LU100168B1

LU100168B1 - Prevention of Bone and Mineral Disorders by Restoring Calcium and Phosphate Homeostasis in Patients Suffering from Chronic Kidney Disease

Info

Publication number: LU100168B1
Application number: LU100168A
Authority: LU
Inventors: Michael Pazianas
Original assignee: Michael Pazianas
Priority date: 2017-04-12
Filing date: 2017-04-12
Publication date: 2018-10-15
Also published as: WO2018189674A1

Abstract

The invention relates to the improvement in the control of calcium (Ca) or phosphate (Pi) homeostasis in a human subject who is suffering from chronic kidney disease (CKD) during any of stages 1 to 4 of CKD (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 associated with CKD (the cardiovascular events are the leading causes of premature death in patients suffering from CKD). 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

Description

Prevention of Bone and Mineral Disorders by Restoring Calcium and Phosphate Homeostasis in Patients Suffering from Chronic Kidney Disease.

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 (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). 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.

There is a high prevalence of chronic kidney disease (CKD) in the general population. In the USA, it is estimated that approximately 14% of the adult population has stage 3-5 CKD alone. In England, data from the 2009-2010 Health Survey and the 2011 Census projected that in 2011, 2.6 million or 6.1% of the population aged 16 or older had stage 3-5 CKD. All these patients already have established or have begun to develop mineral and bone disorders, caused by CKD.

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. Therefore, strict control of both of their concentrations is critical - herein what we refer to as "homeostasis" -where the levels of Ca and Pi are held within a normal range.

Ca is mainly extracellular (99%) and concentration changes can be monitored with relative ease, in striking contrast with Pi, with only 1% of its total presence is in the extracellular fluid. Ca concentration in plasma and extracellular fluid is remarkably constant in a person without any disease state. Through the day, it is estimated that serum Ca fluctuates only by 0.25mM in normal individuals. On the other hand, plasma Pi concentration varies considerably through the day and is significantly affected by diet. It appears that the homeostasis system is particularly sensitive to elevations in the levels of Pi.

Intestine, kidneys and skeleton share the responsibility of securing availability of both elements and the parathyroid glands operate as the command centre which orchestrates the coordination 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)2D3, and fibroblast growth factor 23 (referred to as FGF-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, 1,25(OH)2D 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. At the same time 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.

Actions of Calcium and Phosphate Regulating Hormones

Parathyroid Hormone (PTH) 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 concentration involves the Pi balance as well. In the skeleton for example, Ca and Pi form hydroxyapatite [Cai0(PO4)6(OH)2] and therefore, during the bone resorption process, following the action of PTH, Ca and Pi are released at the same time. The same principle applies in the intestine where PTH indirectly, through 1.25(OH)2D, facilitates the absorption of both elements. It is in the kidney however where PTH eliminates a good part of this "unintentional" production, of Pi. PTH decreases the presence of Pi transporters NaPilla and NaPillc in the proximal epithelial cells where most of Pi reabsorption takes place, thus forcing Pi out of the body. In plasma, PTH has a half-life of about 4 minutes.

1,25(OH)2D 1.25(OH)2D 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)2D are those on the intestine where it regulates the Pi and Ca absorption. Also, increased Pi concentrations supress 1.25(OH)2D production.

Fibroblast Growth Factor 23 (FGF-23)

The action of PTH on the Na-Pi cotransporters NaPilla and NaPillc, leading to the excretion of Pi in the kidney, is complimented by another, recently discovered hormone, the FGF-23 which also indirectly decreases the Pi (and Ca) absorption in the intestine, another major source of Pi, by reducing the production and increasing the catabolism of 1.25(OH)2D in the kidney. 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). The skeleton (the osteocytes and osteoblast) is the principal production site for FGF23. 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

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, aKIotho7' or FgfZS^' mutant mice have a similar phenotype. FGF-23: Other Actions

Cardiovascular Calcification 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. Fgf23-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.

Mineral and Bone Disorders of Chronic Kidney Disease (CKD-MBD)

When the equilibrium created by the Ca and Pi regulating hormones is disturbed, this leads to severe clinical complications. In renal impairment, the loss of renal mass affects the physiological routine absorption, reabsorption and excretion of both Ca and Pi. As a result, and due to the unique role of the kidney, the equilibrium is affected instantly. The ramifications become more obvious in the skeletal and cardiovascular systems. The skeletal complications are universal in moderate and advanced stages of renal impairment, known as renal osteodystrophy.

