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Anaemia


New Treatment Approaches in Chronic Kidney Disease-associated Anaemia Lucia Del Vecchio1


and Francesco Locatelli2 1. Clinical Staff Member; 2. Head, Department of Nephrology, Dialysis, and Renal Transplant, ‘Alessandro Manzoni’ Hospital


Abstract


Recombinant human erythropoietin (rHuEPO) is an effective agent for the treatment of anaemia in patients with chronic kidney disease. However, given its relatively short half-life, it requires a relatively frequent administration schedule. Moreover, it can be administered only subcutaneously or intravenously and is unstable at room temperature, making a strict cold chain control necessary. Pharmacological research has focused on the development of new agents to circumvent these relative disadvantages. Some long-acting erythropoietin-stimulating agents (ESAs) are already available for clinical use that require a less-frequent administration schedule. Peginesatide (Hematide™), which is a small dimeric peptide with a chemical structure unrelated to EPO, has recently ended phase III clinical trials. Other new molecules undergoing clinical development are CNTO 530 and CNTO 528, ACE-011 and hypoxia-inducible transcription factor stabilisers. The latter have the advantage that they can be administered orally but their clinical development faces a significant hurdle following a case of fatal hepatitis. Newer molecules in this class are undergoing clinical evaluation. Other strategies, such as EPO fusion proteins, agonistic antibodies targeting the EPO receptor and gene therapy have only been tested in animal models or are undergoing pre-clinical evaluations. Before clinical approval, all these new strategies need to address safety concerns raised recently about the use of ESAs regarding possible increased cardiovascular risks following targeting to high haemoglobin levels and/or exposure to excessive doses without reaching a target in both higher and lower haemoglobin groups, and reduced survival and tumour control in the oncology setting. Many of these molecules will also need careful evaluation for possible immunogenicity.


Keywords Anaemia, erythropoietin, chronic kidney disease, Hematide™, prolyl hydroxylase inhibitor, erythropoiesis


Disclosure: Lucia Del Vecchio has no conflicts of interest to declare. Francesco Locatelli is on the advisory boards of Affymax, Amgen-Dompé, GlaxoSmithKline, Janssen Cilag, Roche and Takeda and on the Safety Committee of Sandoz. Received: 27 August 2010 Accepted: 9 March 2011 Citation: European Oncology & Haematology, 2011;7(2):132–5 Correspondence: Francesco Locatelli, Department of Nephrology, Dialysis, and Renal Transplant, Alessandro Manzoni Hospital, Via dell’Eremo 9, 23900 Lecco, Italy. E: f.locatelli@ospedale.lecco.it


Anaemia, resulting primarily from insufficient production of erythropoietin to support erythropoiesis, is a common complication of chronic kidney disease (CKD). Approximately 50% of patients with CKD stage III–V have anaemia.1 patients receiving dialysis.2


This percentage increases greatly in Since the late 1980s, the availability of


recombinant human erythropoietin (rHuEPO) has revolutionised the management of anaemia in patients with CKD. Today, erythropoiesis- stimulating agents (ESAs), together with iron supplementation, are the main tool used to achieve anaemia correction in CKD patients.


Over the past two decades, several attempts have been made to develop new ESAs with theoretically improved characteristics compared with rHuEPO, to develop easier manufacturing processes and to develop other strategies that may indirectly increase erythropoiesis. Table 1 summarises new ESAs under clinical development in CKD patients.


Erythropoiesis-stimulating Agents – Molecules on the Market


Epoetin alpha and epoetin beta are synthesised in Chinese hamster ovary cells and share the same amino acid sequence as endogenous EPO but slightly differ in their carbohydrate moieties.3


The patent of both drugs expired some years ago, opening the way to biosimilars. 132


Some of the biosimilars have their own international non-proprietary names (INN) (epoetin zeta), but their molecular structure is close to that of epoetin alpha.


Epoetin theta is similar to epoetin alpha and received marketing approval from the European Medicines Agency (EMA) in 2009 as an originator. Epoetin omega and epoetin delta differ from epoetin alpha and beta because they are synthesised in cells other than those from the Chinese hamster ovary4,5


and, consequently, they differ slightly in


their glycosylation patterns compared with epoetin alpha and beta.6 Epoetin delta was discontinued in 2009 for commercial reasons.


Darbepoetin alpha (Amgen Inc.) is the first EPO analogue with a prolonged half-life. Compared with EPO, it has a modified amino acid sequence, higher sialic acid content and molecular weight, and increased negative charge.7


The half-life of darbepoetin alpha is nearly


two to three times that of rHuEPO depending on the administration route. This characteristic allows a less-frequent administration schedule. Dose requirements are almost independent of the administration route.8


Continuous erythropoietin receptor activator (CERA) (Roche) is another modified EPO molecule containing a large water-soluble


© TOUCH BRIEFINGS 2011


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