Claims for Patent: 10,501,515

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Summary for Patent: 10,501,515

Title:	Hepcidin analogues and uses thereof
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.
Inventor(s):	Mark Leslie Smythe, Gregory Thomas Bourne, Simone Vink, Brian Troy Frederick, Praveen Madala, Anne Pernille Tofteng Shelton, Jacob Ulrik Fog
Assignee:	Protagonist Therapeutics Inc
Application Number:	US16/289,451
Patent Claims:	1. A method of treating a disease of iron metabolism in a subject, comprising administering to the subject an effective amount of at least one peptide according to formula I′: (I′) (SEQ ID NO: 21) R1′-X′-Y′-R2′ or a pharmaceutically acceptable salt thereof, wherein R1′ is hydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C1-C20 alkanoyl or pGlu; R2′ is —NH2 or —OH; X′ is a peptide sequence having the formula Ia′ (Ia′) (SEQ ID NO: 13) X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 wherein X1 is Asp, Ida, pGlu, bhAsp, or absent; X2 is Thr; X3 is His; X4 is Phe, or Dpa; X5 is Pro, or bhPro; X6 is Ile, Cys, or Arg; X7 is Cys, IIe, Leu, or Val; X8 is Ile, Arg, Phe, Gln, Lys, or Glu; X9 is Phe or bhPhe; and X10 is Lys, Phe or absent; wherein if Y′ is absent, X7 is Ile; and Y′ is a peptide sequence having the formula IIa′ (IIa′) (SEQ ID NO: 16) Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Y9-Y10-Y11-Y12-Y13-Y14-Y15 wherein Y1 is Gly, Cys, Ala, Phe, Pro, Glu, 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, IIe, Ala, Pro, Val or absent; Y7 is Trp, Lys, Gly, Ala, IIe, Val or absent; Y8 is Val, Thr, Gly, Cys, Met, Tyr, Ala, Glu, Lys, Asp, Arg or absent; Y9 is Cys, Tyr or absent; Y10 is Met, Lys, Arg, Tyr or absent; Y11 is Arg, Met, Cys, Lys or absent; Y12 is Arg, Lys, Ala or absent; Y13 is Arg, Cys, Lys, Val or absent; Y14 is Arg, Lys, Pro, Cys, Thr or absent; and Y15 is Thr, Arg or absent; wherein the peptide of formula I′ comprises two cysteine residues linked via a disulfide bond, wherein the peptide is optionally PEGylated on R1′, X′, or Y′; wherein a side chain of an amino acid of the peptide is optionally conjugated to a lipophilic substituent or a polymeric moiety; and wherein the disease of iron metabolism is hereditary hemochromatosis, iron hemochromatosis, HFE (human factors engineering) mutation hemochromatosis, hepcidin deficiency, transfusional iron overload, or thalassemia. 2. The method of claim 1, wherein the peptide of Formula I′ is PEGylated on R1′, X′, or Y′, or wherein a side chain of an amino acid of the peptide of Formula I′ is conjugated to a lipophilic substituent or a polymeric moiety. 3. The method of claim 1, wherein R1′ is hydrogen, isovaleric acid, isobutyric acid or acetyl. 4. The method of claim 1, wherein X′ is a peptide sequence having formula Ib′ (Ib′) (SEQ ID NO: 14) X1-Thr-His-X4-X5-X6-X7-X8-Phe-X10 wherein X1 is Asp, Ida, pGlu, bhAsp or absent; X4 is Phe or Dpa; X5 is Pro or bhPro; X6 is Ile, Cys or Arg; X7 is Cys, IIe, Leu or Val; X8 is Ile, Lys, Glu, Phe, Gln or Arg; and X10 is Lys or absent; or having formula Ic′ (Ic′) (SEQ ID NO: 15) X1-Thr-His-X4-X5-Cys-I1e-X8-Phe-X10 wherein X1 is Asp, Ida, pGlu, bhAsp or absent; X4 is Phe or Dpa; X5 is Pro or bhPro; X8 is Ile, Lys, Glu, Phe, Gln or Arg; and X10 is Lys or absent. 