P1510: VAMIFEPORT PREVENTED THE FORMATION OF NON-TRANSFERRIN-BOUND IRON IN A MOUSE MODEL OF ΒETA-THALASSEMIA WITH BLOOD TRANSFUSIONS

Background: β-thalassemia is an inherited anemia caused by mutations in the β-globin gene of hemoglobin (Hb) resulting in ineffective erythropoiesis, formation of red blood cells (RBCs) with short lifespan and organ iron overload. Patients with the most severe form-transfusion-dependent β-thalassemia (TDT), receive regular blood transfusions (BTs) leading to secondary iron overload requiring iron chelation therapy. Moreover, TDT patients often show increase in non-transferrin bound iron (NTBI), released by macrophages recycling damaged RBCs via a ferroportin-dependent mechanism leading to oxidative stress and vascular damage. Previously, we showed that limiting iron availability with the oral ferroportin inhibitor vamifeport (also known as VIT-2763) ameliorated anemia, ineffective erythropoiesis, and the dysregulated iron homeostasis in the Hbb^th3/+ murine model of β-thalassemia under non-transfused conditions¹.

Aims: The aim of the study was to determine the effect of the oral ferroportin inhibitor vamifeport on plasma NTBI levels and ineffective erythropoiesis following a single or repeated BTs in the Hbb^th3/+ mouse model of b-thalassemia.

Methods: Hbb^th3/+ mice were transfused with 200 µl of blood collected from wild-type mice ubiquitously expressing GFP (UBC-GFP mice). Vamifeport (120 mg/kg) was administered in Hbb^th3/+ mice by oral gavage 30 min before a single BT. Repeated BTs were performed in one-week interval for four times. Transfused Hbb^th3/+ mice were treated with 120 mg/kg vamifeport once daily for 4 weeks. Hematological parameters were analyzed using an automated analyzer, erythropoiesis by flow cytometry, and α-globin aggregates by TAU gel electrophoresis.

Results: A single BT significantly increased plasma NTBI levels in Hbb^th3/+ mice as compared to non-transfused mice. NTBI levels were elevated for about 3h and returned to the baseline at 6h post transfusion. Vamifeport significantly reduced plasma NTBI levels in transfused Hbb^th3/+ mice to the levels of non-transfused controls.

Vamifeport as a single therapy or in combination with repeated BTs increased Hb, RBC counts, hematocrit and decreased spleen size, reticulocyte counts, plasma erythropoietin and α-globin aggregates in RBCs of Hbb^th3/+ mice. Both, vamifeport and BTs administered as single therapy improved the ineffective erythropoiesis in spleens of Hbb^th3/+ mice. Importantly, the combination therapy of vamifeport and BTs resulted in lower proportion of immature erythrocytes and higher percentage of mature erythrocytes as compared to either treatment alone, suggesting additive effects of vamifeport and repeated BTs. As expected, repeated BTs increased the transferrin saturation (TSAT), whereas vamifeport decreased TSAT levels either in transfused or non-transfused Hbb^th3/+ mice, reflecting the ability of vamifeport to inhibit ferroportin-mediated iron efflux into the plasma.

Summary/Conclusion: Vamifeport prevented formation of BT-mediated NTBI in the plasma of Hbb^th3/+ mice, suggesting iron restriction by ferroportin inhibition prevents formation of potentially harmful reactive plasma iron species. Vamifeport ameliorated anemia, ineffective erythropoiesis, and the dysregulated iron homeostasis in Hbb^th3/+ mice either as a single therapy or in combination with repeated BTs.