Oral ferroportin inhibitor vamifeport for improving iron homeostasis and erythropoiesis in β-thalassemia: current evidence and future clinical development

References

• Camaschella C. Iron and hepcidin: a story of recycling and balance. Hematology Am Soc Hematol Educ Program. 2013;2013:1–8.
   Google Scholar
• Tavazzi D, Duca L, Graziadei G, et al. Membrane-bound iron contributes to oxidative damage of beta-thalassaemia intermedia erythrocytes. Br J Haematol. 2001;112(1):48–50.
   PubMed Web of Science ®Google Scholar
• Viprakasit V, Ekwattanakit S. Clinical classification, screening and diagnosis for thalassemia. Hematol Oncol Clin North Am. 2018;32(2):193–211.
   PubMed Web of Science ®Google Scholar
• Jaing TH. Is the benefit-risk ratio for patients with transfusion-dependent thalassemia treated by unrelated cord blood transplantation favorable? Int J Mol Sci. 2017;18(11):2472.
   Web of Science ®Google Scholar
• Cabantchik ZI, Breuer W, Zanninelli G, et al. LPI-labile plasma iron in iron overload. Best Pract Res Clin Haematol. 2005;18(2):277–287.
   PubMed Web of Science ®Google Scholar
• Borgna-Pignatti C, Marsella M. Iron chelation in thalassemia major. Clin Ther. 2015;37(12):2866–2877.
   PubMedGoogle Scholar
• Ginzburg Y, Rivella S. β-thalassemia: a model for elucidating the dynamic regulation of ineffective erythropoiesis and iron metabolism. Blood. 2011;118(16):4321–4330.
   PubMed Web of Science ®Google Scholar
• Payne KA, Rofail D, Baladi JF, et al. Iron chelation therapy: clinical effectiveness, economic burden and quality of life in patients with iron overload. Adv Ther. 2008;25(8):725–742.
   PubMed Web of Science ®Google Scholar
• Trachtenberg FL, Mednick L, Kwiatkowski JL, et al. Beliefs about chelation among thalassemia patients. Health Qual Life Outcomes. 2012;10(1):148.
   PubMed Web of Science ®Google Scholar
• Uygun V, Kurtoglu E. Iron-chelation therapy with oral chelators in patients with thalassemia major. Hematology. 2013;18(1):50–55.
   PubMed Web of Science ®Google Scholar
• Ladis V, Chouliaras G, Berdoukas V, et al. Survival in a large cohort of Greek patients with transfusion-dependent beta thalassaemia and mortality ratios compared to the general population. Eur J Haematol. 2011;86(4):332–338.
   PubMed Web of Science ®Google Scholar
• Shander A, Cappellini MD, Goodnough LT. Iron overload and toxicity: the hidden risk of multiple blood transfusions. Vox Sang. 2009;97(3):185–197.
   PubMed Web of Science ®Google Scholar
• Taher AT, Saliba AN. Iron overload in thalassemia: different organs at different rates. Hematology Am Soc Hematol Educ Program. 2017;2017(1):265–271.
   PubMed Web of Science ®Google Scholar
• Musallam KM, Taher AT, Rachmilewitz EA. β-thalassemia intermedia: a clinical perspective. Cold Spring Harb Perspect Med. 2012;2(7):a013482.
   PubMed Web of Science ®Google Scholar
• Origa R, Galanello R, Ganz T, et al. Liver iron concentrations and urinary hepcidin in beta-thalassemia. Haematologica. 2007;92(5):583–588.
   PubMed Web of Science ®Google Scholar
• Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis. 2010;5:11.
   Google Scholar
• Borgna-Pignatti C, Rugolotto S, De Stefano P, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica. 2004;89(10):1187–1193.
   PubMed Web of Science ®Google Scholar
• Vichinsky E. Non-transfusion-dependent thalassemia and thalassemia intermedia: epidemiology, complications, and management. Curr Med Res Opin. 2016;32(1):191–204.
   PubMed Web of Science ®Google Scholar
• Taher AT, Musallam KM, Cappellini MD. Thalassaemia intermedia: an update. Mediterr J Hematol Infect Dis. 2009;1(1):e2009004.
   PubMedGoogle Scholar
• Cappellini MD, Motta I. New therapeutic targets in transfusion-dependent and -independent thalassemia. Hematology Am Soc Hematol Educ Program. 2017;2017(1):278–283.
