Clinical experience with infliximab biosimilar Remsima (CT-P13) in inflammatory bowel disease patients

Abstract

Many reference biological therapies have now reached or are near to patent expiry, and therefore a number of biosimilars have been or will be developed. The term biosimilar can be defined as a biotherapeutic product that is similar in efficacy, safety and quality to the licensed reference product. Biosimilars may lead to a reduced price and significant cost savings for the health community and hopefully more patients globally will have easier access to biological therapy when indicated. CT-P13, which is a TNF-alfa inhibitor, is the first monoclonal antibody biosimilar being used in clinical practice. The drug is approved for all indications as an innovator product although clinical efficacy has only been demonstrated in rheumatic diseases. Until now the number of patients with inflammatory bowel disease (IBD) treated with CT-P13 is confined, but experience is continuously growing. Based on current data, CT-P13 seems to be efficacious and generally well tolerated in IBD especially in patients who are naïve to biological therapy. Knowledge with regard to interchangeability between CT-P13 and the originator infliximab is however, still rather sparse and more data are desired. Immunogenicity and long-term safety related to CT-P13 are other areas of great importance and good and reliable postmarketing pharmacovigilance is therefore required in the coming years.

Introduction

Inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn’s disease (CD) are chronic disabling gastrointestinal disorders that lead to impaired quality of life, frequent surgery and disease complications [Solberg et al. 2007, 2009; Hoivik et al. 2012]. However, the introduction of targeted biological therapies such as TNF-alfa inhibitors into the medical treatment armamentarium have revolutionized management and significantly improved the disease course and outcome for many IBD patients [Rizzo et al. 2014; Stidham et al. 2014]. In response to the high costs of originator biologics, interest has grown in biosimilars. CT-P13 is a biosimilar of the infliximab reference medicinal product (RMP) (Remicade^®; Celltrion, Incheon, Republic of Korea) and the first monoclonal antibody biosimilar to be approved by the European Medicines Agency (EMA) [European Medicines Agency, 2013]. It is sold as Remsima^® (Celltrion) and Inflectra^® (Hospira, Leamington Spa, UK). Since July 2012, CT-P13 has been available in South Korea and soon after in several other countries, and today more than 34,000 patients in more than 40 countries worldwide have received treatment with this product.

Documentation of the clinical efficacy of CT-P13 was originally based on two pivotal clinical trials in rheumatic diseases, a phase I randomized controlled trial (RCT) comparing CT-P13 with infliximab RMP in patients with ankylosing spondylitis (AS) (PLANETAS) [Park et al. 2013] and a phase III RCT comparing CT-P13 with infliximab RMP in patients with rheumatoid arthritis (RA) (PLANETRA) [Yoo et al. 2013]. The safety profiles of the two infliximab formulations were also comparable. Although there are similarities between IBD and rheumatic diseases, the pathological roles of TNF-alfa may vary by disease [Lee, 2014]. In addition, monoclonal antibodies such as infliximab have more than one binding site and molecular target. Thus, it has been suggested that the clinically relevant mechanisms of action of infliximab might differ by indication [Feagan et al. 2014]. Based on this uncertainty, there have been some opposition and concerns in the community of gastroenterology with regard to the approval for all therapeutic areas for which infliximab RMP is indicated, including IBD [Danese et al. 2014]. However, EMA justified the extrapolation to IBD based on the robust comparisons of the physicochemical and in vitro and ex vivo biological analyses in combination with clinical data demonstrating pharmacokinetic and therapeutic equivalence in rheumatology conditions. Extrapolation of data from one indication to another is also a pivotal aspect of biosimilar development [Ebbers, 2014; Feagan et al. 2014; Weise et al. 2014]. This review will focus on the efficacy and safety of CT-P13 in IBD patients based on the available literature.

Biosimilar

A biosimilar is a biological medicine developed to be similar to an existing biological medicine. The active substance of a biosimilar is highly similar in terms of quality, safety and efficacy to a licensed RMP [Rinaudo-Gaujous et al. 2013; Reinisch et al. 2015]. The primary emphasis in biosimilar development focuses on evaluation of the similarity in physicochemical structure and biological function between the biosimilar and originator biologic. There may be minor differences due to their complex nature and production methods, but when approved, its variability and any differences between it and its reference medicine will have been shown not to affect safety or effectiveness [Schreiber, 2015]. As depicted in Figure 1, the stepwise approach can lead to a different paradigm for development of a biosimilar compared with development of a new biological product. CT-P13 and the infliximab RMP are chimeric murine monoclonal immunoglobulin (Ig)G1 antibodies that act by blocking TNF-alfa binding to its receptor thus neutralizing its activity and alleviating mucosal inflammation. They are produced by recombinant DNA technology in independently developed cell lines derived from the same murine hybridoma cell type. They share an identical amino acid sequence and have highly comparable higher-order structures [Jung et al. 2014]. The two drugs are identical in pharmaceutical form, strength, composition and route of administration, thus dosage and administration instructions for each drug are identical [European Medicines Agency, 2013, 2014a, 2014b].