5. The method of claim 1, wherein X1 is Asp, X4 is Phe, and X5 is Pro. 6. The method of claim 1, wherein the peptide of Formula I′ comprises one of the following sequences: (SEQ ID NO: 29) DTHFPICIFGPRSKGWVC; (SEQ ID NO: 38) DTHFPCIIFGPRSKGWVCK; (SEQ ID NO: 128) DTHFPCIIFEPRSKGWVCK; (SEQ ID NO: 164) DTHFPCIIFGPRSKGWACK; (SEQ ID NO: 168) DTHFPCIIFGPRSKGWVCKK; (SEQ ID NO: 57 DTHFPCIIFVCHRPKGCYRRVCR; (SEQ ID NO: 125) DTHFPCIKFGPRSKGWVCK; (SEQ ID NO: 173) DTHFPCIKFKPRSKGWVCK; (SEQ ID NO: 106) DTHFPCIIFGPRSRGWVCK; (SEQ ID NO: 135) DTHFPCIKFGPKSKGWVCK; (SEQ ID NO: 207) DTHFPCIKFEPRSKGCK; (SEQ ID NO: 265) DTHFPCIKFEPKSKGWECK; (SEQ ID NO: 245) DTHFPCIKFEPRSKKCK; (SEQ ID NO: 247) DTHFPCIKFEPRSKGCKK; (SEQ ID NO: 249) DTHFPCIKFKPRSKGCK; or (SEQ ID NO: 250) DTHFPCIKFEPKSKGCK, or a pharmaceutically acceptable salt thereof. 7. The method of claim 1, wherein the peptide of Formula I′ comprises one of the following sequences: (SEQ ID NO: 29) Isovaleric acid-DTHFPICIFGPRSKGWVC-NH2; (SEQ ID NO: 38) Isovaleric acid-DTHFPCIIFGPRSKGWVCK-NH2; (SEQ ID NO: 128) Isovaleric acid-DTHFPCIIFEPRSKGWVCK-NH2; (SEQ ID NO: 164) Isovaleric acid-DTHFPCIIFGPRSKGWACK-NH2; (SEQ ID NO: 168) Isovaleric acid-DTHFPCIIFGPRSKGWVCKK-NH2; (SEQ ID NO: 57) Isovaleric acid-DTHFPCIIFVCHRPKGCYRRVCR-NH2; (SEQ ID NO: 172) Isovaleric acid-DTHFPCI(K(PEG8))FGPRSKGWVCK-NH2; (SEQ ID NO: 173) Isovaleric acid-DTHFPCIKF(K(PEG8))PRSKGWVCK-NH2; (SEQ ID NO: 199) Isovaleric acid-DTHFPICIFGPRS(K(PEG8))GWVCNH2; (SEQ ID NO: 200) Isovaleric acid-DTHFPICIFGPRS(K(PEG4))GWVCNH2; (SEQ ID NO: 201) Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG8))-NH2; (SEQ ID NO: 202) Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG4))-NH2; (SEQ ID NO: 203) Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG2))-NH2; (SEQ ID NO: 183) Isovaleric acid-DTHFPCI(K(Palm))FGPRSKGWVCK-NH2; (SEQ ID NO: 217) Isovaleric acid-DTHFPCIKF)K(Palm))PRSKGWVCK-NH2; (SEQ ID NO: 219) Isovaleric acid-DTHFPCIKFGP(K(Palm))SKGWVCK-NH2; (SEQ ID NO: 220) Isovaleric acid-DTHFPCIKFGPRS(K(Palm))GWVCK-NH2; (SEQ ID NO: 221) Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(Palm))-NH2; (SEQ ID NO: 222) Isovaleric acid-DTHFPCI(K(PEG3-Palm))FGPRSKGWVCK- NH2; (SEQ ID NO: 223) Isovaleric acid-DTHFPCIKF(K(PEG3-Palm))PRSKGWVCK- NH2; (SEQ ID NO: 224) Isovaleric acid-DTHFPCIKFGP(K(PEG3-Palm))SKGWVCK- NH2; (SEQ ID NO: 225) Isovaleric acid-DTHFPCIKFGPRS(K(PEG3-Palm))GWVCK- NH2; (SEQ ID NO: 226) Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG3-Palm))- NH2; (SEQ ID NO: 176) Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG8))-NH2; (SEQ ID NO: 241) Isovaleric acid-DTHFPCI(K(isoGlu-Palm))FEPRSKGCK- NH2; (SEQ ID NO: 242) Isovaleric acid-DTHFPCIKF-K(isoGlu-Palm)-PRSKGCK- NH2; (SEQ ID NO: 243) Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGCK- NH2; (SEQ ID NO: 265) Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGWECK- NH2; (SEQ ID NO: 244) Isovaleric acid-DTHFPCIKFEPRS(K(isoGlu-Palm))GCK- NH2; (SEQ ID NO: 245) Isovaleric acid-DTHFPCIKFEPRSK(K(isoGlu-Palm))CK- NH2; (SEQ ID NO: 246) Isovaleric acid-DTHFPCIKFEPRSKGCK(K(isoGlu-Palm))- NH2; (SEQ ID NO: 248) Isovaleric acid-DTHFPCI-K(Dapa-Palm)-FEPRSKGCK-NH2; (SEQ ID NO: 249) Isovaleric acid-DTHFPCIK(F(Dapa-Palm))PRSKGCK-NH2; (SEQ ID NO: 