Immunologic Research

, Volume 65, Issue 1, pp 419–422 | Cite as

Safety, efficacy and immunogenicity of switching from innovator to biosimilar infliximab in patients with spondyloarthritis: a 6-month real-life observational study

  • Maurizio Benucci
  • Francesca Li Gobbi
  • Francesca Bandinelli
  • Arianna Damiani
  • Maria Infantino
  • Valentina Grossi
  • Mariangela Manfredi
  • Simone Parisi
  • Enrico Fusaro
  • Alberto Batticciotto
  • Piercarlo Sarzi-Puttini
  • Fabiola Atzeni
  • Francesca Meacci
Mechanism in Autoimmunity

Abstract

Biosimilar infliximab (INX) was recently approved by the European Medicine Agency for the treatment of rheumatoid arthritis, ankylosing spondylitis (AS), Crohn’s disease, ulcerative colitis, psoriatic arthritis (PsA), and psoriasis on the grounds that its pharmacokinetics, safety, and efficacy were comparable to those of innovator INX. The aim of this study was to investigate the real-life efficacy, safety, and immunogenicity of switching from innovator to biosimilar INX in patients with spondyloarthritis (SpA). Forty-one patients attending three Italian rheumatology centres with a previous diagnosis of SpA and clinically inactive or moderate disease activity (ASDAS-CRP < 2.1; 22 with AS, five with enteropathic arthritis, 10 with PsA, and four with undifferentiated SpA), who had been treated for more than 6 months with innovator INX in accordance with the ASAS/EULAR guidelines, were switched to biosimilar INX for pharmaco-economic reasons (Tuscany Law No. 450 of 7 April 2015) and followed up for 6 months. A record was kept of their BASDAI, BASFI, ASDAS-CRP, DAS28-CRP (in the presence of peripheral disease), MASES, VAS pain scores, the duration of morning stiffness, and adverse events (AEs). At the time of the switch, the patients had a median age of 50.9 years (range 23–80), a median disease duration of 124.5 months (range 14–372), and a median duration of treatment with innovator INX of 73.7 months (range 6–144). After 6 months of biosimilar INX therapy, there were no statistical differences in their median BASDAI (2.73 ± 1.5 vs. 2.6 ± 1.3, p = .27), BASFI (2.34 ± 1.3 vs. 2.17 ± 1.2, p = 0.051), ASDAS-CRP (1.35 ± 0.3 vs. 1.28 ± 0.2, p = 0.24), DAS28-CRP (2.66 ± 0.67 vs. 2.67 ± 0.35, p = 0.92), MASES (0.35 ± 0.7 vs. 0.17 ± 0.4, p = 0.08), or VAS pain scores (18 ± 14.7 vs. 16.7 ± 11.3, p = 0.55), whereas the median duration of morning stiffness had significantly decreased (7.2 ± 6.9 vs. 5.8 ± 6, p = 0.02). Furthermore, there was no change in circulating INX (4.22 ± 2.89 vs 4.84 ± 2.86 μg/mL, p = 0.80) or anti-INX antibody levels (27.76 ± 17.13 vs 27.27 ± 17.28 ng/mL, p = 0.98). The switch from innovator to biosimilar INX in this Italian multicentre SpA cohort was not associated with any statistically significance differences in efficacy, adverse events or anti-drug antibody level.

Keywords

Biosimilar CT-P13 Switching Spondyloarthritis 

Introduction

Biosimilar drugs such as CT-P13 (a biosimilar of infliximab, a chimerical human-murine monoclonal antibody against tumour necrosis factor, TNF) are generic versions of innovator biological drugs or reference products (RPs) [1]. Regulatory authorities in Europe, the USA and elsewhere have defined strict criteria for the approval of biosimilar drugs which, although they vary from country to country, usually include a high degree of physicochemical and biological similarity to the RP. In addition, clinical studies must establish statistical equivalence in their pharmacokinetics and efficacy, and comparability [2, 3, 4].

