EA046425B1 - TREATMENT OF IRON DEFICIENCY IN SUBJECTS AT RISK OF CARDIOVASCULAR ADVERSE EVENTS AND IRON FOR THE TREATMENT OF ATRIAL FIBRILLATION - Google Patents

Description

Description of related application

This application claims the benefit of US Provisional Patent Application Serial No. 62/803,455, filed February 9, 2019, and Patent Application EP19179820.6, filed June 12, 2019, each of which is hereby incorporated by reference in its entirety.

Field of technology to which the invention relates

The present invention relates to the field of treatment of iron deficiency using intravenous iron carbohydrate complexes in subjects at risk for adverse cardiovascular events. In another aspect, the invention relates to a method for preventing and treating atrial fibrillation (AF).

State of the art

Iron deficiency (ID) impairs the body's ability to produce hemoglobin, an essential oxygen carrier, and impairs the function of key energy-producing enzymes (ATP). Symptoms as a result include fatigue and other signs of energy deprivation such as abnormal heart rate, shortness of breath and chest pain.

Iron deficiency anemia (IDA) develops as a result of depletion of iron stores. This is a widespread phenomenon. Approximately 1 billion people in the world suffer from IDA according to WHO. Daily oral iron supplementation is first-line therapy for most patients, but is often ineffective due to poor adherence, low efficacy, and side effects.

High-dose intravenous (IV) iron supplementation is an attractive treatment option. Patients typically require 1-3 grams of iron per year, and high doses of intravenous iron are effective and rapid in reducing symptoms and increasing hemoglobin levels. High-dose intravenous iron allows treatment to be administered in one or more visits, with intravenous iron being the only option for patients who have failed treatment with oral iron.

Iron isomaltoside 1000 (INN: iron derisomaltose) belongs to a new generation of high-dose iron preparations for intravenous administration. Whereas older low-dose products (ferrous gluconate and iron sucrose) required 5-20 visits, newer generation products allow iron levels to be corrected in one or two visits by rapidly infusing the product.

Ferrous isomaltoside is a commonly used carbohydrate iron complex for the treatment of patients who: (i) are intolerant of oral iron supplementation or demonstrate an unsatisfactory response to oral iron supplementation, or when there is a clinical need for rapid replenishment of iron stores; or (ii) who suffer from chronic kidney disease not requiring hemodialysis (CKD-NTD); or for the treatment of patients with chronic kidney disease on dialysis. It is commercially available in the European Union and many other countries under the trade names Monofer®, Monoferric® and Diafer®. A typical iron isomaltoside treatment regimen consists of either a single infusion of 1000 mg of iron, or a dose of elemental iron up to 20 mg/kg body weight administered as an intravenous infusion, or an intravenous bolus injection of up to 500 mg up to three times a week, with a total The need for iron is determined using the Ganzoni formula or using the following table:_________________________________________________________________________

Hb (g/dl) Patients weighing between 50 kg and <70 kg Patients weighing >70 kg >10 1000 mg 1500 mg <10 1500 mg 2000 mg

ID has serious consequences. Among patients with chronic heart failure (CHF), the risk of death or hospitalization has been reported to be increased in patients with ID compared with patients with normal iron levels. Quality of life (QoL) is greatly reduced and rapidly improves when iron stores are restored. For example, in an open-label, uncontrolled study with a fairly small sample of 20 frail elderly patients, a single rapid intravenous infusion of iron isomaltoside 1000 at relatively high doses without an initial test dose was well tolerated and improved QoL scores (Hildebrandt et al., 2010).

Accumulated experimental and clinical experience has provided the basis for the approval of ID as a potential therapeutic target in patients with chronic heart failure (CHF). Indeed, in recent years, several studies have examined the outcome of intravenous iron therapy in iron-deficient patients with chronic heart failure, including the FAIR-HF study (Assessment of Ferric Carboxymaltose in Patients with Iron Deficiency and Chronic Heart Failure; see also Anker et al., 2009). And

- 1 046425 CONFIRM-HF study (evaluating ferric carboxymaltose for efficacy in patients with iron deficiency in combination with chronic heart failure; see also Ponikowski et al., 2015), enrolling >450 and >300 patients, respectively. Based on a meta-analysis of pooled data from five randomized controlled trials that assessed the effects of intravenous iron therapy (using iron sucrose or ferric carboxymaltose) in iron-deficient patients with systolic HF (HFrEF), Jankowska et al., 2016 indicated that there is It is likely that intravenous iron therapy in iron-deficient patients with systolic HF may improve treatment outcomes, relieve HF symptoms, improve exercise capacity and quality of life, and reduce the risk of hospitalization for HF. However, the number of deaths and adverse event (AE) rates were similar among the five studies included in the meta-analysis.

Attempts have also been made to study how effective iron replenishment is in CHF from a mechanistic point of view, particularly when changes in hemoglobin are minimal. For example, in a randomized, double-blind, placebo-controlled trial, a single full-dose infusion of iron isomaltoside 1000 was shown to replenish iron stores and increase skeletal muscle energetics 2 weeks after infusion (Charles-Edwards et al., 2019). Based on data from the same randomized, double-blind trial, it was observed that iron repletion after a single infusion of full dose iron isomaltoside 1000 in iron-deficient CHF patients with left ventricular ejection fraction (LVEF) <45% attenuated P wave dispersion (Jaumdally et al., 2019 ).

However, none of the studies of intravenous iron supplementation tested their effect on key cardiovascular outcomes. In summary, the 2016 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure conclude that the effect of treatment for iron deficiency in HFpEF/HFmrEF is unknown. Based on the results of the FAIR-HF and CONFIRM-HF studies, the European Society of Cardiology (ESC) guidelines recommend that intravenous ferric carboxymaltoside be considered in patients with iron deficiency (serum ferritin <100 µg/L or ferritin in the range 100-299 µg/L , and transferrin saturation <20%) to relieve symptoms of heart failure, improve exercise capacity and quality of life (Ponikowski et al., 2016). Similarly, the American Heart Society (ACC), the American Heart Association (AHA) Clinical Practice Guidelines Task Force, and the Heart Failure Society of America (HSFA) recommend that patients with New York Heart Association (NYHA) class II and III HF ) and iron deficiency (ferritin <100 ng/mL or 100 to 300 ng/mL if transferrin saturation <20%) may benefit from intravenous iron replacement to improve functional status and quality of life (Yancy et al., 2017).

Based on this understanding, there is a clear need for treatments for iron deficiency that not only replenish iron stores but are also effective in treating chronic heart failure in patients.

An aspect of the invention relates to a method for preventing and treating atrial fibrillation (AF).

Atrial fibrillation (or atrial fibrillation) is associated with significant morbidity and mortality despite recent advances in the treatment of cardiovascular disease. It affects 33.5 million adults worldwide. At age 55 years, the lifetime risk of developing AF is approximately 1 in 5, with a higher incidence in older adults and patients with predisposing disease (valvular heart disease, hypertension, heart failure, coronary artery disease, obesity, and diabetes mellitus). Due to improved detection of occult asymptomatic AF, increasing average age of the population, and increasing prevalence of predisposing conditions, the global burden of AF is increasing. This has widespread health implications, as AF is a leading cause of stroke, heart failure, sudden death, hospitalization and poor quality of life. Although improved understanding of the mechanisms and subtypes of AF (paroxysmal [duration <7 days], persistent [duration 7 days to 1 year], long-term persistent [>1 year, for heart rate control], and chronic [>1 year, for heart rate control abbreviations]) has led to new treatments such as catheter ablation, many patients refuse this invasive procedure, and the outcome of those who consent is suboptimal. Thus, there is a need for new treatments that target the identified features that cause AF.

Increased P wave dispersion/duration on the surface electrocardiogram reflects an increase in the time required to conduct electrical impulses in the atrium, which is the hallmark of AF. Typically, electrical activity begins automatically in the upper right atrium (upper part of the heart) and travels through the left atrium to the atrioventricular node, where it is then transmitted to the ventricles (lower part of the heart). Enlarged

- 2 046425 P wave dispersion reflects atrial conduction delay and is a powerful prognostic factor in individuals who are likely to develop AF spontaneously or after electrocardioversion or cardiac surgery. This increase in atrial conduction block may arise from fibrosis of the atria as a result of the deposition of fibrous material by inflammatory cells, but may also arise from metabolic changes in the myocardium that affect the functioning of the ion channels that coordinate cardiac contractions. These metabolic changes can be caused by conditions that predispose to AF, as well as by AF itself, and lead to decreased cellular energy in the atria. It is now recognized that such atrial power failure is present in patients with AF and results in ion channel dysfunction that prolongs atrial conduction, predisposing to the onset and persistence of AF. Therapeutics that can improve atrial conduction, as evidenced by decreased P wave dispersion/duration, may prevent the onset of AF and/or cause conversion of AF to normal sinus rhythm.

Dietary iron supplements, also known as iron tablets, injections, or infusions, are used to treat and prevent iron deficiency. Because iron is found in many enzymes involved in cellular energy production, iron supplementation (regardless of whether an individual is iron deficient) may increase atrial energetics, reducing P wave duration/dispersion, and thus prevent or treat AF.

An aspect of the invention discloses the use of iron to reduce P wave dispersion/duration for the prevention and treatment of AF, where the AF is paroxysmal, persistent, long-term persistent or chronic.

The essence of the invention

In one aspect of the present invention, iron deficiency is treated in a subject at risk for an adverse cardiovascular event. Thus, subjects are selected for treatment with iron isomaltoside not only on the basis of the criteria typically used to determine the availability of parenteral iron supplementation, i.e., diagnosis of ID or IDA, and/or potential intolerance or inability to absorb oral iron, but also on the basis of the risk of developing them adverse events from the cardiovascular system.

In a second aspect of the present invention, treatment of iron deficiency reduces the incidence or risk of an adverse cardiovascular event in a subject. Thus, subjects who are selected for treatment with iron isomaltoside based on the criteria typically used to determine the availability of parenteral iron supplementation, i.e., diagnosis of ID or IDA, and/or potential intolerance or inability to absorb oral iron, and based on the risk of developing of adverse cardiovascular events demonstrate the beneficial effect of reducing the incidence or risk of an adverse cardiovascular event in a subject.

A third aspect of the invention relates to the treatment of specific groups of subjects, as defined herein, to reduce the incidence or risk of an adverse event from the cardiovascular system, as defined herein.

In accordance with these aspects, the present invention particularly relates to therapeutic methods for treating iron deficiency, which include administering iron isomaltoside to selected subgroups of subjects; and combinations of iron isomaltoside 1000 with other medicinal products that are used either to treat subjects at risk of cardiovascular adverse events or increase the risk of such cardiovascular adverse events.

In an embodiment of this first aspect, the present invention provides a method for treating iron deficiency in a subject at risk for cardiovascular adverse events, which comprises administering an effective amount of iron isomaltoside.

In some embodiments of this first aspect, subjects at risk for an adverse cardiovascular event are subjects having one or more of the following risk factors:

(i) subjects with a history of myocardial infarction (MI), particularly STEMI or ST NSTI;

(ii) subjects with a history of stroke;

(iii) subjects with a history of atrial fibrillation (AF), particularly new-onset AF, paroxysmal AF, or persistent AF;

(iv) subjects with a history of chronic heart failure, in particular heart failure with low ejection fraction (HFrEF);

(v) subjects with a history of valvular heart disease;

- 3 046425 (vi) subjects with a history of arterial hypertension;

(vii) subjects having diabetes;

(viii) subjects with a history of obesity;

(ix) elderly subjects, in particular subjects aged 60 years or older, 65 years or older, 70 years or older, 75 years or older, or 80 years or older;

(x) smokers;

(xi) drinkers;

(xii) subjects suffering from hyperthyroidism and/or associated thyrotoxicosis;

(xiii) subjects having chronic obstructive pulmonary disease (COPD);

(xiv) subjects having cardiomyopathy, in particular hereditary cardiomyopathy or acquired cardiomyopathy;

(xv) subjects having systemic inflammation in the absence of infection, where systemic inflammation is, in particular, that inflammation that is associated with elevated C-reactive protein (CRP) levels greater than about 2-3 mg/L;

(xvi) subjects on dialysis, where the dialysis is, in particular, hemodialysis or peritoneal dialysis;

(xvii) subjects who received one or more of the following:

a) modulators of hypoxia-inducible factor (HIF) signaling pathways, including prolyl hydroxylase inhibitors such as daprodustat, vadadustat, roxadustat, molidustat and desidustat;

b) erythropoiesis stimulants (ES), such as erythropoietin (Epo), epoetin alfa (Procrit/Epogen), epoetin beta (Neorecormon), darbepoetin alfa (Aranesp) and methoxypolyethylene glycol-epoetin beta (Mircera); And

c) hepcidin modulators, such as a hepcidin agonist or a hepcidin antagonist;

(xviii) subjects receiving an anticoagulant and/or NSAID;

(xix) subjects having hereditary hemorrhagic telangiectasia; or (xx) subjects who have hereditary iron-refractory iron deficiency anemia.

In a specific embodiment of this first aspect, the present invention relates to a method of treating iron deficiency in a subject with a history of chronic heart failure (CHF), which includes administering an effective amount of iron isomaltoside. In one embodiment, the subject also has a history of myocardial infarction (MI) and/or stroke. In a preferred embodiment, the CHF is low ejection fraction heart failure (HFrEF).

In another specific embodiment of this first aspect, the subject who is at risk for an adverse cardiovascular event or has a history of congestive heart failure has chronic kidney disease (CKD). In another specific embodiment of this first aspect, the subject at risk for an adverse cardiovascular event or having a history of congestive heart failure does not have chronic kidney disease (CKD). In another specific embodiment of this first aspect, the subject at risk of experiencing an adverse event from the cardiovascular system is a subject having chronic kidney disease (CKD) and a history of chronic heart failure (CHF).

In one embodiment, a subject with a history of congestive heart failure has HFrEF. In another embodiment, the subject with a history of congestive heart failure has New York Heart Association (NYHA) class IIIV heart failure, particularly HFrEF type and New York Heart Association (NYHA) class II-IV congestive heart failure ( NYHA). In another embodiment, the subject has NYHA class I congestive heart failure.

In an embodiment of said second aspect, the present invention provides a method of treating iron deficiency in a subject at risk for an adverse cardiovascular event, wherein treating the iron deficiency reduces the incidence or risk of an adverse cardiovascular event in the subject, wherein the method includes administering an effective amount of iron isomaltoside.

In one embodiment of said second aspect, the cardiovascular adverse event, the incidence or risk of which is reduced, is selected from the group consisting of events that affect the heart (cardiac adverse events); phenomena that affect the peripheral vasculature (adverse events from peripheral vessels); phenomena that affect the cerebral vasculature (adverse events from the cerebrovascular system); respiratory, thoracic and mediastinal adverse events; general adverse events; as well as infections and infestations. In one embodiment, the adverse cardiac events are selected from the group consisting of

- 4 046425 chronic heart failure, atrial fibrillation, cardiac arrest, atrioventricular block, heart failure, sinus node dysfunction, acute myocardial infarction, bradycardia, angina pectoris, myocardial ischemia and ventricular extrasystole; peripheral vascular adverse events selected from the group consisting of hypertension, increased systolic blood pressure, increased blood pressure, increased troponin and hypotension; adverse events from the cerebrovascular system were selected from the group consisting of cerebrovascular accident, cerebral infarction and transient ischemic attack; respiratory, thoracic and mediastinal adverse events selected from the group consisting of dyspnea and pulmonary edema; common adverse events selected from the group consisting of chest pain and death; and infections and infestations constitute septic shock.

In a preferred embodiment of this second aspect of the invention, the adverse cardiovascular event, the incidence or risk of which is reduced, is selected from the group consisting of events that affect the heart (adverse cardiac events); phenomena that affect the peripheral vasculature (adverse events from peripheral vessels); phenomena that affect the cerebral vasculature (adverse events from the cerebrovascular system); and death. In a preferred embodiment, events that affect the heart (adverse cardiac events) are congestive heart failure, myocardial infarction, unstable angina and arrhythmia; events that affect the peripheral vasculature (peripheral vascular adverse events) are hypertension; and events that affect the cerebral vasculature (cerebrovascular adverse events) constitute stroke.

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 selected from the group consisting of chronic heart failure, myocardial infarction, unstable angina, arrhythmia, hypertension, hypotension, stroke and of death.

In another particularly preferred embodiment of this second aspect of the invention, the adverse cardiovascular event, the incidence or risk of which is reduced, is chronic heart failure, atrial fibrillation, hypertension and/or cardiac arrest.

In one embodiment, the specific cardiovascular adverse events associated with chronic heart failure are hospitalization or death due to chronic heart failure. In one embodiment, the specific cardiovascular adverse event associated with chronic heart failure is hospitalization due to exacerbation of chronic heart failure. The present invention is particularly directed to such adverse cardiovascular events, wherein the adverse cardiovascular event is CHF.

In an embodiment of said third aspect, the present 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, comprising administering an effective amount of iron isomaltoside, wherein the subject is:

(A) a subject at risk for an adverse cardiovascular event;

(B) a subject with a history of chronic heart failure (CHF); or (C) a subject who has a history of chronic heart failure (CHF) and is at risk for a cardiovascular adverse event, and where the cardiovascular adverse event is decreasing in incidence or risk:

(a) selected from the group consisting of chronic heart failure, myocardial infarction, unstable angina, arrhythmia, hypertension, hypotension, stroke and death;

(b) is chronic heart failure;

(c) is atrial fibrillation;

(d) is arterial hypertension; or (e) is cardiac arrest.

In a preferred embodiment of this third aspect of the invention, the subject is a subject at risk of experiencing an adverse cardiac event.

- 5 046425 vascular system, and an adverse event from the cardiovascular system, the frequency or risk of which is reduced, is chronic heart failure.

In another preferred embodiment of this third aspect of the invention, the subject is a subject at risk of experiencing an adverse cardiovascular event, and the adverse cardiovascular event that is decreasing in incidence or risk of occurrence is atrial fibrillation.

