Dose equivalency and efficacy of biosimilar erythropoietin stimulating agents: Data from real clinical practice

Abstract Recently, biosimilar erythropoietin stimulating agents become available in Kazakhstan. Important properties of the biosimilar such as dose equivalency to the original medicine (originator) and the ability to maintain hemoglobin target levels remain insufficiently described in many clinical settings. Thus, the current study aims to determine dose equivalency and hemoglobin target levels in a cohort of dialysis patients who were switched from the originator to biosimilar. Retrospective data of 74 patients from different dialysis centers who received at least 6 months of originator and switched to biosimilar and had at least 6 months follow‐up were analyzed. The clinical data of 32 male and 42 female patients were collected. The mean age was 52.5 ± 13.5 years. There is no significant difference in mean levels of hemoglobin during pre‐switching from originator to biosimilar (6 months prior) and post switching period (9 months after). Additionally, a subgroup analysis of 59 patients who received originator (epoetin beta), 6 months before the switch, showed similar level of hemoglobin (110.7 ± 14 vs 113.2 ± 10 g/L, P = .05) 6 months after the switch to biosimilar (epoetin zeta) at the equivalent dose regimen (69.5 ± 29 vs 68.1 ± 30 IU/kg/wk, P = .55). However, after 9 months of switching, patients using lower doses of biosimilar (69.5 ± 29 vs 63.3 ± 30 IU/kg/wk, P < .01), showed significantly higher levels of hemoglobin (110.7 ± 14 vs 114.7 ± 8 g/L, P = .01) compared to preswitching period. In conclusion, long‐term use of lower doses of biosimilar managed to maintain hemoglobin within the target levels.

blood cells and is used in the treatment of anemia caused by renal disease. 3 rESA treatments were shown to raise hemoglobin and hematocrit levels in patients with end stage renal disease on hemodialysis. 3 Despite their proven efficacy and crucial role in the treatment of renal anemia, the high cost of rESA agents is a contributing factor to the increasing cost of treatment, makes them inaccessible to many patients. An alternative option to the use of biologic agents (originator) and a more cost effective choice is the use of biosimilar agents, which have similar, but not identical molecular shape, efficacy, and safety to the original product. 4 They are being widely developed to create price competition and cheaper alternatives to the costly originators.
The lower costs of biosimilars will respite some of the financial pressure on healthcare budgets and allow greater access for patients. This would also provide major advantages for patients and communities such as that financial resources may be more efficiently allocated to other important uses, which makes more innovative therapies available to patients. 5 In addition to being a cost saving phenomenon, switching to biosimlars is something to be considered as a medical issue, particularly if it could occur with other medicines as well. 6 Since the year 2017, biosimilar ESA (bESA) have become available in Kazakhstani trade. Due to their lower prices compared to originator (rESA), a few of the country's dialysis centers switched their patients to bESA. However, important properties of bESA such as dose equivalency to rESA and their ability to maintain hemoglobin (HB) target levels remain unknown, which might have contributed to low switching rate in Kazakhstan. Hence, determining these important properties will increase the enthusiasm toward biosimilar and would encourage many clinicians to switch their patients to a more cost-effective alternative. Therefore, the aim of the current study is to determine the dose equivalency and HB target level in a cohort of dialysis patients who were switched from rESA (originator) to bESA (biosimilar) during real clinical practice.

| Study population
De-identified data without personal information were extracted from dialysis electronic medical information system (Diaverum IRIMS -International Renal Information Management System) including longitudinal laboratory and treatment variables for patients treated between January 2017 and July 2018. Inclusion criteria: End-stage renal disease patients, who were on maintenance hemodialysis, received rESA for at least 6 months and switched to bESA with a minimum record of 6 months follow-up. Exclusion: patients other than those with renal anemia, patients who did not switch from originator to biosimilar, and those who do not meet the minimum time limits for treatment and follow-ups were excluded.

