Biosimilar recombinant human erythropoietins ("epoetins") and future erythropoiesis-stimulating treatments

Expert Opinion on Biological Therapy

Volumn 12, Issue 5, 2012, Pages 581-592

  Jelkmann, Wolfgang ^a  

^a UNIVERSITY OF LÜBECK   (Germany)

Author keywords

anemia; biopharmaceuticals; biosimilars; cancer; chemotherapy; chronic kidney disease

Indexed keywords

ANTIANEMIC AGENT; CONTINUOUS ERYTHROPOIESIS RECEPTOR ACTIVATOR; ERYTHROPOIETIN; HEMOGLOBIN; NOVEL ERYTHROPOIESIS STIMULATING PROTEIN; RECOMBINANT ERYTHROPOIETIN; SB 309; UNCLASSIFIED DRUG;

ANEMIA; CHRONIC KIDNEY DISEASE; CLINICAL EFFECTIVENESS; DRUG HALF LIFE; ERYTHROPOIESIS; GENE THERAPY; GENE TRANSFER; HEALTH CARE COST; HEMODIALYSIS; HUMAN; IMMUNOGENICITY; PURE RED CELL ANEMIA; REVIEW; SAFETY;

ERYTHROPOIESIS; ERYTHROPOIETIN; HUMANS; RECOMBINANT PROTEINS;

EID: 84859620720     PISSN: 14712598     EISSN: None     Source Type: Journal    
DOI: 10.1517/14712598.2012.672968     Document Type: Review

References (100)

