Overview of subsequent entry biologics for the management of inflammatory bowel disease and Canadian Association of Gastroenterology position statement on subsequent entry biologics.

The advent of biologic molecules is one of the most important therapeutic advances to have occurred in the medical management of inflammatory bowel disease (IBD). From a Canadian perspective, the monoclonal antibodies directed against tumour necrosis factor-alpha (TNF-α), namely infliximab (Remicade, Johnson & Johnson, USA) and adalimumab (Humira, AbbVie Corporation, USA), are the only approved and commercially available biologics for the treatment of either Crohn disease (CD) or ulcerative colitis (UC) in Canada. These molecules have a large and complex structure and are generated with the aid of DNA recombination technology. This complexity makes the development of biologically similar substitutes – as is common with smaller, less complex molecules – a challenge. However, following the expiry of the patent on Remicade, a biosimilar infliximab has been developed (CT-P13, Remsima [Celltrion, South Korea], Inflectra [Hospira Inc, USA]). In addition, another biosimilar infliximab has been developed by an Indian pharmaceutical company, Reliance Life Sciences. Standard, small-molecule pharmaceuticals are significantly different from their complex biological counterparts (Figure 1). Most synthesized pharmaceuticals have a molecular size of only a few hundred Daltons (Da) (eg, omeprazole is 345 Da). In comparison, infliximab is 149,000 Da. Moreover, monoclonal antibodies have a complex structure that is influenced by the vector and post-translational modification, among other factors (1–3). In addition, although the overall structure of a monoclonal antibody may be known, the manufacturing platform used by the manufacturer of the reference biologic drug (RBD) is not, due to the proprietary nature of the information. As such, a different biological system that is used to produce a biosimilar agent will likely translate into subtle differences that could be difficult to characterize. Such differences have the potential to translate into clinically relevant differences in efficacy, safety and immunogenicity. Therefore, it will be extremely challenging to ensure that a subsequent entry biologic (SEB) is, in fact, ‘equivalent’ to the RBD. Clinical equivalence can only be proven in clinical trials. Figure 1) Comparison between a biologic monoclonal antibody and an acetylsalicylic acid molecule. From Kozlowski S, Woodcock J, Midthun K, Behrman Sherman R. Developing the Nation’s Biosimilars Program. N Engl J Med 2011;365:385–8. Reprinted with ... It is important for the Canadian gastroenterology community to gain a full understanding of the important issues in the context of the development and entry into the marketplace of such biologic agents. The objectives of the present document are to: Provide a brief primer on the terminology germane to this issue. Describe the current state of SEBs and the existing guidelines from Health Canada and other jurisdictions. Provide perspective on the potential opportunity in the Canadian marketplace for SEBs in the arena of IBD. Provide a brief overview of the existing data, generated from two trials conducted in rheumatoid arthritis and ankylosing spondylitis, for infliximab-Celltrion (Remsima). Identify areas that will require careful thought and attention moving forward. Provide a current position statement from the Canadian Association of Gastroenterology (CAG) regarding SEBs.