Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
  • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
  • A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/18—Growth factors; Growth regulators
  • A61K38/1816—Erythropoietin [EPO]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present invention falls within the field of medicine in general and, more specifically, in the field of treatment of inflammatory anaemia.
• the present invention defines the use of paricalcitol, a selective Vitamin D receptor activator, in the treatment of said pathology.
• Inflammatory anaemia also known as anaemia of inflammation
• EPO erythropoietin
• Hepcidin acts by causing the degradation of ferroportin, main iron exporter from cytoplasmic storage to the blood stream, thereby blocking duodenal iron absorption and the release of iron from macrophages, which remains trapped in the interior thereof. This limits iron availability for haemoglobinisation of erythroblasts. Reduced erythropoiesis also contributes to inflammatory anaemia both by direct action and by reducing the synthesis of erythropoietin, as well as increased resistance to its action, due to different cytokines, together with reduced red blood cell lifespan.
• inflammatory anaemia is a factor associated to a worse prognosis within the different chronic pathologies, this relationship being clear in entities such as heart failure, neoplasms, respiratory diseases and chronic kidney disease (CKD), inter alia, and its presence adds a high economic impact to the treatment of the groups of patients who suffer from this disease.
• CKD chronic kidney disease
• IL-6 proinflammatory cytokines
• IL- ⁇ ⁇ proinflammatory cytokines
• INFa proinflammatory cytokines
• different treatments aimed at inhibiting and/or neutralising said inflammatory markers such as, for example, tocilizumab, I L-6 receptor inhibitor or infliximab and/or etanercept, TNFa inhibitors, have been used as a therapy aimed at rheumatological diseases such as rheumatoid arthritis.
• Vitamin D is also known, as well as its analogues and/or precursors.
• Vitamin D receptor activation has been associated with the inhibition of different inflammatory markers (IL-6, IL-1 ⁇ , INFy and TNFa).
• Vitamin D and its synthetic analogues has been related in observational studies to an improvement in the erythropoietic response of patients suffering from inflammatory anaemia of chronic kidney disease (CKD) who are being treated with erythropoiesis-stimulating agents (ESA) (Capuano A. et al., J Nephrol 2009;22:59-68; Albitar S, et al., Nephrol Dial Transplant 1997;12:514-8; Shuja SB, et al., AdvPerit Dial 2003;19:231 -5; Goicoechea M, et al., Nephron 1998;78:23-7). This beneficial effect would be directly related to the control of secondary hyperparathyroidism manifested by said patients.
• CKD chronic kidney disease
• ESA erythropoiesis-stimulating agents
• Anaemia in CKD shares physico-pathogenic mechanisms similar to those of inflammatory anaemia. Patients with CKD frequently present the inflammatory condition is frequent, which is associated to the reduced synthesis of EPO and to a deficient response thereto.
• the physiopathology of CKD is common to that of anaemia in other types of patients, such as those with heart failure, and also shares similarities in terms of overexpression of other cytokines such as I L-1 ⁇ and IL-6.
• the treatment of anaemia in patients with CKD is sustained in the use of ESA and other drugs such as iron supplements. ESAs are the greatest contributors to the global economic cost of managing these patients.
• Vitamin D and its synthetic analogues such as s calcitriol (Goicoechea et al. Nephron. 1998;78:23-7), paricalcitol (Shuja SB, et al., AdvPerit Dial 2003;19:231 -5) and alfacalcidol (Albitar S, et al., Nephrol Dial Transplant 1997;12:514- 8) have been related to an improved erythropoietic response in patients with anaemia associated with kidney disease and who are being treated with ESA.
• Group C patients have PTH levels of 1037 pg/mL, giving rise to severe hyperparathyroidism, due to which the benefit over anaemia in this last group would be attributable to the control of PTH levels.
• the treatment with paricalcitol in said study reveals a beneficial effect in the erythropoietic response.
