NIV Congres

Introduction: Anemia of chronic disease (ACD) is generally attributed to increased hepcidin production. The first-in-class hepcidin antagonist NOX-H94, a PEGylated anti-hepcidin L-RNA oligonucleotide, is in development for targeted treatment of ACD.

Aim of the study: To investigate whether NOX-H94 prevents the inflammation-induced serum iron decrease during experimental human endotoxemia. Effects on the innate immune response were studied as secondary endpoints.

Materials and Methods: This randomized, double-blind, placebo-controlled trial was carried out in 24 healthy young men. At T = 0 hours (h), 2 ng/kg E. coli endotoxin (LPS) was administered intravenously (iv), followed by 1.2 mg/kg NOX-H94 or placebo iv at T = 0.5 h. Blood was drawn serially for 24 h and at day 3, 8 and 15 after endotoxin administration for measurements of inflammatory parameters, cytokines, NOX-H94 pharmacokinetics, total hepcidin-25 (free and NOX-H94-bound), and iron parameters. The difference of serum iron change from baseline at T = 9 h was defined as primary endpoint. Data are expressed as mean ± SD.

Results: LPS administration led to flu-like symptoms and an increase in CRP, leucocytes and plasma levels of TNF-α, IL-6, IL-10, and IL-1RA that was similar for both treatment groups.

NOX-H94 plasma concentrations peaked at 0.7 ± 0.4 h after the start of administration, after which they declined according to a two-compartment model, with a T½ of 22.5 ± 4.28 h. Total hepcidin-25 rose to a peak of 23.0 ± 5.2 nM at T = 5.5 ± 0.05 h post LPS in control subjects and normalized at about T = 24 h. In the NOX-H94 treated group, total hepcidin-25 concentrations, which include hepcidin-25 bound to NOX-H94, rose to 559 ± 112 nM at T = 9.5 ± 1.5 h post-LPS and normalized slowly until day 15. In the placebo group, serum iron increased from 19.0 ± 7.6 µmol/L at baseline to a peak of 32.6 ± 6.71 µmol/L at T = 3 h, and decreased to its lowest point at T = 12 h, being 8.0 ± 2.95 µmol/L. In the NOX-H94 group, serum iron concentrations rose to 38.3 ± 8.09 µmol/L at T = 6 h and then slowly declined to 9.3 ± 5.83 at T = 24 h. From 6 to 12 h post LPS, the serum iron concentrations in NOX-H94 treated subjects were significantly higher than in placebo treated subjects (p < 0.0001, ANCOVA). At T = 24 h and 48 h, serum iron tended to be lower in NOX-H94 treated subjects than in placebo controls.

Conclusion: Treatment with NOX-H94 had no effect on innate immunity, but effectively prevented the inflammation-induced drop in serum iron concentrations during experimental human endotoxemia. These findings demonstrate the clinical potential of the anti-hepcidin drug NOX-H94 for further development to treat patients with ACD.