Protein Biosimilars: opportunities and challenges

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1 Page 1 of 9 Medical Biotechnology Protein Biosimilars: opportunities and challenges YH Ge 1, MR Wang 1, XM Zhang 1, MG Pedler 2, MY He 1 *, CK Edwards III 2,3 * Abstract Introduction Therapeutic proteins are next-generation drugs in the prevention and treatment of diseases, in particular human critical illness. The expiration of patents in the originally approved biopharmaceutics has stimulated a great excitement and the subsequent development of followon versions of these first-in-line biotherapeutic products, known as Biosimilars or Biobetters. Biosimilars are a new class of drugs intended to offer comparable safety and efficacy (or clinical equivalence) to their original reference products which are brand name drugs and no longer under patent coverage. However, preparing exact copies of biologicals is much more challenging than replicating small molecules due to their structural complexity, intricate manufacturing processes and their potential risks for increased immunogenicity. Therefore, specific regulatory approval pathways and guidelines must be followed when creating Biosimilars. This article reviews the requirements and key considerations for producing Biosimilar agents as well as the important Biosimilar guidelines/regulations from different countries including the World * Corresponding authors s: mingyuehe2001@yahoo.com; drcarledwards@gmail.com 1 Laboratory of Recombinant Protein Therapeutics, Chengdu Institute of Biological Products, Chengdu , PR China 2 Department of Dermatology, University of Colorado at Denver, Anschutz, Medical Centre, Aurora, CO 80025, USA 3 National Key Laboratory of Biotherapy and Cancer Research, Western Sichuan China Medical School and Hospital, Sichuan University, Chengdu, Sichuan Province , PR China Health Organization, Food and Drug Administration and the European Medicines Agency. Conclusion Patents that expired or are soon to expire have provided a great opportunity for companies to make copies or generic versions of these drugs. Despite some challenges, therapeutic development of lower cost Biosimilars will inevitably enter the drug market in the near future, increasing the market competition and patients access to the more cost-effective therapies that they may not have otherwise. Table 1 Branded product Eprex (Janssen-Cilag) Biosimilar approved in Europe Neupogen (Amgen) Genotropin (Pfizer) Humatrope (ela Lilly) Introduction The continuous clinical and commercial success of biologics such as monoclonal antibodies (mab) and recombinant versions of endogenous proteins is transforming the pharmaceutical industry. Protein drugs have been demonstrated to significantly alter and even possibly cure some human critical illness where synthetic small molecule agents have failed 1. In 2010, worldwide sales of all biologics approached nearly the $100 billion mark in and it is expected that more than 50% of new drug approvals will be biologics 3 by 2015, rising to more than 70% by As these drugs begin to come off patent, substantial opportunities exist for other companies to make copies or generic versions of these drugs, now commonly known as Biosimilars or Biobetters. As of the end of 2012, there are a total of 17 Biosimilar and/or Biobetter recombinant protein therapeutics on the market in Europe alone (Table 1). However, the introduction of follow-on versions of biological products is much more difficult than for small molecules. Many biologicals such as mab and recombinant therapeutic proteins are much larger and more complex, the extent to which Biosimilar manufacturer Epoetin Abseamed (Medice Arzneimittel Pütter) Retacrit (Hospira) Binocrit (Sandoz) Epoetin alfa Hexal (Hexal Biotech) Silapo (STADA Arzneimittel) G-CSF (granulocyte colony stimulating factor) Filgastin Hexal (Hexal Biotech) Biograstim (CT Arneimittel) Nivestim (Hospira) Zarzio (Sandoz) Ratiograstim and Filgrastim Ratiopharm (Ratiopharm) Tevagrastim (Teva Pharma) hgh (human growth hormone) Omnitrope (Sandoz) Valtropin (Biopartners)

2 Page 2 of 9 Figure 1: The establishment of Regulations and Guidelines in selected countries involved in Biosimilar development August existing analytical technologies can be used to support the likelihood of clinical comparability between a follow-on version and the original product is much more limited than for small molecule drugs 5. For example, the comparison of two human cell lines, manipulated independently, cannot be considered identical 4. So, it is difficult to demonstrate that two products are absolutely identical. Consequently, a key question for the development and regulation of follow-on biologicals is how much and what kinds of data are needed to establish the clinical similarity 6. In addition, the overall success of developing a Biosimilar will depend very much on the ability of the manufacturer to offer a highly similar, safe and efficacious drug product at a cost saving manner that would encourage its purchase over the original brand name product. Because of these concerns, specific requirements for manufacturing Biosimilars, regulatory approval pathways and guidelines have recently been issued by many countries in the world (Figures 1 and 2), and they now serve as the very important standard for controlling and monitoring Biosimilar production (Table 2, Figure 2). The aim of this review is to discuss the opportunities and challenges of protein Biosimilars. Discussion Nature of Biosimilar products and key considerations Structural complexity Unlike small chemical molecules, proteins are made of living cells. Because even two mammalian cell lines, manipulated independently, cannot be considered the same, protein drugs are virtually very difficult to be copied. Moreover, the structural complexity of proteins renders the final products influenced by many variables, such as the use of

