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-10973838-B2
Publication Date
2021-04-13
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 is directed to methods to treat or inhibit the occurrence of calciphylaxis calcification and/or the consequences thereof in a subject in need thereof. The methods comprise administering an intravenous dose of inositol hexaphosphate at specified dosage levels per kg per day, where the administration effectively treats or inhibits the occurrence of calciphylaxis calcification and/or the consequences thereof in the subject.
The described compositions are based on inositol phosphate compositions, including inositol hexaphosphate and inositol phosphate analogs and derivatives. In particular, the document describes myo-inositol hexaphosphate and SNF472, where SNF472 is described as a hexasodium salt of myo-inositol hexaphosphate, as forms for the intravenous dosing regimen.
The disclosed treatment outcomes include inhibiting hydroxyapatite crystal formation and/or growth, and reducing calciphylaxis-related lesion burden as assessed by the Bates-Jensen Wound Assessment tool. The document further describes reductions in pain and improvements in global wound quality of life using a validated wound-associated QoL questionnaire, as consequences of effectively treating or inhibiting calciphylaxis calcification.
The disclosure also relates to inositol phosphate and phosphate-derivative chemical structures with phosphate, sulfate, or thiophosphate variants and optional heterologous moieties intended to enhance properties. It further describes pharmaceutical salt forms, pharmaceutical compositions, and dosing schedule options including bolus versus non-bolus administration and durations and frequencies within ranges.
Claims Coverage
The independent claims cover methods for treating or inhibiting calciphylaxis calcification and/or its consequences using intravenous inositol hexaphosphate at specified per-kg-per-day dosing levels. Across the independents, the recurring inventive features are the target indication, intravenous inositol hexaphosphate as the active agent, and specified effective dosage levels or schedules.
Intravenous inositol hexaphosphate to treat calciphylaxis calcification
Administering an intravenous dose of inositol hexaphosphate to a subject in need thereof, wherein the administration effectively treats or inhibits the occurrence of calciphylaxis calcification and/or the consequences thereof in the subject.
Effective per kg per day dosing of inositol hexaphosphate
Administering an intravenous dose of inositol hexaphosphate at about 5 mg to 10 mg of inositol hexaphosphate per kg per day, wherein the administration effectively treats or inhibits the occurrence of calciphylaxis calcification and/or the consequences thereof in the subject.
Specified effective daily dose level of inositol hexaphosphate
Administering an intravenous dose of inositol hexaphosphate in a dosage of about 7 mg of inositol hexaphosphate per kg per day, wherein the administration effectively treats or inhibits the occurrence of calciphylaxis calcification and/or the consequences thereof in the subject.
Three-times-weekly intravenous dosing for 12 weeks
Administering an intravenous dose of inositol hexaphosphate 3 days per week for 12 weeks in a dosage of about 7 mg of inositol hexaphosphate per kg per day, wherein the administration of the dosage effectively treats or inhibits the occurrence of calciphylaxis calcification and/or the consequences thereof in the subject.
Collectively, the independent claims cover intravenous administration of inositol hexaphosphate to treat or inhibit calciphylaxis calcification and/or its consequences, with dosage levels centered on about 5 to 10 mg/kg/day, about 7 mg/kg/day, and an explicit regimen of 7 mg/kg/day three days per week for 12 weeks. Dependent claims further specify particular inositol hexaphosphate forms such as SNF472 and refine schedules and measurable consequences.
Stated Advantages
Effectively treats or inhibits the occurrence of calciphylaxis calcification and/or the consequences thereof.
Inhibits hydroxyapatite crystal formation and/or growth.
Improves lesion-related measures as determined by the Bates-Jensen Wound Assessment tool.
Reduces pain.
Improves global wound quality of life (QoL) using a validated wound-associated QoL questionnaire.
Non-accumulating pharmacokinetics (PK) based on postdose plasma concentrations.
Provides safety/tolerability results in the Phase 2 open-label study.
Documented Applications
Treating or inhibiting the occurrence of calciphylaxis calcification and/or the consequences thereof in a subject in need thereof.
Ectopic calcifications, including calciphylaxis, by pharmaceutical compositions containing inositol phosphate derivatives and/or inositol hexaphosphate (including SNF472).
Phase 2 open-label single-arm clinical use of intravenous SNF472 in calciphylaxis with thrice-weekly dosing for 12 weeks, with reported improvements in BWAT wound scores, pain VAS, and Wound-QoL global score.
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