When treatment of the underlying disease is difficult or impractical, the limited options available for treating severe anemia (i.e., RBC transfusion in acute cases and ESAs and parenteral iron in more subacute and chronic cases) suffer from marginal efficiency and high risk. To address this unmet need, several translational studies are now focused on countering hepcidin overexpression. Hepcidin antagonists in development target either the hepcidin molecule or its regulators (e.g., BMP) in the hope that the potential therapeutic efficacy of hepcidin antagonists may extend to even mild anemias.

Via the Inflammatory Signal

Several diseases in the ACI category (e.g., Castleman disease and RA) have benefited from clinical trials with hepcidin-lowering agents (Table 1). Therapeutic monoclonal antibodies against IL-6 receptor (tocilizumab), IL-6 (siltuximab), and TNF-α (golimumab or infliximab) resulted in decreased hepcidin and improved anemia. In addition, downstream inhibition of STAT3 signaling (e.g., curcumin, AG490, and PpYLKTK) has demonstrated effectiveness in decreasing hepcidin in vitro and in pre-clinical studies in vivo. They are, however, unlikely to come to market as a consequence of their non-specific effects (all), competing iron-chelating properties (curcumin), and suboptimal pharmacokinetics (AG490 and PpYLKTK).

Table1. Novel Hepcidin Suppressing Agents as Potential Therapy for Anemia of Chronic Inflammation

Via the Iron Signal

Heparin, a glycosaminoglycan and frequently used agent in the treatment and prophylaxis of blood clots, has a high affinity for BMPs. Thus, heparin inhibits hepcidin expression by binding to and sequestering BMPs. Furthermore, heparins without anticoagulating effects have been developed, demonstrating reversal of anemia in mouse models of ACI and are specifically able to block hepcidin in vitro and in pre-clinical studies in vivo. These agents are poised for randomized clinical trials. Hemojuvulin (HJV) is a BMP co receptor, enhancing hepcidin expression. Soluble HJV, resulting from cleavage of cellular HJV, competes for binding of BMP to BMP receptor. Administration of either neutralizing anti-HJV anti bodies (AbbVie Pharmaceuticals) or sHJV fused with IgG Fc fragment result in hepcidin suppression and correct anemia in murine ACI models. Clinical studies using such agents in renal failure patients are underway.

Antibodies and small molecule inhibitors of BMP/SMAD have also demonstrated pre-clinical efficacy in decreasing hepcidin expression. For example, anti-BMP6 antibodies, dorsomorphin, an inhibitor of BMP/SMAD signaling, and dorsomorphin derivatives, e.g., LDN-193189, reduce hepcidin expression and increase serum iron concentration in mice. However, because dorsomorphin and its derivatives do not specifically target BMP/SMAD signaling to hepcidin, they are considered suboptimal candidates for therapeutic development. TP-0184 (Toledo Pharmaceuticals) and momelotinib (Gilead) are specific ALK2 inhibitors undergoing clinical trials in solid tumors and myelofibrosis, respectively. TP-0184 has recently been shown to suppress hepcidin in mouse models of ACI and cancer, but further studies are required to evaluate its full translational potential in ACI.

Via Erythropoietic Signal

 Novel hypoxia inducible factor (HIF) stabilizers provide promise in the treatment of ACI, enabling hepcidin blockade mediated via erythropoiesis, simultaneously stimulating erythropoiesis and iron availability. For example, propyl hydroxylase domain-2 (PDH2) inhibitors stabilize HIF-1 and HIF-2, stimulating endogenous Epo production to suppress hepcidin and enable greater iron availability for erythropoiesis. In light of the recent discovery of ERFE and its negative regulation of hepcidin, modulation of this pathway is a clear area for future investigation.

Direct Hepcidin Inhibition

 Direct hepcidin inhibitors, e.g., hepcidin neutralizing antibodies, have demonstrated efficacy in increasing iron availability for erythropoiesis, reversing anemia, and increasing responsiveness to ESAs in mouse models of ACI and in monkeys. LY2787106, a monoclonal anti-hepcidin antibody (Eli Lily), has recently demonstrated high tolerability, transient iron mobilization, and increased reticulocytosis in a Phase I study of cancer-related anemia patients. PRS-080, a PEGylated anticalin with specific hepcidin binding and neutralizing capacity (Pieris Pharmaceuticals), demonstrated suppression of hepcidin activity in vitro and in mice with decreased hepcidin and transiently increased transferrin saturation at doses above 0.4 mg/ kg in a Phase I study in healthy volunteers, warranting further investigations in anemic patients. Lastly, NOX-H94, a spiegelmer (PEGylated non-natural occurring mirror-image L-RNA aptamer) hepcidin antagonist (NOXXON Pharma AG), specifically binds hepcidin with high affinity. NOX-H94 improved ACI in monkeys and prevented hypoferremia in LPS-injected humans volunteers. As a consequence, additional clinical trials in renal insufficiency, ACI, and cancer-related anemia are underway.

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