ACE-536, a
recombinant protein containing a modified
activin receptor type IIB, is being developed for the treatment of
anemias caused by ineffective erythropoiesis, such as
thalassemias and
myelodysplastic syndromes.
ACE-536 acts through a mechanism distinct from
erythropoiesis-stimulating agents to promote late-stage erythroid differentiation by binding to
transforming growth factor-β superfamily
ligands and inhibiting signaling through
transcription factors Smad 2/3. The goal of this Phase 1 study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of ascending dose levels of
ACE-536 in healthy volunteers. Thirty-two postmenopausal women were randomized in sequential cohorts of eight subjects each to receive up to two doses of either
ACE-536 (0.0625-0.25 mg/kg) or placebo (3:1 randomization) given subcutaneously every 2 weeks. Mean baseline age was 59.4 years, and
hemoglobin was 13.2 g/dL.
ACE-536 was well tolerated at dose levels up to 0.25 mg/kg over the 1-month treatment period. There were no serious or severe adverse events, nor clinically meaningful changes in safety laboratory measures or vital signs. Mean
ACE-536 AUC0-14d and Cmax increased proportionally after first dose; mean t½ was 15-16 days. Dose-dependent increases in
hemoglobin concentration were observed, beginning 7 days after initiation of treatment and maintained for several weeks following treatment. The proportion of subjects with a
hemoglobin increase ≥1.0 g/dL increased in a dose-dependent manner to 83.3% of subjects in the highest dose group, 0.25 mg/kg.
ACE-536 was well tolerated and resulted in sustained increases in
hemoglobin levels in healthy postmenopausal women.