Systematic switch from innovator infliximab to biosimilar infliximab in inflammatory chronic diseases in daily clinical practice: The experience of Cochin University Hospital, Paris, France

Author’s Accepted Manuscript Systematic switch from Innovator Infliximab to Biosimilar Infliximab in Inflammatory Chronic Diseases in Daily Clinical Practice: The Experience of Cochin University Hospital, Paris, France Jérôme Avouac, Anna Moltó, Vered Abitbol, Adrien Etcheto, Axelle Salcion, Loriane Gutermann, Caroline Klotz, Muriel Elhai, Pascal Cohen, Pierre Antoine Soret, Florence Morin, Ornella Conort, François Chast, Claire Goulvestre, Claire Le Jeunne, Stanislas Chaussade, André Kahan, Christian Roux, Yannick Allanore, Maxime Dougados

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To appear in: Seminars in Arthritis and Rheumatism Cite this article as: Jérôme Avouac, Anna Moltó, Vered Abitbol, Adrien Etcheto, Axelle Salcion, Loriane Gutermann, Caroline Klotz, Muriel Elhai, Pascal Cohen, Pierre Antoine Soret, Florence Morin, Ornella Conort, François Chast, Claire Goulvestre, Claire Le Jeunne, Stanislas Chaussade, André Kahan, Christian Roux, Yannick Allanore and Maxime Dougados, Systematic switch from Innovator Infliximab to Biosimilar Infliximab in Inflammatory Chronic Diseases in Daily Clinical Practice: The Experience of Cochin University Hospital, Paris, F r a n c e , Seminars in Arthritis and Rheumatism, http://dx.doi.org/10.1016/j.semarthrit.2017.10.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Systematic switch from Innovator Infliximab to Biosimilar Infliximab in Inflammatory Chronic Diseases in Daily Clinical Practice: The Experience of Cochin University Hospital, Paris, France. Jérôme Avouac* (1,2), Anna Moltó* (3), Vered Abitbol (4), Adrien Etcheto (3), Axelle Salcion (3), Loriane Gutermann (5), Caroline Klotz (4), Muriel Elhai (1,2), Pascal Cohen (6), Pierre Antoine Soret (4), Florence Morin (7), Ornella Conort (5), François Chast (5), Claire Goulvestre (7), Claire Le Jeunne (6), Stanislas Chaussade (4), André Kahan (1,2), Christian Roux (2), Yannick Allanore (1,2), Maxime Dougados (2,7). (1) Paris Descartes University, Sorbonne Paris Cité, Rheumatology A department, Cochin Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France (2) Paris Descartes University, Sorbonne Paris Cité, INSERM U1016, Cochin Institute, CNRS UMR8104, Paris, France (3) Paris Descartes University, Sorbonne Paris Cité, Rheumatology B department, Cochin Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France (4) Paris Descartes University, Sorbonne Paris Cité, Gastroenterology department, Cochin Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France (5) Paris Descartes University, Sorbonne Paris Cité, department of Pharmacy, Cochin Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France (6) Paris Descartes University, Sorbonne Paris Cité, Internal Medicine department, Cochin Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France (7) Paris Descartes University, Sorbonne Paris Cité, Immunology Laboratory, Cochin Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France (8) INSERM U1153, Clinical epidemiology and biostatistics, PRES Sorbonne Paris-Cité. Paris, France

* These authors equally contributed to this work Corresponding author: Dr. Jérôme Avouac Hôpital Cochin, Service de rhumatologie A, 27 rue du faubourg Saint Jacques, 75014 Paris, France Tel: 33 1 58 41 25 63 Fax: 33 1 58 41 26 24 E-mail: [email protected]

Keywords: infliximab, CT-P13, biosimilar, Infliximab through levels, Rheumatoid Arthritis, Axial Spondyloarthritis, Crohn’s disease, Ulcerative Colitis, Uveitis, Switch Competing interests: None Financial support: None

