D.-H. Yoo

Characteristics for electrocatalytic properties and hydrogen–oxygen adsorption of platinum ternary alloy catalysts in polymer electrolyte fuel cell

Abstract The correlation of crystal structure with catalytic activity of Pt ternary alloys prepared by alloying the Pt–Fe alloy with transition metals, using an electrochemical method in a polymer electrolyte fuel cell was investigated. The electrode prepared by Pt alloy catalysts showed higher cell performance than unalloyed Pt. The plots on the correlation of the lattice parameter with specific activity showed volcanic type behavior. The surface area of weakly bonded hydrogen decreased with a decreasing lattice parameter but at a certain point, it increased again. However, the surface area of strongly bonded hydrogen was constant regardless of the variation of the lattice parameter. The specific activity of Pt alloys increased with a decreasing the surface area of weakly bonded hydrogen, but was independent of the surface area of strongly bonded hydrogen. Also, the specific activity increased with a decreasing oxide reduction area but increasing oxide reduction potential. The cell performance of Pt alloy catalysts improved according to alloying with transition metals because the ratio of surface area of strongly bonded hydrogen to total surface area on the Pt surface increased.

THU0158 Inhibition of Radiographic Progression and Its Association with Clinical Parameters in RA Patients Treated with CT-P13 and Innovator Infliximab in PLANETRA Study

Background CT-P13 is a biosimilar of innovator infliximab (INX), approved by the European Medicines Agency in 2013. Clinical data up to 1 year from PLANETRA have been reported at EULAR 20131 Objectives To compare the radiographic progression between CT-P13 and INX treatment and to assess its association with anti-drug antibody (ADA) and clinical disease activity in active rheumatoid arthritis (RA) patients, who participated in the PLANETRA study. Methods Radiographs obtained at baseline and week 54 were evaluated with the “paired review” method and the evaluation was performed by two independent readers without knowing the time point of the radiographs. The individual component scores of the joint damage progression (JDP) were calculated according to the van der Heijde modification of the Sharp scoring system. The analysis was performed to demonstrate comparability in JDP between two treatment groups using Students t-test and elucidate an association of JDP with ADA and clinical parameters such as ACR20, IgM rheumatoid factor (RF), and anti-CCP. Results Among the 606 patients, 336 patients had radiographs both at baseline and week 54. The mean change from baseline JDP was similar between CT-P13 and INX treatment groups with respect to total Sharp score (TSS), joint space narrowing (JSN) score and erosion score at week 54 (CT-P13, 1.0/0.4/0.7; INX, 0.6/0.7/0.0, respectively). At week 54, a higher progression of TSS could be observed in the ADA positive patients (CT-P13, 1.1; INX, 1.2) compared with the ADA negative patients (CT-P13, 0.9; INX, 0.0), but the scores were comparable between two groups. The ACR20 responders tended to show a similar progression of TSS between two treatment groups (CT-P13, 0.6; INX, 0.5) at week 54. The mean change of TSS in ACR20 non-responders from baseline to week 54 were also comparable between the two treatment groups (CT-P13, 2.0; INX, 0.9). ACR20 responders showed less progression of TSS compared with non-responders in both treatment groups but these results were statistically not significant with respect to response status and treatment groups. At week 54, the progression of TSS was similar between treatment groups for each of the negative and positive baseline IgM RF subgroups (CT-P13, -0.5/1.4; INX, -0.2/0.7, respectively). The patients who belong to the negative and positive baseline anti-CCP subgroups showed also a comparable radiographic progression between treatment groups (CT-P13, 0.5/1.0; INX, 0.2/0.7, respectively). In both CT-P13 and INX, there was less progression of TSS in the patients who had negative baseline IgM RF or anti-CCP but the changes were statistically not significant. Conclusions Patients treated with CT-P13 showed a comparable radiographic progression as compared to those treated with INX at week 54. The ADA and clinical parameters such as ACR20, IgM RF, and anti-CCP showed tendency of association with radiographic progression. References Yoo DH, et al. Ann Rheum Dis 2013;72(S3):73 Disclosure of Interest : D. 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., P. Miranda Grant/research support: CELLTRION, Inc., M. Piotrowski Grant/research support: CELLTRION, Inc., E. Ramiterre Grant/research support: CELLTRION, Inc., S. Shevchuk Grant/research support: CELLTRION, Inc., A. Baranauskaite Grant/research support: CELLTRION, Inc., S. Lee Employee of: CELLTRION, Inc., U. Müller-Ladner Speakers bureau: CELLTRION, Inc. DOI 10.1136/annrheumdis-2014-eular.3056

