Evaluating DISC-0998: A Humanized Anti-Hemojuvelin Monoclonal Antibody's Impact on Hepcidin Production and its Pharmacological Profiles in Preclinical Studies

The text describes a study on a condition known as anemia of inflammation (AI), which is linked to various diseases such as myelofibrosis and chronic kidney disease. The condition is characterized by reduced blood cell production and iron imbalance due to inflammatory cytokines that raise hepcidin levels. Elevated hepcidin causes iron to be stored in cells, reducing its availability in the blood.

The study introduces two monoclonal antibodies (mAbs), DISC-0974 and DISC-0998. DISC-0974 has been observed to increase serum iron levels by interfering with HJV function and reducing hepcidin production, with a Phase 1 clinical trial indicating monthly subcutaneous dosing is feasible.

DISC-0998 is a highly selective mAb with a special mutation designed to increase its half-life. Preclinical studies have shown that it has biological activity, low potential for causing an immune response, and favorable pharmacokinetic and pharmacodynamic properties.

The aim of the study was to assess the relationship between DISC-0998, hepcidin, serum iron, and transferrin saturation (TSAT) in male cynomolgus monkeys. The monkeys were given various doses of DISC-0998, and blood samples were taken to measure various parameters. The results were compared to those from a previous study using DISC-0974.

DISC-0998 showed low clearance and a small volume of distribution, typical for a mAb, and had a longer half-life than DISC-0974, indicating a longer duration of effect. The study also showed a dose-dependent decrease in hepcidin-25 levels along with increased serum iron and TSAT.

The study concluded that DISC-0998 has a promising pharmacokinetic and pharmacodynamic profile in monkeys, suggesting similar or better potency compared to DISC-0974. This supports the continued development of DISC-0998 for treating AI-related disorders, with the potential for less frequent dosing.