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Abstract Objective: To investigate effectiveness of systematic switching treatment from innovator infliximab to biosimilar infliximab, and its associated factors. Methods In this prospective observational study, all adult patients receiving maintenance therapy with innovator infliximab in Cochin University Hospital were systematically switched to biosimilar infliximab. Effectiveness was assessed by the retention rate of biosimilar infliximab at the time of the third infusion. Sensitivity analyses for effectiveness included changes of disease activity parameters and infliximab trough levels between baseline and the last visit as well as the occurrence of adverse events leading to drug discontinuation. Factors associated with biosimilar infliximab discontinuation at the last visit were explored. Results: 260 patients fulfilled the inclusion criteria, including 31 rheumatoid arthritis (RA), 131 axial spondyloarthritis (axSpA) and 64 inflammatory bowel diseases. The retention rate was 85% (221/260 patients) at the time of the third biosimilar infusion. Between baseline and the last visit (mean follow-up of 34 weeks), 59 patients (23%) discontinued biosimilar infliximab, mainly due to experienced inefficacy (n=47, 80%). No clinical or biological factors were associated with biosimilar discontinuation. No serious adverse events occurred. No change in objective disease activity parameters or infliximab trough levels was detected. However, a significant increase of BASDAI (2.942.20 vs. 3.182.21, p=0.046, before vs. after switch, respectively) was observed in patients with axSpA. Innovator infliximab was reestablished in 47/59 patients (80%). Conclusion: No changes in drug trough levels or objective parameters were observed after the systematic switch to biosimilar infliximab in a real clinical practice setting. Only changes in patient-reported outcomes were observed, suggesting attribution effects rather than pharmacological differences.

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Introduction Targeted biological treatments have revolutionized and transformed treatment paradigms for chronic inflammatory disorders in rheumatology, as well as in dermatology, gastroenterology, and ophthalmology. However, their significant costs have been a barrier to their use (1, 2). Recent expiry of patents for some key biologics has led to development of biosimilars. With increasing numbers of biosimilar products, more options are available for patients to access earlier to biological products and possibly switch from costly innovators to biosimilars. Since the approval of the chimeric monoclonal antibody to tumor necrosis factor-ɑ (TNF-ɑ) Infliximab (Remicade®), the biosimilar CT-P13, has entered the market (3). This is the first biosimilar monoclonal antibody, with the trade names Inflectra® or Remsima®, registered by the European Medicines Agency (EMA) in 2013 (4). Since then, new biosimilars of TNF- inhibitors have been developed: Benepali® (biosimilar etanercept), Amjetiva® (biosimilar adalimumab) and Flixabi® (another biosimilar infliximab). Biosimilarity between CT-P13 and its innovator has been demonstrated by physicochemical, non-clinical and clinical studies including two pivotal clinical studies (5, 6), CT-P13 development program included a therapeutic equivalence PLANETRA study in 606 patients with rheumatoid arthritis (RA), on background of methotrexate, which showed equivalent efficacy and comparable safety profile, pharmacokinetics and immunogenicity of CT-P13 with innovator infliximab. Similarly, the PLANETAS trial that included 250 patients with spondyloarthritis demonstrated equivalent pharmacokinetic parameters and comparable safety profile, efficacy and immunogenicity of CT-P13 with innovator infliximab. Thus, based on these comparable results in randomized controlled trials and favorable costs, the medical community of Cochin Hospital decided in October 2015 to systematically propose the switch from innovator to biosimilar infliximab to all treated patients.

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It is important to mention that CT-P13 development program only included patients who were naive of infliximab before receiving the first infusion of CT-P13. Moreover, CT-P13 has been approved for use in indications held by the innovator biologic not directly studied in a comparative clinical trial with the biosimilar, like Crohn’s disease (CD) and ulcerative colitis (UC). This extrapolation reduces or eliminates the need for duplicative clinical studies of the biosimilar by extrapolating all the data collected from one indication for the biosimilar product to all the indications originally approved for the innovator. Thus, given the paucity of data related to the consequences of switching to biosimilar infliximab in daily clinical practice, particularly in the subsets of patients suffering from different diseases than those evaluated during the CT-P13 development program and those receiving long lasting innovator infliximab infusions, we decided to collect clinical outcomes in an observational prospective cohort study in a clinical practice setting. The objective of this study was to investigate on a large array of inflammatory disorders the efficacy in clinical practice (i.e. effectiveness) and safety of systematic switching treatment from innovator infliximab to biosimilar infliximab. In addition, we analysed the outcome of patients re-established back on innovator infliximab in case of biosimilar discontinuation

Patients and methods

Study design: Prospective observational usual care study conducted in Rheumatology, Gastroenterology and Internal Medicine departments of Cochin Hospital. The Dermatology department was not involved, since no patient with psoriasis was receiving infliximab.

Study population: All patients on maintenance therapy with innovator infliximab and followed-up in Cochin Hospital were systematically screened for inclusion.

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Inclusion criteria: Adults who agreed to switch to biosimilar infliximab, and who had received at least 3 infusions of innovator infliximab prior to the switch, were eligible for inclusion. All included patients agreed to participate in the study after informed consent, which was recorded in the medical source file. The protocol and the informed consent document have received Institutional Review Board/Independent Ethics Committee (IRB/IEC) approval before initiation of the study (“Comité de Protection des Personnes” Paris Ile de France I).

