WO2020249712A1 - Treating iron deficiency in subjects at risk of cardiovascular adverse events - Google Patents
Treating iron deficiency in subjects at risk of cardiovascular adverse events Download PDFInfo
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- WO2020249712A1 WO2020249712A1 PCT/EP2020/066270 EP2020066270W WO2020249712A1 WO 2020249712 A1 WO2020249712 A1 WO 2020249712A1 EP 2020066270 W EP2020066270 W EP 2020066270W WO 2020249712 A1 WO2020249712 A1 WO 2020249712A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- the present invention relates to the field of treating iron deficiency with intravenous iron carbohydrate complexes in subjects at risk of cardiovascular adverse events.
- ID Iron deficiency impairs the body’s ability to produce hemoglobin, the key oxygen transporter, and impairs the function of key energy (ATP) producing enzymes.
- Symptoms consequently include fatigue and other signs of energy deprivation such as rapid heartbeat, shortness of breath, and chest pain.
- Iron-deficiency anemia develops when iron stores are depleted. It is widespread. About 1 billion people worldwide suffer from IDA according to the WHO. 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 grams of iron per year and high dose intravenous iron effectively and rapidly improves symptoms and increases hemoglobin levels. High dose intravenous iron allows treatment in one or few visits and intravenous iron is the only option for patients failing oral iron.
- Iron isomaltoside 1000 (INN: ferric derisomaltose) belongs to a new generation of high dose intravenous iron products. While older low dose products (ferric gluconate and iron sucrose) required 5-20 visits, these new generation products allow for iron correction in one or two visits by fast infusion of the product.
- Iron isomaltoside is a commonly used iron carbohydrate complex to treat patients with IDA who (i) have intolerance to oral iron or have had unsatisfactory response to oral iron or when there is a clinical need for rapid repletion of iron stores; or (ii) who have non hemodialysis dependent chronic kidney disease (NDD-CKD); or 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 tradenames Monofer®, Monoferric® and Diafer®.
- a typical treatment regimen of iron isomaltoside would consist either of a single infusion of 1000 mg of iron, a dose of up to 20 mg iron/kg body weight of elemental iron given as intravenous infusion, or as an intravenous bolus injection of up to 500 mg up to three times a week, with the cumulative iron need being determined using either the Ganzoni formula or the following Table:
- iron deficiency is treated in a subject being at risk of a cardiovascular adverse event. Accordingly, subjects are selected for treatment with iron isomaltoside not only based on the criteria commonly used to define eligibility for parenteral iron, i.e. diagnosis of ID or IDA and/or a potential lack of the ability to tolerate or absorb oral iron, but also based on their risk of experiencing a cardiovascular adverse event.
- the treatment of iron deficiency reduces the incidence of, or risk for, a cardiovascular adverse event in the subject.
- the subjects that are selected for treatment with iron isomaltoside based on the criteria commonly used to define eligibility for parenteral iron, i.e. diagnosis of ID or IDA and/or a potential lack of the ability to tolerate or absorb oral iron and based on their risk of experiencing a cardiovascular adverse event benefit from a reduction of the incidence of, or risk for, a cardiovascular adverse event in the subject.
- a third aspect of the invention relates to the treatment of particular groups of subjects, as defined herein, to reduce the incidence of, or risk for, a cardiovascular adverse event, as defined herein.
- the present invention in particular relates to therapeutic methods of treating iron deficiency which comprise administering iron isomaltoside to selected subgroups of subjects; and combinations of iron isomaltoside 1000 with other drugs that are either used to treat subjects at risk of cardiovascular adverse events or increase the risk of such cardiovascular adverse events.
- the present invention relates to a method of treating iron deficiency in a subject being at risk of a cardiovascular adverse event, which comprises administering an effective amount of iron isomaltoside.
- cardiovascular adverse event are subjects having one or more of the following risk factors:
- MI myocardial infarction
- AF atrial fibrillation
- xv subjects having a systemic inflammation in absence of infection, wherein the systemic inflammation is in particular one that is associated with an increased C- reactive protein (CRP) above the range of about 2-3 mg/L;
- CRP C- reactive protein
- prolyl-hydroxylase inhibitors such as daprodustat, vadadustat, roxadustat, molidustat, and desidusta;
- ESA Erythropoiesis-stimulating agents
- Epoetin alfa Procrit/Epogen
- Epoetin beta Epoetin beta (NeoRecormon)
- Darbepoetin alfa Adbepoetin alfa
- Methoxy polyethylene glycol-epoetin beta Mircera
- hepcidin modulators such as a hepcidin agonist or a hepcidin antagonist
- the present invention relates to a method of treating iron deficiency in a subject having a history of congestive heart failure (CHF), which comprises administering an effective amount of iron isomaltoside.
- CHF congestive heart failure
- the subject also has a history of myocardial infarction (MI) and/or a history of stroke.
- MI myocardial infarction
- HFrEF heart failure with reduced ejection fraction
- the subject being at risk of a cardiovascular adverse event or having a history of congestive heart failure has chronic kidney disease (CKD).
- the subject being at risk of a cardiovascular adverse event or having a history congestive heart failure does not have chronic kidney disease (CKD).
- the subject being at risk of a cardiovascular adverse event is a subject having chronic kidney disease (CKD) and a history of congestive heart failure (CHF).
- the subject having a history of congestive heart failure has HFrEF.
- the subject having a history of congestive heart failure has congestive heart failure in New York Heart Association (NYHA) class II-IV, in particular HFrEF-type congestive heart failure in New York Heart Association (NYHA) class II-IV.
- the present invention relates to a method of treating iron deficiency in a subject being at risk of a cardiovascular adverse event wherein the treatment of iron deficiency reduces the incidence of, or risk for, a cardiovascular adverse event in the subject, which method comprises administering an effective amount of iron isomaltoside.
- the cardiovascular adverse event is selected from the group consisting of events that affect the heart (cardiac adverse events); events that affect the peripheral vasculature
- the cardiac adverse events are selected from the group consisting of congestive heart failure, atrial fibrillation, cardiac arrest, atrioventricular block, cardiac failure, sinus node
- the peripheral vascular adverse events are selected from the group consisting of hypertension, increased systolic blood pressure, increase blood pressure, increased troponin, and hypotension;
- the cerebrovascular adverse events are selected from the group consisting of cerebrovascular accident, cerebral infarction, and transient ischemic attack;
- the respiratory, thoracic and mediastinal adverse events are selected from the group consisting of dyspnea and pulmonary edema;
- the general adverse events are selected from the group consisting of chest pain and death; and the infections and infestations are septic shock.
- the cardiovascular adverse event the incidence of, or risk for, which is reduced, is selected from the group consisting of events that affect the heart (cardiac adverse events); events that affect the peripheral vasculature (peripheral vascular adverse events); events that affect the cerebral vasculature (cerebrovascular adverse events); and death.
- cardiac adverse events events that affect the heart
- peripheral vascular adverse events events that affect the peripheral vasculature
- cerebral vasculature Cerebrovascular adverse events
- the events that affect the heart are congestive heart failure, myocardial infarction, unstable angina, and arrhythmia; events that affect the peripheral vasculature (peripheral vascular adverse events) are hypertension; and events that affect the cerebral vasculature (cerebrovascular adverse events) is stroke.
- the cardiovascular adverse event is selected from the group consisting of congestive heart failure, myocardial infarction, unstable angina, arrhythmia, hypertension, hypotension, stroke, and death.
- the cardiovascular adverse event is congestive heart failure, atrial fibrillation, hypertension, and/or cardiac arrest.
- specific cardiovascular adverse events related to congestive heart failure are hospitalization or death due to congestive heart failure.
- a specific cardiovascular adverse event related to congestive heart failure is hospitalization due to worsening congestive heart failure.
- the present invention is in particular directed to those CV adverse events where the CV adverse event is CHF.
- the present invention relates to a method of treating iron deficiency in a subject, wherein the treatment of iron deficiency reduces the incidence of, or risk for, a cardiovascular adverse event in the subject, which method comprises administering an effective amount of iron isomaltoside,
- C a subject having a history of congestive heart failure (CHF) and being at risk of a cardiovascular adverse event
- cardiovascular adverse event the incidence of, or risk for, which is reduced, is:
- the subject is a subject being at risk of a cardiovascular adverse event and the cardiovascular adverse event, the incidence of, or risk for, which is reduced, is congestive heart failure.
- the subject is a subject being at risk of a cardiovascular adverse event and the cardiovascular adverse event, the incidence of, or risk for, which is reduced, is atrial fibrillation.
- the subject is a subject being at risk of a cardiovascular adverse event and the cardiovascular adverse event, the incidence of, or risk for, which is reduced, is cardiac arrest.
- the subject is a subject having a history of congestive heart failure and the cardiovascular adverse event, the incidence of, or risk for, which is reduced, is cardiac arrest or congestive heart failure or both.
- the subject is a subject having a history of congestive heart failure (CHF) and the cardiovascular adverse event, the incidence of, or risk for, which is reduced, is atrial fibrillation.
- CHF congestive heart failure
- the subject is a subject having a history of congestive heart failure (CHF) and the cardiovascular adverse event, the incidence of, or risk for, which is reduced, is cardiac arrest.
- CHF congestive heart failure
- the subject defined herein is a subject being at risk of a cardiovascular adverse event and/or having a history of congestive heart failure, wherein the subject has chronic kidney disease (CKD).
- CKD chronic kidney disease
- the subject defined herein is a subject being at risk of a cardiovascular adverse event and/or having congestive heart failure, wherein the subject does not have chronic kidney disease (CKD).
- CKD chronic kidney disease
- chronic kidney disease is preferably non-dialysis dependent chronic kidney disease (NDD-CKD).
- the subject having a history of congestive heart failure has HFrEF, congestive heart failure in NYHA class II-IV, or both.
- the cardiovascular adverse event, the incidence of, or risk for, which is reduced is cardiovascular death and/or hospitalization due to worsening congestive heart failure.
- iron deficiency is preferably defined as TSAT ⁇ 20% and/or ferritin ⁇ 100 pg/L.
- the iron deficiency is iron- deficiency anemia.
- the subject to be treated has chronic iron loss or malabsorption.
- the subject does not tolerate oral iron or for whom oral iron is not effective.
- the preferred iron carbohydrate complex for use in the invention is an iron isomaltoside, especially ferric derisomaltose (sometimes also referred to as ferric derisomaltoside).
- Figure l is a table summarizing the analysis of the incidence of adjudicated and confirmed treatment-emergent composite cardiovascular (CV) adverse events with incidence > 0.25% by preferred term for study CKD-04, study IDA-03, and the combined studies CKD- 04/IDA-03.
- CV treatment-emergent composite cardiovascular
- Figure 2 is a table summarizing the analysis of treatment-emergent congestive heart failure adverse events for study CKD-04, study IDA-04, and the combined studies CKD- 04/IDA-03 in all patients; patients with or without CHF; or patients with CV risk.
- Figure 3 is a table summarizing the analysis of treatment-emergent congestive heart failure adverse events (logistic regression) for study CKD-04 and the combined studies CKD- 04/IDA-03 in patients with CV risk, with or without CHF in medical history, comparing treatment with iron isomaltoside with treatment with iron sucrose.
- Figure 4 shows the percentage of patients who experienced particular treatment- emergent composite CV adverse events (iron isomaltoside 1000: left-hand bars, iron sucrose: right-hand bars).
- Figure 5 shows the percentage of patients who experienced treatment-emergent CHF adverse events (CKD-04 and IDA-03 combined; iron isomaltoside 1000: left-hand bars, iron sucrose: right-hand bars).
- Figure 6 shows a Kaplan-Meier diagram for the probability of adjudicated composite adverse cardiovascular events (CKD-04).
- Figure 7 shows the change from baseline in hemoglobin (g/dL) by patients with CHF in medical history for the combined studies CKD-04/IDA-03 (iron isomaltoside 1000: dashed line, iron sucrose: full line).
