Inositol phosphates for treatment of ectopic calcification

Abstract

The present disclosure relates to compositions, methods, doses, dosage regimens, articles of manufacture and kits comprising an inositol phosphate, an inositol phosphate analogue, an inositol phosphate derivative, or a combination thereof for treating and / or preventing ectopic calcification, particularly skin calcification, such as calcification defending calcification. In one particular aspect, the disclosure provides a dosage regimen for treating a calcification defense comprising administering myo-inositol hexaphosphate at a dose of 6 mg / kg / day to 9 mg / kg / day three times a week for at least 1 to 8 months.

Description

[0001] This application is a divisional application of the patent application with the invention title "Inositol Phosphates for the Treatment of Ectopic Calcification", application date of October 11, 2018, and application number of 201880098642.6. Technical Field

[0002] The present disclosure relates to compositions and methods for treating and / or preventing ectopic calcification, including administering inositol phosphates, analogs, and derivatives thereof. Background Art

[0003] Skin and subcutaneous calcifications (commonly referred to as ectopic calcifications) occur as complications in many diseases. Ectopic calcifications can be classified as dystrophic, metastatic, idiopathic, or iatrogenic calcifications, or as calciphylaxis. Calciphylaxis corresponds to the calcification of small-sized blood vessels and subcutaneous adipose tissue. In most cases, calciphylaxis is secondary to chronic renal failure and is usually associated with abnormalities in calcium and phosphate metabolism. However, given its specific pathophysiology and specific mode of evolution, it remains an independent entity.

[0004] In addition to their abnormal nature of presence, these calcifications can also cause complications in terms of functional capacity (such as limitations in range of motion and joint function), pain (such as the very painful nature of some calcifications, especially in calciphylaxis), or nutritional levels that can lead to other infectious complications (such as ischemia and necrosis of the skin and subcutaneous tissues).

[0005] Although various treatment methods for these skin and subcutaneous calcifications have been tried and reported (such as bisphosphonates, calcium channel blockers, probenecid), to date, the efficacy of existing treatment methods has not been proven by a sufficient level of evidence.

[0006] Calciphylaxis, also known as calcific uremic arteriolopathy (CUA), is a severe form of vascular calcification that affects approximately 1% to 4% of end-stage renal disease patients, almost all of whom are on hemodialysis. See, e.g., Angelis et al. (1997) Surgery 122:1083-1089; Budisavljevic et al. (1996) J. Am. Soc. Nephrol. 7:978-982; Levin et al. (1993) Am. J. Nephrol. 13:448-453. The one-year mortality rate of calciphylaxis has been reported to be between 45% and 80%, with higher mortality rates associated with ulcerative lesions than non-ulcerative lesions (Nigwekar et al. (2015) Am. J. Kidney Dis. 66:133-146; Hafner et al. (1995) J. Am. Acad. Dermatol. 33:954-962; Fine & Zacharias (2002) Kidney International 61:2210-2217; Weenig et al. (2007) J. Am. Acad. Dermatol. 56:569-579).

[0007] In calciphylaxis, small peripheral vessel calcification leads to progressive, painful, necrotic skin ulcers. Mochel et al. (2013) Am. J. Dermatopathol. 35:582-586. The current treatment paradigm is palliative care and is based on observational clinical data. Options include, for example, intravenous sodium thiosulfate, bisphosphonates, and switching from calcium-based phosphate binders to non-calcium-based phosphate binders, but there is currently no approved therapy for calciphylaxis. Treatment of calciphylaxis typically focuses on symptomatic treatment, including wound care and pain management, rather than treating the underlying cause. Nigwekar et al. (2015) Am. J. Kidney Dis. 66:133-146.

[0008] Thus, in general, new treatment methods are needed to treat calciphylaxis and ectopic calcification. SUMMARY OF THE INVENTION

[0009] The present disclosure provides methods for treating and / or preventing ectopic calcification (such as calciphylaxis calcification) and / or its consequences in a subject in need thereof, comprising administering to the subject a dosage of at least one inositol phosphate (such as inositol hexaphosphate, or an analogue or derivative thereof) or a combination thereof of the present disclosure at a dosage of about 6 mg / kg / day to 9 mg / kg / day, wherein administration of the dosage is effective to treat or prevent ectopic calcification and / or its consequences in the subject.

[0010] In some aspects, the inositol phosphates (e.g., myo-inositol hexaphosphate, or analogs or derivatives thereof) of the present disclosure comprise a compound of Formula I, a pharmaceutically acceptable salt thereof, or a combination thereof:

[0011]

[0012] wherein

[0013] (i) R 1 , R 3 , R 5 , R 7 , and R 9 independently represent OH, a compound of Formula II, a compound of Formula III, or a compound of Formula IV:

[0014]

[0015] (ii) R 2 , R 4 , R 6 , R 8 , R 10 , R 12 , and R 13 represent H;

[0016] (iii) at least one of R 1 , R 3 , R 5 , R 7 , R 9 , and R 11 represents a compound of Formula II, Formula III, or Formula IV, and

[0017] (iv) zero, one, or two of R 1 , R 3 , R 5 , R 7 , R 9 , and R 11 represent a heterologous moiety.

[0018] In some aspects, the heterologous moiety imparts advantageous properties to the inositol phosphates of the present invention, such as an extended half-life moiety that imparts an extended serum half-life, a moiety that modulates metabolism, or a heterologous moiety that increases solubility.

[0019] In some aspects, the heterologous moiety includes, for example, polyethylene glycol, polyglycerol, or a combination thereof. In some aspects, the inositol phosphate of the present disclosure is myo-inositol hexaphosphate. In some aspects, the concentration of the inositol phosphate of the present disclosure (such as inositol phosphate, or an analogue or derivative thereof) in each dosage is between about 10,000 μg / mL and 100,000 μg / mL. In some aspects, the concentration of the inositol phosphate of the present disclosure (such as myo-inositol hexaphosphate, or an analogue or derivative thereof) in each dosage is between about 12.5 mM and about 135 mM.

[0020] In some aspects, the dose is administered as a single daily dosage. In some aspects, the dose is administered as multiple daily dosages. In some aspects, the dose is administered at least once a week. In some aspects, the dose is administered 2, 3, 4, 5, 6, or 7 times a week. In some aspects, the dose is administered for at least one week. In some aspects, the dose is administered for about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. In some aspects, the dose is administered for at least 12 weeks. In some other aspects, the dose is administered for about 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 weeks. In some other aspects, the dose is administered for at least 24 weeks. In some particular aspects, the dose is administered for about 25, 26, 27, 28, 29, 30, 31, or 32 weeks. In some other aspects, the dose is administered for at least 32 weeks.

[0021] In some aspects, administering the dose to a subject inhibits the formation and / or growth of hydroxyapatite crystals. In some aspects, ectopic calcification results from or is associated with the pathological crystallization of calcium. In some aspects, ectopic calcification is calciphylaxis calcification, metastatic calcification, dystrophic calcification, iatrogenic calcification, idiopathic calcification, or subcutaneous heterotopic ossification. In some aspects, the consequences of ectopic calcification are functional complications, pain, nutritional complications, infection, or a combination thereof. In some aspects, the functional complication is a limitation of the range of motion and / or joint function.

[0022] In some aspects, the nutritional complication is ischemia and / or injury. In some aspects, the injury is necrosis of the skin and / or subcutaneous tissue. In some aspects, administering the dose to a subject results in a reduction in injury as determined by the Bates-Jensen Wound Assessment Tool. Bates-Jensen (1992) Decubitus 5(6):20 - 28. In some aspects, the reduction in injury includes a decrease in the severity of the injury, a decrease in the size of the injury, and a decrease in the duration of the injury, or a combination thereof. In some aspects, administering the dose to a subject results in an improvement in wound healing.

[0023] In some aspects, administration of the dose to a subject results in pain relief. In some aspects, administration of the dose to a subject results in an improvement in overall wound quality of life (QoL), as determined by use of a validated wound-related QoL questionnaire. Augustin et al. (2017) Int'l. Wound J. 12:1299-1304. In some aspects, the subject has end-stage renal disease. In certain aspects, the subject is undergoing hemodialysis. In some aspects, the subject is a human.

[0024] In some aspects, the administration is parenteral administration. In some aspects, parenteral administration is by bolus or by intravenous infusion. In some aspects, the administration is topical administration.

[0025] The present disclosure also provides a method for treating or preventing calciphylaxis calcification and / or its consequences in a subject in need thereof, comprising administering to the subject an intravenous dose of an inositol phosphate of the present disclosure (such as phytic acid), or an analogue or derivative thereof, three times a week for 12 or 24 weeks at a dose of about 6 mg / kg / day to 9 mg / kg / day, wherein administration of the dose effectively treats or prevents calciphylaxis calcification and / or its consequences in the subject. In some aspects, a dose of inositol phosphate of about 7 mg / kg / day is administered three times a week for 12 or 24 weeks.

[0026] The present disclosure also provides an intravenous dose of an inositol phosphate of the present disclosure (such as phytic acid), or an analogue or derivative thereof, which is administered to a subject three times a week for 12 or 24 weeks at a dose of about 6 mg / kg / day to 9 mg / kg / day, and which is taken by the patient in a therapeutically effective amount sufficient to treat or prevent calciphylaxis calcification and / or its consequences in the subject. In some aspects, a dose of inositol phosphate of about 3 mg / kg / day is administered three times a week for 12 or 24 weeks.

[0027] The present disclosure also provides a kit or article of manufacture, comprising: at least one container that contains a parenteral or topical dose of an inositol phosphate of the present disclosure (such as phytic acid), or an analogue or derivative thereof; and instructions for administration according to any of the methods of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1It is a simplified schematic diagram of the physiochemical mechanism of action of SNF472 (a preparation of myo-inositol hexaphosphate). SNF472 inhibits cardiovascular calcification, for example, by preventing the formation of new calcium crystals and the growth of existing crystals. SNF472 is an intravenous preparation of myo-inositol hexaphosphate that selectively inhibits the formation and growth of hydroxyapatite crystals (the final common pathway in the pathophysiology of vascular calcification). Phase 1 clinical studies conducted in healthy volunteers and hemodialysis patients have shown that SNF472 is well tolerated and has an inhibitory effect on hydroxyapatite crystal formation. The Phase 2 clinical study presented in the Examples section of this disclosure evaluated wound healing, pain, and quality of life in end-stage renal disease patients undergoing hemodialysis with calciphylaxis treated with SNF472.

[0029] Figure 2A It shows that in the intention-to-treat population using multiple imputation (n = 14), SNF472 treatment led to a statistically significant improvement in the mean total Bates-Jensen Wound Assessment Tool (BWAT) score for major wounds from baseline to week 12.

[0030] Figure 2B It shows that using only the observed data, SNF472 treatment led to a gradual improvement in the mean total BWAT score at each visit, with statistically significant improvements at weeks 10 and 12. Change relative to baseline, *p < 0.05.

[0031] Figure 3 Among them, for major wounds, 12 weeks of SNF472 treatment was associated with an improvement in the relative baseline levels of most components of the Bates-Jensen Wound Assessment Tool. Change relative to baseline, *p < 0.05.

[0032] Figure 4A It shows that in the intention-to-treat population using multiple imputation (n = 14), SNF472 treatment led to a statistically significant improvement in the Visual Analogue Scale (VAS) score for pain in major wounds from baseline to week 12.

[0033] Figure 4B It shows that using only the observed data, SNF472 treatment led to a statistically significant improvement in the Visual Analogue Scale (VAS) score for pain in major wounds from baseline to weeks 6, 8, and 12. Change relative to baseline, *p < 0.05.

[0034] Figure 5 It shows that in the intention-to-treat population treated with multiple imputation (n = 14), SNF472 treatment led to an improvement in the subject-reported quality of life (QoL) score from baseline to week 12.

[0035] Figure 6It is shown that at week 12 of SNF472 treatment, in 8 out of 11 subjects (72.7%), qualitative non-blinded review of the wounds reported improvement relative to baseline. One of the two patients who deteriorated had undetectable serum levels of SNF472. The other patient was the same as at baseline.

[0036] Figure 7 Representative images of the qualitative wound assessment of the primary lesion at baseline and week 12 are shown. *Serum SNF472 concentration in Subject 6 with deteriorating lesions was below the limit of quantification; serum SNF472 concentrations in all other subjects were within the expected range.

[0037] Figure 8 Representative inositol phosphate analogs are shown, where 2 of the 6 Xs are OPSO 2 2- , and the remaining Xs are OSO 3 . Four specific forms of 4,6-di-(O-thiophosphate)-myo-inositol-1,2,3,5-tetra-O-sulfate are shown.

[0038] Figure 9 Inositol phosphate analogs and inositol phosphate derivatives that can be used to implement the methods of the present disclosure are shown. The molecules shown are myo-inositol-pentapentyl phosphate-2-PEG400, myo-inositol hexasulfate (myo-inositol hexasulfate), and scyllo-myo-inositol hexasulfate (scyllo-myo-inositol hexasulfate).

[0039] Figure 10 Inositol phosphate analogs and inositol phosphate derivatives that can be used to implement the methods of the present disclosure are shown. X independently represents a phosphorus- and / or sulfur-containing group, such as phosphate, sulfate, or thiophosphate. R 1 represents a heterologous moiety, such as PEG or PG.

[0040] Figure 11 Exemplary inositol phosphate analogs and inositol phosphate derivatives that can be used to implement the methods of the present disclosure are shown. R 1 represents a heterologous moiety, such as PEG or PG. n can be between 2 and 200.

[0041] Figure 12 Exemplary inositol phosphate analogs and inositol phosphate derivatives that can be used to implement the methods of the present disclosure are shown. n can be between 2 and 200.

[0042] Figure 13 Exemplary inositol phosphate analogs and inositol phosphate derivatives that can be used to implement the methods of the present disclosure are shown. n can be between 2 and 200. Detailed Description

[0043] The present disclosure provides compositions, dosages, dosage regimens, methods, pharmaceutical compositions and formulations, methods of use, production articles and kits generally for treating ectopic calcification, particularly for treating calciphylaxis calcification. The present disclosure provides methods for treating and / or preventing ectopic calcification and / or its consequences in a subject in need thereof, which comprise administering to the subject an amount of an inositol phosphate of the present disclosure (such as inositol phosphate, inositol phosphate analog, inositol phosphate derivative, or a combination thereof) at a dose, for example, of about 6 mg / kg / day to 9 mg / kg / day, wherein administration of the dose is effective to treat and / or prevent ectopic calcification and / or its consequences in the subject.

[0044] The present disclosure also provides dosage forms that contain an amount of an inositol phosphate of the present disclosure (such as inositol phosphate, inositol phosphate analog, inositol phosphate derivative, or a combination thereof) sufficient to administer to a subject the amounts disclosed herein (such as an amount of about 6 mg / kg to 9 mg / kg). Also provided are pharmaceutical compositions and formulations that contain an amount of an inositol phosphate of the present disclosure (such as inositol phosphate, inositol phosphate analog, inositol phosphate derivative, or a combination thereof) sufficient to administer to a subject a dosage, for example, of about 6 mg / kg / day to 9 mg / kg / day.

[0045] The present disclosure also provides production articles and kits that comprise: at least one container that contains an amount of an inositol phosphate of the present disclosure (such as inositol phosphate, inositol phosphate analog, inositol phosphate derivative, or a combination thereof) sufficient to administer to a subject a dosage, for example, of about 6 mg to 9 mg / kg or multiple dosages; and instructions for administering these dosages according to the methods disclosed herein.

[0046] To make the present disclosure more readily understood, certain terms are first defined below. As used in this application, unless otherwise expressly stated herein, each of the following terms shall have the meaning set forth below. Other definitions are set forth throughout the application.

[0047] I. Definitions

[0048] The present disclosure includes aspects in which one member of a group is present in, utilized in, or associated with a given product or method. The present disclosure includes aspects in which more than one or all members of a group are present in, utilized in, or associated with a given product or method.

[0049] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary Of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press provide a general dictionary of many of the terms used in the art to which this disclosure pertains.

[0050] Units, prefixes, and symbols are represented in their accepted form of the International System of Units (SI). Numerical ranges include the numbers defining the range. In the case of a range of values being recited, it is to be understood that each intermediate integer value and each fraction between the recited upper and lower limits of that range, as well as each sub-range between those values, are also specifically disclosed. The upper and lower limits of any range can be independently included in or excluded from the range, and each range including one, both end values or excluding both end values is also covered by the present invention.

[0051] In the case where a value is specifically recited, it is to be understood that a value that is about the same quantity or amount as the recited value is also within the scope of the present invention. In the case of a disclosed combination, each sub-combination of the elements of the combination is also specifically disclosed and within the scope of the present invention. Conversely, in the case where different elements or groups of elements are separately disclosed, their combination is also disclosed. In the case where any element of the present invention is disclosed as having a plurality of alternatives, an instance of the invention in which each alternative is separately excluded or excluded in any combination with other alternatives is also thereby disclosed; more than one element of the invention can have such exclusions, and all combinations of elements having such exclusions are also thereby disclosed.

[0052] About: As used herein, the term "about" refers to a value or a composition within an acceptable error range determined by one of ordinary skill in the art for a particular value or composition, which will depend in part on how the value or composition is measured or determined, i.e., on the limitations of the measuring system. For example, in accordance with the practice in the art, "about" can mean within 1 or more standard deviations. Alternatively, "about" can mean a range of up to 20%. Additionally, particularly with respect to biological systems or methods, the term can mean up to one order of magnitude or up to 5 times the value.

[0053] When specific values or components are provided in this application and the claims, unless otherwise stated, the meaning of "about" should be assumed to be within the acceptable error range of that specific value or component. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the stated numerical values. Thus, "about 10 - 20" means "about 10 to about 20". Generally, the term "about" can modify a numerical value that is above or below the claimed value with a variance of, for example, 10% above or below (higher or lower).