Figure 1.

Different approach for development of a biosimilar compared with a new biological product.

Immunogenicity

Immunogenicity is a well-recognized phenomenon that primarily manifests as the formation of antidrug antibodies (ADAs) and is common to most biologics, including infliximab [Tovey and Lallemand, 2011]. Several previous studies have shown that the generation of ADAs to infliximab is associated with the loss of an initially good therapeutic response, an increased rate of infusion reactions and other adverse events [Allez et al. 2010]. However, it is important to note that the degree of immunogenicity is not the same for all biologics and the extent of immunogenicity seems to differ a lot among individual patients receiving the same biological therapy. This is related to various reasons such as genetic factors, comedication and the dosing and administration schedule of the biologic drug [De Groot and Scott, 2007; Billiet et al. 2015]. Moreover, it is known that some ADAs can be transient and disappear during further treatment. Only minor differences in the formulation, purity or packaging of a biological drug can affect its immunogenicity profile. Therefore, concerns have been raised regarding the potential impact of any differences between a biosimilar and its reference drug on immunogenicity [Ben-Horin et al. 2015]. In both PLANETAS and PLANETRA, the formation of ADAs against CT-P13 and infliximab RMP were measured using an electrochemiluminescence immunoassay method. Findings were similar for the two agents in these two randomized, double-blinded studies despite the fact that the patients with AS received infliximab 5 mg/kg as monotherapy as distinct from patients with RA who received a lower dose of 3 mg/kg but in combination with methotrexate. In patients who participated in the extensions of PLANETAS and PLANETRA, ADA incidence was comparable between maintenance and switch groups and did not increase significantly during the extension phase. All of these data indicate high similarity between the two compounds and support the extrapolation of the CT-P13 to all the indications for which infliximab RMP is approved.

Infliximab RMP

Several multicenter, randomized, double-blind clinical trials have established the efficacy and tolerability of the infliximab RMP in the treatment of IBD [Lemann et al. 2006; Colombel et al. 2010; Panaccione et al. 2014]. The ACCENT I study was the landmark RCT that validated the efficacy of infliximab in CD patients [Hanauer et al. 2002]. This large trial demonstrated that infliximab can induce and maintain remission in CD patients with moderate to severe active disease. With an infliximab RMP dosage of 5 mg/kg, 51% of the patients had a response and 39% were in remission at week 30. In addition this study showed that a scheduled regime for infliximab administration is preferable and has the benefit of applying a flexible treatment regimen with the possibility of infliximab dose escalation for efficacy optimization. These findings have laid the foundation for the handling and dosage of infliximab in clinical practice.

The major experience with infliximab RMP in UC is based on the pivotal ACT trials that were conducted to evaluate the efficacy and safety of infliximab for induction and maintenance in patients with moderate to severe UC [Rutgeerts et al. 2005]. In ACT I, 52% of the patients treated with infliximab RMP 5 mg/kg achieved a response at week 30 and 34% achieved remission. In ACT II, the equivalent outcomes were 47% achieving a response and 26% achieving remission. Both studies demonstrate clearly that those patients who received infliximab RMP were significantly more likely to achieve clinical response and remission, mucosal healing and had a reduced need for corticosteroid.

CT-P13 in clinical studies

So far, there is relatively limited clinical experience with CT-P13 in IBD and only seven studies have been published as full articles (Table 1). Some additional studies have also been presented with an abstract at different meetings, but they will not be discussed in this review.

Table 1.

CT-P13 in clinical studies.