- Figure 8 shows the change from baseline in ferritin (ng/mL) by patients with CHF in medical history for the combined studies CKD-04/IDA-03 (iron isomaltoside 1000: dashed line, iron sucrose: full line).
- Figure 9 shows the change from baseline in TSAT (%) by patients with CHF in medical history for the combined studies CKD-04/IDA-03 (iron isomaltoside 1000: dashed line, iron sucrose: full line).
- Figure 10 shows the percentage of patients who experienced treatment-emergent composite CV adverse events after treatment with IIM 1000, Venofer and FCM (combined studies CKD-04/IDA-03 for IIM 1000 (Ferwon studies); studies using Venofer and FCM based on Injectafer FDA CDER report).
- Figure 11 is a table summarizing the analysis of adverse events for study CKD-04, study IDA-03, and the combined studies CKD-04/IDA-03 using IIM 1000 (Ferwon studies) compared to studies using Venofer and FCM (Injectafer FDA CDER report).
- Treatment or “therapy” of a subject refers to any type of intervention or process performed on, or the administration of an active agent to, the subject with the objective of reversing, alleviating, ameliorating, inhibiting, slowing down, or preventing the onset, progression, development, severity, or recurrence of a symptom, complication, condition, or biochemical indicia associated with a disease.
- A“subject” includes any human or nonhuman animal.
- the term“nonhuman animal” includes, but is not limited to, vertebrates such as nonhuman primates, sheep, dogs, and rodents such as mice, rats and guinea pigs.
- the subject is a human.
- the terms,“subject” and“patient” are used interchangeably herein.
- A“therapeutically effective amount” or“therapeutically effective dose” of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a subject against the onset of a disease or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
- the ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.
- the value refers to the amount of elemental iron provided in mg or g.
- Described herein are therapeutic methods of treating iron deficiency which comprise administering an iron carbohydrate complex, and combinations of an iron carbohydrate complex with additional drugs, wherein the iron carbohydrate complex has certain properties and thus exerts certain effects in subjects under treatment.
- the methods of the invention are thus applicable to complexes that share the mechanism of action.
- iron carbohydrate complex should not induce significant increases in iFGF23 (intact FGF23).
- ferric carboxymaltose (FCM) significantly increases iFGF23 (see, for instance, WO 2013/134273 Al)
- results from clinical trials provide evidence that the risk for increasing iFGF23 and thus triggering iFGF23-mediated effects is low with iron isomaltoside 1000 (Monofer®). See, for instance, Wolf et al., 2019.
- iron isomaltoside IIM
- iron isomaltoside refers to colloidal complexes comprising iron, e.g., as iron oxide hydroxide, and isomaltoside in a matrix-like structure.
- isomaltoside refers to a hydrogenated oligoisomaltose
- the isomaltoside is a mixture of hydrogenated poly- /oligosaccharides having a weight average molecular weight Mw of from 500 to 7,000 Da, such as from 500 to 3,000 Da, from 700 to 1,400 Da and in particular of about 1,000 Da.
- the number average molecular weight (M n ) of such hydrogenated poly-/oligosaccharide is preferably in the range of from 400 to 1,400 Da, and 90 wt-% of these molecules have molecular weights of less than 3,500 Da, in particular less than 2,700 Da, and the molecular weights of the remaining 10% of the molecules are below 4,500 Da, in particular below 3,200 Da.
- said hydrogenated poly-/oligosaccharide is a hydrogenated polyglucose, oligoglucose or a mixture thereof, such as a hydrogenated dextran, hydrogenated dextrin or hydrogenated oligoisomaltose (oligoisomaltoside) or a mixture thereof, with hydrogenated oligoisomaltose, particularly hydrogenated oligoisomaltose wherein the majority (such as at least 60%, e.g. from 70 to 80%) of the molecules has 3-6 monosaccharide units, being preferred.
- the iron carbohydrate complex is an iron hydrogenated oligoisomaltose, in particular an iron(III) hydrogenated oligoisomaltose, wherein the majority (such as at least 60%, e.g. from 70 to 80%) of the oligoisomaltoside molecules has 3-6 monosaccharide units, such as iron(III) isomaltoside 1000 (INN name: ferric derisomaltose).
- Iron isomaltosides are typically characterized by a strong colloidal complex of iron oxide-hydroxide and hydrogenated isomaltose
- the content of dimer saccharide of the hydrogenated poly-/oligosaccharide is preferably 2.9 wt-% or less, 2.5 wt-% or less, or 2.3 wt-% or less, in particular 2.1 wt-% or less or 1.5 wt-% or less, and most preferably 1.0 wt-% or less, based on the total weight of the hydrogenated poly-/oligosaccharide.
- preparations of the hydrogenated poly-/oligosaccharide used for preparing iron carbohydrate complexes of the invention have a content of monomer saccharide of 0.5 wt-% or less.
- Iron hydrogenated dextran complexes prepared from such hydrogenated poly-/oligosaccharide preparations typically have an apparent molecular weight (M p ) in the range of from 120,000 to 180,000 Da, in particular from 130,000 to 160,000 Da.
- M p apparent molecular weight
- the preparation can be purified by membrane processes so as to remove high molecular weight hydrogenated polysaccharides and/or low molecular weight hydrogenated oligosaccharides.
- the hydrogenated poly-/oligosaccharide preparation has been purified by one or more membrane processes having a cut-off value between 340 and 800 Da.
- the hydrogenated poly-/oligosaccharide preparation has been purified by one or more membrane processes using a membrane having a cut-off value that allows for holding back polysaccharides having a molecular weight above 2,700 Da, optionally followed by further hydrolysis, and followed by one or more membrane processes using a membrane having a cut-off value between 340 and 800 Da.
- the purification by said membrane processes takes place prior to the hydrogenation.
- the iron isomaltoside of the invention is a compound having the formula
- X is 0.0311 ⁇ 0.0062, in particular of 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;
- Me is a monovalent metal ion such as a sodium ion or potassium ion, and is preferably a sodium ion.
- the iron complex compound of the invention is a compound having the formula
- X is 0.0311 ⁇ 0.0062, in particular 0.0311 ⁇ 0.0031;
- T is 0.2500 ⁇ 0.1250, in particular 0.2500 ⁇ 0.24750;
- R is 0.1400 ⁇ 0.0420, 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;
- Me is a monovalent metal ion such as a sodium ion or potassium ion, and is preferably a sodium ion.
- the iron complex has an iron content (determined for dry matter) of from 23 to 39 wt-% and is optionally present in the form of an injectable solution having about 100 mg/ml.
- Iron isomaltosides are obtainable as described, for instance, in WO 2010/108493 A1 and WO 2019/048674 Al.
- a preferred example of iron isomaltoside is commercially available in many countries under the tradename Monofer®, Monoferric® or Diafer®.
- Another particular iron carbohydrate complex for use in this invention is ferric bepectate (FBP).
- FBP ferric bepectate
- the term“ferric bepectate” as used herein refers to colloidal complexes comprising an iron core, e.g., as iron oxide hydroxide, coated with a hydroxyethyl- amylopectin derivative.
- Ferric bepectate has also been referred to as polyglucoferron.
- Ferric bepectate and its manufacture are disclosed, for instance, in WO 2012175608 Al. Briefly, hydroxy ethyl starch is dissolved in water. Then, the pH value is adjusted to a value of 8.0 to 10.0. Afterwards, a cyanide compound is added to the hydroxy ethyl starch solution. Then the solution is heated to a temperature of 80 to 99°C and kept at this temperature for a first time period. Finally, the pH value is adjusted to a value of 2.0 to 4.0 and the solution is brought to a temperature of 50 to 90 °C and kept at this temperature for a second time period.
- a starch manufactured by this method is characterized in that it carries a heptonic acid residue on at least one of its termini.
- hydroxyethyl starch is a starch in which some of the hydroxyl groups of the single glucosyl residues are substituted by a hydroxyethyl residue.
- the modification by the heptonic acid residue takes place by converting the terminal glucosyl residue of the hydroxyethyl starch into a heptonic acid residue.
- the hydroxyethyl starch used in the method has a weight average molecular weight (Mw) of less than 200,000 g/mol, in particular of less than 130,000 g/mol, in particular of less than 100,000 g/mol, in particular of less than 90,000 g/mol, in particular of less than 80 000 g/mol and very particular of less than 75,000 g/mol.
- Mw weight average molecular weight
- a very well suited molecular weight is in the range of 55,000 g/mol to 85,000 g/mol.
- Such a hydroxyethyl starch has a comparatively lower molecular weight than (non-modified) hydroxyethyl starches used in the medical field at present.
- a suited method for determining the molecular weight of the hydroxyethyl starch is size exclusion chromatography (SEC).
- SEC size exclusion chromatography
- the hydroxyethyl starch has an average degree of molar substitution of 0.4 to 0.6, in particular of 0.45 to 0.55. An average degree of molar substitution of around 0.50 is particularly preferred.
- the average degree of molar substitution is a measure for the amount of hydroxyl groups being substituted by a hydroxyethyl residue per glucosyl residue.
- the average degree of molar substitution can be three at the maximum.
- An average degree of molar substitution of 0.5 indicates that (on an average or statistic basis) in each second glucosyl residue one hydroxyl group is substituted by a hydroxyethyl residue.
- the hydroxyethyl starch has a weight average molecular weight of 55,000 to 85,000 g/mol, preferably around 70,000 g/mol, and an average degree of molar substitution of 0.45 to 0.55, in particular around 0.50.
- Such a hydroxyethyl starch with a molecular weight of 70,000 g/mol ⁇ 15,000 g/mol and an average degree of molar substitution of 0.5 ⁇ 0.05 can also be referred to as HES 70/0.5.
- a process for manufacturing this heptonic-acid modified hydroxyethyl starch, HES 70/0.5, is described in Example 1, and the formation of the iron complex in Example 2, of WO 2019/048674 Al, all of which is incorporated by reference.
- Iron isomaltosides are the preferred iron carbohydrate complex for use according to the invention.
- Described herein are therapeutic methods of treating iron deficiency which comprise administering iron isomaltoside to selected subgroups of subjects and/or according to defined administration regimens. Accordingly, the present invention also relates to iron isomaltoside for use in said methods, the use of iron isomaltoside for treating iron deficiency and or the use of iron isomaltoside in the manufacture of a medicament for treating iron deficiency.
- the methods of the invention are typically performed on a subject in need thereof.
- a subject in need of the methods of the invention is a subject having, diagnosed with, suspected of having, or at risk for developing iron deficiency.
- Iron-deficiency anemia (IDA) develops when iron stores are depleted.
- Subjects who suffer from ID may have IDA; subjects with IDA necessarily suffer from ID.
- Methods to diagnose ID and IDA are well established in the art and commonly used in clinical practice.
- Subjects having, diagnosed with, suspected of having, or at risk for developing iron deficiency will be given parenteral, in particular intravenous, iron in the form of an iron carbohydrate complex, i.e., iron isomaltoside according to the invention, if oral iron is not tolerated or not effective in the subject, i.e., subjects who have intolerance to oral iron or have had unsatisfactory response to oral iron.
- intravenous iron is indicated is a need to deliver iron rapidly, i.e., when there is a clinical need for rapid repletion of iron stores.
- Subjects having iron deficiency may demonstrate low or inadequate markers of systemic iron status. This means that such subjects may not have sufficient iron stored within their bodies to maintain proper iron levels.
- Most well-nourished, healthy people living in industrialized countries have approximately 4 to 5 grams of iron stored within their bodies. About 2.5 g of this iron is contained in hemoglobin, which carries oxygen through the blood. Most of the remaining approximately 1.5 to 2.5 grams of iron is contained in iron binding complexes that are present in all cells, but that are more highly concentrated in bone marrow and organs such as the liver and spleen. The liver's stores of iron are the primary physiologic reserve of iron in the healthy body.