1. Jelkmann W. Erythropoietin after a century of research: younger than ever. Eur J Haematol 2007;78(3):183-205
2. Weise M, Bielsky MC, De Smet K. Biosimilars - why terminology matters. Nat Biotechnol 2011;29:690-3 Herein, members of the BMWP at the EMA propose a more precise terminology of copy biologicals, which is worth paying attention.
3. Kozlowski S, Woodcock J, Midthun K, Sherman RB. Developing the nation's biosimilars program. N Engl J Med 2011;365(5):385-8
4. WHO. Guidelines on evaluation of similar biotherapeutic products (SBPs). Available from: http://www biosimilars ca/docs/BIOTHERAPEUTICS-FOR- WEB-22APRIL2010 pdf 2009
5. Mellstedt H, Niederwieser D, Ludwig H. The challenge of biosimilars. Ann Oncol 2007;19(3):411-9 (Pubitemid 351325660)
6. Covic A, Cannata-Andia J, Cancarini G, et al. Biosimilars and biopharmaceuticals: what the nephrologists need to know-a position paper by the ERA-EDTA Council. Nephrol Dial Transplant 2008;23(12):3731-7
7. Schellekens H, Moors E. Clinical comparability and European biosimilar regulations. Nat Biotechnol 2010;28(1):28-31
8. Jelkmann W. Biosimilar epoetins and other "follow-on" biologics: update on the European experiences. Am J Hematol 2010;85:771-80
9. Jelkmann W. Recombinant EPO production - points the nephrologist should know. Nephrol Dial Transplant 2007;22(10):2749-53 (Pubitemid 350093453)
10. Kawasaki N, Itoh S, Hashii N, et al. The significance of glycosylation analysis in development of biopharmaceuticals. Biol Pharm Bull 2009;32(5):796-800
11. Kramer I. Pharmacy and pharmacology of biosimilars. J Endocrinol Invest 2008;31(5):479-88 (Pubitemid 352003243)
12. Locatelli F, Pisoni RL, Combe C, et al. Anaemia in haemodialysis patients of five European countries: association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 2004;19(1):121-32 (Pubitemid 38072623)
13. Regidor DL, Kopple JD, Kovesdy CP, et al. Associations between changes in hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients. J Am Soc Nephrol 2006;17(4):1181-91
14. KDOQI, National Kidney Foundation. Am J Kidney Dis 2006;47(5 Suppl 3):S11-S145; Erratum in Am J Kidney Dis 2006; 48(3):518
15. Leaf DE, Goldfarb DS. Interpretation and review of health-related quality of life data in CKD patients receiving treatment for anemia. Kidney Int 2009;75(1):15-24 This review critically evaluates the magnitude and nature of ESA-associated improvements in health-related quality of life of CKD patients.
16. Glaspy JA. Erythropoietin in cancer patients. Annu Rev Med 2009;60:181-92
17. Rizzo JD, Brouwers M, Hurley P, et al. American Society of Hematology/ American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. Blood 2010;116(20):4045-59
18. Glaspy J, Crawford J, Vansteenkiste J, et al. Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes. Br J Cancer 2010;102(2):301-15
19. Jelkmann W, Bohlius J, Hallek M, Sytkowski AJ. The erythropoietin receptor in normal and cancer tissues. Crit Rev Oncol Hematol 2008;67:39-61
20. Elliott S, Sinclair AM, Begley CG. Anti-Epo receptor antibodies do not predict Epo receptor expression. Blood 2006;107(3):1892-5 The authors unveil that the commonly used antibodies are nonspecific and not suitable for detection of erythropoietin receptor (EpoR) protein by immunohistochemical methods. Hence, reports of EpoR expression in tumor cells should be viewed with caution. (Pubitemid 43289368)
21. Laugsch M, Metzen E, Svensson T, et al. Lack of functional erythropoietin receptors of cancer cell lines. Int J Cancer 2008;122(5):1005-11 (Pubitemid 351213997)
22. Sinclair AM, Rogers N, Busse L, et al. Erythropoietin receptor transcription is neither elevated nor predictive of surface expression in human tumour cells. Br J Cancer 2008;98(6):1059-67 (Pubitemid 351399799)
23. Swift S, Ellison AR, Kassner P, et al. Absence of functional EpoR expression in human tumor cell lines. Blood 2010;115(21):4254-63
24. Grillberger L, Kreil TR, Nasr S, Reiter M. Emerging trends in plasma-free manufacturing of recombinant protein therapeutics expressed in mammalian cells. Biotechnol J 2009;4(2):186-201 This review describes advances in manufacturing that have made possible the removal of human and animal-derived products from all steps of recombinant protein production.