Country	Patient numbers	Study design	Effect parameters	Assessment of immunogenicity	Reference
South Korea	173	Open-label, retrospective, multicenter	CDAI	No	Park et al. [2015]
	(95 CD, 78 UC)		Mayo score
South Korea	110	Open-label, retrospective, multicenter	CDAI	No	Jung et al. [2015]
	(59 CD, 51 UC)		Mayo score
	CRP
South Korea	17	Open-label, case series, tertiary center	CDAI	No	Kang et al. [2015]
	(8 CD, 9 UC)		Mayo score
Hungary	210	Open-label, prospective, observational, multicenter	CDAI	Yes	Gecse et al. [2015]
	(126 CD, 84 UC)		FDA
			Mayo score
			CRP
			Platelet count
Hungary	39	Open-label, prospective, observational, tertiary center	CDAI	Yes	Farkas et al. [2015]
	(18 CD, 21 UC)		Mayo score	(50% of patients)
Norway	78	Open-label, prospective, observational, single center	HBI	Yes	Jahnsen et al. [2015]
	(46 CD, 32 UC)		Mayo score
			CRP
			Calprotectin
Poland	39	Open-label, prospective, observational, switching, pediatric	PCDAI	No	Sieczkowskaet al. [2015]
	(32 CD, 7 UC)		PUCAI
			CRP

CDAI, Crohn’s Disease Activity Index; CRP, C-reactive protein; FDA, Fistula Drainage Assessment; HBI, Harvey-Bradshaw Index; PCDAI, Pediatric Crohn’s Disease Activity Index; PUCAI, Pediatric Ulcerative Colitis Activity Index.

Adult IBD

To evaluate the safety and efficacy of CT-P13 (Remsima^®) in patients with IBD in South Korea a postmarketing study was conducted [Park et al. 2015]. Patients with moderate to severe CD (n = 83), fistulizing CD (n = 12) or moderate to severe UC (n = 78) were included and followed for 30 weeks after initiation of CT-P13 treatment. In total 60 patients switched from the infliximab RMP after a median time of 8.7 weeks and 113 patients were biologic naïve. Many patients were already in clinical remission or had a low disease activity according to disease activity indices. By this, it is meant a Crohn’s disease activity index (CDAI) score below 220 or partial Mayo score below 6. Among those with moderate to severe active disease and infliximab naïve when starting treatment with CT-P13, 79% had a clinical response at week 14 and 76.3% at week 30. Moreover 56.1% and 46.1% were in clinical remission at week 14 and 30, respectively. No unexpected treatment-emergent adverse events were observed during the study and the authors conclude that CT-P13 was well tolerated and efficacious in patients with IBD.

In another retrospective multicenter study from South Korea both infliximab-naïve CD and UC patients and patients who switched to CT-P13 from its originator were evaluated at different time points up to 1 year using CDAI and partial Mayo score [Jung et al. 2015]. The treatment-naïve patient group consisted of 32 CD and 42 UC patients and clinical response and remission were obtained in 85% and 58% at week 8, in 93% and 62% at week 30 and in 95% and 60% at week 54. In addition 58% of the UC patients achieved mucosal healing at week 8 and there was a significant reduction in C-reactive protein (CRP) from baseline to week 30 in both patient groups. After switching from infliximab RMP, the efficacy of CT-P13 was maintained in 93% and 67% of CD and UC patients, respectively.

A case series of 17 IBD patients (8 CD and 9 UC) at a tertiary center in South Korea showed clinical response and remission at week 8 in seven out of eight patients with active disease receiving CT-P13 [Kang et al. 2015]. Nine patients (four UC and five CD) in maintenance therapy with the originator compound switched to CT-P13 when in remission and among these, one patient lost effect and another discontinued CT-P13 due to arthralgia which was conceived as a side effect.

In Hungary a prospective, nationwide, multicenter, observational cohort was designed to examine the efficacy, safety and immunogenicity of CT-P13 in the induction treatment of CD and UC [Gecse et al. 2015]. Altogether 210 consecutive IBD (126 CD and 84 UC) patients from 12 sites were included in the study. Amongst the CD and UC patients 22% and 10% respectively had previously received therapy with the originator infliximab, but not during the last 12 months. After 14 weeks from initiation of therapy with CT-P13, 82% of CD and 78% of UC patients had a clinical response and 54% of CD and 59% of UC patients were in clinical remission assessed by CDAI, Fistula Drainage Assessment (FDA) or partial Mayo scores. Notably, the clinical remission rates were significantly higher in patients who were infliximab naïve, compared to those previously treated with infliximab RMP. Among those patients who were week 14 responders, 67.2% of CD and 80% of UC patients maintained clinical response to CT-P13 at week 30 and 53.4% of CD and 68% of UC patients were in clinical remission. Moreover, steroid-free clinical remission was achieved in 50% of CD and 56% of UC patients by week 30. Biochemical response was examined by measuring CRP and platelet count and a significant decrease in both parameters occurred from baseline to week 14 in both CD and UC patients. Therapeutic drug level was monitored and ADAs were measured using conventional and bridging enzyme-linked immunosorbent assay (ELISA) methods. Not surprisingly, baseline ADA positivity was detected in significantly higher numbers of patients who had received previous infliximab treatment as compared to infliximab naïve patients. In addition patients with previous infliximab exposure had a tendency towards lower early mean trough levels of the drug, exhibited decreased response rates and were more likely to develop allergic reactions. Infusion reactions and serious infectious adverse events occurred in 7% and 6% of all patients, respectively.

