ACE-011, a soluble activin receptor type IIA IgG-Fc fusion protein, decreases follicle stimulating hormone and increases bone-specific alkaline phosphatase, a marker of bone formation, in postmenopausal healthy women.
Authors: NG Borgstein, Y Yang, CH Condon, E Haltom, ML Sherman
Journal: Cancer Research (2009)

Abstract Abstract #1160 Breast cancer metastasizes to bone in up to 85% of patients with advanced disease. Skeletal-related morbidity such as pathologic fractures, spinal cord compression, or the need for radiotherapy or surgery to the bone will occur in the majority of these patients within 2 years after diagnosis of metastatic disease. Anti-resorptive agents, such as bisphosphonates, are effective agents in inhibiting osteoclast activity and have been shown to decrease skeletal-related events by 30-40% in breast cancer patients. However, these agents also cause a decrease in markers of bone formation, and have been associated with osteonecrosis of the jaw and renal toxicity. The development of safe anabolic agents to stimulate the formation of new bone may be an effective treatment option for patients with bone metastases. Our previous studies using a soluble form of the extracellular domain of the activin type IIA receptor (ActRIIA) fused to a murine IgG-Fc fragment (RAP-011) in murine models of breast cancer metastases have demonstrated that treatment with an activin antagonist can prevent both skeletal and visceral metastases, prolong survival, and increase bone mass.&amp;#x2028; ACE-011, the human analog of RAP-011, is currently in clinical development for the treatment of bone loss in a variety of disease indications. In a recent single-dose, dose-escalating Phase 1 study in healthy postmenopausal women, administration of ACE-011 demonstrated rapid and sustained dose-dependent increases in the bone formation biomarker, bone-specific alkaline phosphatase (BSAP), as well as dose-dependent decreases in bone resorption biomarkers, C-terminal type 1 telopeptide (CTX) and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b).&amp;#x2028; The increased production of follicle stimulating hormone (FSH) in postmenopausal women in response to activin stimulation is well-established. In this study, ACE-011 treatment in postmenopausal women was associated with a rapid and dose-dependent decrease in serum FSH levels consistent with inhibition of activin. By day 8 after a single dose, a mean percent decrease in FSH from baseline of -15%, -27% and -45% was seen in subjects treated at the 0.3, 1 and 3 mg/kg IV dose levels, respectively. By day 15, a mean percent increase in BSAP from baseline of 15%, 19% and 36% was seen in subjects treated at the corresponding dose levels. Pharmacokinetic-pharmacodynamic Emax modeling was utilized to describe the relationship between ACE-011 exposure and FSH suppression and BSAP stimulation.&amp;#x2028; Taken together, these data support the evaluation of ACE-011 as a novel anabolic agent with the potential to provide a therapeutic benefit in patients with metastatic breast cancer at risk for skeletal complications. Serum FSH levels can be used as a biologically relevant marker of activin inhibition in postmenopausal women treated with ACE-011. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1160.