In another preferred embodiment of this third aspect of the invention, the subject is a subject at risk of experiencing a cardiovascular adverse event, and the cardiovascular adverse event that is decreasing in incidence or risk of occurrence is cardiac arrest.

In another preferred embodiment of this third aspect of the invention, the subject is a subject with a history of congestive heart failure, and the cardiovascular adverse event of reduced incidence or risk is cardiac arrest and/or congestive heart failure.

In another preferred embodiment of this third aspect of the invention, the subject is a subject who has a history of congestive heart failure (CHF) and a cardiovascular adverse event that is decreasing in incidence or risk is atrial fibrillation.

In another preferred embodiment of this third aspect of the invention, the subject is a subject who has a history of congestive heart failure (CHF) and the cardiovascular adverse event of reduced incidence or risk is cardiac arrest.

In a specific embodiment of this third aspect of the invention, a subject as defined herein is a subject at risk for an adverse cardiovascular event and/or with a history of congestive heart failure, where the subject has chronic kidney disease (CKD).

In another specific embodiment of this third aspect of the invention, a subject as defined herein is a subject at risk for an adverse cardiovascular event and/or having chronic heart failure, where the subject does not have chronic kidney disease (CKD).

In these embodiments, the chronic kidney disease (CKD) is preferably chronic kidney disease not requiring dialysis (CKD-NTD).

In even more preferred embodiments of this third aspect of the invention, the subject with a history of congestive heart failure has HFrEF and/or NYHA class II-IV congestive heart failure.

In another embodiment, the subject has NYHA class I congestive heart failure.

In a particularly preferred embodiment of this third aspect of the invention, the adverse cardiovascular event, the incidence or risk of which is reduced, is death due to cardiovascular disease and/or hospitalization due to exacerbation of chronic heart failure.

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

In another embodiment of the invention, the subject to be treated has chronic iron loss or malabsorption. In another embodiment of this first aspect, the subject does not tolerate or is ineffective in responding to an oral iron supplement.

A preferred iron carbohydrate complex for use in the invention is iron isomaltoside, especially iron derisomaltose.

In another aspect, the invention provides a method for reducing P wave dispersion/duration to prevent or treat AF or disorders that predispose to AF (eg, valvular heart disease, hypertension, heart failure, coronary artery disease, obesity and diabetes mellitus) in an animal. suffering from such a condition, which involves administering to such animal a therapeutically effective amount of an iron preparation. The animal is preferably a mammal and most preferably a human.

Treatable AF can be paroxysmal, persistent, long-term persistent, or chronic.

In one embodiment, the iron preparation may be administered orally, intramuscularly, or intravenously.

In other embodiments, the animal, preferably a human, may or may not have iron deficiency.

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Brief description of drawings

Fig. 1 is a flow diagram of a randomized, double-blind, placebo-controlled study in which an analysis was performed to evaluate the effect of intravenous iron supplementation on P wave dispersion in patients with heart failure.

Fig. 2 is an example of an electrocardiogram from the body surface with measurement of the duration of the P wave in each lead. P wave dispersion is then calculated as the difference between the longest and shortest recorded P wave duration.

In fig. Figure 3 shows baseline patient data for intravenous iron compared with sodium chloride control.

In fig. Figure 4 presents the results for all endpoints, indicating that iron significantly reduces P wave dispersion.

In fig. Figure 5 shows the results for P wave dispersion with changes in each individual patient. P wave variance remained unchanged in the placebo (sodium chloride solution) group but was reduced in the iron group, with a P-value in the analysis of covariance of 0.007 being significant.

Fig. 6 is a table summarizing the analysis of the frequency of identified and confirmed combined treatment-emergent cardiovascular (CV) adverse events with an incidence of >0.25% at preferred time points for the CKD-04 study, the IDA study -03 and combined studies CKD-04/IDA-03.

Fig. 7 is a table summarizing the analysis of post-treatment adverse events of chronic heart failure for the CKD-04 study, the IDA-04 study, and the combined CKD-04/IDA-03 studies in all patients; patients with or without CHF; or patients at risk of cardiovascular disease.

Fig. 8 is a table summarizing the analysis of post-treatment adverse events of chronic heart failure (logistic regression) for the CKD-04 study and the combined CKD-04/IDA-03 studies in patients at risk of cardiovascular disease, with or without a history of CHF. , comparing treatment with iron isomaltoside to treatment with iron sucrose.

In fig. Figure 9 shows the percentage of patients who experienced specific combined cardiovascular adverse events after initiation of treatment (iron isomaltoside 1000: left bars, iron-sucrose: right bars).

In fig. Figure 10 shows the percentage of patients who experienced adverse events of CHF after initiation of treatment (CKD-04 and IDA-03 combined; iron isomaltoside 1000: left bars, iron sucrose: right bars).

In fig. Figure 11 shows a Kaplan-Meier plot of the probability of confirmed composite cardiovascular adverse events (CKD-04).

In fig. Figure 12 shows the change from baseline in hemoglobin (g/dL) in patients with a history of CHF in the combined CKD-04/IDA-03 studies (iron isomaltoside 1000: dotted line, iron-sucrose: solid line).

In fig. Figure 13 shows the change from baseline in ferritin (ng/ml) in patients with a history of CHF in the combined CKD-04/IDA-03 studies (iron isomaltoside 1000: dotted line, iron-sucrose: solid line).

In fig. Figure 14 shows the change from baseline in TSAT (%) in patients with a history of CHF in the combined CKD-04/IDA-03 studies (iron isomaltoside 1000: dotted line, iron-sucrose: solid line).

In fig. Figure 15 shows the percentage of patients who experienced combined cardiovascular adverse events after initiation of treatment with IIM 1000, Venofer, and FCM (combined CKD-04/IDA-03 studies for IIM 1000 (Ferwon studies); studies using Venofer and FCM, based on CDER FDA report on Injectafer).

Fig. 16 is a table summarizing the adverse event analysis results for the CKD-04 study, the IDA-03 study, and the combined CKD-04/IDA-03 studies using IIM 1000 (Ferwon studies) compared to the Venofer and FCM studies ( CDER FDA report on Injectafer).

Detailed description

To facilitate understanding of the present specification, definitions of certain terms are first provided. Additional definitions are provided in the detailed description.

Treatment or therapy of a subject refers to any type of intervention or process performed on a subject or administration of an active substance to a subject with the purpose of causing regression, relief, improvement, inhibition, retardation or prevention of the onset, progression, development, severity or recurrence of a symptom, complication, condition or biochemical parameters associated with the disease.

- 7 046425

Subject includes any human or non-human animal. The term non-human animal includes, without limitation, vertebrates such as non-human primates, sheep, dogs and rodents such as mice, rats and guinea pigs. In preferred embodiments, the subject is a human. The terms subject and patient are used interchangeably herein.

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 from the onset of a disease or promotes regression of a disease, as evidenced by a decrease in the severity of symptoms of the disease, an increase in the frequency and duration of asymptomatic periods of the disease or prevention of deterioration or disability due to disease damage. The ability of a therapeutic agent to cause disease regression can be assessed using various methods known to the practitioner, for example, in humans in clinical trials, in animal model systems predictive of efficacy in humans, or by testing the activity of the agent in in vitro assays.

For the purposes of this text, when a dose is given in mg or g of carbohydrate iron complex in accordance with the practice described in the literature, the value stated refers to the amount of elemental iron presented in mg or g.

A. Carbohydrate iron complex.

Disclosed herein are therapeutic methods for the treatment of iron deficiency that include administration of an iron carbohydrate complex and combinations of an iron carbohydrate complex with additional drugs, wherein the iron carbohydrate complex has certain properties and thus produces certain effects in subjects undergoing treatment. Thus, the methods according to the invention are applicable to complexes that have the same mechanism of action. For example, a carbohydrate iron complex should not cause a significant increase in iFGF23 (intact FGF23). While ferrous carboxymaltose (FCM) in particular significantly increases iFGF23 (see e.g. WO 2013/134273 A1), clinical trial results suggest that there is a risk of increasing iFGF23 and thus inducing iFGF23-mediated effects when using isomaltoside iron 1000 (Monofera®) is low. See, for example, Wolf et al, 2019.

Thus, the preferred iron carbohydrate complex of the present invention is iron isomaltoside (IIM). The term iron isomaltoside as used herein refers to colloidal complexes comprising iron, for example in the form of iron hydroxide, and isomaltoside in a matrix structure. The term isomaltoside as used herein refers to hydrogenated oligoisomaltose (oligoisomaltoside).

In specific embodiments, an isomaltoside is a mixture of hydrogenated poly/oligosaccharides having a weight average molecular weight _MW of 500 to 7000 Da, such as 500 to 3000 Da, 700 to 1400 Da, and especially about 1000 Da. The number average molecular weight (Mn) of such hydrogenated poly/oligosaccharide is preferably in the range from 400 to 1400 Da, with 90 wt.% of these molecules having a molecular weight less than 3500 Da, in particular less than 2700 Da, and the remaining 10% of the molecules having a molecular weight lower 4500 Yes, in particular below 3200 Yes. For example, said hydrogenated poly/oligosaccharide is hydrogenated polyglucose, oligoglucose or a mixture thereof, such as hydrogenated dextran, hydrogenated dextrin or hydrogenated oligoisomaltose (oligoisomaltoside) or a mixture thereof, wherein hydrogenated oligoisomaltose, in particular hydrogenated oligoisomaltose, in which the majority (for example, at least 60%, eg 70 to 80%) of the molecules contain 3-6 monosaccharide units is preferred. Thus, in preferred embodiments of the invention, the carbohydrate iron complex is a hydrogenated iron oligoisomaltose, in particular a hydrogenated iron(III) oligoisomaltose, wherein the majority (e.g., at least 60%, e.g., 70 to 80%) of the oligoisomaltoside molecules contain 3-6 monosaccharide units such as iron (III) isomaltoside 1000 (INN: iron derisomaltose). Iron isomaltosides are typically characterized by a strong colloidal iron oxide-hydroxide complex and hydrogenated isomaltose (isomaltoside) chains, which provide a gradual release of iron.

In the specific embodiments described above, the dimeric saccharide content of the hydrogenated poly/oligosaccharide is preferably 2.9% by weight or less, 2.5% by weight or less, or 2.3% by weight or less, especially 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 poly/oligosaccharide. Preferably, the hydrogenated poly/oligosaccharide preparations used to prepare the carbohydrate iron complexes according to the invention have a monomeric saccharide content of 0.5% by weight or less. Hydrogenated iron-containing dextran complexes prepared from such hydrogenated poly/oligosaccharide preparations typically have an apparent molecular weight ( _Mp ) ranging from 120,000 to 180,000 Da, especially from 130,000 to

- 8 046425

160000 Yes. Before contacting the hydrogenated poly/oligosaccharide preparation with the iron preparation, the preparation may be purified using membrane processes to remove high molecular weight hydrogenated polysaccharides and/or low molecular weight hydrogenated oligosaccharides. In specific embodiments, the hydrogenated poly/oligosaccharide preparation has been purified using one or more membrane processes with a cutoff value of 340 to 800 Da. In even more specific embodiments, a hydrogenated poly/oligosaccharide preparation has been purified by one or more membrane processes using a membrane with a cutoff value that allows polysaccharides having a molecular weight greater than 2700 Da to be retained, optionally followed by additional hydrolysis and one or more membrane processes using a membrane with a cutoff value of 340 to 800 Da. Alternatively, purification by these membrane processes occurs prior to hydrogenation.

In a particularly preferred embodiment, the iron isomaltoside according to the invention is a compound having the following formula:

{FeO 3X (O11) _; X (C^l 1Ό 3 )х}.(CH O)..)JC..l 1· O),-)Z(C..l 1· _; O),b. (MeCl)Y, which contains H2O, where:

X is 0.0311±0.0062, in particular 0.0311±0.0031;

R is 0.1400±0.0420, in particular 0.1400±0.0210;

Z is 0.4900±0.1470, in particular O.49OO±O.O735;

Y is 0.1400±0.0130, in particular 0.1400±0.0065; And

Me is a monovalent metal ion such as a sodium ion or a potassium ion, and preferably a sodium ion.

In another particularly preferred embodiment, the iron complex compound according to the invention is a compound having the formula {FeO( ₁ -3χ)(OH)(1 ₊ 3x)(C ₆ H5O7 ^3- )x},(H2O)τ,(C6H ₁ oO6 )R(-C ₆ H ₁ oO5-)z(C ₆ H13O5)R, (MeCl)Y, where:

X represents 0.0311±0.0062, in particular O,O311±O,OO31;

T represents O.25OO±O.125O, in particular O.25OO±O.2475O;

R is 0.1400±0.0420, in particular 0.1400±0.0210;

Z is 0.4900±0.1470, in particular O.49OO±O.O735;

Y is 0.1400±0.0130, in particular 0.1400±0.0065; And

Me is a monovalent metal ion such as a sodium ion or a potassium ion, and preferably a sodium ion.

In specific embodiments, the iron complex has an iron content (determined on a dry matter basis) of 23 to 39% by weight and is optionally present in the form of an injection solution containing approximately 100 mg/ml.

Iron isomaltosides can be prepared as described, for example, in WO 2010/108493 A1 and WO 2019/048674 A1. A preferred example of iron isomaltoside is commercially available in many countries under the trade name Monofer®, Monoferric® or Diafer®.

Another specific iron carbohydrate complex for use in the present invention is ferrous bepectate (FBP). The term ferric bepectate as used herein refers to colloidal complexes comprising an iron-containing core, for example in the form of ferric hydroxide oxide, coated with a hydroxyethyl derivative of amylopectin. Iron bepectate is also called polyglucoferron. Iron bepectate and its preparation are disclosed, for example, in WO 2012175608 A1. Briefly, hydroxyethyl starch is dissolved in water. The pH value is then adjusted to 8.010.0. The cyanide compound is then added to the hydroxyethyl starch solution. The solution is then heated to a temperature of 80-99°C and maintained at this temperature for the first period of time. Finally, the pH value is adjusted to 2.0-4.0 and the solution is heated to a temperature of 50-90°C and maintained at this temperature for a second period of time. The starch obtained in this way is characterized in that it carries a heptonic acid residue at at least one of its ends. Thus, this starch may carry a number of heptonic acid residues per molecule, depending on the number of terminal glycosyl residues present in the starch molecule. This heptonic acid residue increases the hydrophilicity of the hydroxyethyl starch and increases the stability of the complexes that such hydroxyethyl starch forms with ligands such as, for example, metal ions such as iron ions. In a broader sense, hydroxyethyl starch (HES) is a starch in which some of the hydroxyl groups of single glycosyl residues have been replaced by a hydroxyethyl residue. Modification with a heptonic acid residue occurs by converting the terminal glycosyl residue of hydroxyethyl starch into a heptonic acid residue. Preferably, the hydroxyethyl starch used in the 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 80,000 g/mol, and specifically less than 75,000 g/mol. The most suitable molecular weight is in the range from 55,000 g/mol to 85,000 g/mol. This hydroxyethyl starch has

- 9 046425 comparatively lower molecular weight than the (unmodified) hydroxyethyl starches currently used in the medical field. A suitable method for determining the molecular weight of hydroxyethyl starch is size exclusion chromatography (SEC). In a preferred embodiment, the hydroxyethyl starch has an average degree of molar substitution of 0.4-0.6, in particular 0.45-0.55. A particularly preferred average degree of molar substitution is approximately 0.50. The average degree of molar substitution is a measure that indicates the number of hydroxyl groups substituted by a hydroxyethyl residue per glycosyl residue. Since each glucose unit (or glycosyl residue) has three hydroxyl groups, the average degree of molar substitution can be a maximum of three. An average degree of molar substitution of 0.5 indicates that (on average or on a statistical basis) on every second glycosyl residue, one hydroxyl group is replaced by a hydroxyethyl residue. In a preferred embodiment, the hydroxyethyl starch has a weight average molecular weight of 55,000-85,000 g/mol, preferably about 70,000 g/mol, and an average degree of molar substitution of 0.45-0.55, in particular about 0.50. Such hydroxyethyl starch with a molecular weight of 70,000 g/mol ± 15,000 g/mol and an average degree of molar substitution of 0.5 ± 0.05 can also be specified as HES 70/0.5. The method for preparing such heptonic acid modified hydroxyethyl starch, HES 70/0.5, is described in Example 1, and the formation of the iron complex in Example 2 in WO 2019/048674 A1, which are incorporated by reference.

Iron isomaltosides are the preferred iron carbohydrate complex for use according to the invention.

B. Therapeutic methods.

Disclosed herein are therapeutic methods for the treatment of iron deficiency that involve administering iron isomaltoside to selected subgroups of subjects and/or according to specified dosage regimens. Thus, the present invention also relates to iron isomaltoside for use in these methods, to the use of iron isomaltoside for the treatment of iron deficiency and/or to the use of iron isomaltoside in the manufacture of a medicament for the treatment of iron deficiency.

I. Subjects to be treated.

The methods of the invention are typically performed on the subject in need thereof. A subject in need of the methods of the present invention is a subject who has, is diagnosed with, is suspected of having, or is at risk of developing iron deficiency. Iron deficiency anemia (IDA) develops when iron stores are depleted. Subjects suffering from ID may have IDA; subjects with IDA necessarily suffer from ID. Methods for diagnosing ID and IDA are well known in the field and are widely used in clinical practice.

Subjects diagnosed with, suspected of, or at risk of developing iron deficiency will be administered parenteral, particularly intravenous, iron in the form of an iron carbohydrate complex, i.e. The iron isomaltoside of the invention if oral iron is poorly tolerated or ineffective in the subject, i.e. subjects with oral iron intolerance or unsatisfactory response to oral iron. Another situation where intravenous iron is indicated is the need for rapid delivery of iron, i.e. when there is a clinical need for rapid replenishment of iron stores.

Iron deficiency and anemia.

Parameters of iron accumulation.

