KR20220027948A - Treatment of iron deficiency in subjects at risk of cardiovascular adverse events - Google Patents

Abstract

The present invention relates to the field of treatment of iron deficiency with an intravenous iron carbohydrate complex such as iron isomaltoside in a subject at risk for cardiovascular events, wherein the treatment of iron deficiency determines the incidence or risk of cardiovascular events in the subject. reduce

Description

Treatment of iron deficiency in subjects at risk of cardiovascular adverse events

The present invention relates to the field of treatment of iron deficiency with intravenous iron carbohydrate complexes in subjects at risk of cardiovascular adverse events.

Iron deficiency (ID) impairs the body's ability to produce hemoglobin, the primary oxygen carrier, and impairs the ability of primary energy (ATP) to produce enzymes. As a result, symptoms include fatigue and other signs of a lack of energy, such as rapid heartbeat, shortness of breath, and chest pain.

Iron-deficiency anemia (IDA) occurs when iron stores are depleted. This is widespread. According to the WHO, about 1 billion people worldwide suffer from IDA. Daily oral iron is the first-line therapy for most IDA patients, but often fails due to lack of compliance, lack of efficacy, and side effects.

High-dose intravenous (IV) iron is an attractive treatment option. Patients typically require 1-3 g of iron per year, and high doses of intravenous iron provide effective and rapid symptomatic improvement and increased hemoglobin levels. High-dose intravenous iron can be treated in one or several visits, and intravenous iron is the only option for patients who have failed oral iron.

Iron isomaltoside 1000 (INN: ferric derisomaltose) belongs to the next generation of high-dose intravenous iron products. Older low-dose products (ferric gluconate and iron sucrose) required 5-20 visits, but this new generation of products allows iron correction in 1-2 visits due to the rapid infusion of the product. possible.

Iron isomaltoside is indicated for use in (i) patients with IDA who are hypersensitive to oral iron or have an unsatisfactory response to oral iron, or when there is a clinical need for rapid replenishment of iron stores; or (ii) persons with non-hemodialysis dependent chronic kidney disease (NDD-CKD); or an iron carbohydrate complex commonly used to treat ID in 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 treatment regimen for iron isomaltoside is a single infusion of 1000 mg iron as a single infusion of 1000 mg iron or as a cumulative iron requirement determined using the Ganzoni formula or the following table, or up to 20 mg iron/kg body weight given as an intravenous infusion. of elemental iron is administered as an intravenous infusion or consists of an intravenous bolus injection of up to 500 mg up to 3 times per week.

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. An increased risk of death or hospitalization has been reported in patients with ID compared to patients with normal iron status in patients with chronic heart failure (CHF). Quality of life (QoL) is severely affected and improves rapidly once stored iron is restored. For example, in 20 frail geriatric CHF patients with an open-label, uncontrolled design and rather small sample size, a single rapid intravenous infusion of iron isomaltoside 1000 without a relatively high dose and no initial test dose was very well tolerated and improved quality of life measures. Hildebrandt et al ., 2010.

The experimental and clinical evidence collected provided the basis for considering ID as a potential treatment target for patients with chronic heart failure (chronic HF). Indeed, in recent years the FAIR-HF trial (evaluation of ferric carboxymaltose in patients with iron deficiency and chronic heart failure, Anker et al ., 2009) and CONFIRM-HF, including >450 and >300 patients, respectively, in recent years) and CONFIRM-HF Several studies, including trials (Evaluation of ferric carboxymaltose on performance in patients with iron deficiency with chronic heart failure, see Ponikowski et al ., 2015), have investigated the effect of intravenous iron therapy in iron-deficiency patients with chronic heart failure. investigated. Based on a comprehensive data meta-analysis of five randomized controlled trials evaluating the effect of intravenous iron therapy (using iron sucrose or ferric carboxymaltose) in iron-deficiency patients with systolic HF (HFrEF), Jankowska et al . al ., 2016 report that there is evidence that intravenous iron therapy in iron-deficiency patients with systolic heart failure improves outcomes, alleviates symptoms of heart failure, improves exercise capacity and quality of life, and reduces the risk of hospitalization for heart failure. However, the number of deaths and the incidence of adverse events (AEs) were similar in the five meta-analyzed studies.

Also, from a mechanical point of view, attempts have been made to explore how iron supplementation provides a benefit to CHF, especially when Hb changes are minimal. For example, in a randomized, double-blind, placebo-controlled trial, a single total-dose infusion of iron isomaltoside 1000 was shown to replenish stored iron and increase skeletal muscle energy 2 weeks after infusion. Charles-Edwards et al ., 2019. Based on data from the same randomized double-blind trial, a single total-dose infusion of iron isomaltoside 1000 in iron-deficient CHF patients with a left ventricular ejection fraction LVEF ≤ 45%. It was observed that iron supplementation attenuated P-wave dispersion. Jaumdally et al ., 2019.

However, none of the intravenous iron trials tested the effect on major cardiovascular outcomes. Therefore, the 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure concluded that the efficacy of iron deficiency treatment in HFpEF/HFmrEF is unknown. Based on the results of FAIR-HF and CONFIRM-HF, according to the European Society of Cardiology (ESC) guidelines, patients with iron deficiency (serum ferritin < 100 μg/L or ferritin 100-299 μg/L and transferrin saturation < 20 %) recommend that intravenous ferric carboxymaltose be considered for alleviating HF symptoms and improving athletic performance and quality of life. Ponikowski et al ., 2016. Likewise, the American College of Cardiology (ACC), the American Heart Association (AHA) Clinical Practice Guidelines Task Force, and the Heart Failure Society of America (HSFA) New York Heart Association, NYHA) In patients with class II and III HF and iron deficiency (100-300 ng/mL for ferritin < 100 ng/mL or transferrin saturation < 20%), intravenous iron replacement may be reasonable to improve functional status and quality of life. It is recommended that there is Yancy et al ., 2017.

Based on this understanding, there is clearly a need to provide a method of treating iron deficiency that provides benefits as well as supplementation of sufficient stored iron to patients with respect to the management of chronic heart failure.

In one aspect of the invention, iron deficiency is treated in a subject at risk for cardiovascular events. Thus, the criteria commonly used to define eligibility for parenteral iron, i.e., the diagnosis of ID or IDA, and/or the criteria commonly used to define a potential deficiency in the ability to tolerate or absorb oral iron, as well as cardiovascular Subjects are selected for treatment with iron isomaltoside based on the risk of experiencing an adverse event.

In a second aspect of the invention, the treatment of iron deficiency reduces the incidence or risk of cardiovascular adverse events in the subject. Thus, according to the criteria commonly used to define eligibility for parenteral iron, i.e., the diagnosis of ID or IDA, and/or the criteria commonly used to define a potential deficiency in the ability to tolerate or absorb oral iron, cardiovascular A subject is selected for treatment with iron isomaltoside based on benefit from a reduction in the risk of experiencing an adverse event, the incidence of, or risk for, a cardiovascular event in the subject.

In a third aspect of the present invention, it relates to treating a particular group of subjects as defined herein for reducing the incidence or risk of cardiovascular adverse events as defined herein.

According to this aspect, the present invention provides, inter alia, a method of treating iron deficiency comprising administering iron isomaltoside to a selected subgroup of subjects; and to the combination of iron isomaltoside 1000 with other drugs used to treat or increase the risk of cardiovascular events in subjects at risk.

In one embodiment of the first aspect, the present invention is directed to a method of treating iron deficiency in a subject at risk of cardiovascular events comprising administering an effective amount of iron isomaltoside.

In many embodiments of the first aspect, the subject at risk of a cardiovascular event is a subject having one or more of the following risk factors:

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

(ii) subjects with a history of stroke;

(iii) subjects with a history of atrial fibrillation (AF), particularly initially diagnosed AF, proximity AF, or persistent AF;

(iv) subjects with a history of congestive heart failure, particularly heart failure with decreased ejection fraction (HFrEF);

(v) subjects with a history of heart valve disorders;

(vi) subjects with a history of hypertension;

(vii) subjects with diabetes;

(viii) subjects with a history of obesity;

(ix) geriatric subjects, particularly subjects aged 60 years or older, 65 years old or older, 70 years old or older, 75 years old or older, or 80 years old or older;

(x) smokers;

(xi) drinkers;

(xii) subjects with hyperthyroidism and/or thyrotoxicosis associated therewith;

(xiii) subjects with chronic obstructive pulmonary disorder (COPD);

(xiv) subjects with cardiomyopathy, particularly hereditary cardiomyopathy or acquired cardiomyopathy;

(xv) subjects with systemic inflammation in the absence of infection, wherein systemic inflammation is particularly associated with elevated C-reactive protein (CRP) beyond the range of about 2-3 mg/L;

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

(xvii) Subjects treated with one or more of the following:

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

b) erythropoiesis stimulants such as erythropoietin (Epo), epoetin alpha (Procrit/Epogen), epoetin beta (NeoRecormon), darbepoetin alfa (Aranesp) and methoxy polyethylene glycol-epoetin beta (Mircera) ( erythropoiesis-stimulating agents, ESA); and

c) hepcidin modulators such as hepcidin agonists or hepcidin antagonists;

(xviii) subjects treated with anticoagulants and/or NSAIDs;

(xix) subjects with hereditary hemorrhagic telangiectasia; or

(xx) Subjects with hereditary iron refractory iron deficiency anemia.

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

In a further specific embodiment of the first aspect, the subject at risk for cardiovascular events or with a history of congestive heart failure has chronic kidney disease (CKD). In another specific embodiment of the first aspect, the subject at risk for cardiovascular events or a history of congestive heart failure does not have chronic kidney disease (CKD). In another specific embodiment of the first aspect, the subject at risk for cardiovascular events is a subject with a history of chronic kidney disease (CKD) and congestive heart failure (CHF).

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

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

In an embodiment of the second aspect, the cardiovascular adverse event with reduced incidence or risk is a reaction affecting the heart (cardiac adverse event); reactions affecting the peripheral vasculature (peripheral vascular adverse events); reactions affecting the cerebral vasculature (cerebrovascular adverse events); respiratory, thoracic and mediastinal adverse events; common adverse reactions; and infections and infestations. According to one embodiment, the cardiac adverse event is congestive heart failure, atrial fibrillation, heart attack, atrioventricular block, heart failure, sinus node dysfunction, acute myocardial infarction, bradycardia, angina pectoris, myocardial ischemia and ventricular extrasystoles consisting of selected from the group; the peripheral vascular adverse event is selected from the group consisting of hypertension, increased systolic blood pressure, increased blood pressure, increased troponin and hypotension; the cerebrovascular adverse event is selected from the group consisting of cerebrovascular accident, cerebral infarction and transient ischemic attack; Respiratory, thoracic and mediastinal adverse events are selected from the group consisting of dyspnea and pulmonary edema; Common adverse events are selected from the group consisting of chest pain and death, and infections and invasions are septic shock.

In a preferred embodiment of this second aspect of the present invention, the cardiovascular adverse events with reduced incidence or risk include reactions affecting the heart (cardiac adverse events); reactions affecting the peripheral vasculature (peripheral vascular adverse events); reactions affecting the cerebral vasculature (cerebrovascular adverse events); and death. According to a preferred embodiment, the reactions affecting the heart (cardiac adverse events) are congestive heart failure, myocardial infarction, unstable angina and arrhythmia; A reaction affecting the peripheral vascular system (peripheral vascular adverse event) is hypertension; A reaction affecting brain vasculature (cerebrovascular adverse event) is a stroke.

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

In a further particularly preferred embodiment of this second aspect of the invention, the cardiovascular adverse event with reduced incidence or risk is congestive heart failure, atrial fibrillation, hypertension and/or heart attack.

In one embodiment, the specific cardiovascular adverse event associated with congestive heart failure is hospitalization or death due to congestive heart failure. In one embodiment, the specific cardiovascular adverse event associated with congestive heart failure is hospitalization for exacerbation of congestive heart failure. The present invention particularly relates to a CV adverse event wherein the CV adverse event is CHF.

In an embodiment of the third aspect, the present invention is a method of treating iron deficiency in a subject, wherein the incidence or risk of cardiovascular events is reduced in the subject, wherein the treatment of iron deficiency comprises: the incidence of or cardiovascular events in the subject; To reduce the risk, the method comprises administering an effective amount of iron isomaltoside.

wherein the subject is:

(A) subjects at risk of cardiovascular events;

(B) subjects with a history of congestive heart failure (CHF); or

(C) subjects with a history of congestive heart failure (CHF) and at risk for cardiovascular events; and

wherein cardiovascular adverse events with reduced incidence or risk are:

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

(b) congestive heart failure;

(c) atrial fibrillation;

(d) hypertension; or

(e) heart attack.

In a preferred embodiment of this third aspect of the invention, the subject is a subject at risk for a cardiovascular event, and the cardiovascular event with a reduced incidence or risk is congestive heart failure.

In a further preferred embodiment of this third aspect of the invention, the subject is a subject at risk for a cardiovascular event, and the cardiovascular event with a reduced incidence or risk is atrial fibrillation.

In a further preferred embodiment of this third aspect of the invention, the subject is at risk for a cardiovascular event, and the cardiovascular event with a reduced incidence or risk is heart attack.

In a further preferred embodiment of this third aspect of the invention, the subject is a subject with a history of congestive heart failure and cardiovascular adverse events, and the cardiovascular adverse event with reduced incidence or risk is heart attack or congestive heart failure or both. .

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

In a further preferred embodiment of this third aspect of the invention, the subject is a subject with a history of congestive heart failure (CHF) and the cardiovascular adverse event with reduced incidence or risk is heart attack.

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

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

In these embodiments, the chronic kidney disease (CKD) is preferably non-dialysis dependent chronic kidney disease (NDD-CKD).

In another preferred embodiment of this third aspect of the invention, the subject with a history of congestive heart failure has HFrEF, NYHA class II-IV congestive heart failure, or both.

In a particularly preferred embodiment of this third aspect of the invention, the cardiovascular adverse event with reduced incidence or risk is cardiovascular death and/or hospitalization for exacerbation of congestive heart failure.

According to the present 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 a further embodiment of the invention, the subject to be treated has chronic iron loss or malabsorption. In a further embodiment of the above first aspect, the subject is intolerant to oral iron or for which oral iron is ineffective.

A preferred iron carbohydrate complex for use in the present invention is iron isomaltoside, particularly ferric deisomaltose (sometimes referred to as ferric deisomaltoside).