[0054] And / or: As used herein, "and / or" is taken as a specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and / or" used in a phrase such as "A and / or B" herein is intended to include "A and B", "A or B", "A" (alone), and "B" (alone). Similarly, the term "and / or" used in a phrase such as "A, B and / or C" is intended to cover each of the following aspects: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0055] Approximate: As used herein, the term "approximate" applied to one or more values of interest means a value similar to the claimed reference value. In some aspects, the term "approximate" means a value that falls within a range of 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction (greater than or less than) of the claimed reference value, unless otherwise stated or apparent from the context (except in cases where the number would exceed 100% of the possible value).

[0056] Comprising: It is to be understood that in any aspect described in terms of the language "comprising", similar aspects described in terms of "consisting of" and / or "consisting essentially of" are also provided.

[0057] Compound: As used herein, the term "compound" refers to all isomers and isotopes including the described structure. As used herein, the term "isomer" refers to any geometric isomer, tautomer, zwitterion, stereoisomer, enantiomer, or diastereomer of a compound. A compound may include one or more chiral centers and / or double bonds and may thus exist in the form of stereoisomers such as double bond isomers (i.e., geometric E / Z isomers), or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). The present invention encompasses any and all isomers of the compounds described herein, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure), as well as enantiomeric and stereoisomeric mixtures, such as racemates. Mixtures of enantiomers and stereoisomers of a compound and methods for resolving them into their component enantiomers or stereoisomers are well known. The compounds, salts, or complexes of the present invention can be combined with solvents or water molecules by conventional methods to form solvates and hydrates. In some aspects, the term compound is used to refer to the inositol phosphates of the present disclosure.

[0058] Consequences of ectopic calcification: The term "consequences of ectopic calcification" or the term "its consequences" as used in relation to ectopic calcification refers to any complications associated with the presence of ectopic calcification, such as calciphylaxis. Complications of this type can be, for example, functional complications (e.g., limitations in range of motion and joint function), pain, nutritional complications (e.g., ischemia or necrosis of the skin and / or subcutaneous tissue), infection, or combinations thereof.

[0059] Ectopic calcification: As used herein, the term "ectopic calcification" refers to all pathological depositions of calcium salts or any bone growth in tissues, particularly soft tissues. Examples of diseases and / or conditions associated with the pathological crystallization of calcium include, but are not limited to, aortic stenosis, atherosclerosis, calcinosis cutis, calciphylaxis (CUA), cardiovascular disease death, chondrocalcinosis, coronary artery disease, critical limb ischemia, kidney transplant failure, and peripheral artery disease, generalized arterial calcification of infancy (GACI), kidney stones, myocardial infarction, nephrocalcinosis, osteoporosis, primary hyperoxaluria (PH), progression of chronic kidney disease, pseudogout, pseudoxanthoma elasticum (PXE), valvular calcification, vascular calcification, and vascular stiffness. In some aspects, ectopic calcification is, for example, metastatic calcification, dystrophic calcification, iatrogenic calcification, idiopathic calcification, calcification associated with calciphylaxis, subcutaneous heterotopic ossification. In one specific aspect, ectopic calcification is calciphylaxis calcification.

[0060] Effective amount: As used herein, the term “effective amount” of a therapeutic agent with respect to (i) the inositol phosphates of the present disclosure (e.g., inositol phosphates, inositol phosphate analogs, inositol phosphate derivatives); (ii) any dosage form, pharmaceutical composition, or formulation comprising an inositol phosphate of the present disclosure as disclosed herein; or (iii) a combination of an inositol phosphate of the present disclosure with one or more other therapeutic agents, is an amount sufficient to produce a beneficial or desired result. In some aspects, the beneficial or desired result is, for example, a clinical outcome, and thus the “effective amount” depends on the context of its application. For example, in the context of administering a therapeutic agent for treating ectopic calcification, the effective amount of the therapeutic agent is an amount sufficient to reduce or decrease the size of the calcification and / or inhibit its formation and / or growth, compared to the calcification observed in a subject prior to administration of the therapeutic agent or in a control group of subjects not receiving the therapeutic agent. The term “effective amount” may be used interchangeably with “effective dose,” “therapeutically effective amount,” or “therapeutically effective dose.”

[0061] Prevention: As used herein, the term “prevention” refers to measures taken to maintain health and prevent or delay the onset of a disease or condition, or to mitigate the extent and / or severity of symptoms. Thus, the prophylactic use of a therapeutic agent disclosed herein (e.g., (i) an inositol phosphate of the present disclosure (e.g., inositol phosphate, inositol phosphate analogs, inositol phosphate derivatives), or (ii) a combination thereof; or any dosage form, pharmaceutical composition, or (iv) formulation comprising an inositol phosphate of the present disclosure as disclosed herein; or (iv) a combination of an inositol phosphate of the present disclosure with one or more other therapeutic agents) corresponds to an amount sufficient to produce a beneficial or desired result. For example, a clinical outcome of preventing the development of ectopic calcification or delaying the appearance of calcification in a subject.

[0062] Range: As used herein, any concentration range, percentage range, ratio range, or integer range is to be understood to include any integer value within the recited range, and, when appropriate, fractions thereof (such as one-tenth and one-hundredth of an integer), unless otherwise specified.

[0063] SNF472: As used herein, the term “SNF472” refers to an intravenous formulation of myo-inositol hexaphosphate. SNF472 is manufactured by dissolving myo-inositol hexaphosphate in a saline solution, followed by pH adjustment and sterile filtration. SNF472 is prepared in three different strengths: (a) (i) 20 mg / mL and (ii) 90 mg / mL are formulated in a saline solution in 5 mL single-dose vials with a pH of 5.8 to 6.2; and (b) 30 mg / mL is formulated in a saline solution in 10 mL single-dose vials with a pH of 5.6 to 6.4.

[0064] Soft tissue: The term "soft tissue" refers to tissue that connects, supports, or encloses other structures and organs of the body, other than bone tissue.

[0065] Subject: "Subject" or "individual" or "animal" or "patient" or "mammal" refers to any subject, particularly a mammalian subject, for which a diagnosis, prognosis, or treatment is desired. Mammalian subjects include, but are not limited to, humans, domestic animals, farm animals, zoo animals, sports animals, pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cows, dairy cows; primates such as apes, monkeys, orangutans, and chimpanzees; canines such as dogs and wolves; felines such as cats, lions, and tigers; equines such as horses, donkeys, and zebras; bears; edible animals such as cows, pigs, and sheep; ungulates such as deer and giraffes; rodents such as mice, rats, hamsters, and guinea pigs, etc. In some aspects, the mammal is a human subject. In other aspects, the subject is a human patient. In a particular aspect, the subject is a human patient suffering from or at risk of suffering from pathological calcification. In some embodiments, the subject is a human patient suffering from pathological calcification, such as a human patient suffering from ectopic calcification, such as calciphylaxis, which requires treatment.

[0066] Substantially: As used herein, the term "substantially" refers to a qualitative condition that exhibits all or nearly all of the degree or measure of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, achieve completion and / or proceed to absolute totality, or achieve or avoid absolute results. Thus, the term "substantially" is used herein to capture the inherent lack of potential completeness in many biological and chemical phenomena.

[0067] Therapeutic agent: As used herein, the term "therapeutic agent" is used broadly to include compositions comprising the inositol phosphates of the present disclosure, which can provide significant therapeutic benefits to a subject in need thereof, particularly a subject suffering from or at risk of developing ectopic calcification. Thus, a therapeutic agent according to the present disclosure can be, for example, (i) any inositol phosphate of the present disclosure (e.g., inositol phosphate, inositol phosphate analog, inositol phosphate derivative, or a combination thereof), or (ii) any dosage form, pharmaceutical composition, or formulation disclosed herein comprising the inositol phosphates of the present disclosure, or (iii) a combination of the inositol phosphates of the present disclosure with one or more other therapeutic agents, which are administered in an amount sufficient to produce a beneficial or desired result.

[0068] In some specific aspects, the therapeutic agent is a combination composition comprising any inositol phosphate of the present disclosure and at least one other therapeutic agent (see, for example, Table 1) or a combination thereof.

[0069] The term therapeutic agent also encompasses prophylactic, diagnostic, or imaging agents comprising the inositol phosphates of the present disclosure, wherein the therapeutic agent is administered, for example, parenterally or topically. The therapeutic agents of the present disclosure include not only agents for treating ectopic calcification, but also agents that can ameliorate and / or prevent any symptoms associated with the presence of calcification. Thus, as defined herein, the term therapeutic agent will include, for example, agents that can reduce or inhibit inflammation, agents that increase patient mobility, and agents that relieve pain.

[0070] Target tissue: As used herein, "target tissue" refers to any one or more tissue types of interest, wherein delivery of a therapeutic and / or prophylactic agent comprising the inositol phosphates of the present disclosure will result in a desired biological and / or pharmacological effect. Examples of target tissues of interest include specific tissues, organs, and their systems or groups. In a particular application, the target tissue can be subcutaneous tissue.

[0071] Topical administration: As used herein, the term "topical administration" refers to any administration of a composition comprising the inositol phosphates of the present disclosure by a topical route, such as on the skin, orifice, or mucosa. Topical administration as used herein includes the routes of administration to the skin, ear, nose, vagina, urethra, and rectum.

[0072] Treating, treatment, therapy: As used herein, the terms "treating" or "treatment" or "therapy" refer to partially or completely relieving, ameliorating, improving, reducing, delaying the onset of one or more symptoms or characteristics of a disease; inhibiting its progression; reducing its severity; reducing its incidence; or any combination thereof. For example, "treating" calciphylaxis can refer to, for example, inhibiting calcification, reducing the size of calcifications, increasing survival rate, increasing mobility, relieving pain, or any combination thereof.

[0073] Treatment comprising the inositol phosphates of the present disclosure can be administered to subjects who do not exhibit signs of a disease, disorder, and / or condition, and / or to subjects who exhibit only early signs of a disease, disorder, and / or condition, for purposes such as, for example: (i) reducing the risk of development of a pathology associated with the disease, disorder, and / or condition; (ii) delaying the onset of the disease, disorder, and / or condition, or a pathology associated with the disease, disorder, and / or condition; or (iii) alleviating the symptoms and / or sequelae of the disease, disorder, and / or condition, or a pathology associated with the disease, disorder, and / or condition.

[0074] Thus, in general, the term "treatment" refers to counteracting the effects caused by a disease or pathological condition of interest in a subject, including (i) inhibiting the disease or pathological condition, i.e., slowing or stopping its progression; (ii) alleviating the disease or pathological condition, i.e., causing regression of the disease or pathological condition or its symptoms; (iii) stabilizing the disease or pathological condition; and (iv) any combination thereof.

[0075] ug, uM, uL: As used herein, the terms "ug", "uM", and "uL" are used interchangeably with "μg", "μM", and "μL", respectively.

[0076] II. Treatment of Ectopic Calcification

[0077] The present disclosure also provides methods for treating and / or preventing ectopic calcification (e.g., calciphylaxis) and / or its consequences in a subject in need thereof, which comprise administering to the subject at least once a week (e.g., once, twice, or three times a week) a dosage of at least one inositol phosphate (e.g., phytic acid, or an analogue or derivative thereof) or a combination thereof of the present disclosure at a dosage of about 5 mg / kg / day to 10 mg / kg / day (e.g., about 6 mg to about 9 mg / kg / day, such as 6 mg / kg / day or 9 mg / kg / day) for a variable period of time (e.g., about 1 week to about 32 weeks), wherein administration of the dosage is effective to treat and / or prevent ectopic calcification and / or its consequences in the subject.

[0078] In the context of the present disclosure, the term "inositol phosphate" and the terms "inositol phosphate analogue" or "inositol phosphate derivative" refer to compounds covered by Formula I, compounds disclosed in Section III of the present disclosure, compounds disclosed in Section III of the present disclosure incorporating one or more heterologous moieties disclosed in Section IV of the present disclosure, and compounds disclosed in the patents and patent applications referenced herein (which are incorporated herein by reference in their entirety).

[0079] The compounds of the present disclosure do not cover other phosphate-containing compounds known in the art, such as sodium hexametaphosphate, sodium polyphosphate (Graham's salt), or pyrophosphate.

[0080] As used herein, the term "inositol phosphate" (and its grammatical variants) refers to a compound having an inositol ring and one, two, three, four, five, or six phosphate groups or combinations thereof. Myo-inositol hexakisphosphate (IP6) is an exemplary inositol phosphate of the present disclosure. In some aspects, the inositol phosphate is pure (e.g., more than 99% of the inositol phosphate species are the same species, e.g., IP6) or substantially pure (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the inositol phosphate species are the same species, e.g., IP6). In some aspects, the inositol phosphate is a mixture, e.g., it contains variable amounts of IP1, IP2, IP3, IP4, IP5, and IP6. In some aspects, the inositol phosphate is a racemic mixture.

[0081] As used herein, the term "inositol phosphate analogue" (and its grammatical variants) refers to a compound having a ring with a different number of carbons (i.e., 5 or 7 carbons) relative to the inositol ring and / or having at least one sulfate or phosphorothioate group. For example, a compound containing a ring with 5, 6, or 7 carbons and at least one phosphate, sulfate, or phosphorothioate group is considered an inositol phosphate analogue.

[0082] As used herein, the term "inositol phosphate derivative" (and its grammatical variants) refers to an "inositol phosphate" or "inositol phosphate analogue" that has been derivatized with a heterologous moiety (i.e., a group that is not a phosphate, sulfate, or phosphorothioate). For example, an inositol phosphate containing a polyethylene glycol heterologous moiety, or a myo-inositol hexakisphosphate including a polyglycerol heterologous moiety is considered an inositol phosphate derivative.

[0083] As used herein, the term "heterologous moiety" (and its grammatical variants) refers to a group or substituent that is not a phosphate, sulfate, or phosphorothioate in an inositol phosphate derivative and confers desired properties to such a compound. For example, a heterologous moiety (e.g., polyglycerol or polyethylene glycol) can increase the solubility of the compound. In some aspects, the heterologous moiety can confer multiple desired properties; for example, both polyglycerol and polyethylene glycol can increase the solubility of the compound and decrease the clearance rate of the compound.

[0084] As used herein, the terms "inositol phosphates disclosed herein" and "inositol phosphates of the present disclosure" (and their grammatical variants) are general terms that encompass "inositol phosphates", "inositol phosphate analogues", "inositol phosphate derivatives", and combinations thereof. In some aspects, the term "inositol phosphates of the present disclosure" encompasses compositions containing "inositol phosphates", "inositol phosphate analogues", "inositol phosphate derivatives", or combinations thereof, and at least one other therapeutic agent (see, e.g., Table 1).

[0085] Compounds of the present disclosure that contain a ring having 5, 6, or 7 carbons and at least one sulfate or thiophosphate group, but do not have a phosphate group, are still considered "inositol phosphate analogs" or "inositol phosphate analogs" in the context of the present disclosure. Thus, the term "inositol phosphates of the present disclosure" encompasses not only compounds containing phosphate groups, but also compounds without phosphate groups that contain a ring having 5, 6, or 7 carbons and at least one sulfate or thiophosphate group.

[0086] Representative inositol phosphates of the present disclosure are shown in Figures 8 - 13 . Figure 10 Many examples of inositol phosphates are shown, all of which are in the myo conformation. In addition to myo-inositol, the stereoisomers of other naturally occurring inositols are scyllo-, muco-, 1D-chiro-, 1L-chiro-, neo-inositol, allo-, epi-, and cis-inositol. As the name implies, 1L- and 1D-chiro-inositol are the only pair of inositol enantiomers, but they are enantiomers of each other, not enantiomers of myo-inositol. It is to be understood that any exemplary inositol phosphate presented in the present disclosure is not limited to the representative conformations shown. Thus, for example Figure 10 the examples shown will also encompass equivalents corresponding to the scyllo-, muco-, 1D-chiro-, 1L-chiro-, neo-inositol, allo-, epi-, and cis-inositol conformations. The myo-inositol isomer assumes a chair conformation in its most stable conformation, which moves the maximum number of hydroxyl groups to the equatorial positions, where they are farthest apart from each other. In this conformation, in the structure of the natural inositol isomer, five of the six hydroxyl groups (the first, third, fourth, fifth, and sixth) are equatorial, while the second hydroxyl group is axial.

[0087]

[0088] As used herein, the term "dose" or "dose of the present disclosure" refers to the total amount of inositol phosphate of the present disclosure that will be administered to a subject in need thereof over 24 hours, for example, in grams or grams per kilogram.

[0089] In the context of the present disclosure, the term "dosage" or "dosage of the present disclosure" refers to the dose of inositol phosphate of the present disclosure that is administered to a subject over a period of time.

[0090] The dosage can be calculated using the subject's recognized standard body weight. For example, the ideal body weight (IBW) is estimated as follows: IBW (kg) = 50 + 2.3 kg for each inch over 5 feet (male); IBW (kg) = 45.5 + 2.3 kg for each inch over 5 feet (female). Thus, for example, assuming an ideal body weight of 60 kg, the dosage of phytic acid given as part of the protocol comprises a dose of 5 mg / kg of phytic acid administered to the subject daily, which dosage consists of 300 mg of phytic acid. For example, methods known in the art can be used to adjust the dose based on the subject's age, weight, body surface area, renal clearance, gender, pathological condition, route of administration, co-administration of one or more other drugs, and various physiological and psychological factors. See, for example, Pan et al. (2016) Patient Prefer Adherence 10:549-560; Pai et al. (2012) Pharmacotherapy 32:856-868; Hacker et al. (2009) “Pharmacology: Principles and Practice,” Academic Press; and the references cited therein, all of which are incorporated herein by reference in their entirety.

[0091] As used herein, the term “mg / kg” refers to mg of the inositol phosphate of the present disclosure corresponding to each kg of the subject's body weight (body mass).

[0092] Generally, the effective dose of the inositol phosphate of the present disclosure administered according to the methods disclosed herein will depend on, for example, the relative potency of the relevant compound, the severity of the disease being treated, and the body weight of the subject. In some aspects, the dosage of the inositol phosphate of the present disclosure to be administered to a subject can be calculated based on, for example, its ability to inhibit crystallization compared to a reference compound (such as phytic acid).

