부산대학교 도서관

Pathologic elevations in hepcidin, a key regulator of iron homeostasis, contribute to anemia of inflammation in chronic disease. DISC‐0974 is a monoclonal antibody that binds to hemojuvelin and blocks bone morphogenetic protein signaling, thereby suppressing hepcidin production. Reduction of systemic hepcidin levels is predicted to increase iron absorption and mobilize stored iron into circulation, where it may be utilized by red blood cell (RBC) precursors in the bone marrow to improve hemoglobin levels and to potentially alleviate anemia of inflammation. We conducted a first‐in‐human, double‐blind, placebo‐controlled, single‐ascending dose study to evaluate safety, pharmacokinetics, and pharmacodynamics of DISC‐0974 in healthy participants. Overall, 42 participants were enrolled and received a single dose of placebo or DISC‐0974 at escalating dose levels (7–56 mg), administered intravenously (IV) or subcutaneously (SC). DISC‐0974 was well tolerated, with a safety profile comparable to that of placebo. Pharmacokinetic data was dose and route related, with a terminal half‐life of approximately 7 days. The bioavailability of SC dosing was ∼50%. Pharmacodynamic data showed dose‐dependent decreases in serum hepcidin, with reductions of nearly 75% relative to baseline at the highest dose level tested, and corresponding increases in serum iron in response to DISC‐0974 administration. Dose‐dependent changes in serum ferritin and hematology parameters were also observed, indicating mobilization of iron stores and downstream effects of enhanced hemoglobinization and production of RBCs. Altogether, these data are consistent with the mechanism of action of DISC‐0974 and support the selection of a biologically active dose range for evaluation in clinical trials for individuals with anemia of inflammation. [ABSTRACT FROM AUTHOR]