Anaemia Management
Table 3: Summary of Studies Evaluating the Comparability of Biosimilar Epoetin Alfa and Epoetin Zeta with the Originator Epoetin Alfa
Type of Study Subject Population (n) Route of Administration
Biosimilar Epoetin Alfa versus Epoetin Alfa Pharmacokinetic Studies
Healthy volunteers (n=6)
Healthy volunteers (n=6)
Healthy volunteers (n=72)
Therapeutic Study Findings Intravenous/subcutaneous Comparability demonstrated Subcutaneous Subcutaneous
Healthy volunteers (n=80) Intravenous Healthy volunteers (n=80) Subcutaneous Patients with renal anaemia (n=478)
Intravenous
Epoetin Zeta versus Epoetin Alfa Pharmacokinetic Studies
Healthy volunteers (n=48)
Healthy volunteers (n=24)
Therapeutic Studies
Correction Patients with CKD Phase Study (n=609)
Maintenance Patients with CKD Phase Study (n=313)
Efficacy Study Patients with renal anaemia (n=462)
Figure 4: Maintenance of Haemoglobin Levels over Time Following the Switch to Epoetin Zeta in a Single-centre Study in Germany
10 12 14 16
6 8
Start
4 2
0
-2 036 Months
-1 1 2 4 5
Number of patients = 43. Red line is the mean for all patients. Switch to epoetin zeta occurred at time 0.
evaluate a 1:1 dose conversion from epoetin alfa to biosimilar epoetin alfa. The primary endpoint was the difference between treatment groups in the mean absolute change of haemoglobin levels between baseline and evaluation period (the last four weeks of the study). Comparability of biosimilar epoetin alfa to epoetin alfa was demonstrated with respect to the primary endpoint; mean changes in haemoglobin levels were 0.15 ± 0.09 g/dl and 0.06 ± 0.12 g/dl, respectively.59,62
In clinical studies evaluating epoetin zeta, comparability was examined in two pharmacokinetic studies in healthy volunteers after single-dose subcutaneous and intravenous administration and in two therapeutic studies in patients with CKD, one a correction phase study and the
104 Intravenous Subcutaneous Subcutaneous Intravenous Intravenous Comparability demonstrated Comparability demonstrated
Comparability demonstrated Comparability demonstrated Comparability demonstrated for mean changes in haemoglobin levels
Comparability demonstrated Comparability demonstrated Comparability demonstrated
for the correction of haemoglobin levels
Comparability demonstrated for Wizemann et al., 200865
maintaining target haemoglobin levels
Comparability in therapeutic efficacy demonstrated
Krivoshiev et al., 201064 Reference
European Medicines Agency, 200759
European Medicines Agency, 200759
European Medicines Agency, 200759
Sorgel et al., 200961 Sorgel et al., 200960 Haag-Weber et al., 200962
European Medicines Agency, 200858
European Medicines Agency, 200858
Krivoshiev et al., 200863
other a maintenance phase study (see Table 3). In the pharmacokinetic studies, comparability was demonstrated irrespective of the route of administration, but only once results had been corrected for dose, reflecting a higher total protein content in the batches of epoetin alfa.58
The correction phase study was designed to demonstrate the comparability of epoetin zeta and epoetin alfa administered intravenously in the correction of haemoglobin levels. Primary endpoints were the mean haemoglobin level and the mean weekly dose of epoetin per kilogramme of body weight in the last four weeks of the study. Mean haemoglobin levels were no different in those patients receiving epoetin alfa or epoetin zeta (11.63 ± 1.37 g/dl and 11.61 ± 1.27 g/dl, respectively). Furthermore, mean weekly dose was also not different (166.14 ± 109.85 IU/kg and 182.20 ± 118.11 IU/kg, respectively).58,63
The maintenance phase study was designed to compare the therapeutic efficacy of randomised epoetin zeta and epoetin alfa administered intravenously in maintaining target haemoglobin levels following a run-in period when all patients received epoetin alfa. An additional primary endpoint was the mean weekly dose per kilogramme of body weight. Mean haemoglobin levels were no different in the two treatment groups during the course of the study (see Figure 2). Mean haemoglobin levels during the randomised period were 11.54 g/dl for epoetin alfa and 11.35 g/dl for epoetin zeta. In addition, the mean weekly dose was comparable in the two treatment groups during the randomised period (epoetin alfa = 92.58 IU/kg; epoetin zeta = 92.68 IU/kg).58,64,65
A further study compared the
therapeutic efficacy of epoetin alfa with epoetin zeta for maintaining haemoglobin levels following subcutaneous administration with primary endpoints of mean haemoglobin levels and mean weekly dose per kilogramme of body weight during the last four weeks of the 28-week study.64
Mean haemoglobin levels were comparable between
the two treatment groups (epoetin alfa = 11.02 ± 0.94 g/dl; epoetin zeta = 10.94 ± 0.84 g/dl) (see Figure 3).64
Moreover, the mean weekly EUROPEAN NEPHROLOGY
Haemoglobin (g/dL)
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