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Biosimilar epoetins and other “follow-on” biologics: Update on the European experiences Wolfgang Jelkmann To cite this version: Wolfgang Jelkmann. Biosimilar epoetins and other “follow-on” biologics: Update on the European experiences. American Journal of Hematology, Wiley, 2010, 85 (10), pp.771. 10.1002/ajh.21805. hal-00552331 HAL Id: hal-00552331 https://hal.archives-ouvertes.fr/hal-00552331 Submitted on 6 Jan 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. American Journal of Hematology Biosimilar epoetins and other “follow-on” biologics: Update on the European experiences For Peer Review Journal: American Journal of Hematology Manuscript ID: AJH-10-0229.R1 Wiley - Manuscript type: Critical Review Date Submitted by the 10-Jun-2010 Author: Complete List of Authors: Jelkmann, Wolfgang; University, Physiology Anemias, Erythropoietin, Hematology- medical, Neutropenia, Keywords: Pharmacology John Wiley & Sons Page 1 of 30 American Journal of Hematology 1 2 3 Table II. Benefits and problems related to the use of biosimilars 4 5 ________________________________________________________________ 6 Benefits Problems 7 ______________________________________________________________________ 8 9 10 Lower pricing than originator medicines Lack of long-term experience 11 (efficacy, safety, immunogenicity?) 12 13 Pressure on innovator companies Product-specific administration routes 14 15 to reduce prices of originator medicines (s.c. and/or i.v. authorization?) 16 17 Pressure on innovator companies Product-specific indications 18 to develop “second-generationFor Peer products” Review 19 20 with improved pharmacodynamic and/or Product-specific storage and handling 21 pharmacokinetic properties → Instruction of medical staff required 22 (e.g. darbepoetin alfa, 23 methoxy-PEG-epoetin beta, Confusing naming (some identical INN, 24 25 pegfilgrastim) some different INN, different brand names 26 for identical substances) 27 → Difficulties in pharmacovigilance 28 recording 29 30 ______________________________________________________________________ 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 John Wiley & Sons American Journal of Hematology Page 2 of 30 1 2 3 Table I. Primary biosimilar recombinant medicines candidates 4 5 6 ______________________________________________________________________ 7 8 Active substance Main indication Biosimilar marketing authorization 9 10 (INN) EU USA Japan 11 ______________________________________________________________________ 12 13 Epoetin alfa Anemia in association with CKD, + - + 14 15 anemia in association with 16 chemotherapy for cancer 17 18 Epoetin beta For Anemia inPeer association with Review CKD, - - - 19 20 anemia in association with 21 chemotherapy for cancer 22 23 24 25 Filgrastim (G-CSF) Neutropenia in association + - - 26 with cancer 27 28 Somatropin Growth hormone deficiency + + + 29 30 31 32 Insulin Diabetes mellitus - - - 33 34 35 36 Interferon alfa Cancer, hepatitis B/C - - - 37 38 39 40 Interferon beta Multiple sclerosis - - - 41 ______________________________________________________________________ 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 John Wiley & Sons Page 3 of 30 American Journal of Hematology 1 2 3 4 5 6 7 Biosimilar epoetins and other “follow-on” biologics: Update 8 9 on the European experiences 10 11 12 13 Wolfgang Jelkmann 14 15 16 Institute of Physiology, University of Luebeck, Luebeck, Germany 17 18 For Peer Review 19 20 21 22 Correspondence: 23 Wolfgang Jelkmann, M.D. 24 25 Professor of Physiology 26 Institute of Physiology 27 University of Luebeck 28 Ratzeburger Allee 160 29 30 D-23538 Luebeck 31 Germany 32 33 Tel. ++49- 451-500 4150 34 35 Fax: ++49- 451-500 4151 36 37 E-mail: [email protected] 38 39 40 41 42 Running title: Follow-on Biologics 43 44 45 Key words: Anemia, Biopharmaceuticals, Biosimilars, Erythropoietin, Follow-on 46 biologics, Hematopoietic growth factors 47 48 49 50 51 Abstract word count: 115 52 Text word count: 7304 53 No. of Tables: 2 54 55 No. of Figures: 0 56 57 58 59 60 1 John Wiley & Sons American Journal of Hematology Page 4 of 30 1 2 3 Summary 4 5 After the patents of biopharmaceuticals have expired, based on specific regulatory 6 approval pathways copied products (“biosimilars” or “follow-on biologics”) have been 7 launched in the EU. The present article summarizes experiences with hematopoietic 8 medicines, namely the epoetins (two biosimilars traded under five different brand names) 9 10 and the filgrastims (two biosimilars, six brand names). Physicians and pharmacists 11 should be familiar with the legal and pharmacological specialities of biosimilars: The 12 production process can differ from that of the original, clinical indications can be 13 extrapolated, glycoproteins contain varying isoforms, the formulation may differ from the 14 15 original, and biopharmaceuticals are potentially immunogenic. Only on proof of quality, 16 efficacy and safety, biosimilars are a viable option because of their lower costs. 