion is septic shock, according to the method of embodiment 42.

[0257] 44. The method according to Embodiment 41, wherein cardiovascular adverse events are selected from the group consisting of events affecting the heart (cardiac adverse events); events affecting the peripheral vascular system (peripheral vascular adverse events); events affecting the cerebrovascular system (cerebrovascular adverse events); and death.

[0258] 45. The method according to Embodiment 44, wherein the cardiac adverse events affecting the heart are congestive heart failure, myocardial infarction, unstable angina, and arrhythmia; the peripheral vascular adverse events affecting the peripheral vascular system are hypertension; and the cerebrovascular adverse events affecting the cerebrovascular system are stroke.

[0259] 46. ​​The method according to Embodiment 41, wherein the cardiovascular adverse event is selected from the group consisting of congestive heart failure, myocardial infarction, unstable angina, arrhythmia, hypertension, hypotension, stroke, and death.

[0260] 47. The method according to embodiments 41 to 42, wherein the cardiovascular adverse event is selected from the group consisting of congestive heart failure, atrial fibrillation, hypertension, and cardiac arrest.

[0261] 48. The method according to any one of embodiments 41 to 47, wherein the cardiovascular adverse event is congestive heart failure.

[0262] 49. The method according to Embodiment 41, wherein the cardiovascular adverse event is hospitalization or death due to congestive heart failure.

[0263] 50. The method according to Embodiment 49, wherein the cardiovascular adverse event is hospitalization due to congestive heart failure.

[0264] 51. The method according to Embodiment 49, wherein the cardiovascular adverse event is death due to congestive heart failure.

[0265] 52. The method according to Embodiment 41, wherein the cardiovascular adverse event is cardiovascular death and / or hospitalization resulting from the exacerbation of congestive heart failure.

[0266] 53. The method according to any one of embodiments 41 to 43 and 47, wherein the cardiovascular adverse event is atrial fibrillation.

[0267] 54. The method according to Embodiments 41 to 47, wherein the cardiovascular adverse event is hypertension.

[0268] 55. The method according to any one of embodiments 41 to 43 and 47, wherein the cardiovascular adverse event is cardiac arrest.

[0269] 56. The method according to any one of Embodiments 41 to 55, wherein the iron isomaltoside is deliisomaltose ferric.

[0270] 57. A method for treating iron deficiency in a subject, wherein the treatment of iron deficiency reduces the incidence or risk of cardiovascular adverse events in the subject, and the method comprises administering an effective amount of iron isomaltoside. The target is, (A) Patients at risk of cardiovascular adverse events; (B) Subjects with a history of congestive heart failure (CHF); or (C) Patients with a history of congestive heart failure (CHF) and at risk of cardiovascular adverse events. And, Cardiovascular adverse events whose incidence or risk is reduced, (a) congestive heart failure, myocardial infarction, unstable angina, arrhythmia, hypertension, hypotension, stroke, and death; (b) Congestive heart failure; (c) Atrial fibrillation; (d) hypertension; or (e) cardiac arrest A method selected from the group consisting of the following.

[0271] 58. The method according to Embodiment 57, wherein the subject is at risk of cardiovascular adverse events, and the cardiovascular adverse event for which the incidence or risk is reduced is congestive heart failure.

[0272] 59. The method according to Embodiment 57, wherein the subject is at risk of cardiovascular adverse events, and the cardiovascular adverse event for which the incidence or risk is reduced is atrial fibrillation.

[0273] 60. The method according to Embodiment 57, wherein the subject is at risk of cardiovascular adverse events, and the cardiovascular adverse event whose incidence or risk is reduced is cardiac arrest.

[0274] 61. The method according to Embodiment 57, wherein the subject has a history of congestive heart failure (CHF), and the cardiovascular adverse event for which the incidence or risk is reduced is cardiac arrest, congestive heart failure, or both.

[0275] 62. The method according to Embodiment 57, wherein the subject has a history of congestive heart failure (CHF), and the cardiovascular adverse event for which the incidence or risk is reduced is congestive heart failure.

[0276] 63. The method according to Embodiment 57, wherein the subject has a history of congestive heart failure (CHF), and the cardiovascular adverse event for which the incidence or risk is reduced is atrial fibrillation.

[0277] 64. The method according to Embodiment 57, wherein the subject has a history of congestive heart failure (CHF), and the cardiovascular adverse event for which the incidence or risk is reduced is cardiac arrest.

[0278] 65. The method according to any one of embodiments 57 to 64, wherein the subject is at risk of cardiovascular adverse events and / or has a history of congestive heart failure, and the subject has chronic kidney disease (CKD).

[0279] 66. The method according to any one of embodiments 57 to 64, wherein the subject is at risk of cardiovascular adverse events and / or has congestive heart failure, and the subject does not have chronic kidney disease (CKD).

