Biosimilar Erythropoietin Research Articles

Detection of Recombinant Erythropoietin Biosimilars and Analog Substances in Human Urine by Gel Electrophoresis Technique.

Detection of Recombinant Erythropoietin Biosimilars and Analog Substances in Human Urine by Gel Electrophoresis Technique.

A systematic review and meta-analysis of effect of synthetic erythropoietin on hemoglobin in dialysis patients

Introduction: Anemia is a common complication of chronic kidney disease (CKD) due to the insufficient production of erythropoietin by the kidneys. The administration of erythropoietin is one of the most common methods for the treatment of patients with anemia. Objectives: This study aimed to investigate the effect of the administration of synthetic erythropoietin on hemoglobin levels in dialysis patients using a systematic review and meta-analysis. Methods: In order to identify the related studies, the international databases of Web of Science, PubMed, Scopus, and Embase were searched from 2015 to 2020 using standard and valid keywords. The data were analyzed using STATA software (version 14), and a p-value of less than 0.05 was considered statistically significant. Results: In 12 reviewed articles with a sample size of 4,060 individuals, the standard effect size of the effect of synthetic erythropoietin on Hb in dialysis patients was reported as 2.08 (95% CI: 1.53-2.63), which was statistically significant; however, erythropoietin biosimilars did not show similar results. Conclusion: The administration of erythropoietin to hemodialysis patients increases Hb levels by more than 2 units.

Epoetin alfa-epbx: a new entrant into a crowded market. a historical review of the role of erythropoietin stimulating agents and the development of the first epoetin biosimilar in the United States

ABSTRACT Introduction: Erythropoietin stimulating agents (ESAs) have been established both to correct anemia and provide the clinical benefits of increased exercise capacity, reduced transfusion requirements, and improved quality of life. An increase in physician and patient adoption of biosimilars, as well as changes to healthcare reimbursement policies, have driven market competitors to innovate and expand the range of biosimilar products. While erythropoietin biosimilars have been approved by the EMA since 2007, the FDA’s approval of epoetin alfa-epbx in 2018 marks the first erythropoietin biosimilar approved in the United States. Areas covered: In this article, we critically review the biology, clinical use, manufacturing, safety, and efficacy of ESAs and erythropoietin biosimilars. We then review the regulatory framework and potential impact on healthcare costs offered by erythropoietin biosimilars. Expert opinion: Due to the complex nature of manufacturing large-molecule biologics, it is important to recognize the challenges to quality assurance and overall safety posed by the introduction of biosimilars, which undergo much more limited clinical testing than their reference biologic product before coming to market. With many biologic therapies nearing patent expiration, biosimilars will become increasingly common in clinical practice. Ensuring patient safety with these products will require increased post-marketing surveillance and awareness from prescribers.

Evaluation of erythropoietin biosimilars Epotin™, Hemax® and Jimaixin™ by electrophoretic methods used for doping control analysis and specific N-glycan analysis revealed structural differences from original epoetin alfa drug Eprex®

Recombinant human erythropoietin (rEPO) biosimilars are copies of epoetin drugs developed after the first patents ended. However differences in the process of production can result in small structural differences when compared to the reference product. Differences in N-glycosylation profiles are of particular importance for rEPOs, because they can drastically impact the half-life in circulation and activity. Changes of structure can also impact electrophoretic profiles that are used to reveal the presence of a rEPO in a doping control sample. In this study three not well characterized biosimilars were evaluated (Jimaixin™ authorized in China, and Hemax® and Epotin™ authorized in Algeria). As these products could be used for doping, first their EPO profiles were determined using the antidoping methods (electrophoretic separation by the charge (isolectric focusing, IEF-PAGE) or the molecular weight (SDS-PAGE) and specific EPO immunodetection). Compared to the original epoetin alfa Eprex®, it revealed more basic isoforms for Epotin™ and Jimaixin™ after IEF-PAGE and a slightly lower molecular weight after SDS-PAGE in particular for Hemax®. To better understand the reason for these differences, EPO specific N-glycans were evaluated using two complementary approaches: MALDI-TOF mass spectrometry (MS) and hydrophilic interaction liquid chromatography (HILIC) with fluorescence detection. All three biosimilars presented a significant decrease in the major glycan forms of Eprex® along with an increase in less complex forms. Jimaixin™ and Epotin™ presented also a lower amount of fully sialylated forms. HILIC method also showed that O-acetylation level of sialic acid residues might vary from one rEPO to the other.

