Multiple infliximab biosimilar switches appear to be safe and effective in a real‐world inflammatory bowel disease cohort

Abstract Background Switching from originator infliximab (IFX) to biosimilar IFX is effective and safe. However, data on multiple switching are scarce. The Edinburgh inflammatory bowel disease (IBD) unit has undertaken three switch programmes: (1) Remicade to CT‐P13 (2016), (2) CT‐P13 to SB2 (2020), and (3) SB2 to CT‐P13 (2021). Objective The primary endpoint of this study was to assess CT‐P13 persistence following switch from SB2. Secondary endpoints included persistence stratified by the number of biosimilar switches (single, double and triple), effectiveness and safety. Methods We performed a prospective, observational, cohort study. All adult IBD patients on IFX biosimilar SB2 underwent an elective switch to CT‐P13. Patients were reviewed in a virtual biologic clinic with protocol driven collection of clinical disease activity, C‐reactive protein (CRP), faecal calprotectin (FC), IFX trough/antibody levels, and drug survival. Results 297 patients (CD n = 196 [66%], ulcerative colitis/inflammatory bowel disease unclassified n = 101, [34%]) were switched (followed‐up: 7.5 months [6.8–8.1]). This was the third, second and first IFX switch for 67/297 (22.5%), 138/297 (46.5%) and 92/297 (31%) of the cohort respectively. 90.6% of patients remained on IFX during follow‐up. The number of switches was not independently associated with IFX persistence after adjusting for confounders. Clinical (p = 0.77), biochemical (CRP ≤5 mg/ml; p = 0.75) and faecal biomarker (FC<250 µg/g; p = 0.63) remission were comparable at baseline, week 12 and week 24. Conclusion Multiple successive switches from IFX originator to biosimilars are effective and safe in patients with IBD, irrespective of the number of IFX switches.


INTRODUCTION
Infliximab (IFX), a monoclonal antibody inhibiting anti-tumour necrosis factor (TNF), is a widely used biologic therapy whose originator (Remicade®) was the first biologic drug approved for the treatment of inflammatory bowel disease (IBD) in 1998. 1 The first biosimilar of IFX approved by the US Food and Drug Administration and the European Medicines Agency was CTP-13 in 2013. 2 This approval was based on data extrapolated initially from the PLANETRA and PLANETAS studies in rheumatoid arthritis and ankylosing spondylitis. 3,4 Safety and efficacy data in IBD were provided by the NOR-SWITCH 5 and CT-P13 3.4 randomised control trials. 6 This was reflected in an updated ECCO position stating that switching from IFX originator to a biosimilar is acceptable with evidence for safety and efficacy. 7 The reason for the development of biosimilars was mainly economic. 8,9 Reducing costs has increased IFX availability worldwide with many patients benefiting from it as growing evidence proves early therapy is associated to better outcomes. 10,11 Single and double switch appeared to be effective and safe in some observational studies, but data regarding three or more switches are lacking. 12,13 In the present economic climate with multiple biosimilars available at competitive prices, data about multiple biosimilar switches is of increasing importance.
In the Edinburgh IBD Unit, we previously implemented a managed switch programme guiding the transition from IFX originator to the IFX biosimilar CT-P13 which appeared to be safe and effective. 14 Given a further price reductions of IFX biosimilars following successive annual rounds of tendering by National Procurement Scotland, similar switch programmes were implemented in q1 2020 (SB2) and q4 2021 (CT-P13). In the present study we aimed to assess effectiveness and safety of this third IFX biosimilar switch (SB2 to CT-P13) including patients who have had a single, double or triple switch.

Study design and outcomes
We performed a prospective observational cohort study in the Edinburgh IBD unit, a tertiary IBD referral centre in NHS Lothian (Scotland), to investigate the effectiveness and safety of the third IFX biosimilar switch (SB2 to CT-P13) including patients who have had single, double and triple switches. NHS Lothian provides universal, free at point of care healthcare for a population of 912,490 people (estimate mid 2020), including more than 8000 patients with IBD. 15 Three managed switch programmes for IFX have been undertaken in the Edinburgh IBD unit, including: (1) IFX originator to CT-P13 in 2016, 14 (2) CT-P13 to SB2 (March-May 2020), and (3)

Patients
We identified all adult IBD patients receiving IFX biosimilar SB2 in the Edinburgh IBD unit from our infusion suite records who

Key summary
Established knowledge on this subject: • Data on single infliximab biosimilar switch has been proved to be effective and safe.
• Multiple biosimilars are available and data on multiple successive switches are scarce.

New findings:
• In our study we observed similar effectiveness, safety and immunogenicity rates across different number of biosimilar infliximab switches (single, double and triple).
• These results will help making decisions on multiple switches as more and more biosimilars are becoming available and therefore will help saving costs.

Outcomes
The primary endpoint of this study was CT-P13 drug persistence.