FRI0119 What Intrinsic and Extrinsic Factors Affect the Developement of Anti-Drug Antibody to Innovator Infliximab and its Biosimilar CT-P13 in Rheumatoid Arthritis and Ankylosing Spondylitis

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. Table 1. Analysis on ADA results at week 30 by each clinical factors (logistic regression) Odds ratio (95% Confidence Interval) PLANETRA PLANETAS Age (continuous) 0.979 (0.964, 0.994) 1.022 (0.995, 1.050) Gender (Male, Female) 1.242 (0.788, 1.956) 0.601 (0.291, 1.243) Race (White, Other) 0.905 (0.605, 1.354) 1.488 (0.759, 2.914) GC (Yes, No) 1.053 (0.738, 1.503) 0.712 (0.339. 1.497) MTX (<15 mg/week, ≥15 mg/week) 1.164 (0.785, 1.726) – 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 Jürgen 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.

THU0159 Disease Activity Assessment Using the DAS28, CDAI and SDAI and Effect of Anti-Drug Antibody on Clinical Response in a Randomized, Double-Blind, Comparative Trial of CT-P13 and Innovator Infliximab: Planetra Study

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). No statistical differences were shown between CT-P13 and INX within the both ADA subgroups in these efficacy outcomes at Week 54. DAS28 (ESR or CRP) results were not different between two treatment groups over time in each ADA subgroup (p>0.05), but different between ADA subgroups over time within each treatment group (p<0.05). 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. Géher: 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

SAT0146 Randomised double-blind study shows comparable long-term efficacy and safety between rituximab biosimilar CT-P10 and innovator rituximab in patients with rheumatoid arthritis: 48-week results

Background In phase 1 trials (NCT01534884 and NCT01873443), pharmacokinetic equivalence of CT-P10, biosimilar of rituximab, to innovator rituximab (RTX) was demonstrated. In the phase 3 study, equivalence of PK and efficacy up to week 24 were achieved between CT-P10 and RTX (US and EU sourced)1,2. Objectives To investigate the long-term efficacy, pharmacodynamics, immunogenicity and safety of CT-P10 up to week 48. Methods Patients with rheumatoid arthritis were randomly assigned to CT-P10, US-RTX or EU-RTX, in combination with MTX. The patients received 2 treatment courses at Week 0 and 24, each consisting of 2 infusions of 1000mg study drug at 2-week interval. Results A total of 372 patients were randomised, and 330 patients completed the 2nd course treatment. DAS28 scores through Week 48 were comparable between CT-P10 and US/EU-RTX (Figure), as well as the proportion of ACR responses at Week 48 between the CT-P10 and combined rituximab groups; 81.3% and 79.8% for ACR 20, 55.4% and 53.9% for ACR50, and 31.7% and 33.7% for ACR 70, respectively.Figure 1. Efficacy Results – DAS28. B-cell depletion was comparable from after the 1st infusion and up to Week 48. Number (%) of patients with positive anti-drug antibodies in the CT-P10, US-RTX, and EU-RTX was 7 (4.9), 13 (9.4), and 5 (8.6), respectively at Week 48. The safety profile was also similar across groups (Table).Table 1. Summary of Safety Profile [n (%)] CT-P10 US-RTX EU-RTX Reference Products (US-RTX + EU-RTX) (N=161) (N=151) (N=60) (N=211) AE 122 (75.8) 96 (63.6) 37 (61.7) 133 (63.0) Serious Adverse Event 13 (8.1) 14 (9.3) 2 (3.3) 16 (7.6) Infection 61 (37.9) 53 (35.1) 17 (28.3) 70 (33.2) Serious infection 2 (1.2) 3 (2.0) 0 3 (1.4) Infusion related reaction (IRR)* 33 (20.5) 12 (7.9) 13 (21.7) 25 (11.8) Malignancy 0 2 (1.3) 1 (1.7) 3 (1.4) Progressive multifocal leukoencephalopathy 0 0 0 0 *None of IRR were serious or led to study drug discontinuation. Conclusions This phase 3 randomised controlled trial demonstrated the comparability of CT-P10 with two rituximab in terms of efficacy, pharmacodynamics, immunogenicity and safety for 1 year. References Suh CH, et al. 2016 ACR Abstract No. 1634. Yoo DH, et al. 2016 ACR Abstract No. 1635. Disclosure of Interest C.-H. Suh Consultant for: Celltrion, Inc., E. Chalouhi El Khouri Grant/research support from: Celltrion, Inc., P. Miranda Grant/research support from: Celltrion, Inc., F. F Cons Molina Grant/research support from: Celltrion, Inc., P. Shesternya Grant/research support from: Celltrion, Inc., F. Medina-Rodriguez Grant/research support from: Celltrion, Inc., P. Wiland Grant/research support from: Celltrion, Inc., S. Jeka Grant/research support from: Celltrion, Inc., J. Chavez-Corrales Grant/research support from: Celltrion, Inc., T. Linde Grant/research support from: Celltrion, Inc., P. Hrycaj Grant/research support from: Celltrion, Inc., I. Hospodarskyy Grant/research support from: Celltrion, Inc., M. Abello-Banfi Grant/research support from: Celltrion, Inc., J. Jaworski Grant/research support from: Celltrion, Inc., M. Piotrowski Grant/research support from: Celltrion, Inc., W. Park Consultant for: Celltrion, Inc., S. C. Shim Consultant for: Celltrion, Inc., S. J. Lee Employee of: Celltrion, Inc., S. Y. Lee Employee of: Celltrion, Inc., D. H. Yoo Consultant for: Celltrion, Inc.