   PubMedGoogle Scholar
• Franchini M, Forni GL, Marano G, et al. Red blood cell alloimmunisation in transfusion-dependent thalassaemia: a systematic review. Blood Transfus. 2019;17(1):4–15.
   PubMed Web of Science ®Google Scholar
• Taher A, Musallam K, Cappellini MD, eds. Guidelines for the Management of Non Transfusion Dependent Thalassaemia (NTDT). Thalassaemia International Federation: Nicosia, Cyprus. 2nd edition. 2017. [cited 2021 Apr 27]. Available from: https://thalassaemia.org.cy/publications/tif-publications/guidelines-for-the-clinical-management-of-non-transfusion-dependent-thalassaemias-updated-version/
   Google Scholar
• Rigano P, Pecoraro A, Calzolari R, et al. Desensitization to hydroxycarbamide following long-term treatment of thalassaemia intermedia as observed in vivo and in primary erythroid cultures from treated patients. Br J Haematol. 2010;151(5):509–515.
   PubMed Web of Science ®Google Scholar
• Foong WC, Ho JJ, Loh CK, et al. Hydroxyurea for reducing blood transfusion in non-transfusion dependent beta thalassaemias. Cochrane Database Syst Rev. 2016;10(10):CD011579.
   PubMedGoogle Scholar
• Cappellini MD, Porter JB, Viprakasit V, et al. A paradigm shift on beta-thalassaemia treatment: how will we manage this old disease with new therapies? Blood Rev. 2018;32(4):300–311.
   PubMed Web of Science ®Google Scholar
• United States Food and Drug Administration. Reblozyl (luspatercept-aamt) Prescribing Information (2019) [updated November 2019. [cited 2021 Apr 27]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761136lbl.pdf
   Google Scholar
• Bou-Fakhredin R, Bazarbachi AH, Chaya B, et al. Iron overload and chelation therapy in non-transfusion dependent thalassemia. Int J Mol Sci. 2017;18(12):2778.
   Web of Science ®Google Scholar
• Piga A, Perrotta S, Gamberini MR, et al. Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with beta-thalassemia. Blood. 2019;133(12):1279–1289.
   PubMed Web of Science ®Google Scholar
• Leecharoenkiat K, Lithanatudom P, Sornjai W, et al. Iron dysregulation in beta-thalassemia. Asian Pac J Trop Med. 2016;9(11):1035–1043.
   PubMed Web of Science ®Google Scholar
• Aschemeyer S, Qiao B, Stefanova D, et al. Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin. Blood. 2018;131(8):899–910.
   PubMed Web of Science ®Google Scholar
• Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306(5704):2090–2093.
   PubMed Web of Science ®Google Scholar
• Ganz T. Cellular iron: ferroportin is the only way out. Cell Metab. 2005;1(3):155–157.
   PubMed Web of Science ®Google Scholar
• Papanikolaou G, Pantopoulos K. Systemic iron homeostasis and erythropoiesis. IUBMB Life. 2017;69(6):399–413.
   PubMed Web of Science ®Google Scholar
• Gardenghi S, Grady RW, Rivella S. Anemia, ineffective erythropoiesis, and hepcidin: interacting factors in abnormal iron metabolism leading to iron overload in beta-thalassemia. Hematol Oncol Clin North Am. 2010;24(6):1089–1107.
   PubMed Web of Science ®Google Scholar
• Kautz L, Jung G, Valore EV, et al. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet. 2014;46(7):678–684.
   PubMed Web of Science ®Google Scholar
• Coffey R, Ganz T. Erythroferrone: an erythroid regulator of hepcidin and iron metabolism. HemaSphere. 2018;2(2):e35.
   PubMed Web of Science ®Google Scholar
• Gardenghi S, Ramos P, Marongiu MF, et al. Hepcidin as a therapeutic tool to limit iron overload and improve anemia in beta-thalassemic mice. J Clin Invest. 2010;120(12):4466–4477.
   PubMed Web of Science ®Google Scholar
• Khalil S, Delehanty L, Grado S, et al. Iron modulation of erythropoiesis is associated with Scribble-mediated control of the erythropoietin receptor. J Exp Med. 2018;215(2):661–679.
   PubMed Web of Science ®Google Scholar
• Zhang S, Macias-Garcia A, Velazquez J, et al. HRI coordinates translation by eIF2αP and mTORC1 to mitigate ineffective erythropoiesis in mice during iron deficiency. Blood. 2018;131(4):450–461.