Setting: Patients were switched to biosimilar infliximab at the same dose and frequency as innovator infliximab at inclusion visit, which took place between October 2015 and February 2016. Patients were then evaluated at each infusion visits. The final study observation was planned as the last observation collected during the closeout visit in July 2016. A Specific preplanned sub-analysis of patients who restarted innovator infliximab after biosimilar discontinuation was performed. The follow-up of this subgroup of patients was prolonged up to December 2016. Analyses and completion of the database was performed during the first trimester of the year 2017.

Clinical and laboratory data: Data were collected at every patient visit through a face-toface interview and validation from the medical file in a standardized case-report form that included: diagnoses of patients followed in Rheumatology (RA, axial spondyloarthritis, axSpA and other chronic inflammatory disorders), Gastroenterology (CD and UC), and Internal Medicine (Uveitis and other chronic inflammatory diseases); demographic parameters (age, gender, disease duration, body mass index, BMI) and Charlson Comorbidity score (7, 8); current and past medication use was (i.e. number of ongoing treatments for comorbidities, medication history including the number and nature of biologic disease-

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modifying antirheumatic drugs (bDMARDs) taken before infliximab, the number of patients treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) (intake the last 7 days prior to the visit and calculation of the ASAS NSAID Score) (9), and conventional synthetic DMARDs (csDMARDs). Disease activity was assessed in RA using the Disease Activity Score based on evaluation of 28 joints (DAS28) (10); in AxSpA, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (11) and the Ankylosing Spondylitis Disease Activity Score (ASDAS) (12) were used. In patients with inflammatory bowel diseases (IBD), clinical activity was assessed with Harvey Bradshaw index (CD) (13), and partial Mayo score (UC) (14), and in uveitis, we used the uveitis activity score, which is an overall assessment of the disease by the patient and researcher was made using a visual analog scale (VAS) of 0–10 cm, 0 being the lowest (best) possible disease activity and 10 the highest (worst) (15). A “Global Disease Activity Score” ranging from 0 to 10, was computed (including either the DAS28, ASDAS, the Harvey Bradshaw score divided by 3, the Mayo score ceiled at 10 (i.e. all values above 10 will be imputed by 10), or the uveitis activity score (0-10), depending on the disease, to evaluate disease activity in the whole patient population. Serious adverse events at all severity levels were recorded at each infusion visit. Laboratory tests included erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), as well as infliximab trough levels, which were measured in the morning prior to each infusion using a validated enzyme-linked immune-absorbent assay (ELISA, LISA-TRACKER Duo Infliximab, Theradiag, Croissy-Beaubourg, France)

Primary Outcome of the study: The primary outcome was the retention rate of biosimilar infliximab at the time of the third infusion, measured on the overall patient population.

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Secondary outcomes: They included the retention rate of biosimilar infliximab at the last available visit (July 2016), measured in the overall population and in each department, changes in global activity score between baseline and the last visit (whole population), specific activity scores for each disease, infliximab trough levels, and occurrence of serious adverse events. Factors associated with biosimilar infliximab discontinuation at the last visit in July 2016 were explored. Regarding the sub-analysis of patients who restarted innovator infliximab after biosimilar infliximab discontinuation, changes in the parameters assessing disease activity and safety were compared between the biosimilar discontinuation visit and the fourth innovator infliximab infusion visit.

Statistical analysis All data are expressed as mean values ± standard deviation (SD) or number and percentage (%) for continuous and categorical variables, accordingly. Statistical analysis was performed using SAS. Comparisons before-after switch were estimated by paired t-test or Mc Nemar test for continuous and categorical variables, accordingly. Retention rate of biosimilar infliximab was estimated by Kaplan-Meier survival curves. Factors associated with discontinuation were estimated by Cox proportional hazards models.

