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EP-4737477-A2 - HEPCIDIN MIMETICS FOR TREATMENT OF HEREDITARY HEMOCHROMATOSIS

EP4737477A2EP 4737477 A2EP4737477 A2EP 4737477A2EP-4737477-A2

Abstract

The disclosure provides methods for the treatment and/or prevention of iron overload diseases such as hereditary hemochromatosis.

Inventors

  • GUPTA, SUNEEL KUMAR
  • LIU, DAVID Y.
  • MODI, NISHIT BACHULAL
  • VALONE, Frank Horace

Assignees

  • Protagonist Therapeutics, Inc.

Dates

Publication Date
20260506
Application Date
20220614

Claims (15)

  1. A hepcidin mimetic for use in a method for treating hereditary hemochromatosis, hereditary hemochromatosis arthropathy, or joint pain associated with hereditary hemochromatosis arthropathy in a human subject, the method comprising administering to the subject an effective amount of the hepcidin mimetic, wherein the effective amount comprises a dose in the range of 5 mg to 40 mg.
  2. The hepcidin mimetic for use of claim 1, wherein the subject is administered different doses during different time periods over a course of treatment.
  3. The hepcidin mimetic for use of claim 1 or claim 2, wherein the subject is administered the effective amount of the hepcidin mimetic about once a week or about twice a week for at least some time period during the course of treatment; optionally wherein the subject is administered 5 mg to 20 mg of the hepcidin mimetic about twice a week for at least some time period during the course of treatment; or wherein the subject is administered 10 mg to 40 mg of the hepcidin mimetic about once a week for at least some time period during the course of treatment.
  4. The hepcidin mimetic for use of any one of claims 1-3, wherein hepcidin mimetic is a peptide having Formula I: R 1 -X-Y-R 2 (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-C20 alkanoyl, a hydrogen, a C1-C6 alkyl, a C6-C12 aryl, or pGlu; R2 is NH 2 or OH; X is an amino acid sequence of Formula II: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 (II) wherein X1 is Asp, Ala, Ida, pGlu, bhAsp, Leu, D-Asp, or absent; X2 is Thr, Ala, or D-Thr; X3 is His, Lys, D-His, or Lys; X4 is Phe, Ala, Dpa, or D-Phe; X5 is Pro, Gly, Arg, Lys, Ala, D-Pro, or bhPro; X6 is Cys, Ile, Arg, Lys, D-Ile, or D-Cys; X7 is Ile, Cys Leu, Val, Phe, D-Ile, or D-Cys; X8 is Lys, Ile, Arg, Phe, Gln, Glu, Val, Leu, or D-Ile; X9 is Phe or bhPhe; and X10 is absent, Lys, or Phe; wherein if Y is absent, X7 is Ile; and Y is an amino acid sequence of Formula III: Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Y9-Y10-Y11-Y12-Y13-Y14-Y15 (III) wherein Y1 is Glu, Gly, Cys, Ala, Phe, Pro, Lys, D-Pro, Val, Ser, or absent; Y2 is Pro, Ala, Cys, Gly, or absent; Y3 is Arg, Lys, Pro, Gly, His, Ala, Trp, or absent; Y4 is Ser, Arg, Gly, Trp, Ala, His, Tyr, or absent; Y5 is Lys, Met, Arg, Ala, or absent; Y6 is Gly, Ser, Lys, Ile, Ala, Pro, Val, or absent; Y7 is absent, Trp, Lys, Gly, Ala, Ile, or Val; Y8 is absent, Val, Thr, Gly, Cys, Met, Tyr, Ala, Glu, Lys, Asp, or Arg; Y9 is Cys, Tyr, or absent; Y10 is Lys, Met, Arg, Tyr, or absent; Y11 is absent, Arg, Met, Cys, or Lys; Y12 is absent, Arg, Lys, or Ala; Y13 is absent, Arg, Cys, Lys, or Val; Y14 is absent, Arg, Lys, Pro, Cys, or Thr; and Y15 is absent, Thr, or Arg; wherein the peptide of Formula I is optionally PEGylated on X, R1 or Y; wherein a side chain of an amino acid of the peptide is optionally conjugated to a lipophilic substituent or polymeric moiety; wherein the peptide of Formula I optionally has a disulfide bond formed between the thiol groups of two cysteine residues; and wherein Ida is iminodiacetic acid, pGlu is pyroglutamic acid, bhAsp is β-homoaspartic acid, and bhPro is β-homoproline; optionally wherein R1 is isovaleric acid, hydrogen, isobutyric acid or acetyl.