3 Page 3 of 9 Table 2 Countries with Biosimilar guidelines Country of group Issued Who issued Title Turkey August 2008 General Directorate of Pharmaceuticals and Pharmacy Taiwan 21 November 2008 Department of Health Malaysia 30 July 2008 Ministry of Health Malaysia Australia August 2008 EU guidelines were adopted. Instruction manual on Biosimilar medical products. Review criteria for registration and market approval of pharmaceuticals. Registration and market approval of biological products. Guidance document for registration of Biosimilars in Malaysia. India 11 July 2008 Preparation of the quality information for drug submission for new drug approcal biotechnological/biological products. Venezuela 3 August 2000 SRPB-R guidelines: application for health registry of DNA recombinant products, monoclonal and therapeutic antibodies, sub-classification for active substances, already on the market. Brazil 26 October 2005 Technical rules for registration of biological products. Colombia License for manufacturing facilities of biological products. Argentina July 2008 ANMAT Registration and registry modification of biological medicinal product. Middle East Consensus group recommended the implementation of the EMEA guidelines as the basis of regional guidelines for the registration of Biosimilars in the near and middle East. Saudi Arabia August 2008 Drug master file requirements for the registration of Biosimilars. Mexico 9 October 2008 Ley general de mediacmentos biotecnológicos. Canada March May 2009 in appropriate circumstances, a biologic product that is not authorised for sale in Canada may be used as a reference product. WHO 2008 WHO s draft has an EU-modelled biosimilar pathway and a controversial alternative pathway : October 2009 a reference product is a previously approved reference medicinal product for which there is a substantial public record of safety and efficacy. a medicinal product that was licensed of the basis of a full data package. EU 2001 and 2004 EU Directive 2001/83/EU and amended in 2004/27/EU. A reference product requires the use of a reference product authorised in the EU to be used for the entire comparability exercise. Japan 4 March 2009 A reference product is a biosimilar product which has comparable quality, safety and efficacy to a biotechnology-applied product that has been approved in Japan. USA Bills before Congress, including Waxman HR 1427 and Eshoo HR 1548 All bills require an FDA-approved biological reference product, thus mandating testing against US reference products.

4 Page 4 of 9 Figure 2: Approved Biosimilars from a global perspective as of August an expression system (e.g. bacteria, yeast and mammalian cells), growth conditions, purification processes, the actual formulation, storage and transportation. Changes in protein modifications such as glycosylation, phosphorylation, sulphation, methylation, acetylation and hydroxylation may further reduce biological activity and cause an intrinsic molecular heterogeneity 7, which can be difficult to control 6. Additionally, processrelated impurities may increase the likelihood and/or the severity of an immune response to a protein product 8 (see below). Immunogenicity In contrast to small molecule drugs, Biosimilars are more prone to acute and chronic immune responses. Testing for unwanted immunogenicity is therefore integral to product development for ensuring the clinical safety of a biological. Recently, a number of computer modeling programs/ algorithms have been developed to predict protein immunogenicity by identifying potential T-cell epitopes from the primary amino acid sequence of a linear protein In silico tools or use of tissues of animal origin in vitro have also been introduced to assess the potential immunogenicity of biologics prior to moving to clinical development 5. However, human clinical data are still needed for determining immunogenicity despite of the promise of these predictive methods. Since the immunogenicity of Biosimilars and brand name reference products needs to be compared, clinical studies must be designed to demonstrate whether the immunogenicity of the Biosimilar protein is identical, nearly the same or significantly different. Different strategies to assess immunogenicity need to be clearly established and validated on a case-by-case basis, per product, per disease patient group, and also taking into account the expected clinical parameters including previously observed efficacy and reported untoward side effects with the original molecule 11. Moreover, unwanted immunogenicity may occur at a level that is not detected in pre-approval studies, so assessment post-approval,