A total of 39 IBD (18 CD and 21 UC) patients were prospectively enrolled in an observational Hungarian study, and induction therapy with CT-P13 was completed in 16 of the CD and 15 of the UC patients [Farkas et al. 2015]. Only three of the patients had previously been treated with the originator infliximab. CDAI and partial Mayo scores were used to assess efficacy of the treatment. At week 8, clinical response and remission were achieved in respectively 38% and 50% of the patients with CD and the corresponding figures for UC patients were 20% and 67%. In addition, CT-P13 resulted in mucosal healing (Mayo endoscopic subscore 0 or 1) in 11 patients with UC. Serum infliximab and ADA levels were determined in half of the patients and a significant difference was found between patients who had developed ADAs or not. No significant differences in serum infliximab were detected between nonresponders, responders and patients in remission probably due to very small numbers. Adverse reactions included mild arthralgia and an anaphylactic reaction after the second infusion of CT-P13 related to high ADA levels in a patient previously treated with the originator. One UC patient needed a colectomy due to the development of toxic megacolon.

In a prospective observational study performed in a single center in Norway the efficacy, tolerability, and safety of CT-P13 (Remsima^®) was assessed in IBD patients [Jahnsen et al. 2015]. A total of 78 patients with moderate to severe disease (46 CD, 32 UC) were consecutively recruited. A total of 18 patients had previously been treated with TNF-alfa inhibitors, but there was no direct switching from infliximab RMP. Efficacy end points included remission at week 14, measured by a Harvey-Bradshaw Index (HBI) score of ⩽4 for CD or partial Mayo score of ⩽2 for UC. This was achieved in 79% and 56% of CD and UC patients, respectively. In addition a significant reduction from baseline in the inflammatory markers CRP and calprotectin were detected in both patient groups. There were no unexpected adverse events reported during the study. However, immunogenicity with the combination of ADA formation and a trough level of 0 mg/l occurred in eight patients (four CD and four UC) resulting in discontinuation of treatment in seven patients. All of the patients received CT-P13 as monotherapy and two had a prior exposure to the originator. One UC patient was colectomized and one CD patient was operated on with a resection of the small bowel before week 14. In conclusion, this study demonstrated that CT-P13 was efficacious and well tolerated in the early treatment of CD and UC.

Pediatric IBD

In a small study from Poland conducted at three academic hospitals, 39 pediatric IBD patients (32 CD, 7 UC) were followed prospectively after switching from infliximab RMP to CT-P13 due to administrative restrictions [Sieczkowska et al. 2015]. The median time from the start of infliximab RMP treatment until switching to the biosimilar was 46 weeks in CD and all of these patients had completed the induction phase. The median number of infusions was eight. In the UC patient group the median number of infusions of infliximab RMP before switching to the biosimilar was five and two of the patients received only one and two infusions, respectively. In the CD group 69% were in remission at the time of switching and 31% had mild to moderate disease activity. After two infusions with CT-P13 the patients were evaluated and a significant reduction in pediatric CDAI (PCDAI) was found. After a further mean follow-up time period of 8 months after switching, 88% of the patients were in clinical remission. Only four of the seven UC patients were still treated with CT-P13 and in remission according to the pediatric ulcerative colitis activity index (PUCAI) at the end of a mean follow-up period of 5 months. The other three had discontinued the treatment due to adverse events or loss of response. In both patient groups there were no significant differences in the incidence of sporadic mild adverse events prior to and after switching. There are several limitations in this study and the most important ones are the heterogeneous time of switching to CT-P13 during therapy and a great variation in length of the individual follow-up period. Despite these objections this study shows that switching from infliximab RMP to CT-P13 seems to be well tolerated, at least in children with CD.