Mineral and bone disorders start early, when the glomerular filtration rate (GFR) is reduced by CKD and is in the region of 60-90 ml/min as shown by abnormalities found on bone histology.

Although the pathophysiology of renal osteodystrophy has been studied extensively, the initial steps implicated in its genesis are still under investigation. The complexity of the mechanism involved is of course a significant reason for the incomplete understanding of events during the early stage of renal impairment. Nevertheless, the explanation for our slow progress could well be that we never challenged the prevailing dogma with Pi retention as the central point.

Indeed, the currently accepted concept is the forty plus year-old "trade off hypothesis" which implicates Pi retention as the initiating event in the disruption of homeostasis, and therefore, in the past all efforts have been directed to the elevated levels of Pi and their control. This still is the leading direction of research and clinical practice, with rather disappointing mixed results. However, the concurrent Ca retention has been completely ignored, so far.

The introduction of calcitriol (1,25(OH)2D3) in the clinic in the late 1970s/ early 1980s raised hopes that by increasing the levels of the active metabolite of vitamin D 1,25(OH)2D3 we would be able to restore the homeostatic balance of Ca & Pi. Despite an initial improvement, the development of hypercalcaemia and hyperphosphataemia, sooner or later will force the discontinuation of treatment. New vitamin D analogues or derivatives, claiming to be less potent on Ca and Pi absorption in the intestine have been introduced and are currently used widely although their effectiveness is also limited. A new class of agents, the calcimimetics, target the Ca sensing receptor (CasR) in the parathyroid glands and by mimicking the action of Ca, reduce PTH levels and parathyroid cell proliferation and thus improve the hyperparathyroid status and delay the development of tertiary hyperparathyroidism (HPT). They alone or in combination with calcitriol or any of its analogues have become part of the routine practice in patients on dialysis (not those who are not yet on dialysis) where other therapeutic approaches have failed. However, they are far from the solution to this huge clinical challenge.

In the last ten years, the discovery of FGF-23 brought a lot of excitement but it is still not a complete fit for the gaps left by the trade-off hypothesis. Recent studies showed that in the early stages of renal impairment the first detectable changes in serum concentration of the three bone hormones involved is a significant elevation of FGF-23 concentration leading to increased Pi excretion through the kidneys and maintaining normophosphataemia. Therefore, this (compensatory) rise of FGF-23 supports the Pi retention concept without necessarily establishing changes in Pi concentration as the exclusive initiating event in the dysregulation of mineral homeostasis. Furthermore, it does not offer any clinical breakthrough. Indeed, there are no practical gains for the clinicians and the patient as the obvious choice of monoclonal antibody treatment against FGF-23 is not of course the answer because of the resulting hyperphosphataemia.

It is of great importance to recognize that the bone remodelling is not directly concerned with the regulation of plasma Ca, and makes less direct contribution to Ca homeostasis. Of equal importance is the fact that renal bone and mineral disease is primarily a disturbance of mineral homeostasis that leads to a spectrum of metabolic bone diseases such as predominant 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), and Adynamic bone (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). Furthermore, 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.

The patentee addresses the question of Pi retention in the genesis of CKD-MBD and propose the inclusion of Ca retention as an equally significant factor in the genesis and progression of CKD-MBD, and that both need to be addressed. Ca retention explains clearly the mechanism of the initiation of MBD and the sequence of events leading to the development of mineral and bone disorders, including secondary HPT and most importantly allows the development of an effective approach in the clinical management of this and other associated complications.

The Genesis of CKD-MBD

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. Thus, the increased concentrations of Pi, normal Ca levels, and lower PTH will be the new balance point in the adjusted homeostasis, with Pi gaining the upper hand and PTH chasing increased Pi concentrations. At the same time, the increased Pi will trigger an increase in FGF-23 levels which in turn (together with lower PTH levels), will cause a fall in 1,25(OH)2D concentrations. This synchronized response from the three main Ca and Pi regulating hormones will lower both Ca and Pi concentrations but the effects will be more noticeable on Ca levels which are already at a lower normal range compared to those of Pi at higher normal.

