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

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 β 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 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 ≤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. 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 β-thalassemia and ≥0.5 mg/kg for those with transfusion-dependent β-thalassemia. 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 patients with non-transfusion-dependent β-thalassemia 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 requirements. This trial was registered at ClinicalTrials.gov with the number NCT01571635.

Figure 1.

Response to sotatercept treatment in patients with non-transfusion-dependent β-thalassemia. (A) Percentage of sotatercept-treated non-transfusion-dependent β-thalassemia patients achieving mean hemoglobin level increases from baseline of ≥1.0 g/dL and ≥1.5 g/dL sustained for ≥12 weeks by assigned dose group. (B) Average maximum increase in hemoglobin levels within 12 weeks versus baseline levels in responders versus non-responders by dose group. Responders were those patients achieving a ≥1.0 g/dL increase in hemoglobin levels sustained for ≥12 weeks. Error bars show the standard deviation of the mean. Hb: hemoglobin.

Figure 2.

Mean change in hemoglobin levels from baseline up to day 400 in patients with non-transfusion-dependent β-thalassemia treated with different doses of sotatercept. Data are presented by assigned dose level, prior to intrapatient dose escalation. Hb: hemoglobin.

Figure 3.

Percentages of transfusion-dependent β-thalassemia patients treated with different doses of sotatercept who achieved a reduction in transfusion burden of ≥20%, ≥33%, and ≥50% sustained for ≥24 weeks.