Although the number of patients is relatively low especially during follow up after the inducting therapy, one of the strengths in several of these studies is a prospective design. In addition none or only a few patients are excluded and therefore an essential insight in real-life efficacy and safety with CT-P13 in IBD is provided. A main drawback is that all of the studies are uncontrolled and it should be noted that these observations are neither requested nor essential for the demonstration of biosimilarity. Another limitation is that drug monitoring and evaluation of immunogenicity measuring ADAs were only performed sufficiently in two of the studies. Nevertheless, these studies taken together suggest that CT-P13 is effective and generally well tolerated in IBD. However, further data are welcome, and additional studies that will support the validity of indication extrapolation to IBD are ongoing. A randomized parallel group phase III study is underway that will assess the noninferiority in efficacy of CT-P13 compared with infliximab RMP, as well as treatment safety, in adults with CD [ClinicalTrials.gov identifier: NCT02096861]. The primary endpoint of this study is a CDAI 70 response at week 54 of treatment and the first results are expected to be available in early 2016. A global registry study in IBD has also been initiated [ClinicalTrials.gov identifier: NCT02326155]. The study is recruiting adults or children aged ⩾6 years with active CD and adults with fistulizing CD or UC. The primary objective of the study is to monitor the safety of CT-P13 in IBD patients; efficacy and health economic parameters will also be assessed.

Interchangeability

Interchangeability between a biosimilar and infliximab RMP is an important issue that has been much debated [Tothfalusi et al. 2014]. Although the two products are highly similar there is a general agreement that more data documenting that switching to a biosimilar is well tolerated and maintains efficacy, are needed before automatic substitution should be applied [Chamberlain, 2013]. There seems to be differing opinions when it comes to this question and the bottom line is probably that we are not quite sure at the present time. This issue is not part of the EMA approval, leaving the decision-making to the discretion of the national authorities. In the above-described observational studies except for one, only subgroups of patients have switched from the originator to CT-P13. The majority of patients who completed the PLANETRA and PLANETAS studies were followed for another year where all patients received treatment with CT-P13. The objectives of these open-label extension studies were to confirm long-term efficacy and safety, and additionally immunogenicity was investigated. During the study period no definite unfavourable differences have been observed, which suggests that switching from infliximab RMP to CT-P13 is well tolerated at least in rheumatic diseases. However these extension data have only been presented as abstracts, but are now submitted for full publication. In Norway the government is funding the ongoing NOR-SWITCH study which is a randomized, double-blind, parallel group, noninferiority study comparing CT-P13 and infliximab RMP with regards to efficacy, safety and immunogenicity in patients across all indications for which these drugs are approved in Europe [ClinicalTrials.gov identifier: NCT02148640]. The rationale for the study is driven by financial motivation since switching to CT-P13 in patients on stable treatment will lead to considerable cost savings. Patients enrolled have been in a stable remission with infliximab RMP for at least 6 months prior to inclusion. Disease worsening as the primary endpoint in CD is defined as an increase in HBI of ⩾4 points from randomization and a minimum HBI score of seven points and in UC as an increase in partial Mayo score of ⩾3 points from randomization and a minimum partial Mayo score of ⩾5 points. Study results will be available in summer 2016 and amongst the 498 patients included in the study there are 160 patients with CD and 95 with UC.

CT-P13 in clinical use

The introduction of CT-P13 in European countries varies a lot partly because of different systems and praxis of reimbursement, but the decision of whether or not use a biosimilar in an individual patient is mostly made by the treating physician. In addition, several national societies have raised concerns with regard to the use of biosimilars in extrapolated indications and recommend being reticent until more data are available through clinical trials. According to a European survey among gastroenterologists in 2013, there was a lack of confidence in using biosimilar infliximab in IBD [Danese et al. 2014]. In Norway an annual tender system for the supply of biologics was established years ago and cost calculations and impact on healthcare budgets are key factors for drug selection. Since January 2014, almost all IBD patients in Norway starting biological treatment have received CT-P13 and last year the majority of all patients already treated with the originator infliximab have switched because a price reduction of 72% on CT-P13 (Remsima^®) compared to the originator infliximab (see https://farmastat.no/). Also in Denmark they have a national price determination of biologics and during a 3-month period in 2015, all patients treated with infliximab RMP have switched to CT-P13 imposed by the health authorities to reduce the financial burden on the healthcare system (see https://www.dli-mi.dk/Pages/default.aspx). To the best of the author’s knowledge this has been completely unproblematic.

Conclusion

CT-P13 is undoubtedly an important contribution to therapeutic options for IBD and will certainly be widely used because of obvious pharmacoeconomic benefits of a cost-effective drug and comparable efficacy. However, there are still some concerns related to CT-P13. In particular, interchangeability is an issue that needs more clarification.

Hopefully observational studies, pharmacovigilance data, and randomized trials currently being undertaken will give us new data for solving current controversies.