Sotatercept increases the red blood cell production and reduces the transfusion burden in myelodysplastic syndromes

Anemia is the most challenging complication of myelodysplastic syndromes (MDS), one of the most common blood cancers and determining optimal treatment remains an unmet need. Data from a phase II study show that sotatercept, an injectable activin type IIa receptor fusion protein, shows promise as an agent that may reduce the burden of regular blood transfusions or eliminate this need among anemic, lower-risk MDS patients.

Anemia, a hallmark of MDS, is challenging to treat, particularly after failure of erythropoiesis-stimulating agents (ESAs). Sotatercept is a novel, first in class activin type IIa receptor fusion protein that acts on late-stage erythropoiesis to increase mature erythrocyte release into the circulation via a mechanism distinct from erythropoietin. In addition, it stimulates erythropoiesis and increases hemoglobin levels in healthy volunteers, supporting its clinical development for treatment of anemia in patients with lower-risk MDS.

In the Phase II clinical trial, presented at ASH 2014, being the first study to evaluate sotatercept in MDS patients and seeking to determine the optimal dose of the drug, 54 largely transfusion-dependent patients, who had not responded to treatment with erythrocyte-stimulating agents and other available MDS treatments, were enrolled. The treatment was administered once every three weeks for four different doses (0.1, 0.3, 0.5, and 1.0 mg/kg), and was continued among responders. The primary objective of this phase 2, open-label, dose-finding study was to determine a safe, tolerable, and effective dose of sotatercept resulting in erythroid hematological improvement in patients with anemia and IPSS-defined Low or Intermediate-1-risk MDS or with non-proliferative, chronic myelomonocytic leukemia (CMML) (white blood cells < 13,000/µL). A secondary objective included the rate of RBC-transfusion independence (RBC-TI) ≥ 8 weeks. Eligible patients had anemia (≥ 2 RBC units transfusion requirement in the 12 weeks prior to enrollment for Hb ≤ 9.0 g/dL) with no response, loss of response, or low chance of response to ESAs.

After treatment with the experimental drug, 45% (24 of 53) of all evaluable patients experienced either a reduced need for transfusions or an increase in their hemoglobin levels. In addition, 19 of the 45 patients, who were in the highly transfusion-dependent group prior to receiving sotatercept therapy, demonstrated a reduced need for transfusions, including five persons (11.%) who became transfusion-independent (defined as red blood cell transfusion independence [RBC-TI] during 56 days or more). Five of the nine (56%) patients in the less-transfusion-dependent group prior to sotatercept therapy achieved both transfusion independence (RBC-TI ≥56 days) and increased hemoglobin levels (mean Hb increase ≥ 1.5 g/dL sustained for ≥ 8 weeks).

The treatment was generally well tolerated with 37% of patients reported one or more treatment-related adverse events. Fatigue (11%), headache (9.3%), decreased appetite (7.4%), and nausea (7.4%) were the most commonly observed adverse events. Of the 35 patients (65%) who discontinued treatment, 28 discontinued due to a lack of therapeutic effect and 4 due to adverse events. Of those adverse events leading to discontinuation, 3 were suspected to be treatment-related: 1 patient with grade 2 hemolytic anemia, 1 patient with grade 3 hypertension and 1 patient with grade 2 muscular weakness in the sotatercept 0.3, 0.5, and 1.0 mg/kg dose groups, respectively.

In summary, sotatercept was well tolerated in lower-risk MDS patients at the dose levels tested, with promising evidence of clinical activity in this cohort of ESAs-refractory, anemic, lower-risk MDS patients. As such, this drug shows promise as an agent that may reduce the burden of regular blood transfusions or eliminate this need among anemic, lower-risk MDS patients. However larger randomized studies are necessary to confirm these results and evaluate whether a higher dose may provide greater benefit without additional toxicity.


Komrokji R, Garcia-Manero G, Ades L, et al. An Open-Label, Phase 2, Dose-Finding Study of Sotatercept (ACE-011) in Patients with Low or Intermediate-1 (Int-1)-Risk Myelodysplastic Syndromes (MDS) or Non-Proliferative Chronic Myelomonocytic Leukemia (CMML) and Anemia Requiring Transfusion. Presented at ASH 2014; Abstract #3251.

Speaker Rami Komrokji


Rami S. Komrokji, MD, PhD,
Department of Malignant Hematology, Moffitt Cancer Center & Research Institute, Tampa, FL, USA


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