Subjects with iron deficiency may demonstrate low or inadequate markers of systemic iron status. This means that such subjects do not have a sufficient supply of iron in the body to maintain normal iron levels. Most well-nourished and healthy people living in industrialized countries have between 4 and 5 grams of iron in their bodies. About 2.5 g of this iron is found in hemoglobin, which carries oxygen in the blood. Most of the remaining approximately 1.5 to 2.5 grams of iron is found in iron-binding complexes, which are present in all cells but are more concentrated in the bone marrow and organs such as the liver and spleen. Iron reserves in the liver represent the main physiological reserve of iron in a healthy body. Of the body's total iron content, about 400 mg is used in proteins, which use iron for cellular processes such as storing oxygen (myoglobin) or carrying out redox reactions that produce energy (cytochrome proteins). In addition to stored iron, small amounts of iron, usually 3 to 4 mg, circulate in the blood plasma bound to a protein called transferrin.

Free soluble iron compounds (iron (II) or Fe ²⁺ ) are toxic and are usually present in the body only in very low concentrations.

- 10 046425

In individuals with iron deficiency, the body's iron stores are first depleted. Because most of the iron used by the body is required for hemoglobin, the main clinical manifestation of iron deficiency is iron deficiency anemia. Transporting oxygen to tissues, including organs, is vital, and severe anemia is dangerous and potentially fatal due to systemic oxygen deprivation. Subjects with iron deficiency will suffer, and in some cases may die, from organ damage caused by lack of oxygen, long before the cells run out of iron needed for intracellular processes.

There are several markers of systemic iron status that can be measured to determine whether a subject has sufficient iron stores to maintain normal health. These markers may be circulating iron stores and/or iron stored in iron-binding complexes, and are also commonly referred to as iron storage parameters. Parameters of iron accumulation may include, for example, hematocrit, hemoglobin (Hb) concentration, total iron binding capacity (TIB), transferrin saturation (TSAT), serum iron levels, liver iron levels, spleen iron levels, and serum ferritin levels. Of these, hematocrit, hemoglobin (Hb) concentration, total iron binding capacity (TIBC), transferrin saturation (TSAT) and serum iron levels are generally known as circulating iron stores. Liver iron levels, splenic iron levels, and serum ferritin levels are commonly referred to as stored iron or iron stored in iron-binding complexes.

It should be noted that although the above blood parameters are determined in serum, they can also be determined in plasma. Serum and plasma levels are correlated and can be converted to each other.

The present invention provides methods for improving one or more parameters of iron accumulation in a subject in need thereof. The at least one iron accumulation parameter may be selected from serum ferritin levels, transferrin saturation (TSAT), hemoglobin concentration, hematocrit, total iron binding capacity, iron absorption levels, serum iron levels, liver iron levels, spleen iron levels, and their combinations.

In one embodiment, at least one parameter of iron storage is a hemoglobin concentration, and the improvement includes increasing the hemoglobin concentration in the subject. In other embodiments, at least one parameter of iron storage is transferrin saturation, and the improvement includes increasing transferrin saturation in the subject. In other embodiments, at least one parameter of iron storage is serum ferritin levels, and the improvement includes increasing serum ferritin levels of the subject.

Serum ferritin.

Ferritin reserves in the liver are the main source of iron in the body. Ferritin is an intracellular protein that stores iron and regulates its release. In medical terms, the amount of ferritin present in a blood sample and/or liver tissue sample reflects the amount of iron that has accumulated in the liver (although ferritin is ubiquitous and can be found in many other tissues of the body besides the liver). Ferritin serves to store iron in the liver in a non-toxic form and transport it to areas where it is needed. In a healthy subject, normal serum ferritin levels, sometimes called the reference interval, are typically 30 to 300 ng/mL in men and 15 to 200 ng/mL in women. In patients at risk for cardiovascular adverse events, normal serum ferritin levels typically exceed 100 ng/mL. However, in subjects with iron deficiency, serum ferritin levels are usually markedly reduced because the amount of iron available for ferritin binding and stored in the liver is reduced, which occurs when the body loses the ability to absorb and store iron.

The term serum ferritin (s-ferritin) as used herein refers to the level of ferritin in blood serum measured using a two-step enzyme-linked immunosorbent assay (sandwich). Ferritin is the main protein for storing iron in the body. Ferritin concentrations are directly proportional to total body iron stores, making serum ferritin levels a standard diagnostic tool in assessing iron status. Subjects with iron deficiency anemia have serum ferritin levels that are approximately one-tenth the normal level, whereas 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 a disproportionate increase in ferritin levels relative to iron reserves. Elevated ferritin levels are also observed in acute and chronic liver disease, chronic renal failure, and some types of neoplastic diseases.

- 11 046425

In some embodiments, subjects treated in accordance with the methods disclosed herein experience an increase in serum ferritin levels. In some embodiments, the present invention provides methods for increasing serum ferritin levels in a subject in need thereof, comprising administering to the subject iron isomaltoside, wherein the iron isomaltoside provides an increase in serum ferritin.

In some embodiments, ferrous isomaltoside provides a mean increase in serum ferritin that is greater than 100 ng/mL, greater than 110 ng/mL, greater than 120 ng/mL, greater than 130 ng/mL, greater than 140 ng/mL, greater than 150 ng/mL , greater than 160 ng/ml, greater than 170 ng/ml, greater than 180 ng/ml, greater than 190 ng/ml, or greater than 200 ng/ml 4 or 8 weeks after treatment.

In some embodiments, iron isomaltoside provides a mean increase in serum ferritin that is selected from 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 4 or 8 weeks after treatment.

In some embodiments, ferrous 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, 100-375 ng/mL ml or 150-300 ng/ml 4 or 8 weeks after treatment.

In some embodiments, ferrous isomaltoside provides a mean increase in serum ferritin that is 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 1 week after treatment.

In some embodiments, ferrous 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 less than 480 ng/ml, less than 470 ng/ml, less than 460 ng/ml or less than 450 ng/ml 1 week after treatment.

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 1 week after treatment.

Transferrin saturation (TSAT).

In addition to iron storage, a small amount of iron, usually approximately 3-4 mg, circulates in the blood plasma bound to a protein called transferrin. Therefore, 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 iron ions (iron(III) or Fe3 ⁺ ). It is the most abundant and dynamic transporter of iron in the blood, and is therefore an important component of the body's ability to transport stored iron for use throughout the body. Transferrin saturation (or TSAT) is measured as a percentage and is calculated as the ratio of serum iron to total iron binding capacity multiplied by 100. This value tells the clinician how much serum iron is actually bound to the total amount of transferrin that is available to bind iron. For example, a TSAT value of 35% means that 35% of the available transferrin iron-binding sites in the blood sample are occupied by iron. In healthy subjects, typical TSAT values are approximately 15-50% in men and 12-45% in women. In patients at risk for cardiovascular adverse events, normal values are typically above 20%. In an iron-deficient subject, however, TSAT values tend to be markedly decreased because the amount of iron available for transferrin binding is reduced, which occurs as the body loses its ability to absorb and store iron. In some embodiments, the TSAT value is below 20% and/or the ferritin concentration is <100 μg/L.

In some embodiments, subjects treated in accordance with the methods disclosed herein experience increased TSAT values. In some embodiments, the present invention provides methods for increasing TSAT in a subject in need thereof comprising administering to the subject iron isomaltoside, wherein the iron isomaltoside provides an increase in TSAT in the subject.

In some embodiments, ferrous isomaltoside provides an average increase in TSAT that is greater than 1%, greater than 1.5%, greater than 2%, or greater than 2.5% 4 or 8 weeks after treatment.

In some embodiments, ferrous isomaltoside provides an average increase in TSAT that is less than 5%, less than 4%, or less than 3% at 4 or 8 weeks after treatment.

In some embodiments, ferrous isomaltoside provides an average increase in TSAT of 1-5%, 1.5-4%, or 2-3% 4 or 8 weeks after treatment.

- 12 046425

In some embodiments, ferrous isomaltoside provides an average increase in TSAT that is greater than 5%, greater than 6%, or greater than 7% 1 week after treatment.

In some embodiments, ferrous isomaltoside provides an average increase in TSAT that is less than 20%, less than 19%, less than 18%, less than 17%, less than 16%, or less than 15% 1 week after treatment.

In some embodiments, ferrous isomaltoside provides an average increase in TSAT of 5-20% or 5-15% 1 week after treatment.

Hematocrit.

Hematocrit, also called sediment cell volume or red blood cell volume fraction, is the volume percentage of red blood cells in the blood. In healthy subjects, the hematocrit is usually about 45% of the blood volume in men and about 40% of the blood volume in women. However, in subjects with iron deficiency, the hematocrit is often significantly reduced due to low iron absorption and/or poor ability to store iron.

The iron isomaltoside disclosed herein can be administered to subjects to increase hematocrit. The exact timing of administration will generally vary in a particular subject depending, for example, on the severity of iron deficiency experienced by the subject, the level of iron absorption that the subject does or does not experience, and the health care provider's assessment of the condition. In some embodiments, the present invention provides methods for increasing the hematocrit of a subject in need thereof, comprising administering to the subject an iron isomaltoside, wherein the iron isomaltoside provides an increase in the hematocrit of the subject. In some embodiments, the increase is from 1% to 30%, from 1% to 15%, from 1% to 12%, from 1% to 10%, from 1% to 9%, from 1% to 8%, from 1 % to 7%, 1% to 6%, 1% to 5%, 1% to 4%, 1% to 3%, or 1% to 2%.

Hemoglobin concentration.

Hemoglobin concentration, also called mean erythrocyte hemoglobin concentration or MCHC, is the value of the hemoglobin protein concentration in a given volume of sedimented red blood cells. It is usually calculated by dividing the total hemoglobin protein by the hematocrit. Hemoglobin concentration can also be measured as a mass or weight fraction and is presented as a percentage (%). In numerical terms, however, the mass or molar value of hemoglobin concentration and the mass or weight fraction (%) are identical if the erythrocyte density is 1 g/ml and the loss of hemoglobin in the blood plasma is negligible. In healthy subjects, the typical mass or molar hemoglobin concentration ranges from 32 g/dL to 36 g/dL or from 4.9 mmol/L to 5.5 mmol/L, respectively. However, in subjects with iron deficiency, hemoglobin concentrations may be significantly reduced as the body loses its ability to absorb and store iron.

In some embodiments, subjects treated in accordance with the methods disclosed herein experience an increase in hemoglobin concentration. In some embodiments, the present invention provides methods for increasing hemoglobin concentration in a subject in need thereof, comprising administering iron isomaltoside to the subjects, wherein the iron isomaltoside provides an increase in hemoglobin concentration in the subjects.

In some embodiments, ferrous isomaltoside provides an average increase in hemoglobin concentration of 0.1-5.0 g/dL, 0.1-4.0 g/dL, 0.1-3.0 g/dL, or 0.1-2 .0 g/dL 1 week after treatment.

In some embodiments, ferrous isomaltoside provides a mean increase in hemoglobin concentration 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 1 week after treatment.

In some embodiments, ferrous 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. In some embodiments, 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 1 week after treatment.

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 4 or 8 weeks after treatment.

In some embodiments, ferrous isomaltoside provides a mean increase in hemoglobin concentration greater than 0.5 g/dL, greater than 0.7 g/dL, greater than 0.9 g/dL, greater than 1.1 g/dL, greater than 1.3 g/dL or more than 1.5 g/dL 4 or 8 weeks after treatment.

In some embodiments, ferrous 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. In some embodiments, 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 at 4 or 8 weeks after treatment.

- 13 046425

Total iron binding capacity (TIBC).

Total iron-binding capacity (TIBC) is an indicator of the blood's ability to bind iron with the protein transferrin. Typically, TBI is measured by drawing blood and measuring the maximum amount of iron the sample can carry. Thus, the TBI indirectly measures transferrin, which is a protein that transports iron in the blood. In healthy subjects, the typical mass or molar indicator of TLC is in the range of 250-370 μg/dL or 45-66 μmol/L, respectively. In iron-deficient subjects, however, TIR usually exceeds these levels because the body must produce more transferrin in an attempt to deliver iron to red blood cell progenitor cells to produce hemoglobin.

In some embodiments, subjects treated according to the methods disclosed herein experience a decrease in PVSS. In some embodiments, the present invention provides methods for reducing VTOL in subjects in need thereof, comprising administering iron isomaltoside to the subject, wherein the iron isomaltoside reduces VTOL in the subject.

In some embodiments, the reduction is 0.1% to 30%, 0.1% to 28%, 0.1% to 26%, 0.1% to 25%, 0.1% to 24% , from 0.1% to 23%, from 0.1% to 22%, from 0.1% to 21%, from 0.1% to 20%, from 0.1% to 15%, from 0.1 % to 10% or from 0.1% to 5%.

Subjects at risk for cardiovascular adverse events typically have or are at risk for systemic inflammation, which may make iron assessment difficult. As disclosed herein, in subjects at risk for cardiovascular adverse events, normal iron levels are generally considered to be TSAT >20% and/or serum ferritin >100 mcg/L. In one embodiment of the present invention, treatment is appropriate if TSAT is less than 20% and/or serum ferritin is less than 100 μg/L, or in a corresponding embodiment, if TSAT is less than 20% and serum ferritin is less than 300 μg/L. l. In a preferred embodiment, TSAT is less than 20% and/or serum ferritin is less than 100 μg/L. Treatment criteria may also include an upper limit for serum ferritin beyond which repeat dosing is not recommended, e.g., serum ferritin less than 300 mcg/L, less than 400 mcg/L, less than 500 mcg/L, or less than 600 mcg/L . Retreatment criteria may also include higher ferritin and TSAT cutoffs than treatment criteria. For example, in one preferred embodiment, after administration of the initial effective dose, subjects will receive an additional dose if TSAT is less than 25% and/or serum ferritin is less than 100 μg/L, and provided that serum ferritin does not exceed 400 μg/L .

Symptoms.

Symptoms of iron deficiency may occur before the disease progresses to iron deficiency anemia. Symptoms of iron deficiency may include, for example, fatigue, dizziness, pallor, hair loss, irritability, weakness, pica, brittle or grooved nails, Plummer-Vinson syndrome (painful atrophy of the lining of the tongue, pharynx and esophagus), impaired immune function, pagophagia and restless legs syndrome, among other things.

Subjects treated in accordance with the methods disclosed herein experience improvement in iron deficiency. In some embodiments, subjects treated in accordance with the methods disclosed herein experience a reduction in iron deficiency. Such a decrease may occur when the total amount of iron in a subject's body is increased as a result of administration of the iron isomaltoside disclosed herein. In some embodiments, subjects treated in accordance with the methods disclosed herein experience a reduction or elimination of one or more symptoms of iron deficiency, where the symptoms are selected from fatigue, dizziness, pallor, hair loss, irritability, weakness, pica, brittleness or grooved nails, Plummer-Vinson syndrome (painful atrophy of the mucous membrane of the tongue, pharynx and esophagus), impaired immune function, pagophagia, restless legs syndrome and a combination of these.

In some embodiments, the iron deficiency is iron deficiency anemia. Iron deficiency anemia is characterized by low levels of circulating red blood cells and may be caused by inadequate dietary intake, absorption and/or storage of iron. Red blood cells, which contain iron bound to hemoglobin proteins, are usually not produced when there is insufficient iron in the body.

Iron deficiency anemia is usually characterized by pallor (pale color resulting from decreased oxyhemoglobin in the skin and mucous membranes), fatigue, dizziness and weakness. However, the signs of iron deficiency anemia may vary from person to person. Since iron deficiency tends to develop slowly, adaptation to the disease may develop and it may remain for some time

- 14 046425 unrecognized. In some cases, subjects may develop shortness of breath (difficulty breathing), pica (an irresistible urge to eat something unusual), anxiety, often leading to obsessions and OCD-type obsessions, irritability or sadness, angina, constipation, drowsiness, tinnitus, mouth ulcers, palpitations, hair loss, fainting or lightheadedness, depression, shortness of breath on exertion, muscle twitching, pale yellow skin, tingling (numbness) or burning sensation, menstrual irregularities, heavy menstrual period(s) , slow social development, glossitis (inflammation or infection of the tongue), ulcers (inflammatory lesions at the corners of the mouth), koilonychia (spoon-shaped nails) or brittle or brittle nails, poor appetite, pruritis (generalized itching), Plummer-Vinson syndrome (painful mucosal atrophy membrane that covers the tongue, pharynx and esophagus) and restless legs syndrome, among others.

Anemia is usually diagnosed based on a complete blood count measured in a sample of the subject's blood. Typically, automated counters are used that record the total number of red blood cells in the sample, the hemoglobin level, and the size of the red blood cells using flow cytometry. However, a stained blood smear on a microscope slide can be examined with a microscope to count the total number of red blood cells in the sample and diagnose anemia. In many countries, four parameters are measured to determine the presence of anemia (red blood cell count, hemoglobin concentration, mean red blood cell volume, and red blood cell volume distribution). The World Health Organization has established certain threshold values for hemoglobin (Hb) levels, and a diagnosis of anemia can be made when a subject's hemoglobin level falls below these values. These values are as follows: for children aged 0.5-5.0 years, Hb=11.0 g/dl or 6.8 mmol/l; for children 5-12 years old - Hb=11.5 g/dl or 7.1 mmol/l; for adolescents 1215 years old 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 over 15 years old - Hb=13.0 g/dl or 8.1 mmol/l.

Subjects treated in accordance with the methods disclosed herein may experience improvement in anemia. Subjects treated with the methods disclosed herein may experience improvement in iron deficiency anemia. In some embodiments, subjects treated in accordance with the methods disclosed herein experience a reduction in one or more symptoms of anemia or iron deficiency anemia. In some embodiments, subjects treated in accordance with the methods disclosed herein experience resolution of one or more symptoms of anemia or iron deficiency anemia. In some embodiments, one or more symptoms of anemia or iron deficiency anemia are selected from pallor, fatigue, dizziness, weakness, shortness of breath, pica, anxiety, irritability or sadness, angina, constipation, drowsiness, tinnitus, mouth ulcers, palpitations, hair loss , fainting or near-syncope, depression, shortness of breath on exertion, muscle twitching, pale yellow skin, tingling (numbness) or burning sensation, irregular menstrual cycle(s), heavy menstrual period(s), slow social development, glossitis, seizures, koilonychia, poor appetite, pruritis, Plummer-Vinson syndrome, restless legs syndrome and combinations of the above.

