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

Figures & data

Table 1. Advantages and disadvantages of current and potential therapies for NTDT

Therapy	Advantages	Disadvantages	References
Blood transfusion	Effective in supplying normal erythrocytes and reducing ineffective erythropoiesis Evidence of a reduction in some morbidities in observational studies	Risk of infection, alloimmunization, and iron overload Significant financial burden, especially for developing countries	[22,25]
Iron chelation	Effective reduction in systemic and hepatic iron burden Available as an oral formulation	Adverse effects Requires appropriate regimen and dose tailoring Parenteral form may be required High cost	[25,27]
Splenectomy	May reduce the need for transfusions by improving hemoglobin levels	Risk of infection and other major complications Not recommended for patients below 5 years of age	[25]
Hydroxyurea	Data suggest potential efficacy (attractive alternative to avoid the long- and short-term complications of blood transfusions) Efficacy can be assessed relatively quickly (few months) Well tolerated; mild and transient AEs only, no major long-term AEs Available and affordable (especially in developing countries) Available as an oral formulation	Efficacy not confirmed in randomized trials Efficacy may decrease with long-term use Adverse effects Not approved for NTDT	[22–25]
Luspatercept	Improvement in hemoglobin and blood transfusion burden Acceptable safety profile	Molecular target(s) not precisely identified No clinical pediatric data available Risk of thrombosis Safety concerns about pediatric use based on data from preclinical studies Not yet approved for NTDT High cost	[26,28]

AE, adverse event; NTDT, non-transfusion-dependent thalassemia.

Figure 1. Molecular pathways of iron-restricted erythropoiesis through translational control at eIF2#x3B1;P, TfR2/Scrib and mTORC1 signaling. Reproduced from Zhang S, et al. Blood 2018;131(4):450–461 [39], with permission from the American Society of Hematology. #xA9; 2018 by the American Society of Hematology. Left: Steady-state erythropoiesis in the bone marrow under iron sufficiency. In iron and thus heme abundance, HRI homodimer is inactive because of full occupancies of heme onto the 4 HRI heme-binding domains and so is unable to phosphorylate eIF2#x3B1;, thus permitting global protein synthesis, mainly globin proteins in erythroid cells. Sufficient hemoglobin production maintains oxygen-delivering capacity in blood without hypoxia. Middle: Activation of HRI-ISR under iron deficiency mitigates ineffective erythropoiesis. Under iron/heme deficiency, HRI in bone marrow erythroid precursors is activated by the dissociation of heme. HRI then induces ISR, phosphorylating eIF2#x3B1;, which inhibits globin protein synthesis and results in a decrease of hemoglobin content and consequently induction of tissue hypoxia stress. In addition, eIF2#x3B1;P selectively enhances the translation of ATF4 mRNA to alleviate ROS levels. HRI-ISR also inhibits mTORC1 signaling to mitigate ineffective erythropoiesis in the spleen. Right: Elevated mTORC1 signaling and development of ineffective erythropoiesis in mutant mice defective in HRI-ISR signaling in iron deficiency. Hypoxia induced by iron deficiency stimulates Epo production in the kidney and increases Epo in blood circulation. In the spleen, binding of Epo to its receptors in erythroid precursors induces AKT/mTORC1 signaling, thus phosphorylating 4EBP1 and S6K/S6 to increase protein synthesis, promote proliferation, and inhibit erythroid differentiation, which are the characteristics of ineffective erythropoiesis. HRI-ISR serves as feedback to inhibit mTORC1 signaling activity, inhibiting the development of ineffective erythropoiesis in iron deficiency. 4EBP1, eukaryotic translation initiation factor 4E binding protein 1; AKT, protein kinase B; ATF4, activating transcription factor 4; eIF2#x3B1;, eukaryotic translation initiation factor 2 subunit 1; Epo(R), erythropoietin (receptor); Fe, iron; HRI-ISR, heme-regulated eIF2#x3B1; kinase-integrated stress response; mRNA, messenger ribonucleic acid; mTORC1, mammalian target of rapamycin complex 1; P, phosphorylated; ROS, reactive oxygen species; Scrib, scribble; S6(K), ribosomal protein S6 (kinase); TfR2, transferrin receptor 2.

Table 2. Summary of drugs in clinical development targeting the hepcidin–ferroportin axis

