Comparison of Biosimilar CT-P10 and Innovator Rituximab in Patients with Rheumatoid Arthritis (PDF)

MABS 2018, VOL. 10, NO. 6, 934–943 https://doi.org/10.1080/19420862.2018.1487912 REPORT Comparison of biosimilar CT-P10 and innovator rituximab in patients with rheumatoid arthritis: a randomized controlled Phase 3 trial Won Parka, Ljubinka Božić-Majstorovićb, Dragana Milakovicb, Alfredo Berrocal...

MABS 2018, VOL. 10, NO. 6, 934–943 https://doi.org/10.1080/19420862.2018.1487912 REPORT Comparison of biosimilar CT-P10 and innovator rituximab in patients with rheumatoid arthritis: a randomized controlled Phase 3 trial Won Parka, Ljubinka Božić-Majstorovićb, Dragana Milakovicb, Alfredo Berrocal Kasayc, Elias Chalouhi El-Khourid, Fedra Irazoque-Palazuelose, Francisco Fidencio Cons Molinaf, Pavel Shesternyag, Pedro Mirandah, Francisco G. Medina-Rodriguezi, Piotr Wilandj, Slawomir Jekak, Jose Chavez-Corralesl, Olena Garmishm, Thomas Linden, Dmytro Rekalovo, Pawel Hrycajp, Andreas Krauseq, Natalia Fominar, Olena Piuras, Mauricio Abello-Banfit, Chang- Hee Suhu, Seung Cheol Shimv, Sang Joon Leew, Sung Young Leew, Sung Hwan Kimw, and Dae Hyun Yoo x a Medicine/Rheumatology, IN-HA University, School of Medicine, Incheon, Republic of Korea; bUniversity Clinical Centre of the Republic of Srpska, Banja Luka, Bosnia and Herzegovina; cABK Reuma SRL – Medicentro Biociencias, Lima, Peru; dClinica Internacional, Lima, Peru; eCentro de Investigación y Tratamiento Reumatológico S.C., Mexico City, Mexico; fCentro de Investigación en Artritis y Osteoporosis, Mexicali, Mexico; g Krasnoyarsk State Medical University, Krasnoyarsk, Russia; hCentro de Estudios Reumatológicos, Santiago, Chile; iLa Salle University, Mexico City, Mexico; jMedical University of Wroclaw, Wroclaw, Poland; kDepartment of Rheumatology and Connective Tissue Diseases, University Hospital No. 2, Collegium Medicum UMK, Bydgoszcz, Poland; lClinica San Borja, Lima, Peru; mInstitute of Cardiology named by M.D. Strazhesko NAMS of Ukraine, Kyiv, Ukraine; nMVZ für Rheumatologie und Autoimmundiagnostik, Halle (Salle), Germany; oDepartment of Internal Diseases, Zaporizhzhia State Medical University, Zaporizhzhia, Ukraine; pDepartment of Rheumatology and Clinical Immunology, Poznań University of Medical Sciences, Poznań, Poland; qMedical Centre for Rheumatology Berlin-Buch, Immanuel Krankenhaus Berlin, Berlin, Germany; rKemerovo Regional Clinical Hospital, Kemerovo, Russian Federation; sDepartment of Rheumatology, Kyiv Regional Clinical Hospital, Kyiv, Ukraine; tCentro Integral de Reumatologia del Caribe, Barranquilla, Colombia; uDepartment of Rheumatology, Ajou University School of Medicine, Suwon, Republic of Korea; vDepartment of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea; wCELLTRION, Inc., Incheon, Republic of Korea; xDivision of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea ABSTRACT ARTICLE HISTORY This multinational, randomized, double-blind trial, (ClinicalTrials.gov identifier NCT02149121) was Received 13 March 2018 designed to demonstrate equivalence in pharmacokinetics and efficacy between CT-P10 and innovator Revised 16 May 2018 rituximab (RTX) in patients with rheumatoid arthritis (RA). Adults with active RA were treated with CT- Accepted 7 June 2018 P10, United States-sourced RTX (US-RTX; Rituxan®), or European Union-sourced RTX (EU-RTX; MabThera®) KEYWORDS at weeks 0 and 2. The co-primary pharmacokinetic endpoints were area under the serum concentration– Rituximab; CT-P10; time curve (AUC) from time zero to last measurable concentration (AUC0–last), AUC from time zero to rheumatoid arthritis; infinity (AUC0–∞), and maximum concentration (Cmax) after two infusions. The primary efficacy endpoint equivalence; biosimilar 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 pharma- cokinetics 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. Introduction A biosimilar drug is a highly similar version of an already- licensed biological drug, or reference product.8,9 For a biosimi- Rituximab (RTX) is a monoclonal antibody against B cell surface lar to be approved, it must be shown that there are no clinically protein CD20 that is used to treat various B cell-related disor- meaningful differences between the two products.8,9 The step- ders, including rheumatoid arthritis (RA).1 RTX depletes CD20- wise, ‘totality of evidence’ approach adopted by regulatory expressing B cells, which play a critical role in the pathogenesis authorities for biosimilars means that the type of clinical stu- of RA.2–4 The efficacy of RTX in combination with methotrexate dies needed may vary on a case-by-case basis. However, statis- (MTX) in patients with active RA was established in randomized tically proven equivalence between biosimilar and reference controlled trials (RCTs) published over a decade ago.5–7 product in both pharmacokinetics (PK) and efficacy are usually CONTACT Dae Hyun Yoo e-mail [email protected] Division of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 222-1 Wangsimni-Ro, Seongdong-Gu, Seoul 04763, Republic of Korea. Supplemental data for this article can be accessed on the publisher’s website. Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/kmab. © 2018 The Author(s). Published with license by Taylor & Francis. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.  MABS 935 required, as is a demonstration of acceptable safety and EU-RTX combined) at week 24 in a larger patient group. PD, immunogenicity.8,9 immunogenicity, and safety were also assessed. CT-P10 (CELLTRION, Inc., Incheon, Republic of Korea) is a RTX biosimilar approved in Europe and South Korea for the same indications as ‘innovator’ RTX. CT-P10 and RTX share Results an identical primary structure and have highly similar higher- Patients order structures, post-translational modifications, and in vitro activities.10 A Phase 1 study of CT-P10 in patients with RA In total, 495 patients were screened for the study. The first demonstrated equivalent PK to European Union-sourced patient was recruited in August 2014; the last week-24 visit for RTX (EU-RTX; MabThera®; Roche, Welwyn Garden City, the final patient was in January 2016. A total of 372 patients UK) and comparable efficacy, pharmacodynamics (PD), were randomly assigned to treatment (CT-P10, n = 161; RTX, immunogenicity, and safety up to week 72.10–14 CT-P10 and n = 211 [US-RTX, n = 151; EU-RTX, n = 60]) (Figure 1). Of United States-sourced RTX (US-RTX; Rituxan®; Genentech, these, 345 (92.7%) patients completed the course (CT-P10, Inc., South San Francisco, USA) have also been shown to be n = 145 [90.1%] and RTX, n = 200 [94.8%; US-RTX, n = 142 similar in patients with follicular lymphoma, a B cell-related (94.0%); EU-RTX n = 58 (96.7%)]). Among the 372 patients, hematological malignancy for which RTX is approved.15 189 (CT-P10, n = 64; US-RTX, n = 65; EU-RTX, n = 60) This Phase 3 RCT was divided into two parallel parts, each participated in Part 1 of the study. All patients from Part 1 of which assessed different primary endpoints. The objective were included in Part 2 and underwent all assessments per- of Part 1 was to demonstrate PK equivalence of CT-P10, US- formed in Part 2. The most frequently reported reasons for RTX, and EU-RTX over 24 weeks. Part 2 aimed to demon- discontinuation in both Parts 1 and 2 were patient withdrawal strate efficacy equivalence of CT-P10 and RTX (US-RTX and of consent and adverse events (AEs) (Figure 1). The number PK evaluation (Part 1) 189 patients enrolled and randomized (Part 1 all-randomized population) CT- P10 (N=64) US-RTX (N=65) EU-RTX (N=60) 62 included in PK population 63 included in PK population 59 included in PK population 5 withdrawn 5 withdrawn 2 withdrawn 1 withdrew consent 2 withdrew consent 1 withdrew consent 2 adverse event 3 adverse event 1 adverse event 1 lack of efficacy 1 lost to follow-up Efficacy, PD and safety evaluation (Part 2) 372 patients enrolled and randomized (Part 2 all-randomized population)a CT-P10 (N=161) RTX (N=211)b 155 included in efficacy population 203 included in efficacy population 159 included in PD population 206 included in PD population 161 included in safety population 211 included in safety population 16 withdrawnc 11 withdrawnc 7 withdrew consent 5 withdrew consent 2 adverse event 5 adverse event 2 lack of efficacy 1 lack of efficacy 2 major protocol deviation 1 investigator decision 1 lost to follow-up 1 patient died 145 completed 200 completedd Including 59 also included in Part 1 Including 118 also included in Part 1e Figure 1. Patient flow and study analysis populations. a Includes all 189 patients from Part 1. The study comprised two parts that ran in parallel: Part 1 evaluated PK; Part 2 evaluated efficacy, PD and safety (plus immunogenicity). Patients included in Part 1 were randomly assigned (1:1:1) to CT-P10, US-RTX, or EU-RTX; these patients were also included in the Part 2 assessments. Part 2 also recruited additional patients (N = 183) who were randomly assigned (1:1) to either CT-P10 or US-RTX.b151 US-RTX, 60 EU-RTX. cIncludes withdrawals shown for Part 1. d142 US-RTX, 58 EU-RTX. e60 US-RTX, 58 EU-RTX. EU = European Union. PD = pharmacodynamics. PK = pharmacokinetics. RTX = rituximab. US = United States. 936 W. PARK ET AL. of patients included in each treatment group for the PK, Index and Simplified Disease Activity Index was compar- efficacy and other study assessments are shown in Figure 1. able between CT-P10 and RTX (Figure 3E and F). The Demographics and baseline disease characteristics were simi- efficacy profile was also similar in a three treatment group lar among treatment groups (Table 1). comparison (Figure S2). Pharmacokinetics Pharmacodynamics Analysis of the co-primary PK endpoints showed that, for all comparisons, the 90% CIs of the ratio of geometric means for Median B cell counts decreased to below the lower limit of area under the serum concentration–time curve (AUC) from quantification (20 cells/μL) immediately after the first infu- time zero to last measurable concentration (AUC0–last), AUC sion and remained below this level up to 24 weeks in all from time zero to infinity (AUC0–∞), and maximum