Acceleron Pharma, Inc., a biopharmaceutical company developing protein therapeutics for cancer and orphan diseases, has begun phase II study of its novel, investigational protein therapeutic, ACE-536, to treat patients with beta-thalassemia, a genetic haematologic disorder causing chronic and life-threatening anemia and serious complications affecting the spleen, liver and heart. This is the second ongoing phase II trial for ACE-536, which is being developed by Acceleron as part of a global collaboration with Celgene Corporation.

Patients and healthcare providers currently have limited options for the treatment of beta-thalassemia.

“The unmet medical need in beta-thalassemia is enormous as treatment options are limited mainly to blood transfusions and iron chelating agents,” said Professor Antonio Piga, MD, PhD., director of Paediatrics at San Luigi Gonzaga University Hospital in Torino, Italy and coordinating principal investigator of the study. “ACE-536 could address this important unmet need and I am excited to explore the potential benefits of this innovative therapeutic in a phase II study.”

“We are excited to start our second phase II trial for ACE-536,” said Matthew Sherman, MD, chief medical officer of Acceleron. “Both the preclinical and clinical data assembled to date and our understanding of the protein’s novel mechanism of action suggest that ACE-536 may become an important new treatment option for those suffering with beta-thalassemia or other diseases that negatively impact the body’s ability to produce a sufficient number of functional red blood cells.”

The phase II clinical trial is designed as an open-label study to evaluate the safety, tolerability and efficacy of ACE-536 in non-transfusion dependent patients with beta-thalassemia and is being conducted in Europe.  Efficacy measures include increases in haemoglobin and red blood cell levels and biomarkers of erythropoiesis, hemolysis, iron metabolism, and bone metabolism.

Beta-thalassemia is an inherited disease involving mutations in the beta globin gene leading to defective hemoglobin production and serious anemia. In beta-thalassemia patients, there is an over production of red blood cell (RBC) precursors in the bone marrow, often resulting in bone deformities, decreased bone mineral density and bone strength, and pathologic fractures, yet these abundant RBC precursors fail to properly mature into functional red blood cells. This form of defective red blood cell formation is known as ineffective erythropoiesis. Beyond the severe anaemia, many patients also suffer from multiple organ dysfunction, largely due to excess iron deposits, known as “iron overload”, resulting from the ineffective erythropoiesis and the repeated RBC transfusions to address the anaemia. Iron overload can lead to heart failure, liver fibrosis, and diabetes, among other consequences. Current treatment for beta-thalassemia includes regular RBC transfusions and daily iron chelation therapy, which is associated with toxicities.

ACE-536 is a modified type II activin receptor fusion protein that acts as a ligand trap for members in the TGF-ß superfamily involved in erythropoiesis. ACE-536 regulates late-stage erythrocyte (red blood cell) precursor cell differentiation and maturation, distinct from erythropoietin (EPO) which stimulates the proliferation of early-stage erythrocyte precursor cells.  In diseases of ineffective erythropoiesis, such as myelodysplastic syndromes (MDS) and thalassemia, in which there is an over-production of early-stage erythrocyte precursors in the bone marrow, administration of erythropoietin does not correct the underlying cause of the anaemia. By promoting the differentiation of the precursor cells into mature RBCs, ACE-536 has the potential to treat the anemia in MDS and beta-thalassemia patients. In a phase I clinical study in healthy volunteers, ACE-536 produced a dose-dependent increase in red blood cell counts and hemoglobin levels. Acceleron and Celgene are jointly developing ACE-536.