25. Storring PL, Tiplady RJ, Gaines Das R, et al. Epoetin alfa and beta differ in their erythropoietin isoform compositions and biological properties. Br J Haematol 1998;100:79-89 (Pubitemid 28051844)
26. Skibeli V, Nissen-Lie G, Torjesen P. Sugar profiling proves that human serum erythropoietin differs from recombinant human erythropoietin. Blood 2001;98:3626-34
27. EMA. Assessment report. Available from: http://www.ema.europa.eu/ema/ index.jsp? curl=pages/medicines/human/medicines/001033/human-med-001204. jsp&jsenabled=true
28. Nimtz M, Wray V, Rudiger A, Conradt HS. Identification and structural characterization of a mannose-6-phosphate containing oligomannosidic N-glycan from human erythropoietin secreted by recombinant BHK-21 cells. FEBS Lett 1995;365(2-3):203-8
29. Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Br J Cancer 2001;84:3-10 (Pubitemid 32453429)
30. Elliott S, Lorenzini T, Asher S, et al. Enhancement of therapeutic protein in vivo activities through glycoengineering. Nat Biotechnol 2003;21(4):414-21 This report suggests glycoengineering may be generally applicable as a strategy for increasing the in vivo activity and duration of action of proteins. (Pubitemid 36397662)
31. Macdougall IC. Novel erythropoiesis stimulating protein. Semin Nephrol 2000;20(4):375-81
32. Jarsch M, Brandt M, Lanzendorfer M, Haselbeck A. Comparative erythropoietin receptor binding kinetics of C.E.R.A. and epoetin-beta determined by surface plasmon resonance and competition binding assay. Pharmacology 2007;81(1):63-9
33. Available from: http://www.ema.europa. eu/
34. Key C, Mulchchrone B, Wai K. Available from: http://www.quintiles. com/elements/media/inthenews/ reviewing-existing-risk-management-plans. pdf. rajpharma com 2010
35. Schiestl M, Stangler T, Torella C, et al. Acceptable changes in quality attributes of glycosylated biopharmaceuticals. Nat Biotechnol 2011;29(4):310-12 This study shows substantial alterations of the glycosylation profile of marketed glycosylated biopharmaceuticals over time.
36. Brinks V, Hawe A, Basmeleh AH, et al. Quality of original and biosimilar epoetin products. Pharm Res 2011;28(2):386-93
37. Deechongkit S, Wen J, Narhi LO, et al. Physical and biophysical effects of polysorbate 20 and 80 on darbepoetin alfa. J Pharm Sci 2009;98(9):3200-17
38. Anonymous. Erythropoietin concentrated solution. Eur Pharmacopoeia 4th Edition 2002 (monograph 1316):1123-8
39. Jelkmann W. Efficacy of recombinant erythropoietins: is there unity of international units? Nephrol Dial Transplant 2009;24:1366-8 This report recalls that all epoetins are calibrated in mice by bioassays that are not precise enough to ensure identical clinical efficacy.
40. Brockmeyer C, Seidl A. Binocrit: assessment of quality, safety and efficacy of biopharmaceuticals. Eur J Hosp Pharm 2009;15:34-41
41. Sorgel F, Thyroff-Friesinger U, Vetter A, et al. Bioequivalence of HX575 (recombinant human epoetin alfa) and a comparator epoetin alfa after multiple intravenous administrations: an open-label randomised controlled trial. BMC Clin Pharmacol 2009;9:10
42. Haag-Weber M, Vetter A, Thyroff-Friesinger U. Therapeutic equivalence, long-term efficacy and safety of HX575 in the treatment of anemia in chronic renal failure patients receiving hemodialysis. Clin Nephrol 2009;72(5):380-90
43. Sorgel F, Thyroff-Friesinger U, Vetter A, et al. Bioequivalence of HX575 (recombinant human epoetin alfa) and a comparator epoetin alfa after multiple subcutaneous administrations. Pharmacology 2009;83(2):122-30
44. Weigang-Kohler K, Vetter A, Thyroff-Friesinger U. HX575, recombinant human epoetin alfa, for the treatment of chemotherapy-associated symptomatic anaemia in patients with solid tumours. Onkologie 2009;32:168-74
45. Schellekens H. Assessing the bioequivalence of biosimilars. The Retacrit case. Drug Discov Today 2009;14(9-10):495-9 The case of Retacrit, one of the biosimilar epoetins, is discussed as an example of the challenges encountered when assessing the bioequivalence of therapeutic proteins.
