An update on biosimilar drugs for inflammatory bowel disease

Abstract

Biological therapies for inflammatory bowel disease (IBD) have, since their introduction over 15 years ago, been separated from so-called ‘conventional therapies’ in the therapeutic paradigm. Although the TNF inhibitor infliximab is known to improve IBD outcomes in many different ways, several questions remain regarding the optimal way to employ this drug in the clinic, which are the questions not yet explored in clinical trials, in part, due to the drug’s high cost. With the introduction of biosimilar drugs, including the infliximab biosimilar CT-P13, the therapeutic landscape in IBD will change. Access to biological drugs will widen and patients will be treated earlier. The division between ‘conventional’ and ‘biological’ therapy will be replaced by new treatment paradigms. Gaps in knowledge about the best use of anti-TNF therapies in IBD may also be filled due to the enhanced competition between manufacturers and the expected lower costs of biosimilars.

Keywords:

• biologics
• biosimilars
• Crohn’s disease
• CT-P13
• inflammatory bowel disease
• infliximab
• tumor necrosis factor
• TNF ulcerative colitis

Inflammatory bowel disease (IBD), with its two major forms of Crohn’s disease and ulcerative colitis, represents a global public health problem and is estimated to affect more than 3.5 million individuals in Europe alone [1–3]. Long-term control of this chronic disease is necessary due to the debilitating and serious consequences of uncontrolled inflammatory activity as well as an increased mortality rate, compared with the general population [4]. The so-called ‘conventional’ treatment strategies have evolved from the availability of cheap immunosuppressive drugs (i.e., glucocorticoids and oral immunosuppressants) which, due to the fact that they were approved some decades ago, never underwent evidence-based proof-of-efficacy assessments. Somewhat arbitrarily, biological therapies have been separated from conventional therapies in the therapeutic paradigm, mostly due to the unknown safety risks of this new molecular class of drugs when they were first approved, risks that, at the time, were felt to arise from blockade of TNF. The relatively high price of biologics at the point of their introduction was also a contributing factor. However, with the advent of biosimilar drugs, and of several novel or ‘originator’ biologics with new targets, it is now inconceivable to maintain the separation between ‘conventional’ and ‘non-conventional’ therapies.

Infliximab was the first biological therapy to be approved in IBD and has since been followed by other anti-TNF drugs (adalimumab, certolizumab pegol and golimumab), as well as the anti-integrin antibodies, natalizumab and vedolizumab [5]. In addition, a number of other agents are under investigation in IBD, targeting a variety of immunological pathways. These include the monoclonal antibody ustekinumab, which targets the heterodimeric cytokines IL-17 and IL-23, and tofacitinib, a small-molecule inhibitor of JAK [6].

Well over 1 million patients suffering from various forms of immune-related diseases have been treated with infliximab since approval of this drug over 15 years ago, and therapeutic blockade of TNF is now a mainstay of anti-inflammatory therapy [7]. As for all other IBD treatments, anti-TNF therapy does not inhibit an etiologic process but effectively intersects disease pathophysiology. TNF is a central mediator in the disease process and targeted neutralization of the various forms of this cytokine (including membrane-expressed TNF) leads to unsurpassed clinical efficacy in various patient populations, from those with early forms of IBD to those with late, complicated stages of the disease. Indeed, the use of anti-TNF therapy influences the outcome of disease in many ways; for example, by decreasing the occurrence of new complications including IBD-related hospitalization, improving the quality of life, and reducing the activity of fistulae and use of glucocorticoids [8–11]. Perhaps like no other drug, infliximab induces disease control and mucosal healing. However, a series of questions remain regarding infliximab that relate, for example, to the right time to introduce chronic intervention (late vs early disease) as well as to the need for individually optimized dosing (as a significant proportion of patients show low exposure due to faster elimination of the drug). The relatively high price of infliximab has been a key reason why these issues have not been explored yet in formal trials. With the expiration of the patents protecting infliximab, a new era in the use of anti-TNF biologics is beginning, as demonstrated by the approval in Europe and elsewhere of the infliximab biosimilar CT-P13 (Remsima^®, Inflectra^®). In addition, patents protecting adalimumab are due to expire in 2016 and 2018 in USA and Europe, respectively, which will likely be followed by the launch of adalimumab biosimilars [12]. Similarly, biosimilars for golimumab and certolizumab pegol may also be developed in preparation for imminent patent expiry of those drugs. With the approval of CT-P13 and other biosimilars, access to anti-TNF drugs is expected to open up due to the cost savings that are anticipated with biosimilars [13,14], while increased competition may also induce a race for the missing data that, for example, will help shape optimized use of infliximab in the future.