In some embodiments, subjects treated in accordance with the methods disclosed herein may experience improvement in anemia and/or iron deficiency anemia as hemoglobin levels are increased and/or maintained above threshold. In some embodiments, a method of treating anemia is disclosed, comprising administering iron isomaltoside to a subject, wherein the iron isomaltoside provides a hemoglobin level in the subject that is at or above a level of 11.0 g/dL to 13.0 g/dL, including a level selected of 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, comprising administering iron isomaltoside to a subject, wherein the iron isomaltoside provides a hemoglobin level in the subject that is 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, comprising administering iron isomaltoside to the male subject, wherein the iron isomaltoside provides a hemoglobin level in the male subject that is at or above 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, comprising administering iron isomaltoside to the female subject, wherein the iron isomaltoside provides a hemoglobin level in the female subject that is at or above a level selected from 12.0 g/dL and 7 .4 mmol/l.

Risk factors influencing the occurrence of adverse events from the cardiovascular system.

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A particular group of subjects having iron deficiency, as disclosed herein, who are treated according to the present invention, are characterized as being at risk for an adverse event from the cardiovascular system.

According to the invention, a subject at risk of an adverse cardiovascular event is a subject at risk of one or more events selected from the group consisting of events that affect the heart (adverse cardiac events), such as chronic heart failure (CHF), in particular CHF requiring hospitalization or medical intervention, myocardial infarction, unstable angina, in particular angina requiring hospitalization, or arrhythmia; events that affect the peripheral vasculature (peripheral vascular adverse events), such as hypertension and hypotension; events that affect the cerebral vasculature (cerebrovascular adverse events), such as stroke; and/or common adverse events such as death.

In particular, a subject at risk for adverse cardiovascular events according to the invention is a subject having one or more of the following risk factors for cardiovascular events and, in particular, cardiovascular events as defined herein:

Chronic kidney disease (CKD).

Subjects with a glomerular filtration rate (GFR) <60 ml/min/1.73 m ² at 3 months are classified as having CKD, regardless of the presence or absence of kidney damage. Subjects with CKD who require dialysis or kidney transplantation are commonly referred to as subjects with end-stage renal disease (ESRD). Thus, a subject is generally classified as having ESKD if he or she receives a diagnosis of non-dialysis-requiring, earlier stages of CKD. Prior to this, such subjects are referred to as subjects with CKD not requiring hemodialysis. Subjects with non-dialysis-requiring CKD (CKD-NTD) are subjects who have been diagnosed with early-stage chronic kidney disease and have not yet been referred for dialysis for medical reasons. The US National Kidney Foundation has defined 5 stages of chronic kidney disease. Typically, patients with CKD progress from stages 1 to 4 before dialysis becomes medically necessary. However, subjects with advanced CKD, such as stage 5, who have not yet started dialysis or who have not been recommended for transplantation are also commonly referred to as subjects with CKD not requiring dialysis.

As used herein, the term CKD-NTD is intended to include all subjects who have been diagnosed with chronic kidney disease but are not undergoing dialysis while receiving iron isomaltoside. Such subjects may include, for example, subjects who have never undergone dialysis and, in some embodiments, subjects who have undergone dialysis but who were not dialyzed at the time of administration of ferrous isomaltoside.

Cardiovascular disease is a common cause of death in patients with chronic kidney disease (CKD). Despite the high prevalence of traditional risk factors for atherosclerosis in patients with CKD, heart failure, arrhythmia, and sudden cardiac death account for a disproportionately greater burden of cardiovascular disease-related mortality in patients with CKD compared with coronary artery disease (CHD). Left ventricular hypertrophy (LVH) and left ventricular dysfunction can be a consequence of atherosclerosis but are also common nonatherosclerotic mechanisms of cardiovascular damage in CKD. Heart disease, including coronary artery disease, left ventricular hypertrophy (LVH), and heart failure (HF), is common in patients with chronic kidney disease (CKD). LVH is becoming more common as glomerular filtration rate (GFR) declines and dialysis use increases.

LVH is an important predictor of mortality in subjects with CKD, and anemia has emerged as an important, independent risk factor for the development and progression of LVH and HF in CKD, and adverse cardiovascular outcomes, including mortality.

The presence of LVH is clinically important because it is associated with an increased incidence of heart failure, ventricular arrhythmias, death due to myocardial infarction, decreased LV ejection fraction, sudden cardiac death, aortic root dilatation, and cerebrovascular events. Typically, the development of heart failure with LVH is a consequence of decreased left ventricular systolic function and/or diastolic dysfunction. The negative effect of left ventricular remodeling may be an important factor determining the progression of advanced heart failure.

Without being limited by theory, potential mechanisms that may explain the relationship between anemia and the development of LVH include the effects of decreased myocardial oxygen delivery, which likely results in increased myocyte necrosis and apoptosis, increased anemia-related cardiac output, and decreased systemic vascular resistance, increased oxidative

- 16 046425 stress, less efficient oxidative phosphorylation and activation of the sympathetic nervous system.

In CKD, progressive severe anemia is associated with more common and severe forms of LVH, LV dilatation, heart failure, and worse overall and cardiac prognosis in patients with CKD and heart disease. Given that increased anemia in CKD is associated with progressively severe degrees of LVH and heart failure, in accordance with aspects of the present invention, correction of deficits associated with anemia has a positive effect on the clinical features of HF and LVH. This includes the clinical manifestations of HF and the subsequent development and progression of LVH.

Several, mostly short-term, uncontrolled studies have shown that improving anemia to hemoglobin levels of 10–12 g/dL with erythropoietin in patients with heart failure and CKD reduces the clinical manifestations of heart failure and reduces hospitalization, but does not improve hard endpoints. points in subjects with CHF. However, given the relatively unexpected adverse outcomes associated with the use of erythropoietin, there is the possibility of an increased risk of severe complications and/or mortality in patients treated with erythropoietin aimed at achieving normal or near-normal hemoglobin levels.

LVH, which itself is a powerful prognostic marker of adverse cardiovascular outcomes in subjects with CKD, appears to regress as Hb levels increase from less than 10 g/dL to levels greater than 10 g/dL in some subjects. Again, without limitation, it does not appear likely that increasing Hb to more normal levels will result in further regression of LVH or clinical improvement. Initial LVH geometry may be an important factor in determining subsequent clinical response to anemia correction in subjects with LVH.

Chronic heart failure (CHF).

Chronic heart failure and heart failure, chronic, standard MedDRA terms, are used interchangeably herein.

Heart failure is a clinical syndrome characterized by typical symptoms (eg, shortness of breath, ankle swelling, and fatigue) that may be accompanied by signs (eg, increased jugular venous pressure, pulmonary rales, and peripheral edema) caused by structural and/or functional abnormality of the heart leading to decreased cardiac output and/or increased intracardiac pressure at rest or during stress. Thus, the current definition of HF is limited to the stages at which clinical symptoms appear. Before overt clinical symptoms manifest, subjects may present with asymptomatic structural or functional cardiac abnormalities, such as left ventricular (LV) systolic or diastolic dysfunction, which are precursors to HF. Recognizing these precursors is important because they are associated with poor outcomes, and initiating treatment at the precursor stage may reduce mortality in subjects with asymptomatic LV systolic dysfunction.

Chronic heart failure is a term used to describe chronic congestive heart failure, particularly when signs of volume overload are present, most often manifesting as peripheral or pulmonary edema. Chronic heart failure (CHF) can be heart failure with low 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 a specific embodiment of the invention, chronic heart failure (CHF) is heart failure with low ejection fraction, LVEF <40% (HFrEF).

Chronic heart failure (CHF) can also be classified according to the New York Heart Association (NYHA) classification, which classifies patients into one of four categories based on how limited they are during physical activity. Patients without symptoms and limitations such as excessive fatigue, palpitations, or shortness of breath (difficulty breathing) during normal physical activity such as walking, climbing stairs, etc. are considered NYHA Class I. Patients with mild symptoms (mild shortness of breath and/or angina) and little limitation in physical activity are classified as NYHA Class II. Patients with marked activity limitation due to symptoms, even during mild activity, such as walking short distances of 20 to 100 m, who are comfortable only at rest, are considered NYHA class III. Patients whose symptoms occur even at rest and who are unable to perform any physical activity without discomfort are considered NYHA Class IV. In a specific embodiment of the invention, chronic heart failure (CHF) is NYHA class II-IV congestive heart failure. In another embodiment, the subject has NYHA class I congestive heart failure.

- 17 046425

Atrial fibrillation (AF).

Atrial fibrillation (AF) can be initially diagnosed AF (which has not been diagnosed before, regardless of the duration of the arrhythmia or the presence and severity of associated symptoms), paroxysmal AF (self-limiting, in most cases within 48 hours. Some attacks may continue for a maximum 7 days Episodes of AF that are stopped by cardioversion within 7 days should be considered paroxysmal) and persistent AF (which lasts more than 7 days, including episodes stopped by cardioversion either with drugs or DC cardioversion after 7 days or more) , long-term persistent AF (persistent AF with a duration of >1 year when a rhythm control strategy is decided upon), or persistent AF (as determined by the patient (and physician). In a particular embodiment, AF is initially diagnosed AF, paroxysmal AF, or persistent AF.

AF is associated with an increased risk of death, adverse cardiovascular events, and kidney disease, including a higher risk of coronary artery disease, chronic kidney disease, sudden cardiac death, stroke, or acute heart failure.

Arterial hypertension.

Hypertension is defined as an increase in systolic blood pressure >20 mm Hg that results in a value >180 mm Hg, or an increase in diastolic blood pressure >15 mm Hg that results in a value >105 mm Hg.

Arterial hypertension is one of the leading risk factors for heart disease, in particular a risk factor for stroke. It causes approximately 50% of ischemic strokes and increases the risk of hemorrhagic stroke.

There are several mechanisms associated with hypertension that make it such a high risk factor for adverse cardiovascular events. For example, hypertension puts stress on blood vessels by narrowing or blocking them. This can lead to atherosclerosis, or the formation of weak spots in the vessel that easily rupture or protrude from the artery wall, leading to an aneurysm.

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 requires a certain period of time to develop. After a few hours, complete necrosis of myocardial cells can be observed. MI may be the first manifestation of coronary heart disease (CHD).

MI is a term used to describe the presence of characteristic changes in cardiac enzyme markers in the presence of either transient symptoms of acute coronary syndrome or electrocardiogram (ECG) changes consistent with either ischemia or infarction. The preferred biomarker is cardiac troponin cTn (I or T), which has high myocardial tissue specificity and high clinical sensitivity. Alternatively, if a cTn assay is not available, the creatine kinase MB fraction (CKMB) measured by mass analysis can be used. In both assays, an increase in cTn or CKMB concentration is defined as a value greater than the 99th percentile of the normal reference population (upper reference limit (URL)). This discriminative 99th percentile is designated as the decision level for diagnosing MI.

MI in patients with chest discomfort or other ischemic symptoms that develops ST-segment elevation in two adjacent leads is referred to as ST-segment elevation MI (STEMI). Patients without ST-segment elevation on initial evaluation are usually designated as having non-ST-segment elevation MI (NSTEMI). In a preferred embodiment, the myocardial infarction (MI) is a ST-segment elevation myocardial infarction (STEMI) or STEMI.

Subjects with a history of myocardial infarction represent one of the groups at greatest risk for subsequent cardiovascular adverse events. In particular, subjects who have suffered an MI, i.e. Those with a history of MI are at increased risk of recurrent heart attacks and have a six-fold higher annual mortality rate than people of the same age who do not have coronary heart disease.

Stroke.

Stroke is classically characterized as a neurological deficit associated with acute focal damage to the central nervous system due to a vascular factor, including cerebral infarction, cerebral hemorrhage, and subarachnoid hemorrhage.

Subjects with a history of stroke, i.e. Subjects who have had a stroke remain at high risk of developing a subsequent cardiovascular adverse event, particularly recurrent stroke.

- 18 046425

Heart valve defects.

Aortic stenosis is the most common primary valve abnormality leading to surgical or catheter intervention in Europe and North America, with an increasing prevalence due to the aging population.

Mitral regurgitation (MR) is the second most common indication for heart valve surgery in Europe. It is possible to distinguish primary from secondary MR, especially with regard to surgical and transcatheter interventional treatments. In primary MR, one or more components of the mitral valve apparatus are directly affected. The most common etiology is degenerative (prolapse, threshing valve). Endocarditis is one of the causes of primary MR. Secondary MR (also known as functional MR) is defined as MR due to primary left ventricular (LV) dysfunction with normal mitral valve leaflets and chordae. LV dysfunction may be associated with coronary artery disease (CAD) or (non-ischemic) cardiomyopathy.

Subjects with a history of heart valve defects, such as congenital defects, have an increased likelihood of developing valve disorders. Heart valve disease can cause many complications, including adverse cardiovascular events such as heart failure, stroke, blood clots, arrhythmia, or death.

Diabetes.

Severe hyperglycemia is associated with symptoms such as frequent urination, thirst, blurred vision, fatigue, and recurrent infections. In addition to relieving symptoms, the goal of lowering blood glucose levels is to reduce long-term complications of diabetes. Type 2 diabetes mellitus (also known as type 2 diabetes) is a long-term metabolic disorder characterized by elevated blood sugar levels, insulin resistance, and a relative lack of insulin. Common symptoms include increased thirst, frequent urination, and unexplained weight loss. Type 1 diabetes, also known as juvenile diabetes or insulin-dependent diabetes, is a chronic disease in which the pancreas produces little or no insulin. Various factors, including genetics and certain viruses, can contribute to the development of type 1 diabetes. Although type 1 diabetes usually occurs in childhood or adolescence, it can develop in adults. Despite active research, type 1 diabetes cannot be cured. Treatment aims to control blood sugar levels using insulin, diet and lifestyle to prevent complications.

Having diabetes increases the risk of an adverse cardiovascular event by two to four times compared to people without diabetes. Cardiovascular adverse events are the leading cause of death in people with diabetes. This is particularly due to hypertension, blood lipid abnormalities and obesity, all risk factors for adverse cardiovascular events, which are highly prevalent in subjects with diabetes.

For example, uncontrolled diabetes can cause damage to blood vessels, which can lead to atherosclerosis and hypertension. High glucose levels increase the likelihood of the accumulation of fatty deposits (atheromas), which can lead to coronary heart disease and heart attack if they occur in the coronary arteries. Subjects with diabetes are more likely to have a heart attack or stroke than subjects without diabetes, and there is also an increased risk of heart failure compared to subjects without diabetes. Diabetes suppresses the protective effects of estrogen, which may increase the risk of adverse cardiovascular events in premenopausal women who have diabetes.

Obesity.

Obesity is a condition characterized by excess body weight to the point where the body mass index (BMI), an indicator obtained by dividing a person's weight by the square of his height, exceeds 30 kg/ ^m2 . With a BMI of more than 30 kg/m2, that is, obesity, there is a serious risk of developing hypertension (for example, due to visceral fat), diabetes and atherosclerosis, which are risk factors for the occurrence of adverse events from the cardiovascular system. The term history of obesity refers to a patient who is currently identified as obese and/or who has previously been identified as obese.

For example, if you are overweight, high salt intake increases the risk of adverse cardiovascular events, particularly since dietary salt is a significant factor in increasing blood pressure, which can lead to hypertension and its associated risks.

Age, smoking and alcohol consumption.

Elderly subjects who smoke and/or drink have an increased risk of cardiovascular adverse events.

- 19 046425

According to a specific embodiment of the invention, the elderly subject is aged 60 years or more, 65 years or more, 70 years or more, 75 years or more, or 80 years or more. The risk of stroke doubles every ten years after age 55. Systolic blood pressure is an important indicator of the risk of cardiovascular events with increasing age.

A drinking subject refers to a subject with increased alcohol consumption, in particular a subject consuming more than 7 drinks per week.

Drinkers who consume too much alcohol may suffer from or develop problems such as high blood pressure, acute myocardial infarction, or cardiomyopathy. In addition, heavy drinking has been shown to cause myocardial damage and increase the risk of stroke and cardiac arrhythmias.

A smoker is a person who used to smoke tobacco regularly and/or who currently smokes tobacco regularly.

Smoking has been known to be associated with cardiovascular disease since the 1940s. This is due to a number of mechanisms: for example, smoking damages the endothelium (the lining of blood vessels), increases fatty deposits in the arteries, increases clotting, increases low-density lipoprotein cholesterol, decreases high-density lipoprotein cholesterol, and promotes spasm of the coronary arteries. In addition, nicotine, which is an addictive component in tobacco, increases heart rate and blood pressure.

Hyperthyroidism and associated thyrotoxicosis.

Hyperthyroidism is characterized by very high levels of thyroxine. Hyperthyroidism can speed up your metabolism, causing involuntary weight loss and a fast or irregular heartbeat.

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

Chronic obstructive pulmonary disease (COPD).

Chronic obstructive pulmonary disease (COPD) is a disease characterized by persistent respiratory symptoms and airflow limitation that occur due to abnormalities of the airways and/or alveoli, usually caused by significant exposure to noxious particles or gases. The main risk factor is tobacco smoking, but other environmental factors may also contribute.

Cardiomyopathy.

Cardiomyopathies are determined by structural and functional pathologies of the ventricular myocardium, which cannot be explained by coronary heart disease limiting blood flow or increased stress. Historically, this group of diseases has been divided into primary diseases, in which the heart is the only organ involved, and secondary forms, in which cardiomyopathy is a manifestation of a systemic disease. The ESC guidelines adopt a classification system in which cardiomyopathies are defined by specific morphological and functional criteria and then grouped into familial/genetic and nonfamilial/nongenetic subtypes, regardless of the presence of noncardiac disease.

In a specific embodiment of the invention, the cardiomyopathy is a hereditary cardiomyopathy or an acquired cardiomyopathy.

Inflammation.

There is an association between proinflammatory biomarkers and episodic hypertension, metabolic syndrome, coronary heart disease (CHD), acute coronary syndrome (ACS), peripheral arterial disease, stroke, and recurrent coronary and cerebrovascular events. In a particular embodiment, systemic inflammation is associated with elevated levels of C-reactive protein (CRP). CRP is a nonspecific marker of inflammation. A range of approximately 2-3 mg/l is the limit, exceeding which is considered a sign of systemic inflammation. Over the past two decades, the role of inflammation in the pathogenesis of atherosclerosis has been clearly established.