46. Baldamus C, Krivoshiev S, Wolf-Pflugmann M, et al. Long-term safety and tolerability of epoetin zeta, administered intravenously, for maintenance treatment of renal anemia. Adv Ther 2008;25(11):1215-28
47. Krivoshiev S, Todorov VV, Manitius J, et al. Comparison of the therapeutic effects of epoetin zeta and epoetin alpha in the correction of renal anaemia. Curr Med Res Opin 2008;24(5):1407-15 (Pubitemid 351741574)
48. Wizemann V, Rutkowski B, Baldamus C, et al. Comparison of the therapeutic effects of epoetin zeta to epoetin alfa in the maintenance phase of renal anaemia treatment. Curr Med Res Opin 2008;24(3):625-37 (Pubitemid 351428973)
49. Krivoshiev S, Wizemann V, Czekalski S, et al. Therapeutic equivalence of epoetin zeta and alfa, administered subcutaneously, for maintenance treatment of renal anemia. Adv Ther 2010;27(2):105-17
50. Tzekova V, Mihaylov G, Elezovic I, Koytchev R. Therapeutic effects of epoetin zeta in the treatment of chemotherapy-induced anaemia. Curr Med Res Opin 2009;25(7):1689-97
51. Porter S. Human immune response to recombinant human proteins. J Pharm Sci 2001;90(1):1-11 . This is an interesting survey of the literature regarding the measurement and evaluation of immune responses observed during clinical assessment of various recombinant human proteins. (Pubitemid 32050471)
52. Schellekens H. Bioequivalence and the immunogenicity of biopharmaceuticals. Nat Rev Drug Discov 2002;1:457-62 This review describes the main factors that influence the immunogenicity of biopharmaceuticals. (Pubitemid 37361488)
53. Tamilvanan S, Raja NL, Sa B, Basu SK. Clinical concerns of immunogenicity produced at cellular levels by biopharmaceuticals following their parenteral administration into human body. J Drug Target 2010;18(7):489-98
54. Rosenberg AS. Effects of protein aggregates: an immunologic perspective. AAPS J 2006;8(3):E501-7 The review critically views models in uncovering effects of protein aggregates, and changes in product manufacture and packaging that may affect generation of protein aggregates. (Pubitemid 44294011)
55. Sauerborn M, Brinks V, Jiskoot W, Schellekens H. Immunological mechanism underlying the immune response to recombinant human protein therapeutics. Trends Pharmacol Sci 2010;31(2):53-9
56. Scott DW, De Groot AS. Can we prevent immunogenicity of humanprotein drugs? Ann Rheum Dis 2010;69(Suppl 1):i72-6
57. Schellekens H. How to predict and prevent the immunogenicity of therapeutic proteins. Biotechnol Annu Rev 2008;14:191-202 (Pubitemid 351903454)
58. Delluc S, Ravot G, Maillere B. Quantification of the preexisting CD4 T-cell repertoire specific for human erythropoietin reveals its immunogenicity potential. Blood 2010;116(22):4542-5 The authors show in blood samples of almost every second normal donor EPO-specific CD4 T cells, which could be prone to be activated by altered batches of ESAs.
59. Rossert J. Pure Red Cell Aplasia Global Scientific Advisory Board (GSAB) Erythropoietin-induced, antibody-mediated pure red cell aplasia. Eur J Clin Invest 2005;35(Suppl 3):95-9 (Pubitemid 41783611)
60. Casadevall N. What is antibody-mediated pure red cell aplasia (PRCA)? Nephrol Dial Transplant 2005;20(Suppl 4):3-8; Erratum in Nephrol Dial Transplant 2005; 20 (8):1773 This is a very instructive description of clinical aspects of PRCA, occurring in rare patients receiving recombinant ESAs for CKD-associated anemia.
61. Macdougall IC, Roger SD, De Francisco A, et al. Antibody-mediated pure red cell aplasia in chronic kidney disease patients receiving erythropoiesis-stimulating agents: new insights. Kidney Int 2012; [Epub ahead of print] This is an up-to-date review regarding the etiology of anti-EPO antibodymediated pure red cell aplasia and the current approach to therapy.
62. Swanson SJ, Ferbas J, Mayeux P, Casadevall N. Evaluation of methods to detect and characterize antibodies against recombinant human erythropoietin. Nephron Clin Pract 2004;96(3):c88-95 (Pubitemid 38453092)
