International Journal of Editorial Clinical Rheumatology

10 Editorial Introduction of biosimilar monoclonal antibodies: the changing face of rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis treatment

“In general, the difference between a biosimilar and its reference biologic is Int. J. Clin. Rheumatol. similar to the difference between a biologic before and after an approved manufacturing process change.”

Keywords: ankylosing spondylitis • biologics • biosimilars • Crohn’s disease • immunogenicity • • monoclonal antibodies (mAbs) • psoriasis • psoriatic arthritis • ulcerative colitis • rheumatoid arthritis

The introduction of biological medicines manufacturing and monitoring of biosimi- has revolutionized the treatment of chronic lars. Even with biologic drugs that have been inflammatory diseases such as rheumatoid on the market for over 10 years, manufactur- Jürgen Braun arthritis (RA), ankylosing spondylitis (AS) ing changes occur frequently, and, provided Rheumazentrum Ruhrgebiet, Ruhr University Bochum, Claudiusstr. 45, and psoriatic arthritis (PsA) enabling and manufacturers demonstrate that the process 44649 Herne, Germany maintaining clinical remission and improv- change does not alter the safety or efficacy of Tel.: +49 232 559 2131 ing quality of life in many patients [1,2]. As the biologic [5], no label change is required. Fax: +49 232 559 2136 many of these biologics approach patent In general, the difference between a biosimi- [email protected] expiration, biosimilars are now starting to lar and its reference biologic is similar to the become available, potentially allowing clini- difference between a biologic before and after cians to broaden access for patients in need an approved manufacturing process change. of effective treatment as well as providing Biosimilar monoclonal antibodies (mAbs) overall cost benefits to healthcare systems. are a new generation of biologic medications Biosimilars are biological medicines which expected to challenge the pharmaceutical are highly similar but not identical to the market with products that are comparable reference original biologic product [3,4], and in terms of efficacy, safety and quality, while 2 are only made available after the patents potentially providing substantial cost sav- and Supplementary Protection Certificates ings. The time for that seems ideal since have expired. (In European Union member cash-strapped healthcare providers are under countries, a supplementary protection cer- increasing pressure to curb costs. The Euro- 2015 tificate is a unique intellectual property right pean economic situation is characterized by that extends the duration of the exclusive an aging population, driving increases in right which enters into force after expiry of a public expenditure in both health and long- patent upon which it is based). term care [6]. Biosimilar mAbs offer health- Due to the complex nature and variability care providers and payers treatments that of biological medicines (they are proteins pro- are expected to cost in the range of 10–30% duced by living organisms) no two batches less than the originators, potentially saving are ever exactly the same [4]. Thus, being billions of Euros, which could possibly be nonidentical is a normal feature of biotech- used to treat more patients with these drugs, nologic processes [5], and both passive and for example, to initiate treatment earlier in active drifting is expected to occur over time, the course of the disease in order to avoid part of hence the strict regulations to control the structural damage [7].

10.2217/IJR.15.9 © 2015 Future Medicine Ltd Int. J. Clin. Rheumatol. (2015) 10(2), 61–64 ISSN 1758-4272 61 Editorial Braun

