Sotatercept, a novel transforming growth factor β ligand trap, improves anemia in β-thalassemia: a phase II, open-label, dose-finding study

beta-thalassemia, a hereditary blood disorder caused by defective synthesis of hemoglobin beta 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 13 superfamily, correcting ineffective erythropoiesis. In this phase II, open-label, dose-finding study, 16 patients with transfusion-dependent (3-thalassemia and 30 patients with non-transfusion-dependent (3-thalassemia were enrolled at seven centers in four countries between November 2012 and November 2014. Patients were treated with sotatercept at doses of 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 522 months. Response was assessed as a.20`),/,, reduction in transfusion burden sustained for 24 weeks in transfusion-dependent (3-thalassemia patients, and an increase in hemoglobin level of 1..0 g/dL sustained for 12 weeks in non-transfusion dependent (3-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. Thirteen percent of patients reported serious but manageable adverse events. The active dose of sotatercept was 0.3 mg/kg for patients with non-transfusion-dependent (3-thalassemia and 0.5 mg/kg for those with transfusion-dependent ji-thalassemia. Of 30 non-transfusion-dependent 13-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 a1.5 g/dL, sustained for 12 weeks. Four (100%) transfusion-dependent 13-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 13-thalassemia. Most patients with non-transfusion-dependent (3-thalassemia treated with higher doses achieved sustained increases in hemoglobin level. Transfusion-dependent 13-thalassemia patients treated with higher doses of sotatercept achieved notable reductions in transfusion requirements. This trial was registered at ClinicalTrials.gov with the number NCT01571635.