Results Study population: 265 patients were on maintenance therapy with innovator infliximab. Five patients were not eligible for inclusion (Figure 1). No patient declined to participate in this study. In total, 260 patients fulfilled the inclusion criteria, including 182 patients followed-up in Rheumatology, including 131 with axSpA, 31 with RA and 20 with other inflammatory

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rheumatic diseases (14 psoriatic arthritis, 3 juvenile arthritis and 3 undifferentiated inflammatory arthritis). Sixty-four patients were recruited in Gastroenterology (41 CD and 23 UC) and 14 in Internal Medicine (8 with uveitis, 4 with Takayasu’s arteritis and 2 with Behcet’s disease). Patients with RA and other inflammatory rheumatic diseases were older (P<0.001) and were more likely to receive csDMARDs (45/51 patients, 88%, vs. 150/209 patients, 72%, P=0.029) than the other disease groups. Very few patients with RA (4/31, 13%) and the majority of patients with axial spondyloarthritis (90/131, 69%, P<0.001) were male. Patients with uveitis had shorter disease duration than those with other diseases (P<0.001). Very few patients with axial spondyloarthritis (9/131, 7%) or with CD (2/41, 5%) were receiving corticosteroid treatment compared to other disease groups (36/88, 41%, P<0.001). Patients RA and axSpA had received more infusions of innovator infliximab than had patients with other diseases (P=0.032) and patients with UC and those with uveitis had been treated with innovator infliximab for a shorter time than had patients with other diseases (P=0.026). Detailed description of patient characteristics is provided in Table 1.

Treatment with innovator infliximab prior to the switch: MeanSD time from initiation of infliximab prior to the switch was 5.84.9 years and meanSD number of innovator infliximab infusions at inclusion visit was 36.527.8 (Table 1).

Follow-up of patients: MeanSD follow-up period was 33.94.5 weeks.

Analysis of the primary outcome: The distribution of patients at each infusion visit is illustrated in the Flow chart (Figure 1). A total of 221 patients received a third infusion of

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biosimilar infliximab, leading to a retention rate of 85% at the time of the third biosimilar infusion. Figure 2 shows the survival curve for biosimilar infliximab retention rate. A significant lower retention rate was observed in patients followed in Rheumatology compared to those followed in Gastroenterology and Internal Medicine (148/182 patients, 81% vs. 73/78, 94%, p=0.007).

Analysis of secondary outcomes Retention rate of biosimilar infliximab at the last study visit At the last study visit, patients had received a mean of 4.61.1 infusions of biosimilar infliximab, with a mean dose of 413157 mg and a usual inter-dose interval of 8.21.8 weeks (Table S1). At this visit, a total of 201 patients (77%) were still on this treatment (Figure 1). The retention rate was significantly lower in rheumatology (134/182, 74%) compared to the rate observed in Gastroenterology and Internal Medicine (67/78, 86%, p=0.034). Patients with AxSpA had the lowest retention rate (73%) in comparison with the other inflammatory diseases (Table S1).

Description of biosimilar infliximab discontinuation Between baseline and the last visit, 59/260 (23%) patients discontinued biosimilar infliximab, which was mainly due to experienced inefficacy (n=47/59, 80%) (Figure 1). Only five discontinuations were related to safety issues: purpura (two patients with CD), infusion reaction (one patient with axSpA), diagnosis of cholangiocarcinoma (one patient with axSpA) and transitory increased liver enzymes reversible after treatment interruption (one patient with axSpA). In addition 6 patients were lost to follow-up and a single female patient with CD interrupted the treatment due to pregnancy.

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Of the 59 patients who discontinued biosimilar infliximab, 47 (79.7%,) were re-established back on innovator infliximab. Seven patients switched to another biologic therapy (5 patients switched to another TNF- molecule and 2 switched to another class) and 5 maintained biological-free.

Factors associated with biosimilar infliximab discontinuation No clinical or biological factors were independently associated with biosimilar discontinuation in the whole study population. In patients followed-up in Rheumatology, disease (ie RA vs. SpA) had no impact on drug discontinuation (Table S2).

Changes of clinical and biological parameters evaluating disease activity before and after the switch Baseline values of the different disease activity scores are provided in Table 2. No changes of the different disease activity scores were observed between the third to last innovator infliximab infusion (pre-switch) and baseline visit (first biosimilar infliximab infusion) (Table 2). The composite Global Disease Activity Score remained unchanged from baseline to the last visit (1.691.47 to 1.671.32, p=0.442) (Table 2). In patients with RA, the mean DAS28 remained stable from baseline to the last visit: 3.38  1.16 to 3.081.08 (p=0.217) (Table 2). In patients with axSpA, mean BASDAI increased from 2.942.20 to 3.182.22 (p=0.046) and mean ASDAS increased from 1.790.90 to 1.991.08 (p=0.022). Here also CRP remained stable (Table 2).

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In patients with inflammatory bowel diseases, all parameters assessing disease activity, including the Harvey Bradshaw and partial Mayo scores, stayed unchanged during the followup period (Table 2). Similarly, the disease activity score for patients treated with biosimilar infliximab for uveitis was similar between baseline and the last visit (Table 2).