5 Page 5 of 9 Figure 3: Expiration dates for major patents on best-selling biologicals. Twelve compounds of biological products with global sales of more than $67 billion will be exposed to Biosimilar competition, except Enbrel (etanercept), whose US patent has been extended until Estimated patent expiration dates for some of the best-selling biological molecules are shown 15. as part of pharmacovigilance surveillance, is an important requirement 6. Manufacturing process Different production processes may alter a protein production away that could affect the safety, immunogenicity and/or potency of the product. For example, differences in biological systems used to manufacture a protein product may cause different post-translational modifications 12. Potential differences in protein structure/conformation can also arise during the intricate manufacturing process and even minor structural differences can significantly affect effectiveness of the drug 12. Thus, when the manufacturing process for a marketed protein product is changed, the Biosimilar producer must assess the effects of the change and demonstrate, through appropriate analytical testing, functional assays, and/or in some cases animal and/or clinical studies, that the change does not have an adverse effect on the identity, strength, quality, purity or potency of the original product 13. Emergence of protein Biosimilar drugs Many patients who are suffering lifethreatening and/or chronic diseases depend on the availability of biotherapeutic products in order to enhance their quality of life. The most recent trend has been to pursue drugs for diseases that most commonly afflict the aged. Of the three leading causes of death in the United States, cardiovascular disease (CVD), cancer and stroke, CVD is the biggest killer 14. While worldwide recombinant protein drug development continues

6 Page 6 of 9 to grow, it has recently been estimated that $67 billion worth of brand name patents will be expiring before This creates exciting opportunities for many potential Biosimilar molecules to enter the market and increase industry competition. Currently, a number of Biosimilar versions of these products have been developed and approved for the clinical use (Table 1). Figure 3 shows some of the best-selling biological molecules after patent expiration dates. According to a recent online article, the Biosimilars market has earned revenue of approximately $172 million in 2010 and the sales likely reach over $19 billion by However, despite the estimation that the market may reach approximately $39.87 billion by 2017, the Biosimilars industry is not for the faint hearted. This may be due to the requirement of considerable investment for manufacturing a Biosimilar to market as well as the possible failure of the molecule at any stage of the development 11. On the other hand, many companies, both originator and generics development and/or manufacturing companies alike, are increasingly entering this business, and by the end of 2012, this new industry has received impressive investment excitement and opportunities around the world 3. Monoclonal antibody Biosimilars With the approval of the first wave of Biosimilars around the world, it is readily apparent that Biosimilar mab are quickly becoming the next generation of drugs across many regions of the world 17. Patents to mab that have expired or are soon to expire include infliximab (for rheumatoid arthritis and Crohn s disease), trastuzumab (for breast and gastric cancers) and rituximab (for lymphomas and chronic lymphocytic leukemia) 18. So far, there have been a limited number of Biosimilars mab approved; the first being a drug called Remsima, which is a Biosimilar of Johnson & Johnson s RA blockbuster mab drug Remicade (infliximab ). Remsima was developed by a South Korean biotechnology company called Celltrion 19 and the clinical trials have demonstrated the Remsima (CT-P13) comparable to Remicade in pharmacokinetic profile, clinical efficacy and overall safety. In addition, Remsima was approved for several indications, including the treatment of RA, Ankylosing Spondylitis, Ulcerative Colitis, Crohn s disease and Psoriasis. Celltrion is currently preparing to launch Remsima in approximately 100 countries and has already applied to the EMA for the approval of the Biosimilar in the EU 19. Due to the complex, multi-domain structure of chimeric, humanized, or fully-human mab, the EMA has recently issued specific guidelines on mab Biosimilars, demanding additional comparability analysis in addition to complying with the relevant general guidelines for Europe 20. This would demand not only biochemical evaluation in vitro but also extensive functional evaluation in vivo 7,20. Immunogenicity is one of the major concerns of adverse reactions as there is no appropriate animal model to predict immunogenicity in humans to date 7. Thus, initial immunogenicity assessments are mainly a risk-based approach and require an important post marketing vigilance plan 7. Clearly, clinical evaluation of a Biosimilar mab requires a comparative design and analysis between the Biosimilar and the reference product, including the clinical pharmacokinetic and pharmacodynamic analysis 21. Taken together, the development of a Biosimilar mab may be much more demanding than the development of a simple, innovative biological therapy 6. The future of Biosimilars in musculosketal diseases Over the past decade, the availability of targeted biological therapies has revolutionised the treatment of rheumatoid arthritis, psoriasis, psoriatic arthritis and ankylosing spondylitis However, the significant cost of these biologicals is often prohibitive and limits universal access to these effective therapeutic agents 25,26. The first biological therapeutics in rheumatology is now approaching patent expiration and several Biosimilars are now in randomised controlled trials 27. This means that cheaper Biosimilars for the treatment of rheumatic and other musculoskeletal diseases are likely to enter the market in the near future, increasing patient access to these life-changing treatments 28. Despite a few potential problems of developing and manufacturing such complex molecules, it appears that lower cost versions of biological medicines will inevitably lead to the wide scale use of Biosimilar drugs in rheumatological diseases 27, Several recent research reviews have emphasised the importance of understanding the differences between Biosimilars and their reference products, as well as analytical issues that may arise when assessing bioequivalence and interchangeability of Biosimilars 32,33. Using a single global reference product and a need for scientifically-appropriate bridging to be accepted across (regulatory) jurisdictions has also been suggested 33. How are drugs approved and how long does it take? In the United States, as in most countries, there is a formal process by which drugs are approved for marketing 34. The standards of evidence for new drug approval are similar across countries, although the specific approval process can differ. The three largest prescription drug markets in the world (the United States, the European Union and Japan) have taken steps to harmonize their procedures to ensure the timely introduction of new drugs and to reduce the cost of development 4. An overview of