Dialysis.

A subject on dialysis is a subject who is at increased risk of experiencing an adverse event from the cardiovascular system.

In a specific embodiment of the invention, the dialysis is hemodialysis or peritoneal dialysis.

Drug therapy.

There is an increased risk of an adverse cardiovascular event if the subject is being treated with one or more of the following:

(i) modulators of hypoxia-inducible factor (HIF) signaling pathways, including prolyl hydroxylase inhibitors such as daprodustat, vadadustat, roxadustat, molidustat and desidustat;

- 20 046425 (ii) erythropoiesis stimulants (ES), such as erythropoietin (Epo), epoetin alfa (Procrit/Epogen), epoetin beta (Neorecormon), darbepoetin alfa (Aranesp) and methoxypolyethylene glycol-epoetin beta (Mircera); and (iii) hepcidin modulators, such as a hepcidin agonist or a hepcidin antagonist.

Subjects may take one or more erythropoiesis stimulating agents (ESS) to control anemia. SEs work by helping the body produce red blood cells. These red blood cells then travel from the bone marrow into the bloodstream, where they help maintain iron levels in the blood. Erythropoiesis stimulants, commonly abbreviated as ES, are agents similar in structure and/or function to the cytokine erythropoietin, which stimulates the production of red blood cells (erythropoiesis) in the body. Typical SEs are structurally and biologically similar to the natural protein erythropoietin. Examples of commercial SEs include erythropoietin (Epo), epoetin alfa (Procrit/Epogen), epoetin beta (Neorecormon), darbepoetin alfa (Aranesp), and methoxypolyethylene glycol-epoetin beta (Mircera). Currently, two SEs are approved for sale in the United States: epoetin alfa (Procrit, Epogen) and darbepoetin alfa (Aranesp).

SE is commonly prescribed to subjects with ESRD. Such subjects usually have lower hemoglobin levels because they cannot produce enough erythropoietin. Side effects that most commonly occur with SE use include: high blood pressure; swelling; elevated temperature; dizziness; nausea; and pain at the injection site, among other things. In addition to these side effects, several dangerous phenomena occur when using SE. SEs increase the risk of venous thromboembolism (vein thrombosis). SEs can also cause a severe increase in hemoglobin, which increases the risk of heart attack, stroke, heart failure and death.

In another specific embodiment of the invention, the subject is treated with an anticoagulant and/or NSAID.

Hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (also known as Osler-Weber-Rendu disease) is a genetic disorder that is inherited from parents. Its severity can vary greatly from person to person, even within the same family. It causes the formation of abnormal connections between arteries and veins called arteriovenous malformations (AVMs). The most commonly affected areas are the nose, lungs, brain and liver. These AVMs can gradually enlarge, bleed, or rupture, sometimes causing catastrophic complications.

Hereditary iron-refractory iron deficiency anemia.

Hereditary iron-refractory iron deficiency anemia (IRDA) is a hereditary disease characterized by impaired absorption and utilization. It is generally believed that GIFA is associated with genetic mutations leading to upregulation of hepcidin. Specific cases of GIRD are believed to be associated with mutations in the TMPRSS6 gene. GI is generally unresponsive to oral iron supplements but is partially responsive to parenteral iron supplements.

FRF23.

Elevated levels of fibroblast growth factor 23 (FGF23) have become known as a risk factor for cardiovascular disease.

Fibroblast growth factor 23 (FGF23) is a hormone synthesized by osteocytes that regulates phosphate and vitamin D homeostasis. FGF23 undergoes proteolytic cleavage, and as a result, a mixture of uncleaved, i.e., is naturally present. intact FGF23 (iFGF23), and fragments of its cleavage. The intact form, iFGF23, is the active form involved in phosphate metabolism, where it regulates urinary phosphate excretion, with elevated levels of iFGF23 leading to urinary phosphate losses. There are currently two main types of antibody assays, one that captures only iFGF23, and the other that binds to the C-terminus of the hormone and therefore captures both iFGF23 and the C-terminal fragments. Therefore, the last indicator, cFGF23, reflects the total amount of intact FGF23 and C-terminal fragments of FGF23. Thus, there are two tests related to FGF23, iFGF23 and sFGF23, which have different interpretations.

Elevated FGF23 levels are independently associated with established and primary LVH, cardiovascular disease, and mortality in the CKD and non-CKD groups. Moreover, a recent study demonstrated that FGF23 directly causes LVH, suggesting that FGF23 is not a simple biomarker of cardiovascular disease risk. Subjects with CKD typically have very high FGF23 levels due to the body's persistent attempts to compensate for high serum phosphate levels by producing iFGF23 to increase the fractional urinary excretion of phosphate through the kidneys. For this reason, iFGF23 levels are elevated in subjects with CKD, and as a result, other downstream effects of iFGF23 may be more pronounced.

Increased FGF23 levels in CKD help maintain serum phosphate in the normal range, FGF23 concentrations increase as the estimated glomerular rate decreases.

- 21 046425 filtration rate (eGFR) and help maintain normal phosphate homeostasis despite decreased renal mass by stimulating increased phosphate excretion by each nephron and reducing 1,25-dihydroxyvitamin D levels. Parenteral iron supplements inhibit the reabsorption of phosphate in the renal tubules and 1 -alpha-hydroxylation of vitamin D, leading to hypophosphatemia. Data indicate that hypophosphatemia is mediated by increased FGF23.

Prospective studies in predialysis cohorts of CKD, primary and established ESRD, and kidney transplant recipients demonstrate that elevated FGF23 levels are independently associated with CKD progression and cardiovascular events and mortality. These observations were initially thought to be caused by elevated levels of FGF23, which acts as a highly sensitive biomarker of phosphate-induced toxicity. However, FGF23 itself has recently been shown to mediate off-target, direct end-organ toxicity in the heart, suggesting that elevated FGF23 levels may be a novel mechanism for adverse outcomes in CKD.

In certain embodiments, a subject treated in accordance with the methods described herein for one or more cardiovascular adverse events has elevated levels of FGF23. The normal serum level of intact FGF23 in healthy individuals is approximately 26.1 pg/mL, and the normal serum level of FGF23 C-terminal fragments in healthy individuals is approximately 49.0 RU/mL. In some embodiments, the levels of FGF23 (e.g., intact FGF23 and/or C-terminal fragments of FGF23) in the subject are elevated relative to the normal range in healthy individuals. In some embodiments, the levels of intact FGF23 in the subject's serum are between 250 pg/mL and 350 pg/mL, between 200 pg/mL and 300 pg/mL, between 200 pg/mL and 350 pg/mL, between 300 pg/mL and 350 pg/ml, from 300 pg/ml to 400 pg/ml or from 250 pg/ml to 500 pg/ml. In some embodiments, intact FGF23 levels in the subject's serum are greater than 200 pg/mL, 225 pg/mL, 250 pg/mL, 275 pg/mL, 300 pg/mL, 325 pg/mL, or 350 pg/mL. In some embodiments, the levels of the C-terminal fragment of FGF23 in the subject's serum are from 60 rU/mL to 100 rU/ml, from 100 rU/ml to 200 rU/ml, from 200 rU/ml ml to 300 relative units/ml or from 250 relative units/ml to 400 relative units/ml. In some embodiments, levels of the FGF23 C-terminal fragment in the subject's serum are greater than 60 U/ml, 100 U/ml, 125 U/ml, 150 U/ml, 175 U/ml, 200 relative units/ml, 225 relative units/ml, 250 relative units/ml, 275 relative units/ml or 300 relative units/ml.

In some embodiments, subjects treated according to the methods disclosed herein experience an increase in hemoglobin concentration and/or a decrease in FGF23. In certain embodiments, subjects treated according to the methods disclosed herein experience an increase in the subject's hemoglobin level to a level greater than 10 g/dL, greater than 11 g/dL, greater than 12 g/dL, greater than 13 g/dL, or greater than 15 g/dl. In some embodiments, subjects treated according to the methods disclosed herein experience an increase in the subject's hemoglobin level to a level of 10 g/dL to 11 g/dL, 11 g/dL to 12 g/dL, 10 g/dL. up 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 according to the methods disclosed herein experience at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% decreased levels of intact FGF23 in serum or plasma. In some embodiments, subjects treated according to the methods disclosed herein experience a 15-30%, 20-30%, 25-50%, 30-60%, or 15-60% reduction in serum or plasma levels of intact FGF23 . In some embodiments, subjects treated according to the methods disclosed herein experience at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% decreased levels of C-terminal fragments of FGF23 in serum or plasma. In some embodiments, subjects treated according to the methods disclosed herein experience a 15-30%, 20-30%, 25-50%, 30-60%, or 15-60% reduction in levels of FGF23 C-terminal fragments serum or plasma.

Accordingly, in a first preferred embodiment of this aspect of the invention, the specific group of subjects who are treated in accordance with the present invention are subjects with a history of myocardial infarction (MI), history of stroke, history of atrial fibrillation (AF), chronic heart failure (CHF) history, chronic kidney disease (CKD), history of hypertension, diabetes, history of heart valve disease, history of obesity, and/or smoking, drinking and/or elderly subjects. This includes, but is not limited to, subjects with a history of myocardial infarction (MI), a history of stroke, a history of atrial fibrillation (AF), a history of chronic kidney disease (CKD), a history of chronic heart failure (CHF), and/or a history of hypertension . Subjects with a history of myocardial infarction (MI), a history of stroke, and/or a history of chronic heart failure (CHF) are the most preferred group of subjects at risk for an adverse cardiovascular event and, therefore, amenable to treatment in in accordance with the present invention.

- 22 046425

A subject's history of a particular condition, disorder, or disease, such as a history of myocardial infarction, stroke, atrial fibrillation, or congestive heart failure (CHF), is understood to refer to the subject's past and present medical history. A medical history is a record of all medical events and problems experienced by the subject, i.e. about the subject's previous illnesses, diagnoses, and the patient's general health throughout life. A subject with a history of a specific condition, disorder or disease does not have to have the specific condition, disorder or disease at a given point in time to be considered at risk. It is sufficient to have a history of a specific condition, disorder or disease. For example, a subject who has quit smoking is still at risk because of his history of smoking.

In a second preferred embodiment of this aspect of the invention, the particular group of subjects to be treated according to the present invention are subjects with a history of chronic heart failure (CHF). These include, in particular, subjects who also have a history of myocardial infarction (MI) and/or a history of stroke. In a preferred embodiment, the CHF is low ejection fraction heart failure (HFrEF).

In a third preferred embodiment of this aspect of the invention, the specific group of subjects to be treated according to the present invention are subjects with a history of myocardial infarction (MI). In a preferred embodiment, the MI is an ST STEMI or an ST NSTEMI. In a fourth preferred embodiment of this aspect of the invention, the specific group of subjects to be treated according to the present invention are subjects with a history of stroke.

Subjects as defined herein (i.e., those who are at risk for an adverse cardiovascular event and/or have a history of congestive heart failure) include subjects who also have chronic kidney disease (CKD), or subjects without CKD. Those with CKD are a specific subgroup of patients to be treated according to the present invention. In particular, they include subjects having chronic kidney disease (CKD) and chronic heart failure (CHF), where the chronic kidney disease (CKD) is preferably chronic kidney disease not requiring dialysis (CKD-NTD).

In one embodiment, a subject with a history of chronic heart failure has HFrEF. In another embodiment, the subject with a history of congestive heart failure has NYHA class II-IV congestive heart failure, in particular NYHA class II-IV congestive heart failure type HFrEF. In another embodiment, the subject has NYHA class I congestive heart failure.

In some further embodiments of this aspect of the invention, the specific groups of subjects to be treated in accordance with the present invention are subjects having one or more of the following risk factors:

(i) subjects with a history of atrial fibrillation (AF), particularly new-onset AF, paroxysmal AF, or persistent AF;

(ii) subjects with a history of valvular heart disease;

(iii) subjects with a history of hypertension;

(iv) subjects with diabetes;

(v) subjects with a history of obesity;

(vi) elderly subjects, in particular subjects aged 60 years or more, 65 years or more, 70 years or more, 75 years or more, or 80 years or more;

(vii) smokers;

(viii) drinkers;

(ix) subjects having hyperthyroidism and/or associated thyrotoxicosis;

(x) subjects having chronic obstructive pulmonary disease (COPD);

(xi) subjects having cardiomyopathy, in particular genetic cardiomyopathy or acquired cardiomyopathy;

(xii) subjects having systemic inflammation without infection, where systemic inflammation is, in particular, inflammation associated with elevated C-reactive protein (CRP) above the range of approximately 2-3 mg/L;

(xiii) subjects on dialysis, where the dialysis is, in particular, hemodialysis or peritoneal dialysis;

(xiv) subjects treated with one or more of the following:

a) modulators of hypoxia-inducible factor (HIF) signaling pathways, including prolyl hydroxylase inhibitors such as daprodustat, vadadustat, roxadustat, molidustat and desidustat;

- 23 046425

b) erythropoiesis stimulants (ES), such as erythropoietin (Epo), epoetin alfa (Procrit/Epogen), epoetin beta (Neorecormon), darbepoetin alfa (Aranesp) and methoxypolyethylene glycol-epoetin beta (Mircera); And

c) hepcidin modulators, such as a hepcidin agonist or a hepcidin antagonist;

(xv) subjects treated with an anticoagulant and/or NSAID;

(xvi) subjects having hereditary hemorrhagic telangiectasia; or (xvii) subjects who have hereditary iron-refractory iron deficiency anemia.

II. Therapeutic effects.

In addition to delivering iron to a subject, the disclosure provides methods for reducing the incidence or risk of adverse cardiovascular events in subjects as defined herein. Reference to a reduction in the incidence or risk of an adverse cardiovascular event or adverse cardiovascular event is intended to indicate that the incidence or risk of one or more of the enumerated events is reduced.

According to one embodiment of this second aspect of the invention, the adverse cardiovascular event, the incidence or risk of which is reduced, is selected from the group consisting of events that affect the heart (adverse cardiac events); phenomena that affect the peripheral vasculature (adverse events from peripheral vessels); phenomena that affect the cerebral vasculature (adverse events from the cerebrovascular system); respiratory, thoracic and mediastinal adverse events; general adverse events; and infections and infestations.

In a specific embodiment of this second aspect of the invention, the adverse cardiac event, the incidence or risk of which is reduced, is selected from the group consisting of chronic heart failure, atrial fibrillation, cardiac arrest, atrioventricular block, heart failure, sinus node dysfunction, acute myocardial infarction , bradycardia, angina pectoris, myocardial ischemia and ventricular extrasystoles; peripheral vascular adverse events selected from the group consisting of hypertension, increased systolic blood pressure, increased blood pressure, increased troponin and hypotension; adverse events from the cerebrovascular system were selected from the group consisting of cerebrovascular accident, cerebral infarction and transient ischemic attack; respiratory, thoracic and mediastinal adverse events selected from the group consisting of dyspnea and pulmonary edema; common adverse events selected from the group consisting of chest pain and death; and infections and infestations constitute septic shock. According to a preferred embodiment of this second aspect of the invention, the adverse cardiovascular event, the incidence or risk of which is reduced, is selected from the group consisting of events that affect the heart (adverse cardiac events); phenomena that affect the peripheral vasculature (adverse events from peripheral vessels); phenomena that affect the cerebral vasculature (adverse events from the cerebrovascular system); and death. Preferably, events that affect the heart (adverse cardiac events) are chronic heart failure, myocardial infarction, unstable angina and arrhythmia; events that affect the peripheral vasculature (peripheral vascular adverse events) are hypertension; and events that affect the cerebral vasculature (cerebrovascular adverse events) constitute stroke.

According to a particularly preferred embodiment of this second aspect of the invention, the adverse cardiovascular event, the incidence or risk of which is reduced, is selected from the group consisting of chronic heart failure, myocardial infarction, unstable angina, arrhythmia, hypertension, hypotension, stroke and death .

According to another particularly preferred embodiment of this second aspect of the invention, the adverse cardiovascular event, the incidence or risk of which is reduced, is chronic heart failure, atrial fibrillation, hypertension and/or cardiac arrest.

Certain cardiovascular adverse events associated with chronic heart failure are hospitalization, hospitalization due to worsening of chronic heart failure, or death due to chronic heart failure. The present invention is particularly directed to such cardiovascular adverse events, wherein the cardiovascular adverse event is CHF.

III. Therapeutic effects in selected subjects.

Taking into account the specific subject populations as defined herein and the cardiovascular adverse event, frequency or risk of occurrence

- 24 046425 which needs to be reduced, the present invention, in accordance with a third aspect, relates to 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, wherein the method includes administering an effective amount of iron isomaltoside, where the subject is:

(A) a subject at risk for an adverse cardiovascular event as defined herein;

(B) a subject with a history of chronic heart failure (CHF); or (C) a subject who has a history of chronic heart failure (CHF) and is at risk for an adverse cardiovascular event, and where the adverse cardiovascular event, the incidence or risk of which is reduced:

(a) selected from the group consisting of chronic heart failure, myocardial infarction, unstable angina, arrhythmia, hypertension, hypotension, stroke and death;

(b) chronic heart failure;

(c) atrial fibrillation;

(d) arterial hypertension; or (e) cardiac arrest.

According to a preferred embodiment of this third aspect of the invention, the subject is a subject at risk of experiencing a cardiovascular adverse event, wherein the cardiovascular adverse event whose incidence or risk is reduced is chronic heart failure.

According to another preferred embodiment of this third aspect of the invention, the subject is a subject at risk of experiencing a cardiovascular adverse event, wherein the cardiovascular adverse event whose incidence or risk is reduced is atrial fibrillation.

According to another preferred embodiment of this third aspect of the invention, the subject is a subject at risk of experiencing a cardiovascular adverse event, wherein the cardiovascular adverse event whose incidence or risk is reduced is cardiac arrest.

According to another preferred embodiment of this third aspect of the invention, the subject is a subject having a history of chronic heart failure (CHF), wherein the adverse cardiovascular event, the incidence or risk of which is reduced, is cardiac arrest and/or chronic heart failure .