THU0162 Comparable Time To Retreatment with CT-P10 and Innovator Rituximab up To 2 Years in Patients with Active Rheumatoid Arthritis

Background A randomised controlled trial (RCT) and its open label extension trial (OLE) demonstrated comparable pharmacokinetics (PK), efficacy and safety between CT-P10 and innovator rituximab (RTX) (including switched from RTX to CT-P10) up to 2 years in rheumatoid arthritis (RA) patients (NCT01534884 and NCT01873443).1,2 Objectives To compare time to retreatment and confirm clinical similarity in efficacy and safety by the number of treatment courses in the RCT between CT-P10 and RTX in RA patients up to 2 years. Methods One hundred fifty three patients were randomised in 2:1 ratio and received up to 2 treatment courses of either CT-P10 or RTX in RCT, and they had a chance to receive up to 2 additional courses of CT-P10 in OLE. Retreatments were given based on disease activity. Post-hoc analyses using combined data obtained from the RCT and OLE studies were performed in 2 different groups according to the number of treatment courses in RCT as following; Group 1: patients who received 2 courses in RCT; Group 2: patients who received 1 course in RCT. Results A total of 82 patients (59 received CT-P10 and 23 received RTX) were in Group 1 and 20 (13 received CT-P10 and 7 received RTX) were in Group 2. Time to retreatment was similar between CT-P10 and RTX (including switched to CT-P10) in each group (Figure 1). DAS28 improvement at Week 24 of each course was similar between CT-P10 and RTX (including switched to CT-P10) in both groups (Table 1).Table 1. DAS28 Improvement at week 24 in each course Mean ± SD (n) Group 1 (2 courses in RCT) Group 2 (1 course in RCT) CT-P10 RTX CT-P10 RTX DAS28-CRP  Baseline 6.2±0.8 (59) 6.0±0.7 (23) 5.4±1.0 (13) 5.4±0.6 (7)  Changes after 1st course −2.0±1.1 (59)* −1.9±1.1 (23)* −1.9±1.1 (13)* −1.6±1.2 (7)*  Changes after 2nd course −2.3±1.2 (57)* −2.0±1.3 (19)* −1.8±1.3 (10) −1.7±0.9 (6)§  Changes after 3rd course −2.4±1.1 (23) −2.5±1.3 (10)§ N/A N/A DAS28-ESR  Baseline 7.0±0.8 (59) 6.8±0.8 (23) 6.5±1.0 (13) 6.2±0.6 (7)  Changes after 1st course −2.1±1.2 (59)* −2.1±1.2 (23)* −2.3±1.1 (13)* −1.5±1.3 (7)*  Changes after 2nd course −2.5±1.2 (57)* −2.0±1.2 (19)* −2.5±1.2 (11) −2.1±0.8 (6)§  Changes after 3rd course −2.7±1.2 (23) −2.7±1.6 (10)§ N/A N/A RTX, innovator rituximab; DAS28, disease activity score in 28 joints; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; SD, standard deviation. *Course(s) treated during RCT up to 72 weeks. §DAS28 improvement after switching to CT-P10 from RTX. Infusion related reactions by treatment course up to 2 years was similar between the CT-P10 and RTX groups and tended to decrease over time in line with RTX historical data.3 Incidence rate of adverse event, serious adverse event and infection was comparable between CT-P10 and RTX groups. Conclusions The results of the post-hoc analyses demonstrated comparable duration of disease control between CT-P10 and RTX (including switched to CT-P10) with clinical similarity in efficacy for 2 years. The safety profile of CT-P10 was similar to that of RTX and in line with RTX historical data. References Yoo DH, et al. Arthritis Rheum 2013; 65 (Suppl10): S736 Yoo DH, et al. Arthritis Rheum 2015; 67 (Suppl10): 2449–245 van Vollenhoven RF, et al. EULAR 2013 (Madrid, Spain): Poster SAT0131 Disclosure of Interest W. Park Consultant for: CELLTRION,INC., D. H. Yoo Consultant for: CELLTRION,INC., C. H. Suh Consultant for: CELLTRION,INC., S. C. Shim Consultant for: CELLTRION,INC., S. J. Lee Employee of: CELLTRION,INC., S. Y. Lee Employee of: CELLTRION,INC., T. S. Kwon Employee of: CELLTRION,INC., S. M. Kim Employee of: CELLTRION,INC.