1 is an analysis of the incidence of adjudicated and confirmed treatment-emergent combined cardiovascular (CV) adverse events with an incidence ≥ 25% by referral period for Study CKD-04, Study IDA-03, and Combination Study CKD-04/IDA-03. This is a summary table.
2 shows all patients; patients with or without CHF; Or a table summarizing the analysis of treatment-emergent congestive heart failure adverse events for study CKD-04, study IDA-04, and combination study CKD-04/IDA-03 in patients at risk for CV.
FIG. 3 shows treatment-emergent congestive heart failure for study CKD-04 and combination study CKD-04/IDA-03 comparing iron isomaltoside treatment with iron sucrose treatment in patients at risk of CV with or without CHF in the history. This table summarizes the analysis of adverse events (logistic regression).
Figure 4 shows the proportion of patients who experienced specific treatment-emergent combined CV adverse events (iron isomaltoside 1000: left bar, iron sucrose: right bar).
Figure 5 shows the proportion of patients who experienced treatment-emergent CHF adverse events (CKD-04 and IDA-03 combination, iron isomaltoside 1000: left bar, iron sucrose: right bar).
6 shows a Kaplan-Meier diagram for the probability of adjudicated complex cardiovascular adverse events (CKD-04).
7 shows the change from baseline in hemoglobin (g/dL) by CHF patients in the history for the combination study CKD-04/IDA-03 (iron isomaltoside 1000: dashed line, iron sucrose: solid line).
8 shows the change from baseline in ferritin (ng/mL) by CHF patients in the history for the combination study CKD-04/IDA-03 (iron isomaltoside 1000: dashed line, iron sucrose: solid line).
9 shows the change from baseline in TSAT (%) by CHF patients in the history for the combination study CKD-04/IDA-03 (iron isomaltoside 1000: dashed line, iron sucrose: solid line).
Figure 10 shows treatment after treatment with IIM 1000, Venofer and FCM (Combined Study CKD-04/IDA-03 Study on IIM 1000 (Ferwon Study); Study with Venofer and FCM based on Injectafer FDA CDER Report) It represents the proportion of patients who experienced an emergency complex CHF adverse event.
11 is an adverse reaction analysis for the combined study CKD-04/IDA-03 with CKD-04, studies IDA-03 and IIM 1000 (Ferwon study) compared to studies with Venofer and FCM (Injectafer FDA CDER report). This is a summary table.

In order to facilitate understanding of the present specification, certain terms are first defined. Additional definitions are set forth throughout the detailed description.

"Treatment" or "therapy" of a subject is for the purpose of reversing, alleviating, ameliorating, suppressing, slowing down, or preventing the onset, progression, development, severity or recurrence of symptoms, complications, conditions, or biochemical signs associated with a disease. Any type of intervention or procedure performed or administration of an active agent is meant.

A “subject” includes a human or non-human animal. The term "non-human animal" includes, but is not limited to, non-human primates, vertebrates such as sheep and dogs, and rodents such as mice, rats and guinea pigs. In a preferred embodiment, the subject is a human. The terms “subject” and “patient” are used interchangeably herein.

A "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent, when used alone or in combination with another therapeutic agent, is used to protect a subject from the onset of a disease or reduce the severity of symptoms of a disease; Any amount of a drug that promotes disease regression as evidenced by an increase in the frequency and duration of disease asymptomatic periods, or prevention of damage or disability resulting from disease affliction. A therapeutic agent's ability to promote disease regression can be determined using a variety of methods known to the skilled artisan, for example, by assaying the activity of the agent in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or in in vitro assays. can be evaluated using

For the purposes of this text, consistent with literature practice, when specifying a dose in mg or g of an iron carbohydrate complex, the value indicates the amount of elemental iron given in mg or g.

A. Iron Carbohydrate Complex

Described herein are methods of treatment for treating iron deficiency comprising administering an iron carbohydrate complex, and a combination of an iron carbohydrate complex and an additional drug, wherein the iron carbohydrate complex has certain properties and thus has a particular effect in the subject being treated. to perform Thus, the method of the present invention is applicable to complexes that share a mechanism of action. For example, iron carbohydrate complexes should not induce a significant increase in iFGF23 (intact FGF23). In particular, while ferric carboxymaltose (FCM) significantly increases iFGF23 (see, for example, WO 2013/134273 A1), clinical trial results show that the risk of increasing iFGF23 to induce an iFGF23-mediated effect is higher in iron isomaltoside 1000. It provides evidence that it is low (Monofer®). See, for example, Wolf et al ., 2019.

Accordingly, a preferred iron carbohydrate complex of the present invention is iron isomaltoside (IIM). As used herein, the term "iron isomaltoside" refers to colloidal complexes comprising iron, such as iron oxide hydroxide and isomaltosides, in matrix-like structures. As used herein, the term "isomaltoside" refers to a hydrogenated oligoisomaltoside (oligoisomaltoside).

In a specific embodiment, the isomaltoside is a mixture of hydrogenated poly-/oligosaccharides having a weight average molecular weight MW of 500 to 7,000 Da, such as 500 to 3,000 Da, 700 to 1,400 Da, in particular about 1,000 Da. The number average molecular weight (M _n ) of these hydrogenated poly-/oligosaccharides is preferably in the range from 400 to 1,400 Da, 90% by weight of these molecules having a molecular weight of less than 3,500 Da, in particular less than 2,700 Da, and the remainder of the molecule The molecular weight of 10% is less than 4,500 Da, in particular less than 3,200 Da. For example, the hydrogenated poly-/oligosaccharide may be hydrogenated polyglucose, oligoglucose or mixtures thereof, such as hydrogenated dextran, hydrogenated dextrin or hydrogenated oligoisomaltose (oligoisomaltoside) or a mixture thereof. mixtures, and hydrogenated oligoisomaltose, in particular hydrogenated oligoisomaltose, wherein the majority of the molecule (eg at least 60%, eg 70-80%) preferably has 3-6 monosaccharide units . Thus, in a preferred embodiment of the present invention, the iron carbohydrate complex is an iron hydrogenated oligoisomaltose, in particular an iron(III) hydrogenated oligoisomaltose, wherein the majority (eg at least 60%, for example 70 to 80%) oligoisomaltoside molecule has 3-6 monosaccharide units like iron(III) isomaltose 1000 (INN name: ferric derisomaltose). Iron isomaltosides are typically characterized by strong colloidal complexes of iron oxide-iron hydroxide and hydrogenated isomaltose (isomaltoside) chains, resulting in a gradual release of iron.

In certain embodiments described above, the content of dimer sugars 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, based on the total weight of the hydrogenated poly-/oligosaccharide. , in particular not more than 2.1% by weight or not more than 1.5% by weight, most preferably not more than 1.0% by weight. Preferably, the preparation of hydrogenated poly-/oligosaccharide used in the preparation of the iron carbohydrate complex of the present invention has a monomeric saccharide content of 0.5% by weight or less. The iron hydrogenated dextran complexes prepared from these hydrogenated poly-/oligosaccharide formulations typically have an apparent molecular weight (M _p ) in the range of 120,000 to 180,000 Da, in particular 130,000 to 160,000 Da. Prior to contacting the hydrogenated poly-/oligosaccharide preparation with the iron preparation, the preparation may be purified by a membrane process to remove high molecular weight hydrogenated polysaccharides and/or low molecular weight hydrogenated oligosaccharides. In certain examples, the hydrogenated poly-/oligosaccharide formulations were purified by one or more membrane processes having cutoff values of 340 to 800 Da. In an even more specific embodiment, the hydrogenated poly-/oligosaccharide preparation is purified by one or more membrane processes using a membrane having a cutoff value capable of inhibiting polysaccharides having a molecular weight greater than 2,700 Da, optionally subject to further hydrolysis This is followed by one or more membrane processes using membranes with cutoff values between 340 and 800 Da. Alternatively, purification by the membrane process takes place prior to hydrogenation.

In a particularly preferred embodiment, the iron isomaltoside of the present invention is a compound having the formula:

{FeO _(1-3X) (OH) _(1+3X) (C ₆ H ₅ O ₇ ^3- ) _X }, (C ₆ H ₁₀ O ₆ ) _R (-C ₆ H ₁₀ O) containing H ₂ O ₅ -) _Z (C ₆ H ₁₃ O ₅ ) _R , (MeCl) _Y , 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 0.4900±0.0735;

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

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

In a further particularly preferred embodiment, the iron complex compound of the present invention is a compound having the formula:

{FeO _(1-3X) (OH) _(1+3X) (C ₆ H ₅ O ₇ ^3- ) _X }, (H ₂ O) _T , (C ₆ H ₁₀ O ₆ ) _R (-C ₆ H ₁₀ O ₅ -) _Z (C ₆ H ₁₃ O ₅ ) _R , (MeCl) _Y , where

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

T is 0.2500±0.1250, in particular 0.2500±0.24750;

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

Z is 0.4900±0.1470, in particular 0.4900±0.0735;

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

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

In certain embodiments, the iron complex is in the form of an injectable solution having an iron content (determined on dry matter) of 23 to 39% by weight and optionally about 100 mg/ml.

Iron isomaltoside can be obtained, for example, as described in WO 2010/108493 A1 and WO 2019/048674 A1. Preferred examples of iron isomaltoside are commercially available in many countries under the trade names Monofer®, Monoferric® or Diafer®.

Another specific iron carbohydrate complex for use in the present invention is ferric bepectate (FBP). The term “befectate ferric,” as used herein, refers to a colloidal complex comprising an iron core, eg, iron oxide hydroxide, coated with a hydroxyethyl-amylopectin derivative. Befectate ferric is also referred to as polyglucoferron. Befectate ferric and its preparation are disclosed. For example, in WO 2012175608 A1, hydroxyethyl starch is simply dissolved in water. After that, the pH value is adjusted to 8.0 to 10.0. Then, cyanide is added to the hydroxyethyl starch solution to make a solution. It is then heated to a temperature of 80 to 99° C. and maintained at this temperature for the first period. Finally, the pH value is adjusted to a value between 2.0 and 4.0 and the solution is brought to a temperature of 50 to 90° C. and maintained at this temperature for a second period. The starch produced by this method is characterized in that at least one of the ends has a heptonic acid residue. Thus, such starches can have multiple heptonic acid residues per molecule, depending on the number of terminal glucosyl residues present in the starch molecule. This heptonic acid residue increases the hydrophilicity of hydroxyethyl starch and increases the stability of the complex formed by this hydroxyethyl starch and a ligand, for example a metal ion such as an iron ion. More generally speaking, hydroxyethyl starch (HES) is a starch in which some of the hydroxyl groups of a single glucosyl moiety are replaced with hydroxyethyl moieties. Modification with heptonic acid residues occurs by converting the terminal glucosyl residues of hydroxyethyl starch to heptonic acid residues. Preferably, the hydroxyethyl starch used in the process is 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 very particularly 75,000 have a weight average molecular weight (Mw) of less than g/mol. A very suitable molecular weight is in the range from 55,000 g/mol to 85,000 g/mol. This hydroxyethyl starch has a relatively low molecular weight compared to the (unmodified) hydroxyethyl starch 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 molar substitution of from 0.4 to 0.6, in particular from 0.45 to 0.55. An average degree of molar substitution of about 0.50 is particularly preferred. Average molar substitution is a measure of the amount of hydroxyl groups substituted for hydroxyethyl residues per glucosyl residue. Since each glucose unit (or glucosyl moiety) has three hydroxyl groups, the average molar substitution can be up to three. An average molar substitution of 0.5 indicates that (on average or statistical basis) one hydroxyl group at each second glucosyl residue has been replaced by a hydroxyethyl residue. In a preferred embodiment, the hydroxyethyl starch has a weight average molecular weight of 55,000 to 85,000 g/mol, preferably about 70,000 g/mol and an average molar substitution degree of 0.45 to 0.55, in particular about 0.50. This hydroxyethyl starch having a molecular weight of 70,000 g/mol to 15,000 g/mol and an average molar substitution degree of 0.5 to 0.05 may also be referred to as HES 70/0.5. A process for the preparation of this heptonic acid-modified hydroxyethyl starch, HES 70/0.5 is described in WO 2019/048674 A1 for the formation of iron complexes in Examples 1 and 2, all of which are incorporated by reference.

Iron isomaltoside is a preferred iron carbohydrate complex for use in accordance with the present invention.

B. Treatment method

A method of treatment for treating iron deficiency is described, which comprises administering iron isomaltoside to a selected subgroup of subjects and/or according to a defined dosing regimen. Accordingly, the present invention also relates to iron isomaltoside for use in said method, 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. TREATMENT SUBJECT

The methods of the present invention are generally performed on a subject in need thereof. A subject in need of a method of the present invention is one with, diagnosed with, suspected of having, or at risk of developing iron deficiency. Iron deficiency anemia (IDA) occurs when iron stores are depleted. A subject suffering from ID may have IDA. A subject with IDA necessarily suffers from ID. Methods for diagnosing ID and IDA are well established in the art and commonly used in clinical practice. If oral iron is not tolerated or effective in a subject, i.e., a subject who is intolerant to oral iron or has an unsatisfactory response to oral iron, has, has been diagnosed with, is suspected of having, or is at risk of developing iron deficiency. The subject will be given iron in the form of an iron carbohydrate complex, ie iron isomaltoside according to the present invention, parenterally, in particular intravenously. Another situation where intravenous iron is needed as indicated is when there is a need for rapid iron delivery when the clinical need for rapid replenishment of stored iron is necessary.

iron deficiency and anemia

storage iron parameters

Subjects with iron deficiency may exhibit low or inadequate markers of systemic iron status. This means that such subjects may not have enough iron stores in their body to maintain adequate iron levels. Nutrient-rich and healthy people living in industrialized countries store about 4-5 g of iron in their body. About 2.5 g of this iron is contained in hemoglobin, which carries oxygen through the blood. Most of the remaining about 1.5–2.5 g of iron is contained in iron-binding complexes present in all cells, but is more concentrated in bone marrow and organs such as the liver and spleen. The liver's iron stores are the main physiological iron stores of a healthy body. About 400 mg of the body's total iron content is used for proteins that use iron in cellular processes, such as storing oxygen (myoglobin) or performing energy-producing redox reactions (cytochrome proteins). In addition to stored iron, small amounts of iron, typically about 3-4 mg, circulate through plasma bound to a protein called transferrin.

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

People with iron deficiency first deplete the iron stored in the body. Iron deficiency anemia is a major clinical symptom of iron deficiency because most of the iron used by the body is required for hemoglobin. Oxygen transport to tissues, including organs, is essential, and severe anemia is harmful and potentially fatal due to systemic oxygen deprivation. Iron-deficient subjects suffer organ damage and in some cases die from oxygen depletion long before the iron needed for cellular processes is depleted.

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

This blood parameter is determined in serum but can likewise be determined in plasma. Serum and plasma levels are correlated and can be switched.

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

In one embodiment, the at least one iron storage parameter is a hemoglobin concentration, and the improvement comprises increasing the hemoglobin concentration of the subject. In another embodiment, the at least one iron storage parameter is transferrin saturation, and improving comprises increasing transferrin saturation in the subject. In another embodiment, the at least one iron storage parameter is serum ferritin level, and the improvement comprises increasing the serum ferritin level in the subject.

Serum ferritin

Ferritin stored in the liver is the main source of iron stored in the body. Ferritin is an intracellular protein that stores and releases iron in a controlled manner. Medically, the amount of ferritin present in blood samples and/or liver tissue samples reflects the amount of iron stored in the liver (although ferritin is ubiquitous and can be found in many other tissues of the body besides the liver). Ferritin is responsible for storing iron in the liver in a non-toxic form and transporting it to the site where it is needed. Normal ferritin serum levels (sometimes referred to as reference intervals) in healthy subjects are typically 30-300 ng/ml for men and 15-200 ng/ml for women. Normal ferritin serum levels are generally greater than 100 ng/mL in patients at risk for cardiovascular events. However, in iron-deficiency patients, serum ferritin levels generally decrease significantly as the amount of iron that can be stored in the liver by binding to ferritin decreases, which occurs as the body loses its ability to absorb and store iron.

As used herein, the term “serum ferritin” ( s -ferritin) refers to the level of ferritin in serum measured using a two-site immunoenzyme (“sandwich”) assay. Ferritin is the body's main iron storage protein. Since the concentration of ferritin is directly proportional to the body's total iron stores, serum ferritin levels are a common diagnostic tool to assess iron status. Subjects with iron deficiency anemia have serum ferritin levels about one-tenth that of normal subjects, whereas subjects with iron overload (hemochromatosis, hemosiderosis) have much higher than normal serum ferritin levels. Ferritin levels also provide a sensitive means of detecting iron deficiency at an early stage. In both adults and children, chronic inflammation disproportionately increases ferritin levels in relation to iron retention. Elevated ferritin levels are also observed in acute and chronic liver disease, chronic renal failure and some types of neoplastic disease.