- iron Of the body's total iron content, about 400 mg is utilized in proteins that use iron for cellular processes such as oxygen storage (myoglobin) or performing energy-producing redox reactions (cytochrome proteins). In addition to stored iron, a small amount of iron, typically about 3 to 4 mg, circulates through the blood plasma bound to a protein called transferrin.
- Free soluble ferrous iron (iron(II) or Fe 2+ ) is toxic and typically exists only in very low concentration in the body.
- iron-deficiency anemia is the primary clinical manifestation of iron deficiency. Oxygen transport to tissues including organs is vital and severe anemia is harmful and potentially fatal due to systemic lack of oxygen. Iron-deficient subjects will suffer, and in some instances may die, from organ damage caused by oxygen depletion well before cells run out of the iron needed for intracellular processes.
- Iron storage parameters can include, for example, hematocrit, hemoglobin concentration (Hb), total iron-binding capacity (TIBC), transferrin saturation (TSAT), serum iron levels, liver iron levels, spleen iron levels, and serum ferritin levels.
- Hb hemoglobin concentration
- TIBC total iron-binding capacity
- TSAT transferrin saturation
- serum iron levels are commonly known as circulating iron stores.
- the liver iron levels, spleen iron levels, and serum ferritin levels are commonly referred to as stored iron or iron stored in iron-binding complexes.
- the present disclosure provides methods of 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 levels, transferrin saturation (TSAT), hemoglobin concentration, hematocrit, total iron-binding capacity, iron absorption levels, serum iron levels, liver iron levels, spleen iron levels, and combinations thereof.
- the at least one iron storage parameter is hemoglobin
- the at least one iron storage parameter is transferrin saturation, and improving comprises increasing the transferrin saturation of the subject.
- the at least one iron storage parameter is serum ferritin levels, and improving comprises increasing the serum ferritin levels of the subject.
- the liver's stores of ferritin are the primary source of stored iron in the body.
- Ferritin is an intracellular protein that stores iron and releases it in a controlled fashion. Medically, the amount of ferritin present in a blood sample and/or in a sample of liver tissue reflects the amount of iron that is stored in the liver (although ferritin is ubiquitous and can be found in many other tissues within the body in addition to the liver).
- Ferritin serves to store iron in the liver in a nontoxic form and to transport it to areas where it is required.
- a normal ferritin blood serum level sometimes referred to as the reference interval, is usually between 30-300 ng/ml for males, and 15-200 ng/ml for females.
- ferritin blood serum level is usually above 100 ng/mL.
- serum ferritin levels are typically markedly reduced as the amount of iron available to be bound by ferritin and stored in the liver is decreased, which occurs as the body loses its ability to absorb and store iron.
- ferritin refers to the level of ferritin in blood serum as measured using a two-site immunoenzymatic (“sandwich”) assay.
- Ferritin is the major iron storage protein for the body. The concentration of ferritin is directly proportional to the total iron stores of the body, resulting in serum ferritin levels becoming a common diagnostic tool in the evaluation of iron status.
- Subjects with iron-deficiency anemia have serum ferritin levels approximately one tenth of normal subjects, while subjects with iron overload (hemochromatosis, hemosiderosis) have serum ferritin level much higher than normal.
- Ferritin levels also provide a sensitive means of detecting iron deficiency at an early stage. In both adults and children, chronic inflammation results in a disproportionate increase in ferritin levels in relation to iron reserves. Elevated ferritin levels also are observed in acute and chronic liver disease, chronic renal failure and in some types of neoplastic disease.
- subjects treated according to the methods disclosed herein experience an increase in serum ferritin levels.
- the present disclosure provides methods of increasing serum ferritin in a subject in need thereof, the methods comprising administering iron isomaltoside to the subject, wherein the iron isomaltoside provides an increase in serum ferritin.
- the iron isomaltoside provides a mean increase in serum ferritin that is greater than 100 ng/mL, greater than 110 ng/mL, greater than 120 ng/mL, greater than 130 ng/mL, greater than 140 ng/mL, greater than 150 ng/mL, greater than 160 ng/mL, greater than 170 ng/mL, greater than 180 ng/mL, greater than 190 ng/mL, or greater than 200 ng/mL at 4 or 8 weeks after treatment.
- the iron isomaltoside provides a mean increase in serum ferritin that is selected from less than 400 ng/mL, less than 390 ng/mL, less than 380 ng/mL, less than 370 ng/mL, less than 360 ng/mL, less than 350 ng/mL, less than 340 ng/mL, less than 330 ng/mL, less than 320 ng/mL, less than 310 ng/mL, less than 300 ng/mL, less than 290 ng/mL, less than 280 ng/mL, less than 270 ng/mL, less than 260 ng/mL, or less than 250 ng/mL at 4 or 8 weeks after treatment.
- the iron isomaltoside provides a mean increase in serum ferritin of 100 - 400 ng/mL, 100 - 375 ng/mL, 100 - 350 ng/mL, 100 - 325 ng/mL, 100 - 300 ng/mL, 100 - 275 ng/mL, or 150 - 300 ng/mL at 4 or 8 weeks after treatment.
- the iron isomaltoside provides a mean increase in serum ferritin that is greater than 200 ng/mL, greater than 230 ng/mL, greater than 260 ng/mL, greater than 290 ng/mL, greater than 320 ng/mL, greater than 350 ng/mL, greater than 380 ng/mL, greater than 410 ng/mL, or greater than 440 ng/mL at 1 week after treatment.
- the iron isomaltoside provides a mean increase in serum ferritin that is selected from less than 600 ng/mL, less than 590 ng/mL, less than 580 ng/mL, less than 570 ng/mL, less than 560 ng/mL, less than 550 ng/mL, less than 540 ng/mL, less than 530 ng/mL, less than 520 ng/mL, less than 510 ng/mL, less than 500 ng/mL, less than 490 ng/mL, less than 480 ng/mL, less than 470 ng/mL, less than 460 ng/mL, or less than 450 ng/mL at 1 week after treatment.
- the iron isomaltoside provides a mean increase in serum ferritin of 200 - 600 ng/mL, 250 - 600 ng/mL, 300 - 600 ng/mL, 350 - 600 ng/mL, or 400 - 600 ng/mL at 1 week after treatment.
- TSAT Transferrin Saturation
- Transferrin In addition to stored iron, a small amount of iron, typically about 3 to 4 mg, circulates through the blood plasma bound to a protein called transferrin. Therefore, serum iron (5-iron) levels can be represented by the amount of iron circulating in the blood that is bound to the protein transferrin.
- Transferrin is a glycoprotein produced by the liver that can bind one or two ferric iron (iron(III) or Fe3+) ions. It is the most prevalent and dynamic carrier of iron in the blood, and therefore is 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 and total iron-binding capacity, multiplied by 100.
- TSAT value 35% means that 35% of the available iron-binding sites of transferrin in a blood sample are occupied by iron.
- typical TSAT values are approximately 15-50% for males and 12-45% for females.
- normal TSAT values are typically above 20%.
- TSAT values are typically markedly reduced as the amount of iron available to be bound by transferrin is decreased, which occurs as the body loses its ability to absorb and store iron.
- the TSAT value is below 20% and/or the ferritin concentration is ⁇ 100 pg/L.
- subjects treated according to the methods disclosed herein experience an increase in TSAT values.
- the present disclosure provides methods of increasing TSAT in a subject in need thereof, the methods comprising administering iron isomaltoside to the subject, wherein the iron isomaltoside provides an increase in TSAT in the subject.
- the iron isomaltoside provides a mean increase in TSAT that is greater than 1 %, greater than 1.5 %, greater than 2 %, or greater than 2.5 % at 4 or 8 weeks after treatment.
- the iron isomaltoside provides a mean increase in TSAT that is less than 5 %, less than 4 %, or less than 3 % at 4 or 8 weeks after treatment.
- the iron isomaltoside provides a mean increase in TSAT of 1 - 5%, 1.5 - 4 %, or 2 - 3 % at 4 or 8 weeks after treatment.
- the iron isomaltoside provides a mean increase in TSAT that is greater than 5%, greater than 6 %, or greater than 7 % at 1 week after treatment.
- the iron isomaltoside provides a mean increase in TSAT that is less than 20 %, less than 19 %, less than 18 %, less than 17 %, less than 16 %, or les than 15 % at 1 week after treatment.
- the iron isomaltoside provides a mean increase in TSAT of 5 - 20 %, or 5 - 15 % at 1 week after treatment.
- the hematocrit also referred to as packed cell volume or erythrocyte volume fraction, is the volume percentage of red blood cells in the blood.
- the hematocrit is typically about 45% of blood volume for men and about 40% of blood volume for women.
- the hematocrit is often significantly depleted due to poor iron absorption and/or poor iron storage capacity.
- the iron isomaltoside disclosed herein may be administered to subjects to increase hematocrit.
- the exact timing of administration will necessarily vary from subject to subject, depending upon, for example, the severity of the iron deficiency experienced by the subject, the level of iron absorption the subject is or is not experiencing, and the judgment of the treating health care professional.
- the present disclosure provides methods of increasing hematocrit in a subject in need thereof, the methods comprising administering iron isomaltoside to the subject, wherein the iron isomaltoside provides for an increase in the hematocrit of the subject.
- the increase is from 1% to 30%, from 1% to 15%, from 1% to 12%, from 1% to 10%, from 1% to 9%, from 1% to 8%, from 1% to 7%, from 1% to 6%, from 1% to 5%, from 1% to 4%, from 1% to 3%, or from 1% to 2%.
- Hemoglobin Concentration is from 1% to 30%, from 1% to 15%, from 1% to 12%, from 1% to 10%, from 1% to 9%, from 1% to 8%, from 1% to 7%, from 1% to 6%, from 1% to 5%, from 1% to 4%, from 1% to 3%, or from 1% to 2%.
- Hemoglobin concentration also referred to as the mean corpuscular hemoglobin concentration or MCHC, is a measure of the concentration of hemoglobin protein in a given volume of packed red blood cells. It is typically calculated by dividing the total amount of hemoglobin protein by the hematocrit. Hemoglobin concentration may also be measured as a mass or weight fraction and presented as a percentage (%). Numerically, however, the mass or molar measure of hemoglobin concentration and the mass or weight fraction (%) are identical, assuming a red blood cell density of 1 g/ml and negligible hemoglobin loss in the blood plasma.
- a typical mass or molar measure of hemoglobin concentration ranges from 32 g/dl - 36 g/dl, or from 4.9 mmol/L to 5.5 mmol/L, respectively.
- the hemoglobin concentration can be greatly reduced as the body loses its ability to absorb and store iron.
- subjects treated according to the methods disclosed herein experience an increase in hemoglobin concentration.
- the present disclosure provides methods of increasing hemoglobin concentration in a subject in need thereof, the methods comprising administering iron isomaltoside to the subjects, wherein the iron isomaltoside provides an increase in hemoglobin concentration in the subjects.
- the iron isomaltoside provides a mean increase in hemoglobin concentration of 0.1 - 5.0 g/dL, 0.1 - 4.0 g/dL, 0.1 - 3.0 g/dL, or 0.1 - 2.0 g/dL at 1 week after treatment.
- the iron isomaltoside provides a mean increase in hemoglobin concentration greater than 0.1 g/dL, greater than 0.2 g/dL, greater than 0.3 g/dL, greater than 0.4 g/dL, greater than 0.5 g/dL, greater than 0.6 g/dL, greater than 0.7 g/dL, greater than 0.8 g/dL, or greater than 0.9 g/dL at 1 week after treatment.
- the iron isomaltoside provides a mean increase in hemoglobin concentration of less than 1.0 g/dL, less than 0.9 g/dL, less than 0.8 g/dL.
