The role of biosimilars in the treatment of rheumatic diseases Thomas Dörner, 1,2 Vibeke Strand, 3 Gilberto Castañeda-Hernández, 4 Gianfranco Ferraccioli, 5 John D Isaacs, 6,7 Tore K Kvien, 8 Emilio Martin-Mola, 9 Thomas Mittendorf, 10 Josef S Smolen, 11 Gerd R Burmester 1 Handling editor Hans WJ Bijlsma 1 CC12 Department of Medicine, Rheumatology and Clinical Immunology, Charité— University Medicine Berlin, Berlin, Germany 2 Deutsches Rheumaforschungszentrum (DRFZ), Charité—University Medicine Berlin, Berlin, Germany 3 Division of Immunology/ Rheumatology, Stanford University School of Medicine, Palo Alto, California, USA 4 Department of Pharmacology, Cinvestav, Mexico-City, Mexico 5 Rheumatology Division, Catholic University of the Sacred Heart, Rome, Italy 6 Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK 7 Musculoskeletal Directorate, Newcastle upon Tyne hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 8 Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway 9 Rheumatology Unit, La Paz University Hospital, Madrid, Spain 10 Herescon GmbH, Hannover, Germany 11 Department of Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria Correspondence to Professor Thomas Dörner, CC12 Department of Medicine, Rheumatology and Clinical Immunology, Charité— University Medicine Berlin, Chariteplatz 1, Berlin 10117, Germany; thomas.doerner@charite.de Received 21 September 2012 Revised 23 November 2012 Accepted 2 December 2012 Published Online First 19 December 2012 ABSTRACT The first biological therapeutics in rheumatology are approaching patent expiration, encouraging development of ‘follow-on’ versions, known as ‘biosimilars’. Biological agents range from simple replacement hormones to complex monoclonal antibodies and soluble receptors: large, intricate proteins with unique tertiary and quaternary structures that are inherently difficult to replicate. Post-translational modifications, such as glycosylation, may occur from changes in cell lines and/or manufacturing processes, resulting in products that are highly similar, but not identical, to approved ‘ reference’ agents, hence, the term ‘biosimilar ’, rather than ‘bioidentical’. Even minor modifications in manufacturing processes, which iteratively occur with reference products due to improvements in efficiency, scale up to meet commercial demands or changes in manufacturing sites, may alter biological function and/or immunogenicity, potentially changing their safety and efficacy profile. As biosimilars are now in randomised controlled trials for treatment of rheumatic diseases, rheumatologists face decisions regarding equipoise and will need to consider their clinical use versus reference products. A clear understanding of the inherent differences between reference antibodies and biosimilars, their clinical implications and the processes governing regulation, approval and clinical use of biosimilars, is paramount. A panel of international experts in the field of rheumatology recently convened to evaluate and discuss these issues. INTRODUCTION The introduction of biological therapeutics for treatment of rheumatic diseases has significantly improved patient outcomes. 1 With some of these ‘ reference (originator) products’ approaching patent expiration, manufacturers are developing follow-on versions. 2 Biosimilars may improve access to expensive biological agents; however, concerns have been raised regarding their clinical use. In par- ticular, due to the complexities of manufacturing ‘copies’ of biological therapeutics, physicians have questioned whether biosimilars will confer identi- cal biological function, efficacy and toxicity to ref- erence products, both in the short and long term. 34 These concerns are not without substanti- ation, since even minor modifications in manufac- turing processes, which iteratively occur with reference products, may alter biological functions and/or immunogenicity, potentially changing their safety and efficacy profile 5 (table 1). Biological agents range from simple replacement hormones to complex monoclonal antibodies (mAbs) and soluble receptor constructs (Cepts)—large, intricate proteins with unique tertiary and quaternary struc- tures that are inherently difficult to replicate. Post-translational modifications, such as glycosyla- tion, may occur from changes in cell lines and/or manufacturing processes, resulting in products that are highly similar, but not identical to approved ‘ reference’ agents, hence the term ‘biosimilar ’, rather than ‘bioidentical’. The potential for protein modification to alter biological function is espe- cially true for intricate therapeutic proteins, such as mAbs and Cepts. With the expected introduction of biosimilar mAbs and Cepts, it is important that rheumatolo- gists are familiar with biosimilars, so allowing informed treatment decisions. In order to facilitate this, a panel of international experts convened in Berlin in April 2012 for the roundtable on ‘the role of biosimilars in the treatment of rheumatic dis- eases’. The roundtable provided a forum at which to discuss the potential clinical utility of biosimi- lars in rheumatology, implications for product effi- cacy and safety, and their impact on patient care. This article reviews the topics discussed at this meeting, providing physicians with current infor- mation in this rapidly evolving field. RATIONALE FOR THE DEVELOPMENT OF BIOSIMILARS In 2012, worldwide sales of the top three selling TNFα inhibitors (TNFi) reached US$20 billion, 13 with total annual sales for rheumatic disorders approaching US$30 billion per year. This amounts to a US$10 000–30 000 per patient per year finan- cial burden to patients or third-party payers of healthcare. In addition, there is a humanistic burden due to restricted access caused by budget constraints in many countries around the world. Thus, there is significant interest in efficacious, lower-cost biosimilars. DEFINING BIOSIMILAR A biosimilar is ‘a biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product’, with similarity defined as ‘the absence of a relevant difference in the parameter of interest’. 14 Biosimilars should be developed strictly in accord- ance with comparative procedures used for refer- ence products, as mandated by regulatory authorities, such as the European Medicines Editor ’s choice Scan to access more free content ▸ http://dx.doi.org/10.1136/ annrheumdis-2012-202941 322 Ann Rheum Dis 2013;72:322–328. doi:10.1136/annrheumdis-2012-202715 Review on January 25, 2022 by guest. Protected by copyright. http://ard.bmj.com/ Ann Rheum Dis: first published as 10.1136/annrheumdis-2012-202715 on 19 December 2012. Downloaded from