As the reduction of the number of nephrons continues, PTH will keep coming from behind to keep the Ca concentration normal and chasing higher Pi levels. At some stage, the compensatory adjustments of the homeostatic system will be unable to achieve a satisfactory control and the new biochemical setting will become clinically obvious with the establishment of high serum Pi, low normal Ca, high PTH and parathyroid hyperplasia. FGF-23 levels will remain elevated because of the hyperphosphataemia; 1,25(OH)2D concentrations will remain supressed, due to hyperphosphataemia and high FGF-23 levels.

Based on the above presented physiological model of interactions between the calcium regulating hormones and minerals, the patentee provides a scientific basis for the administration of PTH to such patients. The administration of PTH forces the retained portion of Pi out of the system and keeps the PTH dominant in the regulation of Ca and Pi homeostasis; given in appropriate amounts and intervals (discussed below) the levels of Pi should be controlled adequately without the need for FGF-23 levels to rise and thus leading to a fall/normalization in FGF-23 levels. W00010596 discloses the use of PTH in treating osteoporosis. As can be seen in this patent application, the patients selected for the clinical study are women who are post-menopausal and who have suffered at least one fracture and therefore have been diagnosed as osteoporotic. The disease and biological systems involved in osteoporosis are linked with the menopause and genetic factors and the effects of PTH on bone repair are described, as distinct from the correction of the Ca and Pi balance as described herein.

The central element of this invention is that the administration of PTH to a patient who has renal impairment will result in the prevention or improvement of MBD in patients with CKD.

The prior art teaches that teriparatide (PTH 1-34) under the trade name FORSTEO (Europe)/FORTEO (USA) is used for treating osteoporosis and when it is used in patients with coexisting renal impairment (CKD), should be used with caution. Therefore, there is an established unease that the presence of renal impairment could complicate the outcome of treatment, thus making the use PTH less favourable or at least recognizing that this is an unexplored area in treating osteoporosis.

The administration of PTH forces the retained portion of Pi out of the system and keeps the PTH dominant in the regulation of Ca and Pi homeostasis; given in appropriate amounts and intervals (discussed below) the levels of Pi should be controlled adequately without the need for FGF-23 levels to rise and thus leading to a fall/normalization in FGF-23 levels. At the same time, there will be no need for extra production of PTH by the parathyroid glands and thus no need for the parathyroid cells to proliferate in order to meet the extra demands for increased PTH production. This will prevent the development of secondary (and tertiary) HPT, and the complications on the skeleton and cardiovascular system that follow.

The invention relates to the use of PTH in preventing complications of CKD, such as MBD, and in preventing or treating vascular calcification in patients at various stages of renal impairment.

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.

Therefore, we present as a feature of the invention a pharmaceutical formulation comprising PTH for use in the prevention of renal osteodystrophy. Alternatively, or additionally, we present as a feature of the invention a pharmaceutical formulation comprising PTH for use in the treatment or prevention of vascular calcification in a patient suffering from CKD.

Alternatively, we present as a feature of the invention 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).

We present as a feature of the invention 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.

Alternatively, we present as a feature of the invention 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.

The additional main benefit of use as described above also can be one or more of the following; 1. prevention of Renal Osteodystrophy; 2. restoration of Pi and Ca homeostasis; 3. prevention of secondary HPT; 4. prevention of parathyroid gland proliferation; 5. improvement (preferably normalisation) of the increased parathyroid gland proliferation; 6. reduction (preferably normalisation) of FGF-23 levels; 7. increase (preferably normalisation) of 1.25(OH)2D production; 8. prevention of mineral and bone disorders of chronic kidney disease (CKD-MBD); 9. prevention or improvement of skeletal resistance to the calcemic action of PTH; 10. prevention or treatment of vascular calcification (and consequential better control of hypertension in CKD patients and therefore reduction in the cardiovascular event, the leading cause of death in the CKD population); 11. improvement of overall survival time for patients with elevated FGF-23 (a number of studies have suggested that increased levels of FGF-23 are an independent risk factor in mortality rates); by the administration of a therapeutically effective amount of PTH to a patient suffering from CKD (in particular stages 1 to 4).

All or each or a combination of these benefits can be accessed by patients at different stages of CKD (stage 1-4).