• the paricalcitol doses used by Shuja S.B. et al. are very high (> 10 g/dialysis, which is equivalent to a weekly average of 30 ⁇ g week) and are also associated with high calcium levels (9.8 mg/dl) which exceed the maximum levels recommended in international guidelines.
• the present invention proposes, as opposed to that described in the state of the art, the use of paricalcitol in the treatment of inflammatory anaemia, demonstrating that said compound is capable of reducing the levels of inflammatory markers such as IL-6, in addition to plasma hepcidin levels, improving iron availability through the release thereof from cellular deposits, giving rise to an increase in free plasma iron and a progressive reduction in plasma ferritin levels.
• inflammatory markers such as IL-6
• the present invention discloses that the use of paricalcitol is associated with higher levels of transferrin saturation index (TSI), as a result of the greater mobilisation of iron from the cellular deposits, due to which the erythroid precursors have a greater iron supply, thereby reducing the concentration of ESAs required to obtain optimum erythropoietic response, as well as inducing greater synthesis of erythropoietin, which in turn would give rise to a decrease in ESA supply. Therefore, the present invention demonstrates that the administration of paricalcitol to patients with inflammatory anaemia reduces ESA requirements in said patients due to optimised iron absorption and to an increase in plasma EPO levels and decrease in inflammatory markers.
• TTI transferrin saturation index
• the present invention describes the use of paricalcitol in the treatment of said pathology, associated with reduced ESA requirements, optimised iron absorption, stabilisation of Hb levels, increased plasma EPO levels and decrease in inflammatory markers in said patients.
• Paricalcitol (CAS: 131918-61 -1 ) is a synthetic Vitamin D analogue that is marketed under the brand name Zemplar by Abbvie Laboratories. It is a compound which, to date, has been used mainly in the prevention and treatment of secondary hyperparathyroidism (excessive secretion of the parathyroid hormone) associated with chronic kidney disease. Chemically, is the compound 19-nor-1 , 25 - (OH) 2-vitamin D2 or 19-nor-1.25-dihydroxyvitamin D2, being an analogue of 1 .25- dihydroxycholecalciferol, the active form of Vitamin D2 (ergochalciferol). Its chemical structure is:
• the present invention discloses the use of paricalcitol in the manufacture of a pharmaceutical composition for the treatment of inflammatory anaemia, preferably wherein the paricalcitol dose is comprised between 5-10 ⁇ g/week.
• the present invention discloses paricalcitol at a preferred dose of between 5-10 ⁇ g/week, for use in the treatment of inflammatory anaemia.
• inflammatory anaemia is defined as a pathology that presents iron deficiency due to a deregulation in the inflammatory system.
• the diseases that are usually associated with inflammatory anaemia are, for example, chronic kidney disease, cancer, infectious diseases, etc.
• Subjects with inflammatory anaemia cannot absorb iron effectively to produce new red blood cells, even if the amount of iron stored in the body's tissues is normal or even high, with the resulting tissue damage. As a result, the number of new healthy red blood cells gradually decreases.
• the amount of haemoglobin the component of the red blood cells that carries oxygen to body tissues and muscles, also decreases.
• Paricalcitol as described throughout the present invention, for use in the treatment of inflammatory anaemia, can be used in combination with erythopoiesis- stimulating agents.
• the administration of said agents with paricalcitol for treating inflammatory anaemia can be combined, simultaneous or sequential.
• patients with inflammatory anaemia being treated with ESAs have a lower requirement of said compounds when they are administered paricalcitol, with the advantages entailed by said reduced ESA requirement, mainly associated with the side effects of said ESAs.
• the erythropoiesis-stimulating agents are defined as those agents or compounds similar to erythropoietin capable of stimulating erythropoietic processes, which are responsible for producing erythrocytes.
• ESAs include natural erythropoietin or EPO and synthetic ESAs, whose chemical structure is similar to that of EPO and are capable of producing the same biological effects as EPO.