Biosimilar infliximab (bINX) was recently approved by the European Medicine Agency (EMA) for the treatment of rheumatoid arthritis, ankylosing spondylitis (AS), Crohn’s disease, ulcerative colitis, psoriatic arthritis (PsA), and psoriasis on the grounds that its pharmacokinetics, safety and efficacy were comparable to those of innovator INX (iINX). Extensive testing has shown that all of the major physicochemical characteristics and in vitro biological activities of CT-P13 and iINX, including their affinity for soluble and transmembrane TNF, are highly comparable [5, 6].

As biosimilar drugs are cheaper than their RPs, there is considerable interest in determining whether newly diagnosed patients can be effectively and safely treated with a particular biosimilar and whether those already on RP treatment can be switched to its biosimilar without adverse consequences in terms of efficacy or safety [7, 8]. Switching from iINX to bINX offers cost savings but only limited evidence is available, and there are no guidelines. The aim of this study was to investigate the real-life efficacy, safety and immunogenecity of switching from innovator to biosimilar INX in patients with spondyloarthritis (SpA).

Methods

The study involved 41 SpA patients (22 with AS, five with enteropathic arthritis, 10 with PsA and four with undifferentiated SpA) attending three Italian rheumatology centres, who had been treated for more than 6 months with iINX in accordance with the ASAS/EULAR guidelines and showed clinically inactive or moderate disease activity (ASDAS-CRP < 2.1), and were switched to bINX for pharmaco-economic reasons (Tuscany Law No. 450, of 7 April 2015). At baseline and after 6 months, a record made was made of their Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP, disease activity score (DAS28)-CRP (in the presence of peripheral disease), Maastricht Ankylosing Spondylitis Enthesitis Score (MASES), visual analogic scale (VAS) pain scores, the duration of morning stiffness, erythrocyte sedimentation rate (ESR) (mm/hour), and C-reactive protein (CRP) levels (mg/dL). Trough INX and anti-drug antibody (ADA) levels were evaluated during treatment with iINX and 6 months after the switch to bINX using LISA-TRACKER Duo INF (Theradiag, Marne La Vallee, France). A record was also kept of any adverse events (AEs).

The study was approved by the Ethics Committee of Ospedale San Giovanni di Dio (Florence, Italy), and all of the patients gave their informed consent.

Statistical analysis

Analysis of variance (ANOVA) was used in order to establish whether there were any significant differences between the mean values of all of the considered variables at baseline and after 6 months of bINX treatment. ANOVA separates the variance of the data into between- and within-group components, and F represents the ratio of the two estimates. If the F test p value is < 0.05, there is a statistically significant difference between the mean values of all of the variables at a significance level of 5 %, and subsequent multiple range tests indicate which paired variables have significantly different mean values. The data were analysed using SAS statistical software, version 9.2. A p value of < 0.05 was considered significant.

Results

At the time of the switch, the patients had a median age of 50.9 years (range 23–80), a median disease duration of 124.5 months (range 14–372), and a median duration of iINX treatment of 73.7 months (range 6–144). After 6 months of bINX therapy, there were no statistical differences in the median BASDAI (2.73 ± 1.5 vs. 2.6 ± 1.3, p = 0.27), BASFI (2.34 ± 1.3 vs. 2.17 ± 1.2, p = 0.051), ASDAS-CRP (1.35 ± 0.3 vs. 1.28 ± 0.2, p = 0.24), DAS28-CRP (2.66 ± 0.67 vs. 2.67 ± 0.35, p = 0.92), MASES (0.35 ± 0.7 vs. 0.17 ± 0.4, p = 0.08), or VAS pain scores (18 ± 14.7 vs. 16,7 ± 11.3, p = 0.55), but the median duration of morning stiffness was significantly shorter (7.2 ± 6.9 vs. 5.8 ± 6 p = 0.02). Furthermore, there was no change in circulating INX (4.22 ± 2.89 vs. 4.84 ± 2.86 μg/mL, p = 0.80) or anti-INX antibody levels (27.76 ± 17.13 vs. 27.27 ± 17.28 ng/mL, p = 0.98) (Table 1).
Table 1