- the iron isomaltoside provides a mean increase in hemoglobin concentration of 0.5 - 5.0 g/dL, 0.5 - 4.0 g/dL, 0.5 - 3.0 g/dL, or 0.5 - 2.0 g/dL at 4 or 8 weeks after treatment. In some embodiments, the iron isomaltoside provides a mean increase in hemoglobin concentration greater than 0.5 g/dL, greater than 0.7 g/dL, greater than 0.9 g/dL, greater than 1.1 g/dL, greater than 1.3 g/dL, or greater than 1.5 g/dL at 4 or 8 weeks after treatment.
- the iron isomaltoside provides a mean increase in hemoglobin concentration of less than 2.0 g/dL, less than 1.9 g/dL, less than 1.8 g/dL.
- Total iron-binding capacity is a measure of the blood's capacity to bind iron with the protein transferrin.
- TIBC is typically measured by drawing a blood sample and measuring the maximum amount of iron that the sample can carry.
- transferrin which is a protein that transports iron in the blood.
- a typical mass or molar measure of TIBC is in the range of 250-370 pg/dL or 45-66 pmoI/L, respectively.
- the TIBC is typically increased above these levels, as the body must produce more transferrin in an attempt to deliver iron to erythrocyte precursor cells to produce hemoglobin.
- subjects treated according to the methods disclosed herein experience a reduction in TIBC.
- the present disclosure provides methods of reducing TIBC in subjects in need thereof, the methods comprising administering iron isomaltoside to the subject, wherein the iron isomaltoside provides for a reduction in the TIBC of the subject.
- the reduction is from 0.1% to 30%, from 0.1% to 28%, from 0.1% to 26%, from 0.1% to 25%, from 0.1% to 24%, from 0.1% to 23%, from 0.1% to 22%, from 0.1% to 21%, from 0.1% to 20%, from 0.1% to 15%, from 0.1% to 10%, or from 0.1% to 5%.
- Subjects at risk of cardiovascular adverse events will generally be subject to or at risk of systemic inflammation, which can complicate the assessment of iron parameters.
- normal iron parameters would generally be considered to be a TSAT > 20% and/or a serum ferritin > 100 pg/L.
- treatment is appropriate if TSAT is less than 20% and/or serum ferritin is less than 100 pg/L or in a related embodiment if TSAT is less than 20% and serum ferritin is less than 300 pg/L. In a preferred embodiment, TSAT is less than 20% and/or serum ferritin is less than 100 pg/L.
- Treatment criteria may also include an upper limit on serum ferritin beyond which re-dosing is not recommended such as serum ferritin of no more than 300 pg/L, of no more than 400 pg/L, of no more than 500 pg/L, or of no more than 600 pg/L.
- Re-treatment criteria may also include higher limits for ferritin and TSAT than the criteria for treatment. For example, in one preferred embodiment, subsequent to the administration of the initial effective dose, subjects will receive a further dose if TSAT is less than 25% and/or serum ferritin is less than 100 pg/L and provided that serum ferritin is not higher than 400 pg/L.
- Symptoms of iron deficiency can occur before the condition has progressed to iron- deficiency anemia. Symptoms of iron deficiency can include, for example, fatigue, dizziness, pallor, hair loss, irritability, weakness, pica, brittle or grooved nails, Plummer- Vinson syndrome (painful atrophy of the mucous membrane covering the tongue, pharynx and esophagus), impaired immune function, pagophagia, and restless legs syndrome, among others.
- Subjects treated according to the methods disclosed herein will experience an improvement in iron deficiency.
- subjects treated according to the methods disclosed herein experience a decrease in iron deficiency. This decrease may occur as the total amount of iron in the body of the subject is increased through the administration of the iron isomaltoside disclosed herein.
- subjects treated according to the methods disclosed herein experience a decrease in, or an elimination of, one or more symptoms of iron deficiency, wherein the symptoms are selected from fatigue, dizziness, pallor, hair loss, irritability, weakness, pica, brittle or grooved nails, Plummer- Vinson syndrome (painful atrophy of the mucous membrane covering the tongue, pharynx and esophagus), impaired immune function, pagophagia, restless legs syndrome and combinations of the foregoing.
- the symptoms are selected from fatigue, dizziness, pallor, hair loss, irritability, weakness, pica, brittle or grooved nails, Plummer- Vinson syndrome (painful atrophy of the mucous membrane covering the tongue, pharynx and esophagus), impaired immune function, pagophagia, restless legs syndrome and combinations of the foregoing.
- the iron deficiency is iron-deficiency anemia.
- Iron-deficiency anemia is characterized by low levels of circulating red blood cells and can be caused by insufficient dietary intake, absorption and/or storage of iron. Red blood cells, which contain iron bound in hemoglobin proteins, and are typically not formed when the amount of iron in the body is deficient.
- Iron-deficiency anemia is typically characterized by pallor (pale color resulting from reduced oxyhemoglobin in the skin and mucous membranes), fatigue, lightheadedness, and weakness.
- pallor pale color resulting from reduced oxyhemoglobin in the skin and mucous membranes
- fatigue lightheadedness
- weakness weakness
- subjects can develop dyspnea (trouble breathing), pica (unusual obsessive food cravings), anxiety often resulting in OCD-type compulsions and obsessions, irritability or sadness, angina, constipation, sleepiness, tinnitus, mouth ulcers, palpitations, hair loss, fainting or feeling faint, depression, breathlessness on exertion, twitching muscles, pale yellow skin, tingling (numbness) or burning sensations, missed menstrual cycle(s), heavy menstrual period(s), slow social development, glossitis (inflammation or infection of the tongue), angular cheilitis (inflammatory lesions at the mouth's comers), koilonychia (spoon-shaped nails) or nails that are weak or brittle, poor appetite, pruritus (generalized itchiness), Plummer- Vinson syndrome (painful atrophy of the mucous membrane covering the tongue, pharynx and esophagus), and restless legs syndrome
- Anemia is typically diagnosed based on a complete blood count measured from a blood sample from a subject.
- automatic counters are utilized that report the total number of red blood cells in a sample, the hemoglobin level, and the size of the red blood cells by flow cytometry.
- a stained blood smear on a microscope slide can be examined using a microscope in order to count the total number of red blood cells in a sample and diagnose anemia.
- four parameters red blood cell count, hemoglobin concentration, mean corpuscular volume and red blood cell distribution width
- Hb hemoglobin levels
- Hb 11.0 g/dL or 6.8 mmol/L
- Hb 11.5 g/dL or 7.1 mmol/L
- Hb 12.0 g/dL or 7.4 mmol/L
- Hb 12.0 g/dL or 7.4 mmol/L
- Hb 12.0 g/dL or 7.4 mmol/L
- Hb 12.0 g/dL or 7.4 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.
- subjects treated according to the methods disclosed herein experience a decrease in one or more symptoms of anemia or iron-deficiency anemia.
- subjects treated according to the methods disclosed herein experience the elimination of one or more symptoms of anemia or iron-deficiency anemia.
- the one or more symptoms of anemia or iron-deficiency anemia are selected from pallor, fatigue,
- subjects treated according to the methods disclosed herein may experience an improvement in anemia and/or iron-deficiency anemia because hemoglobin levels are raised and/or maintained above a threshold level.
- a method of treating anemia comprising administering iron isomaltoside to the subject, wherein the iron isomaltoside provides a hemoglobin level in the subject that is at or above a level ranging from 11.0 g/dL - 13.0 g/dL, including a level selected from 11.0 g/dL,
- a method of treating anemia comprising administering iron isomaltoside to the subject, wherein the iron isomaltoside provides a hemoglobin level in the subject that is at or above a level selected from 6.8 mmol/L, 7.1 mmol/L, 7.4 mmol/L, and 8.1 mmol/L.
- a method of treating anemia in a male subject comprising administering iron isomaltoside to the male subject, wherein the iron isomaltoside provides a hemoglobin level in the male subject that is at or above a level selected from 13.0 g/dL and 8.1 mmol/L.
- a method of treating anemia in a female subject comprising administering iron isomaltoside to the female subject, wherein the iron isomaltoside provides a hemoglobin level in the female subject that is at or above a level selected from 12.0 g/dL and 7.4 mmol/L.
- a subject being at risk of a cardiovascular adverse event is a subject having a risk for one or more events selected from the group consisting of events that affect the heart (cardiac adverse events), such as congestive heart failure (CHF), in particular CHF requiring hospitalization or medical intervention, myocardial infarction, unstable angina, in particular angina requiring hospitalization, or arrhythmia; events that affect the peripheral vasculature (peripheral vascular adverse events), such as hypertension and hypotension; events that affect the cerebral vasculature (cerebrovascular adverse events), such as stroke; and/or general adverse events, such as death.
- cardiac adverse events events that affect the heart
- CHF congestive heart failure
- peripheral vasculature peripheral vasculature
- cerebral vasculature such as stroke
- general adverse events such as death.
- a subject being at risk of a cardiovascular adverse event is a subject having one or more of the following risk factors for
- cardiovascular events and in particular the cardiovascular events defined herein:
- Subjects with a glomerular filtration rate (GFR) ⁇ 60 ml/min/1.73 m 2 for 3 months are classified as having CKD, irrespective of the presence or absence of kidney damage.
- GFR glomerular filtration rate
- Those subjects with CKD who require either dialysis or kidney transplantation are typically referred to as end-stage renal disease (ESRD) subjects. Therefore, a subject is traditionally classified as an ESRD subject when he or she reaches the conclusion of the non-dialysis dependent, earlier stages, of CKD. Prior to then, those subjects are referred to as non-dialysis dependent CKD subjects.
- Non-dialysis-dependent CKD (NDD-CKD) subjects are those who have been diagnosed with an early stage of chronic kidney disease and who have not yet been medically directed to undergo dialysis.
- the U.S. National Kidney Foundation has defined 5 stages of chronic kidney disease.
- subjects having CKD progress through stages 1 through 4 before dialysis is medically necessary.
- subjects with an advanced stage of CKD, such as stage 5, who have not yet started dialysis or who have not been recommended for transplantation are also typically referred to as non-dialysis dependent CKD subjects.
- NDD-CKD is intended to cover all subjects who have been diagnosed with chronic kidney disease but who are not undergoing dialysis during the administration of iron isomaltoside. Such subjects can include, for example, subjects who have never been subjected to dialysis and, in some embodiments, subjects who have been subjected to dialysis but who are not undergoing dialysis during the administration of iron isomaltoside.
- Cardiovascular disease is a frequent cause of death in subjects with chronic kidney disease (CKD).
- CKD chronic kidney disease
- CAD coronary artery disease
- Left ventricular hypertrophy (LVH) and left ventricular dysfunction can be a consequence of having atherosclerosis but are also common non-atherosclerotic mechanisms of cardiovascular injury in CKD.
- Cardiac disease including coronary artery disease, left ventricular hypertrophy (LVH) and heart failure (HF), is common in subjects with chronic kidney disease (CKD).
- LVH appears to be increasingly prevalent as the glomerular filtration rate (GFR) declines and with increased dialysis usage.
- GFR glomerular filtration rate
- LVH is an important predictor of mortality in subjects with CKD and anemia has emerged as an important, independent risk factor for the development and progression of LVH and HF in CKD, and of adverse cardiovascular outcomes, including mortality.
- LVH LVH is important clinically because it is associated with increases in the incidence of heart failure, ventricular arrhythmias, death following myocardial infarction, decreased LV ejection fraction, sudden cardiac death, aortic root dilation, and a
- left ventricular remodeling may be an important determinant of progression to overt heart failure.
- potential mechanisms that may explain the relationship between anemia and the development of LVH include effects of reduced oxygen delivery to the myocardium, perhaps leading to increased myocyte necrosis and apoptosis, anemia-related increased cardiac output and reduced systemic vascular resistance, increased oxidative stress, less effective oxidative phosphorylation, and activation of the sympathetic nervous system.