concen- treatment groups. Mean ESR and serum levels of CRP, anti- tration (Cmax) were entirely contained within the margin of cyclic citrullinated peptide (CCP), and rheumatoid factor (RF) 80–125%, indicating PK equivalence between CT-P10, US- decreased from baseline at each time point measured in each RTX, and EU-RTX (Table 2). After two infusions on day 0 treatment group. There were no significant differences in PD and day 14, mean serum concentrations of RTX in the PK outcomes between groups (Table S2). population were similar for the CT-P10, US-RTX, and EU- RTX treatment groups (Figure 2). Co-primary and secondary PK endpoint values were similar for all three treatment groups Immunogenicity (Table S1). The number of patients with anti-drug antibodies (ADAs) at baseline was 19 (11.8%) and 20 (9.5%) in the CT-P10 and RTX Efficacy groups, respectively. At week 24, ADAs were detected in 24 For the primary efficacy endpoint, the adjusted least (14.9%) and 49 (23.2%) patients, in the CT-P10 and RTX squares (LS) mean (standard error [SE]) change from groups, respectively. Fourteen patients (seven in each group) baseline in Disease Activity Score using 28 joints-C-reac- were ADA-positive at baseline and week 24. Two patients tested tive protein (DAS28-CRP) at week 24 in the efficacy positive for neutralizing antibodies, one at baseline (CT-P10 population was −2.13 (0.175) for CT-P10 and −2.09 group [0.6%]) and one at week 24 (US-RTX group [0.7%]). (0.176) for RTX (calculated without imputation of missing data, as for other reported efficacy data reported here). The 95% confidence intervals (CI; −0.29, 0.21) of the Safety estimated treatment difference between CT-P10 and RTX (−0.04) were entirely within a systematic literature review- A total of 421 AEs were reported up to week 24 in 205 derived statistical equivalence margin of ±0.5, as well as (55.1%) patients, with a similar proportion of patients in the margin of ±0.6 derived from the pivotal REFLEX each group experiencing AEs (Table 3; Table S3). Most study5 and European League Against Rheumatism AEs were grade 1 or grade 2 in intensity. The most fre- (EULAR) response criteria. The treatment difference quently reported AEs were infusion-related reactions (95% CI) was highly similar in the all-randomized popula- (IRRs) and upper respiratory tract infection. The number tion (−0.04 [−0.28, 0.21]). Mean decreases from baseline of patients considered to have treatment-related AEs was in DAS28-CRP over time were similar in the CT-P10 and similar in both groups (50 [31.1%] and 60 [28.4%] patients RTX groups (Figure 3A). in the CT-P10 and RTX groups, respectively). In total, 19 Secondary efficacy outcomes were also similar between serious AEs were reported in 18 (4.8%) patients, with a groups, including improvement in Disease Activity Score similar proportion in each treatment group (Table 3; using 28 joints-erythrocyte sedimentation rate (DAS28- Table S4). Five patients from the RTX group, and none ESR) (Figure S1). In the efficacy population, the adjusted from the CT-P10 group, were considered to have experi- LS mean (SE) change from baseline in DAS28-ESR at week enced a treatment-related serious AE. AEs leading to perma- 24 was −2.40 (0.180) and −2.35 (0.181) for CT-P10 and nent study drug discontinuation were reported for 3 (1.9%) RTX, respectively (estimated treatment difference for and 5 (2.4%) patients in the CT-P10 and RTX groups, DAS28-ESR, −0.05; 95% CI, −0.31, 0.20). In the all-rando- respectively. The most frequently reported AE leading to mized population, estimated treatment difference (95% CI) permanent study drug discontinuation was IRR, for 2 was also −0.05 (−0.31, 0.20). The proportion of patients (1.2%) and 4 (1.9%) patients in the CT-P10 and RTX groups, with a good/moderate EULAR response, or achieving an respectively. Overall, IRRs were reported in 14.3% of patients American College of Rheumatology (ACR) clinical in the CT-P10 group, 4.6% in the US-RTX group and 20.0% response, up to 24 weeks was similar between the CT- in the EU-RTX group after the first infusion, and 2.6%, 0.7% P10 and RTX groups (Figure 3B–3D). The 95% CIs for and 1.7%, respectively, after the second infusion. There were the estimated treatment difference in ACR20, ACR50, and no cases of progressive multifocal leukoencephalopathy or ACR70 response rates at week 24 demonstrated that there malignancy up to week 24. One death was reported; this were no statistical differences between groups (Figure 3C). occurred in a patient in the CT-P10 group and was not Mean change from baseline in Clinical Disease Activity considered related to study drug (Table 3).  