Mechanism of Action
Sotatercept, the first in a novel class of anemia therapies, is a soluble fusion protein consisting of the extracellular domain of activin receptor type IIA (ActRIIA) linked to the Fc protein of human IgG1. Sotatercept binds with high affinity to activin A and other proteins in the TGF-β superfamily and inhibits signaling through the ActRIIA receptor.
Sotatercept increases hemoglobin levels and RBCs by a novel mechanism: it is not an erythropoietin (EPO)-based product or EPO-mimetic, does not bind the EPO receptor, but rather targets a pathway that is fundamentally distinct from EPO. In preclinical studies, administration of sotatercept or a mouse version of the molecule to mice and cynomolgus monkeys was associated with increases in erythropoiesis and total red cell mass. The precise actions of sotatercept underlying the promotion of erythropoiesis are under investigation.
Sotatercept also affects bone formation. One of the functions of activin A is to inhibit bone growth. Activin A signaling through ActRIIA suppresses activity of cells responsible for building bone (osteoblasts) and stimulates cells responsible for breaking down bone (osteoclasts). By blocking signaling through ActRIIA, sotatercept stimulates bone formation. In numerous animal models of diseases involving bone loss, sotatercept significantly increased bone mineral density, improved bone architecture, and increased bone formation rate and bone mechanical strength. Similar effects were observed in experimental models of cancer-related bone loss (multiple myeloma and breast carcinoma) where treatment with a mouse form of sotatercept resulted in a significant reduction in tumor-induced osteolytic lesions. In the myeloma model, restoration of bone remodeling had a significant indirect effect on tumor burden and increased survival.
Acceleron and Celgene are developing sotatercept in anemia indications where the product’s unique pharmacology could potentially provide an innovative and differentiated alternative to existing anemia therapies.
Anemia, a deficiency of healthy red blood cells (RBCs), is a debilitating condition that often accompanies many chronic diseases including Myelodysplastic Syndrome (MDS), Beta-Thalassemia, and Chronic Kidney Disease. Patients with anemia typically experience fatigue and weakness, which impairs their quality of life and may limit their ability to receive optimal care.
Treatments for anemia include iron repletion, blood transfusion, and for some diseases, recombinant growth factors called erythropoietin stimulating agents (ESAs). ESAs are currently the only approved drugs that stimulate the production of RBCs.
Erythropoiesis stimulating agents (ESAs) have been used extensively to treat anemia in the setting of patients with Chronic Kidney Disease (CKD). However, many CKD patients not only suffer from anemia, but also from bone loss and mineral and bone disorder.
In other conditions, such as β–Thalassemia and myelodysplastic syndromes (MDS), ESAs are not approved or not well suited to treat the underlying anemia. Patients suffering from these conditions often times require red blood cell transfusions to address their anemia.
Sotatercept represents a new approach to anemia treatment. Clinical trials in patients with anemia caused by CKD, β-Thalassemia, myelodysplastic syndromes, Diamond Blackfan, multiple myeloma and myelofibrosis are currently underway to study its potential as a safe, effective treatment for anemia.
Acceleron is developing sotatercept together with Celgene Corporation for patients who suffer from anemia. Sotatercept is currently being studied as a treatment for the treatment of anemia in diseases in which erythropoiesis-stimulating agents are either not approved or are not well-suited to treat the underlying anemia, such as MDS, Beta-Thalassemia and Diamond-Blackfan. Sotatercept is also being studied to treat anemia in patients with Chronic Kidney Disease (CKD), multiple myeloma (MM) and myelofibrosis (MF).
• Phase 2 Study for Anemia in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes. For information on this trial, please click here
• Phase 2 Study for Anemia in Patients with Beta-Thalassemia. For information on this trial, please click here
• Phase 2 Study for Anemia in Patients with End-stage Renal Disease on Dialysis. For information on this trial, please click here
• Phase 2 Study of Intravenous and Subcutaneous sotatercept in Patients with End-stage Renal Disease on Dialysis. For information on this trial, please click here
• Phase 2 Study for Anemia in Patients with Transfusion Dependent Diamond Blackfan Anemia. For information on this trial, please click here
• Phase 2 Study for Patients with Myeloproliferative Neoplasm-Associated Myelofibrosis and Anemia. For information on this trial, please click here
• Phase 2 Study in Combination with Lenalidomide and Dexamethasone for Patients with Relapsed or Refractory Multiple Myeloma. For information on this trial, please click here
In Phase 1 clinical studies in healthy volunteers, sotatercept was generally well tolerated, and, consistent with observations in preclinical studies, increased levels of hemoglobin and hematocrit, biomarkers of bone formation, and bone mineral density. The most common clinically significant adverse events observed included increased hemoglobin and increased hematocrit, which were pharmacologic effects of the drug, and also headache, all of which were manageable and reversible.