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

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.

SUN-275 DOSE EQUIVALENCY AND EFFICACY OF BIOSIMILAR ERYTHROPOIETIN STIMULATING AGENTS: DATA FROM REAL CLINICAL PRACTICE

Renal anemia is a common complication of end stage renal disease (ESRD) that require continuous replacement therapy with recombinant human erythropoietin stimulating agents (rESA) in most patients. Biosimilar erythropoietin stimulating agents (bESA) are available in Kazakhstan and that most of the dialysis centers switched their patients into the more cost effective bESA. However, important properties of bESA such as dose equivalency to rESA and the ability to maintain hemoglobin (HB) target levels were unknown. Thus, the current study aims to determine dose equivalency and HB target levels in a cohort of dialysis patients who were switched from rESA to bESA. Retrospective data of 74 patients from different dialysis centers were analyzed using different statistical methods. Inclusion: patients who received at least 6 months of rESA and switched to bESA and had at least 6 months follow up period. In addition, the results of a further 3 months period were analyzed to determine the long-term effect of bESA on dose equivalency and HB target level. Data of mean of ESA doses in IU/kg/week and mean HB levels in g/L, 6 months prior the reported switch were calculated and compared to the data from 6 months after the switch. 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 HB during pre-conversion from rESA to bESA (6 months prior) and post conversation period (9 months after) [Table 1], in fact the insignificant difference continued to decrease over the post-conversion period. Additionally, a subgroup analysis of patients who received epoetin beta (n=59) 6 months before the switch [Figure 1], showed similar level of HB (110.7±14 vs 113.2±10 g/L, p=0.053) 6 months after conversation to epoetin zeta at the equivalent dose regimen (69.5±29 vs 68.1±30 IU/kg/week, p=0.55). However, after the seven months of conversion, patients using lower doses of ESA (69.5±29 vs 63.3±30 IU/kg/week, p=0.0097), showed significantly higher levels of HB (110.7±14 vs 114.7±8 g/L, p=0.011) compared to pre-conversion period. The analyses of the retrospective data of dialysis patients, showed no inferiority of bESA compared to rESA on dose equivalency and maintaining HB target levels. Also, long-term use of lower doses of bESA managed to maintain HB within the target levels.

Sialic Acids Content Analysis of the Innovator and Biosimilar Darbepoetin Alfa by Fluorometric HPLC Assay

Background:Erythropoietin is a highly glycosylated protein hormone, used medically for the treatment of anemia associated with chronic renal disease. Due to patent expirations, we expect biosimilar erythropoietins to play an increasing role in healthcare in coming years. &lt;/P&gt;&lt;P&gt; Objective: Here, we have developed a chromatograpy method for determination of Neu5AC and Neu5Gc in darbepoetin alfa.Methods:Sialic acids (Sias) analysis provides the contents of the two most abundant sialic acids Neu5Ac and Neu5Gc. It has often been utilized for the evaluation of sialylated glycoprotein to ensure the biopharmtherapeutic safety and efficacy. In this work, the application of the DMB derivatization of Sias from darbepoetin alfa followed by the separation of the resulting adducts based on HPLC-FLD was presented.Results:Our work demonstrated that the method is characteristics of simple operation, and high reproducibility and sensitivity, and easy to set up for compliance analysis in a routine laboratory.Conclusion:By using a water:acetonitrile gradient, high resolution of Sias was obtained within a 1 min analysis time. The detection limits of NeuAc and NeuGc were 2.9 µg/L and 1.5 µg/L, respectively. The RSDs of the intraday and interday precisions in terms of retention time and peak areas of the analytes are below 1%, and from 3.8% to 4.2% respectively. Therefore, this developed method can be widely applied for simple determination of Neu5Ac, Neu5Gc, and O-acetylated Sias in the derivatized samples. Especially, high levels of O-acetylation were detected on darbepoetin alfa N-glycans, which are critical to establishing the bioequivalence of darbepoetin alfa biosimilars.

