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WO2018189674A1 - Prévention des troubles osseux et minéraux par restauration de l'homéostasie phosphocalcique chez les patients souffrant d'une maladie rénale chronique - Google Patents

Prévention des troubles osseux et minéraux par restauration de l'homéostasie phosphocalcique chez les patients souffrant d'une maladie rénale chronique Download PDF

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WO2018189674A1
WO2018189674A1 PCT/IB2018/052500 IB2018052500W WO2018189674A1 WO 2018189674 A1 WO2018189674 A1 WO 2018189674A1 IB 2018052500 W IB2018052500 W IB 2018052500W WO 2018189674 A1 WO2018189674 A1 WO 2018189674A1
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pth
prevention
ckd
fgf
kidney disease
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Michael PAZIANAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides

Definitions

  • the invention relates to the improvement in the control of calcium (Ca) and phosphate (Pi) homeostasis in a human subject who is suffering from chronic kidney disease (CKD) during any of stages 1 to 4 of CKD, preferably 1, 2, 3 or 4, (as defined in National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis.2002;39(suppl 1):S1-S266.). Improvements in homeostasis will have multiple and numerous benefits to a patient suffering from CKD. The patient will benefit from the prevention of mineral and bone disorders and vascular calcification, both universal complications associated with CKD (the cardiovascular events are the leading causes of premature death in patients suffering from CKD).
  • CKD chronic kidney disease
  • the improvement in the control of Ca and Pi homeostasis is achieved through the administration of parathyroid hormone (PTH) or a derivative to the patient.
  • PTH parathyroid hormone
  • CKD chronic kidney disease
  • Ca and Pi are two of the most important elements in sustaining life in man. Ca is essential in vital signalling mechanisms and acts as a cofactor in many enzymes, playing a central role in the clotting cascade and muscle contraction among a multiplicity of other functions. Pi is an irreplaceable component of phospholipids that form all cell membranes, nucleic acid synthesis and forms the basis of cell growth. Pi has a central role in the systemic regulation of pH. Also, phosphorylation and dephosphorylation of proteins is involved in the regulation of most cellular activities and processes. The intracellular signalling network is also dependent on Pi. Both, Ca and Pi are also responsible for the structure and integrity of the skeleton.
  • kidneys and skeleton share the responsibility of securing availability of both elements and the parathyroid glands operate as the command centre which orchestrates the co-ordination of these three organs.
  • Figure 1 sets out the main interactions of parathyroid hormone (referred to as PTH), calcitriol (herein referred to as 1.25(OH) 2 D 3 , and fibroblast growth factor 23 (referred to as FGF-23) and the systems (skeletal, kidney, intestine) involved.
  • PTH parathyroid hormone
  • calcitriol herein referred to as 1.25(OH) 2 D 3
  • FGF-23 fibroblast growth factor 23
  • Ca and Pi are fundamental building blocks of life and the regulation of their concentration in the circulation, and extracellular and intracellular compartments is absolutely essential.
  • PTH, l,25(OH) 2 D and FGF-23 co-ordinate the release of these two elements from the skeleton, their absorption from the food in the intestine and their re-absorption/excretion in the kidney.
  • the skeleton is the primary store and release site into the circulation of Ca and Pi.
  • the intestine where both elements are absorbed with similar intensity, is a site at which Ca and Pi absorption can be controlled by the hormones to maintain the equilibrium.
  • the kidney through the urine, is the ultimate organ involved in selectively retaining or excreting these two elements.
  • PTH Parathyroid Hormone
  • PTH is the most dominant hormone of those involved in Ca and Pi homeostasis. Its primary role is to bring enough Ca in circulation, which is less readily available in food compared with Pi, and keep its concentration inside the physiological range. The concentration of Ca in plasma and extracellular fluid is maintained within a narrow physiological range. There is an inverse sigmoidal relationship between ionized plasma Ca concentration and PTH secretion rate, and small alterations provoke changes in PTH secretion rate. However, manipulation of the Ca
  • 1.25(OH) 2 D suppresses PTH synthesis and secretion directly and indirectly by increasing serum Ca concentrations. Also, stimulates FGF-23 production. The most well documented effects of 1.25(OH) 2 D are those on the intestine where it regulates the Pi and Ca absorption. Also, increased Pi concentrations supress 1.25(OH) 2 D production.
