Treating iron deficiency in subjects 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 in subjects at risk for adverse cardiovascular events by administration of intravenous iron-carbohydrate complexes. [Background technology]

[0002] Iron deficiency (ID) impairs the body's ability to produce hemoglobin, an important oxygen carrier, and impairs the function of important energy (ATP)-producing enzymes. 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 1 billion people worldwide suffer from IDA. Daily oral iron supplementation is the primary treatment for the majority of IDA patients, but it often fails due to poor compliance, lack of efficacy, and side effects.

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

[0005] Iron isomaltoside 1000 (INN: Ferric isomaltose) belongs to a new generation of high-dose intravenous iron products. The rapid infusion of the product allows iron correction in one or two visits, whereas older lower-dose products (ferric gluconate and ferric sucrose) require 5-20 visits.

[0006] Iron isomaltoside is an iron carbohydrate complex that is commonly used to treat patients with IDA (i) who are intolerant to or have had a poor response to oral iron administration, or when there is a clinical need to rapidly replenish iron stores; or (ii) patients with non-hemodialysis-dependent chronic kidney disease (NDD-CKD); or to treat ID on dialysis in patients with chronic kidney disease. It is commercially available in the European Union and many other countries under the trade names Monofer®, Monoferric®, and Diafer®. A typical treatment regimen for iron isomaltoside consists of either a single infusion of 1000 mg iron, a dose of elemental iron 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 a week, and cumulative iron should be determined using either the Ganzoni formula or the following table: TIFF2025041648000001.tif27170

[0007] ID has serious consequences. In patients with chronic heart failure (CHF), patients with ID have been reported to have an increased risk of death or hospitalization compared to patients with normal iron status. Quality of life (QoL) is significantly affected and improves rapidly when iron stores are restored. For example, in a fairly small sample size of 20 frail elderly CHF patients in an open-label, uncontrolled design, a single rapid intravenous infusion of ferric isomaltoside 1000 at a relatively high dose, but no initial test dose, was very well tolerated and improved QoL measures. Hildebrandt et al., 2010.

[0008] Collective experimental and clinical evidence provides a rationale for considering ID as a potential therapeutic target in patients with chronic heart failure (chronic HF). Indeed, in recent years, several studies have investigated the effects of intravenous iron therapy in iron-deficient patients with chronic HF, including the FAIR-HF trial (Assessment of ferric carboxymaltose in patients with iron deficiency and chronic heart failure, see also Anker et al., 2009) and the CONFIRM-HF trial (Performance evaluation of ferric carboxymaltose in patients with combined iron deficiency and chronic heart failure, see also Ponikowski et al., 2015), which encompassed over 450 and 300 patients, respectively. Based on pooled data, a meta-analysis of five randomized controlled trials evaluating the effect of intravenous iron therapy (using iron sucrose or ferric carboxyl maltose) in iron-deficient patients with systolic HF (HFrEF), Jankowska et al., 2016, stated that there is evidence that intravenous iron therapy in iron-deficient patients with systolic HF improves outcomes, relieves HF symptoms, improves exercise capacity and quality of life, and reduces the risk of hospitalization for HF. However, the number of deaths and incidence of adverse events (AEs) were similar in the five studies included in the meta-analysis.

[0009] There have also been attempts to explore from a mechanistic perspective how iron supplementation confers benefit in CHF, particularly where Hb changes are minimal. For example, a randomized, double-blind, placebo-controlled trial showed that a single full-dose infusion of iron isomaltoside 1000 refilled iron stores and increased skeletal muscle energetics 2 weeks after infusion (Charles-Edwards et al., 2019). Based on data from the same randomized, double-blind trial, a single full-dose infusion of iron isomaltoside 1000 was observed to refill iron stores and reduce P-wave variability in iron-deficient CHF patients with left ventricular ejection fraction ≤ 45% (Jaumdally et al., 2019).

[0010] However, none of the intravenous iron trials promoted testing for effects on primary cardiovascular outcomes. Therefore, the 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure concluded that the effect of treating iron deficiency in HFpEF / HFmrEF is unknown. Based on findings from FAIR-HF and CONFIRM-HF, the European Society of Cardiology (ESC) guidelines recommend considering intravenous ferric carboxymaltose in patients with iron deficiency (serum ferritin <100 μg / L, or ferritin between 100–299 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 reasonable to improve functional status and QoL 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 <20%). Yancy et al., 2017.

[0011] Based on this understanding, there is a clear need to provide methods of treating iron deficiency that not only replenish iron stores but also provide patient benefit in managing chronic heart failure. Summary of the Invention

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

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

[0014] A third aspect of the invention relates to the treatment of certain groups of subjects, as defined herein, to reduce the incidence or risk of an adverse cardiovascular event, as defined herein.

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

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

[0017] In embodiments of the first aspect, the subject at risk for an adverse cardiovascular event is a subject having one or more of the following risk factors: (i) subjects with a history of myocardial infarction (MI), specifically STEMI or non-STEMI; (ii) subjects with a history of stroke; (iii) subjects with a history of atrial fibrillation (AF), specifically, first-time diagnosed AF, paroxysmal AF, or persistent AF; (iv) subjects with a history of congestive heart failure, particularly heart failure with reduced ejection fraction (HFrEF); (v) subjects with a history of cardiac valvular disorders; (vi) subjects with a history of hypertension; (vii) Subjects with diabetes mellitus; (viii) subjects with a history of obesity; (ix) Elderly subjects, particularly subjects aged 60 years or older, 65 years or older, 70 years or older, 75 years or older, or 80 years or older; (x) Smoker; (xi) drinker; (xii) Subjects with hyperthyroidism and / or associated thyrotoxicosis; (xiii) subjects with chronic obstructive pulmonary disorder (COPD); (xiv) subjects with cardiomyopathy, particularly hereditary or acquired cardiomyopathy; (xv) subjects with systemic inflammation in the absence of infection, the systemic inflammation being particularly associated with an increase in C-reactive protein (CRP) greater than about 2-3 mg / L; (xvi) subjects undergoing dialysis, in particular hemodialysis or peritoneal dialysis; (xvii) Subjects who have been treated with one or more of the following: a) modulators of the hypoxia inducible factor (HIF) signaling pathway, including prolyl hydroxylase inhibitors, e.g., daprodustat, vadadustat, roxadustat, molidustat, and desidusta; b) Erythropoietin 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) a hepcidin modulator, e.g., a hepcidin agonist or a hepcidin antagonist; (xviii) subjects treated with anticoagulants and / or NSAIDs; (xix) a subject with hereditary hemorrhagic telangiectasia; or (xx) A subject with hereditary iron-refractory iron deficiency anemia.

[0018] In a particular embodiment of said first aspect, the present invention relates to a method of treating iron deficiency in a subject with 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 a history of 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 aspect, the subject at risk of cardiovascular adverse events or the subject with a history of congestive heart failure has chronic kidney disease (CKD).In another specific embodiment of the first aspect, the subject at risk of cardiovascular adverse events or the subject with a history of congestive heart failure does not have chronic kidney disease (CKD).In another specific embodiment of the first aspect, the subject at risk of cardiovascular adverse events is a subject with chronic kidney disease (CKD) and a history of congestive heart failure (CHF).

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

[0021] In an embodiment of said second aspect, the invention relates to a method of treating iron deficiency in a subject at risk of an adverse cardiovascular event, wherein treating the iron deficiency reduces the incidence or risk of the adverse cardiovascular event in the subject, the method comprising administering an effective amount of iron isomaltoside.

[0022] In one embodiment of said second aspect, 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 vasculature (peripheral vascular adverse events); events affecting the cerebrovascular system (cerebrovascular adverse events); respiratory, thoracic and mediastinal adverse events; general adverse events; and infections and invasions. According to one embodiment, 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 premature ventricular contractions; the peripheral vascular adverse event is selected from the group consisting of hypertension, elevated systolic blood pressure, elevated blood pressure, elevated troponin, and hypotension; the cerebrovascular adverse event is selected from the group consisting of cerebrovascular incident, 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.

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

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

[0025] In further particularly preferred embodiments of this second aspect of the invention, the adverse cardiovascular event for which the incidence or risk is reduced is congestive heart failure, atrial fibrillation, hypertension, and / or cardiac arrest.

[0026] According to one embodiment, the specific cardiovascular adverse event related to congestive heart failure is hospitalization or death due to congestive heart failure. According to one embodiment, the specific cardiovascular adverse event related to congestive heart failure is hospitalization due to worsening congestive heart failure. The present invention is particularly directed to adverse CV events, where the adverse CV event is CHF.

[0027] In an embodiment of said third aspect, the invention provides a method of treating iron deficiency in a subject, wherein treating the iron deficiency reduces the incidence or risk of an adverse cardiovascular event in the subject, the method comprising administering an effective amount of iron isomaltoside, The target is, (A) Subjects at risk for adverse cardiovascular events; (B) a subject with a history of congestive heart failure (CHF); or (C) Subjects with a history of congestive heart failure (CHF) and at risk for adverse cardiovascular events and The incidence or risk of adverse cardiovascular events is reduced. (a) congestive heart failure, myocardial infarction, unstable angina, arrhythmias, hypertension, hypotension, stroke, and death; (b) congestive heart failure; (c) atrial fibrillation; (d) hypertension; or (e) Cardiac arrest The present invention relates to a method comprising the steps of:

[0028] In a preferred embodiment of this third aspect of the invention, the subject is a subject at risk of an adverse cardiovascular event, and the adverse cardiovascular event for which the incidence or risk is reduced is congestive heart failure.

[0029] In a further preferred embodiment of this third aspect of the invention, the subject is a subject at risk of an adverse cardiovascular event, and the adverse cardiovascular event the incidence or risk of which is reduced is atrial fibrillation.

[0030] In a further preferred embodiment of this third aspect of the invention, the subject is a subject at risk of an adverse cardiovascular event, and the adverse cardiovascular event the incidence or risk of which is reduced is cardiac arrest.

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

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

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

[0034] In certain embodiments of this third aspect of the invention, the subject as defined herein is a subject at risk of an adverse cardiovascular event and / or has a history of congestive heart failure, and the subject has chronic kidney disease (CKD).

[0035] In another particular embodiment of this third aspect of the invention, the subject as defined herein is a subject at risk of an adverse cardiovascular event and / or has congestive heart failure, and the subject does not have chronic kidney disease (CKD).

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

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

[0038] In particularly preferred embodiments of this third aspect of the invention, the adverse cardiovascular event whose incidence or risk is reduced is cardiovascular death and / or hospitalization due to worsening 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, the iron deficiency is iron deficiency anemia.

