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ObjectiveTo demonstrate pharmacokinetic equivalence of CT-P10 and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA) with inadequate responses or intolerances to antitumour necrosis factor agents.MethodsIn this randomised phase I trial, patients with active RA were randomly assigned (2:1) to receive 1000 mg CT-P10 or RTX at weeks 0 and 2 (alongside continued methotrexate therapy). Primary endpoints were area under the serum concentration–time curve from time zero to last quantifiable concentration (AUC0–last) and maximum serum concentration after second infusion (Cmax). Additional pharmacokinetic parameters, efficacy, pharmacodynamics, immunogenicity and safety were also assessed. Data are reported up to week 24.Results103 patients were assigned to CT-P10 and 51 to RTX. The 90% CIs for the ratio of geometric means (CT-P10/RTX) for both primary endpoints were within the bioequivalence range of 80%–125% (AUC0–last: 97.7% (90% CI 89.2% to 107.0%); Cmax: 97.6% (90% CI 92.0% to 103.5%)). Pharmacodynamics and efficacy were comparable between groups. Antidrug antibodies were detected in 17.6% of patients in each group at week 24. CT-P10 and RTX displayed similar safety profiles.ConclusionsCT-P10 and RTX demonstrated equivalent pharmacokinetics and comparable efficacy, pharmacodynamics, immunogenicity and safety.Trial registration numberNCT01534884.

ObjectivesTo assess the efficacy and safety of switching from the infliximab reference product (RP; Remicade) to its biosimilar CT-P13 (Remsima, Inflectra) or continuing CT-P13 in patients with rheumatoid arthritis (RA) for an additional six infusions.MethodsThis open-label extension study recruited patients with RA who had completed the 54-week, randomised, parallel-group study comparing CT-P13 with RP (PLANETRA;NCT01217086). CT-P13 (3 mg/kg) was administered intravenously every 8 weeks from weeks 62 to 102. All patients received concomitant methotrexate. Endpoints included American College of Rheumatology 20% (ACR20) response, ACR50, ACR70, immunogenicity and safety. Data were analysed for patients who received CT-P13 for 102 weeks (maintenance group) and for those who received RP for 54 weeks and then switched to CT-P13 (switch group).ResultsOverall, 302 of 455 patients who completed the PLANETRA study enrolled into the extension. Of these, 158 had received CT-P13 (maintenance group) and 144 RP (switch group). Response rates at week 102 for maintenance versus switch groups, respectively, were 71.7% vs 71.8% for ACR20, 48.0% vs 51.4% for ACR50 and 24.3% vs 26.1% for ACR70. The proportion of patients with antidrug antibodies was comparable between groups (week 102: 40.3% vs 44.8%, respectively). Treatment-emergent adverse events occurred in similar proportions of patients in the two groups during the extension study (53.5% and 53.8%, respectively).ConclusionsComparable efficacy and tolerability were observed in patients who switched from RP to its biosimilar CT-P13 for an additional year and in those who had long-term CT-P13 treatment for 2 years.Trial registration numberNCT01571219; Results.