- LVH which is itself a powerful prognostic marker for adverse cardiovascular outcomes in subjects with CKD, appears to regress with improvement in Hb levels from less than 10 g/dL to levels up to above 10 g/dL in some subjects. Again, without intending to be limited, it does not appear that raising the Hb further to more normal levels leads to further regression of LVH or clinical improvement. Baseline geometry of LVH may be an important factor in determining the subsequent clinical response to anemia correction in subjects with LVH.
- CHF Congestive Heart Failure
- Congestive heart failure and“cardiac failure congestive”, a standardized MedDRA term, are used interchangeably herein.
- Heart failure is a clinical syndrome characterized by typical symptoms (e.g.
- HF a function of a structural and/or functional cardiac abnormality
- a structural and/or functional cardiac abnormality resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress.
- signs e.g. elevated jugular venous pressure, pulmonary crackles and peripheral oedema
- a structural and/or functional cardiac abnormality resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress.
- systolic or diastolic left ventricular (LV) dysfunction which are precursors of HF. Recognition of these precursors is important because they are related to poor outcomes, and starting treatment at the precursor stage may reduce mortality in subjects with asymptomatic systolic LV dysfunction.
- Congestive HF is a term that is used to describe chronic heart failure, in particular if there is evidence of volume overload, most often displayed as peripheral or pulmonary edema.
- Congestive heart failure may be heart failure with reduced ejection fraction, LVEF ⁇ 40% (HFrEF), heart failure with preserved ejection fraction, LVEF>50% (HFpEF), or heart failure with mid-range ejection fraction, LVEF 40-49% (HFmrEF).
- the congestive heart failure (CHF) is heart failure with reduced ejection fraction, LVEF ⁇ 40% (HFrEF).
- Congestive heart failure may also be classified in accordance with the New York Heart Association (NYHA) Classification which classifies patients in one of four categories based on how much they are limited during physical activity. Patients having no symptoms and no limitation such as undue fatigue, palpitation, or dyspnea (shortness of breath), in ordinary physical activity, e.g. walking, climbing stairs etc., are assigned to NYHA class I. Patients with mild symptoms (mild shortness of breath and/or angina) and slight limitation of physical activity are assigned to NYHA class II. Patients having a marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. walking short distances of 20 to 100 m, and which are comfortable only at rest are assigned to NYHA class III. Patient who experience symptoms even while being at rest and are unable to carry on any physical activity without discomfort are assigned to NYHA class IV. In a particular embodiment of the invention, the congestive heart failure (CHF) is congestive heart failure in NYHA class II-IV.
- NYHA New York Heart
- Atrial fibrillation can be First Diagnosed AF (AF that has not been diagnosed before, irrespective of the duration of the arrhythmia or the presence and severity of AF- related symptoms), Paroxysmal AF (Self-terminating, in most cases within 48 hours. Some AF paroxysms may continue for up to 7 days. AF episodes that are cardioverted within 7 days should be considered paroxysmal), and Persistent AF (AF that lasts longer than 7 days, including episodes that are terminated by cardioversion, either with drugs or by direct current cardioversion, after 7 days or more), Long-standing persistent AF (Continuous AF lasting for >1 year when it is decided to adopt a rhythm control strategy), or Permanent AF (AF that is accepted by the patient (and physician). According to a particular embodiment of the invention, AF is First Diagnosed AF, Paroxysmal AF or Persistent AF.
- AF is associated with an increased risk of death, cardiovascular adverse events and renal diseases, including a higher risk of ischaemic heart disease, chronic kidney disease, sudden cardiac death, stroke, or incident congestive heart failure.
- Hypertension Hypertension is defined as an increase in systolic blood pressure > 20 mm Hg that results in a value > 180 mm Hg or an increase in diastolic blood pressure > 15 mm Hg that results in a value > 105 mm Hg.
- Hypertension is one of the leading risk factors for heart diseases, in particular, a risk factor for stroke. It causes about 50% of ischemic strokes and increases the risk of hemorrhagic stroke.
- hypertension stresses blood vessels due to narrowing or clogging them. This can lead to atherosclerosis or the creation of weak points in the vessel that rupture easily or balloon out the artery wall resulting in an aneurism.
- MI Myocardial Infarction
- MI Myocardial infarction
- CAD coronary artery disease
- MI is a term that is used to describe the presence of characteristic changes in cardiac enzyme markers in the setting of either temporally related symptoms of an acute coronary syndrome or electrocardiographic (ECG) changes consistent with either ischemia or infarction.
- Cardiac Troponin cTn I or T
- CKMB creatine kinase
- an increase in cTn or CKMB concentration is defined as a value exceeding the 99 th percentile of a normal reference population (upper reference limit (URL)). This discriminatory 99 th percentile is designated as the decision level for the diagnosis of MI.
- MI in patients with chest discomfort, or other ischaemic symptoms that develop ST elevation in two contiguous leads is designated as an‘ST elevation MG (STEMI).
- Patients without ST elevation at presentation are usually designated as having a‘non-ST elevation MI (non- STEMI).
- the myocardial infarction (MI) is ST-segment elevation myocardial infarction (STEMI) or non-STEMI.
- Subjects having a history in MI are one of the highest risk groups for further cardiovascular adverse event. In particular, subjects having survived MI, i.e. having a history of MI, are at increased risk of recurrent infarctions and have an annual death rate which is six times higher than that in people of the same age who do not have coronary heart disease.
- Stroke is classically characterized as a neurological deficit attributed to an acute focal injury of the central nervous system by a vascular cause, including cerebral infarction, intracerebral hemorrhage, and subarachnoid hemorrhage.
- Subjects having a history in stroke i.e. subjects who have suffered a stroke, remain at a high risk for further cardiovascular adverse event, in particular for a further stroke.
- Aortic stenosis is the most common primary valve disease leading to surgery or catheter intervention in Europe and North America, with a growing prevalence due to the ageing population.
- Mitral regurgitation is the second-most frequent indication for valve surgery in Europe. It is possible to distinguish primary from secondary MR, particularly regarding surgical and transcatheter interventional management. In primary MR, one or several components of the mitral valve apparatus are directly affected. The most frequent etiology is degenerative (prolapse, flail leaflet). Endocarditis as one of the causes of primary MR.
- Secondary MR (also known as functional MR) is defined as MR due to primary left ventricular (LV) dysfunction with normal mitral valve leaflets and chords. LV dysfunction may be due to coronary heart disease (CHD) or (non-ischemic) cardiomyopathy.
- CHD coronary heart disease
- non-ischemic cardiomyopathy
- Heart valve disease can cause many complications, including cardiovascular adverse events such as HF, stroke, blood clots, arrhythmia, or death.
- Marked hyperglycemia is associated with symptoms including frequent urination, thirst, blurred vision, fatigue and recurring infections. Beyond alleviating symptoms, the aim of blood glucose lowering is to reduce long-term complications of diabetes.
- Diabetes mellitus type 2 (also known as type 2 diabetes) is a long-term metabolic disorder that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. 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 condition in which the pancreas produces little or no insulin. Different factors, including genetics and some viruses, may contribute to type 1 diabetes. Although type 1 diabetes usually appears during childhood or adolescence, it can develop in adults. Despite active research, type 1 diabetes has no cure. Treatment focuses on managing blood sugar levels with insulin, diet and lifestyle to prevent complications.
- Cardiovascular adverse event are the leading cause of mortality for people with diabetes. This is in particular due to hypertension, abnormal blood lipids and obesity, all risk factors for cardiovascular adverse events, which is widely spread in subjects suffering from diabetes.
- uncontrolled diabetes can cause damages to the blood vessels which can lead to atherosclerosis and hypertension.
- High glucose levels increase the likelihood for the buildup of fatty deposits (atheroma) 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 the risk of heart failure is increased compared to subjects without diabetes.
- Diabetes inhibits the protective effects of estrogen which can increase the risk of a cardiovascular adverse event in premenopausal women who have diabetes.
- “Obesity” is a condition characterized by excessive body weight to the extent when the body mass index (BMI), a measurement obtained by dividing a person's weight by the square of the person's height, is over 30 kg/m2. Having a BMI of greater than 30 kg/m 2 , i.e. being obese, there is serious risk for developing hypertension (e.g., due to intra-abdominal fat), diabetes and atherosclerosis which are risk factors for a cardiovascular adverse event.
- BMI body mass index
- cardiovascular adverse event in particular, as dietary salt is a significant factor in raising blood pressure which can lead to hypertension and the associated risks.
- Subjects who are elderly, a smoker, and/or a drinker, have an increased risk for a cardiovascular adverse event.
- the elderly subject is 60 years or above, 65 year or above, 70 years or above, 75 years or above, or 80 years or above.
- the risk of stroke doubles every decade after age 55.
- the systolic blood pressure is an important predictor of the risk of a cardiovascular event by getting older.
- a drinker refers to a subject with elevated alcohol intact, in particular a subject having more than 7 drinks per week.
- Drinkers consuming too much alcohol can suffer from, or develop, problems such as increased blood pressure, acute myocardial infarction or cardiomyopathy. Further, abuse of alcohol has been shown to damage heart muscle and increase the risk of stroke and cardiac arrhythmia.
- a smoker is a person who used to be a regular smoker of tobacco and/or who is currently a regular smoker of tobacco.
- Flyperthyroidism is characterized by too high levels of thyroxine. Flyperthyroidism can accelerate a body's metabolism, causing unintentional weight loss and a rapid or irregular heartbeat.
- Thyrotoxicosis is a condition characterized by an excess of thyroid hormone in the body.
- COPD Chronic Obstructive Pulmonary Disorder
- COPD Chronic obstructive pulmonary disease
- Cardiomyopathy Cardiomyopathies are defined by structural and functional abnormalities of the ventricular myocardium that are unexplained by flow limiting coronary artery disease or abnormal loading conditions. Historically, this group of disorders has been subdivided into primary disease, in which the heart is the only involved organ, and secondary forms where the cardiomyopathy is a manifestation of a systemic disorder. ESC Guidelines adopt a classification system in which cardiomyopathies are defined by specific morphological and functional criteria and then grouped into familial/genetic and non-familial/non-genetic subtypes, irrespective of the presence of extra-cardiac disease.
- the cardiomyopathy is a genetic cardiomyopathy or an acquired cardiomyopathy.
- CRP C-reactive protein
- a subject on dialysis is a subject that is at an increased risk of a cardiovascular adverse event.
- the dialysis is hemodialysis or peritoneal dialysis.
- modulators of the hypoxia-inducible factor (HIF) signaling pathways including prolyl-hydroxylase inhibitors, such as daprodustat, vadadustat, roxadustat, molidustat, and desidusta;
- erythropoiesis-stimulating agents ESA
- ESA Erythropoietin
- Epoetin alfa Procrit/Epogen
- Epoetin beta Epoetin beta
- Darbepoetin alfa Adbepoetin alfa (Aranesp)
- Methoxy polyethylene glycol-epoetin beta Methoxy polyethylene glycol-epoetin beta
- hepcidin modulators such as a hepcidin agonist or a hepcidin antagonist.
- Subjects may take one or more erythropoiesis-stimulating agents (ESAs) in an effort to control anemia.
- ESAs work by helping the body to produce red blood cells. These red blood cells are then released from the bone marrow into the bloodstream where they help maintain blood iron levels.
- Erythropoiesis-stimulating agents commonly abbreviated as ESAs, are agents that are similar in structure and/or function to the cytokine erythropoietin, which stimulates red blood cell production (erythropoeisis) in the body.
- Typical ESAs structurally and biologically, are similar to naturally occurring protein erythropoietin.
- ESAs Erythropoietin
- Epoetin alfa Procrit/Epogen
- Epoetin beta EpoRecormon
- Darbepoetin alfa Adbepoetin alfa
- Methoxy polyethylene glycol-epoetin beta Methoxy polyethylene glycol-epoetin beta
- ESAs are commonly given to ESRD subjects. These subjects usually have lower hemoglobin levels because they can't produce enough erythropoietin.