In some embodiments, a subject treated according to the methods disclosed herein experiences an increase in serum ferritin levels. In some embodiments, the present disclosure provides a method of increasing serum ferritin in a subject in need thereof, the method comprising administering to the subject iron isomaltoside, wherein the iron isomaltoside is a level of serum ferritin. provides an increase.

In some embodiments, the iron isomaltoside 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 at 4 or 8 weeks post treatment. provides a mean increase in serum ferritin greater than /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.

In some embodiments, the iron isomaltoside is less than 400 ng/mL, less than 390 ng/mL, less than 380 ng/mL, less than 370 ng/mL, less than 360 ng/mL, 350 ng at 4 or 8 weeks post treatment. </mL, <340 ng/mL, <330 ng/mL, <320 ng/mL, <310 ng/mL, <300 ng/mL, <290 ng/mL/mL, <280 ng/mL, 270 ng provide a mean increase in serum ferritin selected from less than /mL, less than 260 ng/mL, or less than 250 ng/mL.

In some embodiments, iron isomaltoside is 100 - 400 ng/mL, 100 - 375 ng/mL, 100 - 350 ng/mL, 100 - 325 ng/mL, 100 - 300 ng at 4 or 8 weeks post treatment. /mL, 100 - 275 ng/mL, or 150 - 300 ng/mL of mean increase in serum ferritin.

In some embodiments, the iron isomaltoside 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 at one week post treatment. , greater than 380 ng/mL, greater than 410 ng/mL, or greater than 440 ng/mL of serum ferritin.

In some embodiments, the iron isomaltoside is 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 at one week after treatment. , <540 ng/mL, <530 ng/mL, <520 ng/mL, <510 ng/mL, <500 ng/mL, <490 ng/mL, <480 ng/mL, <470 ng/mL, 460 provides a mean increase in serum ferritin selected from less than ng/mL or less than 450 ng/mL

In some embodiments, iron isomaltoside is administered at 200 - 600 ng/mL, 250 - 600 ng/mL, 300 - 600 ng/mL, 350 - 600 ng/mL, or 400 - 600 ng/mL after one week of treatment. Provides an average increase in serum ferritin.

Transferrin Saturation (TSAT)

In addition to stored iron, small amounts of iron (typically about 3 to 4 mg) circulate through the plasma bound to a protein called transferrin. Therefore, serum iron ( s -iron) levels can be expressed as the amount of iron that is bound to the protein transferrin and circulates in the blood. Transferrin is a glycoprotein produced by the liver that can bind one or two ferric (iron(III) or Fe ³⁺ ) ions. It is the most prevalent and dynamic iron carrier in the blood and is therefore an essential component of the body's ability to transport stored iron for use throughout the body. Transferrin saturation (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 available to bind iron. For example, a TSAT value of 35% means that 35% of the iron binding sites of transferrin available in the blood sample are filled with iron. Typical TSAT values for healthy subjects are about 15-50% for men and 12-45% for women. Normal TSAT values are generally greater than 20% in patients at risk for cardiovascular events. However, in iron-deficiency patients, TSAT values decrease significantly as the amount of iron that can bind transferrin decreases, which usually occurs as the body loses its ability to absorb and store iron. In some embodiments, the TSAT value is less than 20% and/or the ferritin concentration is <100 μg/L.

In some embodiments, subjects treated according to the methods disclosed herein experience an increase in TSAT values. In some embodiments, the present disclosure provides a method of increasing TSAT in a subject in need thereof, the method comprising administering to the subject iron isomaltoside, wherein the iron isomaltoside is a level of TSAT in the subject. provides an increase.

In some embodiments, the iron isomaltoside provides a mean increase in TSAT of greater than 1%, greater than 1.5%, greater than 2%, or greater than 2.5% at 4 or 8 weeks post treatment.

In some embodiments, the iron isomaltoside provides a mean increase in TSAT of less than 5%, less than 4%, or less than 3% at 4 or 8 weeks post treatment.

In some embodiments, the iron isomaltoside provides a mean increase in TSAT of 1-5%, 1.5-4%, or 2-3% at 4 or 8 weeks post treatment.

In some embodiments, the iron isomaltoside provides a mean increase in TSAT of greater than 5%, greater than 6%, or greater than 7% at one week following treatment.

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

In some embodiments, iron isomaltoside provides a mean increase in TSAT of 5 to 20%, or 5 to 15%, one week after treatment.

Hematocrit

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

The iron isomaltoside disclosed herein can be administered to a subject to increase hematocrit. The exact timing of administration will necessarily vary from subject to subject, depending on, for example, the severity of iron deficiency experienced by the subject, the level of iron absorption the subject may or may not experience, and the judgment of the treating healthcare professional. In some embodiments, the present disclosure provides a method of increasing hematocrit in a subject in need thereof, the method comprising administering to the subject iron isomaltoside, wherein the iron isomaltoside is an amount of hematocrit in the subject. provides an increase. In some embodiments, the increase is 1% to 30%, 1% to 15%, 1% to 12%, 1% to 10%, 1% to 9%, 1% to 8%, 1% to 7%, 1 % to 6%, 1% to 5%, 1% to 4%, 1% to 3%, or 1% to 2%.

Hemoglobin Concentration

Hemoglobin concentration, also called mean corpuscular hemoglobin concentration or MCHC, is a measure of the concentration of hemoglobin protein in a given volume of packaged red blood cells. In general, it is calculated by dividing the total amount of hemoglobin protein by the hematocrit. Hemoglobin concentration can also be measured as a mass or weight fraction and expressed as a percentage (%). However, assuming that the red blood cell density is 1 g/ml and the loss of hemoglobin in plasma is negligible, the mass or weight fraction (%) is numerically equivalent to the mass or molar measurement of the hemoglobin concentration. Typical mass or molar measurement ranges for hemoglobin concentrations in healthy subjects are 32 g/dl - 36 g/dl or 4.9 mmol/L - 5.5 mmol/L, respectively. However, in people with iron deficiency, hemoglobin levels can be significantly reduced because the body loses the ability to absorb and store iron.

In some embodiments, a subject treated according to the methods disclosed herein experiences an increase in hemoglobin concentration. In some embodiments, the present disclosure provides a method of increasing hemoglobin concentration in a subject in need thereof, the method comprising administering to the subject iron isomaltoside, wherein the iron isomaltoside is hemoglobin in the subject. provides an increase in concentration.

In some embodiments, the iron isomaltoside produces a mean increase in hemoglobin concentration of 0.1 - 5.0 g/dL, 0.1 - 4.0 g/dL, 0.1 - 3.0 g/dL, or 0.1 - 2.0 g/dL at one week after treatment. to provide.

In some embodiments, the iron isomaltoside is 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 1 week of treatment, and provides an average increase in hemoglobin concentration of greater than 0.7 g/dL, greater than 0.8 g/dL, or greater than 0.9 g/dL.

In some embodiments, iron isomaltoside provides an average increase in hemoglobin concentration of less than 1.0 g/dL, less than 0.9 g/dL, or less than 0.8 g/dL. In some embodiments, 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 at one week after treatment.

In some embodiments, the iron isomaltoside has a mean 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 at 4 or 8 weeks post treatment. provides an increase. 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 at one week after treatment.

In some embodiments, the iron isomaltoside has a mean 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 at 4 or 8 weeks post treatment. provides an increase. .

In some embodiments, the iron isomaltoside is 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 1.5 g/dL greater than 4 or 8 weeks post treatment. Provides an average increase in hemoglobin concentration above g/dL.

In some embodiments, iron isomaltoside provides an average increase in hemoglobin concentration of less than 2.0 g/dL, less than 1.9 g/dL, or less than 1.8 g/dL. In some embodiments, 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 post treatment.

Total Iron Binding Capacity (TIBC)

Total iron binding capacity (TIBC) is a measure of the blood's ability to bind iron with the protein transferrin. TIBC is usually measured by taking a blood sample and measuring the maximum amount of iron the sample can carry. Thus, TIBC indirectly measures transferrin, a protein that transports iron in the blood. Typical mass or molar measurements of TIBC for healthy subjects range from 250-370 μg/dL or 45-66 μmol/L, respectively. However, because the body must produce more transferrin to deliver iron to the red blood cell progenitor cells to produce hemoglobin, TIBC is usually elevated above these levels in iron-deficient subjects.

In some embodiments, a subject treated according to the methods disclosed herein experiences a reduction in TIBC. In some embodiments, the present disclosure provides a method of reducing TIBC in a subject in need thereof, the method comprising administering to the subject iron isomaltoside, wherein the iron isomaltoside reduces TIBC in the subject provides

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

Subjects at risk for cardiovascular events will generally develop or be at risk for systemic inflammation, which may complicate assessment of iron parameters. As disclosed herein, in subjects at risk of cardiovascular events, normal iron parameters will generally be considered TSAT > 20% and/or serum ferritin > 100 μg/L. According to one embodiment of the present invention, treatment is appropriate when the TSAT is less than 20% and/or the serum ferritin is less than 100 μg/L or in a related embodiment, the TSAT is less than 20% and the serum ferritin is less than 300 μg/L . In a preferred embodiment, the TSAT is less than 20% and/or the serum ferritin is less than 100 μg/L. Criteria of treatment may include upper limits of serum ferritin for which re-administration is not recommended, such as serum ferritin below 300 μg/L, below 400 μg/L, below 500 μg/L, or below 600 μg/L. Retreatment criteria may include higher limits for ferritin and TSAT than treatment criteria. For example, in one preferred embodiment, after administration of the initial effective dose, the subject will receive an additional dose if the TSAT is less than 25% and/or the serum ferritin is less than 100 μg/L and the serum ferritin is less than or equal to 400 μg/L. will be.

Symptom

Symptoms of iron deficiency can occur before the condition progresses to iron deficiency anemia. Symptoms of iron deficiency include, for example, fatigue, dizziness, pallor, hair loss, irritability, weakness, nodules, brittle nails, and Plummer-Vinson syndrome (painful atrophy of the mucous membranes covering the tongue, pharynx and esophagus). ), immune dysfunction, gluttony, restless legs syndrome, etc.

Subjects treated according to the methods disclosed herein will experience an improvement in iron deficiency. In some embodiments, a subject treated according to the methods disclosed herein experiences a reduction in iron deficiency. Such a decrease may occur as the total amount of iron in a subject's body is increased through administration of iron isomaltoside disclosed herein. In some embodiments, a subject treated according to the methods disclosed herein experiences a reduction or elimination of one or more symptoms of iron deficiency, wherein the symptoms are fatigue, dizziness, pallor, hair loss, irritability, weakness, deficiency, brittle nails. , Plummer-Vinson syndrome (painful atrophy of the mucous membranes covering the tongue, pharynx and esophagus), immune dysfunction, esophagus, restless legs syndrome, and combinations thereof.

In some embodiments, the iron deficiency is iron deficiency anemia. Iron deficiency anemia is characterized by a low number of circulating red blood cells and may result from insufficient dietary intake, absorption and/or storage of iron. Red blood cells contain iron bound to hemoglobin protein and are not normally formed when the amount of iron in the body is insufficient.

Iron deficiency anemia is usually characterized by paleness (pale color due to a decrease in oxyhemoglobin in the skin and mucous membranes), fatigue, dizziness, and weakness. However, the signs of iron deficiency anemia can vary from subject to subject. Because iron deficiency tends to progress slowly, adaptation to the disease may occur and may not be recognized for a while. In some cases, the subject has difficulty breathing (dyspnea), migraines (cravings for unusual foods), anxiety, irritability or sadness, angina, constipation, drowsiness, tinnitus, mouth ulcers, Palpitations, hair loss, fainting or faint feeling, depression, shortness of breath when exercising, muscle cramps, pale yellow skin, tingling (numbness) or burning, missing menstrual cycles, dense menstrual periods, slow social development, glossitis (inflammation or infection of the tongue) , angular cheilitis (inflammatory lesions in the corners of the mouth), koilonychia (spoon-shaped nails) or weak or brittle nails, loss of appetite, itching (general itchiness), Plummer-Vinson syndrome (tongue) , painful atrophy of the mucous membranes covering the pharynx and esophagus), and restless legs syndrome.

Anemia is usually diagnosed based on a total blood count measured in a blood sample of a subject. Automated counters are usually used that report the total number of red blood cells in the sample, the hemoglobin level, and the size of the red blood cells by flow cytometry. However, a stained blood smear on a microscope slide can be examined using a microscope to count the total number of red blood cells in the sample and to diagnose anemia. In many countries, the presence of anemia is confirmed by measuring four parameters (red blood cell count, hemoglobin concentration, mean blood cell volume, and red blood cell distribution width). The World Health Organization (WHO) has set a specific threshold for the hemoglobin level (Hb) so that an anemia diagnosis can be made when a subject's hemoglobin level falls below that level. Corresponding values are Hb = 11.0 g/dL or 6.8 mmol/L for children 0.5-5.0 years old; Hb = 11.5 g/dL or 7.1 mmol/L for children 5-12 years old; Hb = 12.0 g/dL or 7.4 mmol/L for 12-15 year olds; Hb = 12.0 g/dL or 7.4 mmol/L for non-pregnant women aged 15 years and older; Hb = 11.0 g/dL or 6.8 mmol/L for pregnant women; For men over 15 years of age, Hb = 13.0 g/dL or 8.1 mmol/L.

Subjects treated according to the methods disclosed herein may experience an improvement in anemia. Subjects treated according to the methods disclosed herein may experience an improvement in iron deficiency anemia. In some embodiments, a subject treated according to the methods disclosed herein experiences a reduction in one or more symptoms of anemia or iron deficiency anemia. In some embodiments, a subject treated in accordance with the methods disclosed herein experiences elimination 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 pallor, fatigue, dizziness, weakness, dyspnea, convulsions, anxiety, irritability or sadness, angina, constipation, drowsiness, tinnitus, mouth ulcers, palpitations, hair loss, fainting or faint feeling, depression, difficulty breathing when exercising, muscle cramps, pale yellow skin, tingling (numbness) or burning, missing menstrual cycles, dense menstrual periods, slow social development, glossitis, angular cheilitis, koironicia, loss of appetite , pruritus, Plummer-Vinson syndrome, restless legs syndrome, and combinations thereof.

In some embodiments, a subject treated according to the methods disclosed herein may experience an improvement in anemia and/or iron deficiency anemia because hemoglobin levels are elevated and/or maintained above a threshold level. In some embodiments, a method of treating anemia comprising administering to a subject iron isomaltoside is disclosed, wherein the iron isomaltoside is 11.0 g/dL, 11.5 g/dL, 12.0 g/dL and 13.0 g/dL. Hemoglobin levels in the subject are provided that are in the range of 11.0 g/dL - 13.0 g/dL or higher inclusive of a level selected from dL. In some embodiments, a method of treating anemia comprising administering to a subject iron isomaltoside is disclosed, wherein the iron isomaltoside is 6.8 mmol/L, 7.1 mmol/L, 7.4 mmol/L and 8.1 mmol/L and 8.1 mmol/L. Hemoglobin levels are provided in the subject at or above a level selected from L. In some embodiments, disclosed is a method of treating anemia in a male subject comprising administering to the male subject iron isomaltoside, wherein the iron isomaltoside is at a level selected from 13.0 g/dL and 8.1 mmol/L or greater. Hemoglobin levels in a male subject are provided. In some embodiments, disclosed is a method of treating anemia in a female subject comprising administering to the female subject iron isomaltoside, wherein the iron isomaltoside is at least at a level selected from 12.0 g/dL and 7.4 mmol/L. Hemoglobin levels in female subjects are provided.

