JTZ-951 (enarodustat), a hypoxia-inducible factor prolyl hydroxylase inhibitor, improves iron utilization and anemia of inflammation: Comparative study against recombinant erythropoietin in rat.

Anemia with inflammation-induced defective iron utilization is a pathological condition observed in patients suffering from chronic kidney disease (CKD) or chronic inflammatory disease. There is no reasonable treatment for these conditions, because the effects of erythropoiesis stimulating agents (ESAs) or iron supplementation in the treatment of anemia are insufficient. JTZ-951 (enarodustat) has been characterized as a novel, orally bioavailable inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH), and has been developed as a novel therapeutic agent for anemia with CKD. In this study, the effects of JTZ-951 on iron utilization during erythropoiesis and on anemia of inflammation were compared with those of recombinant human erythropoietin (rHuEPO) using normal rat and rat model of anemia of inflammation. In normal rats, under conditions in which JTZ-951 and rHuEPO showed similar erythropoietic effect, repeated doses of JTZ-951 induced erythropoiesis while retaining the hemoglobin content in red blood cells, while administration of rHuEPO resulted in decrease in some erythrocyte-related parameters. As for iron-related parameters during erythropoiesis, JTZ-951 exhibited more efficient iron utilization compared to rHuEPO. A single dose of JTZ-951 resulted in decrease in hepcidin expression observed within 24 h after administration, but a single dose of rHuEPO did not. In a rat model of anemia of inflammation (also known as a model with functional iron-deficiency), JTZ-951 showed erythropoietic effect, in contrast with rHuEPO. These results suggest that, unlike rHuEPO, JTZ-951 stimulates erythropoiesis by increasing iron utilization, and improves anemia of inflammation.

JTE-852, a novel spleen tyrosine kinase inhibitor, blocks immunoglobulin G-mediated cellular responses and autoimmune reactions in vivo.

AIMS: Immune and inflammatory responses mediated by immunoglobulin (Ig) G are largely responsible for the pathogenesis of autoimmune diseases. Spleen tyrosine kinase (Syk) plays a pivotal role in the IgG-mediated responses; therefore, Syk has emerged as a new therapeutic target for the treatment of autoimmune diseases. In this study, we investigated the inhibitory actions of JTE-852, a novel Syk inhibitor, on IgG-mediated cellular responses and autoimmune reactions in vivo. MAIN METHODS: We examined mediator secretion from human monocytes. We also conducted rat models of reversed cutaneous anaphylaxis (RCA) and reversed passive Arthus (RPA), which are classified as type II and type III hypersensitivities, respectively. In a rat collagen-induced arthritis (CIA) model, JTE-852 or methotrexate was administered preventively (before the onset of arthritis) or therapeutically (after the onset of arthritis). KEY FINDINGS: JTE-852 blocked secretion of reactive oxygen species and tumor necrosis factor-α from monocytes stimulated by IgG crosslinking. In the RCA and RPA models, JTE-852 also suppressed edema and dye leakage, respectively. In the CIA model, JTE-852 showed both preventive and therapeutic effects against joint swelling and bone erosion; on the other hand, methotrexate did not show the therapeutic effect. SIGNIFICANCE: JTE-852 attenuates IgG-mediated responses and signs in animal model of autoimmune diseases. JTE-852 is thus a promising candidate for a novel, orally available drug for the treatment of autoimmune diseases.