According to another preferred embodiment of this third aspect of the invention, the subject is a subject having a history of chronic heart failure (CHF), wherein the cardiovascular adverse event, the incidence or risk of which is reduced, is chronic heart failure.

According to another preferred embodiment of this third aspect of the invention, the subject is a subject with a history of chronic heart failure (CHF), wherein the cardiovascular adverse event of reduced incidence or risk is atrial fibrillation.

According to another preferred embodiment of this third aspect of the invention, the subject is a subject with a history of chronic heart failure (CHF), wherein the adverse cardiovascular event of which the incidence or risk of occurrence is reduced is cardiac arrest.

According to another embodiment of this third aspect of the invention, the subject is a subject at risk of an adverse event from the cardiovascular system and/or having a history of chronic heart failure, who has chronic kidney disease (CKD). According to another embodiment of this third aspect of the invention, the subject is a subject at risk for an adverse cardiovascular event and/or with a history of chronic heart failure who does not have chronic kidney disease (CKD). In particular, they include subjects having chronic kidney disease (CKD) and/or chronic heart failure (CHF), where the chronic kidney disease (CKD) is preferably chronic kidney disease not requiring dialysis (CKD-NTD).

- 25 046425

In some embodiments, subjects with a history of congestive heart failure have HFrEF. In some embodiments, the subjects with a history of congestive heart failure have NYHA class II-IV congestive heart failure, particularly NYHA class II-IV HFrEF-type congestive heart failure. In another embodiment, the subject has NYHA class I congestive heart failure.

In other embodiments, the invention provides methods for reducing the incidence or risk of hospitalizations associated with adverse cardiovascular events in subjects as defined herein.

In some embodiments, the invention provides methods for reducing mortality and severity of disorders, ie, in particular, death, due to adverse events from the cardiovascular system in subjects, as defined herein.

IV. Control of atrial fibrillation.

The invention is also based on the discovery that iron therapy effectively reduces P wave dispersion. Because prolongation of atrial conduction, expressed as increased P wave dispersion/duration, is a hallmark of patients who develop and persist in AF, a decrease in P wave dispersion/duration has crucial for the prevention and treatment of AF. Thus, in one embodiment, the present invention provides a method for reducing P wave dispersion/duration for the prevention or treatment of AF or disorders associated with AF (eg, heart failure, hypertension, valvular heart disease, coronary artery disease, obesity and diabetes mellitus), in an animal suffering from such a condition, which involves administering to such animal a therapeutically effective amount of an iron preparation.

Preferably, the subject to be treated will be a human. However, treatment may be veterinary, such as in horses or cats.

The method according to the invention can be used for the prevention and treatment of AF, including paroxysmal, persistent, long-term and chronic AF.

A warning for AF refers to stopping the first episode or recurrent episodes in an animal that is in normal sinus rhythm during iron therapy. By treatment for AF we mean converting AF to normal sinus rhythm. Prevention and treatment of AF will ultimately reduce the burden of AF, which should result in a reduction in symptoms (eg, palpitations, shortness of breath), exercise intolerance, hospitalization, heart failure, stroke, and death.

Iron preparations are well known and may include oral tablets (eg, ferrous sulfate, ferrous (II) fumarate, iron (II) gluconate, iron polysaccharide, ferrous polymaltose), solutions for intramuscular injection or intravenous injection/infusion (eg, high molecular weight iron dextran, low molecular weight iron dextran, iron sucrose, iron gluconate, iron carboxymaltose, iron isomaltoside).

It is also possible in accordance with the invention to administer an iron supplement to animals that may or may not be iron deficient on blood tests, since many patients have myocardial iron deficiency that responds to dietary supplements despite normal blood tests for iron deficiency.

V. Dosage administration and dosage regimen.

Methods of treating iron deficiency in a subject at risk for an adverse cardiovascular event according to the invention include administering an effective amount of iron isomaltoside.

A typical iron isomaltoside treatment regimen may consist of either a single infusion of 1000 mg of iron, a dose of elemental iron up to 20 mg/kg body weight given as an intravenous infusion, or an intravenous bolus injection up to 500 mg up to three times a week. The total iron requirement can be determined using the Ganzoni formula and, in one embodiment, the calculated dose will be administered. Alternatively, the total dose to be administered is selected according to the following table:___________

Hb (g/dl) Patients weighing between 50 kg and <70 kg Patients weighing >70 kg >10 1000 mg 1500 mg <10 1500 mg 2000 mg

Alternatively, a typical iron isomaltoside treatment regimen is chosen according to the following table: __________________________________________________________________________________________

Hb (g/dl) Body weight <50 kg Body weight from 50 to <70 kg Body weight >70 kg

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>10 20 mg/kg 1000 mg 20 mg/kg maximum up to 1500 mg <10 20 mg/kg 20 mg/kg 20 mg/kg maximum up to 2000 mg

Thus, in some embodiments, the effective amount of iron isomaltoside is from about 500 mg to 2000 mg, such as 500 mg, 1000 mg, 1500 mg, or 2000 mg elemental iron, which can be administered in one dose or more than one dose, in particularly 2 or 3 doses. Alternatively, the effective amount of iron isomaltoside is up to 50 mg iron/kg body weight, in particular up to 30 mg iron/kg body weight, or preferably up to 20 mg iron/kg body weight.

In a specific embodiment, the dose is a single daily dose. For example, a typical single daily dose of iron isomaltoside is 1000 mg of elemental iron.

If repeated, a first dose of 200 to 700 mg, preferably 300 to 600, most preferably up to 500 mg of elemental iron is followed by a second dose of 200 to 700 mg, preferably 300 to 600, and most preferably up to 500 mg of elemental iron . Two doses may be administered over 1 month, 2 weeks, or preferably 1 week. Preferably they are administered within one week. Subsequent additional doses of iron isomaltoside may be administered, for example a third dose of 200 to 700 mg, preferably 300 to 600, most preferably up to 500 mg of elemental iron. Such additional, eg third, dose(s) may be administered over one period of time, i.e. 1 month, 2 weeks or preferably 1 week. These multiple doses are preferably administered as a bolus injection. It is also preferable that each dose is administered at least 2, and especially 3, days apart. For example, if 3 doses are to be administered over one week, it is preferable to administer these doses on days 1, 4 and 7.

In the case of using iron bepectate as a carbohydrate iron complex according to the invention, the calculation of the effective total dose in terms of elemental iron can be carried out in the same way using the Ganzoni formula or on the basis of the tables given above. Alternatively, the effective total dose may be 1000 mg or 1500 mg elemental iron. Suitable single doses of iron bepectate, i.e. the dose administered in one dose is, for example, 500 mg, 1000 mg or 1500 mg, up to 15 mg/kg or, alternatively, up to 20 mg/kg. Alternatively, a suitable single dose may be 15 mg/kg or 20 mg/kg body weight.

In CKD patients on hemodialysis, repeated doses of iron isomaltoside or iron bepectate may be administered in combination with dialysis procedures, such as, for example, 100 mg to 500 mg, preferably 100 mg or 200 mg.

C. Combinations of drugs.

Described hereinafter are combinations of iron isomaltoside with one or more additional drugs for use in the treatment of iron deficiency according to the invention, wherein the additional drug is selected from the group consisting of the following:

(1) an angiotensin-converting enzyme inhibitor (ACEI), such as captopril, enalapril, lisinopril, ramipril or trandolapril;

(2) a beta blocker such as bisoprolol, carvedilol, metoprolol succinate, or nebivolol;

(3) a mineralocorticoid receptor antagonist (MRA), such as eplerenone or spironolactone;

(4) an angiotensin receptor blocker such as candesartan, valsartan or losartan;

(5) an If channel blocker such as ivabradine;

(6) an angiotensin receptor/neprilysin inhibitor such as sacubitril/valsartan; and (7) a diuretic such as furosemide, bumetanide, torsemide, bendroflumethoazide, hydrochlorothiazide, metolazone, indapamide, amiloride, or triamterene.

Also described are combinations of iron isomaltoside with one or more additional drugs for use in the treatment of iron deficiency according to the invention, where the additional drug is a cardiac glycoside such as digoxin or digitoxin.

Additional drug doses generally refer to the amounts of drug administered to adults. Doses for administration to children may be adjusted accordingly.

Particular combinations of iron isomaltoside with one or more additional drugs for use in treating iron deficiency according to the invention are those where the additional drug exposes the subject to a higher risk of adverse cardiovascular events. In this aspect, the additional drug is selected from the group consisting of the following:

- 27 046425 (i) modulators of hypoxia-inducible factor (HIF) signaling pathways, including prolyl hydroxylase inhibitors such as daprodustat, vadadustat, roxadustat, molidustat and desidustat;

(ii) erythropoiesis stimulants (ES), such as erythropoietin (Epo), epoetin alfa (Procrit/Epogen), epoetin beta (Neorecormon), darbepoetin alfa (Aranesp) and methoxypolyethylene glycol-epoetin beta (Mircera); and (iii) hepcidin modulators, such as a hepcidin agonist or a hepcidin antagonist.

Exemplary embodiments.

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

2. The method of Embodiment 1, wherein the subject at risk for the cardiovascular adverse event is a subject with a history of myocardial infarction (MI), a history of stroke, a history of atrial fibrillation (AF), or chronic heart failure. (CHF) history, chronic kidney disease (CKD), history of hypertension, diabetes, history of valvular heart disease, history of obesity, and/or smoking, drinking and/or elderly subject.

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

4. The method according to embodiment 3, wherein the subject at risk of experiencing an adverse event from the cardiovascular system is a subject with a history of myocardial infarction (MI), a history of stroke, and/or a history of chronic heart failure (CHF).

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

6. The method according to embodiment 5, wherein the subject having a history of chronic heart failure (CHF) has a history of myocardial infarction (MI) and/or a history of stroke.

7. The method according to any one of embodiments 2-6, wherein the chronic heart failure (CHF) is low ejection fraction heart failure (HFrEF).

8. The method according to embodiments 1-4, wherein the subject at risk of experiencing an adverse event from the cardiovascular system is a subject with a history of myocardial infarction (MI).

9. The method according to embodiment 8, wherein the myocardial infarction (MI) is a STEMI or a NSTEMI.

10. The method according to embodiments 1-4, wherein the subject at risk of experiencing an adverse event from the cardiovascular system is a subject with a history of stroke.

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

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

13. The method according to any one of embodiments 1-11, wherein the subject at risk of experiencing an adverse event from the cardiovascular system is a subject with a history of chronic kidney disease (CKD) and chronic heart failure (CHF).

14. The method according to embodiment 13, wherein the subject having chronic heart failure has HFrGF.

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

15A. The method of embodiment 13 or 14, wherein the subject has New York Heart Association (NYHA) class I congestive heart failure.

16. The method according to any one of embodiments 11-15 or 15A, wherein the chronic kidney disease (CKD) is chronic kidney disease not requiring dialysis (CKD-NTD).

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

18. The method of embodiment 17, wherein the atrial fibrillation (AF) is newly diagnosed AF, paroxysmal AF, or persistent AF.

19. The method according to embodiment 1 or 2, wherein the subject at risk of experiencing an adverse event from the cardiovascular system is a subject with a history of valvular heart disease.

20. The method according to embodiments 1-3, wherein the subject at risk of experiencing an adverse event from the cardiovascular system is a subject with a history of hypertension.

21. The method according to embodiment 1 or 2, wherein the subject at risk of an adverse event from the cardiovascular system is a subject having diabetes.

22. The method according to embodiment 1 or 2, wherein the subject at risk of experiencing an adverse cardiovascular event has a history of obesity.

23. The method according to embodiment 1 or 2, wherein the subject at risk of an adverse event from the cardiovascular system is an elderly subject who smokes or drinks.

24. The method according to embodiment 23, wherein the elderly subject is 60 years of age or more, 65 years of age or more, 70 years of age or more, 75 years of age or more, or 80 years of age or more.

25. The method according to embodiment 1, wherein the subject at risk of experiencing an adverse event from the cardiovascular system is a subject having hyperthyroidism and/or associated thyrotoxicosis.

26. The method according to embodiment 1, wherein the subject at risk of experiencing an adverse event from the cardiovascular system is a subject having chronic obstructive pulmonary disease (COPD).

27. The method according to Embodiment 1, wherein the subject at risk of an adverse event from the cardiovascular system is a subject having cardiomyopathy.

28. The method according to embodiment 27, wherein the cardiomyopathy is a hereditary cardiomyopathy or an acquired cardiomyopathy.

29. The method of Embodiment 1, wherein the subject at risk for an adverse cardiovascular event is a subject having systemic inflammation in the absence of infection.

30. The method of embodiment 29, wherein systemic inflammation is associated with elevated C-reactive protein (CRP) above the range of approximately 2-3 mg/L.

31. The method according to embodiment 1, wherein the subject at risk of experiencing an adverse event from the cardiovascular system is a subject on dialysis.

32. The method according to embodiment 31, wherein the dialysis is hemodialysis or peritoneal dialysis.

33. The method of Embodiment 1, wherein the subject at risk of the cardiovascular adverse event is a subject treated with one or more of the following:

a) modulators of hypoxia-inducible factor (HIF) signaling pathways, including prolyl hydroxylase inhibitors such as daprodustat, vadadustat, roxadustat, molidustat and desidustat;

b) erythropoiesis stimulants (ES), such as erythropoietin (Epo), epoetin alfa (Procrit/Epogen), epoetin beta (Neorecormon), darbepoetin alfa (Aranesp) and methoxypolyethylene glycol-epoetin beta (Mircera); And

c) hepcidin modulators such as a hepcidin agonist or a hepcidin antagonist.

34. The method of Embodiment 1, wherein the subject at risk for the cardiovascular adverse event is a subject who has been treated with an anticoagulant and/or an NSAID.

35. The method according to embodiment 1, wherein the subject at risk of experiencing an adverse event from the cardiovascular system is a subject having hereditary hemorrhagic telangiectasia.

36. The method according to embodiment 1, wherein the subject at risk of experiencing an adverse event from the cardiovascular system is a subject having hereditary iron-refractory iron deficiency anemia.

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

38. The method according to any of embodiments 1-37, wherein the subject has chronic iron loss or malabsorption.

39. The method of any one of embodiments 1-38, wherein the subject is intolerant to or ineffective for oral iron.

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

41. The method of any one of embodiments 1-40, wherein treating the iron deficiency reduces the incidence or risk of an adverse cardiovascular event in the subject.

42. The method according to embodiment 41, wherein the cardiovascular adverse event is selected from the group consisting of events that affect the heart (cardiac adverse events); phenomena that affect the peripheral vasculature (adverse events from peripheral vessels); phenomena that affect the cerebral vasculature (adverse events from the cerebrovascular system); respiratory, thoracic and mediastinal adverse events; common adverse events; and infections and infestations.

43. The method according to embodiment 42, wherein the adverse cardiac events are selected from the group consisting of chronic heart failure, atrial fibrillation, cardiac arrest, atrioventricular block, heart failure, sinus node dysfunction, acute myocardial infarction, bradycardia, angina, myocardial ischemia and ventricular extrasystole; peripheral vascular adverse events selected from the group consisting of hypertension, elevated systolic blood pressure, elevated blood pressure, elevated troponin, and hypotension; adverse events from the cerebrovascular system were selected from the group consisting of cerebrovascular accident, cerebral infarction and transient ischemic attack; respiratory, thoracic and mediastinal adverse events selected from the group consisting of dyspnea and pulmonary edema; common adverse events selected from the group consisting of chest pain and death; and infections and infestations constitute septic shock.

44. The method according to embodiment 41, wherein the cardiovascular adverse event is selected from the group consisting of events that affect the heart (cardiac adverse events); phenomena that affect the peripheral vasculature (adverse events from peripheral vessels); phenomena that affect the cerebral vasculature (adverse events from the cerebrovascular system); and death.

45. The method according to embodiment 44, wherein the events that affect the heart (adverse cardiac events) are chronic heart failure, myocardial infarction, unstable angina and arrhythmia; events that affect the peripheral vasculature (adverse events from peripheral vessels) are arterial hypertension; and events that affect the cerebral vasculature (cerebrovascular adverse events) are stroke.

46. The method of embodiment 41, wherein the cardiovascular adverse events are selected from the group consisting of chronic heart failure, myocardial infarction, unstable angina, arrhythmia, hypertension, hypotension, stroke, and death.

47. The method of embodiments 41-42, wherein the cardiovascular adverse event is selected from the group consisting of chronic heart failure, atrial fibrillation, hypertension, and cardiac arrest.

48. The method according to any one of embodiments 41-47, wherein the cardiovascular adverse event is chronic heart failure.

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

50. The method of embodiment 49, wherein the cardiovascular adverse event is hospitalization due to chronic heart failure.

51. The method of embodiment 49, wherein the cardiovascular adverse event is death due to chronic heart failure.

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

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

54. The method of embodiments 41-47, wherein the cardiovascular adverse event is hypertension.

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

56. The method according to any one of embodiments 41-55, wherein the iron isomaltoside is an iron derisomaltose.

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, wherein the method includes administering an effective amount of iron isomaltoside, wherein the subject is:

(A) a subject at risk for an adverse cardiovascular event;

(B) a subject with a history of chronic heart failure (CHF); or (C) a subject with a history of chronic heart failure (CHF) and at risk for an adverse cardiovascular event, and where the adverse cardiovascular event, the incidence or risk of which is reduced:

(a) selected from the group consisting of chronic heart failure, myocardial infarction, unstable angina, arrhythmia, hypertension, hypotension, stroke and death;

(b) is chronic heart failure;

(c) is atrial fibrillation;

(d) is arterial hypertension; or (e) is cardiac arrest.

58. The method of embodiment 57, wherein the subject is a subject at risk of experiencing a cardiovascular adverse event, wherein the cardiovascular adverse event whose incidence or risk is being reduced is chronic heart failure.

59. The method of embodiment 57, wherein the subject is a subject at risk of experiencing a cardiovascular adverse event, wherein the cardiovascular adverse event whose incidence or risk is being reduced is atrial fibrillation.