[0093] For example, if a given inositol phosphate of the present disclosure has an equivalent ability to inhibit crystallization as phytic acid, the same dosage will generally be used. Conversely, if a given inositol phosphate of the present disclosure has an ability to inhibit crystallization that is 50% of the ability of phytic acid to inhibit crystallization, the dosage that can generally be administered is twice the dosage of phytic acid. In other words, the estimated dosage of the inositol phosphate of the present disclosure relative to the phytic acid dose is the reciprocal of the ratio between their respective abilities to inhibit crystallization (or other measurable properties related to the potency of the inositol phosphate of the present disclosure for treating ectopic calcification). Thus,

[0094] Dosage 化合物x = Dosage IP6×1 / (Property 化合物x / Property IP6 ), where the property can be, for example, the ability to inhibit hydroxyapatite crystallization, the ability to inhibit nucleation, or the ability to reduce, inhibit, or prevent any symptoms associated with ectopic crystallization (such as calciphylaxis).

[0095] In some aspects, the measurement of the crystallization-inhibiting ability of inositol phosphates in the present disclosure is carried out in vitro. In other aspects, the measurement of the crystallization-inhibiting ability of inositol phosphates in the present disclosure is carried out in vivo.

[0096] In some aspects, the inositol phosphates of the present disclosure comprise a compound of Formula I, a pharmaceutically acceptable salt thereof, or a combination thereof:

[0097]

[0098] where

[0099] (i) R 1 , R 3 , R 5 , R 7 , R 9 and R 11 independently represent OH, a compound of Formula II, or a compound of Formula III, or a compound of Formula IV:

[0100]

[0101] (ii) R 2 , R 4 , R 6 , R 8 , R 10 , R 12 and R 13 represent H;

[0102] (iii) At least one of R 1 , R 3 , R 5 , R 7 , R 9 and R 11 represents a compound of Formula II, Formula III, or Formula IV, and

[0103] (iv) Zero, one, or two of R 1 , R 3 , R 5 , R 7 , R 9 and R 11 represent a heterologous moiety.

[0104] In some aspects, the dosage of the inositol phosphate of the present disclosure comprises from about 5 mg / kg to about 10 mg / kg of inositol phosphate, inositol phosphate analog, inositol phosphate derivative, or a combination thereof, provided that when the inositol phosphate is myo-inositol hexakisphosphate, the dosage is not equal to 5 mg / kg or 10 mg / kg. In certain aspects, when the disease or condition being treated or prevented is associated with chronic kidney disease (CKD), such as a disorder of calcification in a CKD patient (e.g., a stage 5 CKD patient), the dosage is not equal to 5 mg / kg or 10 mg / kg. In some aspects, when the dosing regimen comprises a daily non-bolus dose administered for at least 14 days, the dosage is not equal to 5 mg / kg or 10 mg / kg.

[0105] In some aspects, the dosage of the inositol phosphate (e.g., myo-inositol hexakisphosphate) of the present disclosure is between about 5.0 mg / kg and about 6.0 mg / kg, between about 6.0 mg / kg and about 7.0 mg / kg, between about 7.0 mg / kg and about 8.0 mg / kg, between about 8.0 mg / kg and about 9.0 mg / kg, or between about 9.0 mg / kg and about 10.0 mg / kg.

[0106] In some aspects, the dosage of the inositol phosphate (e.g., myo-inositol hexakisphosphate) of the present disclosure is between about 5.0 mg / kg and about 5.5 mg / kg, between about 5.5 mg / kg and about 6.0 mg / kg, between about 6.0 mg / kg and about 6.5 mg / kg, between about 6.5 mg / kg and about 7.0 mg / kg, between about 7.0 mg / kg and about 7.5 mg / kg, between about 7.5 mg / kg and about 8.0 mg / kg, between about 8.0 mg / kg and about 8.5 mg / kg, between about 8.5 mg / kg and about 9.0 mg / kg, between about 9.0 mg / kg and about 9.5 mg / kg, or between about 9.5 mg / kg and about 10.0 mg / kg.

[0107] In some aspects, the dosage of the inositol phosphate (e.g., myo-inositol hexakisphosphate) of the present disclosure is between about 5.0 mg / kg and about 7.0 mg / kg, between about 6.0 mg / kg and about 8.0 mg / kg, between about 7.0 mg / kg and about 9.0 mg / kg, between about 8.0 mg / kg and about 10.0 mg / kg, between about 5.0 mg / kg and about 8 mg / kg, between about 6.0 mg / kg and about 9.0 mg / kg, between 7.0 mg / kg and about 10.0 mg / kg, between about 5.0 mg / kg and about 9 mg / kg, or between about 6.0 mg / kg and about 10.0 mg / kg.

[0108] In some aspects, the amount of inositol phosphate (e.g., phytic acid) of the present disclosure is about 5.1 mg / kg, about 5.2 mg / kg, about 5.3 mg / kg, about 5.4 mg / kg, about 5.5 mg / kg, about 5.6 mg / kg, about 5.7 mg / kg, about 5.8 mg / kg, about 5.9 mg / kg, about 6.0 mg / kg, about 6.1 mg / kg, about 6.2 mg / kg, about 6.3 mg / kg, about 6.4 mg / kg, about 6.5 mg / kg, about 6.6 mg / kg, about 6.7 mg / kg, about 6.8 mg / kg, about 6.9 mg / kg, about 7.0 mg / kg, about 7.1 mg / kg, about 7.2 mg / kg, about 7.3 mg / kg, about 7.4 mg / kg, about 7.5 mg / kg, about 7.6 mg / kg, about 7.7 mg / kg, about 7.8 mg / kg, about 7.9 mg / kg, about 8.0 mg / kg, about 8.1 mg / kg, about 8.2 mg / kg, about 8.3 mg / kg, about 8.4 mg / kg, about 8.5 mg / kg, about 8.6 mg / kg, about 8.7 mg / kg, about 8.8 mg / kg, about 8.9 mg / kg, about 9.0 mg / kg, about 9.1 mg / kg, about 9.2 mg / kg, about 9.3 mg / kg, about 9.4 mg / kg, about 9.5 mg / kg, about 9.6 mg / kg, about 9.7 mg / kg, about 9.8 mg / kg, about 9.9 mg / kg, or about 10 mg / kg.

[0109] In some aspects, the amount of inositol phosphate (e.g., phytic acid) of the present disclosure is between about 5.1 mg / kg and about 10 mg / kg, between about 5.2 mg / kg and about 10 mg / kg, between about 5.3 mg / kg and about 10 mg / kg, between about 5.4 mg / kg and about 10 mg / kg, between about 5.5 mg / kg and about 10 mg / kg, between about 5.6 mg / kg and about 10 mg, between about 5.7 mg / kg and about 10 mg / kg, between about 5.8 mg / kg and about 10 mg / kg, between about 5.9 mg / kg and about 10 mg / kg, between about 6.0 mg / kg and about 10 mg / kg, between about 6.1 mg / kg and about 10 mg / kg, between about 6.2 mg / kg and about 10 mg / kg, between about 6.3 mg / kg and about 10 mg / kg, between about 6.4 mg / kg and about 10 mg / kg, between about 6.5 mg / kg and about 10 mg / kg, between about 6.6 mg / kg and about 10 mg / kg, between about 6.7 mg / kg and about 10 mg / kg, between about 6.8 mg / kg and about 10 mg / kg, between about 6.9 mg / kg and about 10 mg / kg, between about 7.0 mg / kg and about 10 mg / kg, between about 7.1 mg / kg and about 10 mg / kg, between about 7.2 mg / kg and about 10 mg / kg, between about 7.3 mg / kg and about 10 mg / kg, between about 7.4 mg / kg and about 10 mg / kg, between about 7.5 mg / kg and about 10 mg / kg, between about 7.6 mg / kg and about 10 mg / kg, between about 7.7 mg / kg and about 10 mg / kg, between about 7.8 mg / kg and about 10 mg, between about 7.9 mg / kg and about 10 mg / kg, between about 8.0 mg / kg and about 10 mg / kg, between about 8.1 mg / kg and about 10 mg / kg, between about 8.2 mg / kg and about 10 mg / kg, between about 8.3 mg / kg and about 10 mg / kg, between about 8.4 mg / kg and about 10 mg / kg, between about 8.5 mg / kg and about 10 mg / kg, between about 8.6 mg / kg and about 10 mg / kg, between about 8.7 mg / kg and about 10 mg / kg, between about 8.8 mg / kg and about 10 mg / kg, between about 8.9 mg / kg and about 10 mg / kg, between about 9.0 mg / kg and about 10 mg / kg, between about 9.1 mg / kg and about 10 mg / kg, between about 9.2 mg / kg and about 10 mg / kg, between about 9.3 mg / kg and about 10 mg / kg, between about 9.4 mg / kg and about 10 mg / kg, between about 9.Between 5 mg / kg and about 10 mg / kg, between about 9.6 mg / kg and about 10 mg / kg, between about 9.7 mg / kg and about 10 mg / kg, between about 9.8 mg / kg and about 10 mg / kg, between about 9.9 mg / kg and about 10 mg / kg, or between about 10 mg / kg and about 10 mg / kg.

[0110] In some aspects, the amount of inositol phosphate (e.g., phytic acid) of the present disclosure is between about 5.0 mg / kg and about 5.1 mg / kg, between about 5.0 mg / kg and about 5.2 mg / kg, between about 5.0 mg / kg and about 5.3 mg / kg, between about 5.0 mg / kg and about 5.4 mg / kg, between about 5.0 mg / kg and about 5.5 mg / kg, between about 5.0 mg / kg and about 5.6 mg, between about 5.0 mg / kg and about 5.7 mg / kg, between about 5.0 mg / kg and about 5.8 mg / kg, between about 5.0 mg / kg and about 5.9 mg / kg, between about 5.0 mg / kg and about 6.0 mg / kg, between about 5.0 mg / kg and about 6.1 mg / kg, between about 5.0 mg / kg and about 6.2 mg / kg, between about 5.0 mg / kg and about 6.3 mg / kg, between about 5.0 mg / kg and about 6.4, between about 5.0 mg / kg and about 6.5 mg / kg, between about 5.0 mg / kg and about 6.6 mg / kg, between about 5.0 mg / kg and about 6.7 mg / kg, between about 5.0 mg / kg and about 6.8 mg / kg, between about 5.0 mg / kg and about 6.9 mg / kg, between about 5.0 mg / kg and about 7.0 mg / kg, between about 5.0 mg / kg and about 7.1 mg / kg, between about 5.0 mg / kg and about 7.2 mg / kg, between about 5.0 mg / kg and about 7.3 mg / kg, between about 5.0 mg / kg and about 7.4 mg / kg, between about 5.0 mg / kg and about 7.5 mg / kg, between about 5.0 mg / kg and about 7.6 mg / kg, between about 5.0 mg / kg and about 7.7 mg / kg, between about 5.0 mg / kg and about 7.8 mg / kg, between about 5.0 mg / kg and about 7.9 mg / kg, between about 5.0 mg / kg and about 8.0 mg / kg, between about 5.0 mg / kg and about 8.1 mg / kg, between about 5.0 mg / kg and about 8.2 mg / kg, between about 5.0 mg / kg and about 8.3 mg / kg, between about 5.0 mg / kg and about 8.4 mg / kg, between about 5.0 mg / kg and about 8.5 mg / kg, between about 5.0 mg / kg and about 8.6 mg, between about 5.0 mg / kg and about 8.7 mg / kg, between about 5.0 mg / kg and about 8.8 mg / kg, between about 5.0 mg / kg and about 8.9 mg / kg, between about 5.0 mg / kg and about 9.0 mg / kg, between about 5.0 mg / kg and about 9.1 mg / kg, between about 5.0 mg / kg and about 9.2 mg / kg, between about 5.0 mg / kg and about 9.between about 3 mg / kg, between about 5.0 mg / kg and about 9.4 mg / kg, between about 5.0 mg / kg and about 9.5 mg / kg, between about 5.0 mg / kg and about 9.6 mg / kg, between about 5.0 mg / kg and about 9.7 mg / kg, between about 5.0 mg / kg and about 9.8 mg / kg, between about 5.0 mg / kg and about 9.9 mg / kg, or between about 5.0 mg / kg and about 10 mg / kg.

[0111] In some aspects, the amount of inositol phosphate (e.g., phytic acid) of the present disclosure is administered once daily, i.e., as a single daily dose. In some aspects, the daily dose can be subdivided into smaller doses and administered separately. Thus, in some aspects, the total daily dose can be subdivided into 2, 3, 4 or more sub-doses, i.e., multiple daily doses.

[0112] In some aspects, the amount of inositol phosphate (e.g., phytic acid) of the present disclosure is administered at least once a week. In some aspects, the amount of inositol phosphate (e.g., phytic acid) of the present disclosure is administered at least 2 times a week, at least 3 times a week, at least 4 times a week, at least 5 times a week, at least 6 times a week, or at least 7 times a week.

[0113] In some aspects, the amount of inositol phosphate (e.g., phytic acid) of the present disclosure is administered for at least one week. In some aspects, the dose of inositol phosphate of the present disclosure is administered for about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 27 weeks, about 28 weeks, about 29 weeks, about 30 weeks, about 31 weeks, or about 32 weeks.

[0114] In some aspects, the amount of inositol phosphate (e.g., phytic acid) of the present disclosure is administered for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 21 weeks, at least 22 weeks, at least 23 weeks, at least 24 weeks, at least 25 weeks, at least 26 weeks, at least 27 weeks, at least 28 weeks, at least 29 weeks, at least 30 weeks, at least 31 weeks, or at least 32 weeks.

[0115] In some aspects, the dosage of the inositol phosphate of the present disclosure (such as myo-inositol hexaphosphate) is given for 1 to 4 weeks, 1 to 8 weeks, 1 to 12 weeks, 1 to 16 weeks, 1 to 20 weeks, 1 to 24 weeks, 1 to 28 weeks, 1 to 32 weeks, 4 to 8 weeks, 4 to 12 weeks, 4 to 16 weeks, 4 to 20 weeks, 4 to 24 weeks, 4 to 28 weeks, 4 to 32 weeks, 8 to 12 weeks, 8 to 16 weeks, 8 to 20 weeks, 8 to 24 weeks, 8 to 28 weeks, 8 to 32 weeks, 12 to 16 weeks, 12 to 20 weeks, 12 to 24 weeks, 12 to 28 weeks, 12 to 32 weeks, 16 to 20 weeks, 16 to 24 weeks, 16 to 28 weeks, 16 to 32 weeks, 20 to 24 weeks, 20 to 28 weeks, 20 to 32 weeks, 24 to 28 weeks, 24 to 32 weeks, or 28 to 32 weeks.

[0116] In one specific aspect, the dosage of the inositol phosphate of the present disclosure (such as the dosage of myo-inositol hexaphosphate at 6 mg / kg / day or 9 mg / kg / day) is given 3 times a week. In one specific aspect, the dosage of the inositol phosphate of the present disclosure (such as the dosage of myo-inositol hexaphosphate at 6 mg / kg / day or 9 mg / kg / day) is given 3 times a week for at least 12 weeks.

[0117] In some aspects, the concentration of the inositol phosphate (such as myo-inositol hexaphosphate, or its analogs or derivatives, or a combination thereof) in each dosage of the present disclosure is about 10,000 μg / mL to about 100,000 μg / mL. In one specific aspect, the concentration of the inositol phosphate (such as myo-inositol hexaphosphate, or its analogs or derivatives, or a combination thereof) in each dosage of the present disclosure is between about 20,000 μg / mL and about 90,000 μg / mL.

[0118] In one specific aspect, the concentration of the inositol phosphate (such as myo-inositol hexaphosphate, or its analogs or derivatives, or a combination thereof) in each dosage of the present disclosure is about 20,000 μg / mL. In another specific aspect, the concentration of the inositol phosphate (such as myo-inositol hexaphosphate, or its analogs or derivatives, or a combination thereof) in each dosage of the present disclosure is about 30,000 μg / mL. In yet another specific aspect, the concentration of the inositol phosphate (such as myo-inositol hexaphosphate, or its analogs or derivatives, or a combination thereof) in each dosage of the present disclosure is about 90,000 μg / mL.

[0119] In some aspects, the concentration of inositol phosphate (such as myo-inositol hexaphosphate, or its analogs or derivatives, or a combination thereof) in each dosage of the present disclosure is about 10,000 μg / mL, about 20,000 μg / mL, about 30,000 μg / mL, about 40,000 μg / mL, about 50,000 μg / mL, about 60,000 μg / mL, about 70,000 μg / mL, about 80,000 μg / mL, about 90,000 or about 100,000 μg / mL of the inositol phosphate of the present disclosure.

[0120] In some aspects, the concentration of inositol phosphate (such as myo-inositol hexaphosphate, or its analogs or derivatives, or a combination thereof) in each dosage of the present disclosure is between about 20,000 μg / mL and about 100,000 μg / mL, between about 30,000 μg / mL and about 100,000 μg / mL, between about 40,000 μg / mL and about 100,000 μg / mL, between about 50,000 μg / mL and about 100,000 μg / mL, between about 60,000 μg / mL and about 100,000 μg / mL, between about 70,000 μg / mL and about 100,000 μg / mL, between about 80,000 μg / mL and about 100,000 μg / mL, or between about 90,000 μg / mL and about 100,000 μg / mL of the inositol phosphate of the present disclosure.

[0121] In some aspects, the concentration of inositol phosphate (such as myo-inositol hexaphosphate, or its analogs or derivatives, or a combination thereof) in each dosage of the present disclosure is between about 10,000 μg / mL and about 20,000 μg / mL, between about 10,000 μg / mL and about 30,000 μg / mL, between about 10,000 μg / mL and about 40,000 μg / mL, between about 10,000 μg / mL and about 50,000 μg / mL, between about 10,000 μg / mL and about 60,000 μg / mL, between about 10,000 μg / mL and about 70,000 μg / mL, between about 10,000 μg / mL and about 80,000 μg / mL, or between about 10,000 μg / mL and about 90,000 μg / mL of the inositol phosphate of the present disclosure.