  • Fibroblast Growth Factor 23 (FGF-23)
  • FGF-23 is the best characterised member of a group of phosphaturic molecules, the Phosphatonins. Other members are matrix extracellular phosphoglycoprotein (MEPE), and secreted frizzled-related protein 4 (sFRP-4).
  • MEPE matrix extracellular phosphoglycoprotein
  • sFRP-4 secreted frizzled-related protein 4
  • FGF-23 is predominantly the hormone safeguarding the flow of Pi in the skeleton, the major storage pool (over 85% of the total body) for Pi (and Ca), and its normal mineralization. Excessive production or absence of FGF-23 with normal renal function leads to defects in mineralization with accumulation of osteoid. FGF-23 also has been associated with a positive Ca balance. It promotes renal Ca reabsorption through the TRPV5 channel.
  • Klotho is a crucial component of the system regulating Ca and Pi homeostasis.
  • Klotho forms a complex with FGF receptors and functions as an obligate co-receptor for FGF-23.
  • Membrane- bound klotho is expressed mainly in the renal proximal and distal convoluted tubules (also in the epithelium of the choroid plexus in the brain). Its limited expression in certain tissues, determines the target organs for FGF-23, because the co-expression of Klotho and FGFR1 (or FGFR3 and FGFR4), the receptors for FGF-23, is a prerequisite for the FGF-23 actions. Indeed, ISKIotho 7" or Fgf23 ⁇ / ⁇ mutant mice have a similar phenotype.
  • FGF-23 dysregulation affects skeletal mineralization and its deficiency could cause calcification of non-skeletal tissues of other systems including the cardiovascular system.
  • FGF-23 is expressed in cardiac tissue.
  • Fg/23-null mouse and patients with tumoral calcinosis, an autosomal recessive disorder due to FGF-23 or GALNT3 or Klotho mutations develop severe calcifications that include soft tissue periarticular and vascular calcification.
  • Klotho-knockout mouse exhibits extensive arterial calcification and ectopic calcification in various organs.
  • HPT hyperparathyroidism
  • Hyperparathyroid-mediated high-turnover bone disease osteitis Fibrosa
  • Low turnover Osteomalacia defective mineralization in association with low osteoclast and osteoblast activities
  • Mixed uremic osteodystrophy hyperparathyroid bone disease with a superimposed mineralization defect
  • Osteomalacia defined as a mineralization lag time greater than 100 days
  • the iatrogeic adynamic bone disease diminished bone formation and resorption but not Osteoporosis. Therefore, the pathophysiology of renal osteodystrophy (and the role of PTH) is completely different to that of Osteoporosis where PTH levels remain normal throughout (as is the case with serum Ca and Pi concentrations).
  • an intervention in patients with CKD that could modulate the PTH concentration would help restore mineral homeostasis, in contrast to an intervention in patients with osteoporosis that would help restore the damaged bone architecture.
  • Renal impairment reduces the number of functional nephrons and therefore less Ca and Pi will go through the kidney, resulting initially in increased concentrations of both Ca and Pi in the circulation.
  • This new status will require less PTH to keep Ca at the level of equilibration set by PTH when the kidney function is normal, but at the same time less Pi will be forced out of the system by PTH.
  • the extra amount of Pi that would have been excreted as a result of the previously higher PTH concentration will be added to the initially retained Pi.
  • the normal Ca levels will prevent initially any PTH response and in the new balance point in the adjusted homeostasis, the body will have to use alternative options to control phosphate levels.