In end-stage renal disease (ESRD) in patients with secondary (but not tertiary) HPT, the intermittent administration of PTH will reduce the chronic stimulation of the parathyroid glands, thus would affect the proliferation of parathyroid cells, and delay the transition to tertiary HPT. Improvement in secondary HPT can reduce the increased rate of Ca and Pi release from the skeleton, and would also decrease FGF-23 production and improve 1,25(OH)2D levels. Additionally, any of the benefits listed above can be accessed by a patient with ESRD receiving PTH.

As active ingredient, the composition or solution may 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 composition or solution may also incorporate as active ingredient fragments or variants of fragments of human PTH or of rat, porcine or bovine PTH that have human PTH activity as determined in the ovariectomized rat model of osteoporosis reported by Kimmel et al.. Endocrinology, 1993, 32 (4) : 1577.

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.

Other suitable forms of PTH include PTHrP, PTHrP(l-34), PTHrP(l -36) and analogs of PTH or PTHrP that activate the PTH1 receptor. These forms of PTH are embraced by the term "parathyroid hormone" as used generically herein. 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.

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.

Crystalline forms of human PTH (1-34) that can be employed in the present method are described in U. S. Patent Application Serial No. 60/069, 875, incorporated herein by reference.

Different stages of CKD

The 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.

As defined in the 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.

Dosing Schedules

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. Theoretically however, FGF-23 assays that cross react with C-terminal fragments might be less useful in patients with renal disease. For PTH measurements, 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; - one assay to measure C-terminal FGF23 (cFGF23) (Immunotopics, San Clemente, CA, USA); - a second assay to measure intact FGF23 (iFGF23) (Kainos, Tokyo, Japan) - the ideal assay: - a third assay from Immunotopics to measure iFGF23

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. There is a good correlation between CFGF23 and iFGF23 assays except for FGF23 levels of less than 120 RU/ml by C-terminal assay. The fact that the differences between two assays were found only in lower levels of FGF23 indicates that the three assays are comparable in CKD, dialysis and transplant patients when levels of FGF-23 are above the normal range.

The normal range established by whichever biochemical test used to measure FGF-23 and PTH should be the reference point in identifying the patients who should be treated with PTH in accordance with the invention. Any patient with values above the upper normal limit, will be a candidate for treatment.

It is preferred to use intermittent PTH administration to prevent the build-up of Pi and thus the development of hyperparathyroid bone disease and hypertrophy of the parathyroid glands. Intermittent PTH, preferably teriparatide which consists of the active fragment 1-34, could keep normocalcaemia and normophosphataemia,

Intermittent administration of PTH, will force the retained portion of Pi out of the system and keep the PTH dominance in the regulation of Ca; given in appropriate amounts and intervals will protect the homeostatic balance. Furthermore, it will eliminate/reduce significantly the increased risk of extraskeletal/vascular calcification (where hyperphosphataemia is the main contributor) thus reducing the incidence of deaths of cardiovascular aetiology which is by far the main cause of death in patients on renal replacement therapy.

Overall, with intermittent administration of PTH the practical clinical gains will be significant.

The effects will not be catabolic (as is the case when PTH levels are constantly elevated) and the risk of hypercalcemia should be low because baseline serum Ca is at the low end of normal range and the administered dose should be much lower compared to the one we use for osteoporosis where the aim is to accelerate the bone remodelling process. In the case of renal impairment, the invention seeks to supplement the PTH levels in order to restore the Ca and Pi homeostasis.

Preferably, 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 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 treatment 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.

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). By intermittently we mean: every day, every other day, every 3, 4, 5, 6 or 7 days. By cyclically we mean that a course of treatment is concluded and then a rest period followed by at least one more course of treatment. A cyclical course of treatment 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 treatment 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.

Currently, teriparatide use in patients with osteoporosis is not recommended for more than two years because of safety concerns (development of osteosarcoma). The patentee believes that the two year limit will not be required in CKD patients and therapy will be for longer if not for life of the patient because the goal is to restore the Ca and Pi homeostasis without exerting any additional effects on the remodeling cycle.

Administering Parathyroid Hormone 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. 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.

The 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. Such 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.

Thus, 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.

Especially useful as a buffering agent when preparing lyophilized powders is a tartrate source. Particularly useful stabilizing agents include glycine, sucrose, trehalose and raffinose.