[0122] In some aspects, the concentration of inositol phosphate (e.g., myo-inositol hexaphosphate, or its analogs or derivatives, or combinations thereof) in each dosage of the present disclosure is the inositol phosphate of the present disclosure between about 10,000 μg / mL and about 20,000 μg / mL, between about 20,000 μg / mL and about 30,000 μg / mL, between about 30,000 μg / mL and about 40,000 μg / mL, between about 40,000 μg / mL and about 50,000 μg / mL, between about 50,000 μg / mL and about 60,000, between about 60,000 μg / mL and about 70,000 μg / mL, between about 70,000 μg / mL and about 80,000 μg / mL, between about 80,000 μg / mL and about 90,000 μg / mL, between about 90,000 μg / mL and about 100,000 μg / mL.

[0123] In some aspects, the concentration of inositol phosphate (e.g., myo-inositol hexaphosphate, or its analogs or derivatives, or combinations thereof) in each dosage of the present disclosure is the inositol phosphate of the present invention between about 10,000 μg / mL and about 30,000 μg / mL, between about 20,000 μg / mL and about 40,000 μg / mL, between about 30,000 μg / mL and about 50,000 μg / mL, between about 40,000 μg / mL and about 60,000 μg / mL, between about 50,000 μg / mL and about 70,000 μg / mL, between about 60,000 μg / mL and about 80,000 μg / mL, between about 70,000 μg / mL and about 90,000 μg / mL, or between about 80,000 μg / mL and about 100,000 μg / mL.

[0124] In some aspects, the concentration of inositol phosphate (e.g., myo-inositol hexaphosphate, or its analogs or derivatives, or combinations thereof) in each dosage of the present disclosure is the inositol phosphate of the present disclosure between about 10,000 μg / mL and about 40,000 μg / mL, between about 20,000 μg / mL and about 50,000 μg / mL, between about 30,000 μg / mL and about 60,000 μg / mL, between about 40,000 μg / mL and about 70,000 μg / mL, between about 50,000 μg / mL and about 80,000 μg / mL, between about 60,000 μg / mL and about 90,000 μg / mL, or between about 70,000 μg / mL and about 100,000 μg / mL.

[0125] In some aspects, the concentration of inositol phosphate (such as myo-inositol hexaphosphate, or its analogs or derivatives, or combinations thereof) in each dosage of the present disclosure is between about 10,000 μg / mL and about 50,000 μg / mL, between about 20,000 μg / mL and about 60,000 μg / mL, between about 30,000 μg / mL and about 70,000 μg / mL, between about 40,000 μg / mL and about 80,000 μg / mL, between about 50,000 μg / mL and about 90,000 μg / mL, or between about 60,000 μg / mL and about 100,000 μg / mL of the inositol phosphate of the present disclosure.

[0126] In some aspects, the concentration of inositol phosphate (such as myo-inositol hexaphosphate, or its analogs or derivatives, or combinations thereof) in each dosage of the present disclosure is between about 10,000 μg / mL and about 60,000 μg / mL, between about 20,000 μg / mL and about 70,000 μg / mL, between about 30,000 μg / mL and about 80,000 μg / mL, between about 40,000 μg / mL and about 90,000 μg / mL, or between about 50,000 μg / mL and about 100,000 μg / mL of the inositol phosphate of the present disclosure.

[0127] In some aspects, the concentration of inositol phosphate (such as myo-inositol hexaphosphate, or its analogs or derivatives, or combinations thereof) in each dosage of the present disclosure is between about 10,000 μg / mL and about 55,000 μg / mL, or between about 55,000 μg / mL and about 100,000 μg / mL of the inositol phosphate of the present disclosure.

[0128] In some aspects, the concentration of inositol phosphate (such as myo-inositol hexaphosphate, or its analogs or derivatives, or combinations thereof) in each dosage of the present disclosure is between about 12.5 mM and about 135 mM.

[0129] In some aspects, the concentration of inositol phosphate (such as myo-inositol hexaphosphate, or its analogs or derivatives, or combinations thereof) in each dosage of the present disclosure is between about 12.5 mM and about 125 mM. In some aspects, the concentration of inositol phosphate (such as myo-inositol hexaphosphate, or its analogs or derivatives, or combinations thereof) in each dosage of the present disclosure is about 25 mM, about 39 mM or about 114 mM.

[0130] In some aspects, the concentration of inositol phosphate (e.g., myo-inositol hexaphosphate, or an analogue or derivative thereof, or a combination thereof) in each dosage of the present disclosure is about 12.5 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, about 20 mM, about 21 mM, about 22 mM, about 23 mM, about 24 mM, about 25 mM, about 26 mM, about 27 mM, about 28 mM, about 29 mM, about 30 mM, about 31 mM, about 32 mM, about 33 mM, about 34 mM, about 35 mM, about 36 mM, about 37 mM, about 38 mM, about 39 mM, about 40 mM, about 41 mM, about 42 mM, about 43 mM, about 44 mM, about 45 mM, about 46 mM, about 47 mM, about 48 mM, about 49 mM, about 50 mM, about 51 mM, about 52 mM, about 53 mM, about 54 mM, about 55 mM, about 56 mM, about 57 mM, about 58 mM, about 59 mM, about 60 mM, about 61 mM, about 62 mM, about 63 mM, about 64 mM, about 65 mM, about 66 mM, about 67 mM, about 68 mM, about 69 mM, or about 70 mM. About 71 mM, about 72 mM, about 73 mM, about 74 mM, about 75 mM, about 76 mM, about 77 mM, about 78 mM, about 79 mM, about 80 mM, about 81 mM, about 82 mM, about 83 mM, about 84 mM, about 85 mM, about 86 mM, about 87 mM, about 88 mM, about 89 mM, about 90 mM, 91 mM, about 92 mM, about 93 mM, about 94 mM, about 95 mM, about 96 mM, about 97 mM, about 98 mM, about 99 mM, about 100 mM, about 101 mM, about 102 mM, about 103 mM, about 104 mM, about 105 mM, about 106 mM, about 107 mM, about 108 mM about 109 mM, about 110 mM, about 111 mM, about 112 mM, about 113 mM, about 114 mM, about 115 mM, about 116 mM, about 117 mM, about 118 mM, about 119 mM, about 120 mM, about 121 mM, about 122 mM, about 123 mM, about 124 mM, about 125 mM, about 126 mM, about 127 mM, about 128 mM, about 129 mM, about 130 mM, about 131 mM, about 132 mM, about 133 mM, about 134 mM, or about 135 mM.

[0131] In some aspects, the concentration of inositol phosphate (e.g., myo-inositol hexaphosphate, or an analogue or derivative thereof, or a combination thereof) in each dosage of the present disclosure is between about 12.5 mM and about 20 mM, between 20 mM and about 30 mM, between about 30 mM and about 40 mM, between about 40 mM and about 50 mM, between about 50 mM and about 60 mM, between about 60 mM and about 70 mM, between about 70 mM and about 80 mM, between about 80 mM and about 90 mM, between about 90 mM and about 100 mM, between about 100 mM and about 110 mM, between about 110 mM and about 120 mM, between about 120 mM and about 130 mM, or between about 130 mM and about 135 mM.

[0132] In some aspects, the concentration of inositol phosphate (e.g., myo-inositol hexaphosphate, or an analogue or derivative thereof, or a combination thereof) in each dosage of the present disclosure is between about 12.5 mM and about 30 mM, between 20 mM and about 40 mM, between about 30 mM and about 50 mM, between about 40 mM and about 60 mM, between about 50 mM and about 70 mM, between about 60 mM and about 80 mM, between about 70 mM and about 90 mM, between about 80 mM and about 100 mM, between about 90 mM and about 110 mM, between about 100 mM and about 120 mM, or between about 110 mM and about 135 mM.

[0133] In some aspects, the concentration of inositol phosphate (e.g., myo-inositol hexaphosphate, or an analogue or derivative thereof, or a combination thereof) in each dosage of the present disclosure is between about 12.5 mM and about 40 mM, between 0 mM and about 50 mM, between about 30 mM and about 60 mM, between about 40 mM and about 70 mM, between about 50 mM and about 80 mM, between about 60 mM and about 90 mM, between about 70 mM and about 100 mM, between about 80 mM and about 110 mM, between about 90 mM and about 120 mM, or between about 100 mM and about 135 mM.

[0134] In some aspects, the concentration of inositol phosphate (e.g., myo-inositol hexaphosphate, or an analogue or derivative thereof, or a combination thereof) in each dosage of the present disclosure is between about 12.5 mM and about 50 mM, between 20 mM and about 60 mM, between about 30 mM and about 70 mM, between about 40 mM and about 80 mM, between about 50 mM and about 90 mM, between about 60 mM and about 100 mM, between about 70 mM and about 110 mM, between about 80 mM and about 120 mM, between about 90 mM and about 130 mM, or between about 100 mM and about 135 mM.

[0135] In some aspects, the concentration of inositol phosphate (such as myo-inositol hexaphosphate, or an analogue or derivative thereof, or a combination thereof) in each dosage of the present disclosure is between about 12.5 mM and about 60 mM, between about 20 mM and about 70 mM, between about 30 mM and about 80 mM, between about 40 mM and about 90 mM, between about 50 mM and about 100 mM, between about 60 mM and about 110 mM, between about 70 mM and about 120 mM, between about 80 mM and about 130 mM, or between about 90 mM and about 135 mM.

[0136] In some aspects, the concentration of inositol phosphate (such as myo-inositol hexaphosphate, or an analogue or derivative thereof, or a combination thereof) in each dosage of the present disclosure is between about 12.5 mM and about 135 mM, between about 20 mM and about 135 mM, between about 30 mM and about 135 mM, between about 40 mM and about 135 mM, between about 50 mM and about 135 mM, between about 60 mM and about 135 mM, between about 70 mM and about 135 mM, between about 80 mM and about 135 mM, between about 90 mM and about 135 mM, between about 100 mM and about 135 mM, between about 110 mM and about 135 mM, between about 120 mM and about 135 mM, or between about 130 mM and about 135 mM.

[0137] In some aspects, the concentration of inositol phosphate (such as myo-inositol hexaphosphate, or an analogue or derivative thereof, or a combination thereof) in each dosage of the present disclosure is between about 12.5 mM and about 20 mM, between about 12.5 mM and about 30 mM, between about 12.5 mM and about 40 mM, between about 12.5 mM and about 50 mM, between about 12.5 mM and about 60 mM, between about 12.5 mM and about 70 mM, between about 12.5 mM and about 80 mM, between about 12.5 mM and about 90 mM, between about 12.5 mM and about 100 mM, between about 12.5 mM and about 110 mM, between about 12.5 mM and about 120 mM, between about 12.5 mM and about 130 mM, or between about 12.5 mM and about 135 mM.

[0138] In some aspects, the dosage of inositol phosphate (such as myo-inositol hexaphosphate, or an analogue or derivative thereof, or a combination thereof) of the present disclosure can be administered parenterally, such as, for example, intravenously, intraperitoneally, intramuscularly, intraarterially or subcutaneously. Alternatively, the compound can be administered as a component of a hemodialysis, hemofiltration or peritoneal dialysis solution. In some aspects, parenteral administration is by bolus injection or by intravenous infusion. In certain aspects, the administration is topical.

[0139] In some aspects, the inositol phosphates of the present disclosure can be administered by any suitable method, such as a method that results in non-bolus release or action, such as intravascular (e.g., intravenous) infusion, other parenteral administrations (subcutaneous, subcutaneous depot, intraperitoneal, intramuscular, intradermal, intrathecal, epidural, spinal, or other administrations known to those skilled in the art), topical administrations (intranasal, inhalation, intravaginal, transdermal, or other administrations known to those skilled in the art), enteral (oral, sublingual, rectal, etc.) administrations, oral, spinal, intraperitoneal formulations, or other formulations known to those skilled in the art.

[0140] As used herein, "parenteral administration" of a composition comprising the inositol phosphates of the present disclosure includes any route of administration characterized by physically disrupting the tissue of a subject and administering the composition through the disruption of the tissue. Parenteral administration thus includes, but is not limited to, administering the composition by injection, administering the composition via a surgical incision, administering the composition via a tissue-penetrating non-surgical wound, etc., to administer a composition comprising the inositol phosphates of the present disclosure. In particular, parenteral administration is expected to include, but is not limited to, subcutaneous, intravenous, intraperitoneal, intramuscular, intracardiac injection, and hemodialysis infusion techniques.

[0141] In the specific case of patients undergoing dialysis treatment, a very suitable method of administration consists of administering (e.g., non-bolus administration) the inositol phosphates of the present application via a dialysis device (before or after the filter), rather than directly injecting the inositol phosphates of the present invention intravenously into the patient's body. Thus, when the blood leaves the patient and circulates through the dialysis circuit, the blood can be treated with the inositol phosphates of the present disclosure (e.g., myo-inositol hexakisphosphate), and when the blood containing the inositol phosphates of the present disclosure returns to the body, the inositol phosphates of the present disclosure have been introduced into the blood in a manner that presents a series of advantages.

[0142] In the case of dialysis patients, administering the inositol phosphates of the present disclosure (e.g., myo-inositol hexakisphosphate) via a dialysis device will allow the blood to equilibrate with the dialysis fluid before returning to the body; thus, although the inositol phosphates of the present disclosure (e.g., myo-inositol hexakisphosphate) can chelate ionic calcium, this fact is compensated for when the blood passes through the dialysis filter, thereby eliminating the side effect and significantly improving safety.

[0143] As used herein, the terms "extended release", "slow release", or "non-bolus" refer to a form of administration in which the inositol phosphates of the present disclosure (e.g., myo-inositol hexakisphosphate) are slowly released into the bloodstream, such that they can maintain a significant level in the serum for a longer period of time compared to "bolus" administration. Bolus administration includes, for example, rapid intravenous injection, such as an intravenous infusion of less than 10 seconds (or less than 20, 30, 40, 50, 60 seconds), or less than about 3, 4, 5, 6, 7, 8, 9, or 10 minutes.

[0144] In a specific aspect of the present disclosure, myo-inositol hexakisphosphate (or a formulation comprising myo-inositol hexakisphosphate, such as SNF472) is administered by an intravenous route via intravenous infusion. In another specific aspect of the present disclosure, myo-inositol hexakisphosphate is administered subcutaneously. In another specific aspect of the present disclosure, myo-inositol hexakisphosphate is administered topically.

[0145] In some aspects, when the inositol phosphates of the present disclosure (e.g., myo-inositol hexakisphosphate) are administered to a patient undergoing dialysis, such administration (e.g., via intravenous infusion) can occur during the dialysis treatment.

[0146] In some aspects, the inositol phosphates of the present disclosure (e.g., myo-inositol hexakisphosphate) are administered before the dialysis treatment. In some aspects, the inositol phosphates of the present disclosure are administered after the dialysis treatment.

[0147] In some aspects, the inositol phosphates of the present disclosure (e.g., myo-inositol hexakisphosphate) are administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or about 48 hours before the dialysis treatment.

[0148] In some aspects, the inositol phosphates (e.g., myo-inositol hexakisphosphate) of the present disclosure are administered about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 25 hours, about 26 hours, about 27 hours, about 28 hours, about 29 hours, about 30 hours, about 31 hours, about 32 hours, about 33 hours, about 34 hours, about 35 hours, about 36 hours, about 37 hours, about 38 hours, about 39 hours, about 40 hours, about 41 hours, about 42 hours, about 43 hours, about 44 hours, about 45 hours, about 46 hours, about 47 hours or about 48 hours after dialysis treatment.

[0149] In some aspects, the dosage of the inositol phosphates (e.g., myo-inositol hexakisphosphate) of the present disclosure administered to a subject inhibits the formation and / or growth of hydroxyapatite crystals and their deposition in ectopic calcification. In some aspects, the ectopic calcification is, for example, calciphylaxis calcification, metastatic calcification, dystrophic calcification, iatrogenic calcification, idiopathic calcification or subcutaneous heterotopic ossification.

[0150] In some aspects, the consequences of ectopic calcification are, for example, (i) functional complications; (ii) pain; (iii) nutritional complications; (iv) infection; or (v) a combination thereof. In some aspects, the functional complications are, for example, limitations in range of motion and / or joint function. In some aspects, the nutritional complications are, for example, ischemia and / or lesions. In some aspects, the lesions are, for example, necrosis of the skin and / or subcutaneous tissue.

[0151] In some aspects, the dosage of the inositol phosphates (e.g., myo-inositol hexakisphosphate) of the present disclosure administered to a subject results in a reduction in injury, as determined, for example, by the Bates-Jensen Wound Assessment Tool or other methods known in the art. Bates-Jensen (1992), supra. In some aspects, the reduction in injury includes, for example, a decrease in the severity of the injury, a decrease in the size of the injury, and a decrease in the duration of the injury, or a combination thereof. In some aspects, administering the dosage of the inositol phosphates of the present disclosure to a subject results in an improvement in wound healing. In some aspects, administering the dosage of the inositol phosphates of the present disclosure to a subject results in a reduction in pain.

[0152] In some aspects, administration of a dose of an inositol phosphate of the present disclosure (e.g., myo-inositol hexakisphosphate) to a subject results in an improvement in overall wound quality of life (QoL), as determined, for example, by use of a validated wound-related QoL questionnaire or other methods known in the art. Augustin (2017), supra. In some aspects, the subject has end-stage renal disease. In some aspects, the subject is undergoing hemodialysis. In some aspects, the subject is a human.

[0153] The present disclosure also provides a method of treating or preventing calciphylaxis calcification and / or its consequences in a subject in need thereof, comprising administering an intravenous dosage of myo-inositol hexakisphosphate to the subject three times a week at a dose of about 6 mg / kg / day to 9 mg / kg / day for 12 or 24 weeks, wherein administration of said dose effectively treats or prevents calciphylaxis calcification and / or its consequences in the subject. In some aspects, a dose of about 7 mg / kg / day is administered three times a week for 12 or 24 weeks.

[0154] The present disclosure also provides an intravenous dosage of myo-inositol hexakisphosphate, which is administered to a subject three times a week at a dose of about 6 mg / kg / day to 9 mg / kg / day for 12 or 24 weeks, and is taken by the patient in a therapeutically effective amount sufficient to treat or prevent calciphylaxis calcification and / or its consequences in the subject. In some aspects, a dose of about 3 mg / kg / day is administered three times a week for 12 or 24 weeks.