AB0433 Meta-Analysis of the Safety Data Between Infliximab Biosimilar (CT-P13) and Innovator Infliximab in Rheumatoid Arthritis and Ankylosing Spondylitis

Background CT-P13 is the first biosimilar product of innovator infliximab (INX) approved in 55 countries including EU, and there is a need of better understanding for the safety of CT-P13 compared with INX in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Objectives To compare safety profiles of CT-P13 and INX in the treatment of RA and AS, we systematically reviewed published literatures and conducted meta-analysis. Methods We conducted a systematic search for clinical trials of INX in patients with RA and AS by using PubMed database. We included the published safety profiles in randomized controlled trials (RCT) of INX for RA and AS. Eight of 660 articles in RA and 6 of 52 articles in AS were relevant RCTs and included. Safety parameters provided by INX trials were assessed, and the incidences reported in 1454 patients with the same dose regimen were used. Results were calculated using meta-analysis of incidence and compared with the safety data of CT-P13 clinical programs. Results Overall, the safety profiles of CT-P13 were within the range of historical data of INX in both RA and AS. In the combined RA and AS studies with CT-P13, 42.4% of patients reported infections which was comparable with the rates reported in historical studies with INX (55.2%; range 35.3 – 68.5%), and 3.6% of patients with CT-P13 reported serious infections which was also in line with the rates reported in historical studies with INX (3.2%; range 1.0 – 8.5%). The rate of infusion related reaction was 9.2% and aligned with historical data with INX (18.5%; range 0.0 – 67.4%). Malignancies/lymphoma was reported in 0.5% of patients treated with CT-P13, and the respective incidence with INX was 0.7%; range 0.0 – 1.2%. In addition, there is no noticeable risk in safety of CT-P13 based on the comparison with the historical data of INX in the incidences of the adverse events (100 patient-years) (Table 1).Table 1. Incidences of adverse events in CT-P13 clinical data and INX historical data in RA and AS patients Incidence per 100 patient-years (95% CI) CT-P13 clinical data INX historical data Infections 40.2 (34.5, 46.2) 75.6 (68.0, 83.7) Serious infections 3.4 (1.9, 5.5) 4.8 (3.5, 6.3) Malignancies/Lymphoma 0.4 (0.1, 1.5) 0.5 (0.2, 1.1) Infusion related reaction 8.7 (6.2, 11.8) 23.3 (20.3, 26.7) Conclusions The meta-analysis of published clinical studies of INX provides good evidence that the overall safety profiles of infliximab biosimilar, CT-P13, is consistent with that of the historical safety data of INX in RA and AS patients. References Maini et al. Lancet 1999; 354:1932-9. Abe et al. J Rheumatol 2006; 33:37-44. Schiff et al. Ann Rheum Dis 2008; 67:1096-103. Braun et al. Lancet 2002; 359:1187-93. van der Heijde et al. Arthritis Rheum 2005; 52:582-91. Breban et al. Arthritis Rheum 2008; 58:88-97. Lipsky et al. N Engl J Med 2000; 343:1594-602. St Clair et al. Arthritis Rheum 2004; 50:3432-43. Westhovens et al. Arthritis Rheum 2006; 54:1075-86. Marzo-Ortega et al. Ann Rheum Dis 2005; 64:1568-75. Quinn et al. Arthritis Rheum 2005; 52:27-35. Giardina et al. Rheumatol Int 2010; 30:1437-40. Disclosure of Interest 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. Park Employee of: CELLTRION, Inc., Y. M. Bae Employee of: CELLTRION, Inc., S. H. Kim Employee of: CELLTRION, Inc., S. G. Lee Employee of: CELLTRION, Inc.

