DISC-0974, a Novel, First-in-Class, Anti-Hemojuvelin Monoclonal Antibody Is Predicted to be Efficacious at Low Doses in Humans As Determined By Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling in Non-Clinical Studies

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].

Elevated hepcidin is a hallmark of and plays a critical role in the pathogenesis of anemia of inflammation (and other forms of anemia) by reducing transferrin saturation and erythroid iron availability, leading to failure of erythropoiesis and decreased hemoglobin synthesis. DISC-0974 is being developed to reduce hepcidin synthesis and treat anemia in these patients. A critical early signal of therapeutic effect is the effect of DISC-0974 on transferrin saturation (TSAT). TSAT has therefore been used as the primary pharmacodynamic marker in a series of non-clinical studies to determine the relationship between drug exposure and pharmacological activity.

In non-human primates (NHP) DISC-0974 elicits a dose-dependent reduction in hepcidin levels leading to increases in serum iron and consequently TSAT. PK/PD responses were examined over 60 days for a single 6 mg/kg intravenous dose of DISC-0974 in three male NHPs and in repeat dose studies occurring at 14 day intervals administered 3 times (vehicle, 0.6 and 3 mg/kg) or two times (60 mg/kg). In these studies, the serum iron response saturated in an exposure-dependent manner over the 0.6-60 mg/kg dose range. The onset of iron elevation lagged compared to the DISC-0974 maximal plasma concentrations by 1- 4 days post dose and persisted beyond what could be predicted by DISC-0974 plasma concentration alone. The observed PD responses were well-described by a delayed response PK/PD model of serum iron which was fit globally to all studies.

We will present single and multiple dose simulations showing that low monthly doses of DISC-0974 are sufficient to elicit a biologically significant and controlled PD modulation (serum iron, TSAT, hepcidin) over a sustained period-of-time (Figure 1). DISC-0974 is under development for the treatment of anemia of inflammation associated with high hepcidin.

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