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Discontinuation following biosimilar switching in IBD patients Posted 20/11/2020

Medical management of inflammatory bowel diseases (IBD) has significantly improved since the introduction of biological therapies over the past 20 years. The adoption of biologicals in IBD care has led to an exponential increase in treatment-related costs, resulting in a huge economic impact. As the patents of older biologicals expire, the interest in marketing comparable versions of the reference products increases, enabling opportunities for the development of similar biological products. Biosimilars have the potential to expand access to biological therapies due to price competition and cost savings [1].

Even though biosimilar uptake has greatly increased in Europe over recent years [2], long-term data on the use of biosimilars for IBD are still limited. This is mainly due to the fact that the first biosimilar monoclonal antibody (mAb), Remsima/Inflectra (CT-P13), was approved only recently (2013 in Europe; 2016 in the US; 2015 in Brazil [3]). In addition, most data on biosimilars in IBD originate from real-life experience after switching from a reference biological to a biosimilar [4] and the available randomized controlled studies comparing the reference biological and biosimilars often had a short-term follow-up [5].

In this context, the aim of the systematic review and meta-analysis carried out by Brazilian researchers was to assess the risk and reasons for drug discontinuation in the IBD population that switched from the originator to biosimilars in real-world studies [6]. This was undertaken through a search in scientific databases (Medline, EMBASE and Central Cochrane) and meeting abstracts. Observational studies evaluating adults with IBD who switched from originator biologicals to biosimilars with a mean follow-up period over six months and a mean duration of treatment with the originator reported as over one year were included.

A total of 30 studies comprising 3,594 patients were selected. The main outcome was biosimilar discontinuation in a follow-up period varying between six and 24 months. In addition, the reasons for treatment discontinuation were extracted and meta-analysed.

The discontinuation rates after a switch were 8%, 14% and 21% after 6, 12 and 24 months, respectively. The main reasons for discontinuation were increased loss of response (2%), remission (4%), loss of adherence (4%), adverse effects (5%) and loss of response (7%). Quality-of-evidence varied from low to very low depending on the analysed outcome. The nocebo effect was explicitly analysed as a reason for discontinuation in only one study [7], and the frequency of reported subjective adverse events was low.

Although the reported discontinuation rates are in line with yearly discontinuation rates for reference infliximab in historic cohorts (7%–13%), it is important to emphasize that the populations in those analyses are very heterogeneous, making any direct comparison impossible. Moreover, most of the studies included in this review did not disclose important information that could have influenced the results, such as disease activity at the moment of switch and drug trough levels before and after switch.

In the context of biological switching studies, the nocebo effect relates to a perceived worsening of symptoms that is related to patients’ expectations and that may occur as a result of a negative attitude toward an intervention. In some cases, disease worsening can be misinterpreted, leading to drug withdrawal. Although it was not possible to demonstrate the nocebo effect as a reason for drug discontinuation, the only study that systematically addressed this question found an overall nocebo response of 12%.

Our data shed light on the need for well-conducted prospective studies evaluating long-term outcomes associated with the switch of biological therapy in IBD patients.

Conflict of interest
Several of the authors of the research paper [6] reported conflicts of interest, including having served as speakers and advisory board members for pharmaceutical companies. For full details of the authors’ conflicts of interest, see the research paper [1].

Abstracted by Natália Sousa Freitas Queiroz, Universidade de São Paulo, Faculdade de Medicina, Departamento de Gastroenterologia, São Paulo, SP, Brasil.

Editor’s comment
Readers interested to learn more about biosimilars in IBD are invited to visit www.gabi-journal.net to view the following manuscript published in GaBI Journal:

First biosimilar of infliximab approved in Brazil: response from the Brazilian IBD society

Biosimilar infliximab introduction into the gastroenterology care pathway in a large acute Irish teaching hospital: a story behind the evidence

GaBI Journal is indexed in Embase, Scopus, Emerging Sources Citation Index and more.

Readers interested in contributing a research or perspective paper to GaBI Journal – an independent, peer reviewed academic journal – please send us your submission here.

Related articles
Successfully transitioning patients with IBD to biosimilars

Biosimilars to replace older biologicals for IBD

Biosimilar policies in Europe

European IBD specialists support switching to biosimilars

References
1. Gulacsi L, Pentek M, Rencz F, et al. Biosimilars for the management of inflammatory bowel diseases: economic considerations. Curr Med Chem. 2019;26(2):259-69.
2. GaBI Online - Generics and Biosimilars Initiative. Use of biosimilars in Europe differs across countries [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Nov 20]. Available from: www.gabionline.net/Reports/Use-of-biosimilars-in-Europe-differs-across-countries 
3. GaBI Online - Generics and Biosimilars Initiative. Biosimilars of infliximab [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Nov 20]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-of-infliximab 
4. Avouac J, Moltó A, Abitbol V, et al. Systematic switch from innovator infliximab to biosimilar infliximab in inflammatory chronic diseases in daily clinical practice: the experience of Cochin University Hospital, Paris, France. Semin Arthritis Rheum. 2018;47(5):741-8.
5. Ye BD, Pesegova M, Alexeeva O, et al. Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn’s disease: an international, randomised, double-blind, phase 3 non-inferiority study. Lancet. 2019;393(10182):1699-1707.
6. Queiroz NSF, Saad-Hossne R, Fróes R de SB, et al. Discontinuation rates following a switch from a reference to a biosimilar biologic in patients with inflammatory bowel disease: a systematic review and meta-analysis. Arq Gastroenterol. 2020. Epub ahead of print.
7. Boone NW, Liu L, Romberg-Camps MJ, et al. The nocebo effect challenges the non-medical infliximab switch in practice. Eur J Clin Pharmacol. 2018;74(5):655-61.

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