In contrast to generic drugs, biosimilars are more complicated to develop as this process is very different from copying a chemically well-defined small molecule [15]. Biologics are made in living organisms, and in the case of infliximab, in mouse myeloma cells. While the chemical backbone (i.e., the amino acid sequence) is stable and well defined, post-translational modifications, especially glycosylation, are specific to the very cells used during an individual production run and can result in differences in the characteristics of the generated therapeutic molecules [15]. Each biological drug production process is unique and even originator biologics show significant batch-to-batch variations [16,17]. Therefore, constancy in the characteristics of the generated molecules is highly dependent on the technological skills of the manufacturer and requires significant surveillance by both manufacturers and approving authorities. If a biosimilar is created as another version of the originator molecule, it must fit within defined ‘boundaries of tolerance’ surrounding the originator version, although variations in some ‘quality aspects’ of the two molecules (e.g., type/level of glycosylation) are only deemed important if they are considered clinically relevant. The process of biosimilar development is well regulated, from selection of the production clone, thorough physicochemical comparative exercises, to a full functional and clinical comparison versus the originator biologic in the most sensitive indication. While during the development of an originator biologic much of the work is invested in the late phases of preclinical and clinical research, development of a biosimilar requires enormous investments in earlier molecular, analytical and preclinical studies [17,18].

This supplement will discuss the different steps involved in the development of complex biosimilars, with a focus on the infliximab biosimilar CT-P13. As CT-P13 represents the first monoclonal antibody biosimilar to be approved in Europe, its development path can be used to exemplify many of the issues involved in such a process. The different articles in this supplement detail how the development process is conducted and highlight the clinical requirements for approval and so-called ‘extrapolation’, a process in which all indications of the originator molecule are granted to the new version of the molecule based on the demonstration of comparable efficacy, safety, immunogenicity and pharmacokinetics in physicochemical, functional and clinical testing. Importantly, the first ‘real-world’ clinical experiences with CT-P13 in IBD are also summarized. These experiences represent an entry into larger registries that will carefully monitor the performance of new biosimilars over time.

With the introduction of biosimilars, the therapeutic landscape in immune-mediated diseases such as IBD will thoroughly change. As access to highly effective biological drugs broadens, we will see their wider use and, most importantly, significant clinical benefits, as more patients receive more effective therapy earlier in their disease. The current pyramidal paradigm of therapy with its division between ‘conventional’ and ‘biological’ therapy is outdated and will give way to individualized therapeutic planning. Critically, competition between manufacturers of anti-TNF biologics may not only push the prices down, but also initiate a race to fill the gaps in knowledge about the best use of anti-TNF therapies in IBD. The price decay that is initiated through competing offers on existing biologics will also affect the success of new drugs by raising the bar for them to be classified as step innovations, with premium prices paid for such advances.

Financial & competing interests disclosure

S Schreiber has served as a consultant or advisory member for Abbvie, Boehringer Ingelheim, Celltrion, Ferring, Genentech, Hospira, Janssen, MSD, Mundipharma, Pfizer, Roche, Takeda and UCB. He has also served as a speaker for Abbvie, Celltrion, Falk Pharma, Ferring, Janssen, Hospira, MSD, Mundipharma, Shire Pharmaceuticals and UCB. The author has no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Editorial support (writing assistance, collating author comments, grammatical editing and referencing) was provided by Rick Flemming (Aspire Scientific Limited, Bollington, UK) and was funded by Celltrion Healthcare Co., Ltd (Incheon, Republic of Korea).