Drug Utilization Patterns and Costs of Erythropoiesis-Stimulating Agents in an Outpatient Setting in Greece

Anemia in the elderly is often related to a higher prevalence of chronic diseases such as chronic kidney failure, arthritis, and malignancy. Erythropoiesis-stimulating agents (ESAs) have been used for years to effectively treat anemia and when used appropriately can substantially improve the health status and quality of life of older adults. Following the 2008 recession in Greece, the government introduced ESA price control restrictions, but no prescribing restrictions, in an effort to reduce drug expenditure. ESA prescribing patterns and treatment costs were analyzed to determine inappropriate or appropriate use of these agents and related health care resources in Greece. A retrospective register-based drug utilization study was carried out using data from prescriptions dispensed at the public pharmacy of the largest social insurance fund (IKA-ETAM), for patients receiving ESAs over a six-month period. For each patient, demographic data, ESA dosage regimen, treatment indication and cost, prescriber specialty, and prescription origin were recorded. A total of 14,387 prescriptions from 6,074 patients (median age 74 years) were reviewed. A substantial number of patients (13.5%) were treated for off-label indications, for which the average cost per patient per indication was higher. ESA dosage/frequency of administration varied but was in accordance with recommendations. The percentage of patients who received innovator and biosimilar erythropoietin (EPO) was 88% and 12%, respectively. For the optimization of ESA utilization and the reduction of treatment costs, strict ESA prescription monitoring, development of registries, and criteria for off-label indications and biosimilar use in naive patients under the umbrella of risk-sharing agreements should be proposed.

State-of-the-art biosimilar erythropoietins in the management of renal anemia: lessons learned from Europe and implications for US nephrologists.

The European Medicines Agency (EMA), under a strictly regulated pathway, has approved several biosimilar products since 2005, including biosimilar versions of the erythropoiesis-stimulating agent (ESA) epoetin alfa since 2007. Subsequent to these approvals, the use of biosimilar epoetin alfa in the management of renal anemia has grown steadily throughout Europe. With the enactment of the US Biologics Price Competition and Innovation Act of 2009, a US Food and Drug Administration regulatory approval process for biosimilars was legalized. Thus, biosimilar erythropoietin products are expected to be available for prescription in the USA by mid-decade, presumably at a price that is competitive with the originator brand-name reference products. In this paper, we describe the status of originator and biosimilar ESAs, review the clinical development and regulatory approval of biosimilar erythropoietins in Europe, and summarize relevant efficacy and safety information of biosimilar erythropoietins in relation to their reference products to provide a background for US nephrologists as they appraise biosimilar erythropoietins as treatment options for renal anemia. Key lessons learned from Europe are that (a) EMA-approved biosimilar erythropoietins have comparable efficacy and safety profiles to their reference product erythropoietin; (b) pharmacovigilance preapproval and postapproval are critical, especially with regard to immunogenicity and vascular thromboembolic events; (c) strict preapproval and postapproval requirements must guide the regulatory pathway for biosimilars; and (d) high-quality manufacturing and production processes must be established to ensure quality biosimilar products. The availability of biosimilar erythropoietins in the USA will provide nephrologists with alternative effective, and potentially more affordable, treatment options for patients with renal anemia.