Risk factors for adverse cardiovascular events

A particular group of subjects with iron deficiency as disclosed herein who may receive treatment according to the present invention is characterized as being at risk of cardiovascular adverse events.

According to the present invention, a subject at risk of cardiovascular events is a reaction affecting congestive heart failure (CHF), in particular CHF requiring hospitalization or medical intervention, myocardial infarction, unstable angina, particularly angina requiring hospitalization, or arrhythmia; reactions affecting the peripheral vascular system, such as hypertension and hypotension (peripheral vascular adverse events); reactions affecting the cerebral vasculature, such as stroke (cerebrovascular adverse events); and/or at risk for one or more reactions selected from the group consisting of general adverse events such as death.

More specifically, a subject at risk of a cardiovascular event according to the present invention is a subject having at least one of the following risk factors for a cardiovascular event and in particular a cardiovascular event as defined herein:

Chronic Kidney Disease (CKD)

Subjects with a glomerular filtration rate (GFR) < 60 ml/min/1.73 m ² for 3 months are classified as having CKD with or without renal impairment. CKD patients requiring dialysis or kidney transplantation are commonly referred to as end-stage renal disease (ESRD) patients. Thus, subjects are traditionally classified as ESRD subjects when the conclusion of the non-dialysis dependent early stage of CKD is reached. Previously, these subjects were referred to as non-dialysis dependent CKD subjects. Nondialysis-dependent CKD (NDD-CKD) subjects are those who have been diagnosed with an early stage of chronic kidney disease and have not yet been medically instructed to undergo dialysis. The National Kidney Foundation defines five stages of chronic kidney disease. In general, subjects with CKD progress to stages 1 through 4 as medically necessary prior to dialysis. However, subjects with advanced CKD stage, such as stage 5, who have not yet started dialysis or for whom transplantation is not recommended, are also commonly referred to as non-dialysis dependent CKD subjects.

NDD-CKD, as used herein, is intended to encompass all subjects diagnosed with chronic kidney disease but not on dialysis during iron isomaltoside administration. Such subjects may include, for example, subjects who have never been on dialysis and, in some embodiments, have been on dialysis but have not been on dialysis during administration of iron isomaltoside.

Cardiovascular disease is a frequent cause of death in subjects with chronic kidney disease (CKD). Despite the high prevalence of traditional risk factors for atherosclerosis in subjects with CKD, heart failure, arrhythmias, and sudden cardiac death constitute a disproportionately greater burden of cardiovascular-related death in CKD subjects compared to coronary artery disease (CAD). do. Left ventricular hypertrophy (LVH) and left ventricular dysfunction may be the result of atherosclerosis, but are also common non-atherosclerotic mechanisms of cardiovascular injury in CKD. Heart disease, including coronary artery disease, left ventricular hypertrophy (LVH) and heart failure (HF), is common in subjects with chronic kidney disease (CKD). LVH appears to become more prevalent as glomerular filtration rate (GFR) decreases and dialysis usage increases.

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

The presence of LVH is clinically important because it is associated with an increased incidence of heart failure, ventricular arrhythmias, death after myocardial infarction, decreased LV ejection fraction, sudden cardiac death, aortic muscle dilatation, and cerebrovascular responses. Heart failure with LVH usually results from left ventricular hyposystolic and/or diastolic dysfunction. The deleterious effects of left ventricular remodeling can be an important factor in determining progression to overt heart failure.

Without wishing to be bound by theory, potential mechanisms that may explain the relationship between anemia and the pathogenesis of LVH include the effect of decreased oxygen delivery to the myocardium, possibly due to increased myocyte necrosis and apoptosis, and increased cardiac anemia-related anemia. It leads to stroke volume and decreased systemic vascular resistance, increased oxidative stress, less effective oxidative phosphorylation and sympathetic activation.

An increasingly severe anemia in CKD is associated with more frequent and severe LVH, LV dilatation, HF and worse all-cause and cardiac prognosis in subjects with CKD and heart disease. Given that the increasing anemia in CKD is associated with increasingly severe degrees of LVH and heart failure, according to aspects of the present disclosure, correcting the deficiency associated with anemia has beneficial effects on the clinical features of HF and LVH. These include the clinical symptoms of HF and the subsequent development and progression of LVH.

Several short-term studies, mostly uncontrolled, in subjects with HF and CKD, using erythropoietin to improve anemia to Hb levels of approximately 10–12 g/dL improved clinical symptoms of HF and reduced hospitalization rates, but the hard Hard endpoints suggested no improvement. However, given the somewhat unexpected side effects associated with erythropoietin use, there is the potential for increased morbidity and/or mortality with erythropoietin treatment aimed at meeting normal or near-normal Hb levels.

LVH, by itself a strong prognostic marker for cardiovascular events in subjects with CKD, appears to regress with improvement in Hb levels in some subjects from less than 10 g/dL to up to 10 g/dL or more. Again, without intending to be limiting, higher elevations of Hb to more normal levels do not appear to lead to further regression or clinical improvement of LVH. The baseline geometry of LVH may be an important factor in determining the subsequent clinical response to correction of anemia in subjects with LVH.

Congestive Heart Failure (CHF)

The standardized MedDRA terms "congestive heart failure" and "heart failure congestive" are used interchangeably herein.

Heart failure is accompanied by signs caused by structural and/or functional cardiac abnormalities (e.g., elevated jugular vein pressure, pulmonary convergence, and peripheral edema) that result in decreased cardiac output and/or increased intracardiac pressure at rest or during stress. It is a clinical syndrome characterized by the typical symptoms that may be present (e.g., dyspnea, ankle swelling, and fatigue). Therefore, the current definition of HF is limited to stages where clinical symptoms are evident. Before clinical symptoms become apparent, a subject may exhibit asymptomatic structural or functional cardiac abnormalities, such as systolic or diastolic left ventricular (LV) dysfunction, a precursor of HF. Recognition of these progenitors is important because they are associated with poor outcomes, and initiating treatment at the progenitor stage may reduce mortality in subjects with asymptomatic systolic LV dysfunction.

"Congestive heart failure" is a term used to describe chronic heart failure, especially when there is evidence of volume overload, most often expressed as peripheral or pulmonary edema. Congestive heart failure (CHF) is defined as heart failure with reduced ejection fraction, LVEF<40% (HFrEF), heart failure with preserved ejection fraction, LVEF≥50% (HFpEF), or heart failure with a moderate-range ejection fraction, LVEF 40- 49% (HFmrEF). In a specific embodiment of the invention, congestive heart failure (CHF) is heart failure with reduced ejection fraction, LVEF<40% (HFrEF).

Congestive heart failure (CHF) may also be classified according to the New York Heart Association (NYHA) classification, which classifies patients into one of four categories based on the degree of limitation in physical activity. Patients with no symptoms and no limitations in daily physical activity, such as excessive fatigue, palpitations, dyspnea (dyspnea) in patient walking, stair climbing, etc., are assigned NYHA Class I. Patients with mild symptoms (mild shortness of breath and/or angina) and mild physical activity limitations are assigned NYHA Class II. Patients with marked restriction of activity due to symptoms, even during non-routine activities, such as walking short distances of 20 to 100 m, and comfortable only at rest, are assigned NYHA Class III. Patients who are symptomatic at rest and unable to perform any physical activity without discomfort are assigned a NYHA Grade IV. In a specific embodiment of the invention, the congestive heart failure (CHF) is NYHA class II-IV congestive heart failure.

Atrial Fibrillation (AF)

Atrial fibrillation (AF) includes first diagnosed AF (previously undiagnosed AF, regardless of duration of arrhythmia or presence and severity of AF-related symptoms), paroxysmal AF (in most cases, auto-terminates within 48 hours. Some AFs Seizures can continue for up to 7 days, cardioversion AF episodes within 7 days should be considered paroxysmal) and persistent AF (more than 7 days including episodes terminated by cardioversion) Persistent AF is by drug or or DC cardioversion, after 7 days or more), long-lasting AF (continuous AF lasting ≥ 1 year if decided to adopt a rhythm control strategy), or permanent AF (patient and physician AF) approved by According to a specific embodiment of the present invention, AF may be initially diagnosed AF, paroxysmal AF or persistent AF.

AF is associated with an increased risk of death, cardiovascular adverse events and kidney disease, including an increased risk of ischemic heart disease, chronic kidney disease, sudden cardiac death, stroke, or accidental congestive heart failure.

Hypertension

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

Hypertension is one of the major risk factors for heart disease, especially stroke. It causes about 50% of ischemic strokes and increases the risk of hemorrhagic stroke.

Several mechanisms related to hypertension are risk factors for cardiovascular events. For example, high blood pressure causes stress as blood vessels narrow or become blocked. This can lead to atherosclerosis or a weak spot in the blood vessel that ruptures easily, or the artery wall dilates, leading to an aneurysm.

Myocardial Infarction (MI)

Myocardial infarction (MI) is defined as myocardial cell death due to prolonged ischemia. After myocardial ischemia begins, histological cell death does not occur immediately, but takes a limited time to develop. Complete necrosis of the cardiomyocytes can be recognized after a few hours. MI may be the first sign of coronary artery disease (CAD).

MI is a term used to describe the presence of characteristic changes in cardiac enzyme markers in the setting of electrocardiogram (ECG) changes consistent with transiently relevant symptoms of acute coronary syndrome or ischemia or infarction. Cardiac Troponin cTn (I or T) with high myocardial tissue specificity and clinical sensitivity is used as the preferred biomarker. Alternatively, the MB fraction of creatine kinase (CKMB) determined by mass spectrometry can be used when cTn analysis is not available. In both assays, an increase in cTn or CKMB concentration is defined as a value above the 99th percentile of the normal reference population (upper reference limit (URL)). This discriminatory 99th percentile is designated as the decision level for the diagnosis of MI.

MI in patients with chest discomfort or other ischemic symptoms in which ST elevation occurs in two adjacent leads is designated as 'ST elevation MI' (STEMI). Patients without ST elevation at presentation are generally designated as having 'non-ST elevation MI' (non-STEMI). In a preferred embodiment, the myocardial infarction (MI) is ST-segment elevation myocardial infarction (STEMI) or non-STEMI.

Subjects with a history of MI are one of the highest risk groups for additional cardiovascular events. In particular, subjects who survive MI, ie, those with a history of MI, have an increased risk of recurrent infarction and a six-fold higher annual mortality rate than those of the same year without coronary heart disease.

Stroke

Stroke is classically characterized as a neurological defect due to acute focal damage to the central nervous system due to vascular causes, including cerebral infarction, intracerebral hemorrhage, and subarachnoid hemorrhage.

Subjects with a history of stroke, ie those who have had a stroke, remain at high risk of further cardiovascular events, particularly further strokes.

Heart Valve Disorders

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

Mitral regurgitation (MR) is the second most frequent indication for valve surgery in Europe. It is possible to differentiate between primary and secondary MR, especially with regard to surgical and transluminal interventional management. In primary MR, one or several components of the mitral device are directly affected. The most common etiology is degenerative (prolapse, flail leaflet). One of the causes of primary MR is endocarditis. Secondary MR (also called functional MR) is defined as MR due to primary left ventricular (LV) dysfunction along with normal mitral lobules and ligaments. Left ventricular dysfunction may be due to coronary heart disease (CHD) or (non-ischemic) cardiomyopathy.

For example, a subject with a history of heart valve defects from birth is more likely to develop valve problems. Heart valve disease can lead to many complications, including cardiovascular events such as HF, stroke, blood clots, arrhythmias, or death.

Diabetes

Significant hyperglycemia is associated with symptoms including frequent urination, thirst, blurred vision, fatigue, and recurrent infections. Beyond symptom relief, the goal of lowering blood sugar is to reduce the long-term complications of diabetes. Diabetes mellitus type 2 (also known as type 2 diabetes) is a long-term metabolic disorder characterized by hyperglycemia, insulin resistance, and relative insulin deficiency. Common symptoms include increased thirst, frequent urination, and unexplained weight loss. Type 1 diabetes, once 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 some viruses, can contribute to type 1 diabetes. Type 1 diabetes usually appears in childhood or adolescence, but it can also occur in adults. Despite active research, there is no cure for type 1 diabetes. Treatment focuses on managing blood sugar levels with insulin, diet, and lifestyle to prevent complications.

People with diabetes have a 2- to 4-fold increased risk of cardiovascular events compared to those without diabetes. Cardiovascular adverse events are the leading cause of death in diabetic patients. This is due to all risk factors for cardiovascular adverse events, hypertension, abnormal blood lipids and obesity, which are particularly prevalent in subjects suffering from diabetes.

For example, uncontrolled diabetes can damage blood vessels, leading to atherosclerosis and high blood pressure. 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 have an increased risk of heart failure compared to subjects without diabetes. Diabetes inhibits the protective effects of estrogen, which may increase the risk of cardiovascular events in premenopausal women with diabetes.

Obesity

"Obesity" refers to a condition in which a person's body mass index (BMI), which is a number obtained by dividing a person's weight by the square of their height, exceeds 30 kg/m ² . If you have a BMI greater than 30 kg/m ² , i.e. obesity, you are at a serious risk of developing high blood pressure (eg due to abdominal fat), diabetes and atherosclerosis, which are risk factors for cardiovascular events.

For example, if you are overweight, high salt intake increases the risk of cardiovascular events, especially since dietary salt is an important factor in elevated blood pressure, which can lead to hypertension and related risks.

age, smoking and drinking

Subjects who are elderly, smokers, and/or drinkers are at an increased risk of cardiovascular events.

According to certain embodiments of the present invention, the elderly person is 60 years old or older, 65 years old or older, 70 years old or older, 75 years old or older, or 80 years old or older. The risk of stroke doubles every 10 years after age 55. Systolic blood pressure is an important predictor of the risk of cardiovascular events with advancing age.

A drinker refers to a subject with a high alcohol content, particularly a subject who drinks 7 or more cups per week.

Drinkers who consume too much alcohol may experience or develop problems such as elevated blood pressure, acute myocardial infarction or cardiomyopathy. Alcohol abuse has also been shown to damage heart muscle and increase the risk of stroke and cardiac arrhythmias.

A smoker is a person who used to and/or is now a regular smoker.

Since the 1940s, it has been known that smoking is associated with cardiovascular disease. For example, smoking damages the endothelium (the lining of blood vessels), increases fat deposition in arteries, increases coagulation, increases low-density lipoprotein cholesterol, decreases high-density lipoprotein, and promotes coronary arteries. arterial spasm. In addition, nicotine, which is included as an addictive component in cigarettes, increases heart rate and blood pressure.

Hyperthyroidism and related Thyrotoxicosis

Hyperthyroidism is characterized by too high levels of thyroxine. Hyperthyroidism accelerates the body's metabolism, which can lead to unintended weight loss and a fast or irregular heartbeat.

Thyrotoxicosis is a disease in which the body secretes excessive thyroid hormones.

Chronic Obstructive Pulmonary Disorder (COPD)

"Chronic obstructive pulmonary disease (COPD)" is a disease characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar abnormalities, usually due to significant exposure to noxious particles or gases. The main risk factor is cigarette smoking, but other environmental exposures may contribute.

