Randomized double-blind placebo-controlled PK/PD study on the effects of a single intravenous dose of the anti-hepcidin Spiegelmer NOX-H94 on serum iron during experimental human endotoxemia

Introduction

Anemia is very frequently encountered on the ICU. Increased hepcidin production is one of the cornerstones of the pathophysiology of anemia of inflammation. The first-in-class hepcidin antagonist NOX-H94, a PEGylated anti-hepcidin L-RNA oligonucleotide, is in development for targeted treatment of anemia of inflammation. We investigated whether NOX-H94 prevents the inflammation-induced serum iron decrease during experimental human endotoxemia.

Methods

A randomized, double-blind, placebo-controlled trial in 24 healthy young men. At T = 0 hours, 2 ng/kg E. coli endotoxin was administered intravenously (i.v.), followed by 1.2 mg/kg NOX-H94 or placebo i.v. at T = 0.5 hours. Blood was drawn serially after endotoxin administration for measurements of inflammatory parameters, cytokines, NOX-H94 pharmacokinetics, total hepcidin-25, and iron parameters. The difference of serum iron change from baseline at T = 9 hours was defined as the primary endpoint.

Results

Endotoxin administration led to flu-like symptoms. Inflammatory parameters (CRP, body temperature, leucocytes, and plasma levels of TNFα, IL-6, IL-10, and IL-1RA) peaked markedly and similarly in both treatment groups. NOX-H94 was well tolerated. Plasma concentrations peaked at 0.7 ± 0.4 hours after the start of administration, after which they declined according to a two-compartment model, with a T_1/2 of 22.5 ± 4.28 hours. In the placebo group, serum iron increased from 19.0 ± 7.6 μg/l at baseline to a peak at T = 3 hours, returned close to baseline at T = 6 hours and decreased under the baseline concentration at T = 9 hours, reaching its lowest point at T = 12 hours. In the NOX-H94 group, serum iron concentrations rose until T = 6 hours and then slowly declined until T = 24 hours. From 6 to 12 hours post LPS, the serum iron concentrations in NOX-H94-treated subjects were significantly higher than in placebo-treated subjects (P < 0.0001, ANCOVA).

Conclusion

Experimental human endotoxemia induces a robust inflammatory response and a subsequent decrease in serum iron. Treatment with NOX-H94 had no effect on innate immunity, but effectively prevented the inflammation-induced drop in serum iron concentrations. These findings demonstrate the clinical potential of the anti-hepcidin drug NOX-H94 for further development to treat patients with anemia of inflammation.