Piotr Wiland

Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study

Objectives To 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. Methods This 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). Results Overall, 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). Conclusions Comparable 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 number NCT01571219; Results.

Efficacy and safety of switching from reference infliximab to CT-P13 compared with maintenance of CT-P13 in ankylosing spondylitis: 102-week data from the PLANETAS extension study

Objectives To 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). Methods This 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). Results Overall, 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. Conclusions This 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 number NCT01571206; Results.

Access to biologic treatment for rheumatoid arthritis in Central and Eastern European (CEE) countries

Summary Background The aim of this study was to assess and compare patients’ access to biologic anti-RA drugs in selected Central and Eastern European (CEE) countries and to analyze the determinants of differences between countries. Material/Methods This is a multi-country survey study, based on a combination of desk research and direct contact with national RA stakeholders. Data was collected using a pre-defined questionnaire. Affordability was measured using an affordability index, calculated comparing the index of health care expenditures to the price index, using Poland as an index of 1. Results The percentage of patients on biologic treatment in 2009 was highest in Hungary (5% RA patients on biologic treatment), followed by Slovenia (4.5%), Slovakia (3.5%), Czech Republic (2.92%), Romania (2.2%), Estonia (1.8%), and Croatia, Serbia, Poland (below 1.5%). Infliximab, etanercept, adalimumab and rituximab were included in the reimbursement system in all countries, but abatacept and tocilizumab were included only in Slovakia. In Slovenia, public payer covered 75% of the price, and 25% is covered by supplementary health insurance; in Bulgaria public payer covered 50% of etanercept and adalimumab costs, and 75% of rituximab cost. In other countries, biologic drugs are reimbursed at 100%. Affordability index for biologic drugs was the lowest in Slovenia (0.4). In each country national guidelines define which patients are eligible for biologic treatment. Disease Activity Score (DAS28) of over 5.1 and failure of 2 or more disease-modifying anti-RA drugs, including methotrexate, are commonly used criteria. Conclusions The most important factors limiting access to biologic anti-RA treatment in the CEE region are macroeconomic conditions and restrictive treatment guidelines.

A multicentre randomised controlled trial to compare the pharmacokinetics, efficacy and safety of CT-P10 and innovator rituximab in patients with rheumatoid arthritis

Objective To 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. Methods In 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. Results 103 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. Conclusions CT-P10 and RTX demonstrated equivalent pharmacokinetics and comparable efficacy, pharmacodynamics, immunogenicity and safety. Trial registration number NCT01534884.

Etanercept treatment in juvenile idiopathic arthritis: The Polish registry

Summary Background To evaluate the long-term safety and efficacy of etanercept treatment in Polish patients with juvenile idiopathic arthritis (JIA). Material/Methods The study involved patients, fulfilling the JIA criteria of the International League of Associations of Rheumatology (ILAR), who were started on etanercept therapy after methotrexate and other synthetic disease-modifying antirheumatic drugs (DMARDs) had proven ineffective. Patient data were collected in an electronic registry. Disease improvement was assessed based on Giannini’s criteria. Results The statistical analysis involved 188 patients. Significant improvement was observed in all clinical and laboratory parameters after the first month of therapy and was maintained in the following months. ACR Pediatric 30, 50, 70, 90, and 100 improvement was observed in 81.4%, 65.9%, 27.5%, 16.2%, and 15%, respectively, of patients after 3 months and in 94.7%, 88.4%, 62.1%, 34.7%, and 26.3%, respectively, after 24 months of treatment. Throughout the 72-month safety observation period, 1162 adverse events were reported; the exposure-adjusted AE rate was 2.96 per patient per year. Conclusions In patients with various subtypes of JIA resistant to conventional DMARD treatment, etanercept resulted in significant and long-lasting improvements in disease activity. Combination treatment with etanercept and a DMARD was well tolerated.

OP0157 Clinical Response of Disease Activity, Disability and Mobility Indices in Relation to Anti-Drug Antibody in the Planetas

