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.
Acceleron Pharma Inc, Cambridge, Massachusetts.
Kenneth M
KM
Attie
Mark J
MJ
Allison
Ty
T
McClure
Ingrid E
IE
Boyd
Dawn M
DM
Wilson
Amelia E
AE
Pearsall
Matthew L
ML
Sherman
D030301:Activin Receptors, Type II / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D000368:Aged; D002454:Cell Differentiation / Q000187:drug effects; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000187:drug effects*; D004920:Erythropoiesis / Q000187:drug effects*; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008875:Middle Aged; D017698:Postmenopause / Q000097:blood / Q000187:drug effects
D030301:Activin Receptors, Type II; C425584:activin receptor type II-B