MABS 937 Table 1. Baseline demographics and disease characteristics (all-randomized populations). Part 1 Part 2a CT-P10 US-RTX EU-RTX CT-P10 RTXb Parameter (n = 64) (n = 65) (n = 60) (n = 161) (n = 211) Age, years Mean (SD) 52.4 (10.58) 52.8 (11.84) 50.8 (10.86) 51.5 (11.54) 51.8 (11.14) Gender, n (%) Male 10 (15.6%) 14 (21.5%) 10 (16.7%) 23 (14.3%) 31 (14.7%) Female 54 (84.4%) 51 (78.5%) 50 (83.3%) 138 (85.7%) 180 (85.3%) Race, n (%) White 48 (75.0%) 53 (81.5%) 41 (68.3%) 91 (56.5%) 138 (65.4%) Asian 4 (6.3%) 3 (4.6%) 5 (8.3%) 12 (7.5%) 12 (5.7%) Other 12 (18.8%) 9 (13.8%) 14 (23.3%) 58 (36.0%) 61 (28.9%) Height, cm Mean (SD) 163.8 (9.79) 165.4 (10.68) 162.1 (7.55) 162.1 (9.08) 162.5 (9.08) Weight, kg Mean (SD) 70.6 (17.70) 76.3 (20.21) 69.8 (18.12) 70.6 (17.12) 71.0 (16.91) Region, n (%) EU 28 (43.8%) 31 (47.7%) 21 (35.0%) 38 (23.6%) 65 (30.8%) Non-EU 36 (56.3%) 34 (52.3%) 39 (65.0%) 123 (76.4%) 146 (69.2%) RF or anti-CCP status, n (%) RF positive 53 (82.8%) 55 (84.6%) 49 (81.7%) 127 (78.9%) 174 (82.5%) Anti-CCP positive 53 (82.8%) 55 (84.6%) 53 (88.3%) 131 (81.4%) 178 (84.4%) SJC at baseline Mean (SD) 16.3 (7.84) 14.4 (6.87) 15.2 (10.42) 15.3 (7.99) 14.3 (8.11) TJC at baseline Mean (SD) 24.2 (14.06) 23.4 (13.80) 22.0 (12.89) 22.4 (12.84) 21.8 (12.77) Prior anti-TNF blocker status, n (%) Inadequate response 55 (85.9%) 55 (84.6%) 55 (91.7%) 137 (85.1%) 187 (88.6%) Intolerant case 9 (14.1%) 10 (15.4%) 5 (8.3%) 22 (13.7%) 24 (11.4%) Duration of prior TNF-antagonist use, months Mean (SD) 16.4 (22.06) 13.7 (23.49) 16.6 (18.74) 15.5 (19.98)c 17.0 (27.08) Number of prior TNF-antagonist use, n (%) d 0 0 0 0 2 (1.2%) 0 1 56 (87.5%) 58 (89.2%) 49 (81.7%) 142 (88.2%) 183 (86.7%) 2 8 (12.5%) 7 (10.8%) 11 (18.3%) 17 (10.6%) 28 (13.3%) Prior TNF-antagonist used, n (%) Adalimumab 23 (35.9%) 28 (43.1%) 30 (50.0%) 52 (32.3%) 80 (37.9%) Certolizumab 2 (3.1%) 5 (7.7%) 2 (3.3%) 5 (3.1%) 11 (5.2%) Etanercept 21 (32.8%) 17 (26.2%) 15 (25.0%) 55 (34.2%) 55 (26.1%) Golimumab 5 (7.8%) 6 (9.2%) 7 (11.7%) 17 (10.6%) 26 (12.3%) Infliximab 18 (28.1%) 15 (23.1%) 16 (26.7%) 44 (27.3%) 65 (30.8%) Unspecifiede 1 (1.6%)e 0 0 1 (0.6%)e 0 Investigational drug 2 (3.1%) 1 (1.5%) 1 (1.7%) 2 (1.2%) 2 (1.0%) Baseline CRP, mg/dL Mean (SD) 2.2 (3.56) 2.1 (2.79) 3.4 (4.99) 2.2 (3.22) 2.6 (3.91) Baseline ESR, mm/h Mean (SD) 54.1 (26.35) 53.2 (25.38) 51.5 (20.54) 54.7 (27.89) 54.9 (26.67) Baseline B cell count, cells/mcL Mean (SD)f 200.5 (161.83) 187.0 (115.92) 159.7 (119.09) 201.1 (140.46) 192.4 (134.36) DAS28-CRP Mean (SD) 5.8 (0.86) 5.8 (0.82) 6.0 (0.86) 5.8 (0.89) 5.8 (0.91) DAS28-ESR Mean (SD) 6.8 (0.76) 6.7 (0.77) 6.8 (0.74) 6.7 (0.82) 6.7 (0.81) Time since RA diagnosis, yearg Mean (SD) 9.4 (6.83) 8.2 (5.34) 9.9 (7.39) 10.7 (8.01) 9.1 (7.41) MTX dose, mg/weekh Mean (SD) 15.2 (4.93) 15.5 (5.21) 15.6 (5.01) 14.6 (4.34) 15.0 (4.66) CCP = cyclic citrullinated peptide. CRP = C-reactive protein. DAS28 = Disease Activity Score using 28 joints. ESR = erythrocyte sedimentation rate. EU = European Union. MTX = methotrexate. PK = pharmacokinetics. RA = rheumatoid arthritis. RF = rheumatoid factor. RTX = rituximab. SD = standard deviation. SJC = swollen joint count. TJC = tender joint count. TNF = tumour necrosis factor. US = United States. a All patients in Part 1 were included in Part 2. b The RTX group consists of data from the combined US-RTX and EU-RTX treatment groups. c n = 159. d Two patients had not received prior TNF-antagonist therapy and discontinued due to noncompliance with the inclusion criteria. Patients were excluded from the PK population for not providing at least one post-treatment PK concentration result and were excluded from the primary efficacy analysis for not having information regarding prior anti-TNF blocker status, which was one of the covariates for analysis. e Results did not report whether the patient received adalimumab or certolizumab in the prior blinded clinical trial. f Part 1: CT-P10, n = 61; US-RTX, n = 62; EU-RTX, n = 56. Part 2: CT-P10, n = 148; RTX, n = 194. g Calculated as (date of randomization – date of diagnosis)/365.25. h At first infusion of first course. Discussion regulatory approval in the EU for RTX indications, and here we present the first full report of a Phase 3 study of CT-P10 in Developing a biosimilar and obtaining market authorization is RA. PK equivalence was demonstrated between CT-P10 and a complex process. CT-P10 was the first biosimilar to gain both US-RTX and EU-RTX, and equivalent efficacy between 938 W. PARK ET AL. Table 2. Analysis for the co-primary PK endpoints (PK population). Parameter % Ratiob a b Comparison (unit) Treatment n Geometric LS Mean (T/R) 90% CIb CT-P10 (T) vs. AUC0–last Test 62 162414.81 97.07 (88.08, 106.99) US-RTX (R) (h*µg/mL) Reference 60 167309.07 AUC0–∞ Test 59 162377.28 95.81 (87.39, 105.04) (h*µg/mL) Reference 60 169480.80 Cmax Test 62 367.03 94.92 (89.61, 100.55) (µg/mL) Reference 59 386.65 CT-P10 (T) vs. AUC0–last Test 62 162414.81 94.18 (85.40, 103.86) EU-RTX (R) (h*µg/mL) Reference 59 172450.97 AUC0–∞ Test 59 162377.28 89.89 (81.85, 98.72) (h*µg/mL) Reference 56 180637.81 Cmax Test 62 367.03 89.00 (84.01, 94.28) (µg/mL) Reference 59 412.40 EU-RTX (T) vs. AUC0–last Test 59 172450.97 103.07 (93.32, 113.85) US-RTX (R) (h*µg/mL) Reference 60 167309.07 AUC0–∞ Test 56 180637.81 106.58 (97.03, 117.08) (h*µg/mL) Reference 60 169480.80 Cmax Test 59 412.40 106.66 (100.56, 113.13) (µg/mL) Reference 59 386.65 AUC0–last = area under the serum concentration–time curve from time 0 