  • the central element of this invention is that the administration of PTH to a patient who has renal impairment (CKD), will result in the prevention of MBD.
  • CKD renal impairment
  • PTH has been used so far in the treatment of osteoporosis.
  • the prior art teaches that teriparatide (PTH 1-34) under the trade name FORSTEO (Europe)/FORTEO (USA) is used for treating osteoporosis. Therefore, administration of teriparatide in patients diagnosed with osteoporosis, would help restore the damaged bone architecture, which is the primary pathology.
  • the patentee proposes intermittent administration of PTH at an early stage in a patient with CKD to restore the disturbed mineral homeostasis, which is the primary pathology in ROD.
  • Adynamic bone disease characterized by markedly low-bone turnover resulting from a reduced number of osteoclasts and osteoblasts without osteoid accumulation, is not part of the natural history of renal bone disease.
  • ABD appeared in the late 1980s, at the time when the clinical approach in tackling the effects of secondary hyperparathyroidism on the skeleton (osteitis fibrosa) had changed. The previous established approach was of "watchful waiting”. With the availability of the active vitamin D compound (Calcitriol) in the early/mid 1980s, the management of secondary hyperparathyroidism became very proactive.
  • the use of Calcitriol resulted in oversuppression of the parathyroid glands and declines in PTH, and it was at that time that the first cases of "adynamic” or "aplastic” bone disease were reported.
  • ABD became the dominant type of bone pathology in the patients at renal dialysis centres. Therefore, ABD is iatrogenic, i.e. is a complication of Calcitriol therapy (otherwise ABD would have been diagnosed in the 1960s, 70s and early 80s).
  • the invention relates to the use of PTH in preventing complications of CKD, such as MBD, and in preventing vascular calcification in patients with renal impairment.
  • the therapy Preferably before the therapy is used then it should be established that the patient is not suffering from persistent hypercalcaemia or tertiary HPT beforehand. Such patients are excluded from the use of the therapy disclosed herein.
  • a pharmaceutical formulation comprising PTH for use in the prevention of renal osteodystrophy.
  • a pharmaceutical formulation comprising PTH for use in the prevention of vascular calcification in a patient suffering from CKD.
  • a pharmaceutical formulation comprising PTH for use in the prevention of chronic kidney disease-mineral and bone disorder (such use will also prevent vascular calcification).
  • a method of preventing renal osteodystrophy (such use will also prevent vascular calcification) in a patient in need thereof comprising administering a pharmaceutically-effective amount of a pharmaceutical composition comprising PTH.
  • a method of preventing chronic kidney disease-mineral and bone disorder (also such use will also prevent vascular calcification) in a patient in need thereof comprising administering a pharmaceutically-effective amount of a pharmaceutical composition comprising PTH.
  • PTH As active ingredient PTH we include natural PTH, PTH analogues, PTHrP (PTH related protein), PTHrP analogues and biosimilars of any of these.
  • the PTH incorporate the full length, 84 amino acid form of parathyroid hormone, particularly the human form, hPTH (1-84), obtained either recombinantly, by peptide synthesis or by extraction from human fluid. See, for example, U. S. Pat. No.5, 208, 041, incorporated herein by reference.
  • the amino acid sequence for hPTH (1-84) is reported by Kimura et al. in Biochem. Biophys. Res. Comm., 114(2) : 493.
  • the parathyroid hormone fragments desirably incorporate at least the first 28
  • N-terminal residues such as PTH (1-28), PTH (1-31), PTH (1-34), PTH (1-37),
  • PTH (1-38) and PTH (1-41).
  • Alternatives in the form of PTH variants incorporate from 1 to 5 amino acid substitutions that improve PTH stability and half-life, such as the replacement of methionine residues at positions 8 and/or 18 with leucine or other hydrophobic amino acid that improves PTH stability against oxidation and the replacement of amino acids in the 25-27 region with trypsin-insensitive amino acids such as histidine or other amino acid that improves PTH stability against protease.