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

[0041] A preferred iron carbohydrate complex for use in the present invention is iron isomaltoside, particularly ferric delisomaltose (sometimes called ferric delisomaltoside). [Brief description of the drawings]

[0042] [Figure 1] FIG. 1 is a table summarizing the analysis of the incidence of adjudicated and confirmed treatment-emergent composite cardiovascular (CV) adverse events with an incidence of 0.25% or greater in the favorable setting for the CKD-04, IDA-03, and CKD-04 / IDA-03 combination studies. [Diagram 2] 1 is a table summarizing the analysis of treatment-emergent congestive heart failure adverse events for the CKD-04, IDA-04, and CKD-04 / IDA-03 combination studies in all patients, patients with or without CHF, or patients at CV risk. [Diagram 3] FIG. 1 is a table summarizing the analysis of treatment-emergent congestive heart failure adverse events (logistic regression) for the CKD-04 and CKD-04 / IDA-03 combination studies in patients at CV risk with or without history of CHF, comparing treatment with iron isomaltoside versus iron sucrose. [Figure 4] Graph showing the proportion of patients who experienced a particular treatment-emergent composite CV adverse event (iron isomaltoside 1000: left bars, iron sucrose: right bars). [Diagram 5] Graph showing percentage of patients experiencing treatment-emergent CHF adverse events (CKD-04 and IDA-03 combined; iron isomaltoside 1000: left bars, iron sucrose: right bars). [Figure 6] FIG. 1 is a Kaplan-Meier plot showing the probability of adjudicated composite adverse cardiovascular events (CKD-04). [Figure 7] Graph showing change from baseline in hemoglobin (g / dL) in patients with history of CHF for the CKD-04 / IDA-03 combination trial (iron isomaltoside 1000: dashed line, iron sucrose: solid line). [Figure 8] Graph showing change from baseline in ferritin (ng / mL) in patients with history of CHF for the CKD-04 / IDA-03 combination trial (iron isomaltoside 1000: dashed line, iron sucrose: solid line). [Figure 9] Graph showing change from baseline in TSAT (%) in patients with history of CHF for the CKD-04 / IDA-03 combination trial (iron isomaltoside 1000: dashed line, iron sucrose: solid line). [Figure 10] Graph showing the percentage of patients who experienced a treatment-emergent composite CV adverse event after treatment with IIM1000, Venofer and FCM (CKD-04 / IDA-03 combination study (Ferwon study) for IIM1000; study with Venofer and FCM based on FDA CDER report for Injectafer). [Figure 11] This table summarizes the analysis of adverse events for the CKD-04, IDA-03, and CKD-04 / IDA-03 combination studies (Ferwon studies) using IIM1000 compared to studies using Venofer and FCM (FDA CDER report on Injectafer). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] In order that this description may be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description.

[0044] "Treatment" or "treatment" of a subject refers to any type of procedure or process performed on a subject, or administration of an active agent to a subject, for the purpose of reversing, ameliorating, reversing, inhibiting, slowing, or preventing the onset, progression, manifestation, severity, or recurrence of a symptom, complication, condition, or biochemical manifestation related to a disease.

[0045] A "subject" includes 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 a preferred embodiment, the subject is a human. The terms "subject" and "patient" are used interchangeably herein.

[0046] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent is any amount of drug that, when used alone or in combination with another therapeutic agent, protects a subject against the onset of disease or promotes regression of the disease, based on evidence by reducing the severity of disease symptoms, increasing the frequency and duration of symptom-free periods, or preventing disability or incapacity due to the affliction of the disease. The ability of a therapeutic agent to promote regression of a disease can be assessed in a variety of ways known to the skilled practitioner, for example, in humans using subjects in clinical trials, in animals using model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.

[0047] For the purposes of this document, when specifying a dose of iron carbohydrate complex in mg or g, consistent with literature convention, the value refers to the amount of elemental iron provided in mg or g.

[0048] A. Iron-Carbohydrate Complex Described herein are therapeutic methods for treating iron deficiency, including administering iron carbohydrate complexes and combinations of iron carbohydrate complexes and additional drugs, where the iron carbohydrate complexes have certain properties that allow them to exert certain effects on the subject under treatment. Thus, the methods of the present invention are applicable to complexes that share a common mechanism of action. For example, the iron carbohydrate complexes should not induce a significant increase in iFGF23 (non-damaged FGF23). Although ferric carboxymaltose (FCM) in particular significantly increases iFGF23 (see, for example, WO2013 / 134273A1), the results of clinical trials provide evidence that iron isomaltoside 1000 (Monofer®) increases iFGF23, which is associated with a low risk of causing iFGF23-mediated effects. See, for example, Wolf et al., 2019.

[0049] Thus, the preferred iron carbohydrate complex of the present invention is iron isomaltoside (IIM). As used herein, the term "iron isomaltoside" refers to a colloidal complex containing iron, e.g., iron oxide hydroxide, and iron as isomaltoside in a matrix-like structure. As used herein, the term "isomaltoside" refers to hydrogenated oligoisomaltose (oligoisomaltoside).

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

[0051] In certain of the above embodiments, the hydrogenated polysaccharides / oligosaccharides preferably have a dimeric sugar content of 2.9% by weight or less, 2.5% by weight or less, or 2.3% by weight or less, in particular 2.1% by weight or less, or 1.5% by weight or less, and most preferably 1.0% by weight or less, based on the total weight of the hydrogenated polysaccharides / oligosaccharides. Preferably, the hydrogenated polysaccharide / oligosaccharide preparations used to prepare the iron-carbohydrate complexes of the invention have a monomeric sugar content of 0.5% by weight or less. Iron-hydrogenated dextran complexes prepared from such hydrogenated polysaccharide / oligosaccharide preparations typically have an apparent molecular weight (M) in the range of 120,000 to 180,000 Da, in particular 130,000 to 160,000 Da. p). 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 a particular embodiment, the hydrogenated polysaccharide / oligosaccharide preparation has been purified by one or more membrane processes with a cut-off value between 340 Da and 800 Da. In an even more particular embodiment, the hydrogenated polysaccharide / oligosaccharide preparation has been purified by one or more membrane processes using a membrane with a cut-off value capable of rejecting polysaccharides with a molecular weight of more than 2,700 Da, optionally followed by further hydrolysis and one or more membrane processes using a membrane with a cut-off value between 340 Da and 800 Da. Alternatively, said membrane process purification is carried out before hydrogenation.

[0052] In a particularly preferred embodiment, the iron isomaltoside of the present invention has the formula: H2O-containing {FeO (1-3X) (OH) (1+3X) (C6H5O7 3- ) X},(C6H 10 O6) R (-C6H 10 O5-) Z (C6H 13 O5) R ,(MeCl) Y [In the formula, X is 0.0311±0.0062, in particular 0.0311±0.0031; R is 0.1400 ± 0.0420, specifically 0.1400 ± 0.0210; Z is 0.4900±0.1470, specifically 0.4900±0.0735; Y is 0.1400±0.0130, 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 having the formula:

[0053] In a further particularly preferred embodiment, the iron complex compound of the present invention has the 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, in particular 0.0311±0.0031; T is 0.2500±0.1250, in particular 0.2500±0.24750; R is 0.1400 ± 0.0420, specifically 0.1400 ± 0.0210; Z is 0.4900±0.1470, specifically 0.4900±0.0735; Y is 0.1400±0.0130, 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 having the formula:

[0054] In a particular embodiment, the iron complex has an iron content of 23-39% by weight (determined on dry matter), optionally present 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 isomaltoside are commercially available in many other countries under the trade names Monofer®, Monoferric®, or Diafer®.

[0056] Another specific iron carbohydrate complex for use in the present invention is ferric bepectate (FBP). The term "ferric bepectate" as used herein refers to a colloidal complex containing an iron core, for example as ferric oxide hydroxide, coated with a hydroxyethyl amylopectin derivative. Ferric bepectate is also called polyglucoferron. Ferric bepectate and its preparation are disclosed, for example, in WO2012175608A1. Briefly, hydroxyethyl starch is dissolved in water. The pH value is then adjusted to a value between 8.0 and 10.0. A cyanide compound is then added to the hydroxyethyl starch solution. The solution is then heated to a temperature between 80 and 99°C and maintained at this temperature for a first period of time. Finally, the pH value is adjusted to a value between 2.0 and 4.0 and the solution is brought to a temperature between 50 and 90°C and maintained at this temperature for a second period of time. The starch produced by this method is characterized by having a heptonic acid residue at at least one of its termini. Thus, such starches may have multiple heptonic acid residues per molecule, depending on the number of terminal glucosyl residues present in the starch molecule. The heptonic acid residues increase the hydrophilicity of the hydroxyethyl starch and increase the stability of the complexes formed by the hydroxyethyl starch with ligands such as metal ions, for example iron ions. 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. The modification with heptonic acid residues occurs by converting the terminal glucosyl residues of hydroxyethyl starch into heptonic acid residues. Preferably, the hydroxyethyl starch used in this process has a weight-average molecular weight (Mw) of less than 200,000 g / mol, in particular less than 130,000 g / mol, in particular less than 100,000 g / mol, in particular less than 90,000 g / mol, in particular less than 80000 g / mol, very particularly less than 75,000 g / mol. Very well suited molecular weights are in the range of 55,000 g / mol to 85,000 g / mol.Such hydroxyethyl starches have a significantly lower molecular weight than the (unmodified) hydroxyethyl starches currently used in the medical field. A suitable method for determining the molecular weight of hydroxyethyl starches is size exclusion chromatography (SEC). In a preferred embodiment, the hydroxyethyl starches have an average molar degree of substitution between 0.4 and 0.6, in particular between 0.45 and 0.55. An average molar degree of substitution around 0.50 is particularly preferred. The average molar degree of substitution is a measure for the amount of hydroxyl groups replaced 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 up to 3. An average molar degree of substitution of 0.5 indicates that (on an average or statistical basis) one hydroxyl group of every other glucosyl residue is replaced by a hydroxyethyl residue. In a preferred embodiment, the hydroxyethyl starch has a weight average molecular weight of 55,000 to 85,000 g / mol, preferably around 70,000 g / mol, and an average molar substitution of 0.45 to 0.55, especially around 0.50. Such a hydroxyethyl starch having a molecular weight of 70,000 g / mol ± 15,000 g / mol and an average molar substitution of 0.5 ± 0.05 can also be called HES 70 / 0.5. A process for producing this heptonate modified hydroxyethyl starch, HES 70 / 0.5, is described in Example 1 and the formation of the iron complex in Example 2 of WO2019 / 048674A1, all of which are incorporated by reference.

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

[0058] B. Treatment method The therapeutic method for treating iron deficiency is described herein, which comprises administering iron isomaltoside to a selected subgroup of subjects and / or by a defined dosing regimen.Therefore, the present invention also relates to iron isomaltoside for use in said method, to the use of iron isomaltoside for treating iron deficiency, and / or to the use of iron isomaltoside in the manufacture of a medicament for treating iron deficiency.

[0059] I. Subjects to be treated The method of the present invention is typically carried out on a subject in need thereof.The subject in need of the method of the present invention is one that has iron deficiency, has been diagnosed with iron deficiency, is suspected of having iron deficiency, or is at risk of developing iron deficiency.Iron deficiency anemia (IDA) develops when iron stores are depleted.Subjects with ID may have IDA, but subjects with IDA necessarily suffer from ID.The methods for diagnosing ID and IDA are well established in the art and are commonly used in clinical practice.

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

[0061] Iron Deficiency and Anemia Iron storage parameters Subjects with iron deficiency may show markers of low or insufficient total body iron status. This means that such subjects may not have enough iron stored in the body to maintain adequate iron levels. The majority of well-nourished healthy individuals living in industrialized countries have approximately 4-5 grams of stored iron in the body. About 2.5 grams of this iron is contained in hemoglobin, which carries oxygen through the blood. Most of the remaining approximately 1.5-2.5 grams of iron is contained in iron-binding complexes and is present in all cells, but at higher concentrations in bone marrow and organs such as the liver and spleen. The liver stores iron, which is the main physiological reserve of iron in healthy individuals. Of the total body iron content, approximately 400 mg is available in proteins that use iron for cellular processes such as oxygen storage (myoglobin) or carrying out energy-generating redox reactions (cytochrome proteins). In addition to the 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+ ) are toxic and are typically present in the body only in very low concentrations.

[0063] In iron-deficient individuals, body iron stores are first depleted. Iron deficiency anemia is the primary clinical manifestation of iron deficiency, since most of the iron utilized by the body is required by hemoglobin. Oxygen delivery to tissues, including organs, is essential, and severe anemia is harmful and potentially life-threatening due to systemic oxygen deficiency. Iron-deficient subjects will suffer organ damage caused by oxygen depletion, and in some cases death, long before cells run out of iron required for intracellular processes.