   PubMed Web of Science ®Google Scholar
• Casu C, Oikonomidou PR, Chen H, et al. Minihepcidin peptides as disease modifiers in mice affected by beta-thalassemia and polycythemia vera. Blood. 2016;128(2):265–276.
   PubMed Web of Science ®Google Scholar
• Schmidt PJ, Toudjarska I, Sendamarai AK, et al. An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe(-/-) mice and ameliorates anemia and iron overload in murine beta-thalassemia intermedia. Blood. 2013;121(7):1200–1208.
   PubMed Web of Science ®Google Scholar
• Richard F, van Lier JJ, Roubert B, et al. Oral ferroportin inhibitor VIT-2763: first-in-human, Phase 1 study in healthy volunteers. Am J Hematol. 2020;95(1):68–77.
   PubMed Web of Science ®Google Scholar
• Porter J, Kowdley K, Taher A, et al. Effect of Ljpc-401 (synthetic human hepcidin) on iron parameters in healthy adults. Blood. 2018;132(Suppl 1):2336.
   Google Scholar
• Lal A, Piga A, Viprakasit V, et al. A phase 1, open-label study to determine the safety, tolerability, and pharmacokinetics of escalating doses of LJPC-401 (synthetic human hepcidin) in patients with iron overload. HemaSphere. 2018;2(Suppl 1):396–397.
   Google Scholar
• Nicholls A, Lickliter J, Tozzi L, et al. Hepcidin mimetic PTG-300 induces dose-related and sustained reductions in serum iron and transferrin saturation in healthy subjects. HemaSphere. 2018;2(Suppl 1):397.
   Google Scholar
• McCaleb M, Lickliter J, Dibble A, et al. Transmembrane protease, serine 6 (TMPRSS6) antisense oligonucleotide (IONIS-TMPRSS6-LRX) reduces plasma iron levels of healthy volunteers in a phase 1 clinical study. Blood. 2018;132(Suppl 1):3634.
   Google Scholar
• Porter J. Beyond transfusion therapy: new therapies in thalassemia including drugs, alternate donor transplant, and gene therapy. Hematology Am Soc Hematol Educ Program. 2018;2018(1):361–370.
   PubMedGoogle Scholar
• Nai A, Pagani A, Mandelli G, et al. Deletion of TMPRSS6 attenuates the phenotype in a mouse model of beta-thalassemia. Blood. 2012;119(21):5021–5029.
   PubMed Web of Science ®Google Scholar
• Casu C, Aghajan M, Oikonomidou PR, et al. Combination of Tmprss6- ASO and the iron chelator deferiprone improves erythropoiesis and reduces iron overload in a mouse model of beta-thalassemia intermedia. Haematologica. 2016;101(1):e8–e11.
   PubMed Web of Science ®Google Scholar
• Manolova V, Nyffenegger N, Flace A, et al. Oral ferroportin inhibitor ameliorates ineffective erythropoiesis in a model of beta-thalassemia. J Clin Invest. 2020;130(1):491–506.
   Web of Science ®Google Scholar
• Nyffenegger N, Flace A, Canclini C, et al. Ferroportin inhibitors prevent iron loading in a mouse model of hereditary hemochromatosis. Am J Hematol. 2017;92(8): E471.
   Web of Science ®Google Scholar
• Nyffenegger N, Flace A, Doucerain C, et al. The oral ferroportin inhibitor VIT-2763 improves erythropoiesis without interfering with iron chelation therapy in a mouse model of beta-thalassemia. Int J Mol Sci. 2021;22(2):873.
   Web of Science ®Google Scholar
• Nyffenegger N, Flace A, Varol A, et al. Oral ferroportin inhibitor prevents iron overload in the HFE C282Y mouse model of hereditary hemochromatosis. Oral presentation at the European Iron Club Annual Meeting 2018, Zurich, Switzerland. [cited 2021 Apr 27]. Available from: https://ethz.ch/content/dam/ethz/special-interest/conference-websites-dam/european-iron-club-2018-dam/documents/EIC2018_Abstracts_Book.pdf
   Google Scholar
• Taher AT, Weatherall DJ, Cappellini MD. Thalassaemia. Lancet. 2018;391(10116):155–167.
   Google Scholar
• Taher AT, Porter JB, Viprakasit V, et al. Deferasirox effectively reduces iron overload in non-transfusion-dependent thalassemia (NTDT) patients: 1-year extension results from the THALASSA study. Ann Hematol. 2013;92(11):1485–1493.