63. Thorpe R, Swanson SJ. Current methods for detecting antibodies against erythropoietin and other recombinant proteins. Clin Diagn Lab Immunol 2005;12(1):28-39 This article reviews the different assays used to measure and characterize antibodies towards certain recombinant therapeutic proteins, with emphasis on rhEPO, as well as the benefits, disadvantages, and limitations of the assays used for screening and diagnostic purposes.
64. Shimizu H, Saitoh T, Ota F, et al. Pure red cell aplasia induced only by intravenous administration of recombinant human erythropoietin. Acta Haematol 2011;126(2):114-18
65. Casadevall N, Nataf J, Viron B, et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002;346(7):469-75 This was the first report of several cases of PRCA in patients receiving recombinant ESAs for CKD-associated anemia. (Pubitemid 34441737)
66. Bennett CL, Luminari S, Nissenson AR, et al. Pure red-cell aplasia and epoetin therapy. N Engl J Med 2004;351(14):1403-8 (Pubitemid 39288166)
67. Boven K, Stryker S, Knight J, et al. The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes. Kidney Int 2005;67(6):2346-53 Epidemiologic and other data in this study support the hypothesis that leachates from uncoated rubber syringe stoppers caused the increased incidence of PRCA associated with Eprex, which decreased after syringes with fluoro-resin coated stoppers were used. (Pubitemid 41623396)
68. Hermeling S, Schellekens H, Crommelin DJ, Jiskoot W. Micelle-associated protein in epoetin formulations: a risk factor for immunogenicity? Pharm Res 2003;20(12):1903-7 (Pubitemid 38005518)
69. Villalobos AP, Gunturi SR, Heavner GA. Interaction of polysorbate 80 with erythropoietin: a case study in protein-surfactant interactions. Pharm Res 2005;22(7):1186-94 (Pubitemid 41127077)
70. Sharma B, Bader F, Templeman T, et al. Technical investigations into the cause of the increased incidence of antibody-mediated pure red cell aplasia associated with EPREX. Eur J Hosp Pharm 2004;5:86-91
71. Haag-Weber M, Eckardt KU, Horl WH, et al. Safety, immunogenicity and efficacy of subcutaneous biosimilar epoetin-a (HX575) in non-dialysis patients with renal anemia: a multi-center, randomized, double-blind study. Clin Nephrol 2012;77(1):8-17
72. Seidl A, Hainzl O, Richter M, et al. Tungsten-induced denaturation and aggregation of epoetin alfa during primary packaging as a cause of immunogenicity. Pharm Res 2011; [Epub ahead of print] Following two cases of neutralizing antibodies to a biosimilar epoetin alfa which occurred on SC application in a clinical trial, the authors identified soluble tungsten in the syringes, most likely derived from the pins used to manufacture the syringes. Tungsten-induced formation of aggregates should more generally be considered in the immunogenicity of biopharmaceuticals.
73. Bee JS, Nelson SA, Freund E, et al. Precipitation of a monoclonal antibody by soluble tungsten. J Pharm Sci 2009;98(9):3290-301
74. Jiang Y, Nashed-Samuel Y, Li C, et al. Tungsten-induced protein aggregation: solution behavior. J Pharm Sci 2009;98(12):4695-710
75. Macdougall IC, Ashenden M. Current and upcoming erythropoiesis- stimulating agents, iron products, and other novel anemia medications. Adv Chronic Kidney Dis 2009;16(2):117-30
76. Perez-Oliva JF, Casanova-Gonzalez M, Garcia-Garcia I, et al. Comparison of two recombinant erythropoietin formulations in patients with anemia due to end-stage renal disease on hemodialysis: a parallel, randomized, double blind study. BMC Nephrol 2005;6(1):1-11
77. Goh BL, Ong LM, Sivanandam S, et al. Randomized trial on the therapeutic equivalence between Eprex and GerEPO in patients on haemodialysis. Nephrology (Carlton) 2007;12(5):431-6 (Pubitemid 47366646)
78. Kim TE, Kim KP, Kim BH, et al. Pharmacokinetic and pharmacodynamic comparison of two recombinant human erythropoietin formulations after single subcutaneous administration: an open-label, sequence-randomized, two-treatment crossover study in healthy Korean male volunteers. Clin Ther 2010;32(11):1968-76
79. Schmidt CA, Ramos AS, da Silva JEP, et al. Avaliacao da atividade e caracterizacao de eritropoietin a humana recombinante em produtos farmaceuticos. Arq Bras Endocrinol Metabol 2003;47:183-9