[0155] The present disclosure also provides a kit or a manufactured article, comprising: at least one container that contains a parenteral or topical dosage of an inositol phosphate of the present disclosure; and instructions for administration according to any of the methods in the present disclosure.

[0156] III. Inositol Phosphate Compositions

[0157] As described above, the inositol phosphates of the present disclosure comprise a compound of Formula I, a pharmaceutically acceptable salt thereof, or a combination thereof:

[0158]

[0159] wherein

[0160] (i) at least one of R 1 , R 3 , R 5 , R 7 , R 9 and R 11 independently represents OH, a compound of Formula II, or a compound of Formula III or Formula IV:

[0161]

[0162] (ii) R 2 、R 4 、R 6 、R 8 、R 10 、R 12 and R 13 represent H;

[0163] (iii) R 1 、R 3 、R 5 、R 7 、R 9 and R 11 at least one of which represents a compound of Formula II, Formula III or Formula IV, and

[0164] (iv) R 1 、R 3 、R 5 、R 7 、R 9 and R 11 zero, one or two of which represent a hetero moiety.

[0165] The formulas disclosed herein are intended to cover any diastereomers.

[0166] In some aspects, at least one of R 1 、R 3 、R 5 、R 7 、R 9 and R 11 independently represents H, -X, -OX, -NHX, -NX 2 、-SX, -OSO 3 HX, -OSO 3 X 2 、or a compound of Formula II, Formula III or Formula IV, wherein each X independently represents H, C 1-30 alkyl, C 2-30 alkynyl or Cy 1 , wherein C 1-30 alkyl, C 2-30 alkenyl and C 2-30 alkynyl are independently optionally substituted by one or more R 14 and wherein Cy 1 is optionally substituted by one or more R 15 ;

[0167] Cy 1represents a 3- to 10-membered carbocyclic or heterocyclic ring, which can be saturated, partially unsaturated or aromatic, wherein the heterocyclic ring has 1 to 4 heteroatoms selected from O, S and N, wherein the ring can be bonded to the rest of the molecule through any available C atom, and wherein Cy 1 is optionally fused to 1 to 4 five- or six-membered rings (each of which is a saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring), and wherein the fused heterocyclic ring may contain 1 or 2 heteroatoms selected from O, N and S; each R 13 independently represents H, C 1-30 alkyl, -NH 2 , -NHC 1-30 alkyl or N(C 1-30 alkyl) 2 , wherein each C 1-30 alkyl is independently optionally substituted by one or more halogens, -OH, -CN and -NO 2 groups; R 14 and R 15 each independently represents -OH, C 1-30 alkoxy, C 1-30 alkylsulfinyl, C 1-30 acyloxy, phosphate, halogen, trihalo C 1-30 alkyl, nitrile, azide.

[0168] In some aspects, each X independently represents H, C 1-30 alkyl or Cy 1 , wherein C 1-30 alkyl is optionally substituted by one or more R 14 substituents, and wherein Cy 1 is optionally substituted by one or more R 15 substituents; R 14 and R 15 each independently represents -OH, C 1-30 alkoxy, C 1-30 alkylsulfinyl, C 1-30 acyloxy, phosphate, halogen, trihalo C 1-30 alkyl, nitrile or azide. In some aspects, each X represents H, C 1-30 alkyl or Cy 1 . In some aspects, each X represents H.

[0169] In some aspects, at least one of the groups R 1 , R 3 , R 5 , R 7 , R 9 and R 11 independently represents a compound of formula II, formula III or formula IV, each R13 independently represent H, C 1-30 alkyl, -NH 2 , -NHC 1-30 alkyl or -N(C 1-30 alkyl) 2 , wherein each C 1-30 alkyl is independently optionally substituted by one or more halogen, -OH, -CN and -NO 2 groups; and R 2 , R 4 , R 6 , R 8 , R 10 and R 12 independently represent H.

[0170] In another aspect, R 1 , R 3 , R 5 , R 7 , R 9 and R 11 independently represent a compound of formula II, formula III or formula IV, each R 13 independently represents H or C 1-30 alkyl, wherein each C 1-30 alkyl is independently optionally substituted by one or more halogen, -OH, -CN and -NO 2 groups; and R 2 , R 4 , R 6 , R 8 , R 10 and R 12 independently represent H.

[0171] In another aspect, R l , R 3 , R 5 , R 7 , R 9 and R 11 independently represent a compound of formula II, formula III or formula IV, each R 13 independently represents H or C 1-30 alkyl; and R 2 , R 4 , R 6 , R 8 , R 10 and R 12 independently represent H.

[0172] In another aspect, R l , R 3 , R 5 , R 7 , R 9 and R11 independently represents a compound of Formula II, Formula III or Formula IV, each R 3 independently represents H; and R 2 , R 4 , R 6 , R 8 , R 10 and R 12 independently represents H.

[0173] In one specific aspect, the compound is myo-inositol hexakisphosphate (IP6). In other aspects, the compound is inositol monophosphate (IP1), inositol diphosphate (IP2), inositol triphosphate (IP3), inositol tetraphosphate (IP4) or inositol pentaphosphate (IP5). In some aspects, the compound comprises a combination of IP1, IP2, IP3, IP4, IP6 and IP6. In some aspects, IP6 can be formed into other inositol phosphates (IP5, IP4, IP3, IP2, IP1) by in vivo dephosphorylation. Inositol is presumed to refer to any isomeric form of the molecule.

[0174] The inositol phosphates of the present disclosure also encompass compounds that produce metabolites during physiological dephosphorylation (or in the case of compounds containing sulfate or thiophosphate groups, desulfation or desulfurization).

[0175] In some aspects, the compound administered in a dose according to the methods disclosed herein is a prodrug that produces the inositol phosphates of the present disclosure upon undergoing hydrolysis or other intracellular or extracellular processing.

[0176] The inositol phosphates of the present disclosure also encompass any combination of the inositol phosphates, inositol phosphate analogs and their derivatives disclosed herein.

[0177] All compounds of formula I contain a C—O—P or C—O—S bond, which provides the compound with an affinity for calcium-containing crystals and a bond that is sufficiently labile to be hydrolyzed in vivo, thereby preventing its irreversible binding to calcium-containing crystals (such as hydroxyapatite (HAP) in bone) (such binding would have a negative impact on bone remodeling, as is the case with long-term administration of bisphosphonates, because the compound contains a P—C—P bond that cannot be hydrolyzed by the body). At the other extreme are phosphorylated compounds that do not contain the C—O—P bond (such as pyrophosphates), whose P—O—P bond means that they are too readily hydrolyzed in the intestine, thus meaning that only parenteral administration is feasible. The compounds of the present disclosure having a C—O—P bond, a C—O—S bond, and combinations thereof represent an appropriate midpoint due to their pharmacodynamic effect and the fact that the body exhibits a mechanism for eliminating the compound, thereby reducing the risk of side effects (for example, compounds having a P—C—P bond may exhibit a half-life in the body of several months, thus affecting, for example, bone remodeling).

[0178] In the context of the present disclosure, the term “alkyl” or “alkyl group” refers to a saturated hydrocarbon moiety that can be straight-chain, branched-chain, cyclic, or cyclic with straight-chain or branched-chain side chains. The term alkyl includes partially unsaturated hydrocarbons such as allyl. Examples are methyl, ethyl, n-butyl or isobutyl, n-butyl or cyclohexyl. The term alkyl can extend to alkyl groups that are linked or bridged by heteroatoms. In the context of the present invention, heteroatoms are nitrogen (N), sulfur (S), and oxygen (O).

[0179] “Amine functional group” or “amine group” is the functional group NR′R″, where R′ and R″ are independently selected from hydrogen and C 1 -C 5 alkyl. In some embodiments, R′ and R″ are selected from hydrogen and C 1 -C 3 alkyl. “Hydroxy functional group” or “hydroxy” is OH. “Thiol functional group” or “thiol group” is SH. “Carboxylic acid functional group” or “carboxylic acid group” is COOH or its anion COO - . “Carboxylic acid amide” is CONR′R″, where R′ and R″ independently have the above meanings. “Sulfonic acid” is SO 3 H. “Sulfonic acid amide” is SO 2 NR′R″, where R′ and R″ independently have the above meanings.

[0180] In the context of the present disclosure, “C 1 -C 3 alkyl” refers to a saturated straight-chain or branched-chain hydrocarbon having 1, 2, or 3 carbon atoms, where one carbon-carbon bond can be unsaturated, and one CH 2 moiety can be exchanged for oxygen (ether bridge). C 1 -C3 Non-limiting examples of alkyl groups are methyl, ethyl, propyl, prop-2-enyl, and prop-2-yl.

[0181] In the context of the present disclosure, "C 1 -C 5 alkyl" refers to a saturated straight-chain or branched-chain hydrocarbon having 1, 2, 3, 4, or 5 carbon atoms, where one or two carbon-carbon bonds may be unsaturated, and one CH 2 moiety may be exchanged for oxygen (ether bridge). C 1 -C 5 Non-limiting examples of C 1 -C 3 alkyl include the examples given above for C

[0182] In the context of the present disclosure, "C 3 -C 10 alkyl" refers to a saturated straight-chain or branched-chain hydrocarbon having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, where 1, 2, or 3 carbon-carbon bonds may be unsaturated, and one CH 2 moiety may be exchanged for oxygen (ether bridge).

[0183] The term "C 1-30 alkyl" as a group or part of a group refers to a straight-chain or branched-chain alkyl group containing 1 to 30 carbon atoms, particularly including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, decyl, and dodecyl.

[0184] The term "C 2-30 alkenyl" refers to a straight-chain or branched-chain alkyl chain containing 2 to 30 carbon atoms and also containing one or more double bonds. Examples particularly include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, and 1,3-butadienyl.

[0185] The term "C 2-30 alkynyl" refers to a straight-chain or branched-chain alkyl chain containing 2 to 30 carbon atoms and also containing one or more triple bonds. Examples particularly include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and 1,3-butadiynyl.

[0186] "Cy 1"Group" means a three- to ten-membered carbocyclic or heterocyclic ring that can be saturated, partially unsaturated or aromatic, and is bonded to the remainder of the molecule through any available C atom. When it is a heterocyclic ring, Cy 1 contains 1 to 4 heteroatoms selected from N, O, and S. In addition, Cy 1 can be fused with up to 4 five- or six-membered carbocyclic or heterocyclic rings (which can be saturated, partially unsaturated or aromatic). If the fused ring is a heterocyclic ring, the ring contains one or two heteroatoms selected from N, O, and S. Cy 2 Examples of Cy include phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzimidazolyl, benzofuryl, isobenzofuryl, indolyl, isoindolyl, benzothienyl, benzothiazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, and aziridinyl.

[0187] "C 1-30 alkoxy" as a group or part of a group means -OC 1-30 alkyl, where the C 1-30 alkyl moiety has the same meaning as above. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0188] "C 1-30 alkylsulfinyl" as a group or part of a group means -SOC 1-30 alkyl, where the C 1-30 alkyl moiety has the same meaning as above. Examples include methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, and tert-butylsulfinyl.

[0189] "C 1-30 acyloxy" as a group or part of a group means -COC 1-30 alkyl, where the C 1-30 alkyl moiety has the same meaning as above. Examples include acetyl, propionyl, and 2,2-diisopropylvaleryl.

[0190] "Halogen atom group" or its halogenated abbreviation means fluorine, chlorine, bromine, and iodine.

[0191] "Trihalo C 1-30 alkyl" means C 1-30A group produced by replacing three hydrogen atoms of an alkyl group with three halogen atom groups as defined above. Examples particularly include trifluoromethyl, tribromomethyl, trichloromethyl, triiodomethyl, trifluoroethyl, tribromoethyl, trichloroethyl, triiodoethyl, tribromopropyl, trichloropropyl, and triiodopropyl.

[0192] “-NHC 1-30 alkyl” means a group produced by replacing one hydrogen atom of the -NH 2 group with a C 1-30 alkyl as defined above. Examples particularly include methylamine, ethylamine, propylamine, butylamine, and pentylamine.

[0193] “-N(C 1-30 alkyl) 2 group” means a group produced by replacing two hydrogen atoms of the -NH 2 group with C 1-30 alkyl as defined above. Examples particularly include dimethylamine, diethylamine, diisopropylamine, dibutylamine, and diisobutylamine.

[0194] The expression “optionally substituted with one or more substituents” means the possibility that the group can be substituted with one or more, for example, 1, 2, 3, or 4 substituents. In some aspects, the group can be substituted with 1, 2, or 3 substituents, or even 1 or 2 substituents, as long as the group has sufficient positions available for substitution. If present, the substituents can be the same or different and can be located at any available position.

[0195] In some aspects, for example, the inositol phosphates of the present disclosure used in the methods and compositions disclosed herein include the compounds disclosed in International Publication Nos. WO2017098033 and WO2017098047 and U.S. Patent Application Publication No. US9358243B2, which are hereby incorporated by reference in their entirety. In some aspects, for example, the inositol phosphates of the present disclosure used in the methods and compositions disclosed herein include Figure 8 , 9 , the compounds disclosed in 10, 11, 12, 13.

[0196] In some aspects, for example, the inositol phosphates, inositol phosphate analogs, and their derivatives used in the methods and compositions disclosed herein include compounds of formula (V), formula (VI), or formula (VII):

[0197]

[0198] wherein

[0199] each X is independently selected from OPO 3 2- , OPSO 2 2-or OSO 3 - ;

[0200] Z is an alkyl chain containing from 1 to 3 carbon and / or heteroatoms, optionally containing group X, where X is also selected from OPO 3 2- , OPSO 2 2- or OSO 3 - ; and,

[0201] R 1 is an optional hetero moiety (see Section IV below). In some aspects, the molecule contains more than one hetero moiety, in which case the hetero moieties can be the same or different.

[0202] In certain aspects, Z used in formula (V) is CH 2 , CHX, CHR 1 , CXR 1 , CH 2 -CH 2 , CH 2 -CHX, CHX-CHX, CHR 1 -CHX, CXR 1 -CHX, CHR 1 -CH 2 , CXR 1 -CH 2 , CHR 1 -CHOH, CH 2 -CH 2 -CH 2 , CH 2 -O-CH 2 , CHOH-CH 2 -CH 2 , CHOH-CHOH-CHR 1 , CHOH-CHR 1 -CHOH, CHX-CH 2 -CH 2 , CH 2 -CHX-CH 2 , CHX-CHX-CH 2 , CHX-CH 2 -CHX, or CHX-CHR 1 -CHX, where X is independently selected from OPO 3 2- , OPSO 2 2- and OSO 3 - .

[0203] In some aspects, Z used in formula (V) is (CHX) p CHX(CHX) q ; where p and q independently of one another have values from 0 to 2, provided that (p + q) has a value of 0, 1 or 2; one or two or three Xs can be a hetero moiety (e.g., PEG), and the remaining Xs are independently selected from OPO 3 2- 、OPSO 2 2- and OSO 3 - . In certain aspects, not all of the Xs of Z are OPO 3 2- . In some aspects, not all of the Xs of Z are OSO 3 - .

[0204] In some aspects, one, two or three Xs in the compounds of formula (V), formula (VI) or formula (VII) can be a hetero moiety, and the remaining Xs can be independently selected from OPO 3 2- 、OPSO 2 2- 、or OSO 3 - .

[0205] The above formula (V) describes a five-, six- or seven-membered alkyl ring, and optionally one or more hetero moieties are attached to one of the carbon atoms forming the ring.

[0206] In some aspects, for example, the inositol phosphates, inositol phosphate analogs and derivatives thereof used in the methods and compositions disclosed herein comprise compounds of formula (VIII) or formula (IX):

[0207]

[0208] Wherein:

[0209] (a) X 2 is OSO 3 - , and X 1 , X 3 , X 4 , X 5 and X 6 are independently selected from OPO 3 2- 、OPSO 2 2- or OSO 3 - ;

[0210] (b)X 1 , X 3 and X 5 For OPO 3 2- , and X 2 , X 4 and X 6 For OSO 3 - ;

[0211] (c)X 1 , X 3 and X 5 For OSO 3 - , and X 2 , X 4 and X 6 For OPO 3 2- ;

[0212] (d)X 4 , X 5 and X 6 For OSO 3 - , and X 1 , X 2 and X 3 For OPO 3 2- ;

[0213] (e)X 4 , X 5 and X 6 For OPO 3 2- , and X 1 , X 2 and X 3 For OSO 3 - ;

[0214] (f)X 2 and X 5 For OPO 3 - , and X 1 , X 3 , X 4 and X 6 For OPO 3 - ;

[0215] (g)X 2 and X 5 For OSO 3 - , and X 1 , X3 , X 4 and X 6 is OPO 3 2- ;

[0216] (h) X 2 and X 3 is OPO 3 2- , and X 1 , X 4 , X 5 and X 6 is OSO 3 - ; or

[0217] (i) X 2 and X 3 is OSO 3 - , and X 1 , X 4 , X 5 and X 6 is OPO 3 2- .

[0218] In some aspects, the methods disclosed in U.S. Patent No. 9,612,250 B2 can be used to detect and / or quantify the inositol phosphates or their metabolites of the present disclosure, and the entire text of this patent is incorporated herein by reference. See also U.S. Patent Nos. 8,377,909 B2 and 8,778,912 and U.S. Patent Application Publication No. US20070066574.

[0219] The compounds disclosed herein can exist in any form commonly used in pharmaceutical technology. Specific aspects include, but are not limited to, sodium salts, magnesium salts, potassium salts, ammonium salts, free acids, or mixtures of the foregoing forms. Other pharmaceutically acceptable salts are known to those skilled in the art and can be obtained, in particular, from Haynes et al. (2005) J. Pharmaceutical Sci. 94:2111 - 2120.

