Sotatercept (ACE-011), under development by Acceleron Pharma Inc in collaboration with Celgene Corp, is a chimeric
protein containing the extracellular domain of the
activin receptor 2A (ACVR2A) fused to the Fc domain of human
IgG1.
Sotatercept contains the binding site of ACVR2A and interferes with downstream signaling cascades, in particular the SMAD pathway, by sequestering
activin. The murine counterpart of
sotatercept, referred to as
RAP-011, has been extensively evaluated in preclinical studies, in particular in models of
cancer- and
osteoporosis-related bone loss, and the developing companies envisage that
sotatercept may also have potential for the treatment of
cancer and
cancer-related bone loss. In a phase I clinical trial in postmenopausal females,
sotatercept increased hematocrit levels, and, in a phase II trial in patients with
multiple myeloma, a trend toward improvement in osteolytic lesions as well as antitumor activity was observed. At the time of publication, phase II trials in patients with
anemia were ongoing. Future clinical development will rely on an evaluation of the benefits and complications of
sotatercept administration, focusing in particular on suppression of ovarian function and increases in hematocrit levels without a consequent risk of
hypertension and
thrombosis.