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 John Wiley & Sons Page 5 of 30 American Journal of Hematology 1 2 3 Introduction 4 5 6 Biotechnology, i.e. the combination of cell culture and genetic engineering, has proved 7 beneficial for the production of diagnostics, vaccines and medicines [1]. Between 8 January 1995 and June 2007, 136 biopharmaceuticals were approved in the United 9 10 States (US) and 105 in the European Union (EU), with 67 products receiving approval in 11 both regions [2]. With respect to hematology, the primary DNA technology-based 12 products have been recombinant human erythropoietin (rhEPO; epoetin alfa), which 13 received the US orphan drug designation in 1986 and the marketing approval for anemia 14 15 in chronic kidney disease (CKD) in 1989, and granulocyte-colony stimulating factor (rG- 16 CSF; filgrastim), which obtained the designation in 1990 and the approval in 1994. 17 Recently, the patents of these successful medicines have expired in the EU and 18 elsewhere. Hence,For companies Peer other than the Review innovators have brought up copied 19 20 products [3-5]. Due to the complex nature of biopharmaceuticals, the EU regulators have 21 introduced the name “biosimilars” (“similar biological medicinal products”; US term: 22 “follow-on biologics”) for the copied medicines, and established specific regulatory 23 pathways for their approval, which differ from those for chemical “generics” [3,6]. 24 25 26 Health care authorities and insurance providers expect cost savings from the use of 27 biosimilars. However, there are still concerns with respect to the efficacy and quality of 28 the products [7,8]. Differing from chemically synthesized drugs, biological medicines are 29 30 engineered in living cells. The active substances exhibit complex three-dimensional 31 structures that cannot be fully characterized by the present analytical tools [1,9]. This 32 problem holds especially true for glycoproteins such as EPO, because these are 33 heterogeneous due to the presence of several isoforms [10,11]. 34 35 36 The present article describes first-hand EU experiences with biosimilar recombinant 37 medicines in an attempt to guide follow-on biologics launching plans in the USA and 38 other parts of the world. In particular, core issues will be considered in relation to the 39 40 clinical use of the two hematopoietic growth factors, primarily the rhEPOs (“epoetins”). 41 42 Manufacture of recombinant medicines 43 44 45 Recombinant proteins are produced by cells transfected with a gene or cDNA (the 46 coding sequence of the gene) linked to an expression vector. The recombinant DNA is 47 integrated into the genome of the host cells and stably expressed over time. 48 Transformed bacteria such as Escherichia (E.) coli or transfected yeast and filamentous 49 fungi are suited hosts for the production of non-glycosylated recombinant proteins such 50 51 as growth hormone (GH) or insulin. Only eukaryotic host cells can secrete proteins. 52 Genetically engineered mammalian cells are required for the production of glycoproteins 53 that possess essential O-glycans and/or complex N-glycans. The integrity of the terminal 54 sugars of the N-glycans is of major importance for the pharmacokinetics of 55 56 glycoproteins. 57 58 59 60 3 John Wiley & Sons American Journal of Hematology Page 6 of 30 1 2 3 The main factors influencing the composition of recombinant medicines are: (i) the 4 5 plasmid (promoter, marker genes), (ii) the host cell (origin, species, clone), (iii) the 6 culturing process (fermenter, culture media), (iv) the purification steps, (v) 7 postranslational modifications (oxidation, deamidation; addition of polymers), and (vi) the 8 formulation and packaging [9,10]. Due to the complex manufacturing processes, it is not 9 10 possible to exactly copy a biopharmaceutical. All manufacturers use their own cell lines 11 and apply unique fermentation and purification
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