  • PTH PTHrP
  • PTHrP(l-34) PTHrP(l -36)
  • analogues of PTH or PTHrP (PTH related protein) that activate the PTH1 receptor PTHrP (PTH related protein) that activate the PTH1 receptor.
  • the hormones may be obtained by known recombinant or synthetic methods, such as described in U. S. Pat. Nos.4, 086, 196 and 5, 556, 940, incorporated herein by reference.
  • the preferred hormone is human PTH (1-34), also known as teriparatide.
  • another preferred hormone is abaloparatide, which is a PTHrP.
  • Stabilized solutions of human PTH (1-34), such as recombinant human PTH (1-34) (rhPTH (1-34), that can be employed in the present method are described in U. S. Patent Application Serial No. 60/069, 075, incorporated herein by reference.
  • stages of CKD are defined by measuring the glomerular filtration rate (GFR) and are set as below. For the purposes of the invention these GFR rates form the basis for defining the stage of CKD.
  • GFR glomerular filtration rate
  • PTH PTH
  • the dose, and the intervals between administrations should be based on the FGF-23 and PTH plasma concentrations. Normalization of FGF-23 should be the primary target. Bone specific alkaline phosphatase activity should also be considered. Therefore, the amount of PTH administered may vary according to the stage of CKD of each individual patient is categorized at the time of the assessment by a clinician. Higher amounts of PTH should be required for patients at more advanced stages of CKD. Furthermore, the dosage regimen will be affected by the diet; for example patients with higher Pi intake in their daily diet, will require more frequent PTH administration. Radiological evidence such as hand x-ray findings and other imaging test or biochemical markers of bone turnover could be of additional help in the overall assessment of the patient and thus in determining the dose and frequency of PTH administration.
  • Dosing may be amended in accordance with FGF-23 and PTH levels in the plasma.
  • Clinical experience from the use of different assays measuring intact FGF-23 (Kainos) or FGF-23 C- terminal fragments (Immutopics) is that the same clinically relevant information is obtained with both, with regards to elevated levels of FGF-23 in the patient.
  • FGF-23 assays that cross react with C-terminal fragments might be less useful in patients with renal disease.
  • the Roche immunoassay has some of the least reported cross reactivities with renal fragments but the Tandem MS assay for PTH (1-84) or PTH(l-34) would be ideal. There are at least 3 different assays for FGF-23 measurements, with different normal ranges;
  • C-terminal FGF23 C-terminal FGF23 (cFGF23) (Immunotopics, San Clemente, CA, USA);
  • the antibodies in the C-terminal assay are directed against the C-terminal region of FGF23, and therefore detect both C-terminal fragments and intact FGF23.
  • the antibodies in the intact assay are described as being directed against the C-terminal and the N-terminal region of FGF23 and may therefore detect only iFGF23.
  • Full length FGF-23 is present in the normal circulation and the reference range for healthy adults is 10-50 pg/ml, as established from 104 controls or 29.7 +/- 20 pg/ml from 118 healthy pediatric controls.
  • the reference range of the C-terminal assay was reported to be less than 120-150 RU/ml.
  • a subject receiving parathyroid hormone also receives effective doses of Ca and vitamin D, which can enhance the effects of the hormone.
  • the dose and/or the frequency of PTH in this invention is lower compared with the dosing of PTH in its current approved uses. In patients with severely affected Ca and Pi homeostasis and therefore with levels of FGF-23 that will require higher PTH dosage, adjustment in the frequency of PTH administration will keep the dose down. This is important, in order to minimize the risk of iatrogenic hypercalcaemia.
  • the frequency and amount of PTH required for each individual patient will be determined by the clinician, based on measurements of FGF-23 and PTH and other bone biochemistry tests as described above. Duration of therapy may be practically for life, because the renal function will not return to normal in patients with CKD.