60. The method of embodiment 57, wherein the subject is a subject at risk of experiencing a cardiovascular adverse event, wherein the cardiovascular adverse event whose incidence or risk is being reduced is cardiac arrest.

61. The method of embodiment 57, wherein the subject is a subject with a history of congestive heart failure, wherein the cardiovascular adverse event, the incidence or risk of which is reduced, is cardiac arrest and/or congestive heart failure.

62. The method of embodiment 57, wherein the subject is a subject with a history of congestive heart failure (CHF), wherein the cardiovascular adverse event whose incidence or risk is being reduced is congestive heart failure.

63. The method of Embodiment 57, wherein the subject is a subject with a history of chronic heart failure (CHF), wherein the cardiovascular adverse event whose incidence or risk is being reduced is atrial fibrillation.

64. The method of embodiment 57, wherein the subject is a subject who has a history of chronic heart failure (CHF), wherein the adverse cardiovascular event of which the incidence or risk of occurrence is reduced is cardiac arrest.

65. The method of embodiment 57, wherein the subject is a subject at risk for an adverse cardiovascular event and/or has a history of congestive heart failure, and wherein the subject has chronic kidney disease (CKD).

66. The method of embodiment 57, wherein the subject is a subject at risk for an adverse cardiovascular event and/or has chronic heart failure, and where the subject does not have chronic kidney disease (CKD).

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67. The method of embodiment 65 or 66, wherein the chronic kidney disease (CKD) is chronic kidney disease not requiring dialysis (CKD-NTD).

68. The method according to any one of embodiments 57 or 61-67, wherein the subject with a history of chronic heart failure has HFrEF.

69. The method of any one of embodiments 57, or 61-68, wherein the subject with a history of congestive heart failure has NYHA class IIIV congestive heart failure.

69A. The method of any one of embodiments 57, or 61-68, wherein the subject has NYHA class I congestive heart failure.

70. The method of embodiment 57-69 or 69A, wherein the cardiovascular adverse event, the incidence or risk of which is reduced, is cardiovascular death and/or hospitalization due to worsening chronic heart failure.

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

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

73. The method of any one of embodiments 41-72, wherein the subject has chronic iron loss or malabsorption.

74. The method of any one of embodiments 41-73, wherein the subject is intolerant to oral iron or in whom oral iron is ineffective.

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

76. The method according to any one of embodiments 57-75, wherein the iron isomaltoside is an iron derisomaltose.

77. The method of any one of embodiments 1-76, further comprising, prior to said administration of ferrous isomaltoside, determining whether said patient is at risk for an adverse cardiovascular event.

78. The method of claim 77, wherein said definition includes a stress test that involves measuring one or more cardiac enzyme markers, electrocardiography, ambulatory electrocardiography, imaging (such as chest x-ray, echocardiography, tomography, CT, CAT scan, EBCT, PET, DCA, DSA, multidetector CT, MRI or SPECT), myocardial perfusion imaging (MPI), multi-gated nuclear angiography (MUGA), radionuclide stress test, nuclear stress test or coronary angiography.

79. The method according to paragraph 77 or 78, wherein said iron isomaltoside is administered if said patient is at risk of an adverse event from the cardiovascular system.

The present invention is further illustrated by the following examples, which should not be considered as further limitation. The contents of all figures and all references, Genbank sequences, patents and published patent applications cited in this application are expressly incorporated herein by reference.

Examples

Example 1.

Two randomized, open-label, phase III studies evaluating comparative safety and efficacy were conducted on treatment with iron isomaltoside (IIM, trade name Monofer®, Monoferric®) and iron sucrose (IS, trade name Venofer®) in adult subjects with iron deficiency anemia and dialysis for chronic kidney disease. These studies allowed comparison of the incidence of cardiovascular adverse events occurring after initiation of treatment, particularly in patients with risk factors for cardiovascular disease.

Study design.

The studies were randomized, open-label, comparative studies. Subjects with iron deficiency anemia (IDA) were randomized 1:1 to one treatment of two treatment modalities. Iron isomaltoside 1000 was administered once at a dose of 1000 mg of elemental iron. Iron sucrose was administered as a slow intravenous bolus of 200 mg according to its US label and repeated up to 5 times to achieve a total dose of 1000 mg.

Goals.

The study compared the incidence of protocol-defined cardiovascular adverse events in subjects with IDA and chronic kidney disease not requiring dialysis when treated with ferrous isomaltoside or iron sucrose.

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In this protocol, adverse events from the cardiovascular system were defined as follows:

(1) Chronic heart failure requiring hospitalization or medical intervention:

Chronic heart failure requiring hospitalization or medical intervention was defined as meeting the following criteria:

Requires hospitalization, defined as an inpatient referral or emergency department visit requiring at least a 12-hour stay (or change of date if referral/discharge time is not available); AND

Clinical manifestation of chronic heart failure, including at least one of the following: initial onset or worsening of dyspnea, orthopnea, paroxysmal nocturnal dyspnea, edema, basilar crackles in the lungs, jugular vein distension, or radiographic evidence of worsening heart failure; AND

Additional/intensified therapy:

Intravenous treatment with diuretic, inotropic or vasodilating therapy; OR

Mechanical or surgical intervention (mechanical circulatory support, heart transplant, or ventricular pacing to improve cardiac function) or the use of ultrafiltration, hemofiltration, or dialysis that specifically treat heart failure.

(2) Arrhythmia:

Arrhythmia is defined as any symptomatic deviation from normal sinus rhythm observed in a subject that leads to an assessment performed by a healthcare professional. Evaluation included physical examination during an outpatient visit, ECG, or hospitalization. Arrhythmias included any conduction disturbance, atrioventricular heart block, QTc prolongation, supraventricular/nodal arrhythmia, vasovagal episode, ventricular arrhythmia, or other cardiovascular arrhythmia.

(3) Arterial hypertension.

During the observation period immediately after study drug administration, hypertension was defined as an increase in systolic blood pressure >20 mmHg resulting in a value >180 mmHg, or an increase in diastolic blood pressure >15 mmHg. , which leads to a value of >105 mmHg.

After a subject completed a study visit during which subjects received the drug, hypertension was defined as requiring an unscheduled outpatient physician visit, hospitalization, or a change in drug therapy (eg, administration of antihypertensive agents), in combination with objective criteria, increased blood pressure (increased systolic blood pressure >20 mmHg, which results in a value >180 mmHg, or an increase in diastolic blood pressure >15 mmHg, which results in a value >105 mmHg).

(4) Hypotension.

During the observation period immediately after study drug administration, hypotension was defined as a decrease in systolic blood pressure >20 mmHg resulting in a value of <90 mmHg, or a decrease in diastolic blood pressure >15 mmHg. , which results in a value of <50 mm Hg.

After a subject completed a study visit during which subjects received the drug, hypotension was defined as requiring an unscheduled outpatient physician visit, hospitalization, or a change in drug therapy (eg, fluid/volume resuscitation, continuation of antihypertensive medications), in combination with objective criteria, decrease in blood pressure (a decrease in systolic blood pressure >20 mmHg, which leads to a value <90 mmHg, or a decrease in diastolic blood pressure >15 mmHg, which leads to a value <50 mmHg. Art.).

(5) Myocardial infarction (MI):

Myocardial infarction (MI) was defined as the presence of characteristic changes in cardiac enzyme markers in the presence of transiently associated symptoms of acute coronary syndrome or electrocardiographic (ECG) changes consistent with ischemia or infarction.

Cardioenzyme markers suggestive of MI included:

Corresponding increases and decreases in serum troponin (I or T) or creatine kinase MB, where at least 1 value is >2* upper limit of normal (ULN). If only 1 value was measured, if it was >2* ULN, the event was assessed based on the combined clinical data.

If only total creatine phosphokinase was measured, serial changes (i.e., at least 2 values) had to be >2* ULN.

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Symptoms suggestive of ischemia had to be present for >10 minutes and included chest pain, chest tightness, or tightness. Dyspnea, diaphoresis, or nausea were considered symptoms of ischemia and were assessed using a pool of clinical data.

ECG changes were defined as:

New Q waves in 2 or more contiguous leads; OR

Transition from the ST segment to the T wave in 2 or more contiguous leads + (eg, transient ST segment depression >0.5 mm);

New left bundle branch block; OR

ST segment elevation of 1 mm in 2 or more contiguous leads.

(6) Stroke:

Stroke was defined as a focal neurological deficit of sudden onset that becomes irreversible within 24 hours and results from a vascular cause affecting the central nervous system and is not associated with another readily identifiable cause (eg, tumor or brain injury). Strokes are classified as hemorrhagic, ischemic, or of unknown cause.

(7) Unstable angina requiring hospitalization:

Unstable angina requiring hospitalization is defined as ischemic symptoms meeting the following criteria:

Duration >10 minutes and is considered myocardial ischemia upon final diagnosis; AND

Requires an unscheduled visit to a medical facility and an overnight stay (does not include observation units for monitoring chest pain); AND

At least one of the following:

New dynamic changes on the ECG,

Confirmation of ischemia in an exercise test, with or without cardiac imaging,

Angiographic confirmation of >70% epicardial coronary artery disease and/or thrombosis.

(8) Death due to any cause:

Death from any cause is determined on the date the subject is declared dead.

An additional efficacy measure in the study was to compare the results of treatment with ferrous isomaltoside and ferric carboxymaltose in subjects with IDA in terms of hemoglobin (Hb), ferritin, and transferrin saturation (TSAT).

Final results.

The primary safety outcome was the incidence of protocol-defined hypersensitivity reactions (number of participants with such events) over 8 weeks.

The primary outcome measure was the ability to increase Hb (g/dL) over 8 weeks.

The secondary safety outcome was the incidence of protocol-defined cardiovascular adverse events (number of participants with such events) over 8 weeks.

Secondary efficacy endpoints were changes in s-ferritin (ng/mL) over 8 weeks and changes in transferrin saturation (%) over 8 weeks.

Safety assessments.

The study included the following safety assessments:

Data on AEs will be collected and assessed for relationship to study drug, severity, seriousness, and predictability. They will be reported to regulatory authorities and action will be taken in accordance with international and local requirements.

Objective examinations, vital signs measurements, ECG, height, weight and laboratory safety parameters.

Performance assessments.

The study included the following efficacy assessments:

Hb, s-ferritin, TSAT (s-iron and transferrin).

Duration of the study and number of visits.

For an individual subject, the study duration was 8 weeks (including a screening period of 28 days), with each subject making 6-8 visits.

A set of subjects.

Subjects who met the following study inclusion criteria were included:

1. Men or women >18 years old;

2. Hb <11 g/dl; And

3. Willingness to participate and signing the Informed Consent Form (ICF).

For IDA-03.

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Additional inclusion criteria for the IDA-03 study were as follows:

1. IDA caused by various etiologies*, such as abnormal uterine bleeding, gastrointestinal diseases, cancer, bariatric procedures (gastric bypass surgery) and other conditions leading to significant blood loss;

2. TSAT <20%;

3. S-ferritin <100 ng/ml; And

4. Documented history of intolerance or lack of response to oral iron therapy** for at least one month*** prior to study entry.

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

For CKD-04.

Additional inclusion criteria for the CKD-04 study were as follows:

1. Chronic renal impairment, defined by either (i) eGFR <60 ml/min/1.73 ^m2 at screening (calculated by modification of diet for kidney disease (MDRD)) or (ii) eGFR <90 ml/min/ 1.73 ^m2 for screening and kidney injury, as indicated by a medical history of urine abnormalities and/or moderate/high risk of cardiovascular disease based on the Framingham model;

2. Screening for s-ferritin <100 ng/ml or <300 ng/ml if TSAT <30%; And

3. Either ESP or ESP at a stable dose (±20%) for 4 weeks before randomization.

The mean age of patients was 69 years (range 25-97), and 63% were women.

* The etiology (also if unknown) of IDA was documented in the medical history and confirmed in the original documents.

* *Intolerance and failure to respond to oral iron were documented with signs and symptoms in the medical history and confirmed in the original document.

* **Have had a documented report of intolerance or lack of response to at least one month of prescribed oral iron therapy as determined by the investigator within the past 9 months and will no longer be a candidate for oral iron.

A subject was not eligible for inclusion in this study if he/she met any of the following criteria:

1. Anemia, predominantly caused by factors other than IDA, as determined by the investigator.

2. Hemochromatosis or other iron storage disorders.

3. Previous serious hypersensitivity reactions to any intravenous iron compounds.

4. Treatment with intravenous iron during the last 30 days before screening.

5. Treatment with erythropoietin or erythropoietin-stimulating agents, red blood cell transfusion, radiation therapy and/or chemotherapy within the last 30 days before screening.

6. Planned surgical intervention during the study period.

7. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >3 times the upper limit of normal (eg, decompensated cirrhosis or active hepatitis).

8. Surgery under general anesthesia within the last 30 days before screening.

9. Decompensated liver cirrhosis or active hepatitis (CKD-04 only).

10. Dialysis required for the treatment of CKD.

11. Alcohol abuse or drug use within the last 6 months.

12. Pregnant or breastfeeding women. To avoid pregnancy, women of childbearing potential should use adequate contraception (eg, intrauterine devices, hormonal contraceptives, or double barrier method) throughout the study period and for 7 days after the last dose.

Treatment in study.

Subjects were dosed in one course of iron isomaltoside treatment (Group A) or one course of iron sucrose treatment (Group B), as described below.

Group A: Ferric isomaltoside was administered as a single intravenous infusion of 1000 mg at baseline, diluted in 100 ml 0.9% sodium chloride, and administered over approximately 20 minutes (50 mg iron/min, total dose: 1000 mg).

Group B: Iron sucrose was administered as a slow intravenous bolus injection of 200 mg according to the instructions for use and repeated up to 5 times to achieve a total dose of 1000 mg.

No premedication (eg, antihistamines or steroids) was allowed before study drug administration. If the subject received daily treatment, e.g.

- 35 046425 allergies or asthma, this was not considered premedication, and participation in the study could continue.

Statistical analyses.

The composite primary safety endpoint was analyzed by constructing an exact two-sided 95% CI for the incidence of serious and/or severe non-serious hypersensitivity AEs in the iron isomaltoside treatment group. If the upper limit of the 95% CI was <3%, the safety target was achieved.

In addition, the risk difference between ferrous isomaltoside and iron sucrose was assessed by constructing a 95% confidence interval for the risk difference. Both the unadjusted CI (continuity-corrected) and the 95% Newcomb CI adjusted for strata using the Cochran-Mantel-Haenszel method will be obtained.

Regarding sensitivity, treatment groups were compared between treatment groups using a logistic regression model with treatment and type of underlying disease as covariates and using Fisher's exact tests.

All subjects in the safety analysis group were included in the analysis.

The composite primary efficacy endpoint was analyzed using a restricted maximum likelihood (REML) mixed model for a repeated measures approach (MMRM). All subjects in the initial intention-to-treat (ITT) analysis group with hemoglobin data after the baseline assessment were required to be included along with observed data. The model included fixed, categorical effects of treatment (iron isomaltoside and iron sucrose), week, effect of week by treatment, strata, and continuous fixed covariates of baseline hemoglobin and baseline hemoglobin in each week. An unstructured (co)variance structure was used to model within-subject errors. If the results of this analysis unexpectedly do not converge, the following structures will need to be applied in the following order: first-order dependence on previous values, heterogeneous composite symmetry, composite symmetry. The Kenward-Roger approximation had to be used to estimate the degrees of freedom of the denominator. The main comparisons will be the differences between iron isomaltoside and iron sucrose at week 8 based on least squares means for the week by treatment effect. The estimated mean difference based on this model was presented with a two-sided symmetrical 95% CI, and if the lower bound of the 95% CI was >−0.5 g/dL, the efficacy target was achieved.

Evaluation of initial indicators.

During the baseline clinical visit at the study site, study staff assessed the following:

Inclusion and exclusion criteria were reviewed to confirm that no changes had occurred since screening.

Pregnancy test, where appropriate.

Record relevant medical history, including cases of myocardial infarction, stroke or chronic heart failure.

Registration of concomitant medications.

Objective examination (no later than the visit to assess baseline indicators).

Height measurement.

Weight measurement.

Study of basic physiological parameters.

Randomization.

ECG.

Fatigue assessment using the FACIT fatigue scale.

Pharmacoeconomics assessment using the ISDR questionnaire and the Health Care Resource Utilization Questionnaire.

Laboratory safety studies.

Laboratory studies of effectiveness.

Treatment with iron isomaltoside (group A only).

Treatment with iron sucrose (group B only).

AE assessment and registration.

Estimates in the study.

Estimates of demographic and other baseline indicators.

Information collected included date of birth, gender, race, ethnicity, and smoking behavior. A current smoker is defined as a subject who has smoked within the past 6 months.

Pregnancy test.

All women of childbearing potential underwent a urine pregnancy test. The test was administered and interpreted by research center staff.

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Relevant information about past illnesses.

Relevant information about past illnesses was recorded. Changes in medical history were recorded at subsequent study visits (worsening of symptoms or illness was recorded as AE). The following information was collected: disease and start and end dates. With the exception of the primary disorder causing IDA, onset dates >12 months before study entry were defined as >12 months.

Concomitant drug therapy.

If the subject was receiving any concomitant medication, this was recorded at the baseline visit. Changes in concomitant drug therapy were recorded at follow-up visits during the study. The following information was collected: trade name, indication, route of administration, dose, frequency, unit, and start and end date. Start dates >12 months prior to study inclusion were defined as >12 months.

Objective examination.

The objective examination was based on the investigator's judgment and may include the following:

Head-eyes-ear-nose-throat.

The cardiovascular system.

Respiratory system.

Nervous system.

Gastrointestinal system.

Musculoskeletal system.

Genitourinary system.

Dermatological system.

Other if required.

Height.

Height was measured without shoes.

Weight.

Weight was measured.

Basic physiological indicators.

Heart rate and blood pressure were measured at the following time points while the subject received study drug: approximately 0-10 minutes before the infusion, during the infusion, 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 value (including current systolic blood pressure and heart rate) for the period was noted in the electronic individual recording record (eCRF).

Electrocardiogram.

