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

Abstract

Abstract:Hematide TM is a synthetic peptide-based, PEGylated erythropoiesis-stimulating agent, which is being developed for the chronic treatment of anaemia associated with chronic renal failure. To support the safety of long-term dosing of chronic renal failure patients, a comprehensive toxicology programme was implemented including rat subchronic and chronic studies. Rats were administered 0, 0.1, 1 and 10 mg/kg of Hematide every 3 weeks for 3 months via subcutaneous injection or for 6 months via intravenous injection. The dosing period was followed by a 6-week follow-up period. The primary pharmacology of Hematide resulted in erythroid polycythemia as measured by elevated haemoglobin levels that were time-and dosedependent. The pharmacology profiles were similar regardless of administration route. For example, for male rats at Day 90, subcutaneous dosing resulted in haemoglobin increases of 2.7, 4.5 and 6.9 g/dl for 0.1, 1 and 10 mg Hematide/kg respectively, compared to 2.8, 5.7 and 7.4 g/dl increases for intravenous dosing. Histopathological changes were related to the prolonged severe polycythemia induced in normocythemic animals administered an erythropoiesis-stimulating agent. The findings included extramedullary haematopoiesis in the spleen and liver, bone marrow hypercellularity and organ congestion. Microscopic findings were reversible, demonstrating a return towards control findings within 6 weeks following cessation of dosing. Systemic exposures, based on both area under the curve (AUC) and maximum concentration (C max ), were substantially greater for intravenous than subcutaneous administration. No Hematide-specific antibodies were detected. In conclusion, Hematide is a potent erythropoiesis-stimulating agent, and the studies provide support for the safety of clinical development, including chronic dosing, for the treatment of anaemia associated with chronic renal failure.

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“…Area under curve and maximum concentration was seen to be greater by intravenous than subcutaneous route in a rodent study projecting better bioavailability by intravenous route but this difference was not observed clinically 24,28 .…”

“…The immune responses, which are observed in the repeat dose toxicity studies conducted with the currently marketed ESA, were not observed with peginesatide 28 . Antibodies to peginesatide were not found to cross-react with EPO and vice versa.…”

Peginesatide Clearance, Distribution, Metabolism, and Excretion in Monkeys following Intravenous Administration

“…(Greaves and Faccini, 1992;O'Malley et al, 2005). Furthermore, unlike in rodents (Woodburn et al, 2009), EMH has not been shown to occur in monkeys administered peginesatide up to 20 mg/kg i.v. every 3 weeks for 9 months (Woodburn et al, 2008a,b).…”

“…administration and correlating the ADME properties with the pharmacological activity have been reported (Woodburn et al, 2012). The toxicologic assessment of peginesatide was also performed in both the rat (Woodburn et al, 2009) and the monkey (Woodburn et al, 2008a,b). The monkey and the rat are appropriate species for the nonclinical assessment of peginesatide based on pharmacological, toxicological, and pharmacokinetic (PK) considerations.…”

Phage display as a technology delivering on the promise of peptide drug discovery

“…Phage display technology is a powerful tool in drug discovery, particularly for the identification of ligands with novel functions [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25], however, its application range covers very diverse areas such as nanostructured electronics [26,27], agriculture [28], medical diagnosis [29] and neurobiology [30], just to mention few. The success of phage display can be credited to the fact that highly diverse libraries can be constructed allowing rapid isolation and identification of specific proteinaceous ligands for numerous types of macromolecular targets [6,31].…”