- the side effects that occur most often with ESA use include: high blood pressure; swelling; fever; dizziness; nausea; and pain at the site of the injection, among others.
- ESAs increase the risk of venous thromboembolism (blood clots in the veins). ESAs can also cause hemoglobin to rise too high, which puts the subject at higher risk for heart attack, stroke, heart failure, and death.
- the subject is treated with an anticoagulant and/or an NS AID.
- Hereditary hemorrhagic telangiectasia (also known as Osier- Web er-Rendu disease) is a genetic disorder that is inherited from parents. Its severity can vary greatly from person to person, even within the same family. It causes abnormal connections, called arteriovenous malformations (AVMs), to develop between arteries and veins. The most common locations affected are the nose, lungs, brain and liver. These AVMs may enlarge over time and can bleed or rupture, sometimes causing catastrophic complications.
- AVMs arteriovenous malformations
- Hereditary iron refractory iron deficiency anemia is an inherited disorder characterized by impaired in absorption and utilization. IRIDA is generally understood to be associated with genetic mutations leading to upregulation of hepcidin. Specific cases of IRIDA are understood to be related to mutations in the gene TMPRSS6. IRIDA is generally refractory to oral iron, but partially responsive to parenteral iron.
- FGF23 fibroblast growth factor 23
- Fibroblast growth factor 23 is an osteocyte-derived hormone that regulates phosphate and vitamin D homeostasis. FGF23 undergoes proteolytic cleavage and as a result a mix of uncleaved, i.e. intact FGF23 (iFGF23), and its cleavage fragments are found in vivo.
- the intact form, iFGF23 is the active form in relation to phosphate metabolism where it controls the urinary excretion of phosphate, with increasing levels of iFGF23 leading to urinary wasting of phosphate.
- cFGF23 Two main types of antibody assays currently exist, one which captures only iFGF23 and another which binds to the C-terminal end of the hormone and therefore captures both iFGF23 and C-terminal fragments.
- the latter metric, cFGF23 is therefore a measure of the sum of intact FGF23 and C-terminal FGF23 fragments.
- iFGF23 and cFGF23 Two test related to FGF23 exist, iFGF23 and cFGF23, which have different interpretations.
- Elevated FGF23 levels are associated independently with prevalent and incident LVH, cardiovascular disease events, and mortality in CKD and non-CKD populations.
- CKD subjects tend to have very high FGF23 levels due to ongoing attempts of the body to compensate for the high serum phosphate levels by producing iFGF23 to increase the urinary fractional excretion of phosphate via the kidneys. For this reason iFGF23 levels are elevated in CKD subjects, and as a result other downstream effects of iFGF23 may be more pronounced.
- FGF23 levels help maintain serum phosphate in the normal range in CKD
- FGF23 concentrations increase with decreasing estimated glomerular filtration rate (eGFR) and help maintain normal phosphate homeostasis despite reduced renal mass by stimulating greater per-nephron phosphate excretion and decreasing 1,25-dihydroxyvitamin D levels.
- Parenteral iron suppresses renal tubular phosphate reabsorption and 1 -alpha- hydroxylation of vitamin D resulting in hypophosphatemia. Data indicates that hypophosphatemia is mediated by an increase in FGF23.
- the subject treated in accordance with 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 healthy humans is approximately 26.1 pg/mL and the normal level of C-terminal FGF23 fragments in the serum of healthy humans is
- the subject's FGF23 levels are elevated relative to the normal range in healthy humans.
- the subject's intact FGF23 levels in serum are between 250 pg/mL and 350 pg/mL, 200 pg/mL and 300 pg/mL, 200 pg/mL and 350 pg/mL, 300 pg/mL and 350 pg/mL, 300 pg/mL and 400 pg/mL, or 250 pg/mL and 500 pg/mL.
- the subject's intact FGF23 levels in serum are above 200 pg/mL, 225 pg/mL, 250 pg/mL, 275 pg/mL, 300 pg/mL, 325 pg/mL, or 350 pg/mL.
- the subject's C-terminal FGF23 fragment levels in serum are between 60 RU/mL and 100 RU/mL, 100 RU/mL and 200 RU/mL, 200 RU/mL and 300 RU/mL, or 250 RU/mL and 400 RU/mL. In certain embodiments, the subject's C-terminal FGF23 fragment levels in serum are above 60 RU/mL, 100 RU/mL, 125 RU/mL, 150 RU/mL, 175 RU/mL,
- subjects treated according to the methods disclosed herein experience an increase in hemoglobin concentration and/or a decrease in FGF23.
- subjects treated according to the methods disclosed herein experience an increase in the hemoglobin level of the subject to a level above 10 g/dL, above 11 g/dL, above 12 g/dL, above 13 g/dL, or above 15 g/dL.
- subjects treated according to the methods disclosed herein experience an increase in the hemoglobin level of the subject to a level between 10 g/dL to 11 g/dL, 1 lg/dL to 12 g/dL, 10 g/dL to 13 g/dL, 11 g/dL to 13 g/dL, 11 g/dL to 15 g/dL, or 12 g/dL to 15 g/dL.
- subjects treated according to the methods disclosed herein experience a decrease of at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of intact FGF23 levels in serum or plasma.
- subjects treated according to the methods disclosed herein experience a decrease of 15% to 30%, 20% to 30%, 25% to 50%, 30% to 60% or 15% to 60% of intact FGF23 levels in serum or plasma. In some embodiments, subjects treated according to the methods disclosed herein experience a decrease of at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60% of C-terminal FGF23 fragment levels in serum or plasma. In some embodiments, subjects treated according to the methods disclosed herein experience a decrease of 15% to 30%, 20% to 30%, 25% to 50%, 30% to 60% or 15% to 60% of C- terminal FGF23 fragment levels in serum or plasma.
- a particular group of subjects that are amenable to treatment according to the present invention are subjects having a history of myocardial infarction (MI), a history of stroke, a history of atrial fibrillation (AF), a history of congestive heart failure (CHF), chronic kidney disease (CKD), a history of hypertension, diabetes, a history of heart valve disorder, a history of obesity, and/or being a smoker, a drinker, and/or an elderly subject.
- MI myocardial infarction
- AF atrial fibrillation
- CHF congestive heart failure
- CKD chronic kidney disease
- MI myocardial infarction
- AF atrial fibrillation
- CKD chronic kidney disease
- CHF congestive heart failure
- a history of hypertension subjects having a history of myocardial infarction (MI), a history of stroke, and/or a history of congestive heart failure (CHF), and in particular those with a history of congestive heart failure (CHF), are a particularly preferred group of subjects being at risk of a cardiovascular adverse event and therefore amenable to treatment according to the present invention.
- a subject having a history of a particular condition, disorder or disease such as a history of myocardial infarction, stroke, atrial fibrillation, or congestive heart failure (CHF) is meant to refer to the subject's past and present medical history.
- the medical history is an account of all medical events and problems a subject has experienced, i.e., a subject’s previous medical illnesses, diagnoses, and the patient’s general health throughout the life span.
- a subject having a history of a particular condition, disorder or disease does not necessarily have to have a particular condition, disorder or disease at a given point in time for it to be classified as being at risk.
- a history of a particular condition, disorder or disease is sufficient.
- a subject who has stopped smoking is still at risk because it has a history of smoking.
- a particular group of subjects that are amenable to treatment according to the present invention are subjects having a history of congestive heart failure (CHF). These include, in particular, subjects also having a history of myocardial infarction (MI) and/or a history of stroke.
- CHF is heart failure with reduced ejection fraction (HFrEF).
- a particular group of subjects that are amenable to treatment according to the present invention are subjects having a history of myocardial infarction (MI).
- MI myocardial infarction
- MI is STEMI or non- STEMI.
- a particular group of subjects that are amenable to treatment according to the present invention are subjects having a history of stroke.
- Subjects as defined herein include subjects also having chronic kidney disease (CKD) or subjects not having CKD.
- CKD chronic kidney disease
- Those having CKD are a particular subgroup of patients amenable to treatment according to the present invention.
- these include subjects having 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).
- the subject having a history of congestive heart failure has HFrEF. In another embodiment, the subject having a history of congestive heart failure has congestive heart failure in NYHA class II-IV, in particular HFrEF-type congestive heart failure in NYHA class II-IV.
- particular groups of subjects that are amenable to treatment according to the present invention are subjects having one or more of the following risk factors:
- AF atrial fibrillation
- elderly subjects in particular subjects of 60 years or above, 65 year or above, 70 years or above, 75 years or above, or 80 years or above;
- (xii) subjects having a systemic inflammation in absence of infection, wherein the systemic inflammation is in particular one that is associated with an increased C- reactive protein (CRP) above the range of about 2-3 mg/L;
- CRP C- reactive protein
- prolyl-hydroxylase inhibitors such as daprodustat, vadadustat, roxadustat, molidustat, and desidusta;
- ESA Erythropoiesis-stimulating agents
- Epoetin alfa Procrit/Epogen
- Epoetin beta Epoetin beta (NeoRecormon)
- Darbepoetin alfa Adbepoetin alfa
- Methoxy polyethylene glycol-epoetin beta Mircera
- hepcidin modulators such as a hepcidin agonist or a hepcidin antagonist
- the disclosure provides methods for the reduction of the incidence of, or risk for, cardiovascular adverse events in subjects as defined herein.
- a reference to the reduction of the incidence of, or risk for,“cardiovascular adverse events” or“a cardiovascular adverse event” is meant to indicate that the incidence of, or risk for, one or more of the recited events is reduced.
- the cardiovascular adverse event is selected from the group consisting of events that affect the heart (cardiac adverse events); events that affect the peripheral vasculature (peripheral vascular adverse events); events that affect the cerebral vasculature (cerebrovascular adverse events); respiratory, thoracic and mediastinal adverse events; general adverse events; and infections and infestations.
- the cardiac adverse event is selected from the group consisting of congestive heart failure, atrial fibrillation, cardiac arrest, atrioventricular block, cardiac failure, sinus node dysfunction, acute myocardial infarction, bradycardia, angina pectoris, myocardial ischemia, and ventricular extrasystoles;
- the peripheral vascular adverse events are selected from the group consisting of hypertension, increased systolic blood pressure, increase blood pressure, increased troponin, and hypotension;
- the cerebrovascular adverse events are selected from the group consisting of cerebrovascular accident, cerebral infarction, and transient ischemic attack;
- the respiratory, thoracic and mediastinal adverse events are selected from the group consisting of dyspnea and pulmonary edema;
- the general adverse events are selected from the group consisting of chest pain and death; and the infections and infestations are septic shock.
- the cardiovascular adverse event is selected from the group consisting of events that affect the heart (cardiac adverse events); events that affect the peripheral vasculature (peripheral vascular adverse events); events that affect the cerebral vasculature (cerebrovascular adverse events); and death.
- the events that affect the heart are congestive heart failure, myocardial infarction, unstable angina, and arrhythmia; events that affect the peripheral vasculature (peripheral vascular adverse events) are hypertension; and events that affect the cerebral vasculature
- the cardiovascular adverse event, the incidence of, or risk for, which is reduced is selected from the group consisting of congestive heart failure, myocardial infarction, unstable angina, arrhythmia, hypertension, hypotension, stroke, and death.
- the cardiovascular adverse event, the incidence of, or risk for, which is reduced is congestive heart failure, atrial fibrillation, hypertension, and/or cardiac arrest.
- the cardiovascular adverse event is congestive heart failure.
- the cardiovascular adverse event the incidence of, or risk for, which is reduced, is atrial fibrillation.
- the cardiovascular adverse event is hypertension.
- the cardiovascular adverse event is cardiac arrest.