[0220] IV. Heterologous moieties

[0221] In some aspects, the inositol phosphate derivatives of the present disclosure can include at least one heterologous moiety that has advantageous properties relative to the corresponding molecule lacking such one or more heterologous moieties. Exemplary advantageous properties that the heterologous moiety or combination thereof can confer on the inositol phosphate or inositol phosphate analog are:

[0222] (i) Increased solubility;

[0223] (ii) Increased or decreased degradation or metabolic rate;

[0224] (iii) Increase or decrease the serum half-life;

[0225] (iv) Decrease in the hepatic metabolic rate;

[0226] (v) Increase or decrease the renal clearance rate;

[0227] (vi) Decrease in precipitation;

[0228] (vii) Extension of the shelf life;

[0229] (viii) Increase or decrease in the permeability through physiological barriers (such as the blood-brain barrier, intestinal wall, peritoneum, blood vessel wall, skin, etc.);

[0230] (ix) Thermal stability;

[0231] (x) Resistance to phosphatase and / or sulfatase;

[0232] (xi) Any combination thereof.

[0233] The advantageous properties disclosed above can be evaluated or quantified using methods known in the art without undue experimentation.

[0234] In some aspects, the heterologous moiety is, for example, polyethylene glycol (PEG), polyglycerol (PG).

[0235] PEG: In certain aspects, the heterologous moiety comprises polyethylene glycol (PEG) characterized by the formula R 3 -(O-CH 2 -CH 2 ) n - or R 3 -(O-CH 2 -CH 2 ) n -O-, where R 3 is hydrogen, methyl or ethyl, and the value of n is between 2 and 200.

[0236] In some aspects, n has a value of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 189, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199 or 200.

[0237] In some aspects, n is between 2 and 10, between 10 and 20, between 20 and 30, between 30 and 40, between 40 and 50, between 50 and 60, between 60 and 70, between 70 and 80, between 80 and 90, between 90 and 100, between 100 and 110, between 110 and 120, between 120 and 130, between 130 and 140, between 140 and 150, between 150 and 160, between 160 and 170, between 170 and 180, between 180 and 190, or between 190 and 200.

[0238] In some specific aspects, n has a value of 3 to 200, 3 to 20, 10 to 30 or 9 to 45.

[0239] In some aspects, the PEG is branched PEG. The branched PEG has 3 to 10 PEG chains radiating from a central core group.

[0240] In certain embodiments, the PEG moiety is monodisperse polyethylene glycol. In the context of the present disclosure, monodisperse polyethylene glycol (mdPEG) is a PEG having a single defined chain length and molecular weight. Monodisperse polyethylene glycol is typically produced by separation from a polymerization mixture by chromatography. In certain formulas, the monodisperse PEG moiety is designated by the abbreviation mdPEG.

[0241] In some aspects, the PEG is star PEG. The star PEG has 10 to 100 PEG chains radiating from a central core group.

[0242] In some aspects, the PEG is comb PEG. The comb PEG has multiple PEG chains typically grafted onto a polymer backbone.

[0243] In certain aspects, the molar mass of the PEG is between 100 g / mol and 3000 g / mol, particularly between 100 g / mol and 2500 g / mol, more particularly about 100 g / mol to 2000 g / mol. In certain aspects, the molar mass of the PEG is between 200 g / mol and 3000 g / mol, particularly between 300 g / mol and 2500 g / mol, more particularly about 400 g / mol to 2000 g / mol.

[0244] In some aspects, the PEG is PEG 100 、PEG 200 、PEG 300 、PEG 400 、PEG 500 、PEG 600 、PEG 700 、PEG 800 、PEG 900 、PEG 1000 、PEG 1100 、PEG 1200 、PEG 1300 、PEG 1400 、PEG 1500 、PEG 1600 、PEG 1700 、PEG 1800 、PEG 1900 、PEG 2000 、PEG 2100 、PEG 2200 、PEG 2300 、PEG 2400 、PEG 2500, PEG 1600 , PEG 1700 , PEG 1800 , PEG 1900 , PEG 2000 , PEG 2100 , PEG 2200 , PEG 2300 , PEG 2400 , PEG 2500 , PEG 2600 , PEG 2700 , PEG 2800 , PEG 2900 or PEG 3000 . In one specific aspect, PEG is PEG 400 . In another specific aspect, PEG is PEG 2000 .

[0245] PG: In some aspects, the heterologous moiety is polyglycerol (PG) described by the formula ((R 3 -O-(CH 2 -CHOH-CH 2 O) n -), where R 3 is hydrogen, methyl or ethyl, and n has a value from 3 to 200. In some aspects, n has a value from 3 to 20. In some aspects, n has a value from 10 to 30. In some alternatives of these embodiments, n has a value from 9 to 45. In some aspects, the heterologous moiety is branched polyglycerol described by the formula (R 3 -O-(CH 2 -CHOR 5 -CH 2 -O) n -), where R 5 is hydrogen, or a straight-chain glycerol chain described by the formula (R 3 -O-(CH 2 -CHOH-CH 2 -O) n -), and R 3 is hydrogen, methyl or ethyl. In some aspects, the heterologous moiety is hyperbranched polyglycerol described by the formula (R 3 -O-(CH 2 -CHOR 5 -CH 2 -O) n -), where R 5 is hydrogen, or a straight-chain glycerol chain described by the formula (R 3 -O-(CH 2 -CHOR 6 -CH 2 -O) n-) The glycerol chain described, where R 6 is hydrogen, or a glycerol chain described by the formula (R 3 -O-(CH 2 -CHOR 7 -CH 2 -O) n -), where R 7 is hydrogen, or a glycerol chain described by the formula (R 3 -O-(CH 2 -CHOH-CH 2 -O) n -) A linear glycerol chain described, and R 3 is hydrogen, methyl or ethyl. Hyperbranched glycerol and its synthesis method are described in Oudshorn et al. (2006) Biomaterials 27:5471 - 5479; Wilms et al. (2010) Acc. Chem. Res. 43, 129 - 41, and the references cited therein.

[0246] In some aspects, the molar mass of PG is between 100 g / mol and 3000 g / mol, particularly between 100 g / mol and 2500 g / mol, more particularly about 100 g / mol to 2000 g / mol. In some aspects, the molar mass of PG is between 200 g / mol and 3000 g / mol, particularly between 300 g / mol and 2500 g / mol, more particularly about 400 g / mol to 2000 g / mol.

[0247] In some aspects, PG is PG 100 , PG 200 , PG 300 , PG 400 , PG 500 , PG 600 , PG 700 , PG 800 , PG 900 , PG 1000 , PG 1100 , PG 1200 , PG 1300 , PG 1400 , PG 1500 , PG 1600 , PG 1700 , PG 1800 , PG 1900 , PG 2000 , PG 2100 , PG 2200 , PG 2300 , PG2400 , PG 2500 , PG 1600 , PG 1700 , PG 1800 , PG 1900 , PG 2000 , PG 2100 , PG 2200 , PG 2300 , PG 2400 , PG 2500 , PG 2600 , PG 2700 , PG 2800 , PG 2900 , or PG 3000 . In one specific aspect, PG is PG 400 . In another specific aspect, PG is PG 2000 .

[0248] V. Pharmaceutical Compositions

[0249] The present disclosure also provides pharmaceutical compositions for use in the methods for preventing and / or treating ectopic calcification disclosed herein, wherein the pharmaceutical compositions comprise at least one inositol phosphate of the present disclosure (such as phytic acid or analogs or derivatives thereof, or combinations thereof). In some aspects, the pharmaceutical compositions comprise the inositol phosphate of the present disclosure alone, or in combination with one or more pharmaceutically acceptable excipients or carriers.

[0250] As used herein, the term "excipient" refers to a substance that aids in the absorption of the elements in the pharmaceutical composition, stabilizes the elements, activates or aids in the preparation of the composition. Thus, examples of excipients used in parenteral preparations include, but are not limited to, antimicrobial agents (such as benzalkonium chloride, m-cresol, thimerosal), co-solvents (such as ethanol), buffers and pH regulators (such as carbonate, citrate, phosphate solutions).

[0251] As in the case of excipients, a "pharmaceutically acceptable solvent" is a substance used in the composition to dilute any component contained therein to a determined volume or weight. A pharmaceutically acceptable solvent is an inert substance, or a substance having a similar effect to any element of the pharmaceutical composition of the present disclosure. The role of the solvent is to allow the incorporation of other elements, allow better dosage and administration, or provide consistency and shape to the composition.

[0252] The pharmaceutical composition may comprise from about 1% to about 95% of an active ingredient (i.e., the inositol phosphate of the present disclosure, alone or in combination with, for example, one or more therapeutic agents disclosed in Table 1). In some aspects, for example, the pharmaceutical composition of the present disclosure may comprise from about 20% to about 90% of an active ingredient (i.e., the inositol phosphate of the present disclosure or a combination thereof, alone or in combination with, for example, one or more therapeutic agents disclosed in Table 1).

[0253] Formulations of pharmaceutical compositions suitable for parenteral administration comprise an active ingredient (such as the inositol phosphate of the present disclosure) in combination with a pharmaceutically acceptable carrier (such as sterile water or sterile isotonic saline). Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, for example, in an ampoule or in a multi-dose container containing a preservative. Formulations for parenteral administration include, but are not limited to: suspensions, solutions, emulsions, pastes, and implantable sustained release or biodegradable formulations in oily or aqueous carriers. Such formulations may further comprise one or more additional ingredients, including but not limited to suspending, stabilizing, or dispersing agents.

[0254] In some aspects, in a formulation for parenteral administration, the active ingredient (such as the inositol phosphate of the present invention) is provided in a dry form (i.e., powder or granules), which is to be reconstituted with a suitable solvent (such as sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.

[0255] The pharmaceutical composition may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. The suspension or solution may be formulated according to known techniques and, in addition to the active ingredient (such as the inositol phosphate of the present disclosure), may contain additional ingredients such as the dispersing, wetting, or suspending agents described herein. Such sterile injectable formulations may be prepared using a non-toxic parenterally acceptable diluent or solvent, such as water or 1,3-butanediol. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils, such as synthetic mono- or di-glycerides of fatty acids.

[0256] Other useful parenterally administrable formulations include those that contain the active ingredient in microcrystalline form, in liposomal formulations, or as a component of a biodegradable polymer system. Compositions for sustained release or implantation may contain pharmaceutically acceptable polymers or hydrophobic materials, such as emulsions, ion exchange resins, slightly soluble polymers, or slightly soluble salts.

[0257] Controlled-release or sustained-release formulations of the pharmaceutical compositions of the present disclosure can be prepared using conventional techniques. In some cases, for example, hydroxypropyl methylcellulose, other polymeric matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes or microspheres, or combinations thereof can be used to provide a dosage form in which one or more active ingredients are in a sustained-release or controlled-release form, thereby providing a desired release profile in different proportions.

[0258] Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions of the present disclosure. Accordingly, the present disclosure encompasses single-unit dosage forms suitable for parenteral or topical administration, such as injectable solutions, gels, creams, and ointments suitable for controlled release.

[0259] A common goal of most controlled-release drug products is to achieve improved therapy relative to their non-controlled-release counterparts. Ideally, an optimally designed controlled-release formulation used in medical treatment is characterized by curing or controlling a disease with the least amount of therapeutic agent in the shortest time. Advantages of controlled-release formulations include extended activity of the therapeutic agent, reduced dosing frequency, and improved patient compliance. Additionally, controlled-release formulations can be used to affect the onset time of action or other characteristics, such as the blood level of the therapeutic agent, and can thus affect the occurrence of side effects.

[0260] Most controlled-release formulations are designed to initially release an amount of the therapeutic agent that rapidly produces the desired therapeutic effect and gradually and continuously release additional amounts of the therapeutic agent to maintain that level of therapeutic effect over an extended period of time. To maintain this constant level of the therapeutic agent in the body, the therapeutic agent must be released from the dosage form at a rate that will replace the amount of the therapeutic agent that is metabolized and excreted from the body.

[0261] The controlled release of the active ingredient can be stimulated by various inducing agents, such as pH, temperature, enzymes, water, or other physiological conditions or compounds. In the context of the present disclosure, the term "controlled-release component" is defined herein as one or more compounds that facilitate the controlled release of the active ingredient, which includes but is not limited to polymers, polymeric matrices, gels, permeable membranes, liposomes or microspheres, or combinations thereof.

[0262] In certain embodiments, the formulations of the present disclosure can be, but are not limited to, short-term, rapid elimination, and controlled, e.g., sustained release, delayed release, and pulsatile release formulations.

[0263] The term sustained release is used herein in its conventional meaning to refer to a therapeutic agent formulation, such as a formulation containing the inositol phosphate of the present disclosure, which provides a gradual release of the therapeutic agent over an extended period of time and, although not necessarily, can result in a substantially constant blood level of the therapeutic agent over an extended period of time. This period of time can be up to a month or longer and should be longer than the release time of the same amount of the agent administered as a bolus.

[0264] For sustained release, the compound can be formulated with a suitable polymer or hydrophobic material that provides the compound with sustained release properties. Thereby, the compound for the methods of the present disclosure can be administered in the form of microparticles, for example, by injection, or in the form of wafers or discs by implantation. In certain aspects, the compounds of the present disclosure are administered to a patient alone or in combination with another agent using a sustained release formulation.

[0265] The term delayed release is used herein in its conventional meaning to refer to a therapeutic agent formulation that provides an initial release of the therapeutic agent after some delay following administration of the therapeutic agent. The delay may be from about 10 minutes to about 12 hours. The term pulsatile release is used herein in its conventional meaning to refer to a therapeutic agent formulation that provides release of the therapeutic agent in a manner that produces a pulsatile serum profile of the therapeutic agent following administration. The term "immediate release" is used in its conventional meaning to refer to a therapeutic agent formulation that releases the therapeutic agent immediately following administration.

[0266] As used herein, short term refers to a time period of up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes or about 10 minutes, and any or all or portions of increments thereof, following administration of the therapeutic agent.

[0267] As used herein, rapid elimination refers to a time period of up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes or about 10 minutes, and any or all or portions of increments thereof, following administration of the therapeutic agent.

[0268] Other formulations and dosage forms of the compositions of the present disclosure include dosage forms described in U.S. Patent Nos. 5,235,641, 6,340,475, 6,488,962, 6,451,808, 5,972,389, 5,582,837, and 5,007,790; dosage forms described in U.S. Patent Application Nos. 20030147952, 20030104062, 20030104053, 20030044466, 20030039688, and 20020051820; dosage forms described in PCT Application Nos. WO 03 / 35041, WO 03 / 35040, WO 03 / 35029, WO 03 / 35177, WO 03 / 35039, WO 02 / 96404, WO 02 / 32416, WO 01 / 97783, WO 01 / 56544, WO 01 / 32217, WO 98 / 55107, WO 98 / 11879, WO 97 / 47285, WO 93 / 18755, and WO 90 / 11757, the entire contents of which are incorporated herein by reference.

[0269] The medicaments according to the present disclosure are prepared by methods known in the art, in particular by conventional mixing, coating, granulation, dissolution, or lyophilization.

[0270] The present disclosure also provides a compound or combination of compounds or a pharmaceutical formulation as described in any one of the above aspects of the present disclosure, in the broadest definition given, or as specified in any of the aspects set forth above, for use as a medicament.

[0271] The present disclosure also provides a compound or combination of compounds or a pharmaceutical formulation as described in any one of the above aspects of the present disclosure, in the broadest definition given, or as specified in any of the aspects set forth above, for the treatment and / or prevention of the diseases or conditions disclosed herein.

[0272] The present disclosure also provides a compound or combination of compounds or a pharmaceutical formulation as described in any one of the above aspects of the present disclosure, in the broadest definition given, or as specified in any of the aspects set forth above, for the manufacture of a medicament for the prevention and / or treatment of the diseases or conditions disclosed herein.

[0273] VI. Indications

[0274] The methods, compositions, pharmaceutical compositions and formulations, production articles, and kits of the present disclosure comprising the inositol phosphates of the present disclosure disclosed herein can be used for the treatment and / or prevention of ectopic calcification, particularly skin or subcutaneous calcification, such as calciphylaxis calcification and / or its consequences, in a subject in need thereof.

[0275] Skin and subcutaneous calcifications (commonly known as ectopic calcifications) are associated with the pathological crystallization of calcium and occur as a complication in many diseases. Ectopic calcifications can be classified as dystrophic, metastatic, idiopathic or iatrogenic calcifications, or calciphylaxis.

[0276] Dystrophic calcification occurs despite normal serum calcium and phosphorus levels and is due to local tissue abnormalities and is still growing. The main diseases that these calcifications can cause are: connective tissue diseases (scleroderma, CREST syndrome, juvenile dermatomyositis, lupus), skin and subcutaneous infections (panniculitis), skin tumors (especially dermatofibromas), certain congenital diseases (Ehlers-Danlos disease, Werner syndrome, pseudoxanthoma elasticum).

[0277] Metastatic calcification is a consequence of disorders of calcium and phosphate metabolism (hypercalcemia and / or hyperphosphatemia). Therefore, all diseases that cause these disorders can lead to the development of calcifications.

[0278] Idiopathic calcification occurs without tissue damage or disorders of calcium and phosphate metabolism. The main known diseases in this group are tumor calcification, scrotal calcification, and subepidermal calcified nodules.

[0279] Iatrogenic calcification occurs after injection of calcium or para-aminosalicylic acid. It has also been described in connection with the use of calcium chloride-saturated electrodes.

[0280] Soft tissue calcifications (such as skin or subcutaneous calcifications) can be associated with diseases or pathological conditions selected from the following: primary hyperparathyroidism, vitamin D intoxication, alcoholics' syndrome, hypercalcemia, secondary hyperparathyroidism, renal failure, hyperphosphatemia, especially hereditary hyperphosphatemia, scleroderma, dermatomyositis (especially the juvenile form), mixed connective tissue disease, lupus, CREST syndrome, Ehlers-Danlos syndrome, pseudoxanthoma elasticum, Werner syndrome, late cutaneous porphyria, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, (primary or secondary) venous or arterial insufficiency, diabetes, scrotal calcinosis, myositis ossificans, post-traumatic heterotopic ossification, and any other disease or pathological condition caused by calcium crystal deposition, especially hydroxyapatite or calcium pyrophosphate, such as calciphylaxis.

