Effect of the antihepcidin Spiegelmer lexaptepid on inflammation-induced decrease in serum iron in humans

Abstract

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, double-blind, placebo-controlled trial was carried out in 24 healthy males. At T = 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 = 0.5 hours. The lipopolysaccharide-induced inflammatory response was similar in subjects treated with lexaptepid or placebo regarding clinical and biochemical parameters. At T = 9 hours, serum iron had increased by 15.9 ± 9.8 µmol/L from baseline in lexaptepid-treated subjects compared with a decrease of 8.3 ± 9.0 µmol/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.

© 2014 by The American Society of Hematology.

Figures

Figure 1

Plasma lexaptepid and iron parameters during experimental human endotoxemia. (A) Drug concentration in lexaptepid-treated subjects only. (B) Concentration of hepcidin in lexaptepid- and placebo-treated subjects. (C) Serum iron concentrations. Black arrow indicates the primary end point: change in serum iron levels at 9 hours after LPS administration. (D) Transferrin saturation (TSAT). Data are expressed as mean ± SD. Changes in all parameters over time were analyzed with 2-way analysis of variance with repeated measures, interaction term. Interaction terms are displayed within each graph. In the lexaptepid-treated subjects, hepcidin levels were still elevated at T = 168 hours (day 8) compared with baseline values (Student paired t test: P = .005).

Figure 2

Inflammatory parameters. (A) C-reactive protein (CRP) and (B) white blood cell count. CRP peaked at 24 hours and had fully normalized by day 8 in both treatment groups. Values in panels A and B are depicted as mean and SD. Differences over time were analyzed with 2-way analysis of variance with repeated measures. The P value of the interaction terms are depicted in the respective panels. Plasma concentrations of (C) TNF-α, (D) IL-10, (E) IL-6, and IL-1 receptor antagonist (F) (IL-1RA) are displayed for the treatment groups. As cytokine concentrations were not normally distributed, only median cytokine concentrations are depicted. Areas under the concentration-time curve (AUC) were calculated for each individual and compared between groups as depicted in the inserted bar charts. Differences in areas under the curve between groups were tested with the Mann-Whitney U test. No significant differences in cytokine concentrations between the treatment groups were observed.