Cardiomyopathy

Cardiomyopathy is defined as structural and functional abnormalities of the ventricular myocardium that cannot be explained by blood flow-restricting coronary artery disease or abnormal loading conditions. Historically, this group of disorders has been subdivided into primary diseases, in which the heart is the only relevant organ, and secondary forms, in which cardiomyopathy is a manifestation of systemic impairment. The ESC guidelines define cardiomyopathy according to specific morphological and functional criteria, and then adopt a classification system that classifies cardiomyopathy into familial/hereditary and nonfamilial/nongenetic subtypes with or without extracardiac disease.

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

Inflammation

There is an association between pro-inflammatory biomarkers and incident hypertension, metabolic syndrome, coronary artery disease (CAD), acute coronary syndrome (ACS), peripheral arterial disease, stroke and recurrent coronary and cerebrovascular events. In certain embodiments, systemic inflammation is associated with increased C-reactive protein (CRP). CRP is a non-specific marker of inflammation. A range of about 2-3 mg/L is the limit above which it is considered a sign of systemic inflammation. The role of inflammation in the pathogenesis of atherosclerosis has been firmly established over the past two decades.

Dialysis

A subject on dialysis is a subject with an increased risk of cardiovascular events.

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

Medication

The risk of cardiovascular events is increased if the subject is being treated with one or more of the following:

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

(ii) erythropoiesis stimulants such as erythropoietin (Epo), epoetin alpha (Procrit/Epogen), epoetin beta (NeoRecormon), darbepoetin alfa (Aranesp) and methoxy polyethylene glycol-epoetin beta (Mircera) (erythropoiesis-stimulating agents, ESA); and

(iii) hepcidin modulators, such as hepcidin agonists or hepcidin antagonists;

The subject may be taking one or more erythropoiesis (ESA) to control the anemia. ESA helps the body produce red blood cells. These red blood cells are released from the bone marrow into the bloodstream to help maintain iron levels in the blood. Erythropoiesis stimulants, commonly abbreviated as ESAs, are substances similar in structure and/or function to the cytokine erythropoietin, which stimulates the production of red blood cells (erythropoeisis) in the body. Typical ESA is structurally and biologically similar to the naturally occurring protein erythropoietin. Examples of commercially available ESAs include erythropoietin (Epo), epoetin alfa (Procrit/Epogen), epoetin beta (NeoRecormon), darbepoetin alfa (Aranesp) and methoxy polyethylene glycol-epoetin beta (Mircera). there is Two ESAs currently approved for sale in the United States are Epoetin alfa (Procrit, Epogen) and Darbepoietin alfa (Aranesp).

ESA is generally given to subjects with ESRD. These subjects generally have lower hemoglobin levels because they cannot produce enough erythropoietin. The most frequent side effects of ESA use are: high blood pressure; edema; Heat; dizziness; sickness; and pain at the injection site. In addition to these side effects, there are several safety concerns associated with the use of ESAs. ESA increases the risk of venous thromboembolism (thromboembolism in a vein). ESA can also raise hemoglobin too high, putting the subject at a higher risk for heart attack, stroke, heart failure, and death.

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

Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (also known as Osler-Weber-Rendu disease) is a genetic disorder that is inherited from parents. The severity can vary widely from person to person, even within the same family. This causes abnormal connections between arteries and veins called arteriovenous malformations (AVMs). The most common locations affected are the nose, lungs, brain and liver. These AVMs can enlarge over time and can bleed or rupture, sometimes leading to fatal complications.

Hereditary iron refractory iron deficiency anemia

Hereditary iron-refractory iron deficiency anemia (IRIDA) is an inherited disorder characterized by impaired absorption and utilization. IRIDA is generally understood to be associated with genetic mutations leading to upregulation of hepcidin. It is understood that certain instances of IRIDA are associated with mutations in the TMPRSS6 gene. IRIDA is generally refractory to oral iron but is partially responsive to parenteral iron.

FGF23

Elevated levels of fibroblast growth factor 23 (FGF23) have come to be understood as a risk factor for cardiovascular disease.

"Fibroblast growth factor 23 (FGF23)" is an osteocytic-derived hormone that regulates phosphate and vitamin D homeostasis. FGF23 undergoes proteolytic cleavage, and as a result, uncleaved, that is, intact FGF23 (iFGF23) and its cleaved fragments are found in vivo. In its intact form, iFGF23 is the active form with respect to phosphate metabolism, where it regulates the urine excretion of phosphate, and when the level of iFGF23 is increased, phosphate is wasted in the urine. Currently there are two main types of antibody assays, one that captures only iFGF23 and the other that binds to the C-terminus of the hormone and captures both iFGF23 and C-terminal fragments. Therefore, the latter measurement criterion, cFGF23, is the sum of intact FGF23 and C-terminal FGF23 fragments. Therefore, there are two tests related to FGF23, iFGF23 and cFGF23, which have different interpretations.

Elevated FGF23 levels are independently associated with prevalent and occurring LVH, cardiovascular disease response and mortality in CKD and non-CKD populations. In addition, a recent study demonstrated that FGF23 directly induces LVH, suggesting that FGF23 is not simply a biomarker of cardiovascular risk. CKD subjects tend to have very high FGF23 levels due to the body's continued attempt to compensate for high serum phosphate levels by producing iFGF23 to increase the urine fractional excretion of phosphate through the kidneys. For this reason, iFGF23 levels are elevated in CKD subjects and consequently other downstream effects of iFGF23 may be more pronounced.

Elevated FGF23 levels help keep serum phosphate in the normal range in CKD, and FGF23 concentrations increase with decreasing estimated glomerular filtration rate (eGFR) and stimulate greater nephron phosphate excretion 1 , by reducing 25-dihydroxyvitamin D levels, which helps to maintain normal phosphate homeostasis despite decreased renal mass. Parenteral iron induces hypophosphatemia by inhibiting renal tubular phosphate reabsorption and 1-alpha hydroxylation of vitamin D. The data indicate that hypophosphatemia is mediated by an increase in FGF23.

Pre-dialysis CKD, incidence and prevalence ESRD, and a prospective study of a population of kidney transplant recipients show that elevated FGF23 levels are independently associated with progression of CKD and the incidence and mortality of cardiovascular events. It was originally thought that this observation was driven by elevated FGF23 levels, which act as highly sensitive biomarkers of phosphate-induced toxicity. However, FGF23 itself has now been shown to mediate 'off-target', direct end-organ toxicity in the heart, suggesting that elevated FGF23 levels may be a novel mechanism of adverse events in CKD.

In certain embodiments, a subject treated according to the methods described herein for one or more cardiovascular adverse events has elevated FGF23 levels. The normal level of intact FGF23 in the serum of a healthy person is about 26.1 pg/mL and the normal level of the C-terminal FGF23 fragment in the serum of a healthy person is about 49.0 RU/mL. In certain embodiments, the subject's FGF23 level (eg, intact FGF23 and/or C-terminal FGF23 fragment) is elevated compared to a normal range in a healthy human. In some embodiments, the subject's intact FGF23 level in serum is between 250 pg/mL and 350 pg/mL, between 200 pg/mL and 300 pg/mL, between 200 pg/mL and 350 pg/mL, between 300 pg/mL and 350 pg. /mL, 300 pg/mL to 400 pg/mL, or 250 pg/mL to 500 pg/mL. In certain embodiments, the subject's intact FGF23 level in serum is 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 level of the subject's C-terminal FGF23 fragment in serum is between 60 RU/mL and 100 RU/mL, between 100 RU/mL and 200 RU/mL, between 200 RU/mL and 300 RU/mL, or 250 RU/mL. mL to 400 RU/mL. In certain embodiments, the level of the subject's C-terminal FGF23 fragment in serum is 60 RU/mL, 100 RU/mL, 125 RU/mL, 150 RU/mL, 175 RU/mL, 200 RU/mL, 225 RU/mL , greater than 250 RU/mL, 275 RU/mL or 300 RU/mL.

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

Thus, in a first preferred embodiment of this aspect of the invention, the specific group of subjects eligible for treatment according to the invention has a history of myocardial infarction (MI), a history of stroke, a history of atrial fibrillation (AF), congestion subjects with a history of sexual heart failure (CHF), chronic kidney disease (CKD), hypertension, diabetes, a history of heart valve disorders, a history of obesity and/or smokers, drinkers, and/or geriatric subjects. This includes, inter alia, subjects with a history of myocardial infarction (MI), a history of stroke, a history of atrial fibrillation (AF), a history of chronic kidney disease (CKD), a history of congestive heart failure (CHF), and/or a history of hypertension . Subjects with a history of myocardial infarction (MI), a history of stroke, and/or a history of congestive heart failure (CHF), in particular a subject with a history of congestive heart failure (CHF), are particularly at risk of cardiovascular adverse events and thus the present invention A preferred group of subjects who can receive treatment according to

A subject with a history of a particular condition, disorder or disease, such as a history of myocardial infarction, stroke, atrial fibrillation, or congestive heart failure (CHF) refers to the subject's past and present medical history. The medical history is a description of all medical events and problems experienced by the subject, namely the subject's previous medical illness, diagnosis, and general health of the patient throughout his life. A subject with a history of a particular condition, disorder or disease need not have the particular condition, disorder, or disease at any given time to be classified as at risk. A history of a particular condition, disorder or disease is sufficient. For example, subjects who quit smoking are still at risk because they have a history of smoking.

In a second preferred embodiment of this aspect of the invention, the particular group of subjects eligible for treatment according to the present invention is a subject with a history of congestive heart failure (CHF). This includes, inter alia, subjects with a history of myocardial infarction (MI) and/or a history of stroke. In a preferred embodiment, the CHF is heart failure with reduced ejection fraction (HFrEF).

In a third preferred embodiment of this aspect of the present invention, the particular group of subjects eligible for treatment according to the present invention are subjects with a history of myocardial infarction (MI). In a preferred embodiment, MI is STEMI or non-STEMI. In a fourth preferred embodiment of this aspect of the present invention, the specific group of subjects eligible for treatment according to the present invention are subjects with a history of stroke.

Subjects as defined herein (ie, subjects at risk of cardiovascular events and/or with a history of congestive heart failure) include subjects with chronic kidney disease (CKD) or subjects without CKD. People with CKD are a particular subgroup of patients who may be eligible for treatment according to the present invention. In particular, these include subjects with chronic kidney disease (CKD) and congestive heart failure (CHF), wherein the chronic kidney disease (CKD) is preferably non-dialysis dependent chronic kidney disease (NDD-CKD). Administer iron isomaltoside compared to other iron carbohydrate complexes in group (individuals with a history of chronic kidney disease (CKD) and congestive heart failure (CHF), particularly those with nondialysis dependent chronic kidney disease (NDD-CKD)) The therapeutic benefits of

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

In many further embodiments of this aspect of the invention, the particular group of subjects amenable to treatment according to the invention are those having one or more of the following risk factors:

(i) a subject with a history of atrial fibrillation (AF), particularly first diagnosed AF, paroxysmal AF, or persistent AF;

(ii) subjects with a history of heart valve disorders;

(iii) subjects with a history of hypertension;

(iv) subjects with diabetes;

(v) subjects with a history of obesity;

(vi) geriatric subjects, particularly subjects aged 60 years or older, 65 years old or older, 70 years old or older, 75 years old or older, or 80 years old or older;

(vii) smokers

(viii) drinkers;

(ix) subjects with hyperthyroidism and/or related thyrotoxicosis;

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

(xi) subjects with cardiomyopathy, in particular hereditary cardiomyopathy or acquired cardiomyopathy;

(xii) a subject having systemic inflammation in the absence of infection, wherein the systemic inflammation is an inflammation associated with increased C-reactive protein (CRP), particularly in the range of about 2-3 mg/L;

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

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

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

b) erythropoiesis stimulants such as erythropoietin (Epo), epoetin alpha (Procrit/Epogen), epoetin beta (NeoRecormon), darbepoetin alfa (Aranesp) and methoxy polyethylene glycol-epoetin beta (Mircera) ( erythropoiesis-stimulating agents, ESA); and

c) hepcidin modulators such as hepcidin agonists or hepcidin antagonists;

(xv) subjects treated with anticoagulants and/or NSAIDs;

(xvi) subjects with hereditary hemorrhagic telangiectasia; or

(xvii) Subjects with hereditary iron refractory iron deficiency anemia.

II. therapeutic benefit

In addition to delivering iron to a subject, the present disclosure provides a method for reducing the incidence or risk of cardiovascular adverse events in a subject as defined herein. Reference to a reduction in the incidence or risk of “cardiovascular adverse events” or “cardiovascular adverse events” means that the incidence or risk of one or more of the mentioned events is reduced.

According to one embodiment of this second aspect of the present invention, the reduced incidence or risk of cardiovascular adverse events may include: a reaction affecting the heart (cardiac adverse event); reactions affecting the peripheral vascular system (peripheral vascular adverse events); reactions affecting the cerebral vasculature (cerebrovascular adverse events); respiratory, thoracic and mediastinal adverse events; common adverse reactions; and infection and invasion into the body.

In certain embodiments of this second aspect of the invention, the reduced incidence or risk of cardiac adverse events is congestive heart failure, atrial fibrillation, heart attack, atrioventricular block, heart failure, sinus node dysfunction, acute myocardial infarction, bradycardia, angina pectoris. , myocardial ischemia and ventricular systolic; the peripheral vascular adverse event is selected from the group consisting of hypertension, elevated systolic blood pressure, elevated blood pressure, increased troponin and hypotension; the cerebrovascular adverse event is selected from the group consisting of cerebrovascular accident, cerebral infarction and transient ischemic attack; respiratory, thoracic and mediastinal adverse events are selected from the group consisting of dyspnea and pulmonary edema; Common adverse events are selected from the group consisting of chest pain and death; Infection and invasion are septic shock.

According to a preferred embodiment of this second aspect of the present invention, the reduced incidence or risk of cardiovascular adverse events is selected from the group consisting of reactions affecting the heart (cardiac adverse events); reactions affecting the peripheral vascular system (peripheral vascular adverse events); reactions affecting the cerebral vasculature (cerebrovascular adverse events); and death. Preferably, the reactions affecting the heart (cardiac adverse events) are congestive heart failure, myocardial infarction, unstable angina and arrhythmia; A reaction affecting the peripheral vascular system (peripheral vascular adverse event) is hypertension; A reaction that affects cerebrovascular structures (cerebrovascular adverse events) is stroke.

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

According to a further particularly preferred embodiment of this second aspect of the invention, the reduced incidence or risk of cardiovascular adverse events is congestive heart failure, atrial fibrillation, hypertension and/or heart attack.

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

Thus, in a particularly preferred embodiment of this second aspect of the invention, the reduced incidence or risk of cardiovascular adverse events is atrial fibrillation.

Thus, in a particularly preferred embodiment of this second aspect of the invention, the reduced incidence or risk of cardiovascular adverse events is hypertension.

Thus, in a particularly preferred embodiment of this second aspect of the invention, the reduced incidence or risk of cardiovascular adverse events is heart attack.

Specific cardiovascular adverse events associated with congestive heart failure are hospitalization, hospitalization for exacerbation of congestive heart failure, or death due to congestive heart failure. The present invention particularly relates to a CV adverse event wherein the CV adverse event is CHF.