Data collection
Patient demographics and IBD characteristics were extracted from electronic medical health records. We collected the following data: sex, smoking history, body mass index, IBD type, age at IBD diagnosis, disease extent and behaviour according to the Montreal classification and both previous and ongoing exposure to IBD-related medical therapies. IFX start date, dose, dose interval and previously used IFX brands were recorded.
We prospectively collected clinical scores (HBI and partial Mayo), CRP, FC and IFX drug and antibody levels at baseline, week 12 (�4 weeks) and week 24 (�4 weeks). Data were collected at the infusion suite prior to infusion of IFX. If no recent value of calprotectin was available within the 4 weeks prior to switch, patients were given a stool sample kit at the infusion suite to submit at their GP the same week. Given different IFX intervals, a 4-week time margin was used whilst collecting follow-up data. Furthermore, we recorded IFX dose adjustments as well as IFX stop dates and reason for treatment discontinuation.
Primary non-response was defined as lack of clinical and biochemical response in the first 4 months since IFX was started requiring treatment discontinuation. Secondary loss of response was defined as clinical and biochemical relapse in patients who previously responded. In patients with no detectable IFX trough levels and detectable antibody levels who discontinued IFX, we considered immunogenicity as the reason for treatment discontinuation. Thus, secondary loss of response was considered in the absence of immunogenicity.
All adverse events during follow-up were documented. A serious adverse event was defined as an adverse event leading to IFX suspension or discontinuation, hospitalisation, or death. Adverse events occurring in <5 patients are reported as '<5 events' to avoid the use of personally identifiable information which can be traced back to a person.

Faecal calprotectin
All FC were measured in the Western General Hospital, Edinburgh, with a standard enzyme-linked immunosorbent assay (ELISA) technique (Calpro AS™) resulting in numerical values between 20 and 1250 μg/g.

Infliximab drug levels and antibody assay
Since January 2018, IFX trough levels have been analysed at the Queen Elizabeth University Hospital, Glasgow, using Immundiag-

Ethics
This work was considered a service evaluation/audit as all data were collected as part of routine clinical care. Therefore, no written GROS ET AL.
-181 consent or formal ethical approval was necessary as per departmental policy and Health Research Authority. 19 This piece of work conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a prior approval by the institution's review board.   Table 1).

IFX persistence
Of 297 patients, 28 (9.4%) patients discontinued IFX treatment during follow-up. Median time to IFX discontinuation was

Safety
Six adverse events were reported in five patients. Adverse events included psoriatic reaction, squamous cell carcinoma of the tonsil, arthralgia, severe COVID infection requiring ICU hospitalisation, heart failure requiring ICU admission, and mild skin reaction. Of these adverse events, three were classified as severe adverse events leading to drug discontinuation.     -185 Further evidence that supports a comparable effectiveness of double switching from originator to CT-P13 to SB2, compared to a single switch comes from a study involving 158 patients, 115 of whom had two switches and 43 a single switch. 21 All patients were at the moment of switch in sustained steroid-free clinical remission for at least 6 months. IFX persistence was 94.9% after median 54 weeks of follow-up, which is slightly better compared to our findings (7.5month IFX persistence: 90.6%). This might be explained by the inclusion of only patients in sustained steroid-free clinical remission.
Indeed, clinical remission at switch was independently associated with better drug persistence in previous studies. 13 Real-world studies regarding adalimumab biosimilars have reported similar rates of effectiveness and safety in patients with one switch or two switches. 24,25 A phase III trial in psoriasis demonstrated no differences between patients who underwent four adalimumab biosimilar switches versus those who underwent none. 26 Immunogenicity has been a major concern regarding multiple switches, although both our study and previous literature demonstrated that this seemed to be not happening more often to patients who had multiple switches compared to those who had less number of switches or none. Our study found 14 (7.1%) patients who developed de novo antibodies; none of them underwent three switches.
This triple switch group may represent a selected cohort of patients on relatively long term IFX with a low immunogenicity risk. 27 A previous French study observed that antidrug antibody formation was similar in patients with one switch or two IFX biosimilar switches. 28 Moreover, IFX levels remained stable after switching. 14,21 Our study has several strengths including its prospective nature and the large sample size. Furthermore our study provides data for patients with a single switch, double switch and a triple switches. The prospective registrations of IFX start and stop dates, clinical scores, biochemical parameters and therapeutic drug monitoring contributes to completeness of the data by limiting selection bias during the collection of follow-up data.
Nonetheless there are some limitations to our study. First the study design did not include a control arm that continued SB2, impeding the comparison of effectiveness and safety between groups. Although we were able to compare subgroups based on F I G U R E 3 Harvey-Bradshaw Index, partial Mayo score, CRP, faecal calprotectin and infliximab trough levels at baseline and at 12 and 24 weeks after switch.

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UNITED EUROPEAN GASTROENTEROLOGY JOURNAL number of IFX switches, baseline characteristics were not comparable between subgroups (i.e. different IFX duration). Therefore we performed a multivariable analyses adjusting for these characteristics to assess IFX persistence. Second there were some missing data, although data were prospectively collected. This may have resulted in a conservative estimate of effectiveness outcomes since last observation was carried forwards for patients who discontinued IFX whereas missing data were censored for those who continued IFX.
Third treatment optimisation was not standardised, but was performed at the discretion of the clinician. This reflects real-world practice, allowing direct translation of results into clinical practice but this may have impacted outcomes. Of note, scrutiny of data collection during this study may have resulted into earlier dose adjustments and IFX discontinuation. Finally the cohort was heterogeneous in terms of disease activity, IFX doses and combination therapy.

CONCLUSION
Multiple successive switches from the IFX originator to biosimilars appear effective and safe, irrespective of the number of switches.
These findings are of major socioeconomic importance, especially in low and middle-income countries where the access to healthcare may be limited.