[0280] 67. The method according to embodiment 65 or 66, wherein the chronic kidney disease (CKD) is non-disruptive chronic kidney disease (NDD-CKD).

[0281] 68. The method according to Embodiment 57 or any one of Embodiments 61 to 67, wherein a subject having a history of congestive heart failure has HFrEF.

[0282] 69. The method according to any one of Embodiments 57 or 61 to 68, wherein the subject has a history of congestive heart failure and has congestive heart failure in NYHA class II to IV.

[0283] 70. The method according to embodiments 57 to 69, wherein the cardiovascular adverse event whose incidence or risk is reduced is cardiovascular death and / or hospitalization due to worsening of congestive heart failure.

[0284] 71. The method according to Embodiment 57, wherein the subject at risk of cardiovascular adverse events is a subject with chronic kidney disease (CKD) and a history of congestive heart failure (CHF).

[0285] 72. The method according to any one of embodiments 41 to 71, wherein the iron deficiency is iron deficiency anemia.

[0286] 73. The method according to any one of embodiments 41 to 72, wherein the subject has chronic iron deficiency or malabsorption.

[0287] 74. The method according to any one of Embodiments 41 to 73, wherein the subject is one that does not tolerate or for which oral iron administration is ineffective.

[0288] 75. The method according to any one of embodiments 41 to 74, wherein iron deficiency is defined as TSAT < 20% and / or ferritin < 100 μg / L.

[0289] 76. The method according to any one of embodiments 57 to 75, wherein the iron isomaltoside is ferric delisomaltose.

[0290] 77. The method according to any one of Embodiments 1 to 76, further comprising determining whether the patient is at risk of cardiovascular adverse events before administering the iron isomaltoside.

[0291] 78. The method according to Embodiment 77, wherein the patient is at risk of cardiovascular adverse events, the iron isomaltoside is administered.

[0292] 79. A method for preventing or treating atrial fibrillation (AF) or a disorder that makes the animal more susceptible to AF, in an animal suffering from such a condition, the method according to any one of Embodiments 1 to 78, comprising administering a therapeutically effective amount of iron to such an animal.

[0293] 80. The method according to claim 79, wherein the disorder that makes one more susceptible to AF is selected from heart valve disease, hypertension, heart failure, coronary artery disease, obesity, and diabetes mellitus.

[0294] 81. The method according to claim 79 or 80, wherein the animal is a mammal.

[0295] 82. The method according to claim 81, wherein the animal is a human.

[0296] 83. The method according to any one of claims 79 to 82, wherein the AF is paroxysmal, persistent, long-term, or chronic.

[0297] 84. The method according to any one of claims 79 to 83, wherein the iron preparation is administered orally, intramuscularly, or intravenously.

[0298] 85. The method according to any one of claims 79 to 84, wherein the animal is iron deficient.

[0299] 86. The method according to any one of claims 79 to 85, wherein the animal is not iron deficient.

[0300] 87. The method according to any one of claims 79 to 86, for reducing AF symptoms, such as palpitations or shortness of breath, exercise intolerance, hospitalization, heart failure, stroke, and death.

[0301] 88. The method according to any one of claims 79 to 87, wherein the animal has myocardial iron deficiency.

[0302] 89. The method according to any one of claims 79 to 88, wherein the myocardial iron deficiency responds to supplementation despite having normal blood tests for iron deficiency.

[0303] The present disclosure will be further illustrated by the following embodiments, which should not be construed as further limitations. All figures and all references, Genbank sequences, and the contents of all published patent applications cited throughout this application are incorporated herein by express reference. [Examples]

[0304] Two Phase III randomized, open-label comparative safety and efficacy trials were conducted on adult human subjects with iron deficiency anemia and non-dialysis-dependent chronic kidney disease, involving treatment with iron isomaltoside ("IIM", trade names Monofer®, Monoferric®) and iron sucrose ("IS", trade name Venofer®). These trials allowed for a comparison of the incidence of cardiovascular adverse events associated with treatment, particularly in patients with cardiovascular risk factors.

[0305] Test design The study was a randomized, open-label, comparative trial. Participants with iron deficiency anemia (IDA) were randomly assigned in a 1:1 ratio to one of two treatment courses. Iron isomaltoside 1000 was administered as a single dose of 1000 mg of elemental iron. Iron sucrose was administered as a slow intravenous bolus injection of 200 mg, according to its U.S. labeling, and repeated up to five times to reach a cumulative dose of 1000 mg.

[0306] the goal The study allowed for a comparison of the incidence of protocol-defined cardiovascular adverse events in subjects with IDA and non-dialysis-dependent chronic kidney disease treated with iron isomaltoside or iron sucrose.

