The immunogenicity of biosimilar infliximab: can we extrapolate the data across indications?

Abstract

Biopharmaceuticals or ‘biologics’ have revolutionized the treatment of many diseases. However, some patients generate an immune response to such drugs, potentially limiting clinical efficacy and safety. Infliximab (Remicade^®) is a monoclonal antibody used to treat several immune-mediated inflammatory disorders. A biosimilar of infliximab, CT-P13 (Remsima^®, Inflectra^®), has recently been approved in Europe for all indications in which infliximab is approved. Approval of CT-P13 was based in part on extrapolation of clinical trial data from two indications (rheumatoid arthritis and ankylosing spondylitis) to all other indications, including inflammatory bowel disease. This review discusses the validity of extrapolating immunogenicity data across indications – a process adopted by the EMA as part of their biosimilar approval process – with a focus on CT-P13.

Keywords:

• biologics
• biosimilars
• CT-P13
• extrapolation
• immunogenicity
• inflammatory bowel disease
• infliximab

Financial & competing interests disclosure

S Ben-Horin has received consultancy fees and/or research support from AbbVie, Janssen, Takeda, Schering-Plough, and Celltrion. G Heap has received unrestricted education grants/travel support from AbbVie, Dr Falk Pharma, and Tillotts Pharma UK. T Ahmad has received consultancy fees and/or research support from AbbVie, Merck, Takeda, NAPP, and Celltrion. Y Chowers has received consultancy and lecture fees and/or research support from AbbVie, Janssen, Takeda, and Schering-Plough. H Kim and T Kwon are full time employees of Celltrion. The authors have 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. Editorial support (writing assistance, assembling tables and figures, collating author comments, grammatical editing, and referencing) was provided by Ryan Woodrow (Aspire Scientific Limited, Bollington, UK) and was funded by Celltrion Healthcare Co., Ltd (Incheon, Republic of Korea).

Key issues

• The immunogenicity of monoclonal antibody (mAb) protein therapeutics is an important concern as anti-drug antibodies (ADAs) can impact upon clinical efficacy and safety.

• Many factors can influence the formation of ADAs, including whether the drug is administered in combination with immunomodulators. The formation of ADAs may be variable in different indications and different patients, meaning that predicting the extent of their formation is difficult.

• Infliximab is a mAb therapy used in the treatment of several immune-mediated inflammatory diseases. It is known to induce the formation of ADAs in some patients, resulting in a loss of clinical response and increased risk of adverse events.

• The infliximab biosimilar CT-P13 was approved in Europe for use in all indications in which originator infliximab (or the reference medicinal product [RMP]) is licensed, based in large part on data from two key equivalence trials in rheumatoid arthritis (RA) and ankylosing spondylitis (AS).

• There have been concerns regarding the extrapolation of these data to other indications such as Crohn’s disease and ulcerative colitis, particularly with respect to immunogenicity, as the formation of ADAs can be unpredictable and vary between indications.

• Comparing infliximab immunogenicity data between trials in RA and Crohn’s disease indicates that there is probably not a substantial difference in ADA incidence across these two indications. This suggests that RA would be no less suitable or sensitive for examining the immunogenicity of CT-P13 versus other populations. Examining immunogenicity in AS patients, the majority of whom received infliximab monotherapy, provides an additional tier of confidence on which to base this comparison.

• Key data from the PLANETRA and PLANETAS trials comparing CT-P13 and the infliximab RMP in RA and AS, respectively, show there are no noticeable differences in immunogenicity between these two drugs. Importantly, the dosage administered, patient population, indication studied and usage (or not) of methotrexate did not lead to differences in immunogenicity between the two biologics.

• These data can support confidence among clinicians and patients that extrapolation of immunogenicity data for CT-P13 collected in RA and AS to other indications, in particular inflammatory bowel disease, is clinically valid.

Notes