Background Recently, the European Medicines Agency approved a biosimilar to infliximab, CT-P13. Biosimilars are not only required to have biochemical and pharmacokinetics (PK) equivalence, but also must demonstrate similarity in their therapeutic effectiveness, safety and immunogenicity. The PLANETAS was a randomized double-blind, parallel group study for demonstrating PK equivalence between biosimilar infliximab (CT-P13) and innovator infliximab (INX) in patients with ankylosing spondylitis (AS). Objectives To compare disease activity, disability and mobility indices of CT-P13 and INX and to assess the effect of anti-drug antibody (ADA) on the observed indices in patients participated in the PLANETAS. Methods In the PLANETAS, key secondary endpoints captured the clinical measures of disease activity via ASAS20/40 and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), disability via the Bath Ankylosing Spondylitis Functional Index (BASFI) and mobility via the Bath Ankylosing Spondylitis Metrology Index (BASMI). The Students t test was used to compare mean change of three indices from baseline in both treatment groups. ADA was measured using the electrochemiluminescent methodology. Clinical responses, regardless of treatment groups, were examined in relation to the presence of the ADA. Results 250 patients with AS were treated with either CT-P13 or INX. Baseline comparability was demonstrated with each of these 3 indices. At week 54, BASDAI improved significantly from baseline in both treatment groups (CT-P13: from 6.74 to 3.78 and INX: from 6.57 to 3.70) and this improvement was similar between groups (difference of means -0.29; CI of the difference -0.91 to 0.32). BASFI and BASMI also improved in similar pattern: BASFI (CT-P13: from 6.20 to 3.42 and INX: from 6.24 to 3.46) and BASMI (CT-P13: from 4.0 to 2.8 and INX: from 4.1 to 3.2). At week 54, 50% improvement of the baseline BASDAI (BASDAI50) was achieved in 44.3% for CT-P13 and 46.3% for INX and BASDAI50 response rate was comparable between the two groups (p=0.7737). Overall, no statistical significance in clinical responses between the treatment groups at week 54 was found for all indices. Higher ASAS20/40 responses were seen in the ADA negative patients (72.7%/56.5%) compared with ADA positive patients (54.7%/37.7%) at week 54. Mean change from baseline for BASDAI and BASFI improved significantly in ADA negative subgroup than ADA positive subgroup (BASDAI: -3.13 vs. -2.30 and BASFI: -2.97 vs. -2.18) but no clear association with ADA was seen for BASMI. Conclusions Well-established indices of disease activity, disability and mobility in patients with AS were improved and statistically similar between CT-P13 and INX group. ASAS20/40, BASDAI and BASFI by ADA subgroup showed evidence of a relationship which was higher clinical responses in ADA negative subgroup. Disclosure of Interest W. Park Grant/research support: Celltrion, Consultant for: Celltrion, Speakers bureau: Celltrion, D. H. Yoo Grant/research support: Celltrion, Consultant for: Celltrion, Speakers bureau: Celltrion, S. Szántό: None declared, F. Berghea: None declared, M. Brzosko Grant/research support: Celltrion, P. Wiland Grant/research support: Celltrion, S. Smiyan Grant/research support: Celltrion, R. Araiza-Casillas Grant/research support: Celltrion, F. Díaz-González Grant/research support: Celltrion, J. H. Suh Employee of: Celltrion DOI 10.1136/annrheumdis-2014-eular.3804

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.

Comparison of biosimilar CT-P10 and innovator rituximab in patients with rheumatoid arthritis: a randomized controlled Phase 3 trial

ABSTRACT This multinational, randomized, double-blind trial, (ClinicalTrials.gov identifier NCT02149121) was designed to demonstrate equivalence in pharmacokinetics and efficacy between CT-P10 and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA). Adults with active RA were treated with CT-P10, United States-sourced RTX (US-RTX; Rituxan®), or European Union-sourced RTX (EU-RTX; MabThera®) at weeks 0 and 2. The co-primary pharmacokinetic endpoints were area under the serum concentration–time curve (AUC) from time zero to last measurable concentration (AUC0–last), AUC from time zero to infinity (AUC0–∞), and maximum concentration (Cmax) after two infusions. The primary efficacy endpoint was change from baseline to week 24 in Disease Activity Score using 28 joints-C-reactive protein (DAS28-CRP). Pharmacodynamics, immunogenicity, and safety were also assessed. 372 patients were randomly assigned to CT-P10 (n = 161) or RTX (n = 211 [US-RTX, n = 151; EU-RTX, n = 60]). For the co-primary pharmacokinetic endpoints, 90% confidence intervals (CI) for ratios of geometric means (CT-P10/US-RTX, CT-P10/EU-RTX or EU-RTX/US-RTX) all fell within the equivalence margin of 80–125%. Adjusted least squares (LS) mean (standard error) change from baseline in DAS28-CRP at week 24 was −2.13 (0.175) for CT-P10 and −2.09 (0.176) for RTX. The 95% CI (−0.29, 0.21) of the estimated treatment difference between CT-P10 and RTX (−0.04) was entirely within the efficacy equivalence margin of ±0.5. Pharmacodynamics, immunogenicity, and safety profiles were similar for CT-P10 and RTX. The pharmacokinetics of CT-P10, US-RTX, and EU-RTX were equivalent. CT-P10 and RTX were also equivalent in terms of efficacy and displayed similar pharmacodynamic, immunogenicity, and safety profiles up to week 24.