Changes of infliximab trough levels between baseline and the last visit Mean infliximab trough levels did not significantly change between inclusion and final visits in the whole population (5.815.70 vs. 6.235.77 g/ml, p=0.091). Subgroup analyses according to the disease type did not modify this result (Table 3).

Analysis of the outcome of the patients re-established back on innovator infliximab Among the 59 patients who discontinued biosimilar infliximab, 47 patients were reestablished back on innovator infliximab (5 patients with RA, 33 with axSpA, 5 with other rheumatic diseases, 3 with CD and 1 with uveitis) and were followed-up during 32.35.4 weeks (Table S3). These 47 patients did not differ from the patients maintaining biosimilar infliximab in term of age (49±13 vs. 47±15 years, P=0.392), gender (49% vs. 56% of males, P=0.477), disease duration (17±11 vs. 15±11 years, P=0.567), and comorbidities (Charlson Comorbidity score: 1.1±0.8 vs. 1.0±1.1, P=0.552). The Number of biologics before Infliximab was significantly higher in patients who discontinued biosimilar infliximab (1.1±1.5) compared to those who maintained this therapy (0.5±1.0, P<0.001). These patients have received a mean number of 4.12.6 innovator infliximab infusions after biosimilar discontinuation. Five patients interrupted this treatment because of innovator infliximab secondary lack of efficacy. Infliximab trough levels remained unchanged during the follow-up period (Table 4).

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Parameters assessing disease activity were assessed in patients with RA (n=5) and axSpA (n=33). In RA patients, no significant change was observed on the number of tender and swollen joints, the patient’s global assessment of disease activity and the DAS28 (Table 4). Conversely, patients with axSpA re-established back with innovator infliximab significantly improved the BASDAI (2.982.13 vs. 4.212.07, p=0.012) and the ASDAS (2.021.17 vs. 2.420.92, p=0.041) (Table 4). CRP levels did not vary significantly in both populations (Table 4).

Discussion We report one of the first experiences of a systematic switch from innovator infliximab to its biosimilar in patients with various inflammatory conditions in a single tertiary center. Our study brings additional relevant data to the previous published RCTs, since we focused on a population that was long-term treated with innovator infliximab, we considered diseases that were not included in these trials, such as IBD and uveitis, and we studied the outcome of patients re-established back on innovator infliximab after biosimilar discontinuation. The retention rate of biosimilar infliximab was 77% after a follow-up of 34 weeks in the whole cohort. The analysis of the Danbio registry provided a one-year retention rate of 84% (16). This higher rate may be related to the nature of the recruited population, with a marked difference regarding the proportion of patients with axSpA in both cohorts (35% in the Danbio registry vs. 72% in our study population). The large majority (87%) of patients followed-up in gastroenterology remained on the medication throughout the follow-up of 34 weeks. This is in line with the data from a large real-life IBD sample of 143 patients (99 CD and 44 UC), in which 97% of these patients were still under treatment after a systematic follow-up of 24 weeks (17). These data are supported by the mechanistic comparability of innovator and biosimilar infliximab, with similar

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biological activities of these two drugs in intestinal cells (18). This also may be due to the availability of fewer alternative therapies for patients with IBD, as compared to those available for patients with RA or axSpA. In the majority of patients, innovator infliximab can be switched to biosimilar infliximab without loss of efficacy. Indeed, the clinical efficacy of biosimilar infliximab for various disease activity measures was equivalent to that of innovator infliximab, as well as infliximab through levels, supporting data from formally conducted RCTs. These results are in line with those reported in other prospective studies performed on patients with chronic inflammatory rheumatic disorders (19) and IBD (17), in which no significant changes were detected regarding efficacy and infliximab through levels. Our data are also in line with the results of the NOR-SWITCH trial, a 52-week randomized, double-blind, non-inferiority, phase IV trial, which demonstrated that switching from innovator to biosimilar infliximab in patients with chronic inflammatory conditions was not inferior to continued treatment with innovator infliximab (20). It is noteworthy that we used the same disease-specific composite measures as the NOR-SWITCH study. However, the data were analysed differently in both studies: we analysed the different disease activity indices as continuous variables in our study, whereas the NOR-SWITCH study assessed the proportion of patients with disease worsening, which was defined by predefined changes from baseline in the different composite measures. Biosimilar discontinuation was observed in 59/260 patients (23%) and no clinical or biological factors were independently associated with biosimilar discontinuation. The majority (80%) of biosimilar infliximab discontinuations in our cohort were related to patient’s experienced inefficacy. It mainly concerned patients with axSpA due to a subjective significant increase in patient-reported outcome measures, including BASDAI or ASDAS scores, which is possibly explained by suggestion or attribution effects rather than

