A scientific update on biosimilar infliximab (CT-P13) in rheumatic diseases

Abstract

The development of biologic drugs has undoubtedly enhanced the spectrum of treatments available for immune-mediated inflammatory rheumatic diseases such as rheumatoid arthritis. However, despite their clear clinical benifits, use of biologics is often hindered by their high costs. The manufacture and subsequent approval of more cost-effective ‘biosimilar’ versions of these drugs may address this issue and improve patient access. CT-P13 (Remsima^®, Inflectra^®), a biosimilar of infliximab (Remicade^®), has shown comparable efficacy, safety and pharmacokinetics to its originator drug in clinical studies. The articles in this supplement present a scientific update on the development and use of biosimilars in rheumatic disorders, with specific focus on CT-P13. The information discussed highlights the predicted positive clinical and economic impact of biosimilars on the management of rheumatic diseases.

Keywords:

• biologics
• biosimilars
• CT-P13
• infliximab
• rheumatoid arthritis
• tumor necrosis factor

The introduction of targeted biologic therapies into the treatment paradigm for immune-mediated inflammatory diseases represents one of the most important advances in the recent history of medicine [1]. In the rheumatology setting, the efficacy, tolerability and speed of onset of biologics have led to better disease management and improved outcomes in patients with conditions such as rheumatoid arthritis (RA). Biologic agents have come to play a pivotal therapeutic role in the management of RA because of their capacity to have an impact on the pathophysiologic aspects of the disease process and to reduce or reverse the signs and symptoms of the disease. As a result, patients treated with biologics have experienced improvements in many aspects of their lives that were substantially affected by RA, including physical function, ability to work and overall quality of life [2]. Notably, a recent review of biologic therapy in RA concluded that effects on radiographic progression were improved with early use of biologics and that drug-free remission could be possible if biologics were used early on in the disease [3]. Based on these recognized therapeutic benefits, some rheumatologists advocate that biologics should be used earlier than more traditional disease-modifying anti-rheumatic drugs, instead of using them in patients with well-established disease who have already failed on multiple traditional drugs [1]. However, the cost implications of early biologic therapy are an obstacle to implementation of this approach, even though in the long term, the reduced morbidity and clinical benefits experienced by patients may help balance costs [2].

There is inherent complexity involved in the development and manufacture of biologics due to the method of their production in living cell systems and their intricate protein structure, which can be significantly influenced by even subtle changes in production-related factors. This means that the cost of developing biologics – particularly, structurally complex monoclonal antibodies – is high, a fact reflected in the cost of these drugs to healthcare systems. A recent analysis of disease-modifying anti-rheumatic drug use in Europe found that the cost of biologic treatment for RA for 1 year was higher than the gross domestic product per capita in 26 out of 49 countries surveyed [4]. These economic challenges and the need for prioritization in healthcare systems mean that patient access to effective biologic treatments for chronic, debilitating diseases such as RA can be heavily constrained, especially in lower-income countries [4]. In recent years, however, patent expiry of some biologics has created the opportunity for biopharmaceutical manufacturers to develop biosimilar drugs designed to be as efficacious as the originator products, but importantly with a lower cost for healthcare providers, a model that is analogous in some ways to the development of generic versions of small-molecule drugs. The World Health Organization describes a biosimilar as a ‘biotherapeutic product that is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product’ [5].

Regulatory agencies around the world have adopted different, but broadly related, definitions of a biosimilar drug. Before the approval of any biosimilar, the regulatory authorities require biosimilar manufacturers to adhere to strict non-clinical and clinical development guidelines to ensure safety and efficacy equivalence to the originator product or ‘reference medicinal product’ (RMP). For example, the European Medicines Agency states that a biosimilar should be proven to be highly similar to its RMP in physicochemical and biologic terms [6]. Also, approval typically requires statistically proven equivalence in clinical pharmacokinetics (PK) and efficacy measured in disease states considered most informative, along with integrated or aggregated safety data.

