Proposed Mechanism of Action

Luspatercept (ACE-536) is 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 Luspatercept is hypothesized to target select transforming growth factor (TGF)-β superfamily ligands that regulate late-stage erythropoiesis.1-3 The TGF-β superfamily regulates Smad2/3 signaling, which preclinical studies have suggested contribute to ineffective erythropoiesis.1-3 In preclinical studies, luspatercept has been shown to function as a ligand trap for TGF-β ligands, resulting in a reduction in aberrant Smad2/3 signaling.2,3 This is hypothesized to underlie the effects of luspatercept on promoting late-stage red blood cell (RBC) precursor differentiation and maturation.2

Luspatercept Proposed Mechanism of Action

Preclinical studies have demonstrated that luspatercept, an investigational erythroid maturation agent, acts as a ligand trap for TGF-β ligands.

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.4 Ineffective erythropoiesis and hemolysis are the major mechanisms that cause anemia in patients with beta-thalassemia.5 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.4

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.6-9 Preclinical evidence showing that luspatercept promotes RBC maturation supports a potential role for luspatercept in the treatment of anemia associated with ineffective erythropoiesis.2

Luspatercept in Myelofibrosis (MF)

  • Phase 2 Myelofibrosis (MF) MF anemia

Rationale for Clinical Development

Myelofibrosis, which is a type of neoplasm characterized by clonal myeloproliferation, is associated with reactive bone marrow fibrosis, angiogenesis, osteosclerosis, extramedullary hematopoiesis, and abnormal cytokine expression.10 One of the key clinical manifestations of myelofibrosis is severe anemia as a result of ineffective erythropoiesis, suggesting a potential role for luspatercept through its proposed action against ineffective erythropoiesis as seen in preclinical studies.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.


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  2. Suragani RN, et al. Nat Med. 2014;20:408-414. PMID: 24658078
  3. Attie KM, et al. Am J Hematol. 2014;89:766-770. PMID: 24715706
  4. Suragani RN, et al. Blood. 2014;123:3864-3872. PMID: 24795345
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