[0307] The cardiovascular adverse events defined by the protocol were as follows: (1) Congestive heart failure requiring hospitalization or medical intervention: Congestive heart failure requiring hospitalization or medical intervention was defined as meeting the following criteria: - Inpatient treatment is required, defined as admission to an inpatient ward or visit to the emergency department, resulting in a stay of at least 12 hours (or a change of date if the admission / discharge time is unknown); and - The following: Clinical findings of congestive heart failure including new dyspnea, orthopnea, paroxysmal nocturnal dyspnea, edema, moist rales at the base of the lungs, jugular vein distension, or at least one of these worsening conditions, or radiological evidence of worsening heart failure, as well as - Addition / increase in treatment: • Intravenous treatment with diuretics, inotropes, or vasodilators; or • Mechanical or surgical procedures (mechanical circulatory support, heart transplantation, or ventricular pacing to improve cardiac function), or specifically the use of ultrafiltration, hemofiltration, or dialysis for the treatment of heart failure.

[0308] (2) Arrhythmia Arrhythmia was defined as any symptomatic deviation from normal sinus rhythm experienced by a subject, as assessed by a healthcare provider. Assessments included physical examination upon outpatient visit, ECG, or hospital admission. Arrhythmias included any conduction abnormality, atrioventricular block, QTc interval prolongation, supraventricular / nodular arrhythmias, vasovagal syncope, ventricular arrhythmias, or other cardiovascular arrhythmias.

[0309] (3) Hypertension During the observation period immediately following administration of the investigational drug, hypertension was defined as a systolic blood pressure increase of more than 20 mmHg resulting in a value greater than 180 mmHg, or a diastolic blood pressure increase of more than 15 mmHg resulting in a value greater than 105 mmHg.

[0310] After a subject is released from clinical trial visits for drug therapy, hypertension was defined as requiring an unscheduled outpatient visit, hospitalization, or change in medical treatment (e.g., administration of antihypertensive drugs) in relation to an objective criterion of elevated blood pressure (a systolic blood pressure increase of more than 20 mmHg resulting in a value greater than 180 mmHg, or a diastolic blood pressure increase of more than 15 mmHg resulting in a value greater than 105 mmHg).

[0311] (4) Hypotension During the observation period immediately following administration of the investigational drug, hypotension was defined as a decrease in systolic blood pressure of more than 20 mmHg resulting in a value of less than 90 mmHg, or a decrease in diastolic blood pressure of more than 15 mmHg resulting in a value of less than 50 mmHg.

[0312] After a subject was released from a clinical trial visit for drug therapy, hypotension was defined as requiring an unscheduled outpatient visit, hospitalization, or change in medical treatment (e.g., fluid / excessive volume, retention of antihypertensive medication) in association with an objective blood pressure decline (a decrease in systolic blood pressure of more than 20 mmHg resulting in a value of less than 90 mmHg, or a decrease in diastolic blood pressure of more than 15 mmHg resulting in a value of less than 50 mmHg).

[0313] (5) Myocardial infarction (MI): Myocardial infarction (MI) was defined as the presence of characteristic changes in cardiac enzyme markers in the context of any of the time-related symptoms of acute coronary syndrome, or electrocardiogram (ECG) changes consistent with either ischemia or infarction. The cardiac enzyme markers indicating MI included the following: - Appropriate increases and decreases in serum troponin (I or T) or creatine kinase-MB, with at least one value ≥ 2 × upper normal (ULN). If only one value was measured and it was ≥ 2 × ULN, the event was determined based on the overall clinical evidence. - When measuring total creatine phosphokinase only, a continuous change (i.e., at least two values) was required to be 2 × ULN or greater.

[0314] Symptoms of ischemia had to be present for at least 10 minutes and included chest pain, chest tightness, or chest constriction. Dyspnea, sweating, or nausea were considered symptoms of ischemia and were determined based on the overall clinical evidence.

[0315] The change in ECG was defined as follows: - Novel Q waves in two or more proximity leads; - ST segment progression in response to T-wave changes in two or more adjacent leads (e.g., transient ST segment depression of 0.5 mm or more) - New left branch block; or - 1 mm ST portion elevation in two or more proximity guidance systems.

[0316] (6) Stroke: Stroke was defined as the sudden onset of non-reversible focal neurological impairment within 24 hours, caused by vascular factors, including the central nervous system, and not by another readily identifiable cause (i.e., brain tumor or trauma). Stroke was further classified as hemorrhagic, ischemic, or of unknown cause.

[0317] (7) Unstable angina requiring hospitalization: Unstable angina requiring hospitalization was defined as ischemic symptoms that meet the following criteria: - Lasting for more than 10 minutes and considered to be myocardial ischemia at the time of final diagnosis; - Requiring an unscheduled visit to a medical facility and an overnight stay (excluding a chest pain observation room); and - At least one of the following: • New dynamic ECG changes, • Evidence of ischemia by or without cardiac imaging in stress tests, • Angiographic evidence of lesions and / or thrombosis in more than 70% of the epicardial coronary arteries.