  5. The hepcidin mimetic for use of claim 4, wherein: (a) X is an amino acid sequence of Formula IV: X1-Thr-His-X4-X5-X6-X7-X8-Phe-X10 (IV) wherein X1 is Asp, Ida, pGlu, bhAsp or absent; X4 is Phe or Dpa; X5 is Pro or bhPro; X6 is Cys, Ile, or Arg; X7 is Ile, Cys, Leu, or Val; X8 is Lys, Ile, Glu, Phe, Gln, or Arg; and X10 is absent or Lys; or (b) X is an amino acid sequence of Formula V: X1-Thr-His-X4-X5-Cys-Ile-X8-Phe-X10 (V) wherein X1 is Asp, Ida, pGlu, bhAsp, or absent; X4 is Phe or Dpa; X5 is Pro or bhPro; X8 is Lys, Ile, Glu, Phe, Gln or Arg; and X10 is absent or Lys.
  6. The hepcidin mimetic for use of claim 4, wherein the peptide has Formula VI: R 1 -X-Y-R 2 (VI) or a pharmaceutically acceptable salt thereof, wherein: R 1 is isovaleric acid, hydrogen, isobutyric acid, or acetyl; R 2 is NH 2 or OH; X is an amino acid sequence of Formula VII: X1-Thr-His-X4-X5-Cys-Ile-X8-Phe-X10 (VII) wherein X1 is Asp, Ida, pGlu, bhAsp, or absent; X4 is Phe or Dpa; X5 is Pro or bhPro; X8 is Lys, Ile, Glu, Phe, Gln, or Arg; and X10 is absent or Lys; wherein Y is an amino acid sequence of Formula VIII: Y1-Pro-Y3-Ser-Y5-Y6-Y7-Y8-Cys-Y 10 (VIII) wherein Y1 is Glu, Gly, Val, or Lys; Y3 is Arg or Lys; Y5 is Lys or Arg; Y6 is Gly, Ser, Lys, Ile, or Arg; Y7 is absent or Trp; Y8 is absent, Val, Thr, Asp, or Glu; and Y10 is Lys or absent; wherein the peptide has a disulfide bond formed between the thiol groups of two cysteine residues; wherein the peptide is optionally PEGylated on R 1 , X, or Y; and wherein a side chain of an amino acid of the peptide is optionally conjugated to a lipophilic substituent or polymeric moiety.
  7. The hepcidin mimetic for use of any one of claims 4-6, wherein: (a) the peptide has one of the following sequences or structures: Isovaleric acid-DTHFPCI(K(isoGlu-Palm))FEPRSKGCK-NH 2 (Compound 25; SEQ ID NO:25); Isovaleric acid-DTHFPICIFGPRSKGWVC-NH 2 (Compound 1; SEQ ID NO:1); Isovaleric acid-DTHFPCIIFGPRSKGWVCK-NH 2 (Compound 2; SEQ ID NO:2); Isovaleric acid-DTHFPCIIFEPRSKGWVCK-NH 2 (Compound 3; SEQ ID NO:3); Isovaleric acid-DTHFPCIIFGPRSKGWACK-NH 2 (Compound 4; SEQ ID NO:4); Isovaleric acid-DTHFPCIIFGPRSKGWVCKK-NH 2 (Compound 5; SEQ ID NO:5); Isovaleric acid-DTHFPCIIFVCHRPKGCYRRVCR-NH 2 (Compound 6; SEQ ID NO:6); Isovaleric acid-DTHFPCI(K(PEG8))FGPRSKGWVCK-NH 2 (Compound 7; SEQ ID NO:7); Isovaleric acid-DTHFPCIKF(K(PEG8))PRSKGWVCK-NH 2 (Compound 8; SEQ ID NO:8); Isovaleric acid-DTHFPICIFGPRS(K(PEG8))GWVC-NH 2 (Compound 9; SEQ ID NO:9); Isovaleric acid-DTHFPICIFGPRS(K(PEG4))GWVC-NH 2 (Compound 10; SEQ ID NO:10); Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG8))-NH 2 (Compound 11; SEQ ID NO:11); Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG4))-NH 2 (Compound 12; SEQ ID NO:12); Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG2))-NH 2 (Compound 13: SEQ ID NO:13); Isovaleric acid-DTHFPCI(K(Palm))FGPRSKGWVCK-NH 2 (Compound 14; SEQ ID NO:14); Isovaleric acid-DTHFPCIKF)K(Palm))PRSKGWVCK-NH 2 (Compound 15; SEQ ID NO:15); Isovaleric acid-DTHFPCIKFGP(K(Palm))SKGWVCK-NH 2 (Compound 16; SEQ ID NO:16); Isovaleric acid-DTHFPCIKFGPRS(K(Palm))GWVCK-NH 2 (Compound 