Biosimilar Epoetins in Renal Anaemia – Current Status and Insights from European Practice


Table 2: European Medicines Agency Approved Biosimilar Epoetins Biosimilar Epoetin Alfa


Molecule Originator epoetin Market authorisation holder Date of EMA authorisation


Binocrit® HX575


Epoetin alfa Manufacturer of active substance Rentschler


Epoetin alfa HEXAL® Abseamed® HX575


HX575


Epoetin alfa Rentschler


Biotechnologie Biotechnologie Sandoz GmbH Hexal Biotech


August 2007 August 2007


Epoetin alfa Rentschler


Biotechnologie


Medice Arzneimittel Pütter


August 2007 Information obtained from the European Medicines Association (EMA) summary of product characteristics for each product.86–90


Figure 2: Comparability of Mean Haemoglobin Levels Throughout Study Duration in Patients Receiving Intravenous Epoetin Alfa or Epoetin Zeta


Randomisation Crossover Hospira Stada Arzneimittel December 2007 December 2007


Epoetin Zeta


Retacrit® SB309


Epoetin alfa Norbitec


Silapo® SB309


Epoetin alfa Norbitec


12


10 8 6 4 2


0 0 4 8 12


Epoetin alfa after randomisation


Epoetin zeta after randomisation


Reproduced with permission from Wizemann et al., 2008.65


degree of glycosylation and types of glycan moieties for both biosimilars were different to epoetin alfa, they were not considered unusual.58,59 Heterogeneity of epoetin isoforms was almost identical between epoetin zeta and epoetin alfa (see Figure 1). Comparability of both biosimilars to epoetin alfa for purity and bioactivity was also clearly demonstrated.58,59


Efficacy – Non-clinical Assessment


For non-clinical assessment, the pharmacodynamic comparability of both biosimilars was demonstrated in receptor binding, proliferation and second messenger activation studies in vitro and in the normocythaemic mouse assay in vivo.58,59


In toxicity studies in rats and dogs, all three


products produced effects characteristic of EPO but there were no meaningful differences between the biosimilars and epoetin alfa.58,59 Although both biosimilar epoetin alfa and epoetin zeta demonstrated antigenicity in dogs, the number of animals affected in the biosimilar epoetin alfa study was considered too few to allow meaningful conclusions to be drawn and the antibodies evoked by epoetin zeta were non-neutralising and not associated with adverse effects.58,59


Efficacy – Clinical Assessment


For biosimilar epoetin alfa, comparability was examined in five pharmacokinetic studies in healthy volunteers using both subcutaneous and intravenous routes of administration and a single therapeutic study in patients with renal anaemia (see Table 3).59


In the pharmacokinetic EUROPEAN NEPHROLOGY


Figure 3: Comparability of End-of-study Mean Haemoglobin Levels and Mean Weekly Dosage in Patients Receiving Subcutaneous Epoetin Zeta or Epoetin Alfa for the Maintenance Treatment of Renal Anaemia


AB


14 13 12 11 10 9 8 7


+ +


600 500 400 300 200 100 0


Epoetin zeta Epoetin alfa 16 Week of treatment


Epoetin alfa after crossover


Epoetin zeta after crossover


Run-in 20 24 28 32 36


+


+ Epoetin zeta Epoetin alfa


Mean haemoglobin level (A) and mean weekly dosage per kg body weight (B) during the last four weeks of treatment. The boundaries of the box represent the upper and lower quartiles; the height of the box is the interquartile range; the line within the box is the median; the cross is the arithmetic mean of the group; the error bars are the maximum and minimum values in the group of data plotted. Data reproduced with permission from Krivoshiev et al., 2010.64


studies, comparability of biosimilar epoetin alfa to epoetin alfa was demonstrated for both single and multiple doses irrespective of the route of administration.59–61


The therapeutic study was designed to 103


Haemoglobin level (g/dl)


Haemoglobin (g/dL)


Epoetin dose (IU/week/kg)


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