KER-050, A NOVEL INHIBITOR OF TGFΒ SUPERFAMILY SIGNALING, INDUCES RED
BLOOD CELL PRODUCTION BY PROMOTING MULTIPLE STAGES OF ERYTHROID
DIFFERENTIATION
Marina Feigenson, Remya Nathan, Christopher M Materna, Alana Gudelsky, Evan Lema, Claire C
Tseng, ffolliott M Fisher, Jasbir Seehra and Jennifer L Lachey
Keros Therapeutics, Lexington, MA
Diseases such as myelodysplastic syndrome (MDS) and myelofibrosis (MF) are characterized by
ineffective hematopoiesis. Current treatment options to address anemia in these diseases target
discreet stages in the erythropoietic pathway. However, the defects leading to ineffective
hematopoiesis can occur throughout the pathway; therefore, a treatment that more globally
modulates hematopoiesis may provide a more complete benefit.
The TGFβ superfamily plays a key role in the regulation of hematopoiesis; canonical 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. In a Phase 1 clinical study, KER-050
robustly increased red blood cells (RBCs), hemoglobin (HGB) and platelets, supporting its effect of
upregulating hematopoiesis. Here, we characterize the time course of KER-050-mediated changes
in erythroid precursors in mice to characterize the mechanism of action of KER-050.
Mice treated with a single dose of a research form of KER-050 (RKER-050, 10mg/kg) had increased
RBCs, HGB and hematocrit just 12 hours after administration compared to vehicle-treated mice
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 in peripheral blood, suggesting an increased outflux of reticulocytes into circulation.
In addition, there was a 2-fold increase in late-stage erythroid progenitors in the bone marrow on
Day 2. These results are all consistent with the hypothesis that RKER-050 promotes the maturation
of late-stage erythroid precursors.
RKER-050 also elicited effects on early progenitors. On Day 2 post-dose, there was a 2-fold increase
in CFU-Es with a 46% decrease in poly-erythrochromatic/early orthochromatic erythroid
precursors (fraction EryB) at Day 4, as compared to vehicle, with both populations returning to
vehicle level on Day 7. These data suggest that the increase in early progenitors replenish the
polychromatic erythroblasts, allowing for continued supply of maturing reticulocytes. Consistent
with this hypothesis, RKER-050-mediated changes in erythroid precursors continued to Day 14
where significant increases in erythroid precursors, a 20% increase in circulating reticulocytes and
a continued increase in RBCs were observed. These data demonstrate that the RKER-050 effect on
early progenitors increases erythropoietic tone as early progenitors continue through the
maturation process.
Surprisingly, RKER-050 treatment resulted in a greater than 2-fold increase in serum levels of
erythropoietin starting at Day 4. While these results are counterintuitive given the increased RBCs,
it suggests that RKER-050 is promoting erythropoiesis through a mechanism that dissociates the
RBC-erythropoietin feedback loop.
Overall, these data demonstrate that KER-050 stimulates terminal maturation of late-stage
erythroid precursors, while also expanding the early-stage precursor population and progressing
precursors through the erythropoiesis pathway, and also results in increased erythropoietin. 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, such as
MDS and MF, regardless of the stage of RBC differentiation at which the pathology arises.