β-thalassemia, a hereditary blood disorder caused by defective synthesis of hemoglobin β globin chains, leads to ineffective erythropoiesis and chronic anemia that may require blood transfusions. Sotatercept (ACE-011) acts as a ligand trap to inhibit negative regulators of late-stage erythropoiesis in the transforming growth factor beta superfamily, correcting ineffective erythropoiesis. In this phase II, open-label, dose-finding study, 16 patients with transfusion-dependent β-thalassemia and 30 patients with non-transfusion-dependent β thalassemia were enrolled at 7 centers in 4 countries from November 2012 to November 2014. Patients were treated with sotatercept at 0.1, 0.3, 0.5, 0.75, or 1.0 mg/kg to determine a safe and effective dose. Doses were administered by subcutaneous injection every 3 weeks. Patients were treated for ≤22 months. Response was assessed as a ≥20% reduction in transfusion burden sustained for 24 weeks in transfusion-dependent β-thalassemia patients, and an increase in hemoglobin level of ≥1.0 g/dL sustained for 12 weeks in non-transfusion-dependent β-thalassemia patients. Sotatercept was well tolerated. After a median treatment duration of 14.4 months (range 0.6-35.9), no severe life-threatening adverse events were observed; 13% of patients reported serious but manageable adverse events. The active dose of sotatercept was ≥0.3 mg/kg for non-transfusion-dependent β-thalassemia and ≥0.5 mg/kg for transfusion-dependent β-thalassemia patients. Of 30 non-transfusion-dependent β-thalassemia patients treated with ≥0.1 mg/kg sotatercept, 18 (60%) achieved a mean hemoglobin increase ≥1.0 g/dL, and 11 (37%) an increase ≥1.5 g/dL, sustained for ≥12 weeks. Four (100%) transfusion-dependent β-thalassemia patients treated with 1.0 mg/kg sotatercept achieved a transfusion-burden reduction of ≥20%. Sotatercept was effective and well tolerated in patients with β-thalassemia. Most non-transfusion-dependent β-thalassemia patients treated with higher doses achieved sustained increases in hemoglobin level. Transfusion-dependent β-thalassemia patients treated with higher doses of sotatercept achieved notable reductions in transfusion requirement. The registration number at ClinicalTrials.gov was NCT01571635.
Sotatercept, a novel transforming growth factor beta ligand trap, improves anemia in beta-thalassemia: a phase 2, open-label, dose-finding study / M.D. Cappellini, J. Porter, R. Origa, G.L. Forni, E. Voskaridou, F. Galactéros, A.T. Taher, J. Arlet, J. Ribeil, M. Garbowski, G. Graziadei, C. Brouzes, M. Semeraro, A. Laadem, D. Miteva, J. Zou, V. Sung, T. Zinger, K.M. Attie, O. Hermine. - In: HAEMATOLOGICA. - ISSN 1592-8721. - 104:3(2019 Mar), pp. 477-484. [10.3324/haematol.2018.198887]
Sotatercept, a novel transforming growth factor beta ligand trap, improves anemia in beta-thalassemia: a phase 2, open-label, dose-finding study
M.D. Cappellini
Primo
Conceptualization
;G. Graziadei;
2019
Abstract
β-thalassemia, a hereditary blood disorder caused by defective synthesis of hemoglobin β globin chains, leads to ineffective erythropoiesis and chronic anemia that may require blood transfusions. Sotatercept (ACE-011) acts as a ligand trap to inhibit negative regulators of late-stage erythropoiesis in the transforming growth factor beta superfamily, correcting ineffective erythropoiesis. In this phase II, open-label, dose-finding study, 16 patients with transfusion-dependent β-thalassemia and 30 patients with non-transfusion-dependent β thalassemia were enrolled at 7 centers in 4 countries from November 2012 to November 2014. Patients were treated with sotatercept at 0.1, 0.3, 0.5, 0.75, or 1.0 mg/kg to determine a safe and effective dose. Doses were administered by subcutaneous injection every 3 weeks. Patients were treated for ≤22 months. Response was assessed as a ≥20% reduction in transfusion burden sustained for 24 weeks in transfusion-dependent β-thalassemia patients, and an increase in hemoglobin level of ≥1.0 g/dL sustained for 12 weeks in non-transfusion-dependent β-thalassemia patients. Sotatercept was well tolerated. After a median treatment duration of 14.4 months (range 0.6-35.9), no severe life-threatening adverse events were observed; 13% of patients reported serious but manageable adverse events. The active dose of sotatercept was ≥0.3 mg/kg for non-transfusion-dependent β-thalassemia and ≥0.5 mg/kg for transfusion-dependent β-thalassemia patients. Of 30 non-transfusion-dependent β-thalassemia patients treated with ≥0.1 mg/kg sotatercept, 18 (60%) achieved a mean hemoglobin increase ≥1.0 g/dL, and 11 (37%) an increase ≥1.5 g/dL, sustained for ≥12 weeks. Four (100%) transfusion-dependent β-thalassemia patients treated with 1.0 mg/kg sotatercept achieved a transfusion-burden reduction of ≥20%. Sotatercept was effective and well tolerated in patients with β-thalassemia. Most non-transfusion-dependent β-thalassemia patients treated with higher doses achieved sustained increases in hemoglobin level. Transfusion-dependent β-thalassemia patients treated with higher doses of sotatercept achieved notable reductions in transfusion requirement. The registration number at ClinicalTrials.gov was NCT01571635.File | Dimensione | Formato | |
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