In diseases characterized by chronic inflammation, hepcidin levels are often elevated causing reduced transferrin-bound iron, reduced erythroid iron availability, diminished erythropoiesis and anemia despite the presence of adequate iron stores. Hemojuvelin (HJV) is a key selective regulator of hepcidin production in humans; patients with homozygous loss-of-function in the gene coding for HJV exhibit dramatically reduced hepcidin levels and a severe iron overload syndrome, juvenile hemochromatosis Type 2A.
DISC-0974 is a humanized monoclonal anti-HJV antibody with high binding affinity for human, rat and cynomolgus monkey HJV (100 pM, 240 pM and 110 pM Kd, respectively) [Kovac 2016]. DISC-0974 inhibits the interaction between HJV and the key hepcidin regulatory ligands, bone morphogenetic proteins (BMPs), leading to decreased SMAD phosphorylation (SMAD-P) and reduced hepcidin expression [Kovak 2016].
The multiple-dose pharmacokinetics and pharmacodynamics (PK/PD) of DISC-0974 was first evaluated in healthy NHPs in which regulation of iron metabolism is primarily controlled by BMP/SMAD regulation of hepcidin synthesis. Dose levels were selected to modulate the pharmacodynamic response (transferrin saturation [TSAT]) but to be either below saturation (0.6 mg/kg), or to saturate the TSAT response (3 and 60 mg/kg). As expected from the mechanism of action, hepcidin concentrations decreased following DISC-0974 administration with return to baseline that was exposure dependent. The decrease in hepcidin was associated with increased TSAT, which DISC-0974 modulated in a dose-dependent manner. At 0.6 mg/kg, the TSAT response was maintained below saturation (~65%) after the first dose; saturation increased following subsequent doses, consistent with higher DISC-0974 serum concentrations. At the 3.0 and 60 mg/kg doses TSAT saturation (>85%) was achieved within 5 days post first dose and remained elevated through the end of the study, also consistent with the serum concentrations of DISC-0974.
In vivo efficacy of DISC-0974 was evaluated in an NHP model of inflammation-induced (IL-6) high-hepcidin to establish whether inhibition of BMP/SMAD signaling could effectively control hepcidin increases generated by inflammatory signals. In this study, monkeys were challenged with 6×104 IU IL-6/kg on Day 1 and on Day 4. Groups of N=3 received 0 (vehicle), 0.6 or 6 mg/kg DISC-0974. On Day 11 all groups received a second challenge of 6×104 IU IL-6/kg. TSAT, hepcidin-25 and DISC-0974 concentrations were determined. DISC-0974 was effective in preventing IL-6-induced hepcidin increase in a dose-dependent manner in this model (Figure 1).
In summary, in healthy NHPs, administration of DISC-0974 causes reduction in hepcidin levels leading to release of stored iron from macrophages of the reticuloendothelial system, making iron available for erythropoiesis as demonstrated by the dose-dependent modulation of TSAT. DISC-0974 is also effective in preventing hepcidin increases caused by IL-6, which is generally regarded at the classical cytokine stimulator of hepcidin synthesis. Given the similarity of the mechanism of hepcidin regulation between NHPs and humans, DISC-0974 is anticipated to provide a similar effect in the treatment of anemia of inflammation in humans by lowering cytokine-induced increases in hepcidin and improving iron availability for erythropoiesis.
MacDonald:Disc Medicine: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Blaustein:Disc Medicine: Current Employment, Current equity holder in private company. Nguyen:Disc Medicine: Current Employment, Current equity holder in private company. King:Disc Medicine: Current Employment, Current equity holder in private company. Hong:Disc Medicine: Current Employment, Current equity holder in private company. Savage:Disc Medicine: Current Employment, Current equity holder in private company. Venkatraman:Disc Medicine: Current Employment, Current equity holder in private company. Beconi:Disc Medicine: Current Employment, Current equity holder in private company.
Asterisk with author names denotes non-ASH members.