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

Won Park, Ljubinka Božić-Majstorović, Dragana Milakovic, Alfredo Berrocal Kasay, Elias Chalouhi El-Khouri, Fedra Irazoque-Palazuelos, Francisco Fidencio Cons Molina, Pavel Shesternya, Pedro Miranda, Francisco G Medina-Rodriguez, Piotr Wiland, Slawomir Jeka, Jose Chavez-Corrales, Olena Garmish, Thomas Linde, Dmytro Rekalov, Pawel Hrycaj, Andreas Krause, Natalia Fomina, Olena Piura, Mauricio Abello-Banfi, Chang-Hee Suh, Seung Cheol Shim, Sang Joon Lee, Sung Young Lee, Sung Hwan Kim, Dae Hyun Yoo, Won Park, Ljubinka Božić-Majstorović, Dragana Milakovic, Alfredo Berrocal Kasay, Elias Chalouhi El-Khouri, Fedra Irazoque-Palazuelos, Francisco Fidencio Cons Molina, Pavel Shesternya, Pedro Miranda, Francisco G Medina-Rodriguez, Piotr Wiland, Slawomir Jeka, Jose Chavez-Corrales, Olena Garmish, Thomas Linde, Dmytro Rekalov, Pawel Hrycaj, Andreas Krause, Natalia Fomina, Olena Piura, Mauricio Abello-Banfi, Chang-Hee Suh, Seung Cheol Shim, Sang Joon Lee, Sung Young Lee, Sung Hwan Kim, Dae Hyun Yoo

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.

Keywords: CT-P10; Rituximab; biosimilar; equivalence; rheumatoid arthritis.

Figures

Figure 1.
Figure 1.
Patient flow and study analysis populations. aIncludes 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.
Figure 2.
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.
Figure 3.
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.