III. Therapeutic Benefits in Selected Subjects

Taking into account a particular group of subjects as defined herein and the incidence or risk of cardiovascular adverse events to be reduced, the present invention relates to a method for treating iron deficiency according to a third aspect, wherein the cardiovascular adverse events in said subject reducing the incidence or risk of, the method comprising administering an effective amount of iron isomaltoside, wherein the subject

(A) subjects at risk of cardiovascular events as defined herein;

(B) subjects with a history of congestive heart failure (CHF); or

(C) a subject with a history of congestive heart failure (CHF) and at risk for cardiovascular events,

wherein the reduced incidence or risk of cardiovascular events is:

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

(b) congestive heart failure;

(c) atrial fibrillation;

(d) hypertension; or

(e) heart attack.

According to a preferred embodiment of this third aspect of the invention, the subject is a subject at risk for cardiovascular events, and the reduced incidence or risk of cardiovascular events is congestive heart failure.

According to a further preferred embodiment of this third aspect of the invention, the subject is a subject at risk for cardiovascular events, and the reduced incidence or risk of cardiovascular events is atrial fibrillation.

According to a further preferred embodiment of this third aspect of the invention, the subject is a subject at risk for cardiovascular events and the reduced incidence or risk of cardiovascular events is heart attack.

According to a further preferred embodiment of this third aspect of the invention, the subject is a subject with a history of congestive heart failure (CHF) and the reduced incidence or risk of cardiovascular adverse events is heart attack or congestive heart failure or both. am.

According to a further preferred embodiment of this third aspect of the invention, the subject has a history of congestive heart failure (CHF) and the reduced incidence or risk of cardiovascular adverse events is congestive heart failure.

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

According to a further preferred embodiment of this third aspect of the invention, the subject has a history of congestive heart failure (CHF) and the reduced incidence or risk of cardiovascular adverse events is heart attack.

According to a further preferred embodiment of this third aspect of the invention, the subject is a subject with a history of congestive heart failure (CHF) and the reduced incidence or risk of cardiovascular adverse events is hypertension.

According to another embodiment of this third aspect of the invention, the subject is at risk of cardiovascular events and/or has a history of congestive heart failure with chronic kidney disease (CKD). According to another embodiment of this third aspect of the invention, the subject is at risk of cardiovascular events and/or has a history of congestive heart failure without chronic kidney disease (CKD). In particular, these include subjects with chronic kidney disease (CKD) and/or congestive heart failure (CHF), wherein the chronic kidney disease (CKD) is preferably non-dialysis dependent chronic kidney disease (NDD-CKD).

According to a further particularly preferred embodiment of this third aspect of the invention, the subject has a history of congestive heart failure (CHF) and chronic kidney disease (CKD), in particular non-dialysis-dependent chronic kidney disease (NDD-CKD) and the reduced incidence or risk of cardiovascular events is congestive heart failure.

According to a further particularly preferred embodiment of this third aspect of the invention, the subject has a history of congestive heart failure (CHF) and chronic kidney disease (CKD), in particular non-dialysis-dependent chronic kidney disease (NDD-CKD) and a reduced incidence or risk of cardiovascular adverse events is atrial fibrillation.

According to a further particularly preferred embodiment of this third aspect of the invention, the subject has a history of congestive heart failure (CHF) and chronic kidney disease (CKD), in particular non-dialysis-dependent chronic kidney disease (NDD-CKD) and a reduced incidence or risk of cardiovascular adverse events is heart attack.

According to a further particularly preferred embodiment of this third aspect of the invention, the subject has a history of congestive heart failure (CHF) and chronic kidney disease (CKD), in particular non-dialysis-dependent chronic kidney disease (NDD-CKD) and the reduced incidence or risk of cardiovascular events is hypertension.

In some of these examples, the subject with a history of congestive heart failure has HFrEF. In some embodiments, the subject with a history of congestive heart failure has congestive heart failure in NYHA classes II-IV, particularly HFrEF-type congestive heart failure in NYHA classes II-IV.

In another embodiment, the present disclosure provides a method of reducing the risk of hospitalization or hospitalization associated with a cardiovascular adverse event in a subject as defined herein.

In some embodiments, the present disclosure provides a method of reducing mortality and morbidity, ie, in particular, mortality due to cardiovascular events, in a subject as defined herein.

IV. Dosage and dosing regimen

A method of treating iron deficiency in a subject at risk for cardiovascular events according to the present invention comprises administering an effective amount of iron isomaltoside. Accordingly, the method of the present invention comprises, according to a preferred embodiment, determining whether said patient is iron deficient prior to said administration of iron isomaltoside, and administering said iron isomaltoside if said subject is iron deficient. may include More specifically, the method of the present invention comprises the steps of determining whether said patient is at risk of a cardiovascular event prior to administering iron isomaltoside, and if said patient is at risk of a cardiovascular event, said iron isomaltoside It further comprises the step of administering.

The usual treatment regimen for iron isomaltoside is as a single infusion of 1000 mg of iron or as an intravenous infusion of up to 20 mg of iron/kg body weight of iron given as an intravenous infusion, or a bolus intravenous infusion of up to 500 mg up to three times a week. is composed of The cumulative iron requirement may be determined using the Ganzoni formula and in one embodiment a calculated dose will be administered. or the cumulative 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

Or the general treatment regimen of iron isomaltoside is selected according to the following table.

Hb (g/dL) weight
< 50 kg weight
50 to < 70 kg weight
≥ 70 kg ≥ 10 20 mg/kg 1000 mg 20 mg/kg
up to 1500 mg < 10 20 mg/kg 20 mg/kg 20 mg/kg
up to 2000 mg

Thus, in some embodiments, the effective amount of iron isomaltoside is in an amount ranging from about 500 mg to 2000 mg, for example, 500 mg, 1000 mg, 1500 mg or 2000 mg of elemental iron, in a single dose or more than once. , in particular in two or three doses. Alternatively, an effective amount of iron isomaltoside is an amount of at most 50 mg iron/kg body weight, in particular at most 30 mg iron/kg body weight, or preferably at most 20 mg iron/kg body weight.

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

For repeated administration, a first dose of 200 to 700 mg, preferably 300 to 600, most preferably up to 500 mg of elemental iron, followed by 200 to 7000 mg, preferably 300 to 600, and most preferably A second dose of up to 500 elemental iron follows. Two doses may be administered within one month, two weeks, or preferably within one week. Preferably, it is administered within 1 week. A further dose of iron isomaltoside may follow, for example a third dose of 200 to 700 mg, preferably 300 to 600 and most preferably up to 500 mg of elemental iron. This for example. Third, the dose(s) may be administered within the same time frame, i.e. one month, two weeks, or preferably one week. Such multiple doses are preferably administered as bolus injections. It is more preferred that each dose be administered at least two days apart, in particular three days apart. For example, if three doses are to be administered within a week, it is preferred to administer these doses on days 1, 4 and 7.

When ferric befectate is used as the iron carbohydrate complex of the present invention, the calculation of the effective cumulative dose as elemental iron can likewise be determined based on the Ganzoni formula or the table provided above. Alternatively, 1000 mg or 1500 mg of elemental iron may be an effective cumulative dose. A suitable single dose of ferric befectate, ie a dose administered at a time, 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.

For CKD patients on hemodialysis, repeated doses of iron isomaltoside or ferric befectate may be administered in conjunction with a dialysis session such as, for example, 100 mg to 500 mg, preferably 100 mg or 200 mg.

C. Drug Combinations

Further described herein is a combination of iron isomaltoside with at least one additional drug for use in the treatment of iron deficiency according to the present invention, wherein the additional drug is selected from the group consisting of:

(1) angiotensin-converting enzyme inhibitors (ACEIs) such as captopril, enalapril, lisinopril, ramipril or trandolapril;

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

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

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

(5) If-channel blockers such as ivabradine;

(6) angiotensin receptor neprilysin inhibitors such as sacubitril/valsartan; and

(7) Diuretics such as furosemide, bumetanide, toracemide, bendroflumethazide, hydrochlorothiazide, metolazone, indapamide, amiloride or triamterene.

The dose of additional drug generally refers to the amount of drug administered to an adult. Dosage for infants can be adjusted accordingly.

A particular combination of iron isomaltoside with at least one additional drug for use in treating iron deficiency according to the present invention is such that the additional drug exposes the subject to a higher risk for cardiovascular events. According to this aspect, the additional drug is selected from the group consisting of:

(i) modulators of the hypoxia-inducible factor (HIF) signaling pathway, including prolyl-hydroxylase inhibitors such as daprodustat, baddustat, roxadustat, molydustat and desidusta;

(ii) erythropoiesis stimulants such as erythropoietin (Epo), epoetin alpha (Procrit/Epogen), epoetin beta (NeoRecormon), darbepoetin alfa (Aranesp) and methoxy polyethylene glycol-epoetin beta (Mircera) (ESA); and

(iii) hepcidin modulators, such as hepcidin agonists or hepcidin antagonists.

Exemplary embodiment

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

2. The subject of Example 1 at risk for cardiovascular events is a history of myocardial infarction (MI), a history of stroke, a history of atrial fibrillation (AF), congestive heart failure (CHF), chronic kidney disease (CKD) of, a history of hypertension, diabetes, a history of heart valve disorders, a history of obesity, and/or a method of being a smoker, drinker and/or geriatric subject.

3. The subject of Example 2 at risk of cardiovascular events is a history of myocardial infarction (MI), a history of stroke, atrial fibrillation (AF), a history of chronic kidney disease (CKD), congestive heart failure (CHF) and/or a subject with a history of hypertension.

4. The method of example 3, wherein the subject at risk for cardiovascular events is a subject with a history of myocardial infarction (MI), a history of stroke, and/or a history of congestive heart failure (CHF).

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

6. The method of example 5, wherein the subject with a history of congestive heart failure (CHF) has a history of myocardial infarction (MI) and/or a history of stroke.

7. The method according to any one of examples 2-6, wherein the congestive heart failure (CHF) is heart failure with decreased ejection fraction (HFrEF).

8. The method of examples 1-4, wherein the subject at risk for cardiovascular events is a subject with a history of myocardial infarction (MI).

9. The method of example 8, wherein the myocardial infarction (MI) is STEMI or non-STEMI.

10. The method of examples 1-4, wherein the subject at risk of cardiovascular events is a subject with a history of stroke.

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

12. The method of any one of examples 1-7, wherein the subject is at risk of cardiovascular events and/or has congestive heart failure, and wherein the subject does not have chronic kidney disease (CKD).

13. The method of any one of examples 1-11, wherein the subject at risk for cardiovascular events is a subject with a history of chronic kidney disease (CKD) and congestive heart failure (CHF).

14. The method of example 13, wherein the subject with a history of congestive heart failure has HFrEF.

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

16. The method according to any one of examples 11-15, wherein the chronic kidney disease (CKD) is non-dialysis dependent chronic kidney disease (NDD-CKD).

17. The method of examples 1-3, wherein the subject at risk for cardiovascular events is a subject with a history of atrial fibrillation (AF).

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

19. The method of example 1 or 2, wherein the subject at risk for cardiovascular events is a subject with a history of heart valve disorders.

20. The method of examples 1-3, wherein the subject at risk for cardiovascular events is a subject with a history of hypertension.

21. The method of example 1 or 2, wherein the subject at risk of a cardiovascular event is a subject having diabetes.

22. The method of example 1 or 2, wherein the subject at risk for cardiovascular events has a history of obesity.

23. The method of example 1 or 2, wherein the subject at risk of a cardiovascular event is an elderly subject, a smoker or a drinker.

24. The method of example 23, wherein the elderly subject is at least 60 years old, 65 years old or older, 70 years old or older, 75 years old or older, or 80 years old or older.

25. The method of example 1, wherein the subject at risk for cardiovascular events is a subject having hyperthyroidism and/or thyrotoxicosis associated therewith.

26. The method of example 1, wherein the subject at risk for cardiovascular events is a subject with chronic obstructive pulmonary disorder (COPD).

27. The method of example 1, wherein the subject at risk of cardiovascular events is a subject having cardiomyopathy.

28. The method of example 27, wherein the cardiomyopathy is hereditary cardiomyopathy or acquired cardiomyopathy.

29. The method of example 1, wherein the subject at risk for cardiovascular events is a subject having systemic inflammation in the absence of infection.

30. The method of example 29, wherein the systemic inflammation is associated with increased C-reactive protein (CRP) greater than about 2-3 mg/L.

31. The method of example 1, wherein the subject at risk of a cardiovascular event is a subject on dialysis.

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

33. The method of example 1, wherein the subject at risk for cardiovascular events is a subject treated with one or more of the following:

a) modulators of the hypoxia inducible factor (HIF) signaling pathway, including prolyl-hydroxylase inhibitors such as daprodustat, baddustat, roxadustat, molydustat and desidusta;

b) erythropoiesis stimulants such as erythropoietin (Epo), epoetin alpha (Procrit/Epogen), epoetin beta (NeoRecormon), darbepoetin alfa (Aranesp) and methoxy polyethylene glycol-epoetin beta (Mircera) ( ESA); and

c) Hepcidin modulators, such as hepcidin agonists or hepcidin antagonists.

34. The method of example 1, wherein the subject at risk of a cardiovascular event is a subject being treated with an anticoagulant and/or an NSAID.

35. The method of example 1, wherein the subject at risk of a cardiovascular event is a subject having hereditary hemorrhagic telangiectasia.

36. The method of example 1, wherein the subject at risk of cardiovascular adverse events is a subject having hereditary iron refractory iron deficiency anemia.

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

38. The method of any one of examples 1-37, wherein the subject has chronic iron loss or malabsorption.

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

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

41. The method of any one of examples 1-40, wherein the treatment of iron deficiency reduces the incidence or risk of cardiovascular adverse events in the subject.

42. The cardiovascular event according to example 41, wherein the adverse event is a reaction affecting the heart (cardiac adverse event); reactions affecting the peripheral vasculature (peripheral vascular adverse events); reactions affecting the cerebral vasculature (cerebrovascular adverse events); respiratory, thoracic and mediastinal adverse events; common adverse reactions; and a method selected from the group consisting of infection and invasion.

43. The cardiac adverse event of example 42, in the group consisting of congestive heart failure, atrial fibrillation, heart attack, atrioventricular block, heart failure, sinus node dysfunction, acute myocardial infarction, bradycardia, angina pectoris, myocardial ischemia and ventricular extrasystole. selected; the peripheral vascular adverse event is selected from the group consisting of hypertension, increased systolic blood pressure, increased blood pressure, increased troponin and hypotension; the cerebrovascular adverse event is selected from the group consisting of cerebrovascular accident, cerebral infarction and transient ischemic attack; Respiratory, thoracic and mediastinal adverse events are selected from the group consisting of dyspnea and pulmonary edema; A method in which common adverse reactions are selected from the group consisting of chest pain and death, and infection and invasion are septic shock

44. The cardiovascular adverse event according to embodiment 41, wherein the adverse event is a reaction affecting the heart (cardiac adverse event); reactions affecting the peripheral vasculature (peripheral vascular adverse events); reactions affecting the cerebral vasculature (cerebrovascular adverse events); and death.

45. The reaction of embodiment 44 affecting the heart (cardiac adverse event) is congestive heart failure, myocardial infarction, unstable angina and arrhythmia; A reaction affecting the peripheral vascular system (peripheral vascular adverse event) is hypertension; A method in which the reaction affecting cerebrovascular structure (cerebrovascular adverse reaction) is stroke.

46. The method of example 41, wherein the cardiovascular adverse event is selected from the group consisting of congestive heart failure, myocardial infarction, unstable angina, arrhythmia, hypertension, hypotension, stroke and death.

