Sotatercept with long-term extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: a phase 2, dose-ranging trial

Background Myelodysplastic syndromes are characterised by ineffective erythropoiesis leading to anaemia. Sotatercept (ACE-011) is a novel activin receptor type IIA fusion protein that acts as a ligand trap to neutralise negative regulators of late-stage erythropoiesis. The aim of the study was to establish a safe and effective dose of sotatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes. Methods This open-label, multicentre, dose-ranging, phase 2 trial took place at 11 treatment centres in the USA and France. Eligible patients were aged 18 years or older, had International Prognostic Scoring System-defined low-risk or intermediate-1-risk myelodysplastic syndromes, had anaemia requiring red blood cell (RBC) transfusions, and were ineligible for, or refractory to, erythropoiesis-stimulating agents (ESAs). Patients were not eligible if they had chromosome 5q deletion myelo-dysplastic syndromes without documented failure of lenalidomide. Patients were randomly assigned to receive either 0.1 or 0.3 mg/kg sotatercept subcutaneously, using a permuted-block method with stratification for serum erythropoietin concentration and transfusion burden. Patients were assigned to 0.5, 1.0, and 2.0 mg/kg groups in a non-randomised fashion. The primary efficacy endpoint was the proportion of patients who achieved haematological improvement-erythroid (HI-E), according to International Working Group 2006 criteria. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, number NCT01736683 and at EU Clinical Trials Register, number 2012-002601-22, and is ongoing. Findings Between Dec 5, 2012, and July 22, 2015, 74 patients were enrolled into the study (seven to receive 0.1 mg/kg sotatercept, six to 0.3 mg/kg, 21 to 0.5 mg/kg, 35 to 1.0 mg/kg, and five to 2.0 mg/kg). 36 (49%; 95% CI 38-60) of 74 patients achieved HI-E; 29 (47%; 95% CI 35-59) of 62 patients with a high transfusion burden achieved HI-E (RBC-transfusion reduction from baseline of 4 or more units for at least 56 days), and seven (58%; 95% CI 32-81) of 12 patients with a low transfusion burden achieved HI-E (haemoglobin increase of 1.5 g/dL or more sustained for at least 56 days in the absence of transfusions). The most commonly reported adverse events were fatigue in 19 (26%) of 74 patients and peripheral oedema in 18 (24%) of 74 patients. Grade 3-4 treatment-emergent adverse events (TEAEs) were reported in 25 (34%) of 74 patients; four (5%) patients had grade 3-4 TEAEs that were considered to be treatment related. The most common grade 3-4 TEAEs were lipase increase and anaemia, which each occurred in three (4%) of 74 patients. 17 (23%) of 74 patients had at least one serious TEAE, and one patient died from a treatment-emergent subdural haematoma due to a fall. Interpretation Sotatercept, a novel activin-receptor fusion protein, was well tolerated and effective for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes in whom previous ESA treatment had failed. Treatment with sotatercept could be beneficial for these patients who have few available treatment options.