7 Page 7 of 9 the drug approval process in China seems showing its complexity and time-consuming 35, but its pharmaceutical market has been growing very fast since 2003 (Table 3). The most recently available data on the cost of developing self-originated New Chemical Entities (NCEs) by US pharmaceutical firms estimates the average to be $802 million, suggesting that costs are increasing much faster than the general rate of inflation 33. Thus it seems most likely that drug development will mainly remain in the private sector rather than being nationalized or funded by different governments in different countries. However, in the U.S., the government has been taking on a larger role in paying for innovative new drugs and therefore has a stake in the efficacy of the development process 36. A review of new healthcare legislation in the U.S. is beyond the scope of this review, but it is important to mention these new legislative vehicles aiming to streamline the approval process since these new laws affect every sector of the medical community and these changes are not easily adapted 37. WHO guidelines and evaluation standardization for Biosimilars The World Health Organization (WHO) has provided guidelines and recommendations for manufacturing and evaluating biologicals, including international standards for the quality, safety and efficacy parameters used in the evaluation of biologicals 33. A range of standard products that support regulation of biologicals worldwide have been used by the WHO to assist national regulatory authorities (NRAs) and manufacturers to achieve this goal 38. International written standards, biological reference preparations and physical standards that underpin the assessment of biologicals are also defined, which are available the WHO web site 39 providing the acceptance criteria for licensing these Table 3 Pharma market in the world 2003 Rank 2008 Rank 2013 Rank 1 United States 1 United States 1 United States 2 Japan 2 Japan 2 Japan 3 Germany 3 France 3 China 4 France 4 Germany 4 Germany 5 Italy 5 China 5 France 6 United Kingdom 6 Italy 6 Italy 7 Spain 7 Spain 7 Spain 8 Canada 8 United Kingdom 8 Brazil 9 Brazil 9 Canada 9 Canada 10 China 10 Brazil 10 United Kingdom 11 Mexico 11 Russia 11 Russia 12 Australia 12 Mexico 12 Venezuela 13 India 13 Turkey 13 India 14 Netherlands 14 India 14 South Korea 15 South Korea 15 Australia 15 Turkey 16 Belgium 16 South Korea 16 Mexico 17 Poland 17 Greece 17 Australia 18 Portugal 18 Netherlands 18 Greece 19 Turkey 19 Belgium 19 Poland 20 Greece 20 Poland 20 Belgium products worldwide. Perhaps, the current problem in both developing and developed countries is a limited access to the similar reference products. Biosimilar guidances in U.S. FDA U.S. FDA issued three draft guidance documents on Biosimilars development on 10 February 2012, which define Biosimilar regulatory pathways. For biological products to be approved, data must be provided to demonstrate that they are Biosimilar to, or interchangeable with, a biological reference product that is already approved by FDA. The three Biosimilar guidance documents (Scientific considerations; Quality considerations and Questions and Answers) provide the key scientific and regulatory considerations involved in submitting applications to the agency 40. Europe Biosimilar guidelines and the differences to U.S. The European Medicines Agency (EMA) introduced the first operating framework in 2005 for a path towards developing and marketing Biosimilars 5. Since then, European Biosimilar guidelines have been described 8 and 17 Biosimilars have been approved with most of them on the market 20 (Table 1). There are a few differences between Europe and the U.S. in the way they approach Biosimilars, including exclusivity period, biosimilarity standard and pharmacovigilance requirements. While U.S. provides a 12-year exclusivity period for an innovator biological product and 5-year exclusivity for an innovator-chemical drug, the EU uses a 10-year exclusivity period for both biological products and chemical drugs. The U.S. defines biosimilarity standard as highly similar and