• the synthetic ESAs described in the state of the art include, most notably:
• E poeti n a a (CAS No.: 1 13427-24-0): Eprex, Epopen; Epocept, Nanokine, Epofit, Epogin, Binocrit, Procrit; Epoietin beta (CAS No.: 1 13427-24-0): Eprex, Epopen; Epocept, Nanokine, Epofit, Epogin, Binocrit, Procrit; Epoietin beta (CAS No.: 1 13427-24-0): Eprex, Epopen; Epocept, Nanokine, Epofit, Epogin, Binocrit, Procrit; Epoietin beta (CAS No.: 1 13427-24-0): Eprex, Epopen; Epocept, Nanokine, Epofit, Epogin, Binocrit, Procrit; Epoietin beta (CAS No.: 1 13427-24-0): Eprex, Epopen; Epocept, Nanokine, Epofit, Epogin, Binocrit,
• Neorecormon No.:122312-54-3): Neorecormon, Recormon; Epoietin delta (CAS No.:0261356-80-3): Dynepo; Epoietin zeta (CAS No: 0604802-70-2).
• Another object disclosed in the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising paricalcitol, preferably for being administered to patients who require it, at a dose comprised between 5-10 ⁇ g week, in combination with ESAs and together with pharmaceutically acceptable excipients or vehicles.
• composition of the invention can also comprise another active ingredient.
• said active ingredients are preferably iron supplements.
• Another object disclosed in the present invention relates to the previously described pharmaceutical composition for use as a drug or, alternatively, relates to the use of the composition of the invention in the manufacture of a drug.
• Another object disclosed in the present invention relates to the previously described pharmaceutical composition for use in the treatment of inflammatory anaemia or, alternatively, relates to the use of the composition of the invention in the manufacture of a drug for treating inflammatory anaemia.
• Another object disclosed in the present invention relates to a method for treating inflammatory anaemia, characterised in that paricalcitol is administered to a subject with said disease at a dose comprised between 5-10 ⁇ g week or a pharmaceutical composition as described in the present invention.
• Fig. 1 shows the MIR-EPO study (Study A). ESAs: Neorecormon and CERA.
• the three first months correspond to the ESA dose titration phase and the three remaining months (months 3-6) correspond to the ESA dose maintenance phase (n: number of patients included in each group).
• Fig. 2 shows a regression analysis.
• the graph shows that the dose range of 5- 10 ⁇ g week of paricalcitol (x-axis) predicts a greater decrease in the concentration of ESA dose (Ul/weel) (y-axis).
• ESA dose Ul/weel
• Fig. 3 shows a regression analysis.
• the graph shows how the doses comprised between 5-10 ⁇ g week of paricalcitol predict plasma Hb levels within a range between 10-12 g/dl.
• Fig. 5 shows the analysis of Hb levels (g/dl) in patients treated with paricalcitol or calcitriol.
• Fig. 6 shows the analysis of the variation in ESA requirements depending on the use or not of IV Fe (intravenous iron) supplements.
• the follow-up time expressed in months is shown on the x-axis and the logarithmic expression of the percentage dose of ESA is shown on the y-axis.
• Fig. 7 shows the analysis of ESA dose requirements in the groups of patients treated without paricalcitol (ESA group, black line) and with paricalcitol (ESA group+PRC, grey line).
• the follow-up time expressed in months is shown on the x-axis and the logarithmic expression of the dose of ESA is shown on the y-axis.
• the average difference in month 6 of the treatment between the two groups corresponds to 24% of the dose of ESA.
• IV Fe intravenous Fe
• Fig. 1 1 shows the evolution of the TSI levels (expressed as a %) related to the treatment (continuous line) or not (discontinuous line) with Hidroferol (calcifediol) of increased 25 Vitamin D levels (the numbers that appear in the boxes refer to 25(OH) vitamin D levels, expressed as ng/ml).
• the follow-up time expressed in months is shown on the x-axis and the concentration of plasma iron ( g/dl) is shown on the y- axis.