[0281] An important concept is that various diseases, including those listed in the previous paragraphs, can be treated by preventing, reducing, slowing down or stopping the progression of calcifications in the presence of uremia. Diseases associated with calcium disorders or calcifications caused by such diseases may already be present at the start of administration to reduce or stop the progression of the disease, or may not be present at the start of administration to prevent the appearance or occurrence of the disease.

[0282] Calciphylaxis corresponds to the calcification of small - sized blood vessels and subcutaneous adipose tissue. Calciphylaxis can be treated concurrently with at least the following diseases:

[0283] (i) Hypercalcemia;

[0284] (ii) Hyperphosphatemia;

[0285] (iii) Secondary and tertiary hyperparathyroidism;

[0286] (iv) Hypoparathyroidism; or

[0287] (v) Any combination thereof.

[0288] Other conditions that can benefit from treatment with the inositol phosphates of the present disclosure are, for example, peripheral artery disease, critical limb ischemia, generalized arterial calcification of infancy, aortic stenosis, atherosclerosis, pseudogout, primary hyperoxaluria, and pseudoxanthoma elasticum.

[0289] In the context of the present disclosure, "peripheral artery disease" refers to the narrowing of the peripheral arteries to the legs (most common), stomach, arms, and head. Symptoms include intermittent claudication (pain in the legs while walking, relieved by rest), skin ulcers, skin bluing, cold skin, or poor nail and hair growth.

[0290] In the context of the present disclosure, "critical limb ischemia" refers to severe arterial obstruction that significantly reduces blood flow to the extremities and progresses to severe pain and even skin ulcers, sores, or gangrene. Severe limb ischemia is a very serious condition of peripheral artery disease.

[0291] In the context of the present disclosure, "pseudogout", also known as "calcium pyrophosphate dihydrate (CPPD) crystal deposition disease" or "pyrophosphate arthropathy", is a rheumatic disease thought to be caused by the accumulation of calcium pyrophosphate crystals in connective tissue, especially in joints such as the knee joint.

[0292] In the context of the present disclosure, the term "generalized arterial calcification of infancy" (GACI) refers to a disease affecting the circulatory system that becomes apparent before birth or in the first few months of life and is characterized by abnormal arterial calcification and arterial wall thickening. These changes lead to arterial stenosis and stiffness, resulting in heart failure in some affected individuals, the symptoms and signs of which include dyspnea, edema, cyanosis, hypertension, and cardiac hypertrophy.

[0293] VII. Combination Therapy

[0294] The present disclosure also provides combination therapies, which include administering an inositol phosphate of the present disclosure and at least one other therapeutic agent. Also provided are combination compositions comprising an inositol phosphate of the present disclosure and at least one other therapeutic agent. Accordingly, another aspect of the present disclosure relates to a composition comprising at least one inositol phosphate of the present disclosure as described above and another therapeutic agent.

[0295] As used herein, the term "combination therapy" can interchangeably refer to combination therapies and combination compositions according to the methods and dosages disclosed herein. As used herein, the term "combination composition" does not mean that the components of the combination composition need to be present together. Thus, this expression implies that, in terms of the physical separation of its components, the combination is not necessarily a true combination. For example, the components in a combination composition can be administered separately, sequentially, or their administrations can overlap.

[0296] In some aspects, the other therapeutic agent is selected from, for example, the compositions given in Table 1. In some aspects, the combination therapy can comprise an inositol phosphate of the present invention and a therapeutic agent in Table 1. In other aspects, the combination therapy can comprise an inositol phosphate of the present disclosure and more than one therapeutic agent from Table 1. When there is more than one therapeutic agent from Table 1 in the combination therapy, the therapeutic agents from Table 1 can belong to the same indication or different indications. For example, a combination composition can comprise a therapeutic (such as OPG), a wound healing compound, and a pain control compound.

[0297] Table 1: Exemplary therapeutic agents that can be combined with the inositol phosphates of the present disclosure.

[0298]

[0299]

[0300] 1 Patients with calciphylaxis / hyperparathyroidism

[0301] 2 Patients with calciphylaxis / hyperphosphatemia

[0302] Several compounds described as other therapeutic agents alter the thermodynamics of the crystallization process by changing the concentration of ions present in the calcium-containing crystal structures that lead to ectopic calcification. This subgroup includes calcimimetics, phosphate chelators, thiosulfates, or vitamin D.

[0303] Calcimimetics allow for the control of calcium and phosphate concentrations by regulating blood PTH levels. The compounds include, for example, cinacalcet, NPS R-467, NPS R-568, and KAI-4169.

[0304] In some aspects, the combination composition comprises a vitamin selected from vitamin B, vitamin D, vitamin K, or a combination thereof. Despite having different mechanisms of action, vitamins D have similar effects. Vitamin D is preferably selected from calciferol, ergocalciferol (vitamin D2), cholecalciferol (vitamin D3), doxercalciferol, paricalcitol, alfacalcidol, α-calcidol, calcidiol, calcitriol, derivatives thereof or pharmaceutically acceptable salts, or any combination thereof.

[0305] Phosphate chelators act by chelating phosphate, thereby reducing its systemic concentration in the blood. Phosphate binders may or may not contain a metal. Metal-free chelators include, for example, sevelamer. Metal-containing chelators include, for example, various calcium, iron, lanthanum, aluminum, and magnesium salts. Thiosulfate is a chelator that reduces the free calcium concentration in the blood.

[0306] Other compounds that can be used in combination therapy (such as pyrophosphate, citrate, bisphosphonates, antihypertensives, anti-cholesterols, vitamin B, or vitamin K) kinetically resist altered calcium and phosphate metabolism by attempting to halt the crystallization process, or alter bone metabolism by increasing the amount of inhibitory factors (pyrophosphate, citrate, vitamin B, vitamin K, bisphosphonates) or by reducing the number of promoting factors (necrosis residues or organic matter if antihypertensive, lipid deposits if anti-cholesterol).

[0307] In some aspects, bisphosphonates can be nitrogen-containing or nitrogen-free. In some aspects, diphosphonates can be selected from etidronate, alendronate, risedronate, zoledronate, tiludronate, pamidronate, monitronate, neridronate, pamidronate, olpadronate, clodronate, ibandronate, and combinations thereof.

[0308] In some aspects, the combination therapy can comprise an anti-cholesterol agent selected from statins, fibrates, niacin, acid chelators, ezetimibe, lomitapide, phytosterols, orlistat, or combinations thereof.

[0309] Compounds that can also be used to treat ectopic calcification also include the compounds disclosed in U.S. Patent No. 9,629,872, U.S. Patent No. WO2017131127, U.S. Patent No. 5,362,886, U.S. Patent No. 4,024,175, and U.S. Patent No. 3,159,581, the entire contents of which are incorporated herein by reference in their entirety.

[0310] VIII. Manufactured Articles and Kits

[0311] The present disclosure also provides production articles and kits. Such production articles and kits can include a container (e.g., a box) that contains one or more vials containing a formulation that includes one or more inositol phosphates of the present disclosure and / or a solvent for administration according to the methods disclosed herein. The kits or production articles provided according to the present disclosure can also include a brochure or instructions that describe the methods of administration and dosages disclosed herein. In some aspects, the kit or production article can include a plurality of vials, where each vial contains a single dosage. In other aspects, the kit or production article can include one or more vials, where each vial contains more than one dosage.

[0312] In some aspects, the production article is a bag that contains a solution of an inositol phosphate of the present disclosure. In other aspects, the production article is a bottle (e.g., a glass or plastic bottle) that contains a solution of an inositol phosphate of the present disclosure. In some aspects, the production article is a bag that contains an inositol phosphate of the present disclosure in powder form for reconstitution in a suitable solvent. In other aspects, the production article is a bottle (e.g., a glass or plastic bottle) that contains an inositol phosphate of the present disclosure in powder form for reconstitution in a suitable solvent.

[0313] The kits and production articles can include instructions for one or more administrations of the inositol phosphates of the present disclosure according to the methods and dosages disclosed herein.

[0314] The instructions included in the kits and production articles can be affixed to the packaging material or included as a package insert. Although the instructions are typically written or printed material, this is not limiting. Any medium capable of storing such instructions and communicating them to the end user is contemplated. Such media include, but are not limited to, electronic storage media (e.g., disks, tapes, cartridges, chips), optical media (e.g., CD ROM), etc. As used herein, the term "instructions" can include the address of an Internet website that provides the instructions.

[0315] This application also contains the following items:

[0316] 1. A method for treating or preventing ectopic calcification and / or its consequences in a subject in need thereof, comprising administering to the subject a dosage of an inositol phosphate, or an analogue or derivative thereof, at a dose of about 6 mg / kg / day to 9 mg / kg / day, wherein administration of said dose is effective to treat or prevent ectopic calcification and / or its consequences in said subject.

[0317] 2. The method according to item 1, wherein the inositol phosphate comprises a compound of formula I, a pharmaceutically acceptable salt thereof, or a combination thereof:

[0318]

[0319] wherein

[0320] (i) R 1 、R 3 、R 5 、R 7 、R 9 and R 11 independently represent OH, a compound of formula II, or a compound of formula III, or a compound of formula IV:

[0321]

[0322] (ii) R 2 、R 4 、R 6 、R 8 、R 10 、R 12 and R 13 represent H;

[0323] (iii) at least one of R 1 、R 3 、R 5 、R 7 、R 9 and R 11 represents a compound of formula II, formula III or formula IV, and

[0324] (iv) zero, one or two of R 1 、R 3 、R 5 、R 7 、R 9 and R 11 represent heterologous moieties.

[0325] 3. The method according to any one of items 1 or 2, wherein the inositol phosphate contains 1 to 6 phosphate groups.

[0326] 4. The method according to item 3, wherein the inositol phosphate is inositol hexaphosphate.

[0327] 5. The method according to item 4, wherein the inositol hexaphosphate is myo-inositol hexaphosphate.

[0328] 6. The method according to any one of items 1 to 5, wherein the dose administered to the subject is about 7 mg / kg / day.

[0329] 7. The method according to any one of items 2 to 6, wherein the heterologous moiety contains a moiety that prolongs the half-life.

[0330] 8. The method according to item 7, wherein the heterologous moiety contains polyethylene glycol or polyglycerol.

[0331] 9. The method according to any one of items 1 to 8, wherein the concentration of inositol phosphate, or an analogue or derivative thereof, in each dosage is between about 10,000 μg / mL and about 100,000 μg / mL.

[0332] 10. The method according to any one of items 1 to 8, wherein the concentration of inositol phosphate, or an analogue or derivative thereof, in each dosage is between about 12.5 mM and about 135 mM.

[0333] 11. The method according to any one of items 1 to 10, wherein the dose is administered as a single daily dosage.

[0334] 12. The method according to any one of items 1 to 10, wherein the dose is administered as multiple daily dosages.

[0335] 13. The method according to any one of items 1 to 12, wherein the dose is administered at least once a week.

[0336] 14. The method according to any one of items 1 to 13, wherein the dose is administered 2, 3, 4, 5, 6, or 7 times a week.

[0337] 15. The method according to any one of items 1 to 14, wherein the dose is administered for at least one week.

[0338] 16. The method according to any one of items 1 to 15, wherein the dose is administered for about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32 weeks.

[0339] 17. The method according to any one of items 1 to 16, wherein the dose is administered for at least 12 weeks.

[0340] 18. The method according to any one of items 1 to 17, wherein the dose is administered for at least 24 weeks.

[0341] 19. The method according to any one of items 1 to 18, wherein the dose is administered to the subject to inhibit the formation and / or growth of hydroxyapatite crystals.

[0342] 20. The method according to any one of items 1 to 19, wherein the ectopic calcification is calciphylaxis calcification, metastatic calcification, dystrophic calcification, iatrogenic calcification, idiopathic calcification, or subcutaneous heterotopic ossification.

[0343] 21. The method according to any one of items 1 to 20, wherein the consequences of the heterotopic calcification are functional complications, pain, nutritional complications, infection, or a combination thereof.

[0344] 22. The method according to item 21, wherein the functional complication is a limitation of the range of motion and / or joint function.

[0345] 23. The method according to item 21, wherein the nutritional complication is ischemia and / or injury.

[0346] 24. The method according to item 23, wherein the injury is necrosis of the skin and / or subcutaneous tissue.

[0347] 25. The method according to any one of items 1 to 24, wherein administering the dose to the subject results in a reduction of the injury as determined by the Bates-Jensen Wound Assessment Tool.

[0348] 26. The method according to item 25, wherein the reduction of the injury includes a decrease in the severity of the injury, a reduction in the size of the injury, and a reduction in the duration of the injury, or a combination thereof.

[0349] 27. The method according to any one of items 1 to 26, wherein administering the dose to the subject results in an improvement in the healing of the injury.

[0350] 28. The method according to any one of items 1 to 27, wherein administering the dose to the subject results in a reduction of pain.

[0351] 29. The method according to any one of items 1 to 28, wherein administering the dose to the subject results in an improvement in the overall wound quality of life (QoL) as determined by using a validated wound-related QoL questionnaire.

[0352] 30. The method according to any one of items 1 to 29, wherein the subject has end-stage renal disease.

[0353] 31. The method according to any one of items 1 to 30, wherein the subject is undergoing hemodialysis.

[0354] 32. The method according to any one of items 1 to 31, wherein the subject is a human.

[0355] 33. The method according to any one of items 1 to 32, wherein the administration is parenteral administration.

[0356] 34. The method according to item 33, wherein the parenteral administration is intravenous administration.

[0357] 35. The method according to item 34, wherein the intravenous administration is by bolus injection or by infusion.

[0358] 36. The method according to any one of items 1 to 32, wherein the administration is topical administration.

[0359] 37. A method for treating or preventing calciphylaxis calcification and / or its consequences in a subject in need thereof, comprising administering an intravenous dose of phytic acid, or an analogue or derivative thereof, to the subject three times a week for 12 weeks at a dose of about 6 mg / kg / day to 9 mg / kg / day, wherein administration of the dose effectively treats or prevents calciphylaxis calcification and / or its consequences in the subject.

[0360] 38. An intravenous dose of phytic acid, administered to a subject three times a week for 12 weeks at a dose of about 6 mg / kg / day to 9 mg / kg / day, and taken by the patient in a therapeutically effective amount sufficient to treat or prevent calciphylaxis calcification and / or its consequences in the subject.

[0361] 39. A kit or manufactured article comprising: at least one container containing a parenteral or topical dose of phytic acid, or an analogue or derivative thereof; and instructions for administration according to the method of any one of items 1 to 37.

[0362] Examples

[0363] Example 1

[0364] A Phase 2 open-label single-arm study to evaluate the effect of SNF472 on wound healing in subjects with calciphylaxis

[0365] Background

[0366] Calcification prevention in end-stage renal disease is characterized by painful necrotic skin ulcers and high mortality. There is no approved therapy. SNF472 is an intravenous formulation of phytic acid that selectively inhibits the formation and growth of hydroxyapatite crystals (a common final pathway of vascular calcification). This Phase 2 study evaluated SNF472 in the treatment of calciphylaxis.

[0367] Methods

[0368] In this open-label, single-arm study, subjects with calciphylaxis undergoing hemodialysis received intravenous SNF472 at 6-9 mg / kg three times a week for 12 weeks during dialysis, in addition to standard therapy. The primary endpoint was the Bates-Jensen Wound Assessment Tool (BWAT). The Visual Analogue Scale for pain (VAS), wound Quality of Life (QoL), and qualitative wound image review were secondary endpoints. Quantitative changes from baseline to week 12 for all subjects were analyzed using multiple imputation; descriptive analysis of the qualitative wound image review was performed for subjects who completed 12 weeks of SNF472 treatment.

[0369] Results

[0370] Among the 14 subjects who were enrolled and received SNF472, significant improvements were observed in the total BWAT score (mean, -8.1; P<0.001), Visual Analogue Scale for pain (VAS) (mean, -23.6 mm; P = 0.014), and wound Quality of Life (QoL) score (mean, -0.9; P = 0.003) from baseline to week 12. Qualitative wound image review showed improvement in 8 of 11 subjects who completed 12 weeks of treatment. Adverse events and deaths (N = 2) were consistent with the hemodialysis population. Eight subjects had serious adverse reactions, none of which were considered related to SNF472.

[0371] Conclusions

[0372] The results of this Phase 2 study suggest that SNF472 is well tolerated and that patients with calciphylaxis benefit in multiple parameters, supporting a Phase 3 study of SNF472 for the treatment of calciphylaxis.

[0373] Materials and Methods

[0374] (1) Study Design

[0375] This was an open-label, single-arm, repeated-dose Phase 2 clinical study conducted at 11 study centers in the United States and England to investigate the effect of SNF472 in patients with calciphylaxis. After screening, eligible subjects were enrolled and received SNF472 intravenously three times a week for 12 weeks during hemodialysis. Safety follow-up was conducted 1 week after the last dose of SNF472. SNF472 was administered via the dialysis system by slow infusion over 2.5 to 4 hours. The dose of SNF472 administered per course was 400, 450, 700, or 900 mg (corresponding to 50 to <66 kg, 66 to <81 kg, 81 to <111 kg, or 111 to 150 kg, respectively) based on the subject's dry weight at screening. SNF472 treatment was added to standard therapy according to the standard procedures of the study centers.

[0376] (2) Subjects

[0377] Eligible subjects are males or females aged ≥ 18 years who have been newly diagnosed with calciphylaxis or have recurrent calciphylaxis (new or recurrent diagnosis within 5 weeks of study start) in a latent state without skin lesion involvement for at least 90 days from the start of the study. Subjects are required to be on maintenance hemodialysis and to have pain (at least mild pain) on the pain VAS or to be on analgesics stronger than non-steroidal anti-inflammatory drugs.

[0378] Key exclusion criteria are pregnancy, body weight over 150 kg, body mass index > 35 kg / m 2 and central (abdominal) ulcers, bisphosphonate treatment within 12 months prior to study entry, severe disease with an expected survival ≤ 6 months, and planned parathyroidectomy. Subjects sign a written informed consent form to participate. The study is conducted in accordance with ethical principles derived from the Declaration of Helsinki, which are consistent with the International Conference on Harmonization guidelines on Good Clinical Practice and regulatory requirements.