17; SEQ ID NO: 17); Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(Palm))NH 2 (Compound 18; SEQ ID NO:18); Isovaleric acid-DTHFPCI(K(PEG3-Palm))FGPRSKGWVCK-NH 2 (Compound 19; SEQ ID NO: 19); Isovaleric acid-DTHFPCIKF(K(PEG3-Palm))PRSKGWVCK-NH 2 (Compound 20; SEQ ID NO:20); Isovaleric acid-DTHFPCIKFGP(K(PEG3-Palm))SKGWVCK-NH 2 (Compound 21; SEQ ID NO:21); Isovaleric acid-DTHFPCIKFGPRS(K(PEG3-Palm))GWVCK-NH 2 (Compound 22; SEQ ID NO:22); Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG3-Palm))-NH 2 (Compound 23; SEQ ID NO:23); Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG8))-NH 2 (Compound 24; SEQ ID NO:24); Isovaleric acid-DTHFPCIKF-K(isoGlu-Palm)-PRSKGCK-NH 2 (Compound 26; SEQ ID NO:26); Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGCK-NH 2 (Compound 27; SEQ ID NO:27); Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGWECK-NH 2 (Compound 28; SEQ ID NO:28); Isovaleric acid-DTHFPCIKFEPRS(K(isoGlu-Palm))GCK-NH 2 (Compound 29; SEQ ID NO:29); Isovaleric acid-DTHFPCIKFEPRSK(K(isoGlu-Palm))CK-NH 2 (Compound 30; SEQ ID NO:30); Isovaleric acid-DTHFPCIKFEPRSKGCK(K(isoGlu-Palm))-NH 2 (Compound 31; SEQ ID NO:31); Isovaleric acid-DTHFPCI-K(Dapa-Palm)-FEPRSKGCK-NH 2 (Compound 32; SEQ ID NO:32); Isovaleric acid-DTHFPCIK(F(Dapa-Palm))PRSKGCK-NH 2 (Compound 33; SEQ ID NO:33); Isovaleric acid-DTHFPCIKFEP(K(Dapa-Palm))SKGCK-NH 2 (Compound 34; SEQ ID NO:34); Isovaleric acid-DTHFPCIKFEPRS(K(Dapa-Palm))GCK-NH 2 (Compound 35; SEQ ID NO:35); Isovaleric acid-DTHFPCIKFEPRSK(K(Dapa-Palm))CK-NH 2 (Compound 36; SEQ ID NO:36); Isovaleric acid-DTHFPCIKFEPRSKGC(K(Dapa-Palm))K-NH 2 (Compound 37; SEQ ID NO:37); Isovaleric acid-DTHFPCIKFEPRSKGC(K(Dapa-Palm))-NH 2 (Compound 38; SEQ ID NO:38); Isovaleric acid-DTHFPCIKF(K(PEG11-Palm))PRSK[Sar]CK-NH 2 (Compound 39; SEQ ID NO:39); Isolvaleric acid-DTHFPCIKF-NH 2 (Compound 40; SEQ ID NO:40); Hy-DTHFPCIKF-NH 2 (Compound 41; SEQ ID NO:41); Isolvaleric acid-DTHFPCIIF-NH 2 (Compound 42; SEQ ID NO:42); Hy-DTHFPCIIKF-NH 2 (Compound 43; SEQ ID NO:43); Isovaleric acid-DTKFPCIIF-NH 2 (Compound 44; SEQ ID NO:44); or Hy-DTKFPCIIF-NH 2 (Compound 45; SEQ ID NO:45); or (b) the peptide has one of the following sequences: DTHFPCIKFEPRSKGCK (SEQ ID NO:56); DTHFPICIFGPRSKGWVC (SEQ ID NO:46); DTHFPCIIFGPRSKGWVCK (SEQ ID NO:47); DTHFPCIIFEPRSKGWVCK (SEQ ID NO:48); DTHFPCIIFGPRSKGWACK (SEQ ID NO:49); DTHFPCIIFGPRSKGWVCKK (SEQ ID NO:50); DTHFPCIIFVCHRPKGCYRRVCR (SEQ ID NO:51); DTHFPCIKFGPRSKGWVCK (SEQ ID NO:52); DTHFPCIKFKPRSKGWVCK (SEQ ID NO:53); DTHFPCIIFGPRSRGWVCK (SEQ ID NO:54); DTHFPCIKFGPKSKGWVCK (SEQ ID NO:55); DTHFPCIKFEPKSKGWECK (SEQ ID NO:57); DTHFPCIKFEPRSKKCK (SEQ ID NO:58); DTHFPCIKFEPRSKGCKK (SEQ ID NO:59); DTHFPCIKFKPRSKGCK (SEQ ID NO:60); DTHFPCIKFEPKSKGCK (SEQ ID NO:61); DTHFPCIKF (SEQ ID NO:62); DTHFPCIIF (SEQ ID NO:63); or DTKFPCIIF (SEQ ID NO:64), wherein said peptide is optionally PEGylated on R1, X, or Y; and wherein a side chain of an amino acid of the peptide is optionally conjugated to a lipophilic substituent or polymeric moiety.