• Fig. 13 shows the evolution of the plasma iron levels (ng/ml) throughout the study.
• Fig. 17 shows a correlation analysis between the hepcidin levels (pg/ml) and Hb levels (g/dl) during months 3 to 6 of the study.
• Fig. 18 shows a correlation analysis between the group of patients being treated with ESA (graph on the left) compared to those receiving combined treatment (ESA+PRC) (graph on the right) between the variation in red blood cell levels (M/ul) and plasma hepcidin levels (pg/ml).
• Fig. 20 shows the evolution of Klotho levels (pg/ml,log) during months 3 and 6 of the study.
• Fig. 22 shows the evolution of plasma erythropoietin levels (mUI/ml) in months
• Fig. 23 shows the evolution of median levels of erythropoietin (mUI/ml) according to the type of ESA. It can be observed that the percentage increase in erythropoietin levels is greater in those patients receiving combined treatment with paricalcitol (+PRC), both those being treated with the AAE Neorecormon and those being treated with the ESA CERA.
• PRC paricalcitol
• Fig. 25 shows the evolution of the doses of IV Fe supplements (mg/month) among the group of patients receiving combined treatment (ESA+PRC) and in the group of patients being treated exclusively with ESA.
• the graph shows the values expressed as median ⁇ SD.
• One of the objects of the present invention relates to the use of paricalcitol in the manufacture of a pharmaceutical composition for the treatment of inflammatory anaemia, wherein the dose of paricalcitol to be administered is comprised between 5- 10 ⁇ g week, preferably the dose of paricalcitol to be administered is 1 g/day and, more preferably, the dose of paricalcitol to be administered is 5 ⁇ g, twice a week.
• the present invention in turn describes paricalcitol, to be administered at a dose comprised between 5-10 ⁇ g week, for use in the treatment of inflammatory anaemia.
• the dose of paricalcitol to be administered, for use in the treatment of inflammatory anaemia is 1 g/day and, more preferably, the dose of paricalcitol to be administered is 5 ⁇ g, twice a week.
• paricalcitol may be used , at the dose indicated above, in combination with at least one erythropoiesis-stimulating agent.
• the administration of the ESA can be combined, simultaneous or sequential in relation to the use of paricalcitol.
• the ESAs are selected from among any of the following: EPO, first-generation ESAs: Epoetin alfa (CAS No:1 13427-24-0): Eprex, Epopen; Epoetin beta (CAS No:122312-54-3): Neorecormon; Epoetin delta (CAS No:0261356-80-3): Dynepo and Epoetin zeta (CAS No: 0604802-70-2); second- generation ESAs: Darbepoetin alfa (Aranesp) (CAS No:1 1096-26-7) and/or third- generation ESAs: CERA: "Continuous erythropoietin receptor activator" (Mircera).
• the preferred ESA for use in the present invention is selected from among: Epoetin beta, Neorecormon, Epoetin zeta, Darbepoetin alfa and CERA.
• Another of the objects described in the present invention related to a pharmaceutical composition comprising paricalcitol, to be administered at a dose comprised between 5-10 ⁇ g week, in combination with at least one ESA and together with pharmaceutically approved vehicles or excipients.
• the dose of paricalcitol comprised in the pharmaceutical composition, to be administered to a patient who requires it is 1 ⁇ ⁇ . In another preferred embodiment, the dose of paricalcitol to be administered is 5 ⁇ g twice a week.
• the ESA present in the composition of the i nvention is selected from a mong: EPO, first-generation ESAs: Epoetin alfa (CAS: 1 13427-24-0): Eprex, Epopen; Epoetin beta (CAS:122312-54-3): Neorecormon; Epoetin delta (CAS:0261356-80-3): Dynepo and Epoetin zeta (CAS No: 0604802-70- 2); second-generation ESAs: Darbepoetin alfa (Aranesp) (CAS:1 1096-26-7) and/or third-generation ESAs: CERA: "Continuous erythropoietin receptor activator" (Mircera), preferring any of the following: Epoetin Beta, Neorecormon, Epoetin zeta, Darbepoetin alfa and CERA.
