IP and IP analogs dosage regimens for the treatment of ectopic calcifications
Inventors
Perello Bestard, Joan • Salcedo Roca, Carolina • CANALS HAMANN, Ana-Zeralda
Assignees
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Publication Number
US-12070469-B2
Publication Date
2024-08-27
Expiration Date
Abstract
The present disclosure related to compositions, methods, dosages, dosage regimens, articles of manufacture and kits for the treatment and/or prevention ectopic calcifications, and in particular cutaneous calcifications such as calciphylaxis calcifications comprising inositol phosphate, inositol phosphate analogs, inositol phosphate derivatives, or combinations thereof. In a particular aspect the disclosure provides a dosage regimen to treat calciphylaxis comprising the administration of 6 mg/kg to 9 mg/kg daily doses of myo-inositol hexaphosphate, three times a week, for at least 1 to 8 months.
Core Innovation
The invention relates to a method to treat or inhibit the occurrence of critical limb ischemia and/or the consequences thereof in a subject by administering SNF472, defined as the hexasodium salt of myo-inositol hexaphosphate. The dose regimen specifies about 5 mg of SNF472 per kg per day to about 10 mg of SNF472 per kg per day for about 2 to 32 weeks, and the administration effectively treats or inhibits the occurrence of critical limb ischemia and/or its consequences.
The disclosure defines inositol phosphate/inositol phosphate analog derivative structures using formulas (V)-(IX), with X substituents of OPO3^2−/OPSO2^2−/OSO3^2−, Z as an alkyl chain optionally containing X, and R1 as an optional heterologous moiety. The structures specify allowable Z substructures and substitution patterns, including attachment of heterologous moieties such as PEG/PG, and further specify pharmaceutical salt forms, including hexasodium salt forms.
The disclosure states that heterologous moieties improve properties of the inositol phosphate/inositol phosphate analog derivatives, including solubility and improvements related to half-life and stability, enzyme/phosphatase resistance, and permeability. The disclosure also provides pharmaceutical compositions and formulation approaches and describes administration-type options including controlled-release, delayed-release, and pulsatile release.
The disclosure identifies treating or inhibiting ectopic calcifications, including calciphylaxis and related conditions such as peripheral arterial disease and critical limb ischemia, and states combination-therapy options with osteoprotegerin, corticosteroids, cinacalcet, phosphate chelators, bisphosphonates, and vitamin D/K. Example 1 describes a phase 2 open-label single-arm repeat-dose study using IV SNF472 in calciphylaxis, reporting improvements at week 12 in BWAT total score, pain VAS, and Wound-QoL global score, without SNF472 accumulation, and with tolerability/safety summarized.
Claims Coverage
Two independent claim themes are identified across the inputs: administering SNF472 to treat or inhibit critical limb ischemia and/or its consequences, and claimed structures of inositol phosphate/inositol phosphate analog derivatives. Dependent claims refine the SNF472 method with purity constraints, narrower dose ranges, dosing schedule and frequency, and effectiveness endpoints using named assessment tools and questionnaires.
Treating or inhibiting critical limb ischemia with SNF472
A method to treat or inhibit the occurrence of critical limb ischemia and/or the consequences thereof in a subject comprising administering SNF472 (hexasodium salt of myo-inositol hexaphosphate) in a dosage of about 5 mg of SNF472 per kg per day to about 10 mg of SNF472 per kg per day for about 2 to 32 weeks, wherein the administration effectively treats or inhibits the occurrence of critical limb ischemia and/or the consequences thereof in the subject.
Inositol phosphate and analog derivative structures
Inositol phosphate/inositol phosphate analog derivative structures using formulas (V)-(IX), where X substituents are OPO3^2−/OPSO2^2−/OSO3^2−, Z is an alkyl chain optionally containing X, and R1 is an optional heterologous moiety.
SNF472 purity threshold for dosing
The method of treating or inhibiting critical limb ischemia wherein SNF472 is at least 90% pure for administering the dosage to the subject.
Narrowing the daily SNF472 dose range
The method wherein the dosage is about 6 mg of SNF472 per kg per day to about 9 mg of SNF472 per kg per day.
Single or multiple daily dosing schedule
The method wherein the dosage is administered as a single daily dose or as multiple daily doses.
Dosing frequency per week
The method wherein the dosage is administered between 2, 3, 4, 5, 6, or 7 times per week.
Clinical and patient-reported effectiveness endpoints
The method treating critical limb ischemia and/or the consequences thereof by reducing lesions as determined by the Bates-Jensen Wound Assessment tool, improving lesion healing, reducing pain, improving global wound quality of life using a validated wound-associated QoL questionnaire, or a combination thereof.
Overall claim coverage is directed to administering SNF472 at about 5-10 mg/kg/day for about 2-32 weeks to treat or inhibit critical limb ischemia and/or its consequences, with dependent claims narrowing purity, daily dose range, dosing schedule and frequency, and effectiveness endpoints, and to inositol phosphate/inositol phosphate analog derivative structures defined by formulas (V)-(IX).
Stated Advantages
Effectively treats or inhibits the occurrence of critical limb ischemia and/or the consequences thereof in a subject.
Reduces lesions as determined by the Bates-Jensen Wound Assessment tool.
Improves lesion healing.
Reduces pain.
Improves global wound quality of life using a validated wound-associated QoL questionnaire.
In calciphylaxis study context, improvements are reported at week 12 in BWAT total score, pain VAS, and Wound-QoL global score.
Without SNF472 accumulation (as summarized in Example 1).
Tolerability/safety is summarized (in Example 1).
Heterologous moieties improve properties including solubility, half-life, stability, enzyme/phosphatase resistance, and permeability.
Documented Applications
A method to treat or inhibit the occurrence of critical limb ischemia and/or the consequences thereof in a subject.
Treating calciphylaxis in a phase 2 open-label single-arm repeat-dose study using IV SNF472, with assessments including BWAT total score, pain VAS, and Wound-QoL global score.
Combination therapy contexts with osteoprotegerin, corticosteroids, cinacalcet, phosphate chelators, bisphosphonates, and vitamin D/K for ectopic calcifications including calciphylaxis and related conditions.
Treating or inhibiting ectopic calcifications, including calciphylaxis and related conditions such as peripheral arterial disease and critical limb ischemia.
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