  8. The hepcidin mimetic for use of claim 4, wherein the peptide is: (a) Isovaleric acid-DTHFPCI(K(isoGlu-Palm))FEPRSKGCK-NH 2 (Compound 25; SEQ ID NO:25); (b) Isovaleric acid-DTHFPCIIFGPRSKGWVCK-NH 2 (Compound 2; SEQ ID NO:2), optionally wherein the peptide has a disulfide bond formed between the thiol groups of two cysteine residues; (c) Isovaleric acid-DTHFPCIIFEPRSKGWVCK-NH 2 (Compound 3; SEQ ID NO:3), optionally wherein the peptide has a disulfide bond formed between the thiol groups of two cysteine residues; (d) Isovaleric acid-DTHFPCI(K(PEG8))FGPRSKGWVCK-NH 2 (Compound 7; SEQ ID NO:7), optionally wherein the peptide has a disulfide bond formed between the thiol groups of two cysteine residues; (e) Isovaleric acid-DTHFPCIKF(K(PEG8))PRSKGWVCK-NH 2 (Compound 8; SEQ ID NO:8), optionally wherein the peptide has a disulfide bond formed between the thiol groups of two cysteine residues; (f) Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG8))-NH 2 (Compound 11; SEQ ID NO:11), optionally wherein the peptide has a disulfide bond formed between the thiol groups of two cysteine residues; (g) Isovaleric acid-DTHFPCI(K(Palm))FGPRSKGWVCK-NH 2 (Compound 14; SEQ ID NO:14), optionally wherein the peptide has a disulfide bond formed between the thiol groups of two cysteine residues; (h) Isovaleric acid-DTHFPCIKF(K(Palm))PRSKGWVCK-NH 2 (Compound 15; SEQ ID NO:15), optionally wherein the peptide has a disulfide bond formed between the thiol groups of two cysteine residues; (i) Isovaleric acid-DTHFPCIKFGP(K(Palm))SKGWVCK-NH 2 (Compound 16; SEQ ID NO:16), optionally wherein the peptide has a disulfide bond formed between the thiol groups of two cysteine residues; (j) Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(Palm))-NH 2 (Compound 18; SEQ ID NO:18), optionally wherein the peptide has a disulfide bond formed between the thiol groups of two cysteine residues; (k) Isovaleric acid-DTHFPCI(K(PEG3-Palm))FGPRSKGWVCK-NH 2 (Compound 19; SEQ ID NO:19), optionally wherein the peptide has a disulfide bond formed between the thiol groups of two cysteine residues; (l) Isovaleric acid-DTHFPCIKF(K(PEG3-Palm))PRSKGWVCK-NH 2 (Compound 20; SEQ ID NO:20), optionally wherein the peptide has a disulfide bond formed between the thiol groups of two cysteine residues; (m) Isovaleric acid-DTHFPCIKFGP(K(PEG3-Palm))SKGWVCK-NH 2 (Compound 21; SEQ ID NO:21), optionally wherein the peptide has a disulfide bond formed between the thiol groups of two cysteine residues; (n) Isovaleric acid-DTHFPCIKFGPRS(K(PEG3-Palm))GWVCK-NH 2 (Compound 22; SEQ ID NO:22), optionally wherein the peptide has a disulfide bond formed between the thiol groups of two cysteine residues; (o) Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG3-Palm))-NH 2 (Compound 23; SEQ ID NO:23), optionally wherein the peptide has a disulfide bond formed between the thiol groups of two cysteine residues; (p) Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG8))-NH 2 (Compound 24; SEQ ID NO:24), optionally wherein the peptide has a disulfide bond formed between the thiol groups of two cysteine residues; (q) Isovaleric acid-DTHFPCIKF(K(isoGlu-Palm))PRSKGCK-NH 2 (Compound 26; SEQ ID NO:26), optionally wherein the peptide has a disulfide bond formed between the thiol groups of two cysteine residues; (r) Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGCK-NH 2 (Compound 27; SEQ ID NO:27), optionally wherein the peptide has a disulfide bond formed between the thiol groups of two cysteine residues; (s) Isovaleric acid-DTHFPCIKFEPRS(K(isoGlu-Palm))GCK-NH 2 (Compound 28; SEQ ID NO:28), optionally wherein the peptide has a disulfide bond formed between the thiol groups of two cysteine residues; (t) Isovaleric acid-DTHFPCI(K(Dapa-Palm))FEPRSKGCK-NH 2 (Compound 32; SEQ ID NO:32), optionally wherein the peptide has a disulfide bond formed between the thiol groups of two cysteine residues; or (u) Isovaleric acid-DTHFPCIKFEP(K(Dapa-Palm))SKGCK-NH 2 (Compound 34; SEQ ID NO:34), optionally wherein the peptide has a disulfide bond formed between the thiol groups of two cysteine residues.