- Specific cardiovascular adverse events related to congestive heart failure are hospitalization, hospitalization due to worsening congestive heart failure or death due to congestive heart failure.
- the present invention is in particular directed to those CV adverse events where the CV adverse event is CHF.
- the present invention relates to a method of treating iron deficiency in a subject, wherein the treatment of iron deficiency reduces the incidence of, or risk for, a cardiovascular adverse event in the subject, which method comprises administering an effective amount of iron isomaltoside,
- cardiovascular adverse event the incidence of, or risk for, which reduced is:
- the subject is a subject being at risk of a cardiovascular adverse event and the cardiovascular adverse event, the incidence of, or risk for, which is reduced, is congestive heart failure.
- the subject is a subject being at risk of a cardiovascular adverse event and the cardiovascular adverse event the incidence of, or risk for, which is reduced, is atrial fibrillation.
- the subject is a subject being at risk of a cardiovascular adverse event and the cardiovascular adverse event the incidence of, or risk for, which is reduced, is cardiac arrest.
- the subject is a subject having a history of congestive heart failure (CHF) and the cardiovascular adverse event the incidence of, or risk for, which is reduced, is cardiac arrest or congestive heart failure or both.
- CHF congestive heart failure
- the subject is a subject having a history of congestive heart failure (CHF) and the cardiovascular adverse event the incidence of, or risk for, which is reduced, is congestive heart failure.
- CHF congestive heart failure
- the subject is a subject having a history of congestive heart failure (CHF) and the cardiovascular adverse event the incidence of, or risk for, which is reduced, is atrial fibrillation.
- the subject is a subject having a history of congestive heart failure (CHF) and the cardiovascular adverse event the incidence of, or risk for, which is reduced, is cardiac arrest.
- CHF congestive heart failure
- the subject is a subject having a history of congestive heart failure (CHF) and the cardiovascular adverse event the incidence of, or risk for, which is reduced, is hypertension.
- CHF congestive heart failure
- the subject is a subject being at risk of a cardiovascular adverse and/or having a history of congestive heart failure which has chronic kidney disease (CKD).
- the subject is a subject being at risk of a cardiovascular adverse and/or having a history of congestive heart failure which does not have chronic kidney disease (CKD).
- these include subjects having 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).
- the subject is a subject having a history of congestive heart failure (CHF) and having chronic kidney disease (CKD), in particular non-dialysis-dependent chronic kidney disease (NDD-CKD), and the cardiovascular adverse event the incidence of, or risk for, which is reduced, is congestive heart failure.
- CHF congestive heart failure
- CKD chronic kidney disease
- NDD-CKD non-dialysis-dependent chronic kidney disease
- the subject is a subject having a history of congestive heart failure (CHF) and having chronic kidney disease (CKD), in particular non-dialysis-dependent chronic kidney disease (NDD-CKD), and the cardiovascular adverse event the incidence of, or risk for, which is reduced, is atrial fibrillation.
- CHF congestive heart failure
- CKD chronic kidney disease
- NDD-CKD non-dialysis-dependent chronic kidney disease
- the subject is a subject having a history of congestive heart failure (CHF) and having chronic kidney disease (CKD), in particular non-dialysis-dependent chronic kidney disease (NDD-CKD), and the cardiovascular adverse event the incidence of, or risk for, which is reduced, is cardiac arrest.
- CHF congestive heart failure
- CKD chronic kidney disease
- NDD-CKD non-dialysis-dependent chronic kidney disease
- the subject is a subject having a history of congestive heart failure (CHF) and having chronic kidney disease (CKD), in particular non-dialysis-dependent chronic kidney disease (NDD-CKD), and the cardiovascular adverse event the incidence of, or risk for, which is reduced, is hypertension.
- CHF congestive heart failure
- CKD chronic kidney disease
- NDD-CKD non-dialysis-dependent chronic kidney disease
- subjects having a history of congestive heart failure have HFrEF.
- subjects having a history of congestive heart failure have congestive heart failure in NYHA class of II-IV, in particular HFrEF -type congestive heart failure in NYHA class II-IV.
- the disclosure provides methods for the reduction of the incidence of, or risk for, hospitalizations related to cardiovascular adverse events in subjects as defined herein.
- the disclosure provides methods of reducing mortality and morbidity, i.e., in particular death, due to cardiovascular adverse events in subjects as defined herein.
- the methods of treating iron deficiency in a subject being at risk of a cardiovascular adverse event comprise administering an effective amount of iron isomaltoside. Therefore, the methods of the invention may and, according to a preferred embodiment, do comprise, prior to said administration of iron isomaltoside, determining whether said patient is iron-deficient, and administering said iron isomaltoside if said patient is iron-deficient. More particularly, the methods of the invention further comprise, prior to said administration of iron isomaltoside, determining whether said patient is at risk of a cardiovascular adverse event, and administering said iron isomaltoside if said patient is at risk of a cardiovascular adverse event.
- a typical treatment regimen of iron isomaltoside would consist either of a single infusion of 1000 mg of iron, a dose of up to 20 mg iron/kg body weight of elemental iron given as intravenous infusion, or as an intravenous bolus injection up to 500 mg up to three times a week.
- the cumulative iron need can be determined using the Ganzoni formula and according to one embodiment, the calculated dose will be administered. Alternatively, the cumulative dose that will be administered is chosen according to the following Table:
- an effective amount of iron isomaltoside is an amount ranging from about 500 mg to 2000 mg, e.g. at 500 mg, 1000 mg, 1500 mg or 2000 mg elemental iron, which can be administered in a single dose or in more than one, in particular 2 or 3, doses.
- an effective amount of iron isomaltoside is an amount of up to 50 mg iron/kg body weight, in particular up to 30 mg iron/kg body weight, or preferably up to 20 mg iron/kg body weight.
- the dose is a single daily dose.
- a typical single daily dose of iron isomaltoside is 1000 mg elemental iron.
- the two doses may be administered within 1 month, 2 weeks, or preferably 1 week.
- iron isomaltoside may follow, for instance a third dose of from 200 to 700 mg, preferably from 300 to 600, most preferably of up to 500 mg elemental iron.
- This further, e.g. third, dose(s) may be administered within the same time frame, i.e., 1 month, 2 weeks, or preferably 1 week.
- These multiple doses are preferably administered as a bolus injection. It is further preferred if each dose is administered at least 2 and in particular 3 days apart. For instance, if 3 doses are to be administered within one week, it is preferred to administer these doses on day 1, 4 and 7.
- ferric bepectate When ferric bepectate is used as the iron carbohydrate complex of the invention, the calculation of the effective cumulative dose as elemental iron can likewise be determined based on the Ganzoni formula or the tables provided above.
- lOOOmg or 1500mg of elemental iron can be an effective cumulative dose.
- Appropriate single doses of ferric bepectate, i.e., the dose administered in one sitting, are for example 500mg, lOOOmg, or 1500mg up to 15 mg/kg or alternatively up to 20 mg/kg.
- the appropriate single dose can be 15 mg/kg or 20 mg/kg body weight.
- repeat doses of iron isomaltoside or ferric bepectate may be administered in conjunction with dialysis sessions, such as, for example,
- an angiotensin-converting enzyme inhibitor such as captopril, enalapril, lisinopril, ramipril, or trandolapril;
- beta-blocker such as bisoprolol, carvedilol, metoprolol succinate, or nebivolol
- MRA mineralocorticoid receptor antagonist
- an angiotensin receptor blocker such as candesartan, valsartan, or
- an If-channel blocker such as ivabradine
- an angiotensin receptor neprilysin inhibitor such as sacubitril/valsartan
- a diuretic such as furosemide, bumetanide, torasemide
- bendroflumethoazide hydrochlorothiazide, metolazone, indapamide, amiloride, or triamterene.
- Dosages for the additional drugs usually refer to amounts of drug administered to adults. Dosages for administration to infants may be adjusted accordingly.
- the additional drug puts the subject at higher risk for a cardiovascular adverse event.
- the additional drug is selected from the group consisting of: (i) modulators of the hypoxia-inducible factor (HIF) signaling pathways, including prolyl-hydroxylase inhibitors, such as daprodustat, vadadustat, roxadustat, molidustat, and desidusta;
- ESA erythropoiesis-stimulating agents
- Epo Erythropoietin
- Epoetin alfa Procrit/Epogen
- Epoetin beta Epoetin beta
- Darbepoetin alfa Adbepoetin alfa
- Methoxy polyethylene glycol-epoetin beta Methoxy polyethylene glycol-epoetin beta
- hepcidin modulators such as a hepcidin agonist or a hepcidin antagonist.
- a method of treating iron deficiency in a subject being at risk of a cardiovascular adverse event which comprises administering an effective amount of iron isomaltoside.
- the subject being at risk of a cardiovascular adverse event is a subject having a history of myocardial infarction (MI), a history of stroke, a history of atrial fibrillation (AF), a history of congestive heart failure (CHF), chronic kidney disease (CKD), a history of hypertension, diabetes, a history of heart valve disorders, a history of obesity, and/or being a smoker, a drinker, and/or an elderly subject.
- MI myocardial infarction
- AF atrial fibrillation
- CHF congestive heart failure
- CKD chronic kidney disease
- a cardiovascular adverse event is a subject having a history of myocardial infarction (MI), a history of stroke, a history of atrial fibrillation (AF), chronic kidney disease (CKD), a history of congestive heart failure (CHF), and/or a history of hypertension.
- MI myocardial infarction
- AF atrial fibrillation
- CKD chronic kidney disease
- CHF congestive heart failure
- the subject being at risk of a cardiovascular adverse event is a subject having a history of myocardial infarction (MI), a history of stroke, and/or a history of congestive heart failure (CHF).
- MI myocardial infarction
- CHF congestive heart failure
- CHF congestive heart failure
- CHF congestive heart failure
- MI myocardial infarction
- CHF congestive heart failure
- HFrEF heart failure with reduced ejection fraction
- CKD chronic kidney disease
- NDD-CKD non-dialysis dependent chronic kidney disease
- AF atrial fibrillation
- cardiovascular adverse event is a subject having a history of heart valve disorders.
- cardiovascular adverse event is a subject having diabetes. 22. The method of embodiment 1 or 2, wherein the subject being at risk of a cardiovascular adverse event has a history of obesity.
- cardiovascular adverse event is an elderly subject, a smoker, or a drinker.
- prolyl-hydroxylase inhibitors such as daprodustat, vadadustat, roxadustat, molidustat, and desidusta;
- ESA Erythropoiesis-stimulating agents
- Epoetin alfa Procrit/Epogen
- Epoetin beta Epoetin beta (NeoRecormon)
- Darbepoetin alfa Adbepoetin alfa
- Methoxy polyethylene glycol-epoetin beta Mircera
- hepcidin modulators such as a hepcidin agonist or a hepcidin antagonist.
- cardiovascular adverse event is selected from the group consisting of events that affect the heart (cardiac adverse events); events that affect the peripheral vasculature (peripheral vascular adverse events); events that affect the cerebral vasculature (cerebrovascular adverse events); respiratory, thoracic and mediastinal adverse events; general adverse events; and infections and infestations.
- cardiac adverse events are selected from the group consisting of congestive heart failure, atrial fibrillation, cardiac arrest,
- the peripheral vascular adverse events are selected from the group consisting of hypertension, increased systolic blood pressure, increase blood pressure, increased troponin, and hypotension;
- the cerebrovascular adverse events are selected from the group consisting of cerebrovascular accident, cerebral infarction, and transient ischemic attack;
- the respiratory, thoracic and mediastinal adverse events are selected from the group consisting of dyspnea and pulmonary edema;
- the general adverse events are selected from the group consisting of chest pain and death; and the infections and infestations are septic shock.
- cardiovascular adverse event is selected from the group consisting of events that affect the heart (cardiac adverse events); events that affect the peripheral vasculature (peripheral vascular adverse events); events that affect the cerebral vasculature (cerebrovascular adverse events); and death.