Clinical and laboratory data at baseline and after 6 months of biosimilar INX

Parameters

Baseline

After 6 months

p value

BASDAI

2.73 ± 1.5

2.6 ± 1.3

0.27

BASFI

2.34 ± 1.3

2.17 ± 1.2

0.051

ASDAS-CRP

1.35 ± 0.3

1.28 ± 0.2

0.92

DAS28-CRP

2.66 ± 0.67

2.67 ± 0.35

0.24

MASES

0.35 ± 0.7

0.17 ± 0.4

0.08

VAS pain

18 ± 14.7

16,7 ± 11.3

0.55

Morning stiffness

7.2 ± 6.9

5.8 ± 6

0.02

Infliximab levels ug/mL

4.22 ± 2,89

4.84 ± 2.86

0.80

ADA Infliximab ng/mL

27,76 ± 17.13

27.27 ± 17.28

0.98

BASDAI Bath Ankylosing Spondylitis Disease Activity Index, BASFI Bath Ankylosing Spondylitis Functional Index, ASDAS-CRP Ankylosing Spondylitis Disease Activity Score, disease activity score (DAS28)-CRP (in the presence of peripheral disease), MASES Maastricht Ankylosing Spondylitis Enthesitis Score, VAS visual analogic scale, pain scores; ADA anti-drug antibody

During the first 6 months of bINX treatment, very few patients experienced an AE, and there was no significance difference from the AEs recorded during the 6 months before the switch (p = 1.0). Adverse events led to treatment discontinuation only in one patient (3 %), who stopped bINX treatment after the first two administrations because of the onset of severe palmoplantar psoriasis.

Discussion

This paper provides the first real-life data showing that there no clinical or immunogenic changes appear after switching from iINX to bINX. The FDA and EMA have not yet identified any interchangeable drug nor suggested any criteria supporting their interchangeability [2, 3]. However, it is worth pointing out that interchangeability includes the possibility that a physician or pharmacist can dispense the innovator drug rather than its biosimilar in the USA [3] whereas, in Italy, interchangeability indicates the possibility for a physician to prescribe either of the two drugs, and replaceability the possibility for a pharmacist to dispense one drug instead of the other without the physician’s consent [9]. Accordingly, the EMA recommendation the position paper of Italian rheumatologists declare that naïve patients can be treated with a biosimilar; patients treated with a biological drug should avoid switching to a biosimilar (or vice versa); and repeated switches between the original drug and biosimilar (or vice versa) should be avoided [10].

However, Tuscany Law No. 450 of 7 April 2015 requires switching from an original drug to a biosimilar for economic reasons and allows patients to continue taking the original drug only after this has been specifically authorised. It is for this reason that we switched our patients from iINX to bINX.

Our data showing no significant differences in the safety, efficacy and immunogenicity of the two drugs are in line with the recently published findings of the extension to 102 weeks of the PLANETAS study, in which 86 of the 174 patients were switched to CT-P13 from iINX. The ASAS20 response rates at week 102 in the maintenance and switching group were respectively 80.7 and 76.9 %, the ASAS40 and ASAS partial remission rates were similar, and the ADA positivity rates were comparable (week 102: 23.3 vs. 27.4 %). Adverse events led to treatment discontinuation during the extension study in respectively three (3.3 %) and four patients (4.8 %) [11].

In the same study, ADAs against both CT-P13 and iINX were assessed by means of electrochemiluminescence (ECL), which is currently one of the more highly performing methods because of its sensitivity, and the neutralising capability of the detected ADAs was assayed using a flow-through immunoassay (Gyros Immunoassay, Gyros AB, Sweden), a microfluidic platform that combines sensitivity and reability. However, as this method is still uncommon in most laboratories [12], we used an ELISA method and found no differences in ADA and circulating drug trough levels before and after the switch.

