Combination of a TGF-β Ligand Trap (RAP-GRL) and TMPRSS6-ASO Is Superior for Correcting β-Thalassemia

New partners for Luspatercept in β‐thalassemia

“…1 In this issue of American Journal of Hematology, two back-to-back studies propose potentially novel therapeutic partners to combine with luspatercept for the improvement of anemia in β-thalassemia. 2,3 The work by Guerra and coauthors combines luspatercept with drugs targeting iron overload, aiming at assessing whether reduced iron availability in β-thalassemia further supports the erythroid maturation effect of the drug. 2 Iron overload is a hallmark of β-thalassemia, and iron restrictive approaches, including hepcidin mimetics and inducers, and ferroportin inhibitors, have been proven beneficial for the reduction of anemia in preclinical studies.…”

“…2,3 The work by Guerra and coauthors combines luspatercept with drugs targeting iron overload, aiming at assessing whether reduced iron availability in β-thalassemia further supports the erythroid maturation effect of the drug. 2 Iron overload is a hallmark of β-thalassemia, and iron restrictive approaches, including hepcidin mimetics and inducers, and ferroportin inhibitors, have been proven beneficial for the reduction of anemia in preclinical studies. 4,5 Clinical trials testing several novel iron restriction compounds in β-thalassemia patients have been terminated due to failure in meeting the primary endpoints, halting further clinical development for the disease.…”

“…4,5 Clinical trials testing several novel iron restriction compounds in β-thalassemia patients have been terminated due to failure in meeting the primary endpoints, halting further clinical development for the disease. 2,6 While hemoglobin increase was, in most of the cases, the primary endpoint and, indeed, the desired goal of such trials, this might have not been the right endpoint of these studies at this stage, until finding suitable dosing. These molecules are, in fact, primarily iron restriction compounds and, according to the degree of iron restriction achieved, hemoglobin values might be improved in light of reduced iron-toxicity on erythroid precursors, or decreased in case of continuously limited access of the erythron to iron, resulting in iron-restricted erythropoiesis.…”

“…With the aim of testing whether limited iron availability was of benefit if coadministered with luspatercept, researchers at Children's Hospital of Philadelphia led by Stefano Rivella used an agent analogous to the murine orthologue of luspatercept, RAP-536, combined with the iron restriction agent TMPRSS6-ASO, which elevates hepcidin levels by suppressing its negative regulator TMPRSS6, to treat β-thalassemia-intermedia mice. 2 The study by Tanzi and coauthors tested the effect of RAP-536 treatment associated with erythroid deletion of the transferrin receptor 2 (TfR2) in β-thalassemia animals, as an approach to combine increased erythroid maturation with increased EPO sensitivity. 3 TfR2 has been described as a negative regulator of erythropoiesis, which modulates erythropoietin (EPO) sensitivity and balances RBC production to the available iron.…”

“…3 In both studies, when tested in β-thalassemia animals, the combined approaches proved to be superior in the correction of anemia and improvement of hemoglobin and RBC parameters, compared with the single treatments. 2,3 Moreover, while RAP-536 alone improved RBC production and showed limited effect on splenomegaly and iron parameters, its combination with the TMPRSS6-ASO or erythroid TfR2 deletion not only superiorly improved hemoglobin and RBC count but also corrected splenomegaly and iron overload, triggering a more effective erythropoiesis and an ameliorated iron phenotype (Figure 1). 2,3 These studies also help clarifying luspatercept mode of action, which appears to some extent more complex than previously envisaged.…”