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

• Published in: Blood Vol. 124; no. 17; pp. 2643 - 2646
• Main Authors: van Eijk, Lucas T., John, Aaron S.E., Schwoebel, Frank, Summo, Luciana, Vauléon, Stéphanie, Zöllner, Stefan, Laarakkers, Coby M., Kox, Matthijs, van der Hoeven, Johannes G., Swinkels, Dorine W., Riecke, Kai, Pickkers, Peter
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.10.2014; American Society of Hematology
• Subjects: Adolescent; Adult; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - pharmacokinetics; Anti-Inflammatory Agents - therapeutic use; Brief Report; C-Reactive Protein - metabolism; Clinical Trials and Observations; Double-Blind Method; Endotoxemia - blood; Endotoxemia - chemically induced; Endotoxemia - prevention & control; Hepcidins - antagonists & inhibitors; Hepcidins - blood; Humans; Inflammation - blood; Inflammation - chemically induced; Inflammation - prevention & control; Injections, Intravenous; Interleukin 1 Receptor Antagonist Protein - blood; Interleukin-10; Interleukin-6 - blood; Iron - blood; Leukocyte Count; Lipopolysaccharides; Male; Metabolic Clearance Rate; Oligoribonucleotides - administration & dosage; Oligoribonucleotides - pharmacokinetics; Oligoribonucleotides - therapeutic use; Treatment Outcome; Tumor Necrosis Factor-alpha - blood; Young Adult
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2014-03-559484

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. •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.