Objectives To compare the efficacy and safety of innovator infliximab (INX) and CT-P13, an INX biosimilar, in active rheumatoid arthritis patients with inadequate response to methotrexate (MTX) treatment. Methods Phase III randomised, double-blind, multicentre, multinational, parallel-group study. Patients with active disease despite MTX (12.5–25 mg/week) were randomised to receive 3 mg/kg of CT-P13 (n=302) or INX (n=304) with MTX and folic acid. The primary endpoint was the American College of Rheumatology 20% (ACR20) response at week 30. Therapeutic equivalence of clinical response according to ACR20 criteria was concluded if the 95% CI for the treatment difference was within ±15%. Secondary endpoints included ACR response criteria, European League Against Rheumatism (EULAR) response criteria, change in Disease Activity Score 28 (DAS28), Medical Outcomes Study Short-Form Health Survey (SF-36), Simplified Disease Activity Index, Clinical Disease Activity Index, as well as pharmacokinetic (PK) and pharmacodynamic (PD) parameters, safety and immunogenicity. Results At week 30, ACR20 responses were 60.9% for CT-P13 and 58.6% for INX (95% CI −6% to 10%) in the intention-to-treat population. The proportions in CT-P13 and INX groups achieving good or moderate EULAR responses (C reactive protein (CRP)) at week 30 were 85.8% and 87.1%, respectively. Low disease activity or remission according to DAS28–CRP, ACR–EULAR remission rates, ACR50/ACR70 responses and all other PK and PD endpoints were highly similar at week 30. Incidence of drug-related adverse events (35.2% vs 35.9%) and detection of antidrug antibodies (48.4% vs 48.2%) were highly similar for CT-P13 and INX, respectively. Conclusions CT-P13 demonstrated equivalent efficacy to INX at week 30, with a comparable PK profile and immunogenicity. CT-P13 was well tolerated, with a safety profile comparable with that of INX. ClinicalTrials.gov Identifier NCT01217086

Objectives To compare the pharmacokinetics (PK), safety and efficacy of innovator infliximab (INX) and CT-P13, a biosimilar to INX, in patients with active ankylosing spondylitis (AS). Methods Phase 1 randomised, double-blind, multicentre, multinational, parallel-group study. Patients were randomised to receive 5 mg/kg of CT-P13 (n=125) or INX (n=125). Primary endpoints were area under the concentration-time curve (AUC) at steady state and observed maximum steady state serum concentration (C max,ss ) between weeks 22 and 30. Additional PK, efficacy endpoints, including 20% and 40% improvement response according to Assessment in Ankylosing Spondylitis International Working Group criteria (ASAS20 and ASAS40), and safety outcomes were also assessed. Results Geometric mean AUC was 32 765.8 μgh/ml for CT-P13 and 31 359.3 μgh/ml for INX. Geometric mean C max,ss was 147.0 μg/ml for CT-P13 and 144.8 μg/ml for INX. The ratio of geometric means was 104.5% (90% CI 94% to 116%) for AUC and 101.5% (90% CI 95% to 109%) for C max,ss . ASAS20 and ASAS40 responses at week 30 were 70.5% and 51.8% for CT-P13 and 72.4% and 47.4% for INX, respectively. In the CT-P13 and INX groups more than one adverse event occurred in 64.8% and 63.9% of patients, infusion reactions occurred in 3.9% and 4.9%, active tuberculosis occurred in 1.6% and 0.8%, and 27.4% and 22.5% of patients tested positive for anti-drug antibodies, respectively. Conclusions The PK profiles of CT-P13 and INX were equivalent in patients with active AS. CT-P13 was well tolerated, with an efficacy and safety profile comparable to that of INX up to week 30.

ObjectivesTo investigate the efficacy and safety of switching from infliximab reference product (RP) to its biosimilar or maintaining biosimilar treatment in patients with ankylosing spondylitis (AS).MethodsThis open-label extension study recruited patients with AS who completed a 54-week, randomised controlled study comparing CT-P13 with RP (PLANETAS). CT-P13 (5 mg/kg) was administered intravenously every 8 weeks from week 62 to week 102. Efficacy end points included the proportion of patients achieving Assessment of SpondyloArthritis international Society (ASAS)20. Antidrug antibodies (ADAs) were measured using an electrochemiluminescent method. Data were analysed for patients treated with CT-P13 in the main PLANETAS study and the extension (maintenance group) and those who were switched to CT-P13 during the extension study (switch group).ResultsOverall, 174 (82.9%) of 210 patients who completed the first 54 weeks of PLANETAS and agreed to participate in the extension were enrolled. Among these, 88 were maintained on CT-P13 and 86 were switched to CT-P13 from RP. In these maintenance and switch groups, respectively, ASAS20 response rates at week 102 were 80.7% and 76.9%. ASAS40 and ASAS partial remission were also similar between groups. ADA positivity rates were comparable (week 102: 23.3% vs 27.4%). Adverse events led to treatment discontinuation during the extension study in 3 (3.3%) and 4 (4.8%) patients, respectively.ConclusionsThis is the first study to show that switching from RP to its biosimilar CT-P13 is possible without negative effects on safety or efficacy in patients with AS. In the maintenance group, CT-P13 was effective and well tolerated over 2 years of treatment.Trial registration numberNCT01571206; Results.