• Epoetin Beta Epoetin alfa
• Another of the objects disclosed in the present invention relates to the previously described pharmaceutical composition, characterised in that it may comprise another active ingredient.
• said active ingredient is preferably, at least, an iron supplement.
• Another of the objects disclosed in the present invention relates to the use of the pharmaceutical composition with the doses of paricalcitol described throughout the present invention, in the manufacture of a drug.
• the present invention also relates to the pharmaceutical composition, with the dose of paricalcitol described throughout the present invention, for use as a drug.
• Another of the objects disclosed in the present invention relates to the use of the pharmaceutical composition, with the doses of paricalcitol described throughout the present invention, in the manufacture of a drug for the treatment of inflammatory anaemia.
• the present invention also relates to the pharmaceutical composition, with the doses of paricalcitol described throughout the present invention, for use as a drug in the treatment of inflammatory anaemia.
• the term "active ingredient”, “active substance”, “pharmaceutically active substance”, “active ingredient” or “pharmaceutically active ingredient” means any component that potentially provides a pharmacological activity or other different effect in the diagnosis, cure, mitigation, treatment or prevention of a disease, or that affects the structure or function of the human body or that of other animals.
• the term includes those components that promote a chemical change in the manufacture of the drug and are present therein in an expected modified form that provides the specific activity or effect.
• the pharmaceutical compositions of the present invention can be formulated for administration to an animal and, more preferably, to a mammal, including humans, in a variety of forms known in the state of the art.
• compositions can be, but not limited to, in sterile aqueous solution or in biological fluids such as serum.
• Aqueous solutions may be buffered or not buffered and have additional active or inactive components.
• the additional components include salts for modulating the ionic force, preservatives including, but not limited to, antimicrobial agents, antioxidants, chelating agents and similar, and nutrients including glucose, dextrose, vitamins and minerals.
• the compositions can be prepared for administration in solid form.
• compositions can be combined with various inert vehicles or excipient including, but not limited to, binding agents such as microcrystalline cellulose, tragacanth gum or gelatin; excipients such as starch or lactose; dispersing agents such as alginic acid or corn starch; lubricants such as magnesium stearate; sliding agents such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharine; or agents such as mint or methyl salicylate.
• binding agents such as microcrystalline cellulose, tragacanth gum or gelatin
• excipients such as starch or lactose
• dispersing agents such as alginic acid or corn starch
• lubricants such as magnesium stearate
• sliding agents such as colloidal silicon dioxide
• sweetening agents such as sucrose or saccharine
• agents such as mint or methyl salicylate.
• compositions and/or their formulations can be administered to an animal, including a mammal, and, therefore, to a human, in a variety of forms, including, but not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intrathecal, intraventricular, oral, enteral, parenteral, intranasal or dermal.
• the route of administration is oral or intravenous.
• the dose for obtaining a therapeutically effective amount depends on a variety of factors such as, for example, the age, weight, sex, tolerance,... of the mammal.
• the expression "therapeutically effective amount” relates to the amount of compounds; in the case of the present invention, it relates to the amount of paricalcitol or accompanying active ingredient, or its salts, pro-drugs, byproducts or analogues, or to its combinations, that produce the desired effect and, in general, shall be determined, inter alia, by the characteristics inherent to said prodrugs, by-products and analogues and the therapeutic effect to be achieved.
• the "pharmaceutically acceptable adjuncts", “excipients” and “vehicles” that can be used in said compositions are the vehicles known by the persons skilled in the art.
• excipients could have the function of binding the ingredients together such as, for example, starches, sugars or celluloses, sweetening function, colouring function, protective fu nction of the d rug such as, for example, isolating it from air and/or humidity, filling function of a pill, capsule or any other form of presentation such as, for example, dibasic calcium phosphate, disintegrating function to facilitate the dissolution of the components and their absorption in the intestine, without excluding other types of excipients not mentioned in this paragraph.
