Experience with biosimilar infliximab (CT-P13) in paediatric patients with inflammatory bowel diseases

Abstract

Infliximab was the first monoclonal antibody used in the treatment of inflammatory bowel disease (IBD). Over several years, this antitumour necrosis factor (TNF) treatment proved its efficacy in both induction and maintenance therapy. In many cases this biological treatment stopped the progression of the disease, probably also decreasing morbidity and hospitalization rates, and improving patients’ comfort. When the patent on infliximab started to expire, the first biosimilar of a monoclonal antibody was introduced onto the pharmacological market. Biosimilar infliximab was studied in rheumatology and proved a high similarity to the reference drug. Based on extrapolation, biosimilars were approved to treat adult and paediatric IBD patients. Biosimilar infliximab, mainly because of its lower cost, has started to be in common use in Europe. The first studies have shown a similar efficacy and safety profile in comparison with reference drug. Biosimilar infliximab is raising hopes for improving the availability of this effective treatment.

Introduction

The introduction of biological therapies has dramatically changed the outcomes in patients with inflammatory bowel disease (IBD). The term IBD refers to two important conditions: Crohn’s disease (CD) and ulcerative colitis (UC). Both of these are progressive and, unless treated appropriately, can result in irreversible damage. This becomes of special importance in paediatric patients in whom both the disease and complications related to its treatment can have an impact on their future life.

History of infliximab

Infliximab (IFX) was the first biological treatment approved for patients with IBD. IFX is a chimeric, human-murine monoclonal immunoglobulin (Ig) G1 antitumor necrosis factor-α (anti-TNF-α) antibody. IFX blocks and neutralizes the activity of the TNF. TNF is a pro-inflammatory cytokine which plays a key role in the pathogenesis of inflammatory processes associated with IBD. TNF is synthesized by an array of activated immune cells, and exists in both soluble and transmembrane forms. Both of these can bind to their receptors on TNF-responsive cells, activating intracellular pathways that eventually lead to inflammation and tissue damage. After infusion, IFX can quickly form stable complexes with both forms of TNF, thus inhibiting the pro-inflammatory processes [Papadakis and Targan, 2000]. IFX not only effectively prevents the further progression of the disease, and provides the resolution of clinical symptoms and the normalization of inflammatory markers, but is also involved in mucosal healing. Endoscopic remission (mucosal healing) is recognized as the best prognostic marker for long remission [Kierkus et al. 2012; Neurath and Travis, 2012]. Biological agents are generally well tolerated and accepted by patients. In several studies, the administration of IFX contributed to higher remission induction rates and successful outcomes of further maintenance therapy [Hyams et al. 2000, 2007, 2012; Wynands et al. 2008; Ruemmele et al. 2009]. The efficacy of IFX was also confirmed in children with fistulizing CD [De Ridder et al. 2004; Crandall et al. 2009]. Patients who do not respond adequately to anti-TNF treatment are generally classified as primary and secondary nonresponders. The lack of any clinical effect after the third induction dose, referred to as primary nonresponse, is probably linked to genetic predisposition and the long duration of the disease [Ben-Horin et al. 2014]. Secondary nonresponse is diagnosed whenever the induction therapy has been successful, but the loss of clinical response has been observed at any point of further maintenance treatment. In most cases, secondary nonresponse results from immunogenicity, i.e. the identification of an infused biological agent as a foreign substance and the synthesis of antidrug antibodies by the patient’s immune system. Immunogenicity can develop either shortly after the initiation therapy or at any time of sustained treatment [Hanauer et al. 2002; Baert et al. 2003]. In the presence of anti-TNF antibodies (ATIs), the biological molecule is sequestered faster, which results in a shorter duration of therapeutic response and eventual treatment failure. Furthermore, the presence of ATIs was shown to be associated with greater risk of adverse events (AEs) during the infusion [O’Meara et al. 2014]. Adjunct immunosuppressive treatment can interfere with immunogenicity, preventing the synthesis of ATIs [Vermeire et al. 2007; Ben-Horin et al. 2013]. The efficacy of IFX therapy can be improved due to its monitoring, namely the measurement of the drug level and screening for ATIs [Minar et al. 2016]. Screening for immunogenicity is helpful in the identification of patients who can benefit from modifying the IFX dose or switching to another biological agent. Unfortunately, the routine application of such screening in some countries is fairly limited due to its cost.

