Anaemia Management
Biosimilar Epoetins in Renal Anaemia – Current Status and Insights from European Practice
Gerhard Lonnemann1 and Iain C Macdougall2
1. Professor and Senior Partner, Private Outpatient Clinic and Dialysis Centre, Langenhagen; 2. Consultant Nephrologist and Honorary Senior Lecturer, Department of Renal Medicine, King's College Hospital
Abstract
Renal anaemia associated with chronic kidney disease is caused by inadequate production of erythropoietin, but can be corrected by the use of recombinant human erythropoietins (epoetins). The expiration of patents for innovator epoetins has resulted in the development of ‘generic versions’, termed biosimilar epoetins. In the European Union (EU), market authorisation of biosimilars is carefully regulated by guidelines from the European Medicines Agency (EMA) that are based on the comparability of quality, safety and efficacy between the biosimilar and the innovator product. Two biosimilar epoetins, biosimilar epoetin alfa and epoetin zeta, received authorisation in 2007 and are currently traded under five different brand names. Another product, epoetin theta, which is not strictly speaking a biosimilar but for practical purposes can be regarded as such, received EU approval in 2009. EMA guidelines stipulate the implementation of long-term pharmacovigilance plans to monitor for immunogenicity. To date, no immunogenic responses have been seen in the longest study with epoetin zeta, although two cases of neutralising antibodies were seen in a clinical trial of subcutaneous biosimilar epoetin alfa. Real-world experience shows that biosimilars are as effective as innovator products in correcting renal anaemia. The use of biosimilar epoetins can offer considerable financial advantages over existing innovator products, which is of increasing importance for overburdened healthcare systems.
Keywords Renal anaemia, biosimilar, comparability, chronic kidney disease, erythropoietin, epoetin zeta, European Medicines Agency
Disclosure: Gerhard Lonnemann has no conflicts of interest to declare. Iain C Macdougall has received lecture honoraria, research grants and consultancy fees from several manufacturers of anaemia therapies, including Amgen, Ortho Biotech, Roche, Shire, Affymax and Vifor. Received: 19 September 2011 Accepted: 1 November 2011 Citation: European Nephrology, 2011;5(2):101–7 Correspondence: Gerhard Lonnemann, Outpatient Clinic and Dialysis Centre, Eickenhof 15, D-30851 Langenhagen, Germany. E:
lonnemann@eickenhof-dialyse.de
Support: The publication of this article, including writing and editorial assistance from Touch Briefings, was funded by Hospira. The views and opinions expressed are those of the authors and not necessarily those of Hospira.
Chronic kidney disease (CKD) is a global health problem. Recent estimates indicate that around 10 % of the total population in the US and Europe are affected, rising to around 33 % of those aged over 64 years.1–4
Anaemia is a common and important consequence of CKD.5–8 If
left untreated, renal anaemia causes fatigue, lack of energy and a number of other symptoms,7 life.9–11
as well as having a significant impact on quality of
Moreover, renal anaemia is associated with considerable morbidity and mortality, including an increased risk of cardiovascular disease and more rapid progression of CKD.12–16
Early diagnosis and treatment of renal anaemia is therefore necessary to reduce the burden of CKD.
The pathophysiology underlying renal anaemia is multifactorial but primarily due to insufficient erythropoietin (EPO) production.7,17,18 In adults, EPO synthesis occurs in the kidney and is driven by the oxygen-dependent regulation of transcription factors that promote EPO gene expression.17–19
Once produced, EPO binds to receptors
on erythroid progenitor cells in the bone marrow, causing them to differentiate and proliferate into reticulocytes and red blood cells.17,19,20 The absence of EPO not only leads to reduced erythropoiesis but also the apoptosis of erythroid progenitor cells and a reduced lifespan of red blood cells.7,17–19
Patients with CKD therefore display reduced © TOUCH BRIEFINGS 2011
erythropoiesis and decreased numbers of reticulocytes and red blood cells and are unable to maintain a normal haemoglobin concentration.7 Since the typical physiological response to anaemia is an increase in EPO production, the exact mechanisms leading to reduced EPO production in renal anaemia are not fully understood,7,18
but recent evidence
suggests that this is due to defective hypoxic signalling rather than an inability of the EPO-producing cells to synthesise erythropoietin per se.21
Nonetheless, over the past two decades erythropoiesis-stimulating agents, particularly recombinant human erythropoietins (epoetins), have become the mainstay of renal anaemia therapy by correcting the underlying pathophysiology.22,23
Epoetins are a heterogeneous
mixture of closely related isoforms that differ in their degree of glycosylation and types of glycan moieties. The first generation epoetins, epoetin alfa and epoetin beta,24–27
were subsequently
developed into a hyperglycosylated version of epoetin alfa, darbepoetin alfa and a pegylated version of epoetin beta, methoxy polyethylene glycol-epoetin beta (also known as continuous erythropoietin receptor activator or CERA). Both possess a longer half-life than their parent epoetins and therefore require less frequent dosing (see Table 1).28–32 Trials have demonstrated the effectiveness of epoetins in correcting
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