• ingredients such as, for example, starches, sugars or celluloses, sweetening function, colouring function, protective fu nction of the d rug such as, for example, isolating it from air and/or humidity, filling function of a pill, capsule or any other form of presentation such as, for example, dibasic calcium phosphate, disintegrating function to facilitate the dissolution of the components and their absorption in the intestine, without excluding other types of excipients not mentioned in this paragraph.
• pharmaceutically acceptable relates to the fact that the excipient is permitted and evaluated so that it does not damage the organisms to which it is administered. Additionally, the excipient must be pharmaceutically adequate, i.e. an excipient that allows the activity of the active ingredient or active ingredients, i.e. it must be compatible with the active ingredient; in this case, the active ingredient is paricalcitol.
• a "pharmaceutically acceptable” vehicle relates to the substances, or combination of substances, known i n the pharmaceutical sector, used i n the manufacture of pharmaceutical forms of administration and include, but are not limited to, solids, liquids, solvents or surfactants.
• the vehicle like the excipient, is a substance used in the drug to dilute any of the compounds of the present invention up to a certain volume or weight.
• the pharmaceutically acceptable vehicle is an inert substance or a substance with an identical action to any of the cells of the present invention.
• the function of the vehicle is to facilitate the addition of other compounds, allow improved dosing and administration or give consistency and shape to the pharmaceutical composition.
• Another of the objects disclosed in the present invention relates to a method for treating inflammatory anaemia characterised in that a dose of paricalcitol comprised between 5-10 ⁇ g week is administered to a subject with said disease, or to the composition of the invention, as described throughout the present document.
• the method of the invention is characterised in that the dose of paricalcitol to be administered is 1 g/day. In another preferred embodiment, the method of the invention is characterised in that the dose of paricalcitol to be administered is 5 ⁇ g twice a week.
• the method of the invention is characterised in that paricalcitol, at the aforementioned doses, may be used in combination with at least one ESA.
• the administration of the ESA can be combined, simultaneous or sequential in relation to the use of paricalcitol.
• ESAs are selected from among any of the following: EPO, first-generation ESAs: Epoetin alfa (CAS: 1 13427-24-0): Eprex, Epopen; Epoetin beta (CAS:122312-54-3): Neorecormon; Epoetin delta (CAS:0261356-80-3): Dynepo and Epoetin zeta (CAS No: 0604802-70-2); second-generation ESAs: Darbepoetin alfa (Aranesp) (CAS: 1 1096-26-7) and/or third-generation ESAs: CERA: "Continuous erythropoietin receptor activator" (Mircera).
• the preferred ESA for use in the present invention is selected from among: Epoetin beta, Neorecormon, Epoetin theta, Darbepoetin alfa
• the term "individual” or “subject”, as used in the description, relates to animals, preferably mammals and, more preferably, humans.
• the term “individual” or “subject” is not intended to be limiting in any aspect, and can be of any age, sex and physical condition.
• the word “comprises” and its variants must be interpreted in an inclusive sense, as opposed to an inclusive or exhaustive sense such as, for example, the term “includes.” That is, the term “comprises” must be interpreted in the sense of “includes, but is not limited to,” while the term “includes” must be interpreted in the sense of “includes and is limited to.” Therefore, the word “comprises” and its variants do not aim to exclude other technical characteristics, components or steps.
• This study is a controlled, observational and analytical prospective-type study of cases and controls. The study lasted six months. In the first three months the ESA dose titrations were obtained and, in the remaining three months corresponded to the maintenance phase.
• the data shown in the present invention form part of the MIR-EPO Study (EudraCT:2009-01551 1 -40) https://www.clinicaltrialsregister.eu.