[0064] There are several markers of whole body iron status that can be measured to determine whether a subject has sufficient iron stores to maintain proper health. These markers can be circulating iron stores, iron stored in iron-binding complexes, or both, and are typically also called iron storage parameters. Iron storage parameters can include, for example, hematocrit, hemoglobin concentration (Hb), total iron-binding capacity (TIBC), transferrin saturation (TSAT), serum iron level, liver iron level, spleen iron level, and serum ferritin level. Of these, hematocrit, hemoglobin concentration (Hb), total iron-binding capacity (TIBC), transferrin saturation (TSAT), and serum iron level are commonly known as circulating iron stores. Liver iron level, spleen iron level, and serum ferritin level are commonly called storage iron or iron stored in iron-binding complexes.

[0065] It should be noted that the above blood parameters are determined in serum, but can also be determined in plasma as well. Serum and plasma levels are correlated and can be converted into each other.

[0066] The present disclosure provides a method for improving one or more iron storage parameters in a subject in need thereof. The at least one iron storage parameter can 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, the at least one iron storage parameter is hemoglobin concentration and the improvement comprises an increase in the subject's hemoglobin concentration. In another embodiment, the at least one iron storage parameter is transferrin saturation and the improvement comprises an increase in the subject's transferrin saturation. In yet another embodiment, the at least one iron storage parameter is serum ferritin level and the improvement comprises an increase in the subject's serum ferritin level.

[0068] Serum ferritin Liver-stored ferritin is the main source of stored iron 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 a blood sample and / or a liver tissue sample 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 serves to store iron in a non-toxic form in the liver and transport it to areas of need. In healthy subjects, normal ferritin blood serum levels, sometimes also referred to as the reference range, are usually 30-300ng / ml for men and 15-200ng / ml for women. In patients at risk for adverse cardiovascular events, normal ferritin blood serum levels are usually greater than 100ng / ml. However, in subjects with iron deficiency, serum ferritin levels typically decrease significantly as the amount of iron available for binding by ferritin and storage in the liver decreases because the body loses the 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 immunoenzymatic ("sandwich") assay. Ferritin is the main iron storage protein for the body. The concentration of ferritin is directly proportional to the total iron stores of the body, making serum ferritin levels a common diagnostic tool in the assessment of iron status. Subjects with iron deficiency anemia have serum ferritin levels that are approximately 1 / 10th that of normal subjects, while subjects with iron overload (hemochromatosis, hemosiderosis) have serum ferritin levels that are much higher than normal. Ferritin levels also provide a sensitive means of detecting iron deficiency at an early stage. In both adults and children, chronic inflammation leads to elevated ferritin levels that are disproportionate to iron stores. High ferritin levels are also observed in acute and chronic liver disease, chronic renal failure, and some types of neoplastic disease.

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

[0071] In some embodiments, iron isomaltoside provides a mean increase in serum ferritin of greater than 100ng / ml, greater than 110ng / ml, greater than 120ng / ml, greater than 130ng / ml, greater than 140ng / ml, greater than 150ng / ml, greater than 160ng / ml, greater than 170ng / ml, greater than 180ng / ml, greater than 190ng / ml, or greater than 200ng / ml after 4 or 8 weeks of treatment.

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

[0073] In some embodiments, iron isomaltoside provides a mean increase in serum ferritin 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 provides a mean increase in serum ferritin of greater than 200 ng / mL, greater than 230 ng / mL, greater than 260 ng / mL, greater than 290 ng / mL, greater than 320 ng / mL, greater than 350 ng / mL, greater than 380 ng / mL, greater than 410 ng / mL, or greater than 440 ng / mL after one week of treatment.

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

[0076] In some embodiments, iron isomaltoside provides a mean increase in serum ferritin 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. Thus, serum iron (s-iron) levels can be represented by the amount of iron circulating in the blood that is bound to the protein transferrin. Transferrin is a glycoprotein produced by the liver that 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 and use it throughout the body. Transferrin saturation (or TSAT) is measured as a percentage and is calculated by multiplying the ratio of serum iron to total iron binding capacity by 100. This value tells the clinician 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 adverse cardiovascular 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 binding by transferrin decreases, which occurs because the body loses the ability to absorb and store iron. In some embodiments, TSAT values ​​are less than 20% and / or ferritin concentrations are less than 100 μg / L.

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

[0079] In some embodiments, iron isomaltoside provides a mean 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 provides a mean increase in TSAT of less than 5%, less than 4%, or less than 3% after 4 or 8 weeks of treatment.

[0081] In some embodiments, iron isomaltoside provides a mean increase in TSAT of 1-5%, 1.5-4%, or 2-3% after 4 or 8 weeks of treatment.

[0082] In some embodiments, iron isomaltoside provides a mean increase in TSAT of greater than 5%, greater than 6%, or greater than 7% after one week of treatment.

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

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

[0085] Hematocrit Hematocrit, also called corpuscular volume or red blood cell volume fraction, is the volume percentage of red blood cells in blood. For healthy subjects, hematocrit is typically about 45% of blood volume for men and about 40% of blood volume for women. However, in iron-deficient subjects, hematocrit is often significantly depleted due to poor iron absorption and / or poor iron storage capacity.

[0086] Iron isomaltoside as disclosed herein may be administered to a subject to increase hematocrit. The exact timing of administration will necessarily vary from subject to subject depending, for example, on the severity of iron deficiency the subject is experiencing, the level of iron absorption the subject is or is not experiencing, and the judgment of the treating health care professional. In some embodiments, the disclosure provides a method of increasing hematocrit in a subject in need thereof, the method comprising administering iron isomaltoside to the subject, the iron isomaltoside resulting in an increase in the subject's hematocrit. In some embodiments, the increase is between 1% and 30%, between 1% and 15%, between 1% and 12%, between 1% and 10%, between 1% and 9%, between 1% and 8%, between 1% and 7%, between 1% and 6%, between 1% and 5%, between 1% and 4%, between 1% and 3%, or between 1% and 2%.

[0087] Hemoglobin concentration Hemoglobin concentration, also called mean corpuscular hemoglobin concentration or MCHC, is a measure of the concentration of hemoglobin protein in a given volume of sedimented 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 mass or weight fraction and presented as a percentage (%). However, numerically, the mass or molar measures of hemoglobin concentration and the mass or weight fraction (%) are identical, but assume a red blood cell density of 1 g / ml and negligible hemoglobin loss in the 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 greatly reduced because the body has lost the 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 present disclosure provides a method of 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 provides a mean 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 provides a mean increase in hemoglobin concentration of greater than 0.1 g / dL, greater than 0.2 g / dL, greater than 0.3 g / dL, greater than 0.4 g / dL, greater than 0.5 g / dL, greater than 0.6 g / dL, greater than 0.7 g / dL, greater than 0.8 g / dL, or greater than 0.9 g / dL after one week of treatment.

[0091] In some embodiments, iron isomaltoside provides a mean increase in hemoglobin concentration of less than 1.0 g / dL, less than 0.9 g / dL, less than 0.8 g / dL, or 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 less than 0.3 g / dL one week after treatment.

[0092] In some embodiments, iron isomaltoside provides a mean 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 provides a mean 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 provides a mean increase in hemoglobin concentration of less than 2.0 g / dL, less than 1.9 g / dL, less than 1.8 g / dL, or 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 after 4 or 8 weeks of treatment.

[0095] Total iron binding 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 drawing a blood sample and measuring the maximum amount of iron the sample can carry. Thus, TIBC indirectly measures transferrin, the protein that carries iron in the blood. For healthy subjects, typical TIBC measures in mass or molar terms 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 as the body must produce more transferrin to deliver iron to red blood cell precursor cells to generate hemoglobin.

[0096] In some embodiments, the subject treated by the methods disclosed herein experiences a reduction in TIBC.In some embodiments, the present disclosure provides a method of reducing TIBC in a subject 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 reduction is between 0.1% and 30%, between 0.1% and 28%, between 0.1% and 26%, between 0.1% and 25%, between 0.1% and 24%, between 0.1% and 23%, between 0.1% and 22%, between 0.1% and 21%, between 0.1% and 20%, between 0.1% and 15%, between 0.1% and 10%, or between 0.1% and 5%.

[0098] Subjects at risk of cardiovascular adverse events will generally be subject to or at risk of systemic inflammation, which may 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>100μg / L.According to one embodiment of the present invention, if TSAT is less than 20% and / or serum ferritin is less than 100μg / L, treatment is appropriate, or in a related embodiment, if TSAT is less than 20% and serum ferritin is less than 300μg / L, treatment is appropriate.In a preferred embodiment, TSAT is less than 20% and / or serum ferritin is less than 100μg / L. Treatment criteria may also include an upper limit for serum ferritin above which re-dosing is not recommended, such as serum ferritin of 300 μg / L or less, 400 μg / L or less, 500 μg / L or less, or 600 μg / L or less.Retreatment criteria may also include a higher limit for ferritin and TSAT than treatment criteria.For example, in a preferred embodiment, after administration of the first effective dose, if TSAT is less than 25% and / or serum ferritin is less than 100 μg / L, subject will receive further doses, provided that serum ferritin is less than 400 μg / L.

[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, paleness, hair loss, irritability, weakness, pica, brittle or grooved nails, Plummer-Vinson syndrome (a painful atrophy of the mucous membranes lining the tongue, pharynx and esophagus), immune dysfunction, eating ice, and restless legs syndrome, among others.

[0100] Subjects treated by the methods disclosed herein will experience improvement of iron deficiency. In some embodiments, subjects treated by the methods disclosed herein will experience a reduction in iron deficiency. This reduction can occur because the total amount of iron in the subject's body is increased 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, the symptoms being selected from fatigue, dizziness, paleness, hair loss, irritability, weakness, pica, brittle or grooved nails, Plummer-Vinson syndrome (painful atrophy of the mucous membranes that cover the tongue, pharynx and esophagus), immune dysfunction, eating ice, restless legs syndrome, and combinations of the above.

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

[0102] Iron deficiency anemia is typically characterized by pallor (the pale color of skin and mucous membrane resulting from reduced oxyhemoglobin), fatigue, lightheadedness and weakness.However, the symptoms of iron deficiency anemia may vary between subjects.As iron deficiency tends to develop slowly, adaptation to the disease may occur and may remain unrecognized for some time. In some instances, subjects may experience, among other things, dyspnea (trouble breathing), pica (abnormal, compulsive food cravings), anxiety, irritability or sadness that often results in OCD-type compulsions and obsessions, angina, constipation, drowsiness, tinnitus, mouth ulcers, palpitations, hair loss, fainting or blackouts, depression, shortness of breath on exertion, muscle spasms, pale yellow skin, tingling (numbness) 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 (painful atrophy of the mucous membranes lining the tongue, pharynx, and esophagus), and restless legs syndrome.

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

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

[0105] In some embodiments, a subject treated by the methods disclosed herein may experience improvement in anemia and / or iron deficiency anemia as hemoglobin levels are raised and / or maintained above a threshold level. In some embodiments, a method of treating anemia is disclosed, the method comprising administering to a subject iron isomaltoside, the iron isomaltoside resulting in a hemoglobin level in the subject at or above a level ranging from 11.0 g / dL to 13.0 g / dL, including a level selected from 11.0 g / dL, 11.5 g / dL, 12.0 g / dL, and 13.0 g / dL. In some embodiments, a method of treating anemia is disclosed, the method comprising administering to a subject iron isomaltoside, the iron isomaltoside resulting in a hemoglobin level in the subject at or above 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 of treating anemia in a male subject is disclosed, the method comprising administering to the male subject iron isomaltoside, the iron isomaltoside resulting in a hemoglobin level in the male subject equal to or greater than a level selected from 13.0 g / dL and 8.1 mmol / L. In some embodiments, a method of treating anemia in a female subject is disclosed, the method comprising administering to the female subject iron isomaltoside, the iron isomaltoside resulting in a hemoglobin level in the female subject equal to or greater than a level selected from 12.0 g / dL and 7.4 mmol / L.

