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Luspatercept-aamt (ACE-536) is a recombinant fusion protein with a modified extracellular domain of the human activin receptor type IIB (ActRIIB) linked to a human immunoglobulin G1 (IgG1) Fc domain.1,2 Luspatercept-aamt was shown in preclinical studies to bind several endogenous 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 contributes to ineffective erythropoiesis.1-3 In preclinical studies, luspatercept-aamt has been shown to function as a ligand trap for TGF-β ligands, thereby diminishing abnormally elevated Smad2/3 signaling.2,3 This is hypothesized to underlie the effects of luspatercept-aamt on promoting erythroid maturation through differentiation of late-stage erythroid precursors.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.
Beta-thalassemia is a type of congenital anemia characterized by reduced to no production of β-globin, a protein component of adult hemoglobin.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 such as beta-thalassemia.2 In a preclinical study, a murine version of luspatercept-aamt (RAP-536) reduced or corrected anemia in a beta-thalassemia mouse model.4
Anemia is present at diagnosis in approximately 90% of patients with myelodysplastic syndromes (MDS), often leading to RBC transfusion dependence, which is associated with poor outcomes.6-10 Preclinical evidence showing that luspatercept-aamt promotes RBC maturation supports a potential role for luspatercept-aamt in the treatment of anemia associated with ineffective erythropoiesis.2
Myelofibrosis, which is a type of neoplasm characterized by clonal myeloproliferation, is associated with progressive bone marrow fibrosis, angiogenesis, osteosclerosis, extramedullary hematopoiesis, and abnormal cytokine expression.11 One of the key clinical manifestations of myelofibrosis is severe anemia as a result of ineffective erythropoiesis, suggesting a potential role for luspatercept-aamt through its proposed action on late-stage erythroid precursors as observed in preclinical studies.2
Luspatercept-aamt has been licensed from Acceleron Pharma. Celgene and Acceleron are jointly developing this investigational agent.