• the design of the MIR-EPO Study assessed patients being treated with an erythropietic agent (Epoetin-beta-Neorecormon or CERA). In said patients, the differences between the groups with and without paricalcitol were analysed, due to which the results shown in the present invention related specifically to the following groups:
• Study inclusion criteria Patients ⁇ 18 years old, haemodialysis with the same type of filter for the three months prior to inclusion in the study, KT/V ⁇ 1.2 (according to the Dauguirdas second-generation technique), concentration of Hb between 10.5 and 12g/dl at least for the twelve weeks prior to inclusion in the study, preliminary treatment with stable doses of EPO (beta-epoetin) +/- 1000 Ul for the twelve weeks prior to the start of the study, transferring saturation ⁇ 20 % and serum ferritin level >100 ng/ml.
• EPO beta-epoetin
• Study exclusion criteria Grade IV heart failure (NYHA), active bleeding episode or transfusion history during the study period, non-renal causes of anaemia, neoplasms, folic acid or Vitamin B12 deficiency, haemoglobinopathies, haemolysis, pure red cell aplasia secondary to treatment with erythropoietin, acute or chronic infection or symptomatic or uncontrolled inflammatory disease, poorly controlled hypertension (HTA) requiring the suspension of human recombinant EPO (hrEPO), immunosupressor concomitant treatment with uncontrolled haemoglobin, thrombocytopathies and/or medular aplasia.
• NHA Grade IV heart failure
• non-renal causes of anaemia, neoplasms, folic acid or Vitamin B12 deficiency haemoglobinopathies, haemolysis, pure red cell aplasia secondary to treatment with erythropoietin, acute or chronic infection or symptom
• ESA dose adjustment protocol the dose of ESAs was assessed by determining haematimetry on a monthly basis in the two treatment groups, adjusting the dose of ESA according to the protocol four weeks after starting the treatment, or previously if clinically or analytically required, prolonging the study period 24 weeks ( Figure 1 ).
• the dose of ESA will be increased according to the following parameters:
• the dose of ESA will be reduced according to the following parameters:
• treatment with paricalcitol can be initiated in those patients who require it; however, this will be considered a study exclusion criterion.
• Haemoglobin was determined on a monthly basis prior to the dialysis session and corresponding weekday. The analysis of the samples was performed using flow cytometry (CELL-DYN Sapphire® - Abbott) at the central laboratory of the HUSE.
• o Klotho Human Soluble a-Klotho Assay Kit - IBL.
• TeTraMeltilBenzidina (TMB) TeTraMeltilBenzidina
• ELISA Enzyme- LinkedlmmunoSorbentAssay
• o IL-6 Quantikine ELISA Human IL-6 immunoassay.
• ELISA Enzyme- LinkedlmmunoSorbentAssay
• sandwich type using specific antibodies for mouse monoclonal and polyclonal IL-6.
• Erythropoietin Quantikine IVD ELISA Human Erythropoietin Immunoassay.
• ELISA Enzyme-LinkedlmmunoSorbentAssay
• DAS DoubleAntibodySandwich
• the non-conventional inflammatory parameters were determined in months 3 and 6 of the study, due to the fact that it is considered that the first three months of the study were dedicated to ESA dose titration and the last three months to the maintenance phase, as mentioned previously. As in the case of blood count determinations, the extractions were made prior to the mid-week dialysis session.
• Biobank In order to analyse inflammatory anaemia markers: I L-6, hepcidin, erythropoietin and plasma Klotho levels, samples obtained and stored according to protocol in the biobank of the HUSE were recovered (Code: PNT/BB/PA/000.01 ) and that corresponds to months 3 and 6.
• Hb Haemoglobin
• TSI Transferrin Saturation Index
• PTHi Parathormona intacta.
• Hb Haemoglobin
• ESAs Epoetin beta and CERA
• the optimum doses of paricalcitol for obtaining ideal plasma Hb levels between 10 and 12 g/dl, accompanied by less need for ESA in the treatment of patients with inflammatory anaemia are in the range comprised between 5 and 10 ⁇ g/week.