Development of the biosimilar CT-P13

The expiry of the patent on IFX opened up the possibility of marketing its biosimilars. The first biosimilar IFX (CT-P13) was authorized in Europe in September 2013. CT-P13 (Remsima, Inflectra) was developed by Celtrion, Inc. (Republic of Korea). A biosimilar is a biotherapeutic product that is similar to the licensed reference product in terms of its quality, safety and efficacy [World Health Organization, 2009]. Anti-TNF medications are made in living organisms. The process of their development is complicated due to the large and complex structure of monoclonal antibodies. As a result, even the reference drug might slightly vary from batch to batch [Schiestl et al. 2011; Weise et al. 2014]. A candidate biosimilar needs to satisfy strict criteria with regards to its safety and efficacy, and it is necessary to prove its physicochemical and biological comparability with the originator. Analytical tests of CT-P13 showed that it differed from its originator solely in terms of afucosylation levels, FcγRIIIa receptor binding, and the results of some in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) assays. None of these differences were judged to be clinically relevant, since they were no longer observed under more physiological conditions [Jung et al. 2014].

In the development of biosimilars, comparative nonclinical and clinical studies of originator and biosimilar IFX are needed. In the case of CT-P13, such studies have been conducted in rheumatology. The aim of PLANETAS (Programme evaLuating the Autoimmune disease iNvEstigational drug cT-p13 in AS patients) was to compare the pharmacokinetics, safety, efficacy and immunogenicity of the biosimilar and originator IFX. The study included a large group of 250 patients with ankylosing spondylitis (AS). A comparative analysis of IFX biosimilar efficacy, safety and immunogenicity was the subject of the PLANETRA (Programme evaLuating the Autoimmune disease iNvEstigational drug cT-p13 in RA patients) study. The study included 606 patients with rheumatoid arthritis (RA). Both randomized, double blind, multicentre studies showed that biosimilar IFX was comparable with its originator [Park et al. 2013a; Yoo et al. 2013a]. As a result, CT-P13 was authorized by the European Medicines Agency (EMA) with the same indications as the reference IFX, namely RA, AS, psoriatic arthritis, psoriasis, and adult and paediatric CD and UC.

The authorization of the biosimilar for IBD patients raised concerns among most gastroenterologists. Although biosimilar is a great achievement which can improve patients’ access to effective treatment, the fact that the extrapolation of indications solely on the basis of the evidence from rheumatology trials stimulated a debate on whether the biosimilar can be really equally effective and well-tolerated in IBD patients. No clinical trials were conducted to compare the safety and efficacy of the originator and biosimilar IFX in IBD. Furthermore, the question arose of whether patients with rheumatoid conditions would be sensitive enough to determine the immunogenicity of the biosimilar. Rheumatoid patients are less likely to synthesize AITs against IFX, and ATIs were detected in about 10% of the subjects from this group [Lipsky et al. 2000]. Furthermore, aside from IFX, participants in the rheumatology in the PLANETRA trial mentioned above received methotrexate, which is known to reduce immunogenicity.

The EMA’s decision to choose RA as representative model to biosimilar studies assumed that these groups of patients had more randomized controlled trials and was a major indication of IFX. Concomitant MTX should not interfere with optimal measure immunogenicity, because in this assessment a highly sensitive method [Isaacs et al. 2016] was used. Another doubt about the use of biosimilars might have been prompted by the lack of authorisation of IBD in some countries outside Europe, for example, in Canada. Health Canada approved CT-P13 for use in all labelled indications of the originator IFX except for IBD. Canadian experts emphasized that it was still unclear whether the differences between the originator and the biosimilar IFX, considered clinically irrelevant in rheumatic diseases, did not interfere with the safety and efficacy of the novel agent in CD and UC. Furthermore, in the opinion of Health Canada, it was still not known whether the mechanism of IFX action in rheumatic diseases and IBD was really the same, especially given the importance of ADCC [Health Canada, 2014]. Doubts were expressed in the first European Crohn’s and Colitis Organisation (ECCO) position statement, in which it was concluded that rigorous testing should be performed to assert the efficacy and safety of the biosimilar IFX in IBD patients [Danese et al. 2013]. In response, the European drug regulatory authorities stated that no pharmacokinetic or safety issues were known to be specific for IBD, and therefore exposure to IFX in patients with this condition was likely to be the same as in individuals with rheumatic diseases. Consequently, they stuck to their opinion that the evidence from rheumatology trials was sufficient to confirm the similarity of both drugs and biosimilars may be safely used in IBD [Kurki et al. 2014]. The last Position Statement of the ESPGHAN Paediatric IBD Porto Group emphasized the giving of high priority to perform paediatric trials with long-term follow up. Furthermore, switching to the biosimilar in patients who achieved sustained remission after the reference IFX is not recommended unless the safety of such approach has been confirmed in clinical trials and obligatory postmarketing surveillance should be performed [De Ridder et al. 2015].