[0318] (8) Death due to any cause: The date on which the death of the subject was declared was determined to be the date of death due to some cause.

[0319] The secondary efficacy objective of the study was to compare the effects of treatment with iron isomaltoside and iron carboxymaltose in subjects with IDA (Indicative Deficient Affective Absorbance) in hemoglobin (Hb), s-ferritin, and transferrin saturation (TSAT).

[0320] Evaluation items The primary safety outcome measure was the incidence of protocol-defined hypersensitivity reactions within 8 weeks (the number of participants experiencing such events).

[0321] The primary efficacy outcome measure was the ability to increase Hb (g / dL) within 8 weeks.

[0322] The second safety outcome measure was the incidence of protocol-defined cardiovascular adverse events within 8 weeks (the number of participants experiencing such events).

[0323] The second efficacy outcome measure was the change in s-ferritin (ng / mL) within 8 weeks and the change in transferrin saturation (%) within 8 weeks.

[0324] Safety assessment The test included the following safety assessments: • Collect AE data and evaluate its relevance, severity, severity, and predictiveness. Report these to the authorities and monitor the situation in accordance with international and regional requirements. • Physical examination, vital sign measurements, ECG, height, weight, and safety laboratory parameters.

[0325] Effectiveness assessment The study included the following effectiveness assessments: • Hb, s-ferritin, TSAT (s-iron and transferrin)

[0326] Trial period and number of visits For each individual participant, the trial period was 8 weeks (including a 28-day screening period), and each participant visited the clinic 6 to 8 times.

[0327] Target group The following criteria were met for eligibility: 1. Male or female > 18 years old; 2. Hb ≤ 11 g / dL; and 3. You are willing to participate and will sign the Informed Consent Form (ICF).

[0328] IDA-03 The additional inclusion criteria for the IDA-03 trial were as follows: 1. IDA resulting from various etiologies*, such as abnormal uterine bleeding, gastrointestinal disorders, cancer, debulking procedures (gastric bypass surgery), and other conditions that lead to significant blood loss; 2. TSAT < 20%; 3. S-ferritin ≤ 100 ng / mL; and 4. A documented history of intolerance or non-responsiveness** to oral iron therapy for at least one month prior to trial enrollment.

[0329] The average age of the patients was 44 years (range 18-91 years), and 89% were female.

[0330] CKD-04 The additional inclusion criteria for the CKD-04 trial were as follows: 1. (i) Screening shows eGFR < 60 mL / min / 1.73 m² 2 (Calculated by dietary modification therapy for renal disease (MDRD)), or (ii) eGFR < 90 mL / min / 1.73 m² on screening. 2Chronic kidney disease as defined by any of the following, and kidney injury indicated by abnormalities in urinary composition in medical history, and / or moderate / high-risk cardiovascular disease based on the Framingham model; 2. Screening for s-ferritin ≤100 ng / mL or ≤300 ng / mL if TSAT ≤30%; and 3. No ESA or stable dose (±20%) of ESA during the 4 weeks prior to randomization.

[0331] The average age of the patients was 69 years (range 25-97 years), and 63% were female. *The etiology of IDA (even if unknown) was documented in the patient's history and compared with the original document. **Intolerance and non-response to oral iron treatment were documented in the medical history along with signs and symptoms and cross-referenced with the original documents.** ***Document intolerance or non-responsiveness to prescribed oral iron therapy for at least one month as determined by the principal investigator within the past nine months, and these patients will not be candidates for oral iron therapy again.

[0332] A subject was not eligible for inclusion in this study if they met any of the following criteria: 1. Anemia primarily caused by factors other than IDA, as determined by the principal investigator. 2. Hemochromatosis or other iron storage disorders 3. Previous severe hypersensitivity reactions to any intravenous iron compound. 4. Treatment with intravenous iron within the past 30 days prior to screening 5. Treatment with erythropoietin or erythropoietin stimulants, red blood cell transfusions, radiotherapy and / or chemotherapy within the 30 days prior to screening. 6. Planned surgical procedures during the examination period 7. Alanine aminotransferase (ALAT) and / or aspartate aminotransferase (ASAT) > 3 times the upper limit of normal (e.g., decompensated cirrhosis or active hepatitis) 8. General surgery under anesthesia within the past 30 days prior to screening 9. Decompensated cirrhosis or active hepatitis (CKD-04 only) 10. Dialysis necessary for the treatment of CKD 11. Alcohol or drug abuse within the past six months 12. Pregnant or breastfeeding women. To avoid pregnancy, women of childbearing potential must use appropriate contraception (e.g., intrauterine device, hormonal contraceptives, or double-barrier method) throughout the entire study period and for 7 days after the last dose.