- cardiac adverse events are congestive heart failure, myocardial infarction, unstable angina, and arrhythmia; events that affect the peripheral vasculature (peripheral vascular adverse events) are hypertension; and events that affect the cerebral vasculature (cerebrovascular adverse events) is stroke.
- cardiovascular adverse events are selected from the group consisting of congestive heart failure, myocardial infarction, unstable angina, arrhythmia, hypertension, hypotension, stroke, and death.
- cardiovascular adverse event is selected from the group consisting of congestive heart failure, atrial fibrillation, hypertension, and cardiac arrest.
- a method of treating iron deficiency in a subject, wherein the treatment of iron deficiency reduces the incidence of, or risk for, a cardiovascular adverse event in the subject comprises administering an effective amount of iron isomaltoside, wherein the subject is:
- C a subject having a history of congestive heart failure (CHF) and being at risk of a
- cardiovascular adverse event the incidence of, or risk for, which is reduced, is:
- CKD chronic kidney disease
- NDD-CKD non-dialysis dependent chronic kidney disease
- disorders that predispose to AF are selected from heart valve disease, hypertension, heart failure, coronary artery disease, obesity, and diabetes mellitus.
- Iron isomaltoside 1000 was administered as a single dose of 1000 mg of elemental iron.
- Iron sucrose was administered as 200 mg slow intravenous bolus injections according to its US label and repeated up to 5 times to reach a cumulative dose of 1000 mg.
- Clinical manifestation of congestive heart failure including at least one of the following: new or worsening dyspnoea, orthopnoea, paroxysmal nocturnal dyspnoea, oedema, pulmonary basilar crackles, jugular venous distension, or radiological evidence of worsening heart failure; AND
- Arrhythmia was defined as any symptomatic deviation from normal sinus rhythm experienced by the subject that results in an evaluation by a health care provider.
- the evaluation included a physical examination during an outpatient visit, an ECG, or a hospital admission.
- Arrhythmias included any conduction abnormality, atrioventricular heart block, prolongation of QTc interval, supraventricular/nodal arrhythmia, vasovagal episode, ventricular arrhythmia, or other cardiovascular arrhythmia.
- hypertension was defined as an increase in systolic blood pressure >
- hypertension was defined as requiring an unscheduled outpatient health care visit, a hospital admission, or a change in medical therapy (e.g. administration of antihypertensives) in conjunction with the objective criteria, a rise in blood pressure (an increase in systolic blood pressure > 20 mm Hg that results in a value > 180 mm Hg or an increase in diastolic blood pressure > 15 mm Hg that results in a value > 105 mm Hg).
- a rise in blood pressure an increase in systolic blood pressure > 20 mm Hg that results in a value > 180 mm Hg or an increase in diastolic blood pressure > 15 mm Hg that results in a value > 105 mm Hg.
- hypotension was defined as a decrease in systolic blood pressure > 20 mm Hg that results in a value ⁇ 90 mm Hg or a decrease in diastolic blood pressure > 15 mm Hg that results in a value ⁇ 50 mm Hg.
- hypotension was defined as requiring an unscheduled outpatient health care visit, a hospital admission, or a change in medical therapy (e.g.
- a decrement in blood pressure (a decrease in systolic blood pressure > 20 mm Hg that results in a value ⁇ 90 mm Hg or a decrease in diastolic blood pressure > 15 mm Hg that results in a value ⁇ 50 mm Hg).
- MI Myocardial infarction
- MI myocardial infarction
- Symptoms indicative of ischemia needed to have been present for >_10 minutes and included chest pain, chest pressure, or chest tightness. Dyspnoea, diaphoresis, or nausea was considered symptoms of ischemia and was judged based on the totality of the clinical evidence.
- a stroke was defined as a focal neurological deficit of sudden onset that is not reversible within 24 hours that results from a vascular cause involving the central nervous system and is not due to another readily identifiable cause (i.e. brain tumour or trauma). Strokes were sub-classified as hemorrhagic, ischaemic, or unknown.
- Unstable angina requiring hospitalization was defined as ischemic symptoms meeting the following criteria:
- the secondary efficacy objective of the study was to compare the effects of iron isomaltoside and ferric carboxymaltose treatment in subjects with IDA on hemoglobin (Hb), 5-ferritin, and transferrin saturation (TSAT).
- Hb hemoglobin
- TSAT transferrin saturation
- the primary safety outcome measure was the incidence of protocol defined hypersensitivity reactions (number of participants with such events) within 8 weeks.
- the primary efficacy outcome measure was the ability to increase Hb (g/dL) within 8 weeks.
- the secondary safety outcome measure was the incidence of protocol defined cardiovascular adverse events (number of participants with such events) within 8 weeks.
- the secondary efficacy outcome measures were changes in 5-ferritin (ng/mL) within 8 weeks and changes in transferrin saturation (%) within 8 weeks.
- duration of the study was 8 weeks (including a 28 days screening period) and each subject attended 6-8 visits.
- IDA caused by different aetiologies* such as abnormal uterine bleeding, gastrointestinal diseases, cancer, bariatric procedures (gastric bypass operations), and other conditions leading to significant blood loss;
- the mean age of patients was 44 years (range 18-91) and 89% were woman.
- Chronic renal impairment as defined by either (i) eGFR ⁇ 60 mL/min/1.73m 2 at screening (as calculated by modification of diet in renal disease (MDRD)), or (ii) eGFR ⁇ 90 mL/min/1.73m 2 at screening and kidney damage as indicated by abnormalities in urine composition per medical history and/or intermediate/high risk of car dio- vascular disease based on the Framingham model;
- the mean age of patients was 69 years (range 25-97) and 63% were female.
- AAT Alanine Aminotransferase
- ASAT Aspartate Aminotransferase
- liver cirrhosis or active hepatitis (only for CKD-04)
- Group A iron isomaltoside was administered as a single intravenous infusion of 1000 mg at baseline diluted in 100 mL 0.9 % sodium chloride and given over approximately 20 minutes (50 mg iron/min, cumulative dose: 1000 mg).
- Group B iron sucrose was administered as 200 mg slow intravenous bolus injections according to label and repeated up to 5 times to reach a cumulative dose of 1000 mg.
- premedication e.g. antihistamine or steroids
- the co-primary safety endpoint was analyzed by constructing an exact two-sided 95 % Cl of the incidence of treatment-emergent serious and/or severe non-serious
- the treatment groups were compared between the treatment groups by a logistic regression model with treatment and type of underlying disease as factors as covariate and by Fisher’s exact tests.
- the co-primary efficacy endpoint was analysed using a restricted maximum likelihood (REML)-based mixed model for repeated measures (MMRM) approach. All subjects in the intention-to-treat (ITT) analysis set with post baseline Hb data was to be included with their observed data.
- the model included the fixed, categorical effects of treatment (iron isomaltoside and iron sucrose), week, treatment-by-week interaction, strata, as well as the continuous, fixed covariates of baseline Hb value and baseline Hb-by-week interaction.
- An unstructured (co)variance structure was used to model the within-subject errors.
- Date of birth, gender, race, ethnicity, and smoking habits were collected.
- a current smoker was defined as a subject who had been smoking within the last 6 months.
- a urine pregnancy test was performed for all women of childbearing potential. The test was handled and interpreted by the site personnel.
- Heart rate and blood pressure were measured at the following time points when a subject received study drug: approximately 0-10 minutes before infusion, during infusion, 5- 15 minutes, and 20-40 minutes after the infusion has ended. If vital signs were measured more than once in the given time interval, the lowest measurement of diastolic blood pressure (including the attendant systolic blood pressure and heart rate) for the period was noted in the electronic Case Report Form (eCRF).
- eCRF electronic Case Report Form
- a standard 12 lead ECG was recorded (including date, time, and signature). At baseline and other treatment visits, two ECGs were recorded; one before administration of the study drug and one approximately 30 minutes after start of the dosing. Only one ECG was recorded at the follow-up visits.
- the ECGs did not need to be evaluated by a cardiologist.
- Hb leucocyte s/White Blood Cells (WBC), erythrocytes/Red Blood Cells (RBC), haematocrit, platelets, neutrophil granulocytes, lymphocytes, monocytes, eosinophils, basophils, Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin Concentration (MCHC), and reticulocyte count
- AAT Alanine Aminotransferase
- ASAT Aspartate Aminotransferase
- CRP C-reactive Protein
- Vitamin E was measured at baseline visit as part of the demographic data.
- Hb Hemoglobin was analyzed by the Coulter LH 750 System. Lytic reagents were used for the complete blood count parameters to prepare the blood so that the system could measure the amount of hemoglobin. The lytic reagent rapidly and simultaneously destroyed the erythrocytes and converted the substantial proportion of the hemoglobin to a stable pigment. The absorbance of the pigment was directly proportional to the hemoglobin concentration in the sample. The accuracy of this method equaled that of the hemoglobin cyanide method.
- S-ferritin The Access ferritin assay was a two-site immunoenzymatic (“sandwich”) assay. A sample was added to a reaction vessel with goat anti-ferritin-alkaline phosphatase conjugate, and paramagnetic particles coated with goat anti-mouse: mouse anti-ferritin complexes. Serum or plasma (heparin) ferritin binds to the immobilized monoclonal anti-ferritin on the solid phase, while the goat anti-ferritin enzyme conjugate reacts with different antigenic sites on the ferritin molecules. Separation in a magnetic field and washing removed materials not bound to the solid phase. A chemiluminescent substrate, Lumi-Phos* 530, was added to the reaction vessel and light generated by the reaction was measured with a luminometer.
- TSAT (iron pg/dL/transferrin mg/dL) x 70.9).
- S-iron Serum iron (s-iron) was measured by a calorimetric assay using Roche automated clinical chemistry analyzer based on a immunoturbidimetric assay.
- AEs data were collected and evaluated for relatedness to study drug, seriousness, severity, and expectedness.
- the total patient population has been separated into different subgroups of patients: all patients, all patients with or without CHF, patients with CV risk and patients with CV risk with or without CHF.
- each patient group the incidence of treatment-emergent congestive heart failure adverse events was similar and in most cases significant lower using iron isomaltoside 1000 compared to treatment with iron sucrose. See Figure 2.
- iron isomaltoside 1000 compared to treatment with iron sucrose.
- Odds ratios ⁇ 1 indicate a probability for a treatment-emergent congestive heart failure adverse event that is lower for the treatment with iron isomaltoside 1000 than for the treatment with iron sucrose. See Figure 4.
- the probability of a patient (CKD-04) not experiencing an adjudicated composite adverse cardiovascular event is significantly higher after 8 weeks of treatment with iron isomaltoside 1000 than treatment with iron sucrose. See Figure 6.
- HILDEBRANDT P. R., BRUUN, N. E., NIELSEN, O. W., PANTEV, E. , SHIVA, F. , VIDEB7EK, L. , WIKSTROM, G. and THOMSEN, L. L. (2010), Effects of administration of iron isomaltoside 1000 in patients with chronic heart failure.
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KR1020227000785A KR20220027948A (en) | 2019-06-12 | 2020-06-12 | Treatment of iron deficiency in subjects at risk of cardiovascular adverse events |
MX2021015415A MX2021015415A (en) | 2019-06-12 | 2020-06-12 | Treating iron deficiency in subjects at risk of cardiovascular adverse events. |
BR112021025049A BR112021025049A2 (en) | 2019-06-12 | 2020-06-12 | Treatment of iron deficiency in individuals at risk for adverse cardiovascular events |
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WO2010108493A1 (en) | 2009-03-25 | 2010-09-30 | Pharmacosmos Holding A/S | A stable iron oligosaccharide compound |
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WO2023012242A1 (en) * | 2021-08-03 | 2023-02-09 | Pharmacosmos Holding A/S | Iron complex compounds for subcutaneous use in therapy of iron deficiency in companion animals |
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