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

Abstract

Background: CT-P10 is a biosimilar of innovator rituximab (RTX), a biological therapy used to treat patients with rheumatoid arthritis (RA) who have responded inadequately to anti-tumor necrosis factor agents.

Objective: Our objective was to compare the clinical profile of CT-P10 versus RTX in patients with RA who received up to two courses of treatment and were followed for up to 72 weeks.

Methods: In this multicenter double-blind phase I study, patients were randomized 2:1 to receive CT-P10 1000 mg or RTX 1000 mg at weeks 0 and 2. Based on disease activity, patients could receive a second course of treatment between weeks 24