The key to uptake of biosimilar mAbs sits with ation. Both studies were of 54 weeks’ duration with an rheumatologists or experts in other fields and their open-label extension to 102 weeks. The PLANETAS understanding of the evidence base and of the benefits study was a pharmacokinetic study of 250 patients they provide to patients and the medical community as with AS. The PLANETRA study was a Phase III a whole. It is critical that physicians familiarize them- study of 606 patients with RA. Together, these studies selves with the rigorous regulatory procedure biosimi- confirmed that CT-P 13 is equivalent to the reference lar manufacturers must follow in order to demonstrate product in terms of efficacy and comparable in terms that the drug is comparable to the originator biologic of safety [13,14]. in terms of efficacy, safety and quality. This is critical Whilst immunogenicity has historically been a chal- to have confidence to make decisions about when to lenge for biologics as they are immunogenic by nature, prescribe a biosimilar to patients. there are a number of factors that can trigger an immune This paper focuses on Remsima® (infliximab) as the response other than a reaction to the drug. These can first biosimilar mAb to enter the market for rheumatic include the patient’s disease, particularly diseases such diseases, but there are a number of others expected to as RA known to be associated with immunogenicity, launch over the next few years, including and how the drug is administered [15] . The emergence and [8]. of biosimilars has led to more robust immunogenicity studies [10]; these were used in the evaluation of CT-P Regulating biosimilars 13, which was found to have a comparable immunoge- The EMA process for evaluating a biosimilar is differ- nicity profile to the reference product, raising no safety ent to the process for an originator biologic. The ‘nor- concerns [14] . mal’ regulatory pathway requires a biologic to show clinical efficacy and safety to determine the mode of Data extrapolation: is it reasonable? action. The approach for biosimilars concentrates more Data extrapolation is a scientifically established method on the quality and analytical characteristics and less that has been used for many years [16], including in the on the clinical studies [9], which play more of a confir- approval dossier for and epoetin a few years matory role. The goal is for the biosimilar to have the ago. However, some concern by members of the medi- same, and in some cases better, quality as the reference cal community about the legitimacy of this approach biologic [10] . has been expressed. This may have contributed to the Regulators place significant emphasis onin vitro lower than expected uptake for biosimilars in Europe studies as the first step to the biosimilar comparabil- to date [17] – even though the EMA, alongside other ity exercise as they can detect differences between regulatory bodies such as the FDA, advocates extrapo- the biosimilar and the reference product, such as fac- lation and states that ‘if clinical similarity can be shown tors impacting on pharmacokinetics. From this it is in a key indication, extrapolation of efficacy and safety determined what additional tests may be required. data to other indications of the reference product may Whilst biosimilars are subject to greater scrutiny be possible’ [18]. EMA has started to develop strategies and there is pressure for manufacturers to introduce to better educate clinicians about biosimilars, which sophisticated systems to monitor for safety, Euro- include data extrapolation [17] . pean Union legislation in 2011 With CT-P 13, the drug was tested for safety and did not single them out. The legislation stated that all efficacy in the most sensitive populations (RA and new medicines launched after this date are subject to AS) – the diseases where any differences between the closer monitoring and should be identified by a black biosimilar and the reference product are most likely to triangle, including, but not limited to, biosimilars [11] . manifest – and then extrapolated to Crohn’s disease, ulcerative colitis, PsA and psoriasis [12] . First biosimilar mAb for rheumatoid arthritis, ankylosing spondylitis & psoriatic Interchangeability: is there a case for arthritis switching? Recently, EMA approved CT-P 13 (Remsima®), a bio- As biosimilar mAbs enter the market, it is expected similar of infliximab (Remicade®), for all disease areas that they will be prescribed initially to new patients in which the reference biologic is approved: RA, AS, until rheumatologists gain confidence in their use – Crohn’s disease (adults and children), ulcerative coli- and if more data on switching from one compound to tis (adults and children), PsA and psoriasis [12] . EMA the other have become available. evaluated Remsima on the totality of the evidence, Switching patients from the reference product to including two randomized, double-blind, multicenter CT-P 13 may not be on the agenda in the short term, studies, conducted to confirm EMA’s preclinical evalu- because the data suggesting no significant differences

62 Int. J. Clin. Rheumatol. (2015) 10(2) future science group Introduction of biosimilar monoclonal antibodies Editorial between the maintenance and switch group in terms Concluding remarks of efficacy or safety are derived from open-label stud- Biosimilar mAbs are an important milestone for modern ies [13,14]. However, rheumatologists may be encour- medical therapy strategies to treat chronic inflammatory aged to consider the case for switching based on diseases. Especially patients who have been unable to emerging ‘real-world’ evidence and interchangeability access biologics in the past and the economic burden of data such as the Norwegian Nor-Switch study [19] . healthcare systems could have substantial benefit from Investigators anticipate that the Nor-Switch study, this development. However, all physicians and espe- which is designed to demonstrate the safety and effi- cially rheumatologists need to familiarize themselves cacy of the infliximab biosimilar in that setting, will with the data that support these products, both preclini- support switching patients currently receiving the cal and clinical, to gain confidence to use biosimilars originator. However, this study is still ongoing and for their patients in all different indications. Evaluating data are not yet available. the array of evidence used for EMA approval, the grow- ing body of real world data and their own experience in The cost benefits of biosimilar mABs using these drugs should help to establish this new way Since mAbs are very profitable and can generate sig- to treat patients with a high burden of disease. nificant revenues for manufacturers, it is not surpris- ing that this is now the next generation of biosimilars Financial & competing interests disclosure to watch. Around 40% of all requests for scientific J Braun has received fees for serving as an advisory board advice to EMA between 2003 and 2011 were related member for Mundipharma International Limited. J Braun has to biosimilar mAbs [20]. The experienced expert H. also received honoraria for talks, advisory boards, paid consul- Schellekens expects that biosimilar mAbs will pen- tancies and grants for studies from Abbvie (Abbott), Amgen, etrate the market faster than the first generation of BMS, Boehringer, Celgene, , Centocor, Chugai, EB- biosimilars [21] . EWE Pharma, Janssen, Medac, MSD (Schering-Plough), Mun- With biosimilar mAbs expected to cost 10–30% less dipharma, , (Wyeth), Roche, Sanofi-Aventis and than their biologic counterparts, it may be predicted UCB. The author has no other relevant affiliations or financial that they will save European healthcare systems up to involvement with any organization or entity with a financial 20 billion Euros by 2020 [22]. Substantial cost savings interest in or financial conflict with the subject matter or ma- such as these can potentially be used in a number of terials discussed in the manuscript apart from those disclosed. ways, including providing better access to biologics, Writing assistance was utilized in the production of this particularly in countries with lower gross domestic manuscript. Mundipharma International Limited provided products. funding for writing assistance with this article.

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