SAT0214 Statistical Evalution of Joint Damage Prgression in Patients with Rheumatoid Arthritis Treated with Infliximab or Biosimilar Infliximab (CT-P13) Anti-TNF Therapy: A Role of Sensitivity Analysis for Missing Data Evaluating Similarity

Background Biosimilar infliximab (CT-P13) was the first monoclonal antibody biosimilar of innovator infliximab (INX) approved by the European Medicines Agency. In the PLANETRA study (1), patients with rheumatoid arthritis received 3 mg/kg of CT-P13 (n=302) or INX (n=304) every 8 weeks and were evaluated for joint damage at baseline and at week 54. The joint damage progression (JDP) was determined using the total Sharp score (TSS) in combination with erosion and joint space narrowing (JSN) (2). Objectives To investigate the similarity of JDP between CT-P13 and INX using TSS, erosion and JSN based on data with two different missing data imputations and without imputation. Methods Each radiograph was randomly assigned to two qualified experienced independent readers without the information of the time point of the radiograph images. The two readers scored the images for both time points while remaining blinded. The mean values of two quantified scores were used. Two different missing data imputation methods were used. The first method (Method A) is based on Analysis of Covariance (ANCOVA) with covariates, treatment group, CRP at baseline (CRP ≤2 mg/dL or >2 mg/dL), region (European Union (EU) or non-EU), and joint damage score at baseline. The predicted values from the ANCOVA were used for the missing values. The second method (Method B) is a simple linear extrapolation of the scores on the real time scale. Here, mean, standard deviation, median and range were calculated for each method and 95% confidence intervals (CI) of the JDP between the treatment groups were evaluated along with p-values from t-test. Every individual radiographic score per treatment group was plotted against its cumulative probability for each imputation method and without imputation. Results In the PLANETRA study, the changes of radiographic scores from baseline to week 54 were 1.3±9.3 and 0.7±7.0 for CT-P13 and INX, respectively, when ANCOVA was used for all-randomized patients. In addition, there was no statistical significant difference between CT-P13 and INX (p=0.3171). These results match the ATTRACT study (3), in which infliximab-treated subjects demonstrated also no significant change in the mean radiographic score when baseline scores were compared with those at 54 weeks, with a p-value of 0.43. Particularly, in 3mg/kg every 8 weeks group in the ATTRACT study, the total radiographic score increase from baseline was also 1.3±6.0. The figure shows similarity of TSS between CT-P13 and INX using the probability plot. There was no impact of the choice of imputation (Method A, B or no missing data imputation) on the results. Conclusions In this comparison of JDP during CT-P13 and INX treatment, CT-P13 shows comparable results, which supports the robust similarity either with missing data imputations or with data excluding missing data. The obtained JDP from PLANETRA study also supports the historical data of the early INX trials. References Yoo DH, et al. ARD 2013; 72: 1613-1620. Van der Heijde DM, et al. Arthritis Rheum 2005; 52: 49-60. Maini R, et al. Lancet 1999; 354: 1932-1939. Disclosure of Interest S. J. Lee Employee of: CELLTRION Inc., D. H. Yoo Consultant for: CELLTRION Inc., W. Park Consultant for: CELLTRION Inc., U. Müller-Ladner Speakers bureau: CELLTRION Inc., T. N. Pyo Employee of: CELLTRION Inc. DOI 10.1136/annrheumdis-2014-eular.3461

AB0014 Genetic influence of different measure for tumour necrosis factor inhibitors response in rheumatoid arthritis

