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Diseases such as myelodysplastic syndrome (MDS) and myelofibrosis (MF) are characterized by ineffective hematopoiesis resulting in one or multiple cytopenias. Disease-causing defects occur across multiple cell lineages and stages of hematopoiesis, making development of an effective treatment for all patients challenging. Current treatment options to address anemia in these diseases target discreet stages in erythropoiesis, whereas defects leading to ineffective hematopoiesis can occur throughout the pathway. Therefore, a treatment that more globally modulates hematopoiesis has the potential to treat broad patient groups. The TGFβ superfamily plays a key role in regulating hematopoiesis; as signaling via SMAD2/3 activation results in cell quiescence, inhibiting precursors from progressing through later stages of hematopoiesis. KER-050, a modified ActRIIA ligand trap, promotes hematopoiesis through inhibition of ligands that signal though SMAD2/3, including activins and GDFs. In a Phase 1 clinical study, administration of KER-050 to healthy volunteers led to robust, rapid and sustained increases in red blood cells (RBCs), hemoglobin (HGB) and platelets, supporting an effect on the multiple stages of hematopoiesis. Here, we characterize the time course of KER-050-mediated effects on RBC production and changes in erythroid precursor cell populations in mice to characterize the mechanism of action of KER-050 on erythropoiesis. Mice treated with a single dose of a research form of KER-050 (RKER-050, 10mg/kg) had increased RBCs, HGB and hematocrit (HCT) (+8%, +9%, +7%, respectively) 12 hours after administration compared to vehicle-treated mice (VEH), and this effect was further increased on Day 7. There was also a reduction in the number of enucleated erythroid cells in the bone marrow and a parallel increase in the percent of immature reticulocytes (RET) in peripheral blood, suggesting an increased outflux of RET into circulation. This observation is consistent with RKER-050 promoting the maturation of late stage erythroid precursors leading to increases in RBCs, HGB and HCT as early as 12 hours post treatment and remaining 14 days post a single dose. In studies evaluating the effect of RKER-050 on bone marrow erythroid progenitors, a 2-fold increase in late orthochromatic erythroblasts/RETs (EryC) at Days 2 and 7 post-dose was observed. These data are consistent with RKER-050 promoting maturation and release of late-stage erythroid precursors into circulation. RKER-050 also elicited effects on early progenitors. Day 2 post-dose, there was a 2-fold increase in CFU-Es, with a 46% decrease in poly-erythrochromatic/early orthochromatic erythroid precursors (EryB) at Day 4, as compared to VEH. Day 7 post treatment, both CFU-Es and the EryB population returned to VEH levels. The increase in early progenitors appears to replenish the polychromatic erythroblasts (as shown by the return to VEH level of EryB precursors at Day 7), allowing for continued supply of maturing RETs. Consistent with this hypothesis, RKER-050-mediated changes in erythroid precursors continued to Day 14 with significantly increased early progenitor population (BFU-E +24%) and increased late stage erythroid precursors (EryB +40%, EryC 7-fold) while maintaining increased circulating RETs and RBCs. These data demonstrate that the RKER-050 treatment increases early progenitor cells which continue to mature and contribute to the overall upregulation of erythropoietic tone. Surprisingly, RKER-050 treatment resulted in a greater than 2-fold increase in serum levels of erythropoietin (Epo) at Days 4, 7 and 14. These counterintuitive results demonstrate that RKER-050 promotes erythropoiesis while at the same time increasing Epo. This effect may result in a feed-forward effect on the system and result in a sustained upregulation of erythropoietic tone. Overall, these data demonstrate that KER-050 stimulates terminal maturation of late-stage erythroid precursors, expands the early stage precursor population and progresses precursors through erythropoiesis. Additionally, KER-050 increases Epo within the milieu of elevated RBCs. The ability of KER-050 to target multiple stages along the erythropoiesis cascade makes it an appealing therapeutic candidate for diseases that cause anemia due to ineffective erythropoiesis, including MDS and MF, where defects can arise throughout the erythropoietic pathway. Disclosures Feigenson: Keros Therapeutics: Current Employment. Nathan:Keros Therapeutics: Current Employment. Materna:Keros Therapeutics: Current Employment. Gudelsky:Keros Therapeutics: Current Employment. Lema:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tseng:Mitobridge: Current equity holder in private company; Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Fisher:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Seehra:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lachey:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company.