| Study design and setting
The current study is designed as a retrospective study that included patients from different dialysis centers in three different regions of Kazakhstan (Aktobe, Temirtau, and Almaty regions). In order to get meaningful data, patients with at least 1 year of health assistance prior to the baseline date were selected. Baseline data are defined as data that were collected prior to the switch. Demographic and clinical characteristics of the cohort at the baseline were retrieved. Specifically, age, gender, factors related to anemia such as body mass index (BMI), serum iron level, hemodialysis vintage, and ferritin levels were collected and analyzed. The data were analyzed to determine the long-term effect of bESA on dose equivalency and HB target level. The mean ESA dose expressed in IU/kg/wk and the mean of HB level expressed in g/L were calculated to compare the data, obtained 6 months prior to switching and 6 months after switching from originator to biosimilar. Additional 3 months period were analyzed to determine the long-term effect of biosimilar on dose equivalency and hemoglobin target level. were considered significant. Serum Fe, µmol/L 11.5 ± 3.9

TA B L E 1 Baseline characteristics of study group
Note: Data presented as Mean ± SD or Median (IQR) as appropriate Abbreviations: BMI, body mass index; HD, hemodialysis; KT/V, dialysis adequacy.

| Demographic data
In total, we included 74 dialysis patients who received at least 6 months of rESA and switched to bESA (epoetin zeta patients who were receiving another long acting ESA (darbepoetin alfa), before switching to bESA (epoetin zeta). There were two follow-up periods a 6 months period and a 9 months follow-up period.

| Hemoglobin target level
The patient's mean level HB 6 months before the switching from rESA to bESA is compared to that of the 6 and 9 months periods following switching. The results show no significant difference in mean levels of HB during the pre-and post conversation periods (Table 2).
Notably, the results showed that 14.4% of patients were under the HB target level during the last 6 months prior to switching from rESA to bESA. Interestingly, this figure was reduced to 11.5% at 6 months after switching from rESA to bESA and continued to decrease further to 9.0% at nine months after switching.

| Dose equivalency
A subgroup analyses comparing the HB levels, of 59 patients who were receiving epoetin beta, and those patients who were receiving the long acting ESA (methoxy-polyethylene-glycol epoetin beta and darbepoetin alfa) 6 months before switching to the results of 6 and 9 months after the switching to epoetin zeta were carried out. The HB levels of patients who were receiving the long acting ESA 6 months before switching remained the same as to 6 months (106.7 ± 7.3 vs 109.5 ± 7 g/L, P = .03) and 9 months (106.7 ± 7.3 vs 106.3 ± 12.7 g/L, P = .32) after switching to bESA at an equal dose regimen (91.1 ± 10.3 vs 81.9 ± 0.9 IU/kg/wk, P = .32) (Figure 1).
In addition, the results showed that patients receiving epoetin beta during the last 6 months, had maintained similar level of HB (110.7 ± 14 vs 113.2 ± 10 g/L, P = .05) to that after conversation to epoetin zeta during the following 6 months, at the equivalent dose regimen (69.5 ± 29 vs 68.1 ± 30 IU/kg/wk, P = .55) (Figure 2).
However, during the 7th, 8th, and 9th months after switching, patients switched to epoetin zeta were shown to have significantly higher levels of HB (110.7 ± 14 vs 114.7 ± 8 g/L, P = .01) on lower dose of bESA compared to preswitching period (69.5 ± 29 vs 63.3 ± 30 IU/ kg/wk, P < .01) (Figure 2).  The current study has some limitations including the relatively small sample size of the studied population, which is insufficient to demonstrate statistical significance between the pre-and post switching periods. The second limitation is that the study did not investigate

CO N FLI C T O F I NTE R E S T
The authors declare no conflict of interest.

AUTH O R CO NTR I B UTI O N S
AG, ZM, and MA contributed to the study design and initiation.
NT, ZK, MB, and ST were involved in data collection and some data analyses. AI performed the statistical analyses and figure generation. AG and AI wrote the first draft of the manuscript. MA finalized the manuscript, which was subsequently approved by all authors. All authors read and approved the final manuscript.

E TH I C S S TATEM ENT
The study was approved by the Institutional Review Ethics Committee, and exempted from informed consent since it is a retrospective study.

PR I N CI PA L I N V E S TI G ATO R S TATE M E NT
The authors confirm that the Principal Investigator for this paper is Abduzhappar Gaipov and that he had direct clinical responsibility for patients.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.