The papers published in this supplement present a scientific update on the development and use of biosimilars in rheumatologic disorders, including the publication of new data and additional insights. The focus of the supplement is on CT-P13 (Remsima^®, Inflectra^®), a biosimilar of the infliximab RMP (Remicade^®). In September 2013, CT-P13 became the first biosimilar monoclonal antibody to be authorized for use in the EU, when it was approved for all the therapeutic indications held by the RMP [7]. The first article describes the background for, and complexity of, developing biosimilars, discusses the stringent scientific principles underpinning regulatory approval of these modalities and illustrates how the development of CT-P13 conformed to these standards to gain approval in the EU [8]. Clinical data that contributed to this approval were generated by PLANETAS and PLANETRA, two pivotal randomized clinical trials which directly compared CT-P13 and the infliximab RMP in ankylosing spondylitis and RA, respectively [9,10]. In these randomized clinical trials, the two agents were shown to be highly similar in terms of PK, efficacy and safety. However, to further evaluate the comparability of these two products, Yoo et al. explored whether the efficacy, safety and PK parameters observed with CT-P13 in PLANETAS and PLANETRA are similar to historic data reported with the RMP [11]. Using literature searches, this report analyzes data from previously published infliximab RMP trials involving similar treatment regimens and patient eligibility criteria as PLANETAS and PLANETRA. The findings from this analysis further emphasize the high similarity between CT-P13 and RMP infliximab. Thus, clinical outcomes including various efficacy, safety and PK parameters have been found to be highly comparable between CT-P13 and the RMP, not only in head-to-head randomized clinical trials sponsored by the biosimilar developer but also in indirect comparisons with historical trial data for the RMP.

Additional clinical data contributing to our knowledge of CT-P13 come from a PK study comparing CT-P13 and RMP in healthy volunteers; original data from this investigation can also be found in this supplement [12]. The study compared the PK of CT-P13 with that of RMP sourced either from Europe (EU-RMP) or the USA (US-RMP), and was conducted to meet the US Food and Drug Administration requirements for development of biosimilars [13]. The results confirmed that CT-P13 is equivalent to both formulations of the RMP in terms of PK, and also demonstrated that the safety profiles of single-dose CT-P13, EU-RMP and US-RMP were similar. These findings in healthy volunteers mirror those previously observed in patients enrolled on PLANETAS and PLANETRA.

When considering the approval of a new biosimilar, another key clinical factor that is considered by regulators is immunogenicity. This issue is important since it is known that differences in a biologic drug’s formulation, purity or packaging can affect its immunogenicity profile. Furthermore, alterations in immunogenicity have the potential to affect both drug efficacy and safety. Consequently, it is crucial to gain an understanding of the relative advantages and weaknesses of the different immunoassay methods that may be used to generate immunogenicity data in clinical studies, as this will aid interpretation of study results [14,15]. The paper by Kim et al. compares the immunoassay methods and provides an overview of outcomes when different techniques from the literature were used to measure anti-drug antibodies in the studies of infliximab RMP and CT-P13 [16]. Importantly, the electrochemiluminescent immunoassay – the method used to assess the immunogenicity of CT-P13 and RMP in the comparability studies that led to regulatory approval of CT-P13 – appears to be a sensitive assay with low levels of drug interference. Of note, no relevant differences in the immunogenicity profiles of CT-P13 and infliximab RMP were observed in clinical studies involving up to 54 weeks of treatment [9,10,17,18].

As described above for CT-P13, regulatory authority approved biosimilars are expected to have highly comparable efficacy, safety, PK and immunogenicity profiles to their RMP. However, biosimilars have one important difference versus RMPs: their lower costs. As a result, regulatory authority approved biosimilars such as CT-P13 represent an important step toward improved access to biologic therapies. In their article, Gulácsi et al. describe the economic burden associated with RA and the potential for ‘complex’ biosimilars such as CT-P13 to reduce drug costs, in a manner akin to the savings observed with relatively simple, first-generation biosimilars [19]. The hope is that such savings will lead to greater numbers of patients receiving effective treatment for diseases such as RA. Forecasts suggest that substitution of CT-P13 for infliximab RMP in RA in four European countries could save hundreds of millions of euros, allowing more patients to be treated or for funds to be diverted into other aspects of health care [20].

In conclusion, biologic therapies have transformed the treatment of immune-mediated inflammatory diseases including rheumatic disorders such RA and ankylosing spondylitis, but they are also expensive and, thus, access is limited for many patients. However, as the patents of biologics expire, a new era of biologic therapy has begun. Biosimilars such as CT-P13 are likely to play an increasingly important role in the management of rheumatic diseases by helping to lower costs and address inequalities in patient access. Reduced costs may also result in earlier implementation of biologic therapy. The evidence presented in this supplement represents a valuable resource to help inform prescribing physicians and others when evaluating the place of biosimilars in medical practice.

Acknowledgements

Editorial support (writing assistance, assembling tables and figures, collating author comments, grammatical editing and referencing) was provided by Mark O’Connor (Aspire Scientific Limited, Bollington, UK) and was funded by Celltrion Healthcare Co., Ltd (Incheon, Republic of Korea).

Financial & competing interests disclosure

P Taylor has received grant funding from UCB and served as a consultant to Hospira, Celltrion, UCB, Sandoz, Roche, Pfizer, Merck, Janssen and BMS. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.