References

    1. European Medicines Agency MabThera (rituximab) [Summary of Product Characteristics]. 2018.
    1. Marston B, Palanichamy A, Anolik JH.. B cells in the pathogenesis and treatment of rheumatoid arthritis. Curr Opin Rheumatol. 2010;22(3):307–315. doi:10.1097/BOR.0b013e3283369cb8.
    1. Panayi GS. B cells: a fundamental role in the pathogenesis of rheumatoid arthritis? Rheumatology (Oxford). 2005;44 (Suppl 2):ii3–ii7. doi:10.1093/rheumatology/keh616.
    1. Pescovitz MD. Rituximab, an anti-CD20 monoclonal antibody: history and mechanism of action. Am Journal Transplant. 2006;6(5 Part 1):859–866. doi:10.1111/j.1600-6143.2006.01288.x.
    1. Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, Keystone EC, Loveless JE, Burmester G-R, Cravets MW, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 2006;54(9):2793–2806. doi:10.1002/art.22025.
    1. Edwards JCW, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004;350(25):2572–2581. doi:10.1056/NEJMoa032534.
    1. Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh A, Racewicz AJ, van Vollehoven RF, Li NF, Agarwal S, et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum. 2006;54(5):1390–1400. doi:10.1002/art.21778.
    1. European Medicines Agency Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. 2014.
    1. U.S. Food and Drugs Administration Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. 2015.
    1. Yoo DH, Suh C-H, Shim SC, Jeka S, Cons Molina FF, Hrycaj P, Wiland P, Lee EY, Medina-Rodriguez FG, Shesternya P, et al. A multicentre randomised controlled trial to compare the pharmacokinetics, efficacy and safety of CT-P10 and innovator rituximab in patients with rheumatoid arthritis. Ann Rheum Dis. 2017;76(3):566–570. doi:10.1136/annrheumdis-2016-209540.
    1. Park W, Suh C-H, Shim SC, Cons Molina FF, Jeka S, Medina-Rodriguez FG, Hrycaj P, Wiland P, Lee EY, Shesternya P, et al. Efficacy and safety of switching from innovator rituximab to biosimilar CT-P10 compared with continued treatment with CT-P10: results of a 56-week open-label study in patients with rheumatoid arthritis BioDrugs. 2017;31(4):369–377. doi:10.1007/s40259-017-0233-6.
    1. Yoo DH, Suh C-H, Shim SC, Jeka S, Cons Molina FF, Hrycaj P, Wiland P, Lee EY, Medina-Rodriguez FG, Shesternya P, et al. Efficacy, safety and pharmacokinetics of up to two courses of the rituximab biosimilar CT-P10 versus innovator rituximab in patients with rheumatoid arthritis: results up to week 72 of a phase I randomized controlled trial. BioDrugs. 2017;31(4):357–367. doi:10.1007/s40259-017-0232-7.
    1. Yoo DH, Park W, Suh C-H, Shim SC, Jeka S, Cons Molina FF, Hrycaj P, Spieler W, Wiland P, Brzezicki J, et al. Efficacy and safety of rituximab biosimilar candidate (CTP-10) and innovator rituximab in patients with rheumatoid arthritis: results from phase I randomized controlled trial over 72 weeks. 2015 ACR/ARHP annual meeting: abstract number 2058.
    1. Yoo DH, Park W, Suh C-H, Shim SC, Cons Molina FF, Jeka S, Brzezicki J, Medina-Rodriguez FG, Hrycaj P, Wiland P, et al. Efficacy and safety of switched CT-P10 from innovator rituximab compared to those of maintained CT-P10 in patients with rheumatoid arthritis up to 56 weeks. 2015 ACR/ARHP annual meeting: abstract number 1675.
    1. Kim WS, Buske C, Ogura M, Jurczak W, Sancho JM, Zhavrid E, Kim JS, Hernández-Rivas JÁ, Prokharau A, Vasilica M, et al. Efficacy, pharmacokinetics, and safety of the biosimilar CT-P10 compared with rituximab in patients with previously untreated advanced-stage follicular lymphoma: a randomised, double-blind, parallel-group, non-inferiority phase 3 trial. Lancet Haematol. 2017;4(8):e362–e373. doi:10.1016/S2352-3026(17)30120-5.
    1. Chen K, Page JG, Schwartz AM, Lee TN, DeWall SL, Sikkema DJ, Wang C. False-positive immunogenicity responses are caused by CD20+ B cell membrane fragments in an anti-ofatumumab antibody bridging assay. J Immunol Methods. 2013;394(1–2):22–31. doi:10.1016/j.jim.2013.04.011.
    1. Amaravadi L, Song A, Myler H, Thway T, Kirshner S, Devanarayan V, Ni YG, Garofolo F, Birnboeck H, Richards S, et al. 2015 White Paper on recent issues in bioanalysis: focus on new technologies and biomarkers (Part 3–LBA, biomarkers and immunogenicity). Bioanalysis. 2015;7(24):3107–3124 doi:10.4155/bio.15.226.
    1. Emery P, Deodhar A, Rigby WF, Isaacs JD, Combe B, Racewicz AJ, Latinis K, Abud-Mendoza C, Szczepanski LJ, Roschmann RA, et al. Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab’s Efficacy in MTX iNadequate rEsponders (SERENE)). Ann Rheum Dis. 2010;69(9):1629–1635. doi:10.1136/ard.2009.119933.
    1. Singh JA, Saag KG, Bridges SL, Jr., Akl EA, Bannuru RR, Sullivan MC, Vaysbrot E, McNaughton C, Osani M, Shmerling RH, et al. 2015 American College of Rheumatology Guideline for the treatment of rheumatoid arthritis. Arthritis Care Res. 2016. 2015;68(1):1–25. doi:10.1002/acr.22783.
    1. Putrik P, Ramiro S, Kvien TK, Sokka T, Pavlova M, Uhlig T, Boonen A. Inequities in access to biologic and synthetic DMARDs across 46 European countries. Ann Rheum Dis. 2014;73(1):198–206. doi:10.1136/annrheumdis-2012-202603.
    1. Schellekens H, Smolen JS, Dicato M, Rifkin RM. Safety and efficacy of biosimilars in oncology. Lancet Oncol. 2016;17(11):e502–e509. doi:10.1016/S1470-2045(16)30374-6.
    1. Gulacsi L, Brodszky V, Baji P, Rencz F, Pentek M. The rituximab biosimilar CT-P10 in rheumatology and cancer: a budget impact analysis in 28 European countries. Adv Ther. 2017;34(5):1128–1144. doi:10.1007/s12325-017-0522-y.
    1. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheumat. 1988;31(3):315–324. doi:10.1002/art.1780310302.
    1. Fransen J, van Riel PL. The Disease Activity Score and the EULAR response criteria. Clin Exp Rheumatol. 2005;23(5 Suppl 39):S93–S99.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever