Hepcidin analogues and uses thereof
Inventors
Smythe, Mark Leslie • Bourne, Gregory Thomas • Vink, Simone • Frederick, Brian Troy • Madala, Praveen • Tofteng Shelton, Anne Pernille • Fog, Jacob Ulrik
Assignees
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Publication Number
US-12269856-B2
Publication Date
2025-04-08
Expiration Date
Abstract
The present invention relates, inter alia, to certain hepcidin peptide analogues, including peptides and dimers thereof, and to the use of the peptides and peptide dimers in the treatment and/or prevention of a variety of diseases, conditions or disorders, including treatment and/or prevention of iron overload diseases, which include hereditary hemochromatosis and iron-loading anemias, and other conditions and disorders described herein.
Core Innovation
The disclosure concerns hepcidin peptide analogues and peptide dimers for iron homeostasis, including peptide structural formulas with N-terminal R1 substituents, modular X and Y peptide segments, and cysteine residues required to form disulfide bonds. The peptides are described as having ferroportin activity connected to ferroportin binding, ferroportin internalization, and ferroportin degradation.
A core aspect is the use of defined disulfide-linked cysteine-containing hepcidin peptide constructs, including peptide dimers and homodimers. The dimers are linked via cysteine disulfide and/or covalent linkers, with examples of linkers such as DIG, IDA, β-Ala-IDA, PEG13, and PEG25, and the document also describes optional PEGylation and modular attachment moieties based on R1/R2 and R1′/R2′ and R1″/R2″.
The invention also relates to peptide analogues and peptide dimers in which lipophilic substituents are conjugated to amino-acid side chains, including side chains such as lysine, so that albumin binding is obtained and enzymatic degradation is reduced. The peptide analogues include hydrocarbon chains and acyl groups, including palmitoyl and other acyl groups, and the polymeric moieties include polyethylene glycol species such as PEG/PEO/POG, mPEG, and related PEG derivatives.
The disclosed peptides and peptide dimers are positioned for treating and preventing diseases of iron metabolism, with particular emphasis on iron-overload diseases and related iron metabolism disorders. The disease scope explicitly includes hereditary hemochromatosis variants, transfusional iron overload, and thalassemia-related conditions, and the document further describes reduced plasma iron, improved stability and solubility, and in vitro and in vivo activity comparisons of dimer formats and linkers.
Claims Coverage
The document provides independent claim coverage centered on a single peptide sequence defined by SEQ ID NO: 241, with the disulfide-bond requirement and a specified iron-metabolism disease scope. Dependent claims further refine dosing, formulation, route, and administration parameters, while maintaining the same core peptide/disulfide-bond requirement.
Isovaleric acid-conjugated hepcidin peptide with disulfide bond
A method of treating a disease of iron metabolism in a subject by administering a peptide comprising the sequence Isovaleric acid-DTHFPCI(K(isoGlu-Palm))FEPRSKGCK- (SEQ ID NO: 241) or a pharmaceutically acceptable salt thereof, wherein the peptide comprises a disulfide bond between two cysteine residues.
Treatment of defined iron-metabolism disorders using the disulfide-bond peptide
The method wherein the disease of iron metabolism is selected from hereditary hemochromatosis, iron hemochromatosis, HFE mutation hemochromatosis, ferroportin mutation hemochromatosis, transferrin receptor 2 mutation hemochromatosis, hemojuvelin mutation hemochromatosis, hepcidin mutation hemochromatosis, juvenile hemochromatosis, neonatal hemochromatosis, hepcidin deficiency, transfusional iron overload, thalassemia, thalassemia intermedia, β-thalassemia, or alpha thalassemia.
Daily dosage range for the disulfide-bond peptide
Administering the peptide (or a pharmaceutically acceptable salt) at a daily dosage ranging from about 0.0001 to about 100 mg/kg body weight.
Alternative daily dosage range for the disulfide-bond peptide
Administering the peptide (or a pharmaceutically acceptable salt) at a daily dosage of about 0.001 to about 10 mg/kg body weight per day.
Dosing frequency schedules for administration
Administering the peptide (or a pharmaceutically acceptable salt) according to specified dosing frequency schedules.
Pharmaceutical formulation with a pharmaceutically acceptable carrier
Administering the peptide formulated in a pharmaceutical formulation that includes a pharmaceutically acceptable carrier.
Specified administration routes for the pharmaceutical formulation
Administering a pharmaceutical formulation intended for administration by intramuscular, intravenous, intradermal, or transdermal routes.
Across the independent claim and dependent refinements, the inventive focus is the administration of the SEQ ID NO: 241 hepcidin peptide containing a disulfide bond between two cysteine residues to treat a defined list of iron-metabolism disorders. Dependent claims further specify daily dosage ranges, dosing frequency schedules, formulation requirements with a pharmaceutically acceptable carrier, and selected administration routes.
Stated Advantages
Improved stability/half-life.
Improved solubility/aggregation characteristics.
Reduced plasma iron.
Ferroportin internalization and degradation activity.
Albumin binding is obtained and enzymatic degradation is reduced.
Improved bioavailability.
Documented Applications
Treating or preventing diseases of iron metabolism, including hereditary hemochromatosis variants, transfusional iron overload, and thalassemia-related conditions.
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