Chronic Pharmacological and Safety Evaluation of Hematide™, a PEGylated Peptidic Erythropoiesis-Stimulating Agent, in Rodents

Anaemia in patients with chronic renal failure, which is caused primarily by an inadequate production of erythropoietin by the damaged kidneys [1], results in a reduction in length and quality of the patient's life [2]. The treatment of anaemia associated with kidney disease has been successfully carried out on more than a million patients by the use of recombinant human erythropoietin proteins [3]. However, the short half-life and pharmacological action of the currently available recombinant products, their potential to cause antibodies against endogenous erythropoietin and related analogues, high cost and lack of room temperature stability provide development incentives. Hematide™ is a synthetic peptide-based, PEGylated erythropoiesis-stimulating agent. The molecule was designed to bind and activate the erythropoietin receptor, stimulating red blood cell production [4]. PEGylation generally results in an increase in protein/peptide solubility, an increase in plasma half-life by shielding the molecule from proteolysis and by reducing renal clearance, and a decrease in immunogenicity by masking epitopes [5]. Hematide's novel primary amino acid sequence is unrelated to that of human erythropoietin. Therefore, any potential antibody formed to Hematide is not likely to cross-react with erythropoietin and induce pure red cell aplasia. Hematide's lack of erythropoietin immunological cross-reactivity makes it capable of increasing haemoglobin in rats when their anaemia was caused by anti-erythropoietin antibodies that cross-react with endogenous erythropoietin following the administration of recombinant human erythropoietin [6]. Most importantly, it has eliminated the need for transfusions in patients with anti-erythropoietin antibody-mediated pure red cell aplasia [7]. Hematide is being developed for the treatment of anaemia secondary to chronic renal failure in a patient population that requires lifelong therapy. To support chronic clinical therapy, a series of repeat-dose pharmacodynamic, safety and pharmacokinetic studies was performed in animals, including normocythemic rats. Sprague–Dawley rats were studied after subcutaneous injections of Hematide every 3 weeks for 3 months and after intravenous administration every 3 weeks for up to 6 months.