Originator Erythropoietin Alpha Vs Biosimilar Erythropoietin Alpha vs Erythropoietin Zed Plus Liposomial Iron and b12 and Folates in Patients with Refractory Anemia. Five Center Retrospective Study

BackgroundBiosimilar drugs, including erythropoirtin zed, have a similar, but usually not inferior although not hidentical effects of originator drugs. Safety is hidentical to originator drugs.AimsAim of this study is to verify if in MDS patient with refractory anemia biosimilar erythropoietin alpha and erythropoietin zed, are not inferior to erythropoietin alpha in terms of safety, efficacy and costs.MethodsThis study is a retrospective study.Between july 2008 and december 2013, 101 patients affected by refractory anemia were studied.Median follow-up was 16 months (R10-28). Patients received in group A erythropoietin alpha 40000 IU sc/weekly. In group B patient received biosimilar erythropoietin alpha 40000 IU sc/weekly. In group C patient received biosimilar erythropoietin zed 40000 IU sc/weekly. In all three arms patients received liposomial iron (Sideral®) 14 mg 2 tablets orally/day calcium levofolinate 7.5 mg/day orally + Vitamin B12: 400 mg/day orally. In group A median age was 70 years (R63-73), M/F: 15/28. In group B median age was 64 years (R60-70), M/F: 24/19. In group C median age was 68 years (R62-73), M/F: 10/5.IPSS was low in 30 patients and int-1 in 12 patients, karyotype showed –Y in two patient, del 20q in one patient, trisomy 8 in two patients in group A. IPSS was low in 32 patients and int-1 in 10 patients, karyotype showed –Y in one patients, del 20q in one patient in group B.IPSS was low in 11 patients and int-1 in 4 patients, karyotype was normal in 9 patients and not evaluable in 6 patients. Patients with 5q- were excluded from this study. Median level of haemoglobin was 9 g/dl in group A (R8-11), 8.7 g/dl (R8.5-10.5) in group B and 8.5 in group C. Cost of every month of erythropoietinic therapy was calculed dividing for each patient the sum of complete erythropoietic therapy for each month of follow-up, then in each group of patients median cost of erythropoietic therapy was calculed.ResultsGroup A patients increased Hb level of 1 g/dl after a median time of 5 weeks (R4-9), after a median time of 3.5 weeks (R3-8) in group B and after a memedian time of 4 weeks in group C. No relevant side effects were observed in all three groups groups. Erythropoietin alpha was reduced in group A because Hb achieved a level > 12g/dl after a median of 12 weeks (R 4-18).Biosimilar erythropoietin alpha was reduced in group B because Hb achieved a level > 12g/dl after a median of 10 weeks (R 3-16). Erythropoietin zed was reduced in group C because Hb achieved a level > 12g/dl after a median of 9.5 weeks (R 3-15). In group A maintenance dose was administered with a median of every two weeks (2-4), in group B maintenance dose was administered with a median of every three weeks (2-5), in group C maintenance dose was administered with a median of every three weeks (2-4). Median cost for every month of erythropoietic therapy was 1536 euros/month (R1240-1850) in group A, 1354 euros/month (R954-1550) in group B, 1300 euros/month (R1300-1380) in group C. Five patients need transfusion support in group A,6 patients need transfusion support in group B and 5 in group C.Summary/ConclusionBiosimilar erythropoietin alpha and erythropoietin zed plus liposomial iron (Sideral®) and B12 and folates support seems to be safe, feasible, probably equally cost-effective and substantially not inferior to classical erythropoietin alpha support in patients affected by refractory anemia. This study needs confifrmation on a larger cohort of patients. DisclosuresNo relevant conflicts of interest to declare.

Biosimilar Erythropoietin Alpha Is Effective As Originator Erythropoietin Alpha Plus Liposomial Iron and B12 and Folates in Patients with Refractory Anemia: A Retrospective Real-Life Approach

