Luspatercept (Modified Activin Receptor Type IIB Fusion Protein)

Proposed Mechanism of Action

Luspatercept (ACE-536) has a novel structure consisting of a soluble fusion protein with a modified extracellular domain of the activin receptor type IIB (ActRIIB) linked to the Fc domain of human immunoglobulin G1.1,2 In preclinical studies, luspatercept has been shown to act as a ligand trap for GDF11 and other members of the transforming growth factor (TGF)-β superfamily.1,2 Binding of these ligands of ActRIIB by luspatercept inhibits Smad2/3 signaling in vitro.2 This is hypothesized to underlie the effects of luspatercept on promoting late-stage red blood cell (RBC) precursor differentiation and maturation.2

Luspatercept MOA

Luspatercept by Disease State

Luspatercept in Beta-thalassemia

  • Phase 3 Beta-thalassemia

Rationale for Clinical Development

Beta-thalassemia is a type of congenital anemia characterized by little to no production of β-globin, a hemoglobin protein.3 Ineffective erythropoiesis and hemolysis are the major mechanisms that cause anemia in patients with beta-thalassemia.4 TGF-β superfamily members play a potential role in the regulation of erythropoiesis; therefore, their inhibition may be a potential strategy for the treatment of anemia associated with diseases like beta-thalassemia.2 In a preclinical study, a murine version of luspatercept (RAP-536) reduced or corrected anemia in a beta-thalassemia mouse model.3

Luspatercept in Myelodysplastic Syndromes

  • Phase 3 Myelodysplastic Syndromes

Rationale for Clinical Development

Anemia occurs in the majority of patients with myelodysplastic syndromes (MDS), often leading to RBC transfusion dependence, which is associated with poor outcomes.5-8 Preclinical evidence showing that luspatercept promotes RBC maturation supports a potential role for luspatercept in the treatment of anemia associated with ineffective erythropoiesis.2

The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated.

Luspatercept has been licensed from Acceleron Pharma. Celgene and Acceleron are jointly developing this investigational agent.


  1. Sako D, et al. J Biol Chem. 2010;285:21037-21048.
  2. Suragani RN, et al. Nat Med. 2014;20:408-414.
  3. Suragani RN, et al. Blood. 2014;123:3864-3872.
  4. Mettananda S, et al. Blood. 2015;125:3694-3701.
  5. Greenberg PL, et al. Blood. 2012;120:2454-2465.
  6. Kantarjian H, et al. Cancer. 2008;113:1351-1361.
  7. Malcovati L, et al. Haematologica. 2011;96:1433-1440.
  8. Jansen AJ, et al. Br J Haematol. 2003;121:270-274.