Therapy	Target/MOA	Route of administration	Clinical development stage	Summary of clinical findings to date	References
LJPC-401	Hepcidin mimetic	Subcutaneous	Phase I studies completed; Phase II study in progress (NCT03381833; status unknown)	A Phase I study evaluated single ascending and multiple doses of LJPC-401 (4–20 mg administered subcutaneously) in healthy volunteers. LJPC-401 was well tolerated and dose-related decreases in serum iron levels were observed after single doses of 4, 10 and 20 mg. Decreases in mean serum iron were also observed after each dose of LJPC-401 in the multiple-dose cohort. Dose-related increases in unsaturated iron binding capacity along with dose-related decreases in transferrin saturation were observed. A Phase I study evaluated single escalating doses of LJPC-401 (1–30 mg administered subcutaneously) in patients with iron overload. LJPC-401 was well tolerated at doses between 1 and 30 mg. Reductions in iron levels were observed and appeared to be dose related between 1 and 20 mg. Serum iron reductions were sustained up to Day 8 in most patients.	[43,44]
PTG-300	Hepcidin mimetic	Subcutaneous	Phase I study completed; Phase II study completed (NCT03802201; findings not reported)	A Phase I study evaluated single or repeat doses of PTG-300 (1–80 mg administered subcutaneously) in healthy volunteers. PTG-300 was generally well tolerated and induced a dose-related reduction in serum iron levels with an associated reduction in transferrin saturation. No changes in hematologic indices were observed following a single dose. A small reduction in mean hemoglobin and a reticulocytosis was observed at Day 20 following repeat dosing.	[45]
IONIS TMPRSS6-LRX	Tmprss6	Subcutaneous	Phase I study complete; Phase IIa study ongoing (NCT04059406)	A Phase I study evaluated multiple doses of IONIS TMPRSS6-LRX in healthy volunteers (20–60 mg administered subcutaneously at Weeks 1, 4, 6 and 8) in healthy volunteers. Treatment-emergent adverse events were generally mild and a reduction in serum iron and transferring saturation was observed at Week 10 following 20 and 40 mg doses.	[46]
Vamifeport (VIT-2763)	Ferroportin inhibitor	Oral	Phase I study complete (healthy volunteers); Phase IIa ongoing (NCT04364269; NTDT); Phase IIb study planned (TDT)	A Phase I study evaluated single- (5–240 mg) and multiple- (60 or 120 mg BID) ascending oral doses of vamifeport (VIT-2763) in healthy volunteers. Vamifeport was well tolerated. A rapid, temporary decrease in serum iron levels was observed with single doses ≥60 mg and all multiple doses; multiple doses of vamifeport also temporarily decreased the mean calculated transferrin saturation, maximally at about 4–8 h after the morning dose.	[42]

BID, twice daily; MOA, mechanism of action; NTDT, non-transfusion-dependent thalassemia; TDT, transfusion-dependent thalassemia.

Figure 2. Chemical structure and mechanism of action of vamifeport (VIT-2763)

Table 3. Key findings from preclinical studies of vamifeport (VIT-2763)

Model	Key findings	References
In vitroJ774 murine macrophage cell line	IC50 for ferroportin binding comparable between vamifeport and hepcidin Vamifeport and hepcidin use similar pathways of ferroportin internalization and degradation	[50]
In vitroT47D human breast cancer cell line	Dose-dependent inhibition of cellular iron efflux Vamifeport slightly more potent than hepcidin	[50]
In vivoMurine model of acute hypoferremia	Dose-dependent decrease in serum iron (comparable with hepcidin)	[50]
In vivoAnemic rats	Dose-dependent attenuation of serum iron levels 3 h after iron bolus	[50]
In vivoMurine model of hereditary hemochromatosis	Vamifeport corrected serum iron to the levels of wild-type mice Prevented iron accumulation in the liver	[51,53]
In vivoMurine model of NTDT	Anemia improved Dose-dependent reduction in toxic α-globin aggregates in RBCs, thereby improvingimbalance of α- and β-globin Extended the lifespan of RBCs Improved RBC function Prevention of iron loading Ameliorated ineffective erythropoiesis and splenomegaly	[50]

IC₅₀, half maximal inhibitory concentration; NTDT, non-transfusion-dependent thalassemia; RBC, red blood cell.

Figure 3. Hepcidin–ferroportin axis in non-transfusion-dependent thalassemia (A) and how it is affected by vamifeport (VIT-2763) (B). A. Iron homeostasis is mediated primarily via the hepcidin–ferroportin axis. Hepcidin regulates iron levels by targeting the iron transporter ferroportin for degradation. Erythropoiesis exerts a strong control over iron homeostasis, so that when erythropoiesis is impaired, iron absorption is increased, irrespective of iron stores. In patients with NTDT, anemia and hypoxia arising from ineffective erythropoiesis stimulates erythropoiesis and suppresses hepcidin. The reduced level of hepcidin causes an increase in the absorption of dietary iron and release of recycled iron from macrophages, ultimately resulting in saturation of the iron-binding capacity of transferrin and consequently generation of non-transferrin-bound iron that results in organ iron overload and further drives ineffective erythropoiesis, splenomegaly, and anemia. B. Vamifeport, a novel oral ferroportin inhibitor, acts like hepcidin to target ferroportin for degradation, thereby blocking iron export into plasma. By limiting plasma iron levels, vamifeport acts to prevent organ iron overloading, reduce spleen size, and improve erythropoiesis and anemia. FPN, ferroportin; NTDT, non-transfusion-dependent thalassemia

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

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

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

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

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

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

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

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, 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