[0333] Test treatment The subjects received either one course of iron isomaltoside (Group A) or one course of iron sucrose (Group B), as shown below: Group A: Iron isomaltoside was administered as a single intravenous infusion of 1000 mg at baseline, diluted in 100 mL of 0.9% sodium chloride, over approximately 20 minutes (50 mg iron / min, cumulative dose: 1000 mg). Group B: Iron sucrose was administered as a slow intravenous bolus injection of 200 mg according to the instructions, and this was repeated up to 5 times to reach a cumulative dose of 1000 mg.

[0334] Prior to administration of the study drug, pre-treatment (e.g., antihistamines or steroids) was prohibited. If a subject was receiving daily treatment for, for example, allergies or asthma, this was not considered "prior treatment," and they could continue participating in the study.

[0335] statistical analysis The primary safety endpoints were analyzed by constructing accurate two-sided 95% confidence intervals (CIs) for the incidence of serious and / or severe non-serious hypersensitivity adverse events (AEs) that occurred as a result of treatment in the iron isomaltoside treatment group. Safety objectives were met when the upper limit of the 95% CI was less than 3%.

[0336] Furthermore, the risk difference between iron isomaltoside and iron sucrose was assessed by constructing a 95% confidence interval (CI) of the risk difference. Both unadjusted CIs (with continuity correction) and stratified 95% Newcombe CIs using the Cochran-Mantel-Haenszel method were created.

[0337] Regarding susceptibility, the treatment groups were compared using a logistic regression model with the treatment and type of the underlying disease as a covariate, and using Fisher's exact test.

[0338] All subjects of the safety analysis were included in the analysis.

[0339] Co-primary efficacy endpoints were analyzed using a repeated measures mixed model (MMRM) method based on restricted maximum likelihood (REML). All subjects of analysis based on intention to treat (ITT) set on post-baseline Hb data were included along with these observational data. The model included treatment (iron isomaltoside and iron sucrose), week, week-treatment interaction, stratification, and fixed classification effects of continuous fixed covariates of baseline Hb values ​​and baseline Hb-week interaction. An unstructured (co)variance structure was used to model within-subject errors. If the analysis unexpectedly failed to converge, the following structures were applied in the following order: first-order ante-dependence, heterogeneous compound symmetry, and compound symmetry. The Kenward-Rodger approximation was used to estimate the degrees of freedom in the denominator. The primary comparison was between iron isomaltoside and iron sucrose at week 8 based on the least-squares mean of the treatment-week interaction effect. The estimated mean difference based on this model was reported using a bilaterally symmetrical 95% confidence interval (CI), and the efficacy target was met if the lower bound of the 95% CI was 0.5 g / dL or greater.

[0340] Baseline assessment The following were assessed by the trial staff at the clinical baseline visit at the clinical trial site: • Inclusion and exclusion criteria will be reviewed to ensure that no changes have occurred since the screening. • If applicable, take a pregnancy test. • Relevant medical history, including a history of myocardial infarction, stroke, or congestive heart failure. • Records of concurrent drug therapy • Physical examination (not performed after the baseline visit) • Height measurement • Weight measurement • Testing vital signs Randomization ECG • Fatigue assessment using the FACIT fatigue scale • Assessment of pharmacoeconomics using ISDR questionnaires and health resource use questionnaires. • Safety laboratory testing • Laboratory testing for effectiveness • Treatment with iron isomaltoside (Group A only) • Treatment with iron sucrose (Group B only) • Evaluation and recording of AE (Environmental Analysis)

[0341] Exam Assessment Demographics and baseline assessment We collected information on birth date, sex, race, ethnicity, and smoking habits. Habitual smokers were defined as those who had smoked within the past six months.

[0342] Pregnancy test Urine pregnancy tests were administered to all women of childbearing potential. The tests were handled and interpreted by clinical trial site staff.

[0343] Relevant medical history Relevant medical history was recorded. Changes in medical history were recorded at subsequent visits during the trial (worsening of symptoms or disease was recorded as an AE). The following was collected: disease, as well as onset and discontinuation dates. Except for underlying conditions causing IDA, an onset date occurring more than 12 months prior to enrollment in the trial was defined as more than 12 months prior.

[0344] Concurrent drug therapy If a subject was receiving any concurrent drug therapy, this was recorded at the baseline visit. Changes in concurrent drug therapy were recorded at subsequent visits during the study. The following information was collected: brand name, indication, route, dose, frequency, unit, and start and stop dates. An start date occurring more than 12 months prior to enrollment in the study was defined as more than 12 months prior.