47. The method of examples 41-42, wherein the cardiovascular adverse event is selected from the group consisting of congestive heart failure, atrial fibrillation, hypertension and heart attack.

48. The method of any one of examples 41-47, wherein the cardiovascular adverse event is congestive heart failure.

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

50. The method of example 49, wherein the cardiovascular adverse event is hospitalization for congestive heart failure.

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

52. The method of example 41, wherein the cardiovascular adverse event is cardiovascular death and/or hospitalization due to exacerbation of congestive heart failure.

53. The method according to any one of examples 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 examples 41-43 and 47, wherein the cardiovascular adverse event is heart attack.

56. The method of any one of examples 41-55, wherein the iron isomaltose is ferric deisomaltose.

57. A method of treating iron deficiency in a subject, wherein the treatment of iron deficiency comprises administering an effective amount of iron isomaltoside and reduces the incidence or risk of cardiovascular adverse events in the subject, wherein the subject comprises:

(A) subjects at risk of cardiovascular events;

(B) subjects with a history of congestive heart failure (CHF); or

(C) a subject with a history of congestive heart failure (CHF) and at risk for cardiovascular events,

wherein the reduced incidence or risk of cardiovascular events is:

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

(b) congestive heart failure;

(c) atrial fibrillation;

(d) hypertension; or

(e) A method that is a heart attack.

58. The method of example 57, wherein the subject is at risk for cardiovascular events and the reduced incidence or risk of cardiovascular events is congestive heart failure.

59. The method of example 57, wherein the subject is at risk for cardiovascular events and the reduced incidence or risk of cardiovascular events is atrial fibrillation.

60. The method of example 57, wherein the subject is at risk for cardiovascular events and the reduced incidence or risk of cardiovascular events is heart attack.

61. The method of example 57, wherein the subject is a subject with a history of congestive heart failure (CHF) and the reduced incidence or risk of cardiovascular adverse events is heart attack or congestive heart failure or both.

62. The method of example 57, wherein the subject is a subject with a history of congestive heart failure (CHF) and the reduced incidence or risk of cardiovascular adverse events is congestive heart failure.

63. The method of example 57, wherein the subject has a history of congestive heart failure (CHF) and the reduced incidence or risk of cardiovascular adverse events is atrial fibrillation.

64. The method of example 57, wherein the subject has a history of congestive heart failure (CHF) and the reduced incidence or risk of cardiovascular adverse events is heart attack.

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

66. The method according to any one of examples 57-64, wherein the subject is at risk of cardiovascular events and/or has congestive heart failure and the subject is free of chronic kidney disease (CKD).

67. The method of embodiment 65 or 66, wherein the chronic kidney disease (CKD) is non-dialysis dependent chronic kidney disease (NDD-CKD).

68. The method of any one of examples 57 or 61-67, wherein the subject with a history of congestive heart failure has HFrEF.

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

70. The method of examples 57-69, wherein the reduced incidence or risk of cardiovascular adverse events is cardiovascular death and/or hospitalization due to exacerbation of congestive heart failure.

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

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

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

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

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

76. The method of any one of examples 57-75, wherein the iron isomaltoside is ferric deisomaltose.

77. The method of any one of examples 1-76, further comprising determining whether said patient is at risk of cardiovascular events prior to administering iron isomaltoside.

78. The method of example 77, wherein said iron isomaltoside is administered if said patient is at risk of cardiovascular events.

79. Atrial fibrillation (atrial fibrillation ( AF) or a method for the prevention or treatment of a disorder prone to AF.

80. The method of claim 79, wherein the disorder predisposed to AF is selected from heart valve disease, hypertension, heart failure, coronary artery disease, obesity and diabetes.

81. The method of item 79 or 80, wherein said animal is a mammal.

82. The method of item 81, wherein said animal is a human.

83. The method of any one of items 79-82, wherein said AF is paroxysmal, persistent, prolonged or chronic.

84. The method of any one of items 79-83, wherein said iron formulation is administered via oral, intramuscular or intravenous route.

85. The method of any one of items 79-84, wherein said animal is iron deficient.

86. The method of any one of items 79-85, wherein said animal is not iron deficient.

87. The method according to any one of items 79 to 86, for reducing AF symptoms such as palpitations or dyspnea, hyperkinesis, hospitalization, heart failure, stroke and death.

88. The method of any one of items 79-87, wherein said animal has myocardial iron deficiency.

89. The method of any one of items 79-88, wherein said myocardial iron deficiency responds to the supplement despite a normal blood test for iron deficiency.

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

Example

Treatment with iron isomaltoside (“IIM”, trade names Monofer®, Monoferric®) and iron sucrose (“IS”, trade name Venofer®) in adult human subjects with iron deficiency anemia and non-dialysis-dependent chronic kidney disease and In this regard, two Phase III randomized, open-label comparative safety and efficacy studies were conducted. These studies made it possible to compare the incidence of treatment-related cardiovascular events, particularly in patients with cardiovascular risk factors.

Study Design

The study was a randomized, open-label, comparative study. Subjects with iron deficiency anemia (IDA) were randomized 1:1 to one course of two treatments. Iron isomaltoside 1000 was administered as a single dose of 1000 mg elemental iron. Iron sucrose was administered as a slow intravenous bolus of 200 mg per US label and repeated up to 5 times to reach a cumulative dose of 1000 mg.

Objectives

This study allowed a comparison of developmental protocols defined as cardiovascular events when treated with iron isomaltoside or iron sucrose in subjects with IDA and nondialysis-dependent chronic kidney disease.

The protocol defined as cardiovascular adverse events is as follows.

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

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

- Requires hospitalization, defined as an inpatient hospital stay or emergency room visit (change date if inpatient/discharge time is not possible) requiring a minimum hospital stay of at least 12 hours; and

- Clinical signs of congestive heart failure, including at least one of the following: new or worsening dyspnea, orthopnoea, paroxysmal nocturnal dyspnea, edema, pulmonary basilar crackles, jugular vein dilatation, or heart failure. radiological evidence of exacerbation; and

- Addition/Increase Therapy:

° Intravenous treatment with diuretics, inotropes or vasodilators; or

° Mechanical or surgical intervention (mechanical circulation support to improve heart function, heart transplantation or ventricular rhythm control) or the use of ultrafiltration, hemofiltration or dialysis to treat heart failure.

(2) Arrhythmias:

Arrhythmia was defined as a symptomatic deviation from normal sinus rhythm experienced by a subject assessed by a health care provider. Assessments included an outpatient visit, ECG, or physical examination during hospitalization. Arrhythmias include conduction abnormalities, atrioventricular heart block, QTc interval prolongation, supraventricular/nodal arrhythmias, vasovagal episodes, ventricular arrhythmias, or other cardiovascular arrhythmias.

(3) high blood pressure

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

After subjects are released from the study visit while receiving medication, hypertension is the objective criterion, an increase in blood pressure (systolic blood pressure >20 mmHg increase in systolic blood pressure resulting in >180 mmHg value or >15 mmHg diastolic blood pressure resulting in >105 mmHg value) increase) was defined as requiring an unscheduled outpatient health care visit, hospitalization, or change in medical regimen (eg, administration of antihypertensive drugs).

(4) hypotension

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

After subjects are released from the study visit while receiving drug, hypotension is the objective criterion, blood pressure reduction (>20 mmHg systolic pressure reduction resulting in < 90 mmHg value or >15 mmHg diastolic blood pressure reduction resulting in <50 mmHg value) was defined as requiring an unscheduled outpatient health care visit, hospitalization, or change of medical regimen (e.g., fluid/volume replenishment, retention of antihypertensive agents).

(5) myocardial infarction (MI):

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

Cardiac enzyme markers indicative of MI include:

- Appropriate elevations and drops in serum troponin (I or T) or creatine kinase-MB, where at least 1 value is ≥ 2 x upper limit of normal (ULN). If only one value was measured, a response was judged based on full clinical evidence if ≥ 2 x ULN.

- If only total creatine phosphokinase is measured, the continuous change (ie at least 2 values) must be ≥ 2 x ULN.

Symptoms indicative of ischemia must be present for at least 10 minutes and include chest pain, chest compressions, or chest tightness. Dyspnea, sweating, or nausea were considered symptoms of ischemia and were judged on the basis of full clinical evidence.

ECG changes were defined as:

- new Q wave in 2 or more consecutive reads;

- ST-segment to T-wave evolution in 2 or more consecutive reads + (eg ≥ 0.5 mm transient ST-segment depression);

- new left bundle branch block; or

- 1 mm ST-segment rise on 2 or more consecutive leads.

(6) stroke:

Stroke was defined as a focal neurological defect of sudden, irreversible onset within 24 hours due to vascular causes involving the central nervous system and not due to other readily identifiable causes (eg, brain tumor or trauma). Stroke was subclassified as hemorrhagic, ischemic, or unknown.

(7) Unstable angina requiring hospitalization:

Unstable angina requiring hospitalization was defined as an ischemic condition meeting the following criteria:

- lasts 10 minutes and was considered myocardial ischemia at final diagnosis; and

- Unscheduled medical facility visits and overnight hospitalizations (not including chest pain observation rooms); and

- One or more of the following:

° new dynamic ECG changes,

° Evidence of ischemia on stress tests with and without cardiac imaging;

° Angiographic evidence of ≥ 70% lesions and/or thrombi in epicardial coronary arteries.

(8) Death from any cause:

All-cause death was adjudicated on the date the subject was declared dead.

The secondary efficacy objective of this study was to compare the effects of treatment with iron isomaltoside and ferric carboxymaltose in subjects with IDA on hemoglobin (Hb), s -ferritin and transferrin saturation (TSAT).

Endpoints

The primary safety outcome measure was the incidence of a protocol (number of participants with such a response) defined as hypersensitivity reactions within 8 weeks.

The main efficacy outcome measure was the ability to increase Hb (g/dL) within 8 weeks.

The secondary safety outcome measure was the incidence of the protocol (number of participants with these events) defined as cardiovascular events within 8 weeks.

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

safety assessment

The study included the following safety assessments:

° AE data are collected and assessed for relevance, severity, severity and predictability. They are reported to the authorities and follow up in accordance with international and local requirements.

° Physical examination, vital sign measurements, ECG, height, weight and safety laboratory parameters.

Efficacy evaluation

This study included the following efficacy evaluations:

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

Study duration and number of visits

For individual subjects, the study duration was 8 weeks (including a screening period of 28 days) and each subject participated in 6-8 visits.

subject population

Subjects who met the following eligibility criteria were included:

1. Male or female > 18 years of age;

2. Hb ≤ 11 g/dL; and

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

For IDA-03

Additional inclusion criteria for the IDA-03 study were:

1. IDA due to various causes, such as abnormal uterine bleeding, gastrointestinal disease, cancer, bariatric procedures (gastric bypass surgery), and other conditions that lead to severe bleeding;

2. TSAT < 20%;

3. S -ferritin ≤ 100 ng/mL; and

4. Documented history of intolerance or non-response to oral iron therapy ^** for at least 1 month ^*** prior to study enrollment.

The mean age of the patients was 44 years (range 18-91 years) and 89% were female.

For CKD-04

Additional inclusion criteria for the CKD-04 study were:

1. Defined as (i) eGFR < 60 mL/min/1.73 m ² at screening (calculated by Dietary Modification of Kidney Disease (MDRD)), or (ii) eGFR < 90 mL/min/1.73 m ² at screening renal impairment as indicated by an abnormality in urine composition with a medical history based on the Framingham model and/or moderate/high risk of cardiovascular disease;

2. Screening s-ferritin ≤ 100 ng/mL, or TSAT ≤ 30% if ≤ 300 ng/mL; and

3. ESA-free or stable dose (+/- 20%) of ESA for 4 weeks prior to randomization

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

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

**Intolerance and non-response to oral iron treatment were documented as signs and symptoms in the medical history and confirmed in the original document.

*** In the past 9 months, at the investigator's judgment, there have been documents of intolerance or non-response to prescribed oral iron therapy for at least 1 month and they will not be candidates for oral iron again.

Subjects were not eligible for inclusion in this study if they met one of the following criteria:

1. According to the judgment of the researcher, anemia mainly caused by factors other than IDA

2. Hemochromatosis or other iron storage disorders

3. Previous severe hypersensitivity reactions to intravenous iron compounds

4. Intravenous iron treatment within the last 30 days prior to screening

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

6. Surgical Procedures Planned for the Study Period

7. Alanine aminotransferase (ALAT) and/or aspartate aminotransferase (ASAT) > 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 cirrhosis or active hepatitis (CKD-04 only)

10. Dialysis Required to Treat CKD

11. Alcohol or drug abuse within the past 6 months

12. Pregnant or lactating women. To avoid pregnancy, women of childbearing potential should use an appropriate method of contraception (eg, intrauterine device, hormonal contraceptive or double barrier method) for the entire study period and for 7 days after the last dose.

research treatment

Subjects received one course of treatment with iron isomaltoside (Group A) or one course of treatment with iron sucrose (Group B) as described below.

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

° Group B: Iron sucrose was administered as a slow intravenous bolus of 200 mg according to the label, repeated up to 5 times to reach a cumulative dose of 1000 mg.

No prior dosing (eg antihistamines or steroids) prior to study drug administration was permitted. If a subject is receiving treatment on a daily basis, for example for allergies or asthma, it is not considered "pre-medication" and can continue to participate in the study.

statistical analysis

Co-primary safety endpoints were analyzed by constructing an accurate two-sided 95% CI of the incidence of treatment-emergent severe and/or severe non-severe hypersensitivity reactions in the iron isomaltoside treatment group. If the upper bound of the 95 % CI is < 3 %, the safety goal is met.

In addition, the risk difference between iron isomaltoside and iron sucrose was evaluated by constructing a 95% CI of the risk difference. Both unadjusted CIs (with continuity correction) and 95% Newcombe CIs adjusted for strata are generated using the Cochran-Mantel-Haenszel method.

For sensitivity, the treatment group was compared with the logistic regression model using the treatment group and the type of treatment and underlying disease as covariates, and the treatment group using Fisher's exact test.

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

Joint primary efficacy endpoints were analyzed using a Restricted Maximum Likelihood (REML)-based mixed model for a repeated measures (MMRM) approach. All subjects in an intention-to-treat (ITT) analysis established with post-baseline Hb data had to be included in the observed data. The model included fixed categorical effects of treatment (iron isomaltoside and iron sucrose), week-by-week, treatment-specific interactions, bioburden, as well as persistent and fixed covariates of baseline Hb values and baseline Hb-week interactions. . An unstructured (co)variance structure was used to model the within-subject error. If this analysis unexpectedly does not converge, then the following structures should be applied in the following order: First-order ante-dependence, heterogeneous compound symmetry, compound symmetry. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom. The primary comparison will be the contrast between iron isomaltoside and iron sucrose at week 8 based on least-squares mean for treatment interaction effects by week. The estimated mean difference based on this model was reported as a two-sided symmetric 95% CI, and efficacy targets were met if the lower bound of the 95% CI was > -0.5 g/dL.