[0106] Risk factors for adverse cardiovascular events A particular group of subjects with iron deficiency as disclosed herein, to whom treatment according to the invention is applicable, are characterized as being at risk for adverse cardiovascular events.

[0107] According to the present invention, a subject at risk of an adverse cardiovascular event is a subject at risk for one or more events selected from the group consisting of events affecting the heart (adverse cardiac events), such as congestive heart failure (CHF), particularly CHF requiring hospitalization or medical treatment, myocardial infarction, unstable angina, particularly angina requiring hospitalization, or arrhythmias; events affecting the peripheral vasculature (adverse peripheral vascular events), such as hypertension and hypotension; events affecting the cerebrovascular system (adverse cerebrovascular events), such as stroke; and / or general adverse events, such as death.

[0108] More specifically, a subject at risk of an adverse cardiovascular event according to the present invention is a subject having one or more of the following risk factors for a cardiovascular event, in particular a cardiovascular event as defined herein:

[0109] Chronic Kidney Disease (CKD) Glomerular filtration rate (GFR) < 60 ml / min / 1.73 m for 3 months 2 A subject who is at or above the age of 18 is classified as having CKD, regardless of the presence or absence of kidney damage. Those CKD subjects who require either dialysis or kidney transplantation are typically referred to as end-stage renal disease (ESRD) subjects. Therefore, when a subject reaches the end of the conservative stage, which is an earlier stage of CKD, he or she is traditionally classified as an ESRD subject. Before this time, these subjects are referred to as conservative CKD subjects. Conservative CKD (NDD-CKD) subjects are subjects who have been diagnosed with early chronic kidney disease and are not yet medically instructed to undergo dialysis. The US National Kidney Foundation defines five stages of chronic kidney disease. Typically, subjects with CKD progress through stages 1 to 4 before dialysis becomes medically necessary. However, subjects with advanced stages of CKD, such as stage 5, who have not yet started dialysis or are not yet recommended for transplantation, are also typically referred to as conservative CKD subjects.

[0110] As used herein, NDD-CKD is intended to cover all subjects who have been diagnosed with chronic kidney disease but are not undergoing dialysis during administration of iron isomaltoside. Such subjects include, for example, subjects who have never undergone dialysis, and in some embodiments, subjects who have undergone dialysis but are not undergoing dialysis during administration of iron isomaltoside.

[0111] Cardiovascular disease is a frequent cause of death in subjects with chronic kidney disease (CKD). Despite the high prevalence of traditional risk factors for atherosclerosis in CKD subjects, heart failure, arrhythmias, and sudden cardiac death constitute a disproportionately large burden of cardiovascular-related mortality in CKD subjects compared with coronary artery disease (CAD). Left ventricular hypertrophy (LVH) and left ventricular dysfunction may be the consequence of having atherosclerosis, but are also common nonatherosclerotic mechanisms of cardiovascular injury in CKD. Cardiac disease, including coronary artery disease, left ventricular hypertrophy (LVH), and heart failure (HF), is common in subjects with chronic kidney disease (CKD). As glomerular filtration rate (GFR) declines, LVH appears to become more common and dialysis use increases.

[0112] LVH is an important predictor of mortality in subjects with CKD, and anemia has been found to be a significant independent risk factor for the development and progression of LVH and HF in CKD, and for the development and progression of adverse cardiovascular outcomes, including mortality.

[0113] The presence of LVH is clinically significant because it is associated with heart failure, ventricular arrhythmias, death following myocardial infarction, reduced LV ejection fraction, sudden cardiac death, aortic root dilation, and increased incidence of cerebrovascular events. In general, the development of heart failure due to LVH results from reduced left ventricular systolic function and / or diastolic dysfunction. The deleterious effects of left ventricular remodeling may be an important determinant of progression to overt heart failure.

[0114] Without intending to be limited by theory, possible mechanisms that may explain the relationship between anemia and the development of LVH include the effects of 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, reduced 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 poorer prognosis of all causes and cardiac in subjects with CKD and cardiac disease.If the increasing anemia in CKD is associated with the increasingly severe degree of LVH and cardiac failure, correcting the deficiency of anemia according to the present disclosure has beneficial effects on the clinical characteristics of HF and LVH.Clinical characteristics include the clinical manifestation of HF, and the subsequent appearance and progression of LVH.

[0116] Multiple, mostly uncontrolled, short-term studies suggest that correcting anemia with erythropoietin to Hb levels of approximately 10-12 g / dL in subjects with HF and CKD improves clinical manifestations of HF and reduces hospitalization rates, but does not improve hard endpoints in CHF subjects. 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 subjects.

[0117] LVH is itself a strong prognostic marker of adverse cardiovascular outcomes in subjects with CKD, but appears to be reversed in some subjects by improving Hb levels from less than 10 g / dL up to levels greater than 10 g / dL. Again, without intending to be limiting, further elevation of Hb above normal levels does not appear to result in further regression or clinical improvement of LVH. The baseline profile of LVH may be an important factor in determining the subsequent clinical response to anemia correction in subjects with LVH.

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

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

[0120] "Congestive HF" is a term used to describe chronic heart failure, especially when there is evidence of volume overload, most often manifested 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 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 places patients into one of four categories based on how limited they are during physical activity. Patients who have no symptoms and no limitations, such as excessive fatigue, palpitations, or dyspnea (shortness of breath), during ordinary physical activities, such as walking, climbing stairs, etc., 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 have significant limitations in activity due to symptoms even during less than ordinary activities, such as walking short distances of 20 to 100 meters, and who only feel well 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 a specific embodiment of the present invention, the congestive heart failure (CHF) is NYHA class II-IV congestive heart failure.

[0122] Atrial fibrillation (AF) Atrial fibrillation (AF) can be first-time diagnosed AF (AF not previously diagnosed, regardless of duration of arrhythmia or the presence and severity of AF-related symptoms), paroxysmal AF (spontaneously terminating in most cases within 48 hours. Some AF episodes may last up to 7 days. AF episodes that are cardioversioned within 7 days should be considered paroxysmal), and persistent AF (AF lasting longer than 7 days, including episodes that are terminated by cardioversion after 7 days or more, either with drugs or by direct current cardioversion), long-term persistent AF (continuous AF that has lasted for more than 1 year at the time the decision is made to employ a rhythm control strategy), or permanent AF (AF that is accepted by the patient (and physician). In certain embodiments of the invention, the AF is first-time diagnosed AF, paroxysmal AF, or persistent AF.

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

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

[0125] Hypertension is one of the major risk factors for heart disease, and in particular for stroke. Hypertension causes about 50% of ischemic strokes and increases the risk of hemorrhagic stroke.

[0126] There are several mechanisms involved in hypertension that make it such a high risk factor for adverse cardiovascular events. For example, hypertension places stress on blood vessels due to narrowing or clogging of the blood vessels. This can lead to atherosclerosis or the formation of weak spots in blood vessels that easily rupture or expand the arterial wall, resulting in aneurysms.

[0127] Myocardial infarction (MI) Myocardial infarction (MI) is defined as the death of myocardial cells due to prolonged ischemia. After the onset of myocardial ischemia, histological cell death does not occur immediately, but takes a finite period to manifest. After several hours, complete necrosis of myocardial cells can be observed. MI can be the first manifestation of coronary artery disease (CAD).

[0128] MI is a term used to describe the presence of characteristic changes in myocardial enzyme markers in the context of any of the time-related symptoms of acute coronary syndromes, or electrocardiogram (ECG) changes consistent with either ischemia or infarction. 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 ​​above the 99th percentile (upper reference limit (URL)) of the normal reference population. This discriminatory 99th percentile is referred to as the decision level for the diagnosis of MI.

[0129] An MI in a patient with chest discomfort or other ischemic symptoms who develops ST-segment elevation in two adjacent leads is referred to as an "ST-elevation MI" (STEMI). Patients without ST-segment elevation at presentation are typically referred to as having a "non-ST-segment elevation MI (non-STEMI)." In a preferred embodiment, the myocardial infarction (MI) is an ST-segment elevation myocardial infarction (STEMI) or non-STEMI.

[0130] Subjects with a history of MI are one of the groups at highest risk for further cardiovascular adverse events.In particular, subjects who survive MI, i.e., have a history of MI, are at increased risk of recurrent infarction and have a six-fold higher annual mortality rate than those of the same age who do not have coronary heart disease.

[0131] stroke Stroke is classically characterized as a neurological deficit resulting from an acute focal injury in the central nervous system of vascular origin, including cerebral infarction, intracerebral hemorrhage, and subarachnoid hemorrhage.

[0132] Subjects with a history of stroke, ie, those who have suffered a stroke, remain at increased risk for further adverse cardiovascular events, particularly for further strokes.

[0133] Heart valve disorders Aortic stenosis is the most common primary valvular disease leading to surgical or catheter procedures in Europe and North America and is increasing in prevalence due to the aging of the population.

[0134] Mitral regurgitation (MR) is the second most frequent predictor for valve surgery in Europe. It is possible to distinguish primary MR from secondary MR, especially with regard to surgical and transcatheter procedural 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 as one of the causes 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 chords. LV dysfunction can result from coronary heart disease (CHD) or (non-ischemic) cardiomyopathy.

[0135] For example, subjects with a history of congenital heart valve defects are at increased risk of developing valve problems. Heart valve disease can lead to many complications, including adverse cardiovascular events, such as HF, stroke, blood clots, arrhythmias, or death.

[0136] diabetes Significant hypoglycemia is associated with symptoms including frequent urination, thirst, blurred vision, fatigue, and recurrent infections. Beyond symptom relief, the aim of lowering blood glucose is to reduce the long-term complications of diabetes. Diabetes mellitus type 2 (also known as type 2 diabetes) is a long-term metabolic disorder characterized by high blood sugar, insulin resistance, and a relative lack of insulin. Common symptoms include increased thirst, frequent urination, and unexplained weight loss. Type 1 diabetes, formerly known as juvenile onset diabetes or insulin-dependent diabetes, is a chronic condition in which the pancreas produces little or no insulin. A variety of factors, including genetics and some viruses, can contribute to type 1 diabetes. Type 1 diabetes usually appears during childhood or adolescence, but can also manifest in adults. Despite active research, there is no cure for type 1 diabetes. Treatment focuses on managing blood sugar levels and preventing complications through insulin, diet, and lifestyle.

[0137] Having diabetes increases the risk of adverse cardiovascular events by 2-4 times compared to non-diabetic individuals. Adverse cardiovascular events are the leading cause of mortality for people with diabetes. This is particularly due to hypertension, abnormal blood lipids, and obesity, all of which are risk factors for adverse cardiovascular events and are prevalent in subjects 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 (atheromas) developing, which, if developed in coronary arteries, can lead to coronary heart disease and heart attacks.Diabetic subjects are more likely to have heart attacks or strokes than non-diabetic subjects, and are at increased risk of heart failure compared to non-diabetic subjects.Diabetes can inhibit the protective effects of estrogen, which can increase the risk of cardiovascular adverse events in premenopausal women with diabetes.

[0139] Obesity "Obesity" is a condition characterized by excess body weight such that the body mass index (BMI), a measurement obtained by dividing a person's weight by the square of their height, exceeds 30 kg / m2. 2 Having a BMI above 100%, ie, being obese, puts one at serious risk of developing hypertension (eg, due to intra-abdominal fat), diabetes, and atherosclerosis, which are risk factors for adverse cardiovascular events.

[0140] In particular, dietary salt is a significant factor that can increase blood pressure and thereby lead to hypertension and associated risks, so that being overweight, for example, increases the risk of adverse cardiovascular events due to high salt intake.

[0141] Age, smoking, and alcohol consumption Subjects who are elderly, smoke, and / or drink alcohol are at increased risk for adverse cardiovascular events.