Standard 12-lead ECGs (including date, time, and signature) were recorded. At the baseline visit and other visits after the start of treatment, two ECGs were recorded - one before the administration of the study drug and approximately 30 minutes after the start of the dose. Only one ECG was recorded at follow-up visits after completion of treatment.

ECGs did not require evaluation by a cardiologist.

Laboratory research.

It was suggested that blood samples should be collected before study drug administration and, if possible, that they should be collected at the same time of day at all visits to reduce any diurnal variation in parameters.

Laboratory studies were carried out in the central laboratory. A laboratory manual containing all laboratory procedures was provided to each center.

Laboratory evaluations for inclusion in the study.

To study the possibility of inclusion in the study, the following laboratory parameters were assessed:

Complete blood count: hemoglobin, leukocytes, red blood cells, hematocrit, platelets, neutrophil granulocytes, lymphocytes, monocytes, eosinophils, basophils, mean erythrocyte hemoglobin, mean erythrocyte volume, mean erythrocyte hemoglobin concentration and reticulocyte count.

Biochemistry:

s-ferritin;

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

C-reactive protein (CRP).

Estimated glomerular filtration rate (eGFR).

Vitamin E.

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Vitamin E levels were measured at the baseline visit as part of the demographic data.

Laboratory safety assessments.

The following laboratory safety indicators were analyzed:

Complete blood count: hemoglobin, leukocytes, red blood cells, hematocrit, platelets, neutrophil granulocytes, lymphocytes, monocytes, eosinophils, basophils, mean erythrocyte hemoglobin, mean erythrocyte volume, mean erythrocyte hemoglobin concentration and reticulocyte count.

Biochemistry:

S-sodium, s-potassium, s-calcium, s-urea, s-creatinine, s-albumin,

S-bilirubin, AST, ALT,

SRB.

Laboratory assessments of performance indicators.

The following laboratory efficiency parameters were analyzed:

Hb: Hemoglobin was analyzed using a Coulter LH 750 system. Lytic reagents were used to measure CBC parameters to prepare the blood so that the system could measure the amount of hemoglobin. The lytic reagent quickly and simultaneously destroyed red blood cells and converted a significant part of the hemoglobin into a stable pigment. The optical absorption of the pigment is directly proportional to the hemoglobin concentration in the sample. The accuracy of this method is comparable to the accuracy of the cyanide method for hemoglobin analysis.

S-Ferritin: The Access Ferritin Assay was a two-step enzyme immunoassay (sandwich) assay. A goat anti-ferritin antibody-alkaline phosphatase conjugate sample and paramagnetic particles coated with goat anti-mouse immunoglobulin:mouse anti-ferritin antibody complexes were added to the reaction vessel. Serum or plasma ferritin (heparin) binds to immobilized monoclonal ferritin antibody on the solid phase, whereas goat anti-ferritin antibody conjugate reacts with other antigenic sites on ferritin molecules. Magnetic separation and washing remove materials not bound to the solid phase. Lumi-Phos* 530 chemiluminescent substrate was added to the reaction vessel and the light generated by the reaction was measured using a luminometer.

TSAT (s-iron and transferrin will be collected to calculate TSAT; TSAT=(iron μg/dL/transferrin mg/dL)*70.9).

S-iron: Serum iron (s-iron) was measured by calorimetric assay using a Roche automated clinical chemistry analyzer based on an immunoturbidimetric assay.

Adverse events (AE).

Data on AEs were collected and assessed for relationship to study drug, severity, severity, and predictability.

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

The total number of patients diagnosed with CVD risk according to their medical history was N=518 (N=345 in the IIM group; N=173 in the IS group). A total of N=226 patients (N=144 in the IIM group; N=82 in the IS group) were diagnosed at risk for cardiovascular disease and CHF according to their medical history. There were N=292 patients diagnosed with cardiovascular disease risk without CHF (N=144 in the IIM group; N=82 in the IS group). There were N=2748 patients without CHF (N=144 in the IIM group; N=82 in the IS group).

Totality CKD-04 IDA-03 CKD-04/IDA-03 Iron ISOmaltoZide Iron sucrose Iron ISOmaltoZide JellyZosaccharoZa FROM iron smaltozide JellyZosaccharoZa N% % N % N % N % N % All patients 1019 100.0 506 100, 0 989 100, 0 494 100.0 2008 100.0 1000 100.0 All patients with CHF 158 15.5 86 17.0 10 1.0 6 12 168 8.4 92 9, 2 All patients without CHF 061 84.5 420 83, 0 979 99.0 488 98.8 1840 91, 6 908 90.8 Patients at risk of CVD 319 31.3 160 31, 6 26 2.6 13 2.6 34 5 17.2 173 17.3 CVD risk: (Part} Stratification factor in studies: History of myocardial infarction, stroke, chronic heart failure (CHF) CHF: Patients with a medical history of chronic heart failure or

Results.

Key findings include the apparent effect of iron isomaltoside 1000 on treatment-emergent adverse events of chronic heart failure in patients at risk for cardiovascular adverse events.

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A total of 1525 patients were enrolled in the CKD-04 study and received isomaltoside 1000 or iron sucrose. 4.1% of 1019 patients treated with iron isomaltoside 1000 in the CKD-04 study had combined cardiovascular events, with an incidence of 6.9% in the iron sucrose group (506 patients).

A total of 1525 patients were enrolled in the IDA-03 study and received either isomaltoside 1000 or iron sucrose. 0.8% of 989 patients receiving iron isomaltoside 1000 and 1.2% of 494 patients receiving iron experienced combined cardiovascular events. In the pooled CKD-04/IDA-03 study, combined cardiovascular events were observed in 2.5% of 2008 patients receiving iron isomaltoside 1000 compared with 4.1% of patients receiving iron sucrose (p=0.0176), which resulted in a 60% reduction in combined cardiovascular events when treated with iron isomaltoside 1000. In each study, the incidence of chronic heart failure, hypertension, atrial fibrillation, hypotension, and cardiac arrest was lower in the iron isomaltoside 1000 treatment group compared with the iron sucrose treatment group. See figure 6.

The general patient population was divided into different patient subgroups: all patients, all patients with or without CHF, patients at CVD risk, and patients at CVD risk with or without CHF. In each patient group, the incidence of treatment-emergent adverse events of chronic heart failure was similar and in most cases was significantly lower with iron isomaltoside 1000 compared with iron sucrose treatment. See Figure 7. For example, in the pooled study CKD-04/IDA-03, 6.5% of all patients with CHF had post-treatment adverse events of chronic heart failure when treated with iron sucrose, while treatment with iron isomaltoside 1000 resulted in only 1 .8% of such adverse events in this group of patients. Worsening/exacerbation of heart failure occurred in 5.4% of cases with the use of iron sucrose in this group of patients, compared with only 1.8% with treatment with iron isomaltoside 1000. A similar significant reduction in adverse events of chronic heart failure that occurred after initiation of treatment was observed. In patients at risk for CVD, the incidence of chronic heart failure was 1.2% in the IIM treatment group and 3.5% in the IS treatment group, with worsening chronic heart failure observed in 1.2% in the IIM treatment group and 1.7% in the IIM treatment group. % in the IS treatment group. In patients at risk for CVD and with CHF, the incidence of chronic heart failure was 1.4% in the IIM treatment group and 4.9% in the IS treatment group, with worsening chronic heart failure observed in 1.4% in the IIM treatment group. and 3.7% in the IS treatment group. The significance of the results of this study is further illustrated in Figure 10, which provides an example of data from the CKD-04/IDA-03 combination study in the form of a bar graph.

Hazard ratios for treatment with iron isomaltoside 1000 compared with iron sucrose are shown in Figure 8. Hazard ratios <1 indicate the likelihood of an adverse event of chronic heart failure after initiation of treatment, which is lower for treatment with iron isomaltoside 1000 than for treatment with iron sucrose. See figure 9.

The likelihood that a patient (CKD-04) will be free of a combined adverse cardiovascular event is significantly higher after 8 weeks of treatment with iron isomaltoside 1000 than with iron sucrose. See figure 11.

In the pooled CKD-04/IDA-03 study (all patients), iron isomaltoside 1000 resulted in a greater increase in Hb compared to baseline at weeks 1 and 2 (p < 0.001), while non-inferiority of change in Hb was demonstrated compared to with baseline at weeks 4 and 8 (primary efficacy endpoint). See figure 12.

In fig. Figure 13 shows the change in ferritin (ng/mL) from baseline in patients with a history of CHF for the combined CKD-04/IDA-03 studies (iron isomaltoside 1000: dotted line, iron sucrose: solid line).

In fig. Figure 14 shows the change in TSAT (%) from baseline in patients with a history of CHF for the combined CKD-04/IDA-03 studies (iron isomaltoside 1000: dotted line, iron sucrose: solid line).

In fig. Figure 15 shows the percentage of patients who experienced treatment-emergent combined cardiovascular adverse events after treatment with IIM 1000, Venofer and FCM (combined CKD-04/IDA-03 studies for IIM 1000 (Ferwon studies); studies using Venofer and FCM based on FDA CDER Report on Injectafer).

Fig. 16 is a table summarizing the adverse event analysis results for the CKD-04 study, the IDA-03 study, and the combined CKD-04/IDA-03 studies using IIM 1000 (Ferwon studies) compared to the Venofer and FCM studies ( CDER FDA report on Injectafer).

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In summary, studies show that the incidence of cardiovascular adverse events is lower with iron isomaltoside 1000 compared to iron sucrose in CKD-04 and treatment.

In conclusion, studies have demonstrated that the incidence of cardiovascular adverse events is lower with iron isomaltoside 1000 compared with iron sucrose in CKD-04, as well as in the pooled analysis of CKD-04 and IDA-03 by composite endpoint of the cardiovascular system, as well as chronic heart failure in particular. In addition, the incidence of adverse cardiovascular events is lower with iron isomaltoside 1000 compared with iron sucrose and the numerical differences with iron sucrose are generally higher in subgroups of patients with CHF (history of CHF/CVD risk factor and CHF ). Compared with Venofer and FCM (CDER report), the incidence of the composite endpoint (and most subendpoints, including death from any cause) is lower with iron isomaltoside 1000 treatment.

Treatment with iron isomaltoside results in a higher increase in Hb from baseline to weeks 1 and 2 and a similar response at week 8 in patients with a history of chronic heart failure.

Example 2.

The study was conducted to determine the effect of iron on P wave dispersion.

This study was a post hoc analysis of a randomized, double-blind, placebo-controlled trial that was approved by the South and Central Berkshire Ethics Committee, the UK Medicines and Healthcare Products Authority and the Independent Research Governing Board of King's College Hospital. King's College London University and King's College Hospital NHS Foundation Trust were co-authors. King's Health Partners Clinical Research Office supervised the study and ensured adherence to International Conference on Harmonization Good Clinical Practice guidelines and the Declaration of Helsinki. Written informed consent was obtained from all patients. fig. 1 is a flow diagram of the study. This study included 25 patients with chronic heart failure in normal sinus rhythm, 15 of whom were randomized to intravenous sodium chloride placebo solution and 10 to intravenous ferric isomaltoside.

Patients with stable symptomatic chronic heart failure and left ventricular ejection fraction <45% were recruited from specialist heart failure clinics at King's College Hospital, London. The main exclusion criteria were a history of acquired iron overload, known hemochromatosis, or hemochromatosis in first-degree relatives; allergic disorder (eg asthma, eczema and anaphylactic reactions); previous hypersensitivity to intravenous iron preparations or the excipients contained in them; active infection, bleeding, malignancy, hemolytic anemia, rheumatoid arthritis and myelodysplasia; and HIV/AIDS.

After enrollment in the study, patients were assessed for endpoints that included a 12-lead body surface electrocardiogram to measure P wave dispersion (the difference between the maximum and minimum P wave duration in all leads), heart rate (HR), PR interval, QRS duration , QT interval and corrected QT interval (QTc). Figure 2 is an example of a surface electrocardiogram measuring P wave duration. An echocardiogram was also performed to measure LVEF, left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left atrial (LA) and right atrium (RA) volumes. ) with and without indication of body surface area. After baseline assessments, patients received an infusion of a full replacement dose of iron isomaltoside or an equivalent volume of placebo with saline. After 2 weeks, the final indicators were re-evaluated. Student's t test or Fisher's exact test was used statistically to evaluate baseline characteristics between groups. Analysis of covariance was used to statistically compare results for week 2 endpoints between groups, adjusting for baseline value of each variable.

Baseline characteristics of the 2 groups are shown in Fig. 3. The groups were well matched to these baseline characteristics. In fig. Figure 4 shows the effect of iron on each endpoint at 2 weeks using statistical analysis of covariance. At 2 weeks, iron treatment had no significant effect on any of the endpoints except P wave dispersion. Iron treatment significantly reduced P wave dispersion by 10 ms (adjusted between-group difference -10 ms, 95% CI -17 ms and - 3 msec, P=0.007) after 2 weeks. Iron supplementation continued to be associated with a significant reduction in P wave dispersion after

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Claims (16)

adjustments for atrial size using indexed LA and RA volumes (−11 msec, 95% CI −18 msec and −4 msec, P=0.005). In summary, these data indicate that iron supplementation was associated with a decrease in P wave dispersion, and a decrease in P wave dispersion is necessary for the prevention and treatment of AF. Equivalents: Those skilled in the art will know, or will be able to determine through no more than routine experimentation, many equivalents to the specific embodiments disclosed herein. Such equivalents are intended to be covered by the following claims. Non-patent publications 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 Rome 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. Jankowska EA, Kasztura M, Sokolski M, Bronisz M, Nawrocka S, Oles'kowska-Florek W, Zymlin'ski R, Biegus J, Siwolowski P, Banasiak W, Anker SD, Filippatos G, Cleland JGF, Ponikowski P. Iron deficiency defined as depleted iron stores accompanied by unmet cellular iron requirements identifies patients at the highest risk of death after an episode of acute heart failure. Eur Heart J 2014; 35:2468–2476. Ponikowski 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 Since 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/jjacc.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 2326 2019, New Orleans, Session OR13 - OR13. Rare Bone Diseases and Mineral Metabolism, abstract OR13-3. HILDEBRANDT, P. R., BRUUN, N. E., NIELSEN, O. W., PANTEV, E., SHIVA, F., VIDEBYK, L., WIKSTROM, G. and THOMSEN, L. L. (2010), Effects of administration of iron isomaltoside 1000 in patients with chronic heart failure. A pilot study. Transfusion Alternatives in Transfusion Medicine, 11: 131-137. doi: 10.1111/j.l778-428X.2010.01145.x Charles-Edwards G, Amaral N3, Sleigh A, Ayis S, Catibog N3, McDonagh T3, Monaghan M, AminYoussef 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 FERRICHF II SUBSTUDY. Journal of the American College of Cardiology Mar 2019, 73 (9 Supplement 1) 833; DOI: 10.1016/S0735-1097(19)31440-8 CLAIM 1. A method of reducing the incidence or risk of an adverse cardiovascular event in a subject having iron deficiency, wherein the method includes administering an effective amount of iron isomaltoside to the subject, wherein the subject is: (A) a subject who is at risk for an adverse cardiovascular event; (B) a subject who has a history of chronic heart failure (CHF); or - 41 046425 (C) by a subject who has a history of chronic heart failure (CHF) and is at risk for an adverse cardiovascular event, where the adverse cardiovascular event, the incidence or risk of which is reduced: (a) selected from the group consisting of chronic heart failure, myocardial infarction, unstable angina, arrhythmia, hypertension, hypotension, stroke and death; (b) is chronic heart failure; (c) is atrial fibrillation; (d) is arterial hypertension; or (e) is cardiac arrest. 2. The method of claim 1, wherein the subject is a subject at risk of experiencing a cardiovascular adverse event, wherein the cardiovascular adverse event of reduced incidence or risk is chronic heart failure. 3. The method of claim 1, wherein the subject is a subject at risk of experiencing a cardiovascular adverse event, wherein the cardiovascular adverse event of reduced incidence or risk is atrial fibrillation. 4. The method of claim 1, wherein the subject is a subject at risk of experiencing a cardiovascular adverse event, wherein the cardiovascular adverse event of reduced incidence or risk is cardiac arrest. 5. The method of claim 1, wherein the subject is a subject with a history of chronic heart failure, wherein the cardiovascular adverse event of reduced incidence or risk is cardiac arrest and/or chronic heart failure. 6. The method according to claim 1, where the subject is a subject with a history of chronic heart failure (CHF), and the adverse event from the cardiovascular system, the frequency or risk of which is reduced, is atrial fibrillation. 7. The method according to claim 1, where the subject is a subject with a history of chronic heart failure (CHF), and the adverse event from the cardiovascular system, the frequency or risk of which is reduced, is cardiac arrest. 8. The method according to any one of claims 1 to 7, wherein the subject is a subject at risk of an adverse event from the cardiovascular system and/or having a history of chronic heart failure, where the subject has chronic kidney disease (CKD). 9. The method according to any one of claims 1 to 7, wherein the subject is a subject at risk of an adverse event from the cardiovascular system and/or having chronic heart failure, where 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-dialysis chronic kidney disease (CKD-NTD). 11. The method according to any one of claims 1 or 5-10, wherein the subject with a history of chronic heart failure has HFrEF. 12. The method according to any one of claims 1 or 5-11, wherein the subject with a history of chronic heart failure has NYHA class II-IV chronic heart failure. 13. The method according to any one of claims 1 to 12, wherein the adverse event from the cardiovascular system, the frequency or risk of which is reduced, is cardiovascular death and/or hospitalization due to worsening chronic heart failure. 14. The method according to any one of claims 1 to 13, where iron deficiency is defined as TSAT <20% and/or ferritin <100 μg/L. 15. Method according to any one of claims 1 to 14, wherein iron isomaltoside is iron derisomaltose. 16. The method according to any one of claims 1 to 15, wherein the subject is also being treated with another agent used to treat or prevent adverse events from the cardiovascular system, including, but not limited to, chronic heart failure (CHF), cardiac arrest, myocardial infarction, unstable angina, arrhythmia, hypertension, hypotension, stroke and atrial fibrillation. -