  9. The hepcidin mimetic for use of claim 4, wherein the peptide is selected from the group consisting of: (a) Isovaleric acid-DTHFPCI(K(isoGlu-Palm))FEPRSKGCK-NH 2 (Compound 25; SEQ ID NO:25); (b) Isovaleric acid-DTHFPCIKF(K(PEG3-Palm))PRSKGWVCK-NH 2 (Compound 20; SEQ ID NO:20); (c) Isovaleric acid-DTHFPCIKF(K(isoGlu-Palm))PRSKGCK-NH 2 (Compound 26; SEQ ID NO:26); (d) Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGCK-NH 2 (Compound 27; SEQ ID NO:27); and (e) Isovaleric acid-DTHFPCIKFEPRS(K(isoGlu-Palm))GCK-NH 2 (Compound 28; SEQ ID NO:28), wherein the amino acids are L-amino acids.
  10. The hepcidin mimetic for use of any one of claims 1-9, wherein the method comprises measuring transferrin saturation (TSAT) and/or serum iron level in the subject before and after the hepcidin mimetic is administered to the subject, optionally wherein the TSAT level is measured at trough level of the hepcidin mimetic following administration to the subject; optionally wherein the subject's TSAT level and/or serum iron level is decreased, further optionally wherein the subject's TSAT level is decreased to less than 45% or to less than 40%; still further optionally wherein the subject's TSAT level is maintained at less than 45% over the course of treatment with the hepcidin mimetic, optionally wherein the course of treatment comprises at least 24 weeks.
  11. The hepcidin mimetic for use of any one of claims 1-10, wherein the hepcidin mimetic is administered to the subject subcutaneously.
  12. The hepcidin mimetic for use of any one of claims 1-11, wherein the subject received phlebotomies for at least six months prior to treatment, optionally with a phlebotomy frequency of 0.25 - 1 phlebotomy per month; further optionally wherein during the treatment, the subject required substantially fewer or no phlebotomies, optionally with a phlebotomy frequency of less than 0.1, less than 0.05, or no phlebotomies per month.
  13. A compound having the formula: or a pharmaceutically acceptable salt thereof, or a peptide having the sequence: Isovaleric acid-DTHFPCI(K(isoGlu-Palm))FEPRSKGCK-NH 2 (SEQ ID NO:25), or a pharmaceutically acceptable salt thereof, wherein the thiol groups of two cysteine residues in the peptide optionally form a disulfide bond; for use in a method of treating hereditary hemochromatosis in a human subject, the method comprising administering to the subject an effective amount of the compound, peptide, or pharmaceutically acceptable salt thereof, wherein the effective amount comprises a dose in the range of 5 mg to 40 mg, and optionally wherein the subject is administered different doses during different time periods over a course of treatment.
  14. A hepcidin mimetic for use in a method of treating hereditary hemochromatosis arthropathy or joint pain associated with hereditary hemochromatosis arthropathy in a human subject, the method comprising administering to the subject an effective amount of the hepcidin mimetic; optionally wherein the effective amount comprises a dose in the range of 5 mg to 40 mg, and further optionally wherein the subject is administered different doses during different time periods over a course of treatment.
  15. The hepcidin mimetic for use of claim 14, wherein the hepcidin mimetic is Compound 25:

Description

RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application Serial No. 63/210,453, filed June 14, 2021, U.S. Provisional Patent Application Serial No. 63/252,001, filed October 4, 2021, and U.S. Provisional Patent Application Serial No. 63/349,841, filed June 7, 2022, which is incorporated herein by reference in their entireties. SEQUENCE LISTING This application is being filed electronically via EFS-Web and includes an electronically submitted sequence listing in .txt format. The .txt file contains a sequence listing entitled PRTH_070_02WO _ST25.txt created on June 13, 2022 and having a size of 24 kilobytes. The sequence listing contained in this .txt file is part of the specification and is incorporated herein by reference in its entirety. FIELD OF THE INVENTION The present disclosure relates, inter alia, to methods for the treatment and/or prevention of iron overload diseases, such as hereditary hemochromatosis. BACKGROUND Iron plays an important role in many cellular and organismal activities, from cell division to oxygen transport (see, e.g., Casu, C. et al., Blood 2018: 131(16): 1790-1794). However, excess iron promotes the formation of toxic reactive oxygen species (ROS), which can damage DNA, proteins, and lipid membranes, and lead to organ dysfunction or failure, and humans and other vertebrates have evolved regulatory systems to optimize the absorption and organ distribution of iron. Unfortunately, however, several genetic or acquired disorders of iron homeostasis dysregulate iron absorption or distribution, causing organ damage and creating conditions for overwhelming infections or inflammation, with associated morbidity and mortality. Hepcidin is a 25 amino acid peptide hormone produced primarily in the liver in proportion to plasma iron concentration and iron stores. Hepcidin is a key regulator of iron homeostasis, since it binds and degrades the only known iron exporter, ferroportin-1, which is expressed on the surfaces of cells involved in iron absorption, recycling, and storage. Given the central role of iron homeostasis in a variety of diseases and disorders, agents capable of modulating iron levels, e.g., in erythrocytes and organs, are being developed as therapeutic agents. However, there remains a need for methods for using iron modulating agents to restore iron homeostasis, e.g., for the treatment of hereditary hemochromatosis. The present invention addresses this need. SUMMARY OF THE INVENTION The present disclosure provides methods, clinically effective dosages and dosing regimens of hepcidin mimetics that restore iron homeostasis in human, e.g., humans with hereditary hemochromatosis. In certain embodiments, the methods modulate pharmacodynamic markers associated with efficacy in the treatment of disease and disorders associated with dysregulation of iron homeostasis, such iron overload diseases and disorders, including, e.g., hereditary hemochromatosis (HH). In certain embodiments, dosages, dosage regimens, and methods disclosed herein are used to treat hereditary hemochromatosis, hereditary hemochromatosis arthropathy, or joint pain associated with hereditary hemochromatosis arthropathy. In one aspect, the disclosure provides a method for treating an iron overload disease, e.g., HH, in a human subject, comprising providing to the subject an effective amount of a hepcidin mimetic, such as Compound 25. In certain embodiments, the subject has been diagnosed with hereditary hemochromatosis. In certain embodiments, the subject is receiving or requires phlebotomy treatment prior to the treatment disclosed herein. In particular embodiments, the subject is administered a first effective amount for a first time period, and a second effective amount for a second time period. In certain embodiments, the subject is administered a third or more effective amounts for a third or more time periods. In certain embodiments, the frequency of administration during the first and second time periods are the same or different. In certain embodiments, the frequency of administration during the third or more time periods are each the same or different from that of the first and second time period and each other. In particular embodiments, each time period independently comprises about one week, about two weeks, about four weeks, about one month, about two months, about four months, about six months, or about one year. In certain embodiments, the dosage and or frequency of administration is altered following testing of the subject's serum iron and/or TSAT saturation levels after a time period of treatment, so as to achieve parameters disclosed herein. In a related aspect, the disclosure provides a method for treating hereditary hemochromatosis arthropathy or joint pain associated with hereditary hemochromatosis arthropathy in a human subject, comprising administering to the subject an effective amount of a hepcidin mimetic. In particular embodiments, the effective amount com