[0142] According to certain embodiments of the present invention, the elderly subject is 60 years of age or older, 65 years of age or older, 70 years of age or older, 75 years of age or older, or 80 years of age or older. After age 55, the risk of stroke doubles every decade. Systolic blood pressure is an important predictor of risk of cardiovascular events with age.

[0143] Drinkers were defined as subjects with significant alcohol intake intact, specifically those who consumed >7 drinks per week.

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

[0145] Smokers were defined as former and / or current regular cigarette smokers.

[0146] Since the 1940s, it has been known that smoking is 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 clogging, raises low-density lipoprotein cholesterol, reduces high-density lipoprotein, and promotes coronary artery spasm. In addition, nicotine, the addictive component in tobacco, accelerates the heart rate and increases blood pressure.

[0147] Hyperthyroidism and related thyrotoxicosis Hyperthyroidism is characterized by too high levels of thyroxine. It speeds up the body's metabolism and can cause unintentional weight loss and rapid or irregular heartbeat.

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

[0149] Chronic Obstructive Pulmonary Disorder (COPD) "Chronic obstructive pulmonary disease (COPD)" is a disease characterized by persistent respiratory symptoms and airflow limitation due to abnormalities of the airways and / or alveoli, usually caused by significant exposure to harmful particles or gases. The primary risk factor is tobacco smoking, although other environmental exposures may also contribute.

[0150] Cardiomyopathy Cardiomyopathy is defined by structural and functional abnormalities of the ventricular myocardium that cannot be explained by flow-limiting coronary artery disease or abnormal loading conditions. Historically, this group of disorders has been subdivided into primary diseases, in which the heart is the only organ involved, and secondary forms, in which cardiomyopathy is a manifestation of a systemic disorder. The ESC guidelines adopt a classification system that defines cardiomyopathies by specific morphological and functional criteria, regardless of the presence of extracardiac disease, and then groups them into familial / hereditary and nonfamilial / nonhereditary subtypes.

[0151] In certain embodiments of the invention, the cardiomyopathy is an inherited or acquired cardiomyopathy.

[0152] inflammation There is a relationship between proinflammatory biomarkers and incident hypertension, metabolic syndrome, 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 an increase in C-reactive protein (CRP). CRP is a non-specific marker of inflammation. A range of about 2-3 mg / L is the limit above which systemic inflammation is considered to be indicative. The role of inflammation in the pathogenesis of atherosclerosis has been firmly established in the past two decades.

[0153] dialysis Dialysis subjects are at high risk for adverse cardiovascular events.

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

[0155] Drug therapy The risk for adverse cardiovascular events is increased when a subject is treated with one or more of the following: (i) Modulators of the hypoxia-inducible factor (HIF) signaling pathway, including prolyl hydroxylase inhibitors, e.g., daprodustat, vadadustat, roxadustat, molidustat, and digitusta; (ii) Erythropoietin 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) a hepcidin modulator, e.g., a hepcidin agonist or a hepcidin antagonist.

[0156] Subjects take one or more erythropoietin stimulating agents (ESAs) in an effort to control anemia. ESAs function 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. Erythropoietin stimulating agents, commonly abbreviated as ESAs, are agents similar in structure and / or function to the cytokine erythropoietin, which stimulates the body's production of red blood cells (erythropoiesis). Typical ESAs are structurally and biologically similar to the naturally occurring protein erythropoietin. Examples of commercially available ESAs include erythropoietin (Epo), epoetin alpha (Procrit / Epogen), epoetin beta (NeoRecormon), darbepoetin alpha (Aranesp), and methoxypolyethylene glycol-epoetin beta (Mircera). The two ESAs currently approved for marketing in the United States are epoetin alfa (Procrit, Epogen) and darbepoetin alfa (Aranesp).

[0157] ESAs are commonly given to ESRD subjects. These subjects usually have low hemoglobin levels because they cannot produce enough erythropoietin. The most common side effects from the use of ESAs include high blood pressure; swelling; fever; dizziness; nausea; and pain at the site of injection, among others. In addition to these side effects, there are several safety issues that the use of ESAs brings. ESAs increase the risk of venous thromboembolism (blood clogging in veins). ESAs can also raise hemoglobin too high, putting subjects at higher risk for heart attack, stroke, heart failure, and death.

[0158] In a further particular embodiment of the invention, the subject is being treated with an anticoagulant and / or an NSAID.

[0159] Hereditary hemorrhagic telangiectasia Hereditary hemorrhagic telangiectasia (also known as Osler-Weber-Rendu disease) is a genetic disorder inherited from a parent. Its severity can vary greatly from person to person, even within the same family. People develop abnormal connections between arteries and veins, called arteriovenous malformations (AVMs). The most common locations affected are the nose, lungs, brain, and liver. These AVMs can enlarge over time and may bleed or rupture, sometimes causing devastating complications.

[0160] Hereditary iron-refractory iron deficiency anemia Hereditary iron-refractory iron deficiency anemia (IRIDA) is an inherited disorder characterized by impaired absorption and utilization. IRIDA is generally understood to be related to genetic mutations that result in upregulation of hepcidin. A specific case of IRIDA is understood to be related to mutations in the gene TMPRSS6. 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 increasingly recognized as 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 proteolytic cleavage, resulting in a mix of uncleaved, i.e. intact FGF23 (iFGF23) and its cleaved fragments being found in vivo. The intact form, iFGF23, is the active form for phosphate metabolism that controls urinary excretion of phosphate, with high levels of iFGF23 resulting in urinary excretion of phosphate. Two main antibody assay types currently exist, one that captures only iFGF23 and the other that binds to the C-terminal end of the hormone and thus captures both iFGF23 and the C-terminal fragment. Thus, the latter metric, cFGF23, is a measure of the sum of intact and C-terminal FGF23 fragments. Thus, there are two tests for FGF23, iFGF23 and cFGF23, which have different interpretations.

[0163] High FGF23 levels are independently related to common and incident LVH, cardiovascular disease events, and mortality in CKD and non-CKD populations.Moreover, recent studies have demonstrated that FGF23 directly induces LVH, suggesting that FGF23 is not a simple biomarker of cardiovascular risk.CKD subjects tend to have very high FGF23 levels due to the body's constant attempt to counterbalance high serum phosphate levels by producing iFGF23 and increasing the fraction of phosphate excreted in urine via the kidney.For this reason, iFGF23 levels are elevated in CKD subjects, and as a result, other downstream effects of iFGF23 may be more pronounced.

[0164] Elevated FGF23 levels help maintain serum phosphate within the normal range in CKD, but as estimated glomerular filtration rate (eGFR) decreases, FGF23 concentrations increase, stimulating more phosphate excretion per nephron and reducing 1,25-dihydroxyvitamin D levels, 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, resulting in hypophosphatemia. Data indicate that hypophosphatemia is mediated by elevated FGF23.

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

[0166] In a specific embodiment, the subject treated according to the method described herein for one or more cardiovascular adverse events has high FGF23 level.The normal level of non-damaged FGF23 in the serum of healthy human is approximately 26.1pg / mL, and the normal level of C-terminal FGF23 fragment in the serum of healthy human is approximately 49.0RU / mL.In certain embodiments, the FGF23 level (e.g., non-damaged FGF23 and / or C-terminal FGF23 fragment) of the subject is high relative to the normal range in healthy human. In some embodiments, the non-damaged FGF23 level in the serum of the subject is between 250pg / mL and 350pg / mL, between 200pg / mL and 300pg / mL, between 200pg / mL and 350pg / mL, between 300pg / mL and 350pg / mL, between 300pg / mL and 400pg / mL, or between 250pg / mL and 500pg / mL.In certain embodiments, the non-damaged FGF23 level in the serum of the subject is greater than 200pg / mL, 225pg / mL, 250pg / mL, 275pg / mL, 300pg / mL, 325pg / mL, or 350pg / mL. In some embodiments, the C-terminal FGF23 fragment level in the serum of the subject is between 60RU / mL and 100RU / mL, between 100RU / mL and 200RU / mL, between 200RU / mL and 300RU / mL, or between 250RU / mL and 400RU / mL.In certain embodiments, the C-terminal FGF23 fragment level in the serum of the subject is more than 60RU / mL, 100RU / mL, 125RU / mL, 150RU / mL, 175RU / mL, 200RU / mL, 225RU / mL, 250RU / mL, 275RU / mL, or 300RU / 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 a level of more than 10 g / dL, more than 11 g / dL, more than 12 g / dL, more than 13 g / dL, or more than 15 g / dL. In certain embodiments, subjects treated by the methods disclosed herein experience an increase in the subject's hemoglobin concentration to a level 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 with the methods disclosed herein experience a reduction in serum or plasma levels of non-damaged FGF23 of at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%. In certain embodiments, subjects treated with the methods disclosed herein experience a reduction in serum or plasma levels of non-damaged FGF23 of at least 15% to 30%, 20% to 30%, 25% to 50%, 30% to 60%, or 15% to 60%. In some embodiments, subjects treated with the methods disclosed herein experience a reduction in serum or plasma levels of C-terminal FGF23 fragments of at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%. In some embodiments, subjects treated by the methods disclosed herein experience a 15% to 30%, 20% to 30%, 25% to 50%, 30% to 60%, or 15% to 60% reduction in C-terminal FGF23 fragment levels in serum or plasma.

[0168] Thus, in a first preferred embodiment of this aspect of the invention, a particular group of subjects to which the treatment according to the invention can be applied is those with a history of myocardial infarction (MI), stroke, atrial fibrillation (AF), congestive heart failure (CHF), chronic kidney disease (CKD), hypertension, diabetes, valvular heart disease, obesity, and / or smokers, alcohol drinkers, and / or elderly subjects. These include in particular those 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), especially those with a history of congestive heart failure (CHF), are a particularly preferred group of subjects at risk of adverse cardiovascular events and therefore can be applied to the treatment according to the invention.

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

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

[0171] In a third preferred embodiment of this aspect of the invention, a particular group of subjects to whom the treatment according to the invention can be applied are subjects 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 invention, a particular group of subjects to whom the treatment according to the invention can be applied are subjects with a history of stroke.

[0172] Subjects as defined herein (i.e. subjects at risk of adverse cardiovascular events and / or with a history of congestive heart failure) include subjects who also have chronic kidney disease (CKD) or who do not have CKD. Subjects with CKD are a particular subgroup of patients to which the treatment according to the invention can be applied. In particular, these include subjects with chronic kidney disease (CKD) and congestive heart failure (CHF), the chronic kidney disease (CKD) being preferably conservative chronic kidney disease (NDD-CKD). In the group (subjects with a history of chronic kidney disease (CKD) and congestive heart failure (CHF), especially conservative 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, the subject with a history of congestive heart failure has HFrEF. In another embodiment, the subject with a history of congestive heart failure has NYHA class II-IV congestive heart failure, particularly HFrEF type congestive heart failure in NYHA class II-IV.

[0174] In further embodiments of this aspect of the invention, a particular group of subjects to which the treatment according to the invention can be applied are those with one or more of the following risk factors: (i) Subjects with a history of atrial fibrillation (AF), specifically first-time diagnosed AF, paroxysmal AF, or persistent AF; (ii) subjects with a history of cardiac valvular disease; (iii) subjects with a history of hypertension; (iv) subjects with diabetes; (v) subjects with a history of obesity; (vi) Elderly subjects, particularly subjects aged 60 years or older, 65 years or older, 70 years or older, 75 years or older, or 80 years or older; (vii) smokers; (viii) drinker; (ix) Subjects with hyperthyroidism and / or related thyrotoxicosis; (x) Subjects with chronic obstructive pulmonary disorder (COPD); (xi) A subject having a cardiomyopathy, particularly a hereditary or acquired cardiomyopathy; (xii) subjects with systemic inflammation in the absence of infection, the systemic inflammation being particularly associated with an increase in C-reactive protein (CRP) greater than about 2-3 mg / L; (xiii) subjects undergoing dialysis, in particular hemodialysis or peritoneal dialysis; (xiv) Subjects who have been treated with one or more of the following: a) modulators of the hypoxia inducible factor (HIF) signaling pathway, including prolyl hydroxylase inhibitors, e.g., daprodustat, vadadustat, roxadustat, molidustat, and digitusta; b) Erythropoietin 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) a hepcidin modulator, e.g., a hepcidin agonist or a hepcidin antagonist; (xv) subjects treated with anticoagulants and / or NSAIDs; (xvi) a subject with hereditary hemorrhagic telangiectasia; or (xvii) A subject with hereditary iron-refractory iron deficiency anemia.