BackgroundBiosimilar drugs have a similar, but usually not inferior although not hidentical effects of old registred drugs. Safety is hidentical to old registred drug.AimsAim of this study is to verify if in MDS patient with refractory anemia biosimilar erythropoietin alpha is not inferior to erythropoietin alpha in terms of safety, efficacy and costs.MethodsThis study is a dicentric, nonrandomized, retrospective study.Between july 2008 and june 2012, 92 patients affected by refractory anemia were studied.Median follow-up was 22 months (R3-34). Patients received in group A erythropoietin alpha 40000 IU sc/weekly. In group B patient received biosimilar erythropoietin alpha 40000 IU sc/weekly. In both groups patients received liposomal iron (Sideral®) 14 mg, 2 tablets orally/day calcium levofolinate 7.5 mg/day orally + Vitamin B12: 400 mg/day orally.In group A median age was 70 years (R63-75), M/F: 18/28; in group B median age was 64 years (R60-70), M/F: 25/21. IPSS was low in 30 patients and int-1 in 13 patients in group A, and low in 32 patients and int-1 in 11 patients, in group B.Patients with 5q- were excluded from this study.Median level of haemoglobin was 8.5 g/dl in group A (R8-11) and 9.2 g/dl (R8.5-11.5) in group B.ResultsGroup A patients increased Hb level of 1 g/dl after a median time of 5 weeks (R4-9) and after a median time of 4 weeks (R3-8) in group B. No relevant side effects were observed in both groups.Erythropoietin alpha was reduced in group A because Hb achieved a level > 12g/dl after a median of 12 weeks (R 4-18). Biosimilar erythropoietin alpha was reduced in group B because Hb achieved a level > 12g/dl after a median of 10.5 weeks (R 3-16). In group A maintenance dose was administered with a median of every two weeks (2-4), In group B maintenance dose was administered with a median of every three weeks (2-5). Median cost for every month of erythropoietic therapy was 1536 euros/month (R1240-1850) in group A and 1354 euros/month (R954-1550) in group B. Five patients need transfusion support in group A and seven patients need transfusion support in group BSummary/conclusionBiosimilar erythropoietin alpha plus liposomal iron (Sideral®) and B12 and folates support seems to be safe, feasible, probably equally cost-effective and substantially not inferior to classical erythropoietin alpha support in patients affected by refractory anemia. This study needs confifrmation on a larger cohort of patients. DisclosuresNo relevant conflicts of interest to declare.

Cost savings from anemia management with biosimilar epoetin alfa and increased access to targeted antineoplastic treatment: a simulation for the EU G5 countries.

We simulated the budget impact of biosimilar erythropoiesis-stimulating agent (ESA) in EU G5 countries. Three models were built to estimate the number of patients who could be provided with antineoplastic therapy with rituximab, bevacizumab or trastuzumab from cost savings of biosimilar erythropoietin use in a hypothetical panel of 100,000 patients. The associated number of patients needed to convert to biosimilar ESA to provide such treatments was also calculated. Under fixed dosing, the savings from 100% conversion were €110,592,159, translating into an additional 9770 rituximab, 3912 bevacizumab, or 3713 trastuzumab treatments. Under weight-based dosing, the savings from 100% conversion were €146,170,333, corresponding to an additional 12,913 rituximab, 5171 bevacizumab or 4908 trastuzumab treatments. The number of patients needed to convert ranged from four to 51. Using biosimilar ESA for supportive cancer care yields significant savings and increases accessibility to primary antineoplastic therapy in a budget neutral way.

Production and analysis of a biosimilar erythropoietin in Egypt

Although management of chronic diseases has been a major challenge for health care systems in developed and developing countries, biopharmaceuticals have been successful in treating many life-threatening conditions. However, the high cost of these agents restricts their availability to countries where patients and/or health care systems are able to afford them. Licensing these biopharmaceuticals as biosimilars after expiration of their patents might increase access to such medicines at an affordable price in developing countries. South Egypt Drug Industries Company (SEDICO) is an Egyptian pharmaceutical company that has had the opportunity to manufacture some of these drugs. SEDICO biotechnology products, such as insulin, erythropoietin, streptokinase, angiokinase, follicle-stimulating hormone, aprotinin, filgrastim, and somatropin, have been available on the Egyptian market for more than 6 years. For this paper, erythropoietin, which has been investigated over a number of years, was chosen as a representative example of SEDICO biotechnology products. Our findings confirm that SEDICO erythropoietin can compete with the originator epoetins on the Egyptian market with high quality and at a lower cost.