250) Isovaleric acid-DTHFPCIKFEP(K(Dapa-Palm))SKGCK-NH2; (SEQ ID NO: 251) Isovaleric acid-DTHFPCIKFEPRS(K(Dapa-Palm))GCK-NH2; (SEQ ID NO: 252) Isovaleric acid-DTHFPCIKFEPRSK(K(Dapa-Palm))CK-NH2; (SEQ ID NO: 253) Isovaleric acid-DTIFPCIKFEPRSKGC(K(Dapa-Palm))K- NH2; or (SEQ ID NO: 254) Isovaleric acid-DTHFPCIKFEPRSKGC(K(Dapa-Palm))-NH2, or a pharmaceutically acceptable salt thereof, wherein the peptide of Formula I′ comprises two cysteine residues linked via a disulphide bond. 8. The method of claim 1, wherein the peptide of formula I′ comprises one of the following sequences: (SEQ ID NO: 29) DTHFPICIFGPRSKGWVC; (SEQ ID NO: 38) DTHFPCIIFGPRSKGWVCK; (SEQ ID NO: 128) DTHFPCIIFEPRSKGWVCK; (SEQ ID NO: 164) DTHFPCIIFGPRSKGWACK; (SEQ ID NO: 168) DTHFPCIIFGPRSKGWVCKK; (SEQ ID NO: 57 DTHFPCIIFVCHRPKGCYRRVCR; (SEQ ID NO: 125) DTHFPCIKFGPRSKGWVCK; (SEQ ID NO: 173) DTHFPCIKFKPRSKGWVCK; (SEQ ID NO: 106) DTHFPCIIFGPRSRGWVCK; (SEQ ID NO: 135) DTHFPCIKFGPKSKGWVCK; (SEQ ID NO: 207) DTHFPCIKFEPRSKGCK; (SEQ ID NO: 265) DTHFPCIKFEPKSKGWECK; (SEQ ID NO: 245) DTHFPCIKFEPRSKKCK; (SEQ ID NO: 247) DTHFPCIKFEPRSKGCKK; (SEQ ID NO: 249) DTHFPCIKFKPRSKGCK; or (SEQ ID NO: 250) DTHFPCIKFEPKSKGCK. 9. The method of claim 1, wherein the peptide comprises one of the following sequences: (SEQ ID NO: 29) Isovaleric acid-DTHFPICIFGPRSKGWVC-NH2; (SEQ ID NO: 38) Isovaleric acid-DTHFPCIIFGPRSKGWVCK-NH2; (SEQ ID NO: 128) Isovaleric acid-DTHFPCIIFEPRSKGWVCK-NH2; (SEQ ID NO: 164) Isovaleric acid-DTHFPCIIFGPRSKGWACK-NH2; (SEQ ID NO: 168) Isovaleric acid-DTHFPCIIFGPRSKGWVCKK-NH2; (SEQ ID NO: 57) Isovaleric acid-DTHFPCIIFVCHRPKGCYRRVCR-NH2; (SEQ ID NO: 172) Isovaleric acid-DTHFPCI(K(PEG8))FGPRSKGWVCK-NH2; (SEQ ID NO: 173) Isovaleric acid-DTHFPCIKF(K(PEG8))PRSKGWVCK-NH2; (SEQ ID NO: 199) Isovaleric acid-DTHFPICIFGPRS(K(PEG8))GWVCNH2; (SEQ ID NO: 200) Isovaleric acid-DTHFPICIFGPRS(K(PEG4))GWVCNH2; (SEQ ID NO: 201) Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG8))-NH2; (SEQ ID NO: 202) Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG4))-NH2; (SEQ ID NO: 203) Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG2))-NH2; (SEQ ID NO: 183) Isovaleric acid-DTHFPCI(K(Palm))FGPRSKGWVCK-NH2; (SEQ ID NO: 217) Isovaleric acid-DTHFPCIKF)K(Palm))PRSKGWVCK-NH2; (SEQ ID NO: 219) Isovaleric acid-DTHFPCIKFGP(K(Palm))SKGWVCK-NH2; (SEQ ID NO: 220) Isovaleric acid-DTHFPCIKFGPRS(K(Palm))GWVCK-NH2; (SEQ ID NO: 221) Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(Palm))-NH2; (SEQ ID NO: 222) Isovaleric acid-DTHFPCI(K(PEG3-Palm))FGPRSKGWVCK- NH2; (SEQ ID NO: 223) Isovaleric acid-DTHFPCIKF(K(PEG3-Palm))PRSKGWVCK- NH2; (SEQ ID NO: 224) Isovaleric acid-DTHFPCIKFGP(K(PEG3-Palm))SKGWVCK- NH2; (SEQ ID NO: 225) Isovaleric acid-DTHFPCIKFGPRS(K(PEG3-Palm))GWVCK- NH2; (SEQ ID NO: 226) Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG3-Palm))- NH2; (SEQ ID NO: 176) Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG8))-NH2; (SEQ ID NO: 241) Isovaleric acid-DTHFPCI(K(isoGlu-Palm))FEPRSKGCK- NH2; (SEQ ID NO: 242) Isovaleric acid-DTHFPCIKF-K(isoGlu-Palm)-PRSKGCK- NH2; (SEQ ID NO: 243) Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGCK- NH2; (SEQ ID NO: 265) Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGWECK- NH2; (SEQ ID NO: 244) Isovaleric