80. Schellekens H. Biosimilar epoetins: how similar are they? Eur J Hosp Pharm 2004;3:43-7 This study shows major differences in the types of glycoforms of commercial copy epoetins, when compared with the innovator products.
81. Park SS, Park J, Ko J, et al. Biochemical assessment of erythropoietin products from Asia versus US Epoetin alfa manufactured by Amgen. J Pharm Sci 2008;98:1688-99 This study shows major differences in the types of glycoforms, protein unfolding, in vitro potency, presence of covalent aggregates, and presence of cleavage products in copy epoetins marketed in Asia, when compared with the innovator epoetin alfa.
82. Yang J, Joo KW, Kim YS, et al. Two cases of pure red-cell aplasia due to anti-erythropoietin antibodies. J Nephrol 2005;18(1):102-5 (Pubitemid 40723760)
83. Keithi-Reddy SR, Kandasamy S, Singh AK. Pure red cell aplasia due to follow-on epoetin. Kidney Int 2008;74:1617-22
84. Praditpornsilpa K, Kupatawintu P, Mongkonsritagoon W, et al. The association of anti-r-HuEpo-associated pure red cell aplasia with HLA-DRB1*09-DQB1*0309. Nephrol Dial Transplant 2008;24(5):1545-9
85. Praditpornsilpa K, Tiranathanagul K, Kupatawintu P, et al. Biosimilar recombinant human erythropoietin induces the production of neutralizing antibodies. Kidney Int 2011;80(1):88-92
86. Niederwieser D, Schmitz S. Biosimilar agents in oncology/haematology: from approval to practice. Eur J Haematol 2011;86(4):277-88
87. Barosi G, Bosi A, Abbracchio MP, et al. Key concepts and critical issues on epoetin and filgrastim biosimilars. A position paper from the Italian Society of Hematology, Italian Society of Experimental Hematology, and Italian Group for Bone Marrow Transplantation. Haematologica 2011;96(7):937-42
88. Kromminga A, Schellekens H. Antibodies against erythropoietin and other protein-based therapeutics: an overview. Ann NY Acad Sci 2005;1050:257-65 (Pubitemid 41129443)
89. Macdougall IC, Wiecek A, Tucker B, et al. Dose-finding study of peginesatide for anemia correction in chronic kidney disease patients. Clin J Am Soc Nephrol 2011;6(11):2579-86 This is the first assessment of the efficacy of peginesatide in correcting renal anemia in CKD patients not yet on dialysis.
90. Macdougall IC, Rossert J, Casadevall N, et al. A peptide-based erythropoietin-receptor agonist for pure red-cell aplasia. N Engl J Med 2009;361(19):1848-55 This is the first assessment of the efficacy and safety of peginesatide in patients with PRCA due to anti-EPO antibodies.
91. Bouman-Thio E, Franson K, Miller B, et al. A Phase I, single and fractionated, ascending-dose study evaluating the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of an erythropoietin mimetic antibody fusion protein (CNTO 528) in healthy male subjects. J Clin Pharmacol 2008;48(10):1197-207
92. Sathyanarayana P, Houde E, Marshall D, et al. CNTO 530 functions as a potent EPO mimetic via unique sustained effects on bone marrow proerythroblast pools. Blood 2009;113(20):4955-62
93. Bruegge K, Jelkmann W, Metzen E. Hydroxylation of hypoxia-inducible transcription factors and chemical compounds targeting the HIF-hydroxylases. Curr Med Chem 2007;14:1853-62 (Pubitemid 47163403)
94. Hsieh MM, Linde NS, Wynter A, et al. HIF prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques. Blood 2007;110(6):2140-7 (Pubitemid 47443933)
95. Bernhardt WM, Wiesener MS, Scigalla P, et al. Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. J Am Soc Nephrol 2010;21(12):2151-6 This is a first trial 1 study showing that the HIF-stabilizer, FG-2216, stimulates EPO production in humans.
96. Available from: http://www.fibrogen. com/press/release/pr-1300378657
97. Fraisl P, Aragones J, Carmeliet P. Inhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease. Nat Rev Drug Discov 2009;8(2):139-52
98. Nagel S, Talbot NP, Mecinovic J, et al. Therapeutic manipulation of the HIF hydroxylases. Antioxid Redox Signal 2010;12(4):481-501
99. Lippin Y, Dranitzki-Elhalel M, Brill-Almon E, et al. Human erythropoietin gene therapy for patients with chronic renal failure. Blood 2005;106(7):2280-6 This is the first epo gene therapy trial in humans. (Pubitemid 41510797)
100. Available from: http://www faqs org/secfilings/ 110225/MEDGENICS-INC-S- 12011