• the probability of having Hb levels higher than 10g/dl was assessed in the group of patients included in Study C which, according to current guidelines, can be considered a level in which the administration of ESAs is not required, observing that the possibility of presenting Hb levels higher than or equal to 10g/dl is six times greater in patients receiving combined treatment (ESA+PRC) versus those being treated exclusively with ESA (73% versus 27%, p ⁇ 0.01 , X 2: : 7.91 , OR: 6.1 (IC 95%: 1 .6-23.38).
• ESA+PRC Student A
• Paricalcitol was administered to dialysis patients one to three times a week, as with the administration of the specific ESA used , due to which joint administration would not create difficulties or changes in the usual treatment regimes of these patients.
• the dose range of paricalcitol includes doses of 5 ⁇ g week. These doses would allow their use in patients with anaemia without CKD, due to the improved profile presented by paricalcitol compared to other agonists of Vitamin D, such as calcitriol, with respect to calcium-phosphorus metabolism, and also because an oversuppression of PHT hormone levels associated with the production of a dynamic bone disease would not occur, which would be an important safety aspect for the administration of paricalcitol. That is, the dose range proposed by the present invention can be used safely both in patients with CKD and secondary hyperparathyroidism, and in patients without CKD or secondary hyperparathyroidism, exclusively presenting inflammatory anaemia.
• PTHi Parathormona intacta
• TSI Transferrin Saturation Index
• Vitamin D deficiency is associated with the risk of anaemia, due to which it is presupposed that supplementation with Vitamin D or analogues thereof, could be associated with clear beneficial effects; however, it was observed that the effect of hidroferol (calcifediol), the biologically active form of Vitamin D is not beneficial over TSI. In addition, it was observed that patients being treated with calcifediol presented lower TSI levels at the end of the study (6 months) ( Figure 11 ).
• Iron (Fe 2+ ) levels in months 0, 3 and 6 of the study were: 70 ⁇ 28, 68 ⁇ 30 and
• ESA+PRC revealed a decrease in Klotho levels (pg/ml) (log) in the two groups of patients during the follow-up time (between month 3 and 6).
• results shown demonstrate that the higher plasma Klotho levels in those patients receiving combined treatment are associated to a higher level of free plasma iron and improved TSI (%), which determine a lower rate of red blood cell destruction (inhibition of eryptosis) and, additionally, it would be associated to a greater facility for producing red blood cells at bone marrow level.
• haemoglobin variability is associated with a discreet but higher mortality rate in patients being treated with ESAs.
• Hb level variability was analysed throughout the study in both groups of patients. The results show that this variability is lower in those patients receiving combined treatment with ESA and paricalcitol with respect to those being treated exclusively with ESA (Figure 27).
• the lower hepcidin levels are associated with high Hb levels and with higher number of red blood cells, this inverse correlation occurs in those patients being treated with paricalcitol and is consistent with the properties attributed to hepcidin; however, in the data shown in the present invention, correlation is not observed between the decrease in hepcidin levels and the hypothetical increase in the number of red blood cells in patients not being treated with paricalcitol, which suggests a physiological blockage phenomenon in the decrease in hepcidin in this group of patients.
• ESA ESA showed that the group being treated with paricalcitol required less doses of erythropoietic agents with respect to the group without paricalcitol to maintain similar plasma Hb levels. This effect was independent of the administration of iron supplements, as observed in the study.
• the determination of plasma erythropoietin levels show how, over time, those patients being treated with paricalcitol, raised their plasma levels. This effect was independent of the administration of ESA and its doses, as precisely in this group of patients the doses administered were lower. The explanation to this phenomenon could be related to a lower elimination of plasma erythropoietin levels or, what seems more likely, with a greater endogenous synthesis thereof.
• the anti-inflammatory properties together with the increase in erythropoietin levels in patients receiving paricalcitol, confer it an interesting role as an adjunct therapy in patients with anaemia of inflammatory characteristics, as a consequence of optimised iron absorption and the decrease in erythropoietic agent requirements.

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