Safety, immunogenicity and efficacy of subcutaneous biosimilar epoetin-α (HX575) in non-dialysis patients with renal anemia: a multi-center, randomized, double-blind study.

BACKGROUND: HX575 is a biosimilar version of epoetin-α that is approved for the treatment of anemia associated with chronic kidney disease (CKD) using the intravenous route of administration. Here we report data from a study of anemic pre-dialysis patients to assess the safety, immunogenicity and efficacy of subcutaneous (s.c.) administration of HX575 vs. Erypo®/Eprex® (Ortho Biotech, Neuss, Germany). METHODS: This was a randomized, double-blind study in adult patients (n = 337) with Stage III - V CKD and a hemoglobin (Hb) level of 7.5 - 11.0 g/dl. Eligible patients were randomized to 52 weeks of treatment with HX575 or Erypo®/Eprex® at a starting dose of 25 IU/kg body weight 3 times weekly or 75 IU/kg body weight once weekly during Weeks 1 - 5. This could be adjusted after 5 weeks to maintain Hb levels between 10 and 12 g/dl. The primary objective was to assess the safety and immunogenicity of HX575 compared with Erypo®/Eprex®. Efficacy endpoints were mean absolute change in Hb from baseline to end of Week 13 and mean weekly epoetin dosage in Weeks 11 - 13. RESULTS: HX575 was equivalent to Erypo®/Eprex® in terms of maintaining Hb levels and epoetin dose requirements. Two patients in the HX575 group developed neutralizing antibodies (NAbs) to erythropoietin, which resulted in the study being terminated prematurely. Aside from these two events, reported adverse events were as expected for patients with Stage III - V CKD and similar in both treatment groups. CONCLUSIONS: This study demonstrated the efficacy and therapeutic equivalence of s.c. HX575 compared with the reference epoetin-α, but 2 patients developed NAbs during treatment with s.c. HX575 in this study. Results of a thorough root-cause analysis reported elsewhere indicate that increased tungsten exposure in pre-filled syringes precipitated immunogenic reactions.

Bioequivalence of HX575 (recombinant human epoetin alfa) and a comparator epoetin alfa after multiple intravenous administrations: an open-label randomised controlled trial.

BACKGROUND: HX575 is a human recombinant epoetin alfa that was approved for use in Europe in 2007 under the European Medicines Agency biosimilar approval pathway. Therefore, in order to demonstrate the bioequivalence of HX575 to an existing epoetin alfa, the pharmacokinetic and pharmacodynamic response to steady state circulating concentrations of HX575 and a comparator epoetin alfa were compared following multiple intravenous administrations. METHODS: An open, randomised, parallel group study was conducted in 80 healthy adult males. Subjects were randomised to multiple intravenous doses of 100 IU/kg body weight of HX575 or of the comparator epoetin alfa three-times-weekly for four weeks. Serum epoetin concentrations were measured using an enzyme-linked immunosorbent assay and pharmacokinetic parameters for the two treatments were compared. The time course and area under the effect curve ratio of haematological characteristics were used as surrogate parameters for efficacy evaluation. RESULTS: The haematological profiles of both treatments were similar, as determined from their population mean curves and the AUECHb ratio and 90% confidence interval (99.9% [98.5-101.2%]), the primary pharmacodynamic endpoint of this study. The pharmacokinetic parameters after the treatments showed minor differences after single dosing, but not at steady state doses. After multiple doses, HX575 was bioequivalent to the comparator with respect to the rate and extent of exposure of exogenous epoetin (AUCtau ratio and 90% confidence interval: 89.2% [82.5-96.2%]). Study medication was well tolerated with no clinically relevant differences between safety profiles of the treatments. Anti-epoetin antibodies were not detected. CONCLUSION: HX575 and the comparator epoetin alfa were bioequivalent at steady state circulating drug concentrations with respect to their pharmacokinetic profile and pharmacodynamic action. This supports the conclusion that HX575 and the comparator epoetin alfa, when administered intraveneously, will be equally efficacious and may be interchangeable as therapy.

HX575, recombinant human epoetin alfa, for the treatment of chemotherapy-associated symptomatic anaemia in patients with solid tumours.

BACKGROUND: Recombinant human epoetin alfa, HX575, is the first biosimilar erythropoiesis-stimulating agent (ESA) with European marketing authorisation. The primary objective of this double-blind, randomised, multicentre study was to assess the efficacy and safety of HX575 in treating chemotherapy-associated symptomatic anaemia in patients with solid tumours. PATIENTS AND METHODS: The patients (n = 114) were treated with HX575 or active control (epoetin alfa) at 150 IU/kg body weight 3 times weekly for 12 weeks, increased to 300 IU/kg body weight 3 times weekly if the haemoglobin/reticulocyte increase was insufficient after 4 or 8 weeks. RESULTS: With HX575, haemoglobin increased by > or =20 g/l in 62% (37/60 patients). The confidence interval (48.2%, 73.9%) was entirely above the pre-defined 30% threshold. Both groups showed similar results for safety profiles and secondary efficacy parameters. Transfusion requirements were 32% (19/60) (HX575) and 38% (13/34) (epoetin alfa). CONCLUSIONS: In treating chemotherapy-associated symptomatic anaemia in patients with solid tumours, the biosimilar ESA, HX575, is efficacious with a safety profile as expected for the therapeutic area.

Bioequivalence of HX575 (recombinant human epoetin alfa) and a comparator epoetin alfa after multiple subcutaneous administrations.

AIM: To compare the steady-state pharmacokinetics and pharmacodynamics (PK/PD) of two erythropoesis-stimulating agents (ESA), HX575 (Binocrit, Sandoz GmbH, Holzkirchen, Germany), human recombinant epoetin alfa approved as the first biosimilar ESA, and a comparator epoetin alfa, following multiple subcutaneous administrations. METHODS: An open, randomized, parallel group study was conducted in 80 healthy adult males. Subjects were randomized to multiple subcutaneous doses of 100 IU/kg body weight of HX575 or of the comparator epoetin alfa 3 times weekly for 4 weeks. RESULTS: The hematological profiles of both treatments were similar, as determined from the population mean curves and area under the effect curve (AUEC) ratios. HX575 met the predefined biosimilarity criteria with respect to the ratio and 90% confidence interval of the AUEC(Hb) (98.9% [97.7-100.2%]), the primary PD endpoint. The PK of the two treatments were also similar as shown by the AUC(0-48) ratios and 90% confidence intervals, 94.3% [84.7-105.0%] and 96.9% [88.2-106.5%], respectively. Study medication was well tolerated and neutralizing anti-epoetin antibodies were not detected. CONCLUSIONS: HX575 and the comparator epoetin alfa were bioequivalent with respect to their PK/PD, supporting the conclusion that both, when administered subcutaneously, will be equally efficacious and may be interchangeable as therapy.