[0175] II. Therapeutic Benefits In addition to delivering iron to a subject, the present disclosure provides a method for reducing the incidence or risk of adverse cardiovascular events in a subject as defined herein. Reference to reducing the incidence or risk of "adverse cardiovascular events" or "adverse cardiovascular event" is meant to refer to reducing the incidence or risk of one or more of the listed events.

[0176] According to one embodiment of this second aspect of the 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 vasculature (peripheral vascular adverse events); events affecting the cerebrovascular system (cerebrovascular adverse events); respiratory, thoracic and mediastinal adverse events; general adverse events; and infections and invasions.

[0177] In certain embodiments of this second aspect of the invention, the cardiac adverse event whose incidence or risk is reduced 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 premature ventricular contractions; the peripheral vascular adverse event is selected from the group consisting of hypertension, elevated systolic blood pressure, elevated blood pressure, elevated troponin, and hypotension; the cerebrovascular adverse event is selected from the group consisting of cerebrovascular incident, 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.

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

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

[0180] According to further particularly preferred embodiments of this second aspect of the invention, the adverse cardiovascular event for which the incidence or risk is reduced is congestive heart failure, atrial fibrillation, hypertension, and / or cardiac arrest.

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

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

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

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

[0185] Particular adverse cardiovascular events related to congestive heart failure are hospitalization, hospitalization due to worsening congestive heart failure, or death due to congestive heart failure. The present invention is particularly directed to adverse CV events where the adverse CV event is CHF.

[0186] III. Therapeutic Benefit in Selected Subjects Considering the particular group of subjects defined herein, and the incidence or risk of adverse cardiovascular events to be reduced, the present invention provides according to a third aspect a method of treating iron deficiency in a subject, whereby treating the iron deficiency reduces the incidence or risk of adverse cardiovascular events in the subject, the method comprising administering an effective amount of iron isomaltoside, The target is, (A) a subject at risk for an adverse cardiovascular event, as defined herein; (B) a subject with a history of congestive heart failure (CHF); or (C) Subjects with a history of congestive heart failure (CHF) and at risk for adverse cardiovascular events and The incidence or risk of adverse cardiovascular events is reduced. (a) congestive heart failure, myocardial infarction, unstable angina, arrhythmias, hypertension, hypotension, stroke, and death; (b) congestive heart failure; (c) atrial fibrillation; (d) hypertension; or (e) Cardiac arrest The present invention relates to a method comprising the steps of:

[0187] According to a preferred embodiment of this third aspect of the invention, the subject is a subject at risk of an adverse cardiovascular event, and the adverse cardiovascular event the incidence or risk of which is reduced is congestive heart failure.

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

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

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

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

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

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

[0194] According to a further preferred embodiment of this third aspect of the invention, the subject is a subject with a history of congestive heart failure (CHF) and the adverse cardiovascular 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 subject is a subject at risk of cardiovascular harm and / or has a history of congestive heart failure, and the subject has chronic kidney disease (CKD). According to another embodiment of this third aspect of the present invention, the subject is a subject at risk of cardiovascular harm and / or has a history of congestive heart failure, and the subject does not have chronic kidney disease (CKD). In particular, these include subjects with chronic kidney disease (CKD) and / or congestive heart failure (CHF), and the chronic kidney disease (CKD) is preferably conservative chronic kidney disease (NDD-CKD).

[0196] According to further particularly preferred embodiments of this third aspect of the invention, the subject has a history of congestive heart failure (CHF) and is a subject with chronic kidney disease (CKD), in particular conservative chronic kidney disease (NDD-CKD), and the adverse cardiovascular event for which the incidence or risk is reduced is congestive heart failure.

[0197] According to further particularly preferred embodiments of this third aspect of the invention, the subject has a history of congestive heart failure (CHF) and is a subject with chronic kidney disease (CKD), in particular conservative chronic kidney disease (NDD-CKD), and the adverse cardiovascular event for which the incidence or risk is reduced is atrial fibrillation.

[0198] According to further particularly preferred embodiments of this third aspect of the invention, the subject has a history of congestive heart failure (CHF) and is a subject with chronic kidney disease (CKD), in particular conservative chronic kidney disease (NDD-CKD), and the adverse cardiovascular event whose incidence or risk is reduced is cardiac arrest.

[0199] According to further particularly preferred embodiments of this third aspect of the invention, the subject has a history of congestive heart failure (CHF) and is a subject with chronic kidney disease (CKD), in particular conservative chronic kidney disease (NDD-CKD), and the adverse cardiovascular event for which the incidence or risk is reduced is hypertension.

[0200] In some of these embodiments, the subject with a history of congestive heart failure has HFrEF. In some embodiments, the subject with a history of congestive heart failure has NYHA class II-IV congestive heart failure, particularly HFrEF congestive heart failure in NYHA class II-IV.

[0201] In other embodiments, the present disclosure provides a method for reducing the incidence or risk of hospitalization for an adverse cardiovascular event in a subject as defined herein.

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

[0203] IV. Medication and Administration Regimens The method of treating iron deficiency in a subject 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 comprise, and according to a preferred embodiment does comprise, 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 infusion of 1000 mg iron, a dose of elemental iron of up to 20 mg iron / kg body weight given as an intravenous infusion, or a dose of up to 500 mg given as an intravenous bolus injection, up to three times a 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 following table: TIFF2025041648000002.tif27170

[0205] Alternatively, a typical treatment regimen for iron isomaltoside is selected according to the table below. TIFF2025041648000003.tif42170

[0206] Thus, in some embodiments, an effective amount of iron isomaltoside is an amount of elemental iron in the range of about 500 mg to 2000 mg, e.g., 500 mg, 1000 mg, 1500 mg, or 2000 mg, which may be administered in a single dose or in two or more doses, particularly two or three doses. Alternatively, an effective amount of iron isomaltoside is an amount of 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 elemental iron.

[0208] For repeated administration, a first dose of elemental iron of 200-700 mg, preferably 300-600, most preferably up to 500 mg, is followed by a second dose of elemental iron of 200-700 mg, preferably 300-600, 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 may be followed, for example a third dose of elemental iron of 200-700 mg, preferably 300-600, most preferably up to 500 mg. 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 further preferred if each dose is administered at least 2 days, especially 3 days, apart. For example, if three doses are administered within a week, the doses are preferably administered on days 1, 4, and 7.

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

[0210] For CKD patients on 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 conjunction with the 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 invention, wherein the additional drugs are (1) Angiotensin-converting enzyme inhibitors (ACEIs), such as captopril, enalapril, lisinopril, ramipril, or trandolapril; (2) beta-blockers, e.g., bisoprolol, carvedilol, metoprolol succinate, or nebivolol; (3) Mineralocorticoid 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, metolazone, indapamide, amiloride, or triamterene Further described herein is a combination selected from the group consisting of:

[0212] Dosages for additional drugs generally refer to the amount of drug administered to an adult. Dosages for administration to small children may be adjusted accordingly.

[0213] Particular combinations of iron isomaltoside and one or more additional drugs for use in treating iron deficiency according to the present invention are those in which the additional drug places the subject at higher risk for an adverse cardiovascular event. According to this embodiment, the additional drug is (i) Modulators of the hypoxia-inducible factor (HIF) signaling pathway, including prolyl hydroxylase inhibitors, e.g., daprodustat, vadadustat, roxadustat, molidustat, and digitusta; (ii) Erythropoietin 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) a heptidine modulator, e.g., a heptidine agonist or a heptidine antagonist. is selected from the group consisting of:

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

[0215] 2. The method of embodiment 1, wherein the subject at risk of an adverse cardiovascular event is a subject with a history of myocardial infarction (MI), a history of stroke, a history of atrial fibrillation (AF), a history of congestive heart failure (CHF), chronic kidney disease (CKD), a history of hypertension, diabetes, a history of heart valve disorders, a history of obesity, and / or a smoker, a drinker, and / or an elderly subject.

[0216] 3. The method of embodiment 2, wherein the subject at risk of an adverse cardiovascular event is a subject with a history of myocardial infarction (MI), a history of stroke, a history of atrial fibrillation (AF), chronic kidney disease (CKD), a history of congestive heart failure (CHF), and / or a history of hypertension.

[0217] 4. The method of embodiment 3, wherein the subject at risk of an adverse cardiovascular event is a subject with a history of myocardial infarction (MI), a history of stroke, and / or a history of congestive heart failure (CHF).

[0218] 5. A method of 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 of embodiment 5, wherein the subject with a history of congestive heart failure (CHF) has a history of myocardial infarction (MI), and / or a history of stroke.

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

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

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

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

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

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

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

[0227] 14. The method of embodiment 13, wherein the subject with a history of congestive heart failure has HFrEF.

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

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

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

[0231] 18. The method of embodiment 17, wherein the atrial fibrillation (AF) is first-time diagnosed AF, paroxysmal AF, or persistent AF.

[0232] 19. The method of embodiment 1 or 2, wherein the subject at risk of an adverse cardiovascular event is a subject with a history of a cardiac valve disorder.

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

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

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

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

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

[0238] 25. The method of embodiment 1, wherein the subject at risk of an adverse cardiovascular event is a subject with hyperthyroidism and / or associated thyrotoxicosis.

[0239] 26. The method of embodiment 1, wherein the subject at risk of an adverse cardiovascular event is a subject with chronic obstructive pulmonary disorder (COPD).

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

[0241] 28. The method of embodiment 27, wherein the cardiomyopathy is an inherited cardiomyopathy or an acquired cardiomyopathy.

[0242] 29. The method of embodiment 1, wherein the subject at risk of an adverse cardiovascular event is a subject with systemic inflammation without infection.

[0243] 30. The method of embodiment 29, wherein the systemic inflammation is associated with an increase in C-reactive protein (CRP) above the range of about 2-3 mg / L.

[0244] 31. The method of embodiment 1, wherein the subject at risk of an adverse cardiovascular event is a subject on dialysis.

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

[0246] 33.Subjects at risk for adverse cardiovascular events have one or more of the following: a) modulators of the hypoxia inducible factor (HIF) signaling pathway, including prolyl hydroxylase inhibitors, e.g., daprodustat, vadadustat, roxadustat, molidustat, and digitusta; b) Erythropoietin 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 2. The method of embodiment 1, wherein the subject is a subject being treated with

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

[0248] 35. The method of embodiment 1, wherein the subject at risk of an adverse cardiovascular event is a subject with hereditary hemorrhagic telangiectasia.

[0249] 36. The method of embodiment 1, wherein the subject at risk of an adverse cardiovascular event is a subject with hereditary iron-refractory iron deficiency anemia.

[0250] 37. The method of any one of the preceding embodiments, wherein the iron deficiency is iron deficiency anemia.

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

[0252] 39. The method of any one of embodiments 1 to 38, wherein the subject is a subject who does not tolerate or for whom oral iron administration is ineffective.

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

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

[0255] 42. The method of embodiment 41, wherein the cardiovascular adverse event is 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 invasions.