  • the ceiling of an effective dose of parathyroid hormone for the therapy as described herein should be the 20 meg subcutaneously (SC) once daily used for teriparatide or its equivalent for other PTH analogues and this dose could be considered for selected patients with advanced perturbation of Ca and Pi homeostasis, most likely patients close to the final stage of renal impairment.
  • SC subcutaneously
  • the hormone can be administered regularly (e. g., once daily), intermittently (e. g., irregularly during a day or week), or cyclically (e. g., regularly for a period of days or weeks followed by a period without administration).
  • intermittently we mean: every other day, every 3, 4, 5, 6 or 7 days.
  • cyclically we mean that a course of therapy is concluded and then a rest period followed by at least one more course of therapy.
  • a cyclical course of therapy can be administration for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days or longer.
  • a rest period can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days or longer.
  • An additional course of therapy can be for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days or longer.
  • Administration can be more than once a day and can include, 2 or 3 times a day.
  • a parathyroid hormone can typically be administered parenterally, preferably by subcutaneous injection or by infusion, by methods and in formulations well known in the art. Preferably the dosing should be as a bolus injection. Also, with new developments in technology, oral or nasal preparations could be equally effective.
  • Teriparatide which is the N-PTH terminal (1-34), the active part of PTH, is the preferred agent, because longer molecules are expected to metabolize and produce fragments of unknown function.
  • Stabilized formulations of human PTH (1-34) - teriparatide - that can advantageously be employed in the present method are described in U. S. Patent Application Serial No.60/069, 075, incorporated herein by reference.
  • This patent application also describes numerous other formulations for storage and administration of parathyroid hormone.
  • a stabilized solution of a parathyroid hormone can include a stabilizing agent, a buffering agent, a preservative, and the like.
  • the stabilizing agent incorporated into the solution or composition includes a polyol which includes a saccharide, preferably a monosaccharide or disaccharide, e. g., glucose, trehalose, raffinose, or sucrose; a sugar alcohol such as, for example, mannitol, sorbitol or inositol, and a polyhydric alcohol such as glycerine or propylene glycol or mixtures thereof.
  • a preferred polyol is mannitol or propylene glycol.
  • the concentration of polyol may range from about 1 to about 20 wt-%, preferably about 3 to 10 wt-% of the total solution.
  • the buffering agent employed in the solution or composition of the present invention may be any acid or salt combination which is pharmaceutically acceptable and capable of maintaining the aqueous solution at a pH range of 3 to 7, preferably 3-6.
  • Useful buffering systems are, for example, acetate, tartrate or citrate sources.
  • Preferred buffer systems are acetate or tartrate sources, most preferred is an acetate source.
  • concentration of buffer may be in the range of about 2 mM to about 500 mM, preferably about 2 mM to 100 mM
  • the stabilized solution or composition of the present invention may also include a parenterally acceptable preservative.
  • preservatives include, for example, cresols, benzyl alcohol, phenol, benzalkonium chloride, benzethonium chloride, chlorobutanol, phenylethyl alcohol, methyl paraben, propyl paraben, thimerosal and phenylmercuric nitrate and acetate.
  • a preferred preservative is m-cresol or benzyl alcohol; most preferred is m-cresol.
  • the amount of preservative employed may range from about 0.1 to about 2 wt-%, preferably about 0.3 to about 1.0 wt-% of the total solution.
  • the stabilized teriparatide solution can contain mannitol, acetate and mcresol with a predicted shelf-life of over 15 months at 5 C.
  • the parathyroid hormone compositions can, if desired, be provided in a powder form containing not more than 2% water by weight, that results from the freeze-drying of a sterile, aqueous hormone solution prepared by mixing the selected parathyroid hormone, a buffering agent and a stabilizing agent as above described.
  • a buffering agent when preparing lyophilized powders is a tartrate source.
  • Particularly useful stabilizing agents include glycine, sucrose, trehalose and raffinose.
  • parathyroid hormone can be formulated with typical buffers and excipients employed in the art to stabilize and solubilize proteins for parenteral administration.