Background The genetic studies of tumour necrosis factor inhibitors (TNFi) response in patients with rheumatoid arthritis (RA) have largely relied on the changes in complex disease scores as a measure of treatment response. It is expected that genetic architecture of such complex score is heterogeneous and not very suitable for pharmacogenetic studies. Objectives We aimed to select the most optimal phenotype for TNFi response using heritability estimates using genome-wide association studies (GWAS) in the Korean population. Methods Disease Activity Scores based on 28 joint counts (DAS28) and Clinical Disease Activity Index (CDAI) were assessed at baseline, and after 6 months in 370 Korean RA patients who started TNFi due to moderate or high disease activity. Genotypes were generated on the Illumina HumanOmni2.5Exome array (2.5 million variants) in TNFi-treated Korean patients with RA. We estimated heritability using a linear mixed-modelling approach (GCTA) for the TNFi drug-response phenotype ΔDAS28, ΔCDAI and its separate components, such as Δ swollen joint count (SJC), Δ tender joint count (TJC), Δ erythrocyte sedimentation rate (ESR), Δ visual-analogue scale of general health (VAS-GH) and Δ provider global assessment of disease activity (PrGA). Furthermore, a multivariate GWAS approach was implemented, analysing separate DAS28 and CDAI components simultaneously Results The highest heritability estimates were found for ΔPrGA (h2=0.76) and ΔTJC (h2=0.73); lower heritability was found for ΔDAS28 (h2=0.32) with estimates for ΔESR (h2=0.66), ΔSJC (h2=0.62), ΔCDAI (h2=0.60) and ΔVAS-GH (h2=0.53) (all p-value<0.005). Conclusions Our results indicate that multiple SNPs together explain a substantial portion of the variation in change in provider global assessment of disease activity in TNFi-treated patients with RA. In conclusion, optimal phenotype based on heritability suggests the use of changes in clinical disease activity index (CDAI) including provider global assessment than DAS28 in pharmacogenetic study. Disclosure of Interest None declared

AB0040 Immune modulatory effects of mesenchymal stem cell to mononuclear cells from patients with active adult onset still's disease

Background Adult onset Stills disease (AOSD) is an inflammatory disorder of unknown etiology, which is accompanied by increased levels of serum pro-inflammatory cytokine. Mesenchymal stem cells (MSCs) have immunomodulatory capacities and might be a promising therapeutic option in the treatment of refractory autoimmune diseases. Both cell-to-cell contact and the release of soluble factors mediate immune modulatory functions of MSCs. Objectives We aimed to determine if MSCs could modulate serum cytokine level in patients with active untreated AOSD, either through paracrine secretion or via direct contacts with the MSCs. Methods Human peripheral blood mononuclear cells (hPBMCs) from 6 patients with active AOSD were co-cultured for 72 hours with human MSCs (hMSCs at a ratio of 10 to 1). We compared the cytokine levels before and after direct or indirect (transwell cultures) exposition to activated mononuclear cells (LPS, 10ng/ml) or T cell-inducing conditions (anti-CD3 [5 μg/ml], anti-CD28 [5 μg/ml], recombinant human IL-2 [5 ng/ml]). Cytokine levels were detected by multiplex cytokine detection kit by flow cytometry, or ELISA with culture supernatant. In vitro platform for studying the effects of MSCs on individual cytokines, the Wilcoxon signed-rank test was employed for comparison of serum cytokine levels. Results Treatment of mononuclear cells with hMSCs resulted in significant reduction of mean TNF-α level (mean 463.4 pg/ml vs 137.8 pg/ml, p<0.05) and IL-1 β (mean 1887.1 pg/ml vs 1127.9 pg/ml, p<0.05). When the hMSCs were present during the T-cell differentiation, there was a significant decrease in the mean secreted TNF-α (mean 10953.5 pg/ml vs 454.9 pg/ml, p<0.05), IFN-γ (mean 14301.0 pg/ml vs 5090.4 pg/ml, p<0.05) and sIL-2 receptor (mean 3550.8 pg/ml vs 2506.4 pg/ml, p<0.05). On the contrary, level of TGF-β was significantly increased (mean 4088.8 pg/ml vs 5104.8 pg/ml, p<0.05). But, there was a significant increase in the amount of IL-6 (mean 2215.5 pg/ml vs 25130.6 pg/ml, p<0.05) and IL-17 α (mean 1357.0 pg/ml vs 2453.6 pg/ml, p<0.05). Two chamber experiments also showed similar pattern of cytokine modulation. Conclusions This preliminary experiment demonstrated that MSCs can modulate cyokine profiles of AOSD mononuclear cells by decreasing pro-inflammatory cytokines, and increasing anti-inflammatory cytokine such as TGF-β. However, up-regulation of IL-6 and IL-17 might be a hurdle to overvome in the clinical application of MSCs in AOSD patients. References Serum cytokine profiles in patients with Adult onset Stills disease. J Rheumatol. 2003 Nov;30(11):2422–7. Human mesenchymal stem cells modulated allogeneic immune cell responses. Blood. 2005 Feb 15;105(4):1815–22. Epub 2004 Oct 19. Acknowledgements none. Disclosure of Interest None declared