[0345] Physical examination A physical examination was conducted at the discretion of the principal investigator. The physical examination may include: · Head-eyes-ears-nose-throat · Cardiovascular system · Respiratory system • Nervous system · Gastrointestinal system • Musculoskeletal system · Genitourinary system · Skin system • Others, if necessary.

[0346] height Height was measured after removing shoes.

[0347] body weight I weighed myself.

[0348] Vital signs Heart rate and blood pressure were measured at the following points in time when subjects received the study drug: approximately 0–10 minutes before infusion, during infusion, 5–15 minutes and 20–40 minutes after the end of infusion. If vital signs were measured more than once within a given time interval, the lowest diastolic blood pressure measurement during that period (including associated systolic blood pressure and heart rate) was recorded in the electronic case report form (eCRF).

[0349] electro-cardiogram Standard 12-lead ECGs were recorded (including date, time, and signature). Two ECGs were recorded at baseline and at other procedural visits: one before administration of the study drug and one approximately 30 minutes after initiation of the drug. Only one ECG was recorded at follow-up visits.

[0350] ECG did not require evaluation by a cardiologist.

[0351] Laboratory assessment Blood samples were required to be collected before administration of the test drug, and, where possible, to be collected at the same time on all visits to reduce any diurnal variation in parameters.

[0352] Laboratory assessments were conducted in the central laboratory. A laboratory manual detailing all experimental procedures was provided to each clinical trial site.

[0353] Laboratory Eligibility Assessment The following laboratory assessments were conducted for eligibility: • Complete hematology set: Hb, leucocytes (WBC), erythrocytes (RBC), hematocrit, platelets, neutrophils, lymphocytes, monocytes, eosinophils, basophils, mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), and reticulocyte count. · Biochemistry S-ferritin • Alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) • C-reactive protein (CRP) • Estimated glomerular filtration rate (eGFR).

[0354] Vitamin E Vitamin E levels were measured at baseline visits as part of the demographic data.

[0355] Safety laboratory assessment The following safety laboratory assessments were analyzed: • Blood test: White blood cells (WBC), red blood cells (RBC), hematocrit, platelets, neutrophils, lymphocytes, monocytes, eosinophils, basophils, MCH, MCV, MCHC, and reticulocyte count · Biochemistry • s-sodium, s-potassium, s-calcium, s-urea, s-creatinine, s-albumin • s-bilirubin, ASAT, ALAT CRP

[0356] Laboratory assessment of effectiveness The following efficacy laboratory parameters were analyzed: • Hb: Hemoglobin was analyzed using the Coulter LH750 system. Blood was prepared using a lysis reagent as a whole blood cell count parameter so that the system could measure the amount of hemoglobin. The lysis reagent rapidly and simultaneously destroyed red blood cells and converted a significant proportion of hemoglobin into a stable dye. The absorption rate of the dye was directly proportional to the hemoglobin concentration in the sample. The accuracy of this method was equivalent to that of the hemoglobin cyanide method. The S-ferritin:Access ferritin assay was a bilateral immunoenzyme ("sandwich") assay. Samples were added to a reactor containing a goat anti-ferritin alkaline phosphatase conjugate, and paramagnetic particles were coated with a goat anti-mouse:mouse anti-ferritin complex. Serum or plasma (heparin) ferritin bound to immobilized monoclonal anti-ferritin in the solid phase, while the goat anti-ferritin enzyme conjugate reacted with different antigenic sites on the ferritin molecule. Separation was performed using a magnetic field, and any removed material that did not bind to the solid phase was washed away. A chemiluminescent substrate, Lumi-Phos*530, was added to the reactor, and the light generated by the reaction was measured with a luminometer. • TSAT (Calculate TSAT by collecting s-iron and transferrin; TSAT = (iron μg / dL / transferrin mg / dL) × 70.9). • S-iron: Serum iron (s-iron) was measured by a calorimetry assay using a Roche automated clinical chemistry analyzer based on an immunoturbidimetric assay.

[0357] Adverse events (AEs) AE data were collected and evaluated for their relevance, severity, severity, and predictive power to the investigational drug.

[0358] As summarized in the table below, a total of 260 patients (168 in the IIM group; 92 in the IS group) were diagnosed with CHF according to their medical history.

[0359] A total of 518 patients (345 in the IIM group; 173 in the IS group) were diagnosed with CV risk based on their medical history. Of these, 226 patients (144 in the IIM group; 82 in the IS group) were diagnosed with CV risk and CHF based on their medical history. A total of 292 patients (144 in the IIM group; 82 in the IS group) were diagnosed with CV risk but did not have CHF. A total of 2748 patients did not have CHF (144 in the IIM group; 82 in the IS group). TIFF0007897915000004.tif64170

[0360] result Key findings include the clear effect of iron isomaltoside 1000 on congestive heart failure adverse events that occurred as a result of the procedure in patients at risk of cardiovascular adverse events.