Baseline evaluation

The following were assessed by study staff at the clinical baseline visit at the site:

° Review inclusion and exclusion criteria to ensure no change since screening

° Pregnancy test, if applicable

° Record relevant medical history, including history of myocardial infarction, stroke or congestive heart failure

° Concomitant drug record

° Physical examination (not performed after baseline visit)

° height measurement

° Weighing

° Vital Signs Test

° Randomization

° ECG

° Fatigue evaluation by FACIT Fatigue Scale

° Pharmacoeconomic evaluation by ISDR questionnaire and medical resource use questionnaire

° Safety laboratory testing

° Efficacy laboratory testing

° Treatment with iron isomaltoside (group A only)

° Treatment with iron sucrose (group B only)

° AE assessment and recording

study evaluation

Demographics and Baseline Assessments

Date of birth, gender, race, ethnicity, and smoking habits were collected. Current smokers were defined as subjects who smoked within the last 6 months.

pregnancy test

Urine pregnancy tests were performed on all women of childbearing potential. Tests were handled and interpreted by field personnel.

Related medical history

Relevant medical history was recorded. Changes in medical history were recorded at follow-up visits during the study (exacerbations of symptoms or disease were recorded as AEs). The following were collected: disease and start and stop dates. Except for the underlying disease causing IDA, a start date that occurred >12 months prior to enrollment in the study was set to >12 months.

concomitant medications

If subjects were receiving concomitant medications, they were recorded at the baseline visit. Changes in concomitant medications were recorded at follow-up visits during the study period. The following were collected: trade name, indication, route, dose, frequency, unit, start date and stop date. A start date that occurred > 12 months prior to enrollment in the study was set to > 12 months.

Physical examination

A physical examination was performed at the discretion of the investigator and may include:

° Head-Eyes-Ears-Nose-Neck

° cardiovascular system

° Respiratory system

° nervous system

° Digestive system

° Musculoskeletal system

° urogenital system

° Dermatology

° If necessary, other

key

Height was measured without shoes on.

weight

The weight was measured.

vital signs

Heart rate and blood pressure were measured at the following time points when subjects received study drug: approximately 0-10 minutes before infusion, during infusion, 5-15 minutes and 20-40 minutes after end of infusion. If vital signs were measured more than once during a given time interval, the lowest diastolic blood pressure (including concomitant systolic blood pressure and heart rate) measurement for that period was recorded on an electronic Case Report Form (eCRF).

electrocardiogram

A standard 12-lead ECG was recorded (with date, time and signature). Two ECGs were recorded at baseline and at other treatment visits: one before study drug administration and one approximately 30 minutes after initiation of dosing. Only one ECG was recorded at the follow-up visit.

ECG does not need to be evaluated by a cardiologist.

laboratory evaluation

Blood samples were taken prior to study drug administration and, if possible, were requested to be drawn at the same time of the day at all visits to reduce weekly variability in parameters.

Laboratory evaluations were performed in a central laboratory. A laboratory manual describing all laboratory procedures was provided at each site.

Competency laboratory assessment

The following qualification laboratory assessments were performed:

° Whole hematology set: Hb, leukocytes/leukocytes (WBC), erythrocytes/red blood cells (RBC), hematocrit, platelets, neutrophil granulocytes, lymphocytes, monocytes, eosinophils, basophils, mean particulate hemoglobin (MCH) , Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin Concentration (MCHC), and Reticulocyte Count

° Biochemistry:

o S -ferritin

o Alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT)

o C-reactive protein (CRP)

o Estimated glomerular filtration rate (eGFR)

vitamin E

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

Safety Lab Assessment

The following safety laboratory assessments were analyzed.

° Complete hematology set: leukocyte/WBC, erythrocyte/RBC, hematocrit, platelet, neutrophil granulocyte, lymphocyte, monocyte, eosinophil, basophil, MCH, MCV, MCHC and reticulocyte count

° Biochemistry:

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

o S -bilirubin, ASAT, ALAT

o CRP

Efficacy laboratory evaluation

The following efficacy laboratory parameters were analyzed.

° Hb: Hemoglobin was analyzed by Coulter LH 750 System. Lysis reagents were used for the total blood count parameters to prepare the blood so that the system can measure the amount of hemoglobin. The lysis reagent rapidly and simultaneously destroys red blood cells and converts a significant portion of hemoglobin into a stable pigment. The absorbance of the pigment was directly proportional to the hemoglobin concentration of the sample. The accuracy of this method was the same as that of the hemoglobin cyanide method.

° S-Ferritin: The Access ferritin assay was a two site immunoenzyme ("sandwich") assay. Samples were added to a reaction vessel with paramagnetic particles coated with goat anti-ferritin-alkaline phosphatase conjugate and goat anti-mouse:mouse anti-ferritin complex. Serum or plasma (heparin) ferritin binds to monoclonal anti-ferritin immobilized on the solid phase, whereas goat anti-ferritin enzyme conjugates react with other antigenic sites of the ferritin molecule. It was separated in the magnetic field and the material not bound to the solid phase was removed by washing. A chemiluminescent substrate, Lumi-Phos* 530, was added to the reaction vessel, and the light generated by the reaction was measured with a luminometer.

° TSAT ( s - Collect iron and transferrin to calculate TSAT. TSAT = (Iron μg/dL/transferrin mg/dL) x 70.9).

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

Adverse events (AEs)

AE data were collected and relevance, severity, severity, and expectations with study drug were assessed.

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, as summarized in the table below.

A total of N = 518 (N = 345 in the IIM group, N = 173 in the IS group) were diagnosed at risk of CV based on medical history. Of these, a total of N = 226 patients (N = 144 in the IIM group, N = 82 in the IS group) were diagnosed with CV risk and CHF according to their medical history. A total of N = 292 patients diagnosed at risk for CV without CHF (N = 144 in the IIM group, N = 82 in the IS group). A total of N = 2748 patients were CHF-free (N = 144 in the IIM group, N = 82 in the IS group).

CKD-04
IDA-03
CKD-04/IDA-03
iron isomaltoside iron sucrose iron isomaltoside iron sucrose iron isomaltoside iron sucrose ratio N % 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 156 15.5 86 17.0 10 1.0 6 1.2 168 8.4 92 9.2 All patients without CHF 861 84.5 420 83.0 979 99.0 488 98.8 1840 91.6 908 90.8 Patients at risk for CV 319 31.3 160 31.6 26 2.6 13 2.6 345 17.2 173 17.3 CV risk: (some) stratification factors of the trial: history of myocardial infarction, stroke, or congestive heart failure (CHF) CHF: Patients with history of congestive heart failure

result

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

A total of 1,525 patients were enrolled in the CKD-04 study and were treated with isomaltoside 1000 or iron sucrose. In the CKD-04 study, 4.1% of 1019 patients treated with iron isomaltoside 1000 had a complex cardiovascular event, and the incidence was 6.9% in the iron sucrose group (506 patients).

A total of 1,525 patients were enrolled in IDA-03 follow-up and were treated with isomaltoside 1000 or iron sucrose, 0.8% of 989 patients treated with iron isomaltoside 1000, and 1.2% of 494 patients treated with iron combined Cardiovascular events were experienced. In the combined CKD-04/IDA-03 study, complex cardiovascular events were observed in 2.5% of 2008 patients treated with iron isomaltoside 1000 compared to 4.1% (p = 0.0176) with iron sucrose, suggesting that patients Complex cardiovascular events were reduced by 60% when treated with maltoside 1000. In each study, the rates of congestive heart failure, hypertension, atrial fibrillation, hypotension, and heart attack were lower in the iron isomaltoside 1000 group compared to the iron sucrose group. See Figure 1.

The overall patient population was divided into different subgroups of patients: all patients, all patients with or without CHF, patients at risk for CV, and patients at risk for CV with or without CHF. The incidence of treatment-emergent congestive heart failure adverse events in each patient group was similar and in most cases was significantly lower with iron isomaltoside 1000 compared to iron sucrose treatment. see Figure 2. For example, in the combination study CKD-04/IDA-03, 6.5% of CHF patients had treatment-emergent congestive heart failure adverse events when treated with iron sucrose, whereas treatment with iron isomaltoside 1000 reduced the 1.8% experienced these adverse events. Worsening/exacerbation of heart failure occurred in 5.4% of cases with iron sucrose in this patient group compared to only 1.8% with iron isomaltoside 1000 treatment. A similar significant reduction in treatment-emergent congestive heart failure adverse events was observed. In patients at cardiovascular risk, the incidence of congestive heart failure was 1.2% in the IIM-treated group and 3.5% in the IS-treated group, and the exacerbation of congestive heart failure was 1.2% in the IIM-treated group and 1.7% in the IS-treated group. In patients with CV risk and CHF, the incidence of congestive heart failure was 1.4% in the IIM-treated group and 4.9% in the IS-treated group, and exacerbation of congestive heart failure occurred in 1.4% of the IIM-treated group and 3.7% of the IS-treated group. did. The significance of the study results is further illustrated in Figure 5, which exemplarily presents data for the combined CKD-04/IDA-03 study in the form of a bar chart.

The odds ratios for iron isomaltoside 1000 versus iron sucrose treatment are shown in FIG. 3 . An odds ratio <1 indicates a lower probability of treatment-emergent congestive heart failure adverse events with iron isomaltoside 1000 treatment than with iron sucrose treatment. See Figure 4.

The probability that a patient (CKD-04) will not experience an adjudicated complex cardiovascular event is significantly higher after 8 weeks of treatment with iron isomaltoside 1000 than treatment with iron sucrose. See Fig. 6. This

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

In summary, the study did not include the combined cardiovascular endpoints as well as the treatment of iron isomaltoside 1000 versus iron sucrose in CKD-04 in a pooled analysis for CKD-04 and IDA-03 specifically for congestive heart failure. shows a lower incidence of cardiovascular adverse events. Moreover, the incidence of CV adverse events and the numerical differences for iron sucrose are generally higher in the CHF patient subgroup (history CHF/CV risk factors and CHF). Compared to Venofer and FCM (CDER report), the incidence for the composite endpoint (and most subcategories, including all-cause mortality) is lower for iron isomaltoside 1000 treatment.

Treatment with iron isomaltoside resulted in a greater increase in Hb from baseline to weeks 1 and 2 and a similar response at week 8 in patients with congestive heart failure in the history.

Equivalent:

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments disclosed herein. Such equivalents are intended to be encompassed 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 Rothe B, Pocock SJ, Poole-Wilson PA, Ponikowski P. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009; 361:2436-2448.

Ponikowski P, van Veldhuisen DJ, Comin-Colet J, Ertl G, Komajda M, Mareev V, McDonagh T, Parkhomenko A, Tavazzi L, Levesque V, Mori C, Roubert B, Filippatos G, Ruschitzka F, Anker SD. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J 2015; 36:657-668.

Jankowska EA, Kasztura M, Sokolski M, Bronisz M, Nawrocka S, Oles´kowska-Florek W, Zymlin´ski R, Biegus J, Siwo³owski 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.

lez-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.Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonz

lez-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,　Ponarow GC,　West; C. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2017 Aug 8; 70(6):776-803. doi: 10.1016/j.jacc.2017.04.025. Epub 2017 Apr 28.

Myles Wolf, MD, Janet Rubin, MD, Maureen Achebe, MD, Michael John Econs, MD, Munro Peacock, MD, Erik Allen Imel, MD, Lars L. Thomsen, MD, Thomas O. Carpenter, MD, Thomas Joseph Weber, MD, Heinz Zoller, MD. Effects of Iron Isomaltoside versus Ferric Carboxymaltose on Hormonal Control of Phosphate Homeostasis: The PHOSPHARE IDA04/05 Randomized Controlled Trials. ENDO 2019, March 23-26 2019, New Orleans, Session OR13 - OR13. Rare Bone Diseases and Mineral Metabolism, abstract OR13-3.

HILDEBRANDT, PR, BRUUN, NE, NIELSEN, OW, PANTEV, E. , SHIVA, F. , VIDEBÆK, L. , WIKSTRΦM, G. and THOMSEN, LL (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.1778-428X.2010.01145.x

Charles-Edwards G,　Amaral N3,　Sleigh A,　Ayis S,　Catibog N3,　McDonagh T3,　Monaghan M,　Amin-Youssef G,　Kemp GJ,　Shah AM,　Okonko DO. Effect of Iron Isomaltoside on Skeletal Muscle Energetics in Patients With Chronic Heart Failure and Iron Deficiency. Circulation. 2019 May 21; 139(21):2386-2398. doi:10.1161/CIRCULATIONAHA.118.038516.

Hannah　Jaumdally,　Mohamad F.　Barakat,　Geoffrey　Charles-Edwards,　GeorgeAmin-Youssef,　Ajay M.　Shah,　Paul,Scott,　Darlington O.　O.Konko. IRON ISOMALTOSIDE DIMINISHES ATRIAL ELECTRICAL INHOMOGENEITY IN CHRONIC HEART FAILURE WITHOUT ALTERING ATRIAL SIZE: A FERRIC-HF II SUBSTUDY. Journal of the American College of Cardiology　Mar 2019,　73　(9 Supplement 1) 833; DOI:　10.1016/S0735-1097(19)31440-8

Claims (15)

A method of treating iron deficiency in a subject, wherein the incidence or risk of a cardiovascular adverse event is reduced in the subject, the method comprising administering an effective amount of iron isomaltoside; wherein the object is
(A) subjects at risk of cardiovascular events;
(B) subjects with a history of congestive heart failure (CHF); or
(C) a subject with a history of congestive heart failure (CHF) and at risk for cardiovascular events,
wherein the reduced incidence or risk of cardiovascular events is:
(a) selected from the group consisting of congestive heart failure, myocardial infarction, unstable angina, arrhythmia, hypertension, hypotension, stroke and death;
(b) congestive heart failure;
(c) atrial fibrillation;
(d) hypertension; or
(e) cardiac arrest.
The method of claim 1 , wherein the subject is at risk for a cardiovascular event and the cardiovascular event with reduced incidence or risk is congestive heart failure.
The method of claim 1 , wherein the subject is at risk for a cardiovascular event and the cardiovascular event with reduced incidence or risk is atrial fibrillation.
The method of claim 1 , wherein the subject is at risk for a cardiovascular event and the cardiovascular event with reduced incidence or risk is heart attack.
The method of claim 1 , wherein the subject is a subject with a history of congestive heart failure and cardiovascular adverse events, and the cardiovascular adverse event with reduced incidence or risk is heart attack or congestive heart failure or both.
The method of claim 1 , wherein the subject has a history of congestive heart failure (CHF) and cardiovascular adverse events, and the cardiovascular adverse event with reduced incidence or risk is atrial fibrillation.
The method of claim 1 , wherein the subject has a history of congestive heart failure (CHF) and cardiovascular adverse events, and the cardiovascular adverse event with reduced incidence or risk is heart attack.
8. The method of any one of claims 1-7, wherein the subject is at risk of cardiovascular events and/or has a history of congestive heart failure, wherein the subject has chronic kidney disease (CKD). A method characterized by having.
8. The method of any one of claims 1-7, wherein the subject is at risk of cardiovascular events and/or has congestive heart failure, wherein the subject does not have chronic kidney disease (CKD). How to.
10. The method according to claim 8 or 9, characterized in that the chronic kidney disease (CKD) is non-dialysis dependent chronic kidney disease (NDD-CKD).
11. The method of any one of claims 1 or 5-10, wherein the subject with a history of congestive heart failure has HFrEF.
12. The method of any one of claims 1 or 5-11, wherein the subject with a history of congestive heart failure has congestive heart failure of NYHA class II-IV.
13 . The method according to claim 1 , wherein the cardiovascular adverse event with reduced incidence or risk is cardiovascular death and/or hospitalization for exacerbation of congestive heart failure.
14 . The method according to claim 1 , wherein iron deficiency is defined as TSAT < 20% and/or ferritin < 100 μg/L.
15. The method according to any one of claims 1 to 14, characterized in that the iron isomaltose is ferric derisomaltose.

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