acid-DTHFPCIKFEPRS(K(isoGlu-Palm))GCK- NH2; (SEQ ID NO: 245) Isovaleric acid-DTHFPCIKFEPRSK(K(isoGlu-Palm))CK- NH2; (SEQ ID NO: 246) Isovaleric acid-DTHFPCIKFEPRSKGCK(K(isoGlu-Palm))- NH2; (SEQ ID NO: 248) Isovaleric acid-DTHFPCI-K(Dapa-Palm)-FEPRSKGCK-NH2; (SEQ ID NO: 249) Isovaleric acid-DTHFPCIK(F(Dapa-Palm))PRSKGCK-NH2; (SEQ ID NO: 250) Isovaleric acid-DTHFPCIKFEP(K(Dapa-Palm))SKGCK-NH2; (SEQ ID NO: 251) Isovaleric acid-DTHFPCIKFEPRS(K(Dapa-Palm))GCK-NH2; (SEQ ID NO: 252) Isovaleric acid-DTHFPCIKFEPRSK(K(Dapa-Palm))CK-NH2; (SEQ ID NO: 253) Isovaleric acid-DTIFPCIKFEPRSKGC(K(Dapa-Palm))K- NH2; or (SEQ ID NO: 254) Isovaleric acid-DTHFPCIKFEPRSKGC(K(Dapa-Palm))-NH2, 10. The method of claim 1, wherein the disease of iron metabolism is hereditary hemochromatosis, iron hemochromatosis, HFE (human factors engineering) mutation hemochromatosis, hepcidin deficiency, transfusional iron overload, or thalassemia. 11. The method of claim 1, wherein the disease of iron metabolism is hereditary hemochromatosis (HH). 12. The method of claim 1, wherein the disease of iron metabolism is a thalassemia, optionally thalassemia intermedia, alpha thalassemia, or β-thalassemia. 13. The method of claim 12, wherein the disease of iron metabolism is β-thalassemia. 14. The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIIFGPRSKGWVCK-NH2 (SEQ ID NO:38) or Isovaleric acid-DTHFPCIIFEPRSKGWVCK-NH2 (SEQ ID NO:128). 15. The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCI(K(PEG8))FGPRSKGWVCK-NH2 (SEQ ID NO:172) or Isovaleric acid-DTHFPCIKF(K(PEG8))PRSKGWVCK-NH2 (SEQ ID NO:173). 16. The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG8))—NH2 (SEQ ID NO:201). 17. The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCI(K(Palm))FGPRSKGWVCK-NH2 (SEQ ID NO:183). 18. The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKF(K(Palm))PRSKGWVCK-NH2 (SEQ ID NO:217). 19. The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKFGP(K(Palm))SKGWVCK-NH2(SEQ ID NO:219) or Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(Palm))—NH2 (SEQ ID NO:221). 20. The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCI(K(PEG3-Palm))FGPRSKGWVCK-NH2(SEQ ID NO:222). 21. The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKF(K(PEG3-Palm))PRSKGWVCK-NH2 (SEQ ID NO:223). 22. The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKFGP(K(PEG3-Palm))SKGWVCK-NH2(SEQ ID NO:224). 23. The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKFGPRS(K(PEG3-Palm))GWVCK-NH2(SEQ ID NO:225) or Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG3-Palm))—NH2(SEQ ID NO:226). 24. The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG8))—NH2 (SEQ ID NO:176). 25. The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCI(K(isoGlu-Palm))FEPRSKGCK-NH2(SEQ ID NO:241). 26. The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKF(K(isoGlu-Palm))PRSKGCK-NH2(SEQ ID NO:242). 27. The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGCK-NH2(SEQ ID NO:243). 28. The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKFEPRS(K(isoGlu-Palm))GCK-NH2(SEQ ID NO:244). 29. The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCI(K(Dapa-Palm))FEPRSKGCK-NH2(SEQ ID NO:248). 30. The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKFEP(K(Dapa-Palm))SKGCK-NH2(SEQ ID NO:250).