[0361] A total of 1,525 patients were enrolled in the CKD-04 trial and treated with either isomaltoside 1000 or iron sucrose. In the CKD-04 trial, 4.1% of the 1,019 patients treated with iron isomaltoside 1000 experienced a composite cardiovascular event, while the incidence was 6.9% (506 patients) in the iron sucrose treatment group.

[0362] A total of 1,525 patients were enrolled in the IDA-03 clinical trial and treated with either isomaltoside 1000 or iron sucrose. 0.8% of the 989 patients treated with iron isomaltoside 1000 and 1.2% of the 494 patients treated with iron experienced a composite cardiovascular event. In the CKD-04 / IDA-03 combined trial, composite cardiovascular events were observed in 2.5% of the 2,008 patients treated with iron isomaltoside 1000 compared to 4.1% in the iron sucrose group (p=0.0176), resulting in a 60% reduction in composite cardiovascular events when patients were treated with iron isomaltoside 1000. In each trial, the rates of congestive heart failure, hypertension, atrial fibrillation, hypotension, and cardiac arrest were lower in the iron isomaltoside 1000 group compared to the iron sucrose group. See Figure 1.

[0363] The entire patient population was divided into various patient subgroups: all patients, all patients with or without CHF, patients at risk of cardiovascular disease (CV), and patients at risk of CV with or without CHF. In each patient group, the incidence of congestive heart failure adverse events resulting from the treatment was similar, and in most cases, it was significantly lower when using iron isomaltoside 1000 compared with treatment with iron sucrose. See Figure 2. For example, in the CKD-04 / IDA-03 combination study, 6.5% of all patients with CHF experienced congestive heart failure adverse events when treated with iron sucrose, whereas only 1.8% of the same patient group experienced such adverse events when treated with iron isomaltoside 1000. The incidence of worsening / exacerbation of heart failure occurred in 5.4% of the patient group treated with iron sucrose, compared to only 1.8% when treated with iron isomaltoside 1000. A similarly significant reduction was observed in congestive heart failure adverse events resulting from the treatment. In patients at risk of cardiovascular disease (CV), the incidence of congestive heart failure was 1.2% in the IIM treatment group and 3.5% in the IS treatment group, with exacerbation of congestive heart failure occurring in 1.2% of the IIM group and 1.7% of the IS group. In patients at risk of CV and CHF, the incidence of congestive heart failure was 1.4% in the IIM treatment group and 4.9% in the IS treatment group, with exacerbation of congestive heart failure occurring in 1.4% of the IIM group and 3.7% of the IS group. The significance of the results of the above study is further illustrated in Figure 5. This figure exemplifies the data from the CKD-04 / IDA03 combination study in the form of a bar graph.

[0364] Figure 3 shows the odds ratio for treatment with iron isomaltoside 1000 versus iron sucrose. An odds ratio of <1 indicates the probability of congestive heart failure adverse events occurring with treatment, which is lower with iron isomaltoside 1000 than with iron sucrose. See Figure 4.

[0365] The probability of patients not experiencing a determined composite cardiovascular adverse event (CKD-04) is significantly higher 8 weeks after treatment with iron isomaltoside 1000 than 8 weeks after treatment with iron sucrose. See Figure 6.

[0366] In the CKD-04 / IDA-03 combination study (all patients), iron isomaltoside 1000 resulted in a higher increase in Hb from baseline at weeks 1 and 2 (p<0.001), and non-inferiority in the change in Hb from baseline was demonstrated at weeks 4 and 8 (primary efficacy endpoint). See Figure 7.

[0367] In summary, the trial shows that the incidence of cardiovascular adverse events is lower with treatment with iron isomaltoside 1000 compared with iron sucrose, particularly in CKD-04 for composite cardiovascular endpoints and congestive heart failure, as well as in pooled analyses across CKD-04 and IDA-03. Furthermore, the incidence of CV adverse events and numerical differences compared to iron sucrose are generally higher in the CHF patient subgroup (with CHF / CV risk factors and CHF in their medical history). Compared to Venofer and FCM (CDER report), the incidence of composite endpoints (and most sub-items, including death from any cause) is lower with treatment with iron isomaltoside 1000.

[0368] Treatment with iron isomaltoside elicits a higher increase in Hb from baseline up to weeks 1 and 2, and a similar response at week 8, in patients with a history of congestive heart failure.

[0369] Equal form Those skilled in the art can recognize or confirm many equivalent forms of the specific embodiments disclosed herein by means of conventional experiments alone. Such equivalent forms are intended to be encompassed in the following claims.

