FIRST-IN-CLASS ORAL FERROPORTIN INHIBITOR: MODE OF ACTION AND EFFICACY IN A MOUSE MODEL OF BETA-THALASSEMIA INTERMEDIA
Author(s): ,
Vania Manolova
Affiliations:
CPRD,Vifor (International) Ltd.,St. Gallen,Switzerland
,
Naja Nyffenegger
Affiliations:
CPRD,Vifor (International) Ltd.,St. Gallen,Switzerland
,
Anna Flace
Affiliations:
CPRD,Vifor (International) Ltd.,St. Gallen,Switzerland
,
Patrick Altermatt
Affiliations:
CPRD,Vifor (International) Ltd.,St. Gallen,Switzerland
,
Cédric Doucerain
Affiliations:
CPRD,Vifor (International) Ltd.,St. Gallen,Switzerland
,
Hanna Sundström
Affiliations:
CPRD,Vifor (International) Ltd.,St. Gallen,Switzerland
Franz Dürrenberger
Affiliations:
CPRD,Vifor (International) Ltd.,St. Gallen,Switzerland
EHA Library. Manolova V. 06/14/19; 267343; S142
Vania Manolova
Vania Manolova
Contributions
Abstract

Abstract: S142

Type: Oral Presentation

Presentation during EHA24: On Friday, June 14, 2019 from 12:00 - 12:15

Location: Hall E106

Background
β-thalassemia is a rare genetic disease in which ineffective erythropoiesis leads to anemia and iron overload. Currently, no efficacious oral medication with a good tolerability profile is available to patients with β-thalassemia. Correction of unbalanced iron absorption by induction of hepcidin synthesis or supplementation of hepcidin mimetics has been shown to normalize the dysregulated iron metabolism in β-thalassemia1. However, hepcidin modulation or replacement strategies all require parenteral drug administration. Restricting iron availability by VIT-2763, the first-in-class clinical stage oral ferroportin (Fpn) inhibitor, ameliorated anemia and the dysregulated iron homeostasis in the Hbbth3/+ mouse model of β-thalassemia intermedia2.

Aims
To address the mode of action and preclinical efficacy of VIT-2763 in a mouse model of β-thalassemia intermedia.

Methods
The potency of VIT-2763 and hepcidin in an iron efflux assay was investigated using T47D cells which express endogenous human Fpn. Fpn internalization was studied using MDCK cells constitutively expressing human Fpn with a fluorescent tag. The efficacy of VIT-2763 was studied in a mouse  model of β-thalassemia intermedia (Hbbth3/+).

Results
The potency and mode of action of VIT-2763 and hepcidin were compared in a set of cell-based assays. Strikingly, VIT-2763 (EC50 = 68±21 nM, mean±standard deviation, n=6) blocked iron efflux in cells with similar potency to hepcidin (EC50 = 123±46 nM mean±standard deviation, n=6), despite being structurally unrelated and more than five-fold smaller in molecular weight than hepcidin. However, VIT-2763 showed slower kinetics and triggered incomplete Fpn internalization and degradation compared to hepcidin. These data might indicate that VIT-2763 directly and efficiently blocks Fpn-mediated iron export in addition to Fpn internalization. A kinetic study in the Hbbth3/+ mouse model of β-thalassemia intermedia  revealed that VIT-2763 dosed for one week significantly reduced hemichromes in red blood cells (RBCs), increased RBC counts and hemoglobin, thereby indicating rapid improvement of erythropoiesis. Over time, VIT-2763 further ameliorated the RBC phenotype, such as decreased formation of reactive oxygen species, improved mitochondria clearance in mature RBCs and extended RBC life-span. Moreover, VIT-2763 corrected the elevated blood leukocyte counts in Hbbth3/+ mice, likely through effects on myeloid precursors in the spleen.  A proof-of concept clinical study with VIT-2763 as a novel, first in-class oral drug targeting Fpn for the treatment of β-thalassemia is currently in the planning phase.