DD-012 Pharmacists and biosimilars: when “strong” actions means “strong” outcomes

BackgroundDespite new documents published from EMA and the Italian Drug Agency with the aim of clarifying the quality assurance, efficacy and safety of biosimilar drugs, the clinicians are still reluctant...

Comparison of the Therapeutic Effects of Two Recombinant Erythropoietin Beta, Biosimilar and Reference Formulations in Patients with Chronic Kidney Disease under Hemodialysis

Anemia is common in patients with chronic kidney diseases under hemodialysis and it’s managed with recombinant erythropoietin formulation. The objective of the study is to compare the safety and efficacy of two recombinant erythropoietin formulations in patients undergoing hemodialysis with chronic kidney diseases. In this randomized, controlled, prospective, parallel open study 70 patients were treated for 24 weeks with either reference β recombinant erythropoietin (100 IU/kg) or biosimilar β recombinant erythropoietin (100 IU/kg). The primary efficacy endpoint was the hemoglobin and hematocrit levels from baseline to 24 week of treatment. The secondary endpoints were safety, weekly doses of both erythropoietins required to maintain hemoglobin levels and immunogenicity. There was no significant difference between the two preparations in terms of hemoglobin and hematocrit levels achieved. The weekly doses of both erythropoietins required to maintain hemoglobin levels were the same in both groups. The frequency of adverse events was similar in the two groups of treatment. Two patients of the reference erythropoietin group developed anti-erythropoietin antibodies. The biosimilar erythropoietin was comparable since the safety and efficacy point of view with the innovator erythropoietin in hemodialysis patients based on hemoglobin changes. The biosimilar erythropoietin when administered subcutaneously will be equally efficacious and may be interchangeable as therapy.

PHP25 - Consumption of Biosimilar Drugs in Campania Region in the Years 2009-2012

The expiration of biotech drugs patent has led to the creation of drugs copies of originator products, defined ‘biosimilars’. No European country allows automatic substitution between the originator and the biosimilar. In Italy, due to the lack of a national legislation, some Regions have issued directives to encourage the use of biosimilars, recognizing a potential saving of resources. Campania Region was the first region to legislate on the matter, (decree no. 15 of 11.30.2009) supporting the prescription of biosimilars to the naive patient. The aim of our study is to describe trends in biosimilars consumption in Campania region and evaluate how biosimilar products are replacing the originators in the respective markets. IMS Health regional database was used to analyze biosimilar drugs consumption patterns (erythropoietins, G-CSF, somatropin) in the years 2009- 2012. Information was retrieved about different distribution channels (retail, direct distribution, hospital). Consumptions are expressed in Counting Units (CU) and trends have been calculated using Compound Average Grow Rate (CAGR). The study especially focused on consumption trends of erythropoietin (ATC B03XA) in the years 2009-2012. In 2012 the penetration rate of biosimilars was 40.1% (evaluated as the biosimilars share of the total erythropoietins, G-CSF, somatropin market). These values are double than those at national level, that are estimated to be 19.7% of consumption. Focus on erythropoietin trends showed a strong increase in biosimilars consumption (451 CU in 2009 vs 140,327 CU in 2012) after the introduction of regional measures to promote the prescription of biosimilars to the naive patient. In 2012, biosimilar erythropoietins and reference drugs show similar market shares (37.0% and 33.7% of the total erythropietins market respectively) showing a high substitution effect. Our analysis outlines the significant effects of regional measures on market penetration rates of biosimilars.