In line with the EMA regulations, in European countries where IFX was no longer protected by a patent, biosimilars started to be available. An advantage of biosimilars was the lower price, so they started to replace the originator IFX in most hospitals in Poland. As a result, gastroenterologists frequently face a dilemma: whether to treat IBD with the biosimilar despite the lack of evidence from gastroenterology clinical trials, or to stick to conventional therapies and/or surgical treatment.

Despite gastroenterologist concerns, the overall evidence suggests the justification of the EMA’s decision. Another study which confirmed the equivalence in clinical pharmacokinetics of the biosimilar IFX and reference products (EU and US licensed reference IFX) was performed in a group of healthy volunteers. A total of 223 healthy subjects were divided into three groups and given one dose of the biosimilar or the EU/US licensed originator. The subjects were followed up for 57 days and all potential AEs were recorded. The study showed that all three IFX formulations were equivalent in terms of their pharmacokinetics. Furthermore, they did not differ in terms of their mean serum concentrations and tolerance profiles. The most common AEs recorded after the single dose of IFX included nasopharyngitis, headache and rhinitis; the incidence of these AEs did not differ between the study groups. No serious treatment-related AEs were recorded [Park et al. 2015].

Biosimilars in practice

Although the biosimilar IFX is being used increasingly, only a few papers describing the initial experiences with CT-P13 in adult patients with IBD have been published thus far. Moreover, aside from a few conference abstracts [Jarzębicka et al. 2015; Sieczkowska et al. 2015], we lack any evidence of the use of this agent in the induction treatment of paediatric IBD, or in children with rheumatic diseases. Finally, only limited data exist with regards to the sustained treatment of adult rheumatology patients with the biosimilar IFX. Recently, Takeuchi and colleagues published the results of their comparative analysis of the long-term efficacy and safety of CT-P13 and the originator IFX. In this study, Japanese patients with RA were followed up for 54 weeks. The study confirmed the pharmacokinetic equivalence of both drugs, which corresponded to their similar efficacy, safety profiles and incidence of AEs. Furthermore, the authors did not find any significant differences in the immunogenicity of the biosimilar and originator IFX, and the proportion of antibody-positive patients was shown to increase over time irrespective of the treatment type [Takeuchi et al. 2015]. The results of PLANETRA and PLANETAS studies regarding the efficacy of the biosimilar IFX in maintenance therapy are yet to be published, and currently only limited data in the form of conference abstracts are available [Park et al. 2013b; Yoo et al. 2013b].

Biosimilars in adult IBD

Three European studies analysed the efficacy of induction therapy with CT-P13 in Hungarian (two studies) and Norwegian patients with IBD [Farkas et al. 2015; Jahnsen et al. 2015; Gecse et al. 2016]. The efficacy of induction treatment is summarized in Table 1. In a recent study, safety was assessed until week 30; 17.1% of patients experienced AEs. Infusion reactions occurred in 6.7% of patients and incidence was higher in patients who were previously treated by the originator IFX [Gecse et al. 2016]. No unexpected safety concerns emerged during the course of both the other studies [Farkas et al. 2015; Jahnsen et al. 2015] and the incidence of AEs was similar to that reported from previous studies of the originator IFX. Two UC patients (one from each study) showed an allergic reaction after the second infusion of the biosimilar IFX. Both these patients tested positively for ATIs and had been previously treated with the reference IFX. This implies that a history of previous treatment with IFX, either originator or biosimilar, can increase the risk of ATI formation and infusion reaction. The European findings are consistent with the results of a Korean study [Jung et al. 2015]. Longer observation of the study by Jung and colleagues showed that 75% of individuals with CD and 50% of UC patients were still in remission at week 54 [Jung et al. 2015].

Table 1.

Efficacy of the biosimilar infliximab in induction remission treatment.