   PubMed Web of Science ®Google Scholar
• Schmidt PJ, Racie T, Westerman M, et al. Combination therapy with a Tmprss6 RNAi-therapeutic and the oral iron chelator deferiprone additively diminishes secondary iron overload in a mouse model of β-thalassemia intermedia. Am J Hematol. 2015;90(4):310–313.
   PubMed Web of Science ®Google Scholar
• Sinniah R, Doggart JR, Neill DW. Diurnal variations of the serum iron in normal subjects and in patients with haemochromatosis. Br J Haematol. 1969;17(4):351–358.
   PubMed Web of Science ®Google Scholar
• Guillygomarc’h A, Christian J, Romain M, et al. Circadian variations of transferrin saturation levels in iron-overloaded patients: implications for the screening of C282Y-linked haemochromatosis. Br J Haematol. 2003;120(2):359–363.
   PubMed Web of Science ®Google Scholar
• Ganz T, Olbina G, Girelli D, et al. Immunoassay for human serum hepcidin. Blood. 2008;112(10):4292–4297.
   PubMed Web of Science ®Google Scholar
• Garbowski MW, Ma Y, Fucharoen S, et al. Clinical and methodological factors affecting non-transferrin-bound iron values using a novel fluorescent bead assay. Transl Res. 2016;177:19–30.e5.
   PubMed Web of Science ®Google Scholar
• Erslev AJ, McKenna PJ. Effect of splenectomy on red cell production. Ann Intern Med. 1967;67(5):990–997.
   PubMed Web of Science ®Google Scholar
• Algiraigri AH, Wright NAM, Paolucci EO, et al. Hydroxyurea for nontransfusion-dependent beta-thalassemia: a systematic review and meta-analysis. Hematol Oncol Stem Cell Ther. 2017;10(3):116–125.
   PubMedGoogle Scholar
• Ansari SH, Lassi ZS, Khowaja SM, et al. Hydroxyurea (hydroxycarbamide) for transfusion-dependent beta-thalassaemia. Cochrane Database Syst Rev. 2019;3(3):CD012064.
   PubMedGoogle Scholar
• Loukopoulos D, Voskaridou E, Stamoulakatou A, et al. Hydroxyurea therapy in thalassemia. Ann N Y Acad Sci. 1998;850:120–128.
   PubMed Web of Science ®Google Scholar
• Koren A, Levin C, Dgany O, et al. Response to hydroxyurea therapy in beta-thalassemia. Am J Hematol. 2008;83(5):366–370.
   PubMed Web of Science ®Google Scholar
• Dixit A, Chatterjee TC, Mishra P, et al. Hydroxyurea in thalassemia intermedia–a promising therapy. Ann Hematol. 2005;84(7):441–446.
   PubMed Web of Science ®Google Scholar
• Fucharoen S, Siritanaratkul N, Winichagoon P, et al. Hydroxyurea increases hemoglobin F levels and improves the effectiveness of erythropoiesis in beta-thalassemia/hemoglobin E disease. Blood. 1996;87(3):887–892.
   PubMed Web of Science ®Google Scholar
• Taher AT, Musallam KM, Karimi M, et al. Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study. Blood. 2010;115(10):1886–1892.
   PubMed Web of Science ®Google Scholar
• Bradai M, Pissard S, Abad MT, et al. Decreased transfusion needs associated with hydroxyurea therapy in Algerian patients with thalassemia major or intermedia. Transfusion. 2007;47(10):1830–1836.
   PubMed Web of Science ®Google Scholar
• Karimi M, Darzi H, Yavarian M. Hematologic and clinical responses of thalassemia intermedia patients to hydroxyurea during 6 years of therapy in Iran. J Pediatr Hematol Oncol. 2005;27(7):380–385.
   PubMed Web of Science ®Google Scholar
• Algiraigri AH, Wright NAM, Paolucci EO, et al. Hydroxyurea for lifelong transfusion-dependent beta-thalassemia: a meta-analysis. Pediatr Hematol Oncol. 2017;34(8):435–448.
   PubMed Web of Science ®Google Scholar
• Markham A. Luspatercept: first approval. Drugs. 2020;80(1):85–90.
   PubMed Web of Science ®Google Scholar
• European Medicines Agency. Reblozyl (luspatercept) summary of product characteristics (2020) [updated 11 September 2020]. [cited 2021 Apr 27]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/reblozyl#product-information-section
   Google Scholar