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pharmacological differences. This is sustained by the stability of infliximab through levels and other objective measures (e.g. CRP and swollen joints) over time. In addition, subjective disease activity measures were markedly improved after that patients were re-established back to innovator infliximab, supporting suggestion effects. This is supported by a recent study assessing patient acceptance of infliximab biosimilars in chronic rheumatic disorders across Germany, which demonstrates that there is some reluctance from patients to accept biosimilars. This highlights the importance of patient and physician communication and the need to educate patients who are unsure to allow them to be involved in decision-making (21). Indeed, incorporating the patients' perspective is now considered an essential feature in outcomes research, since patient reported outcome measures could provide important perspectives, not captured by the clinical response criteria based on the physician’s perspective, with the potential of better informing treatment decisions in clinical practice. A low number of adverse events were registered during follow-up (5 safety issues leading to treatment discontinuation). No serious infection was observed. This is consistent with available data that suggest the long-term safety of TNF-α inhibitors (22-26). Acute infusion reaction to infliximab was observed only in a single patient, which could be explained by the long duration of infliximab use in the study population (mean of 6 years) and the fact that most adverse reactions are observed during induction or the first year of treatment (27). There are several strengths to our study, including its sample size, a follow-up of more than 8 months, the close collaboration between Rheumatology, Gastro-Enterology and Internal Medicine departments, no patient exclusion from switching, determination of infliximab trough levels, and a well characterized study sample, systematically assessed in a tertiary center with high experience of the care of patients with chronic inflammatory disorders. However, limitations of this study should also be considered when interpreting the findings,

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in particular the absence of a control group and the low number of patients with uveitis, which did not allow us to perform specific analyses in this subgroup. We also acknowledge the relative merits of using a global disease activity score, which has not been formerly validated yet, but allowed us to combine very different individual disease activity measures into a single score. Patients were all correctly controlled with innovator infliximab before the switch. Therefore, our results may not be extrapolated to a random population of patients who receive biosimilar infliximab or who are inadequately managed with innovator infliximab. In conclusion, our results confirm effectiveness of biosimilar infliximab with no major safety issues in a clinical practice setting. This work supports the adoption of switching from reference infliximab to biosimilar infliximab by scientific societies and Health providers in France. Further studies with larger samples of patients and potentially focusing on the costeffectiveness of systematic switch to biosimilars should be conducted to confirm our findings.

Acknowledgements: Gerturde TOUANGA NGOTI and Clotilde SIMON, Unité de Recherche Clinique Cochin/Necker

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Table 1: Study population at inclusion RHEUMATOLOGY Global population N=260

RA n=31

axSpA n=131

GASTROENTEROLOGY

INTERNAL MEDICINE

Other rheumatic diseases n=20

Crohn’s disease n=41

Ulcerative Colitis n=23

Uveitis n=8

Other n=6

Age (years), mean (SD)

47 (15)

61 (13)

49 (12)

55 (20)

38 (12)

38 (14)

34 (7)

35 (24)

Gender (male), n (%)

143 (55)

4 (13)

9 (45)

23 (56)

12 (52)

4 (50)

1 (17)

BMI (kg/m2), mean (SD)

26.2 (5.5)

27.9 (7.9)

90 (69) 26.1 (4.8)

26.3 (3.1)

No data

No data

21.2 (2.6)

25.0 (8.6)

15 (11)

20 (12)

15 (14)

11 (8)

10 (9)

6 (4)

1.0 (1.1)

1.4 (0.7) 15 (48)

0.9 (0.8)

0.6 (1.2)

0.6 (0.8)

6 (30)

2 (5)

4 (14)

0.4 (0.7) 8 (100)

17 (15) 1.0 (1.5) 3 (50)

1.2 (2.3)

1.2 (6.4)

5.5 (15.2)

5 (25)

0 (0)

0 (0)

11.0 (11.9) 0 (0)

3.5 (4.0) 1 (17)

18 (90)

24 (59)

9 (38)

6 (75)

3 (50)

1.0 (1.9)

0.2 (0.5)

0.1 (0.2)

0.0 (0.0)

0.5 (1.2)

Disease duration (years), mean (SD) Charlson Comorbidity score, mean (SD) Corticosteroid treatment, n (%)

47 (18)

Prednisone equivalent dose (mg), mean (SD) NSAID intake last 7 days, n (%) csDMARD, n (%)

1.6 (5.9)

Number of biologics before Infliximab, mean (SD)