to the last measurable concentration. AUC0–∞ = AUC from time 0 extrapolated to infinity. CI = confidence interval. Cmax = maximum serum concentration after the second infusion. EU = European Union. LS = least squares. PK = pharmacokinetics. R = reference. RTX = rituximab. T = test. US = United States. a Outliers were excluded from the statistical analysis (n = 3 in US-RTX for AUC0–last and Cmax and n = 2 in US-RTX for AUC0–∞). In addition, some patients were excluded from the statistical analysis for AUC0–∞ since R-square was lower than 0.8 in the terminal phase and the terminal slope could not be calculated (n = 3 in CT-P10; n = 1 in US-RTX; n = 3 in EU-RTX). b Point estimates and 90% CIs for differences on the log scale were exponentiated to obtain estimates for ratios of geometric LS means on the original scale. 1000.000 CT-P10 US-RTX EU-RTX 100.000 Mean concentration (μg/mL) 10.000 1.000 0.100 0.010 0.001 0 14 28 42 56 70 84 98 112 126 140 154 168 Time (days) Figure 2. Mean (SD) serum concentration of study drug (PK populationa). EU = European Union. PK = pharmacokinetics. RTX = rituximab. SD = standard deviation. US = United States.aCT-P10, N = 62; US-RTX, N = 63; EU-RTX, N = 59. CT-P10 and the combined RTX group with similar PD, in the primary efficacy analysis. Results up to week 24 are immunogenicity, and safety profiles displayed up to week 24. reported here, but the study is ongoing and longer-term safety The strengths of this trial include its randomized design, and efficacy will be assessed up to week 72. objective and well-established outcome measures, high patient While this study demonstrated PK equivalence, for the retention rates, and the three-way comparison of PK that comparison between CT-P10 and EU-RTX, the upper and included CT-P10 and both licensed reference products (US- lower 90% CIs for both Cmax and AUC0–∞ fell below 100%, RTX and EU-RTX). PK results in this study were similar to which may suggest that exposure to CT-P10 was lower than to those observed in a Phase 1 study comparing CT-P10 to EU- EU-RTX. Visual inspection of PK data confirmed that the RTX.10 Importantly, in this report the PK was also shown to range of serum concentration distribution for CT-P10-treated be equivalent between CT-P10 and US-RTX. Considering the patients substantially overlapped with that for EU-RTX and equivalence of EU-RTX and US-RTX shown in Part 1, it is US-RTX-treated patients (Figure S3). A trend towards higher appropriate to assess efficacy equivalence of CT-P10 against a serum rituximab levels was observed in a small proportion of combined RTX group, where both PK and efficacy of CT-P10 EU-RTX-treated patients at the earlier time-points. However, could be considered “as equivalent” to each form of RTX as this difference did not result in any overt impact on PK each of these reference products was to each other. Because similarity between the three treatment groups. PK similarity patients were randomized 1:1:1 for Part 1, and then 1:1 in Part between CT-P10 and EU-RTX has previously been established 2, an overall 1:1 distribution of CT-P10- and RTX-treated in a Phase 1 study (NCT01534884). We are therefore satisfied patients was not created in the efficacy analysis. To address that there is sufficient assurance that individual PK concen- this possible limitation, study part was included as a covariate tration levels seen with CT-P10 and reference products are  MABS 939 No response Moderate response Good response CT-P10 RTX A. 8 B. 100 15.5 16.3 16.8 16.3 7 80 6 Mean score ± SE Response (%) 5 42.6 41.4 60 4 58.7 59.1 3 40 2 20 40.6 42.4 1 CT-P10 –1.28 –1.73 –2.15 –2.33 –2.38 –2.34 23.2 24.6 RTX –1.14 –1.60 –1.95 –2.17 –2.26 –2.28 0 0 Baseline Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 CT-P10 RTX CT-P10 RTX EULAR-CRP EULAR-ESR C. D. CT-P10 RTX CT-P10 RTX 100 100 80 72.9 75.9 80 ACR20 Response (%) Response (%) 60 60 47.1 50.2 ACR50 40 40 27.1 30.5 ACR70 20 20 113/155 154/203 73/155 102/203 42/155 62/203 0 0 ACR20 ACR50 ACR70 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 E. F. CT-P10 RTX CT-P10 RTX 60 60 50 50 Mean score ± SE Mean score ± SE 40 40 30 30 20 20 10 10 0 0 Baseline Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Baseline Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 CT-P10 –17.03 –21.36 –24.71 –25.93 –26.13 –25.59 CT-P10 –17.67 –22.26 –25.87 –27.40 –27.44 –26.91 RTX –14.85 –18.94 –22.18 –24.34 –24.14 –24.46 RTX –15.43 –20.09 –23.58 –25.64 –25.78 –25.98 Figure 3. Efficacy outcomes (efficacy populationa). (A) Mean change from baselineb in DAS28-CRP. (B) Proportions of patients with good, moderate, or no EULAR response at week 24c. (C) Proportions of patients achieving clinical response at week 24 according to the ACR20, ACR50, and ACR70 criteria. (D) ACR response over time. (E) Mean change from baseline in clinical disease activity index. (F) Mean change from baseline in simplified disease activity index. ACR = American College of Rheumatology. CI = confidence interval. CRP = C-reactive protein. DAS28 = Disease Activity Score using 28 joint counts. ESR = erythrocyte sedimentation rate. EULAR = European League Against Rheumatism. RTX = rituximab. SE = standard error. aCT-P10, N = 155; RTX, N = 203. bData shown are non- adjusted arithmetic means. cTwo patients in the CT-P10 group were non-evaluable at week 24 as they had undergone joint surgery during the study and were excluded. likely due to random fluctuations, and not any intrinsic prop- targeted biologic therapies are difficult to measure due to erties of either drug.10 the potential for false positives in immunogenicity assays, Previous clinical trials established the efficacy of RTX in thought to be caused by cell membrane fragments (CMF) combination with MTX in reducing symptoms in patients expressing CD20.16 The cutoff point for this assay was deter- with RA.5–7 These studies reported variable proportions of mined statistically with a false positive rate of 5%, and so the RTX-treated patients achieving ACR and EULAR responses at ADA positive rate observed at screening in this study was 24 weeks (ACR20, 51–73%; ACR50, 27–43%; ACR70, within the range of false positivity anticipated by Amaravadi 12–23%; and EULAR moderate-to-good, 65–83%), and et al. (2–11%).17 In this study, confirmatory and titration changes from baseline in DAS28-ESR at 24 weeks (−1.90 to methods were improved by using ofatumumab, another −2.60).5–7 The findings of the present study demonstrate not anti-CD20 antibody, which reduced potential interference of only that the efficacy of CT-P10 is comparable to RTX, but circulating CD20 CMFs by preventing the binding of CD20 in that it is of similar magnitude to that reported in the pivotal the sample to labelled rituximab reagents in the assay. RCTs of RTX in combination with MTX.5–7 However, further non-specific binding by other unknown Overall, 39 and 73 patients were ADA-positive at baseline factors remains possible. No difference was observed between and at week 24, respectively; 14 were positive at both time- groups in ADA-positivity at baseline, and neutralizing anti- points. True ADA levels in patients treated with CD20- bodies were observed in only two patients. Furthermore, we 940 W. PARK ET AL. Table 3. Adverse events up to week 24 (safety population). In conclusion, this Phase 3 study demonstrated the PK and Number of patients CT-P10 US-RTX EU-RTX RTXa efficacy equivalence of CT-P10 and RTX in patients with RA. (%) (n = 161) (n = 151) (n = 60) (n = 211) PD and immunogenicity findings were also comparable AE 96 (59.6%) 76 (50.3%) 33 (55.0%) 109 (51.7%) between groups, and no unexpected safety concerns were raised. Treatment-related 50 (31.1%) 38 (25.2%) 22 (36.7%) 60 (28.4%) SAE 9 (5.6%) 9 (6.0%) 0 9 (4.3%) Treatment-related 0 5 (3.3%) 0 5 (2.4%) IRR 25 (15.5%) 8 (5.3%) 12 (20.0%) 20 (9.5%) Patients and methods Pruritus 9 (5.6%) 3 (2.0%) 4 (6.7%) 7 (3.3%) Rash 8 (5.0%) 4 (2.6%) 3 (5.0%) 7 (3.3%) Patients Throat irritation 5 (3.1%) 1 (0.7%) 3 (5.0%) 4 (1.9%) Infection 40 (24.8%) 36 (23.8%) 11 (18.3%) 47 (22.3%) Eligible patients were aged 18–75 years with active RA diag- Upper respiratory 17 (10.6%) 18 (11.9%) 4 (6.7%) 22 (10.4%) tract infection nosed per revised 1987 ACR classification criteria23 Urinary tract 9 (5.6%) 5 (3.3%) 1 (1.7%) 6 (2.8%) ≥6 months before randomization. Active disease was defined infection Lower respiratory 4 (2.5%) 7 (4.6%) 2 (3.3%) 9 (4.3%) by ≥6 swollen joints and ≥6 tender joints, and serum CRP tract infection ≥1.5 mg/dL or an ESR ≥28 mm/hour. Patients had received Influenza 1 (0.6%) 0 2 (3.3%) 2 (0.9%) MTX treatment (7.5 to 25 mg/week orally or parenterally) Malignancy 0 0 0 0 Death 1 (0.6%)b 0 0 0 for the past ≥12 weeks, with the last four weeks at a stable Discontinuation 3 (1.9%) 4 (2.6%) 1 (1.7%) 5 (2.4%) dose before screening, and had experienced an inadequate due to AEs response or were intolerant to anti-TNF agents. Full elig- AE = adverse event. EU = European Union. IRR = infusion-related reaction. ibility criteria are presented in Table S5 (supplementary RTX = rituximab. SAE = serious adverse event. US = United States. Note: The total number of AEs included all patient events. At each level of information). summarization, a patient was counted only once if they reported one or more events. Only the most severe event was counted. a The RTX group consists of data from the combined US-RTX and EU-RTX treat- Study design ment groups. b One patient, who had an ongoing medical history of hypertension, thrombo- This was a randomized, double-blind, parallel-group, active- cytosis, and anaemia of chronic disease, initially experienced cellulitis and thrombosis of the right brachial vein and was hospitalized approximately controlled Phase 3 study conducted in 76 centers in Europe, two months after receiving the first dose of study drug. The condition of the Asia Pacific, and Latin America (ClinicalTrials.gov identifier patient worsened and the patient died due to acute respiratory distress NCT02149121). A total of 361 patients were planned to be syndrome approximately three weeks after hospitalization. The death was considered unrelated to the