[0379] (3) Assessments

[0380] The investigators record the severity of the primary wound (the largest wound) at weeks 1, 2, 4, 6, 8, 10, 12, and 13 (follow-up) using the BWAT (Bates-Jensen & Sussman “Tools to measure wound healing.” In: Wound Care: A collaborative practice manual for health professionals. Edited by SUSSMAN, C., BATES-JENSEN, B., Philadelphia, PA, Lippincott Williams & Wilkins, 2012, pp 131-161). The BWAT uses a scale of 1 (best) to 5 (worst) for each of the following 13 items: size, depth, edges, undermining or pocketing, type of necrotic tissue, amount of necrotic tissue, type of exudate, amount of exudate, color of surrounding skin, edema of surrounding tissue, induration of surrounding tissue, granulation tissue, epithelialization. The total BWAT score is the sum of these individual scores and can range from 13 to 65. Two additional items (location and shape) are not scored.

[0381] During the same visit as the BWAT assessment, the subjects recorded the intensity of wound pain using a VAS from 0 (no pain) to 100 (the most severe possible pain). At weeks 1, 6, and 12, the subjects completed a wound Quality of Life (QoL) questionnaire, which consisted of 17 questions regarding relevant QoL impairments, coded from 0 (none at all) to 4 (a great deal) (Augustin (2017), ibid.).

[0382] In addition to the overall score, other items were used to calculate subscale scores for impairment of the physical (items 1 - 5), psychological (items 6 - 10), and daily life (items 11 - 16).

[0383] At baseline and every 2 weeks up to week 12, wound images of each subject were obtained. Two reviewers examined each image and discussed cases when there was discordance between their assessments. In the first step, the baseline and week 12 images of each subject were randomly labeled as "A" and "B" to blind the reviewers. The blinded reviewers determined which was worse, or if both were the same. In the second step, the reviewers examined all images without blinding and scored the wound as deteriorated, improved, or unchanged from baseline at each visit.

[0384] Safety assessments included emergency treatment adverse events at any time; ECG (follow - up) at weeks 1, 6, 12, and 13; clinical laboratory screening at weeks 1, 6, 12, and 13 (follow - up). Pharmacokinetic blood sampling was performed on day 1 and day 5 of week 12.

[0385] (4) Statistical analysis

[0386] The primary pharmacodynamic endpoint was the absolute change in the total BWAT score for the primary lesion from baseline to week 12. The secondary pharmacodynamic endpoints for wound healing were the absolute changes in the total BWAT score and component scores from baseline during follow - up, and the qualitative changes at baseline in the wound images. Other secondary pharmacodynamic endpoints were the absolute change in the pain VAS score from baseline and the absolute changes in the QoL overall score and QoL subscale scores at weeks 6 and 12 from baseline.

[0387] The primary analysis set for pharmacodynamics was the intention - to - treat population, which included subjects who received at least one dose of SNF472 and had at least one post - baseline pharmacodynamic measurement. Paired Student's t - tests were used to analyze the primary endpoint and quantitative secondary endpoints. For missing data, multiple imputation was used to assess the absolute change relative to baseline.

[0388] Sensitivity analyses for quantitative endpoints in the intention-to-treat population were performed using the last-observation-carried-forward method and without imputation (observed cases). Other sensitivity analyses for quantitative endpoints were performed using the subgroup of subjects who received at least 75% of the SNF472 dose as per the study protocol and did not violate the protocol in a manner that could affect the assessment of the efficacy of the study drug. Absolute changes in quantitative endpoints from baseline to week 12 were also evaluated using multiple imputation in the intention-to-treat population for subgroups based on the use of sodium thiosulfate at baseline. Imaging results were summarized using descriptive statistics.

[0389] Analysis of pharmacokinetic data included all subjects who received at least one dose of SNF472 and for whom primary pharmacokinetic parameters (post-dose SNF472 concentration) could be determined. Descriptive statistics were presented by visit and time point. Cumulative amounts from day 1 to week 12 were evaluated by comparing the differences in post-dose concentrations between visits. A cumulative amount was defined as such if the 90% CI of the difference did not include the value 0.

[0390] Safety analyses included all subjects who received at least one dose of SNF472. Incidences of adverse events and serious adverse events in the subjects were descriptively summarized. For each 12-lead ECG variable, absolute changes measured from pre-dose to post-dose at each visit, as well as absolute changes measured from baseline to all other pre-dose measurements, were descriptively summarized.

[0391] Results

[0392] (1) Subject disposition

[0393] All 14 subjects who participated in the study received at least one dose of SNF472 and were included in the pharmacodynamic (intention-to-treat), safety, and pharmacokinetic analyses. Eleven (78.6%) subjects completed the study and were included in the per-protocol analysis (Table 2).

[0394] Table 2. Subject disposition (intention-to-treat population)

[0395]

[0396] Values are n (%).

[0397] Reasons for early study discontinuation were withdrawal of subject consent (n = 1), death (n = 1), and death due to withdrawal from hemodialysis (n = 1).

[0398] (2) Baseline characteristics

[0399] The mean (standard deviation) age of the study participants was 60.5 (14.1) years (range 34 - 90) (Table 3).

[0400] Table 3. Demographics and Baseline Characteristics

[0401]

[0402] Data are mean ± standard deviation unless otherwise stated.

[0403] a One subject discontinued warfarin at week 3 and another subject continued warfarin.

[0404] b One subject discontinued sodium thiosulfate at week 2 and the other subjects continued sodium thiosulfate; at week 7, another subject started sodium thiosulfate.

[0405] The mean duration of hemodialysis at baseline was 3.8 (1.1) years. Eleven (78.6%) were female and ten (71.4%) were white. At baseline, 11 subjects (78.6%) used sodium thiosulfate and 2 subjects (14.3%) used warfarin. During the study, one subject each discontinued sodium thiosulfate (week 2) and warfarin (week 3). Another subject started sodium thiosulfate during the study (week 7). Among the 11 subjects receiving sodium thiosulfate at baseline, the mean duration of sodium thiosulfate use was 19 days (range 2 - 30 days) before the first SNF472 dose. Ten (71.4%) subjects had firm calcified subcutaneous tissue around the injury at baseline. Thirteen (92.9%) subjects had severe pain at baseline. None of the subjects with severe pain were receiving opioid treatment.

[0406] (3) Total score of the Bates-Jensen Wound Assessment Tool

[0407] For the primary endpoint of the total score of the Bates-Jensen Wound Assessment Tool (BWAT) for the primary injury in all subjects, the mean (standard deviation) score improved from 33.6 (9.6) at baseline to 25.6 (7.3) at week 12 ( Figure 2A ). Treatment with SNF472 was associated with a statistically significant improvement, with a mean (SD) change from baseline to week 12 of -8.1 (8.5) (95% confidence interval, from -12.7 to -3.4; P < 0.001; Table 4).

[0408] Table 4: Changes from baseline to week 12 in primary and secondary quantitative endpoints treated with SNF472 (intention-to-treat population using multiple imputation)

[0409]

[0410] BWAT, Bates-Jensen Wound Assessment Tool; VAS, Visual Analogue Scale.

[0411] Possible scores: total BWAT, 13 (best) to 65 (worst); pain VAS, 0 mm (no pain) to 100 mm (possibly the most severe pain); wound QoL, 0 (no impairment) to 4 (very impaired).

[0412] Using only the observational data, the total BWAT score improved progressively and showed a statistically significant improvement compared with the baseline at weeks 10 and 12 ( Figure 2B ). From baseline to week 12, significant improvements were observed in the BWAT component scores for perilesional induration (mean change, -1.3; P = 0.011), color of the skin around the wound (mean change, -1.2; P = 0.034), granulation tissue (mean, -1.2; P = 0.024), and amount of exudate (mean change, -1.0; P = 0.026; Figure 3 ). Sensitivity analysis (Table 5) showed consistent improvements in BWAT in the group following the study protocol using multiple imputation (P = 0.002) from baseline to week 12, in the intention-to-treat group using observational data (P = 0.041), and in the intention-to-treat group using the last observation carried forward method (P = 0.021).

[0413] (4) Pain

[0414] For the secondary endpoint of pain VAS for the primary lesion in all subjects, the mean (standard deviation) score improved from 71.8 (29.2) mm at baseline to 48.1 (28.6) mm at week 12 ( Figure 4A ). Treatment with SNF472 was associated with a statistically significant improvement, with a mean (standard deviation) change from baseline to week 12 of -23.6 (30.0) mm (95% confidence interval, from -42.6 to -4.7; P = 0.015; Table 4). Using only the observational data, the pain VAS scores improved significantly from baseline to weeks 6, 8, and 12 ( Figure 4B ).

[0415] Sensitivity analysis (Table 5) showed consistent improvements in pain in the group following the study protocol using multiple imputation (P = 0.017) from baseline to week 12, in the intention-to-treat group using observational data (P = 0.020), and in the intention-to-treat group using the last observation carried forward method (P = 0.032).

[0416] Table 5. Sensitivity analysis: Changes from baseline to week 12 using SNF472 treatment

[0417]

[0418] ITT, intention to treat; LOCF, last observation carried forward

[0419] (5) Quality of life

[0420] For the secondary endpoint of the overall score of Wound-QoL, the mean (standard deviation) score improved from 2.44 (0.89) at baseline to 1.54 (0.90) at week 12 ( Figure 5 ). The mean (standard deviation) change with SNF472 treatment from baseline to week 12 was statistically significantly improved by -0.9 (0.87) (95% confidence interval, from -1.49 to -0.31; P = 0.003; Table 5). From baseline to week 12, the Wound-QoL subscales also showed statistically significant mean (SD) improvements: physical, -0.86 (0.87), P = 0.004; and mental, -1.33 (1.14), P < 0.001( Figure 5 ). The improvement in daily life (mean, -0.65; standard deviation, 0.99) was close to statistical significance (P = 0.051; Figure 5 ).

[0421] Sensitivity analysis (Table 5) showed consistent improvement in the overall Wound-QoL score in the group following the study protocol with multiple imputation from baseline to week 12 (P = 0.016), in the intention-to-treat group with observed data (P = 0.006), and in the intention-to-treat group with the last observation carried forward method (P = 0.003).

[0422] (6) Subgroup analysis using sodium thiosulfate

[0423] Only 2 subjects received SNF472 without using sodium thiosulfate, thus limiting the interpretation of the subgroup analysis. However, in the subjects who received SNF472 without sodium thiosulfate, mean improvements in BWAT and pain VAS from baseline to week 12 were observed, including a statistically significant improvement in the total BWAT score (P = 0.003).

[0424] (7) Qualitative wound assessment

[0425] In the non-blind review, where the reviewers knew which image was associated with each visit, it was reported that for 8 out of 11 subjects at week 12, the quality of the primary lesion improved; many subjects showed qualitative improvements at week 6 of SNF472 treatment( Figure 6 ). Representative images of qualitative wound healing assessments at baseline and week 12 are provided in Figure 7 , including 2 cases of wound healing and 1 case of deterioration.

[0426] (8) Pharmacokinetics

[0427] The median (range) serum SNF472 concentration after dosing was 15,845 (1830 - 411,197) ng / mL on Day 1 and 13,679 (2808, 40,192) ng / mL on Day 5 of Week 12. The mean change in SNF472 concentration after dosing from Day 1 to Day 5 of Week 12 was -2522 ng / mL, indicating that SNF472 does not accumulate after repeated dosing. Serum SNF472 concentrations were within the expected range in all subjects, except for 1 subject in whom SNF472 was below the limit of quantification after dosing at Week 12. In this subject, the wound also deteriorated, as Figure 7 shown.

[0428] (9) Safety

[0429] At least 1 emergency treatment adverse event was reported in 13 subjects (92.9%) (Table 6).

[0430] Table 6. Summary of Emergency Treatment Adverse Events (Safety Analysis Set)

[0431]

[0432] ECG, electrocardiogram.

[0433] a The researchers considered that none of these deaths and other serious adverse events were related to SNF472 treatment.

[0434] Adverse events reported in more than 1 subject were arteriovenous fistula thrombosis, cellulitis, diarrhea, fluid overload, hypertension, hypoesthesia, nausea, QT interval prolongation, and skin injury (2 subjects each [14.3%]). Most adverse events were mild or moderate in severity. Five (35.7%) subjects had grade 3 (severe) adverse events, and no subject had grade 4 (life-threatening) adverse events. Two (14.3%) subjects had grade 5 (fatal) adverse events (cardiopulmonary arrest and cardiogenic shock). After the cardiopulmonary arrest event, hemodialysis was discontinued. Except for these 2 subjects, no subject discontinued study treatment due to adverse events. Seven (50.0%) subjects had serious adverse events. Infections and infestations were the most common serious adverse events at the system organ level (including 1 subject each with cellulitis, gangrene, infection, sepsis, and urinary tract infection). Other serious adverse events included 1 subject each with abdominal wound dehiscence, cardiogenic shock, cardiopulmonary arrest, dry gangrene, fluid overload, hematemesis, hypertensive emergency, and pulmonary edema. The researchers considered that no serious adverse events were related to SNF472 treatment.

[0435] No clinically relevant trends in ECG intervals were observed from pre-dose to post-dose or between pre-dose assessments on Day 1, Day 1 of Week 6, and Day 5 of Week 12. Electrocardiogram abnormalities were not clinically significant in most of the subjects evaluated, either pre-dose or post-dose, in several assessments. Three subjects had ECG abnormalities reported as adverse events: QT interval prolongation (2 subjects) and tachycardia (1 subject). The investigator considered 1 adverse event of QT interval prolongation unlikely to be related to the treatment with SNF472; it occurred during the follow-up 21 days after the last SNF472 dose. The other ECG adverse events were considered possibly related. The severity of each ECG abnormal adverse event was mild to moderate, asymptomatic, and resolved without treatment.

[0436] Discussion

[0437] This is the first multicenter, international, prospective, interventional study of the treatment of calciphylaxis. Statistically significant improvement in wound healing of major lesions was observed with treatment with SNF472. Statistically significant improvement in pain and wound quality of life scores was also observed with treatment with SNF472. No accumulation of SNF472 over time was observed with repeated dosing. SNF472 was generally well tolerated; serious adverse events were consistent with the study population. These results support a Phase 3 study of SNF472 for the treatment of calciphylaxis (CUA).

[0438] It should be understood that the "Detailed Description" section (as opposed to the "Summary of the Invention" and "Abstract" sections) is intended to be used to interpret the claims. The Summary of the Invention section and the Abstract section may set forth one or more but not all exemplary embodiments contemplated by the inventors, and thus are not intended to limit the invention and the appended claims in any way.

[0439] The present invention has been described above by means of functional building blocks that can show the implementation of specific functions and their relationships. For convenience of description, the boundaries of these functional building blocks have been arbitrarily defined here. Other boundaries can be defined as long as the specified functions and their relationships are properly executed.

[0440] The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, without departing from the general concept of the invention, readily modify and / or adapt it for various applications such as the specific embodiments by applying the knowledge of those skilled in the art, without undue experimentation. Therefore, such adaptations and modifications are intended to be within the meaning and scope of the equivalent forms of the disclosed embodiments, based on the teachings and guidance presented herein. It should be understood that the language or terminology herein is for the purpose of description and not of limitation, and thus the terminology or wording of this specification will be interpreted by those skilled in the art in light of the teachings and guidance.

[0441] The breadth and scope of the present invention should not be limited by any of the above exemplary embodiments, but should be defined only in accordance with the appended claims and their equivalents.

[0442] The claims in this application are different from the claims in the parent application or other related applications. Accordingly, the applicant cancels any disclaimers made in the parent application or any prior application with respect to the scope of the claims related to this application. Accordingly, it is recommended that the examiner may need to reexamine any prior disclaimers and the cited references avoided therefor. In addition, the examiner is reminded that any disclaimers made in this application should not be read into or used against the parent application.

Claims

1. A method of treating or preventing ectopic calcification and / or its consequences in a subject in need thereof, comprising administering to the subject a dosage of inositol phosphate, or an analogue or derivative thereof, at a dose of from about 6 mg / kg / day to 9 mg / kg / day, wherein administration of said dose is effective to treat or prevent ectopic calcification and / or its consequences in said subject.

2. The method according to claim 1, wherein said inositol phosphate comprises a compound of formula I, a pharmaceutically acceptable salt thereof, or a combination thereof: Wherein (i)R 1 、R 3 、R 5 、R 7 、R 9 and R 11 independently represent OH, a compound of formula II, or a compound of formula III, or a compound of formula IV: (ii) R 2 、R 4 、R 6 、R 8 、R 10 、R 12 and R 13 represent H; (iii) R 1 , R 3 , R 5 , R 7 , R 9 and R 11 at least one of the compounds of Formula II, Formula III or Formula IV, and (iv) R 1 、R 3 、R 5 、R 7 、R 9 and R 11 represent zero, one or two heterogeneous parts.

3. The method according to any one of claims 1 or 2, wherein said inositol phosphate comprises from 1 to 6 phosphate groups.

4. The method according to claim 3, wherein said inositol phosphate is inositol hexaphosphate.

5. The method according to claim 4, wherein said inositol hexaphosphate is myo-inositol hexaphosphate.

6. The method according to any one of claims 1 to 5, wherein said dose administered to the subject is about 7 mg / kg / day.

7. The method according to any one of claims 2 to 6, wherein said heterologous moiety comprises a moiety that prolongs the half-life.

8. The method according to claim 7, wherein said heterologous moiety comprises polyethylene glycol or polyglycerol.

9. The method according to any one of claims 1 to 8, wherein the concentration of inositol phosphate, or an analogue or derivative thereof, in each dosage is between about 10,000 μg / mL and about 100,000 μg / mL.

10. The method according to any one of claims 1 to 8, wherein the concentration of inositol phosphate, or an analogue or derivative thereof, in each dosage is between about 12.5 mM and about 135 mM.

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