Conclusion
Iron restriction by pharmacologically targeting the Fpn-hepcidin axis with the first in-class oral Fpn inhibitor VIT-2763 provides a novel therapeutic opportunity in β-thalassemia.

References: 1 Casu C, et al. Hepcidin agonists as therapeutic tools. Blood. 2018; 2 Manolova V, et al. Ferroportin inhibitors improve ineffective erythropoiesis and prevent iron loading in a b-thalassemia disease model. Abstract, BioIron Congress 2017.

Session topic: 27. Thalassemias

Keyword(s): Hepcidin, Inhibitor, Iron, Thalassemia

Abstract: S142

Type: Oral Presentation

Presentation during EHA24: On Friday, June 14, 2019 from 12:00 - 12:15

Location: Hall E106

Background
β-thalassemia is a rare genetic disease in which ineffective erythropoiesis leads to anemia and iron overload. Currently, no efficacious oral medication with a good tolerability profile is available to patients with β-thalassemia. Correction of unbalanced iron absorption by induction of hepcidin synthesis or supplementation of hepcidin mimetics has been shown to normalize the dysregulated iron metabolism in β-thalassemia1. However, hepcidin modulation or replacement strategies all require parenteral drug administration. Restricting iron availability by VIT-2763, the first-in-class clinical stage oral ferroportin (Fpn) inhibitor, ameliorated anemia and the dysregulated iron homeostasis in the Hbbth3/+ mouse model of β-thalassemia intermedia2.

Aims
To address the mode of action and preclinical efficacy of VIT-2763 in a mouse model of β-thalassemia intermedia.

Methods
The potency of VIT-2763 and hepcidin in an iron efflux assay was investigated using T47D cells which express endogenous human Fpn. Fpn internalization was studied using MDCK cells constitutively expressing human Fpn with a fluorescent tag. The efficacy of VIT-2763 was studied in a mouse  model of β-thalassemia intermedia (Hbbth3/+).

Results
The potency and mode of action of VIT-2763 and hepcidin were compared in a set of cell-based assays. Strikingly, VIT-2763 (EC50 = 68±21 nM, mean±standard deviation, n=6) blocked iron efflux in cells with similar potency to hepcidin (EC50 = 123±46 nM mean±standard deviation, n=6), despite being structurally unrelated and more than five-fold smaller in molecular weight than hepcidin. However, VIT-2763 showed slower kinetics and triggered incomplete Fpn internalization and degradation compared to hepcidin. These data might indicate that VIT-2763 directly and efficiently blocks Fpn-mediated iron export in addition to Fpn internalization. A kinetic study in the Hbbth3/+ mouse model of β-thalassemia intermedia  revealed that VIT-2763 dosed for one week significantly reduced hemichromes in red blood cells (RBCs), increased RBC counts and hemoglobin, thereby indicating rapid improvement of erythropoiesis. Over time, VIT-2763 further ameliorated the RBC phenotype, such as decreased formation of reactive oxygen species, improved mitochondria clearance in mature RBCs and extended RBC life-span. Moreover, VIT-2763 corrected the elevated blood leukocyte counts in Hbbth3/+ mice, likely through effects on myeloid precursors in the spleen.  A proof-of concept clinical study with VIT-2763 as a novel, first in-class oral drug targeting Fpn for the treatment of β-thalassemia is currently in the planning phase.

Conclusion
Iron restriction by pharmacologically targeting the Fpn-hepcidin axis with the first in-class oral Fpn inhibitor VIT-2763 provides a novel therapeutic opportunity in β-thalassemia.

References: 1 Casu C, et al. Hepcidin agonists as therapeutic tools. Blood. 2018; 2 Manolova V, et al. Ferroportin inhibitors improve ineffective erythropoiesis and prevent iron loading in a b-thalassemia disease model. Abstract, BioIron Congress 2017.

Session topic: 27. Thalassemias

Keyword(s): Hepcidin, Inhibitor, Iron, Thalassemia

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