Population	Disease	Number of patients	Week	Response (%)	Remission (%)
Norwegian	CD	46	14	no data	79
	UC	32	14	no data	56
Hungarian	CD	18	8	87.5	50
	UC	21	8	86.7	66.7
Hungarian	CD	126	14	81.4	53.6
	UC	84	14	77.6	58.6
Korean	CD	32	8	90.6	84.4
	UC	42	8	81	38.1

CD, Crohn’s disease; UC, ulcerative colitis.

Biosimilars in paediatric IBD

To date, the efficacy of induction therapy with the biosimilar IFX has been assessed in only 12 paediatric patients with CD. Only six patients from this group received all three doses of the biosimilar. Nevertheless, clinical responses were observed already following the first induction dose of CT-P13; 10/12 patients (83%) showed a significant decrease in the paediatric Crohn’s disease activity index (PCDAI) scores and a drop off in the inflammatory marker levels. AEs were recorded in only two subjects. One of them showed an allergic reaction to the second dose of the biosimilar, which eventually resulted in the treatment’s discontinuation. The reaction was not associated with an increase in arterial blood pressure. The treatment with the biosimilar IFX was the second attempt of anti-TNF therapy in this patient. The second AE was a temporary increase in arterial blood pressure during the infusion of the biosimilar IFX. Further treatment was uneventful and the patient received all the induction doses [Sieczkowska et al. 2015].

The first evidence of the efficacy and safety of the IFX biosimilar in the induction therapy of paediatric UC originates from a study of six subjects; 50% completed the induction therapy and showed a decrease in the paediatric ulcerative colitis activity index (PUCAI) scores. In another two patients, the treatment was discontinued prematurely due to the persistent flaring up of the disease after the first dose. Finally, one patient showed an allergic reaction during the infusion of the drug, which also led to the treatment’s discontinuation [Jarzębicka et al. 2015].

Altogether, the abovementioned data imply that the efficacy of the biosimilar IFX, expressed as a clinical response and clinical remission rates after three induction doses, is effective and similar to that documented in previous studies of the originator. Also, AEs occurred only sporadically, similar to the case of the reference IFX. In fact, an observational prospective study is being initiated to evaluate the efficacy and safety of the use of the biosimilar IFX (Remsima) in both CD and UC. Children aged six years or older can be recruited in this study [ClinicalTrials.gov identifier: NCT02326155].

Switching

The unavailability of the reference IFX has made it necessary to switch to the biosimilar in most Polish hospitals. A total of 32 CD and 7 UC patients have been switched to the biosimilar IFX at various stages of treatment. At the time of switching, 88% of CD and 57% of UC patients presented while in remission. Although it should be remembered that the follow-up period was relatively short, from patients who continued therapy 16/20 (80%) CD and all 4 UC patients sustained this remission. No significant flare up was observed. From all patients, only one with CD experienced infusion reaction which led to treatment discontinuation [Sieczkowska et al. 2016].

The switching of adult patients to the biosimilar IFX has been the subject of two published studies. Jung and colleagues presented the outcomes of 27 patients with CD and 9 individuals with UC who had been switched to the biosimilar IFX. Despite the switching, up to 92.6% of CD patients and 66.7% of individuals with UC sustained their remission [Jung et al. 2015]. In another study, involving five patients with CD and four with UC, a total of eight subjects still showed a satisfactory therapeutic response after switching to the biosimilar IFX [Kang et al. 2015].

Conclusion

Both our experience and the results of recent studies imply that the biosimilar IFX does not differ considerably from its originator. CT-P13 seems to have a similar efficacy to the reference product. The incidence of AEs does not differ significantly compared with incidences with the use of the reference IFX. In line with the mentioned statements, pharmacovigilance, especially with regards to its long-term efficacy in patients in maintenance remission therapy, should be observed. However, even at this stage of the research, the introduction of the biosimilar IFX can be considered beneficial for clinical practice. The administration of the biosimilar is supposed to markedly reduce treatment costs [Brodszky et al. 2016], which raises the possibility of implementing this anti-TNF therapy in a larger number of patients. Lower medication costs will probably prevent cuts in the expenditures on the otherwise effective biological treatment. As a result, more patients will be able to benefit from the therapy. Perhaps the biological treatment will be even considered a top-down therapy [Clinicaltrials.gov identifier: NCT02517684]. Recent evidence suggests that top-down therapies might be more effective than step-up strategies in moderate to severe paediatric CD [Lee et al. 2015]. The determination of the drug level and screening for ATIs are intended to be integral components in the therapeutic process; perhaps the savings associated with the implementation of the biosimilar IFX will be reflected by the widespread use of these methods in clinical practice.