[0370] Non-patent literature Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, Luscher TF, Bart B, Banasiak W, Niegowska J, Kirwan BA, Mori C, von Eisenhart Rothe B, Pocock SJ, Poole-Wilson PA, Ponikowski P. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009; 361:2436-2448. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, Ertl G, Komajda M, Mareev V, McDonagh T, Parkhomenko A, Tavazzi L, Levesque V, Mori C, Roubert B, Filippatos G, Ruschitzka F, Anker SD. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J 2015; 36:657-668. TIFF0007897915000005.tif42170Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C,Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P; Authors / Task Force Members;Document Reviewers. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Eur J Heart Fail. 2016 Aug; 18(8):891-975. doi: 10.1002 / ejhf.592. Epub 2016 May 20. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C. 2017 ACC / AHA / HFSA Focused Update of the 2013 ACCF / AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology / American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2017 Aug 8; 70(6):776-803. doi: 10.1016 / j.jacc.2017.04.025. Epub 2017 Apr 28. Myles Wolf, MD, Janet Rubin, MD, Maureen Achebe, MD, Michael John Econs, MD, Munro Peacock, MD, Erik Allen Imel, MD, Lars L. Thomsen, MD, Thomas O. Carpenter, MD, Thomas Joseph Weber, MD, Heinz Zoller, MD. Effects of Iron Isomaltoside versus Ferric Carboxymaltose on Hormonal Control of Phosphate Homeostasis: The PHOSPHARE IDA04 / 05 Randomized Controlled Trials. ENDO 2019, March 23-26 2019, New Orleans, Session OR13 - OR13. Rare Bone Diseases and Mineral Metabolism, abstract OR13-3. TIFF0007897915000006.tif42170Charles-Edwards G, Amaral N3, Sleigh A, Ayis S, Catibog N3, McDonagh T3, Monaghan M, Amin-Youssef G, Kemp GJ, Shah AM, Okonko DO. Effect of Iron Isomaltoside on Skeletal Muscle Energetics in Patients With Chronic Heart Failure and Iron Deficiency. Circulation. 2019 May 21; 139(21):2386-2398. doi:10.1161 / CIRCULATIONAHA.118.038516. Hannah Jaumdally, Mohamad F. Barakat, Geoffrey Charles-Edwards, GeorgeAmin-Youssef, Ajay M. Shah, Paul Scott, Darlington O. Okonko. IRON ISOMALTOSIDE DIMINISHES ATRIAL ELECTRICAL INHOMOGENEITY IN CHRONIC HEART FAILURE WITHOUT ALTERING ATRIAL SIZE: A FERRIC-HF II SUBSTUDY. Journal of the American College of Cardiology Mar 2019, 73 (9 Supplement 1) 833; DOI: 10.1016 / S0735-1097(19)31440-8

Claims

1. A pharmaceutical product for the treatment of iron deficiency, comprising an effective amount of iron isomaltoside, for reducing the incidence or risk of cardiovascular death and / or hospitalization due to exacerbation of congestive heart failure (CHF) in subjects with a history of congestive heart failure (CHF).

2. The pharmaceutical product according to claim 1, wherein the subject having a history of congestive heart failure has heart failure with reduced ejection fraction (HFrEF) or heart failure with an intermediate ejection fraction (HFmrEF).

3. The pharmaceutical product according to claim 1 or 2, wherein the subject has a history of congestive heart failure and has congestive heart failure classified as NYHA class II to IV.

4. A pharmaceutical product according to any one of claims 1 to 3, wherein iron deficiency is defined as TSAT < 20%.

5. The pharmaceutical product according to any one of claims 1 to 4, wherein iron deficiency is defined as ferritin < 100 μg / L.

6. The pharmaceutical product according to any one of claims 1 to 5, wherein the cardiovascular death is death due to congestive heart failure.

7. A pharmaceutical product according to any one of claims 1 to 6, wherein the subject has symptomatic heart failure.

8. The pharmaceutical product according to any one of claims 1 to 7, wherein the iron isomaltoside is ferric deliisomaltose.

9. The pharmaceutical product according to any one of claims 1 to 8, wherein iron isomaltoside is administered in an amount of elemental iron of 20 mg / kg body weight, up to a maximum of 2000 mg of elemental iron.

10. The pharmaceutical product according to any one of claims 1 to 9, wherein iron isomaltoside is administered in an amount of elemental iron in the range of 500 mg to 2000 mg.

11. The pharmaceutical product according to any one of claims 1 to 10, wherein the subject is being treated with another drug used to treat congestive heart failure.

12. A pharmaceutical product according to any one of claims 1 to 11, wherein the target is a person with chronic kidney disease (CKD).

13. The pharmaceutical product according to claim 12, wherein the subject has chronic kidney disease in the non-dialysis stage (NDD-CKD).

14. The pharmaceutical product according to any one of claims 1 to 13, wherein the iron deficiency is iron deficiency anemia.

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