[0256] 43. The method of embodiment 42, wherein 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 extrasystoles; the peripheral vascular adverse event is selected from the group consisting of hypertension, elevated systolic blood pressure, elevated blood pressure, elevated troponin, and hypotension; the cerebrovascular adverse event is selected from the group consisting of cerebrovascular incidents, 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.

[0257] 44. The method of embodiment 41, wherein the cardiovascular adverse event is selected from the group consisting of: 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); and death.

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

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

[0260] 47. The method of embodiment 41-42, 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 of any one of embodiments 41 to 47, wherein the cardiovascular adverse event is congestive heart failure.

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

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

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

[0265] 52. The method of embodiment 41, wherein the cardiovascular adverse event is cardiovascular death and / or hospitalization due to worsening congestive heart failure.

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

[0267] 54. The method of embodiment 41-47, wherein the cardiovascular adverse event is hypertension.

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

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

[0270] 57. A method of treating iron deficiency in a subject, wherein treating the iron deficiency reduces the incidence or risk of an adverse cardiovascular event in the subject, the method comprising administering an effective amount of iron isomaltoside; The target is, (A) Subjects at risk for adverse cardiovascular events; (B) a subject with a history of congestive heart failure (CHF); or (C) Subjects with a history of congestive heart failure (CHF) and at risk for adverse cardiovascular events and The incidence or risk of adverse cardiovascular events is reduced. (a) congestive heart failure, myocardial infarction, unstable angina, arrhythmias, hypertension, hypotension, stroke, and death; (b) congestive heart failure; (c) atrial fibrillation; (d) hypertension; or (e) Cardiac arrest The method of claim 1, wherein the

[0271] 58. The method of embodiment 57, wherein the subject is at risk of an adverse cardiovascular event, and the adverse cardiovascular event whose incidence or risk is reduced is congestive heart failure.

[0272] 59. The method of embodiment 57, wherein the subject is a subject at risk for an adverse cardiovascular event, and the adverse cardiovascular event whose incidence or risk is reduced is atrial fibrillation.

[0273] 60. The method of embodiment 57, wherein the subject is a subject at risk of an adverse cardiovascular event, and the adverse cardiovascular event whose incidence or risk is reduced is cardiac arrest.

[0274] 61. The method of embodiment 57, wherein 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 or congestive heart failure, or both.

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

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

[0277] 64. The method of embodiment 57, wherein 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.

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

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

[0280] 67. The method of embodiment 65 or 66, wherein the chronic kidney disease (CKD) is conservative chronic kidney disease (NDD-CKD).

[0281] 68. The method of any one of embodiments 57 or 61 to 67, wherein the subject with a history of congestive heart failure has HFrEF.

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

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

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

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

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

[0287] 74. The method of any one of embodiments 41 to 73, wherein the subject is a subject who does not tolerate or for whom oral iron administration is ineffective.

[0288] 75. The method of 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 of any one of embodiments 57 to 75, wherein the iron isomaltoside is ferric delisomaltose.

[0290] 77. The method of any one of embodiments 1 to 76, further comprising determining whether the patient is at risk for an adverse cardiovascular event prior to administration of the iron isomaltoside.

[0291] 78. The method of embodiment 77, wherein the iron isomaltoside is administered if the patient is at risk for an adverse cardiovascular event.

[0292] 79. A method for preventing or treating atrial fibrillation (AF) or a disorder predisposing to AF in an animal suffering from such a condition, other than for reducing P-wave variability / duration, comprising administering to such an animal a therapeutically effective amount of an iron supplement, as described in any one of embodiments 1 to 78.

[0293] 80. The method of claim 79, wherein the disorder predisposing to AF is selected from valvular heart disease, hypertension, heart failure, coronary artery disease, obesity, and diabetes mellitus.

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

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

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

[0297] 84. The method of any one of claims 79 to 83, wherein the iron supplement is administered via oral, intramuscular, or intravenous routes.

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

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

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

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

[0302] 89. The method of 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 is further illustrated by the following examples, which should not be construed as further limiting. The contents of all figures and all references, Genbank sequences, patents and published patent applications cited throughout this application are expressly incorporated herein by reference. EXAMPLES

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

[0305] Test Design The study was a randomized, open-label, controlled trial. Subjects with iron deficiency anemia (IDA) were randomly assigned 1:1 to one course of one of two treatments. Iron isomaltoside 1000 was administered as elemental iron in a single dose of 1000 mg. Iron sucrose was administered as a slow intravenous bolus injection of 200 mg according to its US label, repeated up to five times to reach a cumulative dose of 1000 mg.

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

[0307] The protocol-defined cardiovascular adverse events 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: - Requires inpatient care, defined as admission to an inpatient ward or visit to an emergency department with a stay of at least 12 hours (or change of date if admission / discharge time is not known); and - Clinical evidence of congestive heart failure, including at least one of the following: new dyspnea, orthopnea, paroxysmal nocturnal dyspnea, edema, basilar moist rales, jugular venous distention, or worsening of these, or radiological evidence of worsening heart failure; - Add / increase healing: Intravenous treatment with diuretics, inotropes, or vasodilator therapy; or · Mechanical or surgical procedures (mechanical circulatory support, heart transplantation or ventricular pacing to improve cardiac function) or the use of ultrafiltration, hemofiltration or dialysis specifically to treat heart failure.

[0308] (2) Arrhythmia Arrhythmia was defined as any symptomatic deviation from normal sinus rhythm experienced by the subject as assessed by a health care provider. Evaluations included physical examination during outpatient visits, ECG, or hospital admission. Arrhythmias included any conduction abnormality, atrioventricular block, prolongation of the QTc interval, supraventricular / nodal arrhythmias, vasovagal attacks, ventricular arrhythmias, or other cardiovascular arrhythmias.

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

[0310] After release of the subject from the study visit where the subject received medical therapy, hypertension was defined as an objective measure of elevated blood pressure (an increase in systolic blood pressure of more than 20 mmHg resulting in a value above 180 mmHg, or an increase in diastolic blood pressure of more than 15 mmHg resulting in a value above 105 mmHg) requiring an unscheduled outpatient medical visit, hospital admission, or change in medical therapy (e.g., administration of antihypertensive medication).

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

[0312] Following release of a subject from a study visit where the subject received medical therapy, hypotension was defined as an objective measure of attenuation of blood pressure (a decrease in systolic blood pressure of more than 20 mmHg resulting in a value less than 90 mmHg, or a decrease in diastolic blood pressure of more than 15 mmHg resulting in a value less than 50 mmHg) associated with an unscheduled outpatient medical visit, hospital admission, or a change in medical therapy (e.g., fluid / volume overload, withholding antihypertensive medication).

[0313] (5) Myocardial infarction (MI): Myocardial infarction (MI) was defined as the presence of characteristic changes in cardiac enzyme markers in the setting of any time-related episode of acute coronary syndrome or electrocardiogram (ECG) changes consistent with either ischemia or infarction. Cardiac enzyme markers indicative of MI included: - Appropriate increases and decreases in serum troponin (I or T) or creatine kinase-MB, with at least one value ≥ 2 × upper limit of normal (ULN). If only one value was measured and this was ≥ 2 × ULN, the event was adjudicated based on the totality of clinical evidence. - If only total creatine phosphokinase was measured, consecutive changes (i.e., at least two values) were required to be ≥ 2 × ULN.

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

[0315] ECG changes were defined as follows: - new Q waves in two or more adjacent leads; - ST-segment progression to T-wave changes in 2 or more contiguous leads (e.g., transient ST-segment depression of 0.5 mm or more) - New left bundle branch block; or - ST-segment elevation of 1 mm in 2 or more contiguous leads.

[0316] (6) Stroke: Stroke was defined as the sudden onset of focal neurological deficits that were not reversible within 24 hours, attributable to vascular causes involving the central nervous system and not due to another readily identifiable cause (i.e., brain tumor or trauma). Strokes were subclassified as hemorrhagic, ischemic, or unknown.

[0317] (7) Unstable angina requiring hospitalization: Unstable angina requiring hospitalization was defined as an ischemic episode that met the following criteria: - lasts for more than 10 minutes and is considered to be myocardial ischemia at the time of final diagnosis; - Requiring unscheduled visits to a health care facility and overnight hospitalization (not including a chest pain observation unit); and - At least one of the following: New dynamic ECG changes, Evidence of ischemia on stress testing with or without cardiac imaging; · Angiographic evidence of 70% or more lesions and / or thrombus in epicardial coronary arteries.

[0318] (8) Death from any cause: Death from any cause was determined as the date the subject was pronounced dead.

[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 on hemoglobin (Hb), s-ferritin, and transferrin saturation (TSAT).

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

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

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

[0323] Secondary efficacy outcome measures were change in s-ferritin (ng / mL) within 8 weeks and change in transferrin saturation (%) within 8 weeks.

[0324] Safety Assessment The study included the following safety assessments: Collect AE data and assess them for relevance, severity, severity and predictability, and report these to authorities and follow up in accordance with international and regional requirements. · Physical examination, vital signs measurements, ECG, height, weight and safety laboratory parameters.

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

[0326] Study duration and number of visits For each subject, the study duration was 8 weeks (including a 28-day screening period), with each subject attending 6 to 8 clinic visits.

[0327] Target population Subjects meeting the following eligibility criteria were included: 1. Male or female > 18 years of age; 2. Hb ≤ 11 g / dL; and 3. Willing to participate and sign the Informed Consent Form (ICF).

[0328] IDA-03 Additional inclusion criteria for the IDA-03 study were: 1. IDA due to various etiologies*, such as abnormal uterine bleeding, gastrointestinal disease, cancer, weight loss procedures (gastric bypass) and other conditions resulting in significant blood loss; 2.TSAT<20%; 3. S-ferritin ≦100ng / mL; and 4. Documented history of intolerance or non-responsiveness** to oral iron therapy for at least 1 month*** prior to study enrollment.

[0329] The mean age of patients was 44 years (range 18–91 years), and 89% were women.

[0330] CKD-04 Additional inclusion criteria for the CKD-04 study were: 1.(i) eGFR < 60 mL / min / 1.73 m at screening 2 (calculated by Modified Diet in Renal Disease (MDRD)), or (ii) eGFR < 90 mL / min / 1.73 m at screening. 2chronic kidney impairment as defined by either: and kidney damage as indicated by abnormalities in urine composition in medical history, and / or moderate / high risk of cardiovascular disease based on the Framingham model; 2. If TSAT ≤ 30%, screening for s-ferritin ≤ 100ng / mL or ≤ 300ng / mL; and 3. Either no ESA or a stable dose (± 20%) of an ESA in the 4 weeks prior to randomization.

[0331] The mean age of patients was 69 years (range 25–97 years), and 63% were women. *The etiology of IDA (if unknown) was documented in the medical history and cross-checked with source documents. **Intolerance and non-response to oral iron treatment was documented along with signs and symptoms in medical history and cross-referenced with source documentation. ***Documented intolerance or non-responsiveness to prescribed oral iron therapy for at least 1 month within the past 9 months as determined by the investigator and will not be a candidate for oral iron again.

[0332] Subjects were not eligible for inclusion in this study if they met any of the following criteria: 1. Anemia primarily due to factors other than IDA as determined by the investigator 2. Hemochromatosis or other iron storage diseases 3. Previous severe hypersensitivity reaction to any intravenous iron compound 4. Treatment with intravenous iron within the past 30 days prior to screening 5. Treatment with erythropoietin or erythropoietin-stimulating agents, red blood cell transfusions, radiation therapy, and / or chemotherapy within the past 30 days prior to screening 6. Planned surgical procedures during the study 7. Alanine aminotransferase (ALAT) and / or aspartate aminotransferase (ASAT) >3x upper limit of normal (e.g. decompensated cirrhosis or active hepatitis) 8. Surgery under general anesthesia within the past 30 days prior to screening 9. Decompensated cirrhosis or active hepatitis (CKD-04 only) 10. Dialysis required to treat CKD 11. Alcohol or drug abuse within the past 6 months 12. Pregnant or lactating women. To avoid pregnancy, females of childbearing potential should use adequate contraception (e.g., intrauterine device, hormonal contraceptive or dual barrier method) throughout the study and for 7 days after the final dose.