8 Page 8 of 9 no clinically meaningful difference in terms of the safety, purity and potency. The EMA, however, has stated that the differences between the similar biological product and the reference product will have to be justified by appropriate studies on a case-bycase basis. In Europe, a drug s adverse side effects are required to be monitored during clinical trials and after the market, whereas the U.S. FDA is still seeking comments and has not published any rules regarding such requirements. Conclusion Patents that expired or are soon to expire have provided a great opportunity for companies to make copies or generic versions of these drugs. Despite some challenges, therapeutic development of lower cost Biosimilars will inevitably enter the drug market in the near future, increasing the market competition and patients access to the more cost-effective therapies that they may not have otherwise. Due to the complicated manufacturing process of replicating biologicals, many countries have issued critical Biosimilar guidelines/regulations which must be followed when producing the follow-on versions of these biotherapeutics products. It is expected that the Biosimilar market will continue growing in the near future and could reach $10 billion in US/EU by the end of Acknowledgements Research at Chengdu Institute of Biological Products, China, is supported by SinoPharm, China. This project is also supported by a national grant (no. 2011ZX ) from China. References 1. Weiss WA, Taylor, SS, Shokat KM. Recognizing and exploiting differences between RNAi and small molecule inhibitors. Nat Chem Biol Dec;3(12): Aggarwal S. What s fueling the biotech engine 2010 to Nat Biotechnol Dec;29(12): Files/531111; net/biosimilars/general/biosimilars-toreplace-70-of-chemical-drugs 5. Dranitsaris G, Dorward K, Hatzimichael E, Amir E. Clinical trial design in Biosimilar drugs development. Invest New Drug Apr;31(2): Barbosa MDFS, Kumar S, Loughrey H, Singh SK. Biosimilars and biobetters as tools for understanding and mitigating the immunogenicity of biotherapeutics. Drug Discovery Today Dec;17(23 24): Knezevic I. Evaluation of similar biotherapeutic products (SBPs): scientific principles and their implementation. Biologicals Sep;39(5): Barbosa MD. Immunogenicity of biotherapeutics in the context of developing Biosimilars and Biobetters. Drug Discov Today Apr;16(7 8): Zelenetz AD, Ahmed I, Braud EL, Cross JD, Davenport-Ennis N, Dickinson BD, et al. NCCN Biosimilars white paper: regulatory, scientific, and patient safety perspectives. J Nati Compr Canc Netw Sep;9(4):S Berkowitz SA, Engen JR, Mazzeo JR, Jones GB. Analytical tools for characterizing biopharmaceuticals and the implications for Biosimilars. Nat Rev Drug Discovery Jun 29;11(7): Centers for Disease Control and Prevention (CDC). Invasive cancer incidence United States, MMWR Morb Mortal Wkly Rep Feb 22;62(07): (highlight)/us$67%20billion%20worth 16. Dranitsaris G, Dorward K, Hatzimichael E, Amir E. Clinical trial design in Biosimilar drug development. Invest New Drugs Apr;31(2): Declerck PJ. Biosimilar monoclonal antibodies: a science-based regulatory challenge. Expert Opin Biol Ther Feb;13(2): Top-25-biotech-drugs-the-next-biosimilars-targets/(highlight)/Top%2025%20 biotech%20drugs Infliximab%20in%20Korea GB/document_library/Scientific_guideline/2012/06/WC pdf July Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Office of Communication, Outreach and Development, HFM-40 Center for Biologics Evaluation and Research Food and Drug Administration. 2012;1(1): McInnes IB, Schett G. Mechanisms of disease. The pathogenesis of rheumatoid arthritis. NEJM Dec;365(23): Gottlieb AB, Leonardi C, Kerdel F, Mehlis S, Olds M, Williams DA. Efficacy and safety of briakinumab versus etanercept and placebo in patients with moderate to severe chronic plaque psoriasis. Br J Dermatol Sep;165(3): Galvin-Banqueri M, Marin GR, Santos RB, Bautista PFJ. Biological treatments for moderate-to-severe psoriasis: indirect comparison. J Clin Pharm Ther Apr;38(2): Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, et al. National Arthritis Data Workshop. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum Jan;58(1): Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, et al. National Arthritis Data Workshop. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum Jan;58(1): Scheinberg MA, Kay J. The advent of Biosimilar therapies in rheumatology O Brave New World. Nat Rev Rheumatol Jun 5;8(7): Subramanyam M. Clinical development of Biosimilars: an evolving landscape. Bioanalysis Mar;15(5):

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