RAP-536, A Soluble Activin Receptor Type IIb Murine IgG-Fc Fusion Protein, Prevents Myelodysplastic Syndrome Related Anemia

Abstract 978

Myelodysplastic syndrome (MDS) is a premalignant disease characterized by ineffective hematopoiesis. MDS patients can live for extended periods of time but can develop severe anemia or may progress to acute leukemia. Current therapies require patients to receive chemotherapy and/or blood transfusions to either prevent progression to leukemia or improve anemia. The majority of therapies approved for anemia target the erythropoietin (EPO) pathway. However, recent studies suggest an increased risk of mortality associated with recombinant erythropoietin (EPO) and its derivatives, which may stimulate tumor progression and increase the occurrence of thromboembolic events. While Lenalidomide has shown efficacy in reducing red cell transfusion rates, particularly in the del(5q) subset of MDS patients, additional therapies that increase red blood cell mass would be beneficial. Proteins in the TGF-β superfamily have been reported to play a role in red blood cell (RBC) development, but they act via a different pathway from EPO. RAP-536 is a murine soluble receptor fusion protein based on the activin receptor type IIB (ActRIIB) that binds to certain TGF-β ligands and prevents signaling through the ActRIIB receptor. The purpose of the current study is to evaluate the hematopoietic effect of RAP-536 in a mouse model of MDS.

To investigate the effects of RAP-536 in a model of MDS, three month old NUP98-HOX13 transgenic mice (10/dose group) were treated with Vehicle (VEH), or RAP-536 (10 mg/kg) twice per week for the duration of the study. Wild-type littermates (10/dose group) were dosed with VEH or RAP-536 (10 mg/kg) and used as controls. Blood samples and blood smears were collected monthly to conduct CBC measurements and assess changes in blood cells.

On study day 0, immediately prior to the first dosing, the NUP98-HOX13 transgenic male mice had significantly decreased levels of RBC (-8.8%, P<0.05), hematocrit (-8.4%, P<0.05) and leukocytes (-67.6%, P<0.001) compared to their wild-type control littermates. Similar trends were seen in female NUP98-HOX13 transgenic mice with RBC (-1.1%) and hematocrit (-2.2%) decreased but not significantly and leukocytes (-68%, P<0.01) decreased significantly compared to the wild type controls.

After 1 month of dosing, male NUP98-HOX13 transgenic mice treated with RAP-536 had significantly increased RBC counts (+9.2%, P<0.01), hemoglobin (+13.1%, P<0.01) and hematocrit (+10.8%, P<0.01) compared to their VEH controls. Female NUP98-HOX13 transgenic mice treated with RAP-536 had significant increases in RBC (+3.0%, P<0.05) and hematocrit (+4.9%, P<0.05) when compared to VEH controls. There were no significant changes in leukocyte counts between RAP-536 and VEH treated NUP98-HOX13 transgenic mice in either the male or female cohorts. RAP-536 treatment also had no effect on leukocyte number in wild-type mice. It should be noted that all of the transgenic mice had lower leukocyte counts compared to their wild-type littermates.

After 4 months of dosing, NUP98-HOX13 transgenic mice treated with RAP-536 had increased RBC counts (+25.4%, P<0.01), hemoglobin (+22.8%, P<0.01) and hematocrit (+21.9%, P<0.01) in males as well as females (+16.2%, P<0.05; +16.9%, P<0.01; +18.4%, P<0.01) compared to VEH treated controls. All transgenic mice continued to have lower leukocyte counts compared to wild type controls, but there were no significant changes in leukocyte counts between RAP-536 and VEH treated NUP98-HOX13 transgenic mice in either the male or female cohorts.

These data suggest that the use of a modified soluble ActRIIB receptor acts to increase red blood cell mass and represents a novel therapy for severe anemia in patients with Myelodysplastic syndrome and other hematopoietic diseases.