In addition, 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 Pharmaceutical Sciences,"15th Ed.; Mack Publishing Co., Easton (1975). 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

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. According to the invention, a formulation of one or more parathyroid hormones, such as human PTH (1-84) or human PTH (1-34), can be used for manufacturing a composition or medicament suitable for administration by parenteral administration. 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. For example, 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.

Claims

1. Une formulation pharmaceutique comprenant de l'hormone parathyroïdienne, ou un fragment ou un variant d'un fragment d'hormone parathyroïdienne, pour restaurer l'homéostasie du calcium et du phosphate chez un patient souffrant de maladie rénale chronique.A pharmaceutical formulation comprising parathyroid hormone, or a fragment or variant of a parathyroid hormone fragment, for restoring calcium and phosphate homeostasis in a patient with chronic kidney disease.

2. Formulation pharmaceutique selon la revendication 1, dans laquelle les taux d'hormone FGF-23 sont en outre réduits.The pharmaceutical formulation of claim 1, wherein the levels of FGF-23 hormone are further reduced.

3. Une formulation pharmaceutique selon la revendication 1 ou 2, destinée à être utilisée dans la prévention de l'ostéodystrophie rénale.3. A pharmaceutical formulation according to claim 1 or 2 for use in the prevention of renal osteodystrophy.

4. Formulation pharmaceutique selon la revendication 3, destinée à être utilisée dans la prévention des troubles minéraux et osseux d'une maladie rénale chronique.4. Pharmaceutical formulation according to claim 3, for use in the prevention of mineral and bone disorders of chronic kidney disease.

5. Formulation pharmaceutique selon la revendication 1 ou 2, destinée à être utilisée dans le traitement ou la prévention de la calcification vasculaire.Pharmaceutical formulation according to claim 1 or 2 for use in the treatment or prevention of vascular calcification.

6. Formule pharmaceutique selon l'une quelconque des revendications 1 à 5, destinée à être utilisée dans la prévention de l'hyperparathyroïdie secondaire.6. Pharmaceutical formulation according to any one of claims 1 to 5, for use in the prevention of secondary hyperparathyroidism.

7. Formulation pharmaceutique selon l'une quelconque des revendications 1 à 5, destinée à être utilisée dans la prévention de l'hyperparathyroïdie tertiaire.A pharmaceutical formulation according to any one of claims 1 to 5 for use in the prevention of tertiary hyperparathyroidism.

8. Formulation pharmaceutique selon l'une quelconque des revendications 1 à 5, destinée à être utilisée dans la prévention de la prolifération de la glande parathyroïde.8. Pharmaceutical formulation according to any one of claims 1 to 5, for use in the prevention of proliferation of the parathyroid gland.

9. Formule pharmaceutique selon la revendication 1 ou 2, destinée à être utilisée pour augmenter la production de 1,25 (OH) 2D.The pharmaceutical formulation of claim 1 or 2 for use in increasing the production of 1,25 (OH) 2D.

10. Composition pharmaceutique selon l'une quelconque des revendications 1 à 9, dans laquelle le patient est à n'importe quel stade de 1 à 4 de maladie rénale chronique, comme décrit dans la National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: évaluation, classification, and stratification Am J Kidney Dis. 2002;39 (suppl 1):S1-S266.The pharmaceutical composition of any one of claims 1 to 9, wherein the patient is at any stage of 1 to 4 chronic renal disease as described in the 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.

11. Composition pharmaceutique selon l'une quelconque des revendications 1 à 9, dans laquelle l'hormone parathyroïdienne est la teriparatide.The pharmaceutical composition according to any one of claims 1 to 9, wherein the parathyroid hormone is teriparatide.

12. Composition pharmaceutique selon la revendication 10, dans laquelle la teriparatide est administrée par intermittence.The pharmaceutical composition of claim 10, wherein the teriparatide is administered intermittently.

13. Composition pharmaceutique selon la revendication 11, dans laquelle la teriparatide est administrée moins d'une fois par jour.13. The pharmaceutical composition of claim 11, wherein the teriparatide is administered less than once a day.

14. Composition pharmaceutique selon la revendication 12, dans laquelle le teriparatide est administré une fois, deux ou trois fois par semaineThe pharmaceutical composition of claim 12, wherein the teriparatide is administered once, two or three times a week