[0333] Test procedure Subjects received either one treatment course of iron isomaltoside (Group A) or one treatment course of iron sucrose (Group B) as follows: · 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 and given 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 as per label, repeated up to five times to reach a cumulative dose of 1000 mg.

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

[0335] statistical analysis The co-primary safety endpoint was analyzed by constructing exact two-sided 95% CIs for the incidence of treatment-emergent serious and / or severe non-serious hypersensitivity AEs in the iron isomaltoside-treated groups. Safety objectives were met if the upper bound of the 95% CI was <3%.

[0336] Additionally, risk differences between iron isomaltoside and iron sucrose were assessed by constructing 95% CIs for the risk differences, generating both unadjusted CIs (with continuity correction) and stratified 95% Newcombe CIs using the Cochran-Mantel-Haenszel method.

[0337] For susceptibility, treatment groups were compared by logistic regression models with treatment and type of underlying disease as a function of covariates and between treatment groups by Fisher's exact test.

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

[0339] Coprimary efficacy outcomes were analyzed using a repeated measures mixed model (MMRM) approach based on restricted maximum likelihood (REML). All subjects in the analysis with intention to treat (ITT) set with post-baseline Hb data were included with these observations. The model included fixed categorical effects of treatment (iron isomaltoside and iron sucrose), week, week-by-treatment interaction, strata, and continuous fixed covariates of baseline Hb value and baseline Hb-by-week interaction. An unstructured (co)variance structure was used to model within-subject error. When unexpectedly this analysis did not converge, the following structures were applied in the following order: first-order ante-dependence, heterogeneous compound symmetric, compound symmetric. 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 least-squares means of the treatment-by-week interaction effects. Estimated mean differences based on this model were reported with two-sided symmetric 95% CIs, and efficacy objectives were met if the lower bound of the 95% CI was ≥ 0.5 g / dL.

[0340] Baseline Assessment The following were assessed by study staff at the clinical baseline visit at the study site: Inclusion and exclusion criteria reviewed to ensure no changes have occurred since screening Pregnancy test, if applicable Recording of relevant medical history, including history of myocardial infarction, stroke, or congestive heart failure Records of concomitant medications Physical examination (not performed after the baseline visit) Height measurement Weight measurement Vital signs check Randomization ECG Assessment of fatigue using the FACIT fatigue scale Pharmacoeconomic assessment using ISDR questionnaire and health resource utilization questionnaire Safety Lab Testing Efficacy Laboratory Testing Treatment with iron isomaltoside (group A only) Treatment with iron sucrose (group B only) Assessment and recording of AEs

[0341] Exam Assessment Demographics and Baseline Assessment Date of birth, sex, race, ethnicity, and smoking habits were collected. Current smokers were defined as those who had smoked within the past 6 months.

[0342] Pregnancy testing Urine pregnancy tests were administered to all women of childbearing potential and were handled and interpreted by study site personnel.

[0343] Relevant medical history Relevant medical history was recorded. Changes in medical history were recorded at subsequent visits during the study (worsening symptoms or disease were recorded as AEs). The following were collected: disease, and start and stop dates. Start dates were set as >12 months if they occurred >12 months before enrollment in the study, except for underlying diseases causing IDA.

[0344] Concomitant drug therapy If subjects were taking any concomitant medication, this was recorded at the baseline visit. Changes in concomitant medication were recorded at subsequent visits during the study. The following were collected: trade name, indication, route, dose, frequency, unit, and start and stop dates. Start dates occurring more than 12 months prior to enrollment in the study were defined as >12 months.

[0345] Physical Examination A physical examination was performed at the discretion of the 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 · Other, if necessary.

[0346] height Height was measured without shoes.

[0347] body weight Body weight was measured.

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

[0349] electro-cardiogram A standard 12-lead ECG was recorded (including date, time, and signature). At baseline and other treatment visits, two ECGs were recorded: one before administration of study medication and one approximately 30 minutes after starting the dose. Only one ECG was recorded at follow-up visits.

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

[0351] Laboratory Assessment Blood samples were required to be drawn prior to administration of study medication and, when possible, at the same time on all visits to reduce any day-to-day variability in parameters.

[0352] Laboratory assessments were performed in a central laboratory. A laboratory manual describing all experimental procedures was provided to each study site.

[0353] Qualification Laboratory Assessment The following laboratory assessments were performed for suitability: Complete hematology set: Hb, leucocytes / White Blood Cells (WBC), erythrocytes / Red Blood Cells (RBC), hematocrit, platelets, neutrophil granulocytes, 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 was measured at the baseline visit as part of the demographic data.

[0355] Safety Laboratory Assessment The following safety laboratory assessments were analyzed: Complete blood set: White blood cells / WBC, Red blood cells / RBC, Hematocrit, Platelets, Neutrophil granulocytes, Lymphocytes, Monocytes, Eosinophils, Basophils, MCH, MCV, MCHC and Reticulocyte counts · Biochemistry s-Sodium, s-Potassium, s-Calcium, s-Urea, s-Creatinine, s-Albumin s-Bilirubin, ASAT, ALAT CRP

[0356] Efficacy Laboratory Assessment The following efficacy laboratory parameters were analyzed: · Hb: Hemoglobin was analyzed by Coulter LH750 system. Blood was prepared using a lytic reagent for complete blood count parameters so that the system could measure the amount of hemoglobin. The lytic reagent rapidly and simultaneously destroyed red blood cells and converted a significant proportion of the hemoglobin into a stable dye. The absorbance of the dye was directly proportional to the hemoglobin concentration in the sample. The accuracy of this method was equal to that of the hemoglobin cyanide method. · The S-Ferritin:Access Ferritin assay was a two-sided immunoenzymatic ("sandwich") assay. Samples were added to a reaction vessel containing 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 binds to the immobilized monoclonal anti-ferritin on the solid phase, and the goat anti-ferritin enzyme conjugate reacts with a different antigenic site on the ferritin molecule. Separation in a magnetic field and washing away removed material that did not bind to the solid phase. A chemiluminescent substrate, Lumi-Phos*530, was added to the reaction vessel, and the light generated by the reaction was measured with a luminometer. TSAT (collect s-iron and transferrin to calculate TSAT; TSAT = (μg iron / dL / mg transferrin / dL) x 70.9). · S-iron: Serum iron (s-iron) was measured by a calorimetric assay using a Roche automated clinical chemistry analyzer based on an immunoturbidimetric assay.

[0357] Adverse Events (AEs) AE data were collected and assessed for relationship to study drug, severity, severity, and predictability.

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

[0359] A total of N=518 patients were diagnosed with CV risk according to their medical history (N=345 in IIM group; N=173 in IS group). Of these, a total of N=226 patients (N=144 in IIM group; N=82 in IS group) were diagnosed with CV risk and CHF according to their medical history. A total of N=292 patients were diagnosed with CV risk without CHF (N=144 in IIM group; N=82 in IS group). A total of N=2748 were patients without CHF (N=144 in IIM group; N=82 in IS group). TIFF2025041648000004.tif64170

[0360] result Key findings include a clear impact of iron isomaltoside 1000 on treatment-emergent congestive heart failure adverse events in patients at risk for cardiovascular adverse events.

[0361] A total of 1525 patients were enrolled in the CKD-04 trial and treated with either isomaltoside 1000 or iron sucrose. 4.1% of the 1019 patients treated with iron isomaltoside 1000 in the CKD-04 trial had a composite cardiovascular event, with an incidence of 6.9% (506 patients) in the iron sucrose treatment group.

[0362] A total of 1525 patients were enrolled in the IDA-03 trial and treated with either isomaltoside 1000 or iron sucrose. 0.8% of 989 patients treated with iron isomaltoside 1000 and 1.2% of 494 patients treated with iron experienced a composite cardiovascular event. In the combined CKD-04 / IDA-03 trial, composite cardiovascular events were observed in 2.5% of 2008 patients treated with iron isomaltoside 1000 versus 4.1% with iron sucrose (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-treated group compared to the iron sucrose-treated group. See Figure 1.

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

[0364] The odds ratios for treatment with iron isomaltoside 1000 versus iron sucrose are shown in Figure 3. An odds ratio <1 indicates the probability of treatment-emergent congestive heart failure adverse events, which is lower with iron isomaltoside 1000 treatment than with iron sucrose treatment. See Figure 4.

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

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

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

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

[0369] Equivalent form Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments disclosed herein which equivalents are intended to be encompassed by 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. TIFF2025041648000005.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. TIFF2025041648000006.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. 1. A method of treating iron deficiency in a subject, wherein treating the iron deficiency reduces the incidence or risk of an adverse cardiovascular event in the subject, the method comprising administering an effective amount of iron isomaltoside; The target is, (A) a subject at risk for an adverse cardiovascular event; (B) a subject with a history of congestive heart failure (CHF); or (C) Subjects with a history of congestive heart failure (CHF) and at risk for adverse cardiovascular events. and The incidence or risk of adverse cardiovascular events is reduced. (a) congestive heart failure, myocardial infarction, unstable angina, arrhythmias, hypertension, hypotension, stroke, and death; (b) congestive heart failure; (c) atrial fibrillation; (d) hypertension; or (e) Cardiac arrest The method of claim 1, wherein the

2. 2. The method of claim 1, wherein the subject is at risk for an adverse cardiovascular event, and the adverse cardiovascular event for which the incidence or risk is reduced is congestive heart failure.

3. 2. The method of claim 1, wherein the subject is at risk for an adverse cardiovascular event, and the adverse cardiovascular event whose incidence or risk is reduced is atrial fibrillation.

4. 2. The method of claim 1, wherein the subject is at risk for an adverse cardiovascular event and the adverse cardiovascular event whose incidence or risk is reduced is cardiac arrest.

5. 2. The method of claim 1, wherein the subject has a history of congestive heart failure and the adverse cardiovascular event for which the incidence or risk is reduced is cardiac arrest or congestive heart failure, or both.

6. 2. The method of claim 1, wherein the subject has a history of congestive heart failure (CHF) and the adverse cardiovascular event for which the incidence or risk is reduced is atrial fibrillation.

7. 2. The method of claim 1, wherein the subject has a history of congestive heart failure (CHF) and the adverse cardiovascular event for which the incidence or risk is reduced is cardiac arrest.

8. 8. The method of any one of claims 1 to 7, wherein the subject is at risk of an adverse cardiovascular event and / or has a history of congestive heart failure, and the subject has chronic kidney disease (CKD).

9. 8. The method of any one of claims 1 to 7, wherein the subject is at risk of an adverse cardiovascular event and / or has congestive heart failure, and the subject does not have chronic kidney disease (CKD).

10. The method according to claim 8 or 9, wherein the chronic kidney disease (CKD) is non-prediagnostic chronic kidney disease (NDD-CKD).

11. 11. The method of any one of claims 1, or 5-10, wherein the subject with a history of congestive heart failure has HFrEF.

12. 12. The method of any one of claims 1, or 5-11, wherein the subject with a history of congestive heart failure has congestive heart failure in NYHA class II-IV.

13. 13. The method of any one of claims 1 to 12, wherein the adverse cardiovascular event whose incidence or risk is reduced is cardiovascular death and / or hospitalization due to worsening congestive heart failure.

14. 14. The method of any one of claims 1 to 13, wherein iron deficiency is defined as TSAT<20% and / or ferritin<100 μg / L.

15. 15. The method of any one of claims 1 to 14, wherein the iron isomaltoside is ferric delisomaltose.

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