A phase 1 study of ACE‐536, a regulator of erythroid differentiation, in healthy volunteers

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. Am. J. Hematol. 89:766–770, 2014. © 2014 Wiley Periodicals, Inc.