A recent study of 250 consecutive patients with rheumatic diseases treated with Remicade (an iINX) and 77 retrospectively selected controls measured anti-IFX antibody kevels at drug trough levels in parallel using three different bridging ELISA assays: the Promonitor ANTI-IFX kit, which uses Remicade to detect antibodies, and two assays using either Inflectra or Remsima with the same format. The anti-INX antibodies of Remicade-treated patients cross-react with Inflectra or Remsima. Although additional epitopes may be present in the biosimilar, the results suggest that epitopes influencing the immune response to IFX are also present [13].

There are a total of five published observational studies of patients switching from iIFX to CTP13 [14]. The clinical efficacy and safety of CT-P13 were evaluated in 110 Korean inflammatory bowel disease (IBD) patients (59 with Crohn’s disease (CD), and 51 with ulcerative colatis (UC), including 36 patients (27 CD and nine UC) switching from iINX to CT-P13 [15]: the clinical remission, response and safety profiles of CTP13 were comparable with the historical data of the iINX, and drug efficacy was maintained in 92.6 % of the CD and 66.7 % of the UC patients who switched treatment [15]. The satisfactory clinical efficacy and safety of CT-P13 have been confirmed by other observational studies of respectively 173 (83 with CD, 12 with fistulising CD [FCD], and 78 with UC) and 17 Korean IBD patients (8 with CD, 9 with UC), including 60 (40 CD, 4 FCD, 16 UC 16) and nine switching patients (5 CD, 4 UC) [16, 17]. The other two observational studies included 32 paediatric CD and 39 RA patients who switched therapy in Europe without any change in efficacy or safety [18, 19].

On the contrary, application of the same Tuscany Law No. 450 of 7 April 2015 at another centre led to disease relapse in seven out of 23 patients (30.43 %) a mean 1.71 months after the start of bINX [20].

A number of registry and post-marketing studies are currently evaluating CT-P13 in various indications (RA, AS, CD, UC, AS, PsA and psoriasis), and clinical outcomes after switching from iIFX, and three randomised clinical trials involving about 800 patients [14].

Six regulatory authorities of different countries have so far indicated their positions concerning the interchangeability or substitutability of biosimilars and RPs, all of which have generally positive views. The most recent position statements issued by Medicine Evaluation Boards of the Netherlands and Finnish agencies indicate that switching to biosimilars should be allowed, and the Australian PBAC has stated that the substitution of biosimilars and RPs is allowed if the biosimilar is equivalent in terms of efficacy and safety [14].

Our real-life experience shows that the switch from iINX to CT-P13 is feasible, safe and efficacious. It could also lead to savings useful for the sustainability of national healthcare systems, although a careful assessment of the adverse events and immunogenicity of the switch is still necessary.

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Maurizio Benucci
    • 1
  • Francesca Li Gobbi
    • 1
  • Francesca Bandinelli
    • 1
  • Arianna Damiani
    • 1
  • Maria Infantino
    • 2
  • Valentina Grossi
    • 2
  • Mariangela Manfredi
    • 2
  • Simone Parisi
    • 3
  • Enrico Fusaro
    • 3
  • Alberto Batticciotto
    • 4
  • Piercarlo Sarzi-Puttini
    • 4
  • Fabiola Atzeni
    • 4
  • Francesca Meacci
    • 2
  1. 1.Rheumatology Unit, Azienda Sanitaria di FirenzeS. Giovanni di Dio HospitalFlorenceItaly
  2. 2.Allergology and Immunology LaboratoryS.Giovanni di Dio HospitalFlorenceItaly
  3. 3.Rheumatology UnitCittà della Salute e della Scienza di Torino University HospitalTurinItaly
  4. 4.Rheumatology UnitL. Sacco University HospitalMilanItaly

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