Background: HX575, licensed under the brand names Binocrit®, Epoetin Alfa Hexal®, and Abseamed®, was approved in 2007 as the first biosimilar recombinant human erythropoietin alfa (epoetin alfa) in the EU using Erypo®/Eprex® as reference product.
Objectives: The aim of this study was to investigate the bioequivalence and potency of registered epoetin alfa products that have not been compared before in a randomized controlled clinical study.
Methods: The study was conducted in two parts: part A compared the European-marketed HX575 and the US-marketed Epogen®; part B compared the European-marketed Erypo®/Eprex® and HX575 manufactured at two different drug substance production sites (HX575-TT denoting the already-approved technology-transfer product from an additional manufacturing site). In analyses across both study parts, Epogen® was exploratorily compared with Erypo®/Eprex®. A dense-sampling 48-hour pharmacokinetic profile was recorded at steady state after 11 doses of 100 IU epoetin alfa per kg of bodyweight. The hemoglobin response over 4 weeks of study medication administration was analyzed as the primary efficacy surrogate parameter using an ANCOVA model with the baseline value as co-variate. The per-protocol population comprised a total of 268 subjects, 76 in part A (equally randomized to HX575 or Epogen®) and 192 in part B (equally randomized to HX575, HX575-TT, or Erypo®/Eprex®). Pairs of study arms were compared in terms of the ratio of the mean epoetin alfa area under the curve (AUC) and the ratio of the mean hemoglobin area under the effect curve (AUEC).
Results: Bioequivalence was shown in all pair-wise comparisons with the 90% confidence intervals of the AUC ratios falling within the standard bioequivalence limits of 80-125%. Moreover, an equivalent pharmacodynamic response was achieved with all compared epoetin alfa products, as confirmed by the hemoglobin AUEC ratio's 90% CI falling within the predefined acceptance margins of 96.8-103.2%. Thus, bioequivalence and equivalent potency was demonstrated for HX575 and Epogen® in part A of the study, as well as for HX575, HX575-TT and Erypo®/Eprex® in part B of the study. Pair-wise comparison across study parts indicated similar pharmacokinetic and pharmacodynamic profiles of Epogen® and Erypo®/Eprex®. All compared epoetin alfa products were well tolerated and had a similar safety profile. No subject developed anti-erythropoietin antibodies upon administration of study medication.
Conclusion: The results show, for the first time in a prospective randomized clinical study, equivalent bioavailability at steady state and similar potency of the US-marketed Epogen® and the European-marketed Binocrit®. Differences in the formulation between the epoetin alfa products had no apparent clinical impact. The high degree of similarity between Epogen® and Erypo®/Eprex® provides justification for linking and comparing results from clinical studies that were conducted using either US- or European-marketed epoetin alfa products.