Single-Dose, Randomized, Double-Blind, Placebo-Controlled Study of ACE-011 (ActRIIA-IgG1) in Postmenopausal Women

Abstract

The effects of ACE-011 on safety, pharmacokinetics, and bone biomarkers were evaluated in healthy, postmenopausal women. Our data indicate that ACE-011 results in a sustained increase in biomarkers of bone formation and reduction in markers of bone resorption. The activin type IIA receptor (ActRIIA) is the high-affinity receptor for activin. ACE-011 is a dimeric fusion protein consisting of the extracellular domain of the human ActRIIA linked to the Fc portion of human IgG1. ACE-011 binds to activin, preventing activin from binding endogenous receptors. A randomized, double-blind, placebo-controlled study was conducted to evaluate the safety and tolerability of ACE-011. Forty-eight healthy, postmenopausal women were randomized to receive either a single dose of ACE-011 or placebo and were followed for 4 mo. Dose levels ranged from 0.01 to 3.0 mg/kg intravenously and from 0.03 to 0.1 mg/kg subcutaneously. Safety and pharmacokinetic (PK) analyses and the biological activity of ACE-011, as assessed by markers of bone turnover, and follicle stimulating hormone (FSH) levels were measured. No serious adverse events (AEs) were reported. AEs were generally mild and transient. The PK of ACE-011 was linear over the dose range studied, with a mean half-life of 24-32 days. The absorption after subcutaneous dosing was essentially complete. ACE-011 caused a rapid and sustained dose-dependent increase in serum levels of bone-specific alkaline phosphatase (BSALP) and a dose-dependent decrease in C-terminal type 1 collagen telopeptide (CTX) and TRACP-5b levels. There was also a dose-dependent decrease in serum FSH levels consistent with inhibition of activin. ACE-011 is a novel agent with biological evidence of both an increase in bone formation and a decrease in bone resorption. ACE-011 may be an effective therapy in a variety of diseases involving bone loss.

Bone Anabolic Agents for the Treatment of Multiple Myeloma

“…A phase I dose-escalation trial in healthy postmenopausal women showed dose-dependent increase in serum levels of bALP, persisting up to 120 days after a single intravenous injection of 3-mg/kg. Increase in serum levels of procollagen type I N-terminal propeptide (PINP, a marker of collagen deposition) was also observed, in contrast serum cross-linked C-telopeptide of type I collagen (CTX, a marker of bone resorption) levels were reduced by sotatercept [95]. Adverse events were mild and transient consisting of headache, toothache, infusion site reaction and infusion site hemorrhage.…”

“…Adverse events were mild and transient consisting of headache, toothache, infusion site reaction and infusion site hemorrhage. Progressive and persistent hypertension was also observed in one patient due to a rapid and significant increase in hemoglobin levels at 1 week after administration of the second dose of sotatercept [95]. Given these promising results, the bone anabolic effects of sotatercept (ACE-011) have been assessed in 30 stage II/III MM patients with osteolytic lesions receiving standard chemotherapy, consisting of melphalan, prednisone and thalidomide (NCT00747123).…”

Thalassemia 2016: Modern medicine battles an ancient disease

“…A role for this gene in human erythropoiesis was found indirectly and serendipitously. The first clue came during a trial of a novel drug designed to treat osteoporosis, in which it was noted that the subjects developed an average of 12% rise in Hb [68]. This was unexpected and it quickly led to the hypothesis that this drug, sotatercept, could be used to treat anemia.…”

Towards a cure for Fibrodysplasia ossificans progressiva

“…Noteworthy, clinical trials performed with ActRIIFc ligand traps have revealed a number of considerable side effects (19,20), which likely would turn out to be devastating in the case of FOP. In this sense, administration of an activin A specific antibody may result to be more tolerable for patients.…”