Clinical efficacy and safety of XM01, a biosimilar recombinant human erythropoietin, in the management of anemia

Since the expiration of the patent for epoetin alfa in Europe in 2004, the European Medicines Agency has approved three biosimilar erythropoietins. Using the European Medicines Agency's European Public Assessment Reports and scientific publications, we review the evidence regarding the clinical efficacy and safety of HX575 (Sandoz/Novartis) relative to the originator product Eprex/Erypo (Johnson & Johnson). Clinical efficacy is assessed as a function of therapeutic equivalence of a biosimilar and originator product, while safety is evaluated in terms of immunogenicity, venous thromboembolism, and mortality. Five studies that examined chronic renal failure and oncology populations are reviewed. In the renal setting, these stud- ies include a randomized controlled trial on Hb maintenance in patients receiving long-term hemodialysis, a randomized safety trial in patients with chronic kidney disease not yet requiring renal replacement therapy, and a post-approval saftey commitment study. Studies in the cancer setting include a clinical validation study in patients with solid tumors receiving antineoplastic chemotherapy and a retrospective clinical audit of Binocrit in routine clinical practice. Based on available therapeutic equivalence and safety data, the clinical and safety outcomes of treatment with HX575 are likely to be similar to those of the originator product Eprex/Erypo. Both products can be considered interchangeable in the management of anemia in the approved indications, and patients transferred from the reference product to the biosimilar product are expected to show the same efficacy and safety outcomes. There is no evidence of the interchangeability of HX575 with other biosimilar or originator erythropoietins other than Eprex/Erypo. In keeping with European Medicines Agency guidance about traceability, it is recommended that clinicians document the product prescribed by its commercial name, especially when switching patients from an originator to a biosimilar or vice versa.

Mass spectrometric glycoform profiling of the innovator and biosimilar erythropoietin and darbepoetin by LC/ESI-MS

The recent patent expirations of erythropoietin (EPO) have promoted the development of biosimilars. Two and one biosimilar EPO products were approved in 2007 in Europe and in 2010 in Japan, respectively. Glycosylation heterogeneity of EPO is very complex, and its pattern has a large impact on its in vivo activity. In this study, glycoform profilings of biosimilar and innovator EPO products were performed using LC/ESI-MS. Glycoforms of EPO were detected within the range of m/z 1700–3600 at the 10+–16+ charge states. The charge-deconvoluted spectra showed complex glycoform mass profiles at 28,000–32,000Da, and most of the observed peaks were assigned to the peptide (18,236Da)+glycans with the compositions of NeuAc10–14Hexn+3HexNAcnFuc3 (n=16–26) with or without some O-acetylations (+42Da) and attachment of NeuGc for NeuAc or oxidation (+16Da). Analysis of de-N-glycosylated EPO showed the distributions of O-glycans of NeuAc1–2Hex1HexNAc1 and site occupancy. Each EPO product showed a characteristic glycoform profile with respect to sialylation, glycan size, O-acetylation of sialic acids and O-glycosylation. Analysis of darbepoetin suggested that glycans of darbepoetin were highly sialylated and O-acetylated. LC/ESI-MS was shown to be useful to evaluate the similarity of the glycoform profiles of EPO.

糖鎖タンパク質性バイオ医薬品の開発：国産初遺伝子組換えエリスロポエチン製剤承認取得の経緯

糖鎖タンパク質性バイオ医薬品の開発：国産初遺伝子組換えエリスロポエチン製剤承認取得の経緯

New Strategies for Managing Anemia of Chronic Kidney Disease

Anemia is a prevalent and premature comorbidity in chronic kidney disease (CKD) and associated with multiple adverse clinical consequences including increased mortality. Today Erythropoiesis-stimulating agents (ESAs), together with iron supplementation, are the cornerstones of therapy for correcting anemia in CKD patients. As no generally accepted dosing algorithms for these agents exist, current recommendations prefer a partial but not complete anemia correction thereby favoring a more conservative and individualized ESA and iron dosing. Here we discuss in detail current evidence derived from large randomized trials about the proposed hemoglobin targets to aim at in CKD and End-Stage renal disease patients and report recent data from the thriving European market of biosimilar erythropoietins. We summarize promising investigational strategies including peginesatide and prolyl hydroxylase inhibitors for stabilization of the hypoxia inducible factor and provide a clinical review of novel high dose iron formulations like ferumoxytol or iron (III)-carboxymaltose. Taking these findings together, treatment strategies for anemia of CKD have got considerably more complicated so that a careful balance between maximization of patient`s quality of life while minimizing all risks associated with anemia treatment has become a major task of current nephrology.