  • Art recognized pharmaceutical carriers and their formulations are described in Martin, "Remington's
  • a parathyroid hormone can also be delivered via the lungs, mouth, nose, by suppository, or by oral formulations.
  • Uses of Formulations of a parathryoid Hormone can also be delivered via the lungs, mouth, nose, by suppository, or by oral formulations.
  • the present invention also encompasses instructions printed on the box in which the vial is packaged.
  • the instructions contain information such as sufficient dosage and administration information so as to allow a worker in the field to administer the drug. It is anticipated that a worker in the field encompasses any doctor, nurse, or technician who might administer the drug.
  • the present invention also relates to a pharmaceutical composition including a formulation of one or more parathyroid hormones, such as human PTH (1-84) or human PTH (1-34), and that is suitable for parenteral administration - it can be administered sub cutaneously or ideally as an infusion.
  • a formulation of one or more parathyroid hormones such as human PTH (1-84) or human PTH (1-34)
  • the invention also relates to methods for manufacturing compositions including a formulation of one or more parathyroid hormones, such as human PTH (1-84) or human PTH (1-34), in a form that is suitable for parenteral administration.
  • a liquid or solid formulation can be manufactured in several ways, using conventional techniques.
  • a liquid formulation can be manufactured by dissolving the one or parathyroid hormones, such as human PTH (1-84) or human PTH (1-34), in a suitable solvent, such as water, at an appropriate pH, including buffers or other excipients, for example to form one of the stabilized solutions described hereinabove.

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Abstract

L'invention concerne l'amélioration de la régulation de l'homéostasie phosphocalcique (Pi-Ca) chez un sujet humain qui souffre d'une maladie rénale chronique (MRC) à l'un quelconque des stades 1 à 4 de la maladie (telle que définie dans la National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J rénal Dis. 2002; 39 (Suppl 1) : S1-S266). Les améliorations de l'homéostasie procureront de multiples et nombreux bénéfices à un patient souffrant de MRC. Le patient bénéficiera de la prévention des troubles minéraux et osseux et de la calcification vasculaire associée à la MRC (les événements cardiovasculaires étant les principales causes de mort prématurée chez les patients atteints de MRC). L'amélioration de la régulation de l'homéostasie phosphocalcique (Pi-Ca) est obtenue par administration d'hormone parathyroïde (PTH) ou d'un de ses dérivés au patient.
PCT/IB2018/052500 2017-04-12 2018-04-10 Prévention des troubles osseux et minéraux par restauration de l'homéostasie phosphocalcique chez les patients souffrant d'une maladie rénale chronique Ceased WO2018189674A1 (fr)

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LU100168A LU100168B1 (en) 2017-04-12 2017-04-12 Prevention of Bone and Mineral Disorders by Restoring Calcium and Phosphate Homeostasis in Patients Suffering from Chronic Kidney Disease
LULU100168 2017-04-12

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
US11541104B2 (en) * 2018-10-29 2023-01-03 Asahi Kasei Pharma Corporation Method for preventing or treating osteoporosis, characterized by administering teriparatide or salt thereof at a frequency of twice a week

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US5208041A (en) 1991-05-23 1993-05-04 Allelix Biopharmaceuticals Inc. Essentially pure human parathyroid hormone
US5556940A (en) 1994-06-20 1996-09-17 National Research Council Of Canada Parathyroid hormone analogues for the treatment of osteoporosis
US6907597B1 (en) 2000-10-13 2005-06-14 Ati International Srl Method and apparatus for constructing an executable program in memory
US6987597B2 (en) 2001-12-31 2006-01-17 Texas Instruments Incorporated Pulse width modulation sequence generation
JP2004143107A (ja) * 2002-10-25 2004-05-20 Kureha Chem Ind Co Ltd 低代謝回転骨に起因する腎性骨異栄養症治療用医薬組成物
US20080176787A1 (en) * 2005-09-06 2008-07-24 Paul Morley Parathyroid hormone analogues and methods of use
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