16 (10) 1.2 (1.9) 9 (7)

38 (15)

2.3 (2.5) 4 (13)

141 (54)

27 (87)

0.5 (1.0)

0.3 (0.8)

0.4 (1.5) 28 (21) 54 (41) 0.7 (1.0)

51 63 6 4 5 4 3 0 1 5

3 0 0 1 2 1 2 0 0 2

39 44 5 2 0 1 0 0 0 1

7 5 1 1 2 2 1 0 1 2

1 8 0 0 0 0 0 0 0 0

0 5 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0

1 1 0 0 1 0 0 0 0 0

Time on treatment (years) with innovator infliximab, mean (SD)

5.8 (4.9)

7.4 (5.5)

6.7 (5.0)

5.3 (5.1)

4.7 (4.0)

3.1 (2.7)

2.9 (3.3)

5.0 (5.3)

Number of infusions of innovator infliximab, mean (SD)

36.5 (27.8)

46.0 (38.9)

41.0 (27.3)

28.6 (21.0)

32.5 (24.8)

21.5 (15.5)

23.0 (18.3)

27.4 (21.2)

8.9

8.9

8.6

8.7

10.8

8.4

6.1

7.2

Etanercept, n Adalimumab, n Golimumab, n Certolizumab n Abatacept, n Tocilizumab, n Anakinra, n Rituximab, n Usketinumab, n Other, n

Time since last

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infusion of innovator infliximab (weeks), mean (SD)

(4.1)

(3.6)

(2.9)

(2.4)

(7.5)

(1.8)

(2.1)

(2.2)

Dosage of last innovator infliximab infusion (mg), mean (SD)

409 (154)

327 (149)

400 (94)

391 (78)

524 (250)

427 (176)

312 (58)

310 (107)

Usual inter-dose interval (weeks), mean (SD)

7.9 (1.8)

8.3 (1.7)

8.0 (2.0)

8.1 (2.0)

7.9 (1.3)

8.1 (1.3)

5.3 (1.4)

7.2 (1.8)

Table 2: Changes of clinical and biological parameters evaluating disease activity between baseline and the last visit Parameter, mean (SD)

Global disease activity score (0-10)

Parameter, mean (SD) DAS28 Number of swollen joints Number of tender joints Disease activity global (0-10) ESR (mm/h) CRP (mg/L)

Parameter, mean (SD) ASDAS BASDAI Fatigue (0-100) Axial pain (0-100) Peripheral pain (0-100) Enthesitic pain (0-100) Stiffness intensity (0100) Stiffness duration (0100) Disease activity global (0-100) CRP (mg/L) Uveitis flares since last visit

Parameter, mean (SD)

GLOBAL POPULATION Third to last (TTL) Baseline visit* innovator infusion (n=260) (n=260) Switch Pre-swith 1.68 (1.40) 1.69 (1.47)

RHEUMATOID ARTHRITIS TTL innovator infusion Baseline visit* (n=31) (n=31) 3.55 (1.32) 3.38 (1.16) 2.19 (5.31) 2.87 (5.46)

Last visit** (n=201) Post-switch

Pvalue***

1.67 (1.32)

0.442

Last visit** (n=24) 3.08 (1.08) 2.16 (4.80)

Pvalue*** 0.217 0.409

1.29 (2.52) 3.21 (2.69)

1.68 (2.62) 3.14 (2.28)

1.70 (3.29) 3.52 (2.41)

0.342 0.055

19.04 (10.69) 5.95 (6.06)

23.66 (13.39) 5.72 (4.64)

19.83 (14.19) 6.52 (11.32)

0.278 0.290

Last visit** (n=95) 1.99 (1.08) 3.18 (2.22) 44.82 (28.35) 36.01 (27.31) 21.20 (24.75) 27.01 (27.84) 27.67 (25.50)

Pvalue*** 0.022 0.046 0.014 0.002 0.483 0.027 0.022

AXIAL SPONDYLOARTHRITIS TTL innovator infusion Baseline visit* (n=131) 1.70 (0.82) 1.79 (0.90) 2.83 (2.02) 2.94 (2.20) 42.46 (28.52) 41.14 (28.41) 28.88 (23.58) 29.48 (26.99) 18.79 (21.97) 19.87 (24.23) 23.34 (26.63) 23.19 (27.58) 23.62 (23.26) 23.28 (25.24) 19.70 (22.88)

20.60 (24.26)

23.38 (25.52)

0.194

29.57 (22.75)

29.67 (21.95)

35.77 (26.45)

0.002

5.98 (11.14) 0.01 (0.12)

