Key Points The hepcidin inhibitor NOX-H94, a structured mirror-image RNA oligonucleotide, and its in vitro and in vivo characterization are described. First published hepcidin inhibitor that entered clinical trials for the treatment of anemia due to functional iron deficiency.

NOX-A12 is a PEGylated mirror-image oligonucleotide (a so-called Spiegelmer) that binds to CXCL12 (stromal cell-derived factor-1, SDF-1) with high affinity thereby inhibiting CXCL12 signaling on both its receptors, CXCR4 and CXCR7. In animals, NOX-A12 mobilized white blood cells (WBCs) and hematopoietic stem and progenitor cells (HSCs) into peripheral blood (PB). In healthy volunteers, single doses of NOX-A12 had a benign safety profile and also dose-dependently mobilized WBCs and HSCs into PB. HSC peak mobilization reached a plateau at five times the baseline level at an i.v. dose of 5.4 mg/kg. In accordance with the plasma half-life of 38 h, the duration of the WBC and HSC mobilization was long lasting and increased dose-dependently to more than 4 days at the highest dose (10.8 mg/kg). In conclusion, NOX-A12 may be appropriate for therapeutic use in and beyond mobilization of HSCs, e.g., in long-lasting mobilization and chemosensitization of hematological cancer cells.

Mitogen-activated protein kinase-activated protein kinase 2 (MK2) is one of several kinases activated through direct phosphorylation by p38 mitogen-activated protein kinase. MK2 regulates LPS-induced TNF mRNA translation, and targeted mutation of the MK2 gene renders mice more resistant to d-galactosamine plus LPS-induced liver damage. In the present study, we investigated the role of MK2 in immune defense against Listeria monocytogenes infection. MK2-deficient mice displayed diminished resistance to L. monocytogenes due to impaired control of bacterial growth. The increase in bacterial load in MK2−/− mice was associated with normal levels of IL-1β, IL-6, and IFN-γ, whereas TNF production was strongly attenuated. In line, MK2-deficient bone marrow-derived macrophages showed impaired release of TNF, but not of IL-1β, in response to various bacterial stimuli in addition to decreased phagocytosis of fluorescence-labeled bacteria. Furthermore, spleen cells from MK2−/− mice displayed diminished IFN-γ synthesis after stimulation with L. monocytogenes. In contrast, MK2 deficiency had no effect on macrophage generation of NO or on oxidative burst activity in response to L. moocytogenes. These results indicate an essential role of MK2 in host defense against intracellular bacteria probably via regulation of TNF and IFN-γ production required for activation of antibacterial effector mechanisms.

Key Points• Lexaptepid modulates the inflammation-induced decrease in serum iron during experimental human endotoxemia.• Hepcidin targeting with the novel compound lexaptepid may be a viable approach to the treatment of anemia of inflammation in humans.Increased hepcidin production is key to the development of anemia of inflammation. We investigated whether lexaptepid, an antihepcidin L-oligoribonucleotide, prevents the decrease in serum iron during experimental human endotoxemia. This randomized, doubleblind, placebo-controlled trial was carried out in 24 healthy males. At T 5 0 hours, 2 ng/kg Escherichia coli lipopolysaccharide was intravenously administered, followed by an intravenous injection of 1.2 mg/kg lexaptepid or placebo at T 5 0.5 hours. The lipopolysaccharide-induced inflammatory response was similar in subjects treated with lexaptepid or placebo regarding clinical and biochemical parameters. At T 5 9 hours, serum iron had increased by 15.9 6 9.8 mmol/L from baseline in lexaptepidtreated subjects compared with a decrease of 8.3 6 9.0 mmol/L in controls (P < .0001). This study delivers proof of concept that lexaptepid achieves clinically relevant hepcidin inhibition enabling investigations in the treatment of anemia of inflammation. This trial was registered at www.clinicaltrial.gov as #NCT01522794. (Blood. 2014;124(17):2643-2646

Background and PurposeAnaemia of chronic disease is characterized by impaired erythropoiesis due to functional iron deficiency, often caused by excessive hepcidin. Lexaptepid pegol, a pegylated structured l‐oligoribonucleotide, binds and inactivates hepcidin.Experimental ApproachWe conducted a placebo‐controlled study on the safety, pharmacokinetics and pharmacodynamics of lexaptepid after single and repeated i.v. and s.c. administration to 64 healthy subjects at doses from 0.3 to 4.8 mg·kg−1.Key ResultsAfter treatment with lexaptepid, serum iron concentration and transferrin increased dose‐dependently. Iron increased from approximately 20 μmol·L−1 at baseline by 67% at 8 h after i.v. infusion of 1.2 mg·kg−1 lexaptepid. The pharmacokinetics showed dose‐proportional increases in peak plasma concentrations and moderately over‐proportional increases in systemic exposure. Lexaptepid had no effect on hepcidin production or anti‐drug antibodies. Treatment with lexaptepid was generally safe and well tolerated, with mild and transient transaminase increases at doses ≥2.4 mg·kg−1 and with local injection site reactions after s.c. but not after i.v. administration.Conclusions and ImplicationsLexaptepid pegol inhibited hepcidin and dose‐dependently raised serum iron and transferrin saturation. The compound is being further developed to treat anaemia of chronic disease.