Efficacy of recombinant erythropoietins: is there unity of international units?

The European Medicines Evaluation Agency (EMEA) has developed guidelines to ensure similarity, ‘in terms of quality, safety and efficacy’, between similar biological medicinal products (biosimilars) in comparison to the originators (http://www.emea.eu.int). The quality and safety of biosimilar recombinant human erythropoietins (rhEPOs) has been previously discussed [ 1–3 ]. The present comment focuses on the comparability of the in vivo potency of rhEPOs, which is relevant to the economic use of erythropoiesis stimulating agents (ESAs), because biosimilar rhEPOs have been priced by up to 30% lower than the originators in some countries of the European Union (EU). According to the International Nonproprietary Name (INN), experts of the World Health Organization (WHO), ‘epoetins’ are rhEPOs with the same amino acid sequence and glycosylation sites as endogenous EPO [ 4 ]. Amino acid changes are indicated by distinct prefixes (e.g. ‘darbepoetin’) and glycan differences by Greek letters. The composition of the glycans of rhEPOs depends on the transfected cell culture and product purification procedures [ 5 ]. Indeed, the originator epoetins alfa and beta, which are engineered in Chinese hamster ovary (CHO) cells, exhibit differences in the sugar composition of their N - and O -glycans [ 6,7 ]. However, one epoetin alfa biosimilar (HX575) has received EMEA approval as ‘epoetin alfa’, although it contains more high-mannose structures and less N -glycolyl-neuraminic and diacetylated neuraminic acids than the originator (Eprex®/Erypo®) [ 8 ]. A second epoetin alfa biosimilar (SB309), which has received the INN ‘epoetin zeta’, has less O -glycans, N -glycolyl-neuraminic acid and O -acetyl neuraminic acid than the reference product [ 9 ].