study drug. enrolled in the entire study. Of these, the first 189 study patients were randomly assigned to Part 1 in a 1:1:1 ratio to CT-P10, US-RTX, or EU-RTX for the PK evaluation. All noted no noticeable trends in PK, PD, efficacy or safety patients in Part 1 were also included in Part 2 of the study. according to baseline ADA-positivity in the current study. In Part 2, newly enrolled patients (n = 183) were randomly Incidence of IRR in the CT-P10 treatment group after the assigned (1:1) to either CT-P10 or US-RTX (Figure 1). Part 2 first infusion (14.3%) was less than observed in the EU-RTX ran independently and in parallel with Part 1. Further details treatment group (20.0%) and greater than in the US-RTX are provided in online supplementary material A. Patients treatment group (4.6%). After the second infusion the inci- received two intravenous (IV) infusions of 1,000 mg CT- dence of IRR was low in all groups (CT-P10, 2.6%; EU-RTX, P10, US-RTX, or EU-RTX separated by a 2-week interval. 1.7% and US-RTX, 0.7%). The proportions observed in this MTX (7.5–25 mg orally or parenterally, weekly) and folic study are slightly lower than historical studies of RTX where acid (≥5 mg orally, weekly) were co-administered with study the incidence of IRRs following the first infusion has ranged drug. Methylprednisolone (100 mg IV), an antipyretic (acet- from 23–32%, and declined following the second infusion aminophen/paracetamol 500–1,000 mg, orally), and an anti- (6–9%).5,7,18 However, the present results demonstrate a histamine (chlorpheniramine 2–4 mg [or equivalent], orally) similar pattern of IRR predominantly occurring during the were administered 30–60 minutes before each infusion of first infusion. study drug. RTX therapy is an established treatment option for patients The study was performed according to the principles of the with RA with an inadequate response or intolerance to anti- Declaration of Helsinki and International Conference on tumour necrosis factor (TNF) biologics.19 Patient access to Harmonisation Good Clinical Practice guidelines. The study innovator biologics such as RTX can, however, be restricted design was approved by an independent ethics committee for by cost, particularly in lower income countries.20 Biosimilars each investigational site. All patients provided written offer financial savings and reductions in time for development informed consent. and manufacture because the companies developing them can rely on the research efforts implemented for the reference Assessments product without jeopardizing efficacy and safety.21 The increased availability of these therapeutic agents due to Blood samples for PK and B cell kinetic analyses were col- lower cost may improve patient care and lower the burden lected from all patients within 15 minutes before and after, on healthcare providers. As such, both patients with RA and and one hour (±15 minutes) after study drug infusion. healthcare systems are expected to benefit from the develop- Additional samples were collected from patients in Part 1 ment of RTX biosimilars.22 for PK analysis and from all patients for B cell kinetic analysis  MABS 941 24 hours (±2 hours) after the start of each study drug infusion one full dose of study drug and provided at least one post-treat- (first infusion only for B cell kinetics), and on days 7, 21, 28, ment PD result were included in the PD population. All patients 56, 84, 112, and 168 (see supplementary material B). DAS28 that received study drug were included in the safety population. and ACR response were evaluated at baseline and at 4-weekly Primary PK and efficacy endpoints, and PD endpoints, were intervals. EULAR response criteria were derived from DAS28. analyzed using an analysis of covariance (ANCOVA) model Safety was monitored throughout the study. Immunogenicity with treatment group as a fixed effect and gender, region, race, was measured at baseline and at week 24 (see supplementary study part (efficacy endpoints only), prior anti-TNF blocker material C). status, and RF or CCP status fitted as covariates. Additional ANCOVAs of DAS28-ESR data were performed in the efficacy population and of DAS28-CRP and DAS28-ESR data in all Endpoints patients randomly assigned to treatment. Exact binomial ana- The two parts of the study had different primary endpoints. lyses were performed to assess any treatment differences in ACR The co-primary endpoints for Part 1 were AUC from time response rates. Continuous data were described using descrip- zero to last measurable concentration over both doses of study tive statistics, and categorical data were summarized using drug (AUC0–last), AUC from time zero extrapolated to infinity patient counts and percentages, unless otherwise specified. over both doses of study drug (AUC0–∞), and observed max- PK parameters were calculated by standard imum concentration after the second infusion of study drug non-compartmental methods (linear trapezoidal rule) using (Cmax). The primary endpoint for Part 2 was the LS mean Phoenix WinNonlin v6.4. All analyses were conducted