DISC-0974: Pioneering Anti-Hemojuvelin mAb Lowers Hepcidin and Enhances Transferrin Saturation in IL-6 Induced Hypoferremia Model

In chronic inflammatory conditions, increased levels of hepcidin can lead to reduced iron availability for erythropoiesis, despite adequate iron stores, resulting in anemia. Hemojuvelin (HJV) is a crucial regulator of hepcidin production. Patients with a homozygous loss-of-function mutation in the gene coding for HJV show markedly reduced hepcidin levels and suffer from juvenile hemochromatosis Type 2A, a severe iron overload disorder.

DISC-0974 is a humanized monoclonal antibody against HJV, with high binding affinity to human, rat, and cynomolgus monkey HJV. DISC-0974 inhibits the interaction between HJV and bone morphogenetic proteins (BMPs), thereby reducing SMAD phosphorylation and hepcidin expression.

The pharmacokinetics and pharmacodynamics (PK/PD) of DISC-0974 were evaluated in healthy non-human primates (NHPs), where iron metabolism is primarily regulated by BMP/SMAD-mediated hepcidin synthesis. Dose levels were chosen to modulate the pharmacodynamic response (transferrin saturation [TSAT]), with doses set at 0.6 mg/kg (below saturation), and 3 and 60 mg/kg (to achieve TSAT saturation). DISC-0974 administration led to a dose-dependent decrease in hepcidin concentrations, which was associated with increased TSAT. At 0.6 mg/kg, TSAT was below saturation (~65%) after the first dose but increased with subsequent doses. At 3.0 and 60 mg/kg doses, TSAT saturation (>85%) was quickly achieved and sustained through the study period.

DISC-0974 efficacy was tested in an NHP model of inflammation-induced (IL-6) high-hepcidin. Monkeys were administered IL-6 and either vehicle, 0.6 mg/kg, or 6 mg/kg DISC-0974. DISC-0974 effectively prevented IL-6-induced hepcidin increases in a dose-dependent manner.

In conclusion, DISC-0974 administration in healthy NHPs reduces hepcidin levels, mobilizing iron stored in macrophages and making it available for erythropoiesis. It also effectively counters IL-6-induced hepcidin increases. Due to similarity in hepcidin regulation mechanisms between NHPs and humans, DISC-0974 is expected to offer similar benefits in treating anemia of inflammation in humans by reducing hepcidin and improving iron availability for erythropoiesis.