Kai Riecke

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

Safety, pharmacokinetics and pharmacodynamics of the anti‐hepcidin Spiegelmer lexaptepid pegol in healthy subjects

Anaemia 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.

Abstract 3847: The anti-hepcidin Spiegelmer® Lexaptepid Pegol (NOX-H94) as treatment of anemia of chronic disease in patients with multiple myeloma, low grade lymphoma, and CLL: A phase II pilot study

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Lexaptepid pegol (LP) is a PEGylated L-stereoisomer RNA aptamer that binds and neutralizes hepcidin. Hepcidin, a 25 amino acid peptide induced by inflammatory stimuli is a pivotal regulator of iron resorption and iron release from intracellular stores, which are severely impaired in anemia of chronic disease. Disturbances in iron metabolism resulting in functional iron deficiency are a key component of anemia of chronic disease which frequently complicates malignant disease. We evaluated the pharmacokinetics, pharmacodynamics, safety and efficacy of hepcidin blockade by LP as sole treatment of anemia of chronic disease in patients with multiple myeloma, low grade Non-, or Hodgkin lymphoma. Twelve patients with functional iron deficiency anemia with the following baseline characteristics, presented as median (range), were enrolled: age 64 years (35-77), Hb 9.6 g/dL (8.0-10.7), serum ferritin 317 µg/L (193-2805), serum iron 29 µg/dL (18-97), TSAT 12% (6-46). LP was injected i.v. at a dose of 1.2 mg/mg, TIW for 4 weeks. Blood counts, serum biochemistry, and iron status were evaluated weekly until two weeks post treatment and at week four after the end of therapy. The primary endpoint was increase in Hb by ≥1 g/dL at any time between start of therapy until 1 week after end of treatment. The study has the clinicaltrials.gov identifier NCT 01691040. Five of the 12 patients reached the target Hb increase of ≥1 g/dL, 3 patients achieved this goal within 2 weeks. Four of the 5 responding patients had hypochromic anemia (MCH 22-26 pg) and moderately increased baseline ferritin levels (200-350 µg/L). Median serum ferritin decreased from 317 to 232 µg/L (p=0.014) in the entire cohort of patients, and from 253 to 203 µg/L in responders (p=n.s). Reticulocyte hemoglobin increased from 22.0 to 25.2 pg (p=0.019) in responding patients, while in non-responders no increase was noted (30.0 to 30.1 pg). Similarly, a trend to increased reticulocyte index was observed in the responding patients (median: 0.9 to 1.3, p=n.s.) only. Soluble transferrin receptor levels (sTFR) showed a trend to decrease in responders (10.6 to 10.3 mg/L, p=n.s.), but remained unchanged in non-responders. Treatment with LP was well tolerated without major adverse reactions. In conclusion, LP induced a significant increase in Hb levels (≥1 g/dL) in 5 of 12 patients. Responding patients showed an increase in red cell and reticulocyte hemoglobin, and decrease in sTFR. These results support the concept of hepcidin inhibition for treatment of cancer associated anemia with functional iron deficiency. Patients with signs of iron deficiency as documented by hypochromic anemia, no excessive increase in ferritin and high sTFR levels showed a higher likelihood to respond to LP. Citation Format: Pencho Georgiev, Mihaela Lazaroiu, Luminita Ocroteala, Janet Grudeva-Popova, Emanuil Gheorghita, Mariana Vasilica, Sanda M Popescu, Andrei Cucuianu, Luciana Summo, Frank Schwoebel, Kai Riecke, Heinz Ludwig. The anti-hepcidin Spiegelmer® Lexaptepid Pegol (NOX-H94) as treatment of anemia of chronic disease in patients with multiple myeloma, low grade lymphoma, and CLL: A phase II pilot study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3847. doi:10.1158/1538-7445.AM2014-3847