Ker-050, a Modified Actriia Ligand Trap, Alleviates Cytopenia Arising from Multiple Etiologies

• Published in: Blood 2020-11, Vol.136 (Supplement 1), p.38-38
• Main Authors: Feigenson, Marina, Nathan, Remya, Babbs, Keith, Materna, Christopher, Tseng, Claire C, Fisher, Ffolliott, Seehra, Jasbir, Lachey, Jenn
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2020-140167

Hemopoietic system control the production of circulating blood cells that have important functions from transport of oxygen and carbon dioxide, blood clotting to fighting infections. Not surprisingly, the system is tightly regulated and failure to replenish RBC can result in anemia and inadequate platelets increases the risk of bleeding. Impaired hematopoiesis and the consequential cytopenias are associated with aging, diseases characterized by ineffective hematopoiesis including myelodysplastic syndrome (MDS) and myelofibrosis and diseases that lead to loss of growth factors. A therapeutic that could act more globally on the hematopoietic pathway would have the potential to overcome cytopenia in many diseases. Signaling of the TGFβ superfamily regulates several stages of RBC maturation, and recent studies demonstrate that inhibition of TGFβ signaling can induce RBC production and increase circulating RBCs, HGB, and hematocrit (HCT). KER-050, a modified ActRIIA ligand trap, has been shown to increase RBCs in rodents and non-human primates, and to increase both RBCs and PLTs in healthy human volunteers. In the current studies, we aimed to test the efficacy of KER-050 in alleviating cytopenias caused by multiple conditions and to further delineate the effect of KER-050 on platelets. First, we examined whether RKER-050 (a research form of KER-050) can reverse anemia associated with aging and frailty. After 6 weeks of twice weekly treatment, 2-year-old aged, vehicle-treated (AV) mice had significantly lower RBCs, HGB, and HCT (-14.0%, -13.5%, -10.9%, respectively) relative to 11-week-old young vehicle-treated mice (YV). However, aged mice treated with RKER-050 had higher RBCs, HGB, and HCT (+12.3%, +10.0%, +9.1%, respectively) compared to AV, with levels indistinguishable from those of YV. These data support that RKER-050 can improve anemia that arises from aging. Next, we evaluated the efficacy of RKER-050 in the treatment of anemia in an animal model of MDS. NUP98-HOXD13 mice, a murine model of MDS, aged to 6 months and confirmed as anemic prior to treatment, were dosed twice weekly with either vehicle or RKER-050 for 6 weeks. Over this treatment period, vehicle-treated MDS mice continued to have significantly reduced RBCs, HGB, and HCT compared to wildtype controls. In contrast, RKER-050-treated MDS mice had increases in RBCs, HGB, and HCT (+10.9%, +11.2%, + 9.8%, respectively), achieving values comparable to the wild type control animal of the same age. Th