4.44 (6.69) 0.01 (0.12)

5.03 (8.26) 0.01 (0.12)

0.271 1.000

Last visit** (n=32)

Pvalue***

CROHN’S DISEASE TTL innovator infusion Baseline visit* (n=41)

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Harvey Bradshaw index

Parameter, mean (SD) Partial Mayo Score

Parameter, mean (SD) Disease activity score (010)

0.93 (2.27)

0.83 (2.10)

0.56 (1.48)

0.397

ULCERATIVE COLITIS TTL innovator infusion Baseline visit* (n=23) 0.52 (1.29) 0.71 (1.31)

Last visit** (n=23) 0.33 (0.66)

Pvalue*** 0.218

UVEITIS TTL innovator infusion Baseline visit* (n=8) 2.00 (3.07) 2.50 (4.11)

Last visit** (n=6) 1.12 (2.10)

Pvalue*** 0.485

* Baseline visit: first infusion of biosimilar infliximab ** Patients still on biosimilar infliximab at the last visit *** Comparison between values from last (post-switch) and baseline (switch) visit Table 3: Changes of infliximab trough level between baseline and the last visit INFLIXIMAB PLASMA LEVEL (g/ml), mean (SD) GLOBAL POPULATION Baseline visit (n=260) 5.81 (5.70)

Last visit* (n=201) 6.23 (5.77)

P-value 0.091

RHEUMATOID ARTHRITIS Baseline visit (n=31) 3.70 (5.36)

Last visit* (n=24) 3.21 (4.35)

P-value 0.552

AXIAL SPONDYLOARTHRITIS Baseline visit (n=131) 5.88 (5.82)

Last visit* (n=95) 5.70 (5.42)

P-value 0.617

CROHN DISEASE Baseline visit (n=41) 5.56 (4.99)

Last visit* (n=32) 6.45 (5.42)

P-value 0.0461

ULCERATIVE COLITIS Baseline visit (n=23) 6.56 (6.21)

Last visit* (n=23) 9.40 (7.37)

P-value 0.165

UVEITIS Baseline visit (n=8) 10.30 (6.24)

Last visit* (n=6) 12.86 (6.77)

P-value 0.478

* Patients still on biosimilar infliximab at the last visit

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Table 4: Changes of clinical and biological parameters evaluating disease activity between baseline and the last visit for patient re-established back with innovator infliximab Parameter, mean (SD) Infliximab plasma level (g/ml), mean (SD)

Parameter, mean (SD) DAS28 Number of swollen joints Number of tender joints Disease activity global ESR (mm/h) CRP (mg/L)

Parameter, mean (SD) ASDAS BASDAI Fatigue (0-100) Axial pain (0-100) Peripheral pain (0-100) Enthesitic pain (0-100) Stiffness intensity (0-100) Stiffness duration (0-100) Disease activity global (0-100) CRP (mg/L) Uveitis flares since last visit

GLOBAL POPULATION (n=47) Baseline visit * Last visit** 6.28 (3.81) 5.53 (3.81)

P-value 0.342

RHEUMATOID ARTHRITIS (n=5) Baseline visit * Last visit** 3.58 (1.71) 3.20 (0.67) 6.50 (11.09) 5.80 (11.48) 2.50 (2.64) 2.00 (2.12) 65.00 (17.32) 54.00 (28.81) 9.50 (5.07) 10.60 (7.44) 2.47 (1.71) 3.20 (2.47)

P-value 0.656 0.924 0.750 0.072 0.792 0.602

AXIAL SPONDYLOARTHRITIS (n=33) Baseline visit * Last visit**

2.42 (0.92) 4.21 (2.07) 57.06 (36.99) 47.33 (29.81) 30.14 (24.42) 34.64 (29.64) 28.71 (28.19) 32.19 (33.16) 58.82 (23.42) 5.42 (10.91) 0.06 (0.24)

2.02 (1.17) 2.98 (2.13) 49.54 (28.90) 35.64 (27.03) 21.11 (23.17) 27.54 (27.51) 27.11 (28.11) 23.19 (27.48) 34.06 (22.47) 6.82 (10.18) 0.00 (0.00)

P-value 0.041 0.012 0.081 0.034 0.028 0.117 0.718 0.072 <0.001 0.592 0.163

* Baseline visit: first infusion of innovator infliximab since biosimilar discontinuation ** Patients still on innovator infliximab at the last visit Figure legends: Figure 1: Flow chart of the study Figure 2: Estimation of the retention rate of biosimilar infliximab by Kaplan Meier survival curve

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