using change from baseline in disease activity measured by DAS28- SAS software v9.1.3 (SAS Institute, Cary, NC, USA) or higher. CRP at week 24. Secondary endpoints included additional PK parameters for Parts 1 and 2, and additional efficacy para- Acknowledgments meters plus PD, immunogenicity, and safety outcomes for Part 2. A full list is provided in supplementary material D. Medical writing support (writing assistance, assembling tables and fig- ures, collating author comments, copyediting, grammatical editing, and referencing) was provided by Joanna Chapman PhD at Aspire Scientific Limited (Bollington, UK) and was funded by CELLTRION, Inc. Statistical analysis (Incheon, Republic of Korea). Part 1 of the study was powered to demonstrate PK equivalence of CT-P10, US-RTX, and EU-RTX in AUC0–last, AUC0–∞, and Cmax. Equivalence was to be demonstrated if the 90% CI for the geo- Disclosure of interest metric mean ratio of CT-P10 to US-RTX and EU-RTX in these WP received consulting fees from CELLTRION during the conduct of the endpoints was within 80–125%. In Part 1, a sample size of 189 study. SJL, SYL, and SHK are employees of CELLTRION. DHY is a scientific consultant and on the speaker’s bureau of CELLTRION, and has received patients (PK population: all patients who received two full doses research grants not related to this clinical study. PM received fees from [at weeks 0 and 2] of study drug and provided at least one post- CELLTRION for conducting the trial and has performed trials for treatment PK concentration result) was based on overall 90% CELLTRION outside the submitted work. LB-M and DM received fees from power, two one-sided α equal to 0.05, an interpatient coefficient CELLTRION for conducting the trial. AK has received fees from CELLTRION of variation in AUC0–last of 30%, and an assumed drop-out rate of for conducting the trial and grants and personal fees from Roche outside the submitted work. ABK, ECE-K, FI-P, FFCM, PS, FMR, PW, SJ, JC-C, OG, TL, 20%. The target sample size for Part 2 of the study (n = 361 in the DR, PH, NF, OP, MA-B, C-HS, and SCS declare no conflicts of interest. efficacy population [all patients who received at least one full dose of study drug and provided at least one post-treatment efficacy result]) allowed for a drop-out rate of 10% and provided 82% Funding power for demonstration of similarity based on a 95% CI for the This work was supported by CELLTRION, Inc. (Incheon, South Korea). estimate of the difference in change in DAS28 score from baseline at week 24 between CT-P10 and RTX groups. The Part 2 power calculation assumed a clinical equivalence margin of ±0.60, which Contributors was sufficient to exclude clinically relevant effects and consistent WP, C-HS, SCS, SJL, SYL, SHK, and DHY were involved in conception with a change in DAS28 of ≤0.6 representing ‘no response’ and design of the study, acquisition of data, and/or analysis and inter- according to EULAR response criteria.24 A tighter statistical pretation of data. LB-M, DM, ABK, ECE-K, FI-P, FFCM, PS, PM, FGM- equivalence margin of ±0.5 was used for evaluation of the primary R, PW, SJ, JC-C, OG, TL, DR, PH, AK, NF, OP, and MA-B were involved efficacy endpoint. This statistical margin was derived from a in the acquisition of data. All authors reviewed drafts of the manuscript systematic literature review of DAS28 responses to RTX in and approved the final version. patients with RA who had an inadequate response to one or more TNF-antagonists. Using the observed standard deviations Abbreviation of the change in DAS28 with the efficacy population sample size, the post-hoc statistical power was about 95% for the equivalence ACR American College of Rheumatology ADAs anti-drug antibodies margin of ±0.5 and the two, one-sided 2.5% α. Data from four AEs adverse events RCTs identified in this review were used to determine an appro- ANCOVA analysis of covariance priate equivalence margin.5–7,18 All patients who received at least AUC area under the serum concentration–time curve 942 W. PARK ET AL. AUC0–last area under the serum concentration–time curve from 8. European Medicines Agency. Guideline on similar biological time zero to last measurable concentration medicinal products containing biotechnology-derived proteins as AUC0–∞ area under the serum concentration–time curve from active substance: non-clinical and clinical issues. 2014. http:// time zero to infinity www.ema.europa.eu/docs/en_GB/document_library/Scientific_ CCP cyclic citrullinated peptide guideline/2015/01/WC500180219.pdf CI confidence interval 9. U.S. Food and Drugs Administration. Scientific considerations in Cmax maximum concentration demonstrating biosimilarity to a reference product: guidance for CMF cell membrane fragments industry. 2015. https://www.fda.gov/downloads/Drugs/ DAS28-CRP Disease Activity Score using 28 joints-C-reactive protein GuidanceComplianceRegulatoryInformation/Guidances/ DAS28-ESR Disease Activity Score using 28 joints-erythrocyte sedi- UCM291128.pdf mentation rate 10. 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