Background Infliximab, a chimeric anti-TNF antibody, is well known to potentially induce anti-drug-antibodies (ADA), which may result in loss of efficacy and cause side effects such as infusion reactions. However, it is not well known which factors affect ADA formation. Objectives A retrospective analysis for factors related to immunogenicity was performed using the data sets of two recent randomized controlled trials documenting biosimilarity between innovator infliximab (INX) and CT-P13 (PLANETRA and PLANETAS). Methods A total of 852 patients (602 patients with rheumatoid arthritis (RA) in PLANETRA and 250 patients with ankylosing spondylitis (AS) in PLANETAS) were treated with either 3mg/kg (RA) or 5mg/kg (AS) of CT-P13 or INX. ADA assessment was performed at weeks 14, 30 and 54. The determination of ADA utilized an electrochemiluminiscence assay (ECLA, MSD, Rockville, Maryland, USA). Age, gender and race as intrinsic factors and methotrexate (MTX) or glucocorticoid (GC) as extrinsic factors were analyzed with a logistic regression. Results The immunogenicity results were overall similar between CT-P13 and INX during the study period in both trials whilst there was a noticeable difference between patients with RA and AS (1). In PLANETRA, gender, race, GC and MTX did not impact on ADA positive rate but the impact of age was statistically significant (Table 1). In PLANETAS, none of age, gender, race or GC had impact on ADA positive rate (Table 1). The interactions between treatment and each factor showed that the effect of factors (age, gender, race, GC and MTX) on ADA development was not statistically different between CT-P13 and INX. Conclusions On the basis of similar immunogenicity between CT-P13 and INX in AS and RA patients, we only found age as an influencing factor in patients with RA. This finding may be related to the immunosenecence in the elderly. Furthermore, no influence by medication was detected: neither GC nor MTX seemed to have an impact on ADA formation in these two trials. References Jurgen Braun et al., Striking Discrepancy in the Development of Anti-Drug Antibodies (ADA) in Patients with Rheumatoid Arthritis (RA) and Ankylosing Spondylitis (AS) in Response to Infliximab (INF) and Its Biosimilar CT-P13, ACR 2014 Disclosure of Interest J. Braun Grant/research support from: CELLTRION, Inc., Consultant for: CELLTRION, Inc., Speakers bureau: CELLTRION, Inc., W. Park Grant/research support from: CELLTRION, Inc., Consultant for: CELLTRION, Inc., Speakers bureau: CELLTRION, Inc., D. H. Yoo Grant/research support from: CELLTRION, Inc., Consultant for: CELLTRION, Inc., Speakers bureau: CELLTRION, Inc., C. H. Suh Grant/research support from: CELLTRION, Inc., Consultant for: CELLTRION, Inc., S. C. Shim Grant/research support from: CELLTRION, Inc., Consultant for: CELLTRION, Inc., S. J. Lee Employee of: CELLTRION, Inc., S. Y. Lee Employee of: CELLTRION, Inc., J. H. Yun Employee of: CELLTRION, Inc., S. Y. Kim Employee of: CELLTRION, Inc., S. M. Lee Employee of: CELLTRION, Inc.

Background CT-P13 is a biosimilar to innovator infliximab (INX) approved by the European Medicines Agency. From the PLANETRA, which is randomized, double-blind, active-controlled trial to assess efficacy and safety of CT-P13 in rheumatoid arthritis (RA) patients, therapeutic equivalence was demonstrated via the primary endpoint (ACR20 at Week30) 1 . Several secondary endpoints exist that can capture valuable information to the clinician. Objectives To compare efficacy via the DAS28, CDAI, and SDAI of CT-P13 and INX in patients with RA and effect of anti-drug antibody (ADA) on the clinical outcome measures. Methods In PLANETRA, 606 patients with RA were treated with either 3 mg/kg of CT-P13 or INX with methotrexate at usual schedule up to Week 54. Key secondary endpoints were CDAI, SDAI, and DAS28. ADA was measured at baseline and at Week 14, 30 and 54 by an electrochemiluminescent assay. Results The mean baseline DAS28 scores reflected high disease activity (DAS28-ESR, 6.7 vs 6.6; DAS28-CRP, 5.9 vs 5.8; CT-P13 vs INX). The mean change in DAS28-ESR over 54 weeks was -2.4 in both treatment groups. The baseline CDAI and SDAI scores were similar between treatment groups (mean CDAI, 40.7 vs 39.6; SDAI, 42.4 vs 41.4; CT-P13 vs INX, respectively). At week 54, CDAI decreased by -25.7 and -24.0 and SDAI decreased by -26.3 and -24.6 in the CT-P13 and INX groups, respectively. Statistically significant difference between groups was not shown in these assessments. The proportion of patients who become ADA positive was comparable between CT-P13 (52.3%) and INX (49.5%). More improvement on DAS28-ESR was shown in ADA negative subgroup than in ADA positive subgroup at Week 54, similarly in both treatment groups (CT-P13, -2.8 vs -2.1; INX, -2.7 vs -2.0). SDAI score decreased more in ADA negative subgroup than ADA positive subgroup up to Week 54 (CT-P13, -28.5 vs -24.3; INX, -26.7 vs -22.3). Similar trends were found in DAS28-CRP and CDAI at Week 54 (p 0.05), but different between ADA subgroups over time within each treatment group (p Conclusions These results demonstrate the efficacy of CT-P13 which is comparable to that of INX, based on various clinical outcome measures. The ADA development could diminish the clinical response achieved by infliximab, and the magnitude of influence was similar in both CT-P13 and INX treatment groups throughout the study. References Yoo D.H., et al. Ann Rheum Dis 2013;72:1613-20. Disclosure of Interest : D.-H. Yoo Grant/research support: CELLTRION, Inc., Consultant for: CELLTRION, Inc., Speakers bureau: CELLTRION, Inc., W. Park Grant/research support: CELLTRION, Inc., Consultant for: CELLTRION, Inc., Speakers bureau: CELLTRION, Inc., M. Brzosko Grant/research support: CELLTRION, Inc., P. Geher: None declared, D. Andersone Grant/research support: CELLTRION, Inc., J. Jaworski Grant/research support: CELLTRION, Inc., D. Rekalov Grant/research support: CELLTRION, Inc., B. Oparanov Grant/research support: CELLTRION, Inc., R. Kausiene Grant/research support: CELLTRION, Inc., C. Pacheco-Tena Grant/research support: CELLTRION, Inc., S. Lee Employee of: CELLTRION, Inc. DOI 10.1136/annrheumdis-2014-eular.3707

Background CT-P13 is a biosimilar product of infliximab (INX). Data up to week 30 has been reported at EULAR 2012.1 Objectives To compare the efficacy and safety of CT-P13 and INX in active rheumatoid arthritis (RA) patients up to week 54. Methods Patients with active RA (1987 ACR criteria) and inadequate response to methotrexate (MTX) were randomised (1:1) to receive either CT-P13 (3mg/kg) or INX (3mg/kg) at weeks 0, 2, 6 and then every 8 weeks up to week 54 in combination with MTX (12.5–25mg/week). Results Of 606 patients randomised at baseline, 457 patients were treated up to week 54. At week 54, ACR20 was highly similar between groups (CT-P13, 57.0% [172/302]; INX, 52.0% [158/304]; 95% CI: -0.03–0.13). ACR50 and ACR70 scores were also comparable between groups (CT-P13, 33.1% and 16.2%; INX, 31.6% and 15.1%, respectively). In the CT-P13 and INX groups respectively, 26.4% and 27.8% of patients reached remission with DAS28-CRP; additionally, 14.3% and 14.8% reached low disease activity compared to approximately 80% high disease activity in both groups at baseline. The proportion of patients testing positive for anti-drug antibodies (ADAs) was comparable between CT-P13 (52.3%) and INX (49.5%). More patients with negative ADA results achieved ACR20 responses (CT-P13, 73.9%; INX, 67.2%) compared with patients with positive results (CT-P13, 53.2%; INX, 48.1%). Total Sharp scores at baseline and week 54 were comparable (CT-P13, 104.6 and 70.4; INX, 103.6 and 73.0). Cmax of CT-P13 or INX at all doses ranged from 66.1µg/mL–112.2µg/mL and 60.3µg/mL–104.5µg/mL, respectively. The safety profiles of CT-P13 and INX were also comparable (table). Conclusions CT-P13 showed comparable efficacy and PKs to those of INX up to week 54. CT-P13 was well tolerated with a safety profile comparable to that of INX up to week 54. References Yoo D et al. A randomized, double-blind, phase 3 study demonstrates clinical equivalence of CT-P13 to infliximab when co-administered with methotrexate in patients with active rheumatoid arthritis. Ann Rheum Dis 2012;71(Suppl 3):359. Disclosure of Interest D. H. Yoo Consultant for: CELLTRION Inc., A. Racewicz Grant/research support from: CELLTRION Inc., J. Brzezicki Grant/research support from: CELLTRION Inc., R. Yatsyshyn Grant/research support from: CELLTRION Inc., E. Tobias Arteaga Grant/research support from: CELLTRION Inc., A. Baranauskaite Grant/research support from: CELLTRION Inc., C. Abud-Mendoza Grant/research support from: CELLTRION Inc., S. Navarra Grant/research support from: CELLTRION Inc., Consultant for: Pfizer Ltd., Speakers bureau: CELLTRION Inc., R. Eullaran Grant/research support from: CELLTRION Inc., V. Kadinov Grant/research support from: CELLTRION Inc., I. Goecke Sariego Grant/research support from: CELLTRION Inc., P. Byrne Grant/research support from: CELLTRION Inc., W. Park Consultant for: CELLTRION Inc., S. J. Lee Consultant for: CELLTRION Inc., Employee of: CELLTRION Inc., H. U. Kim Employee of: CELLTRION Inc., U. Muller-Ladner Speakers bureau: CELLTRION Inc.

Background CT-P13 was developed as a biosimilar product to infliximab (Remicade®), a chimeric monoclonal antibody approved in the European Union in 1999 for the treatment of rheumatoid arthritis (RA), ankylosing spondylitis, Crohn’s disease, ulcerative colitis, psoriasis, and psoriatic arthritis. Objectives To compare the clinical efficacy and overall safety of CT-P13 with those of infliximab in patients with active RA. Methods Six hundred six patients with active RA despite previous treatment with disease-modifying anti-rheumatic drugs including methotrexate were randomized 1:1 to receive either CT-P13 or infliximab (3 mg/kg, 2-hour IV infusion per dose) plus methotrexate and folic acid. The treatment period consisted of a dose-loading phase (weeks 0, 2, and 6) and a maintenance phase (weeks 14, 22, and 30). The primary endpoint was the proportion of patients achieving 20% improvement in ACR20 at week 30. The exact binomial test with 95% confidence intervals (CIs) for ACR20 within a margin of ±15% was used to define equivalence between the 2 treatments. Secondary efficacy and safety endpoints (including ACR50/70; frequency of adverse events [AEs]) were also evaluated. This report presents results up to study week 30 (as approved by the European Medicines Agency). Results At week 30, ACR20 response rates were 60.9% for CT-P13 vs 58.6% for infliximab (2% difference; 95% CI -6% to 10%) in the intent-to-treat population, and 73.4% vs 69.7% (4% difference; 95% CI: -4% to 12%) in the per-protocol population. Outcomes for the secondary efficacy and safety endpoints were also comparable as follows. ACR50 rates in the per-protocol population were 42.3% vs 40.6% (2% difference; 95% CI -7% to 10%), and ACR70 rates were 20.2% vs 17.9% (2% difference; 95% CI -5% to 9%) in the CT-P13 and infliximab arms, respectively, all indicating equivalence in clinical efficacy at week 30. AEs considered by the investigators to be related to study treatment were reported for 106 (35.2%) patients and 108 (35.9%) patients in the CT-P13 and infliximab arms, respectively. Related AEs due to infection were reported in 46 (15.3%) patients and 51 (16.9%) patients in the CT-P13 and infliximab arms, respectively. 15 (5%) CT-P13-treated and 17 (6%) infliximab-treated patients experienced at least 1 infusion reaction. Tuberculosis was reported in 3 patients in the CT-P13 arm and in 1 patient in the infliximab arm. Conclusions CT-P13 and infliximab are equivalent in terms of ACR20 in patients with RA. In addition, CT-P13 was well tolerated, with an efficacy and safety profile comparable to that of infliximab up to week 30. Disclosure of Interest D. Yoo: None Declared, P. Miranda: None Declared, M. Piotrowski: None Declared, E. Ramiterre: None Declared, V. Kovalenko: None Declared, N. Prodanovic: None Declared, M. Tee: None Declared, S. Gutierrez-Urena: None Declared, R. Jimenez: None Declared, O. Zamani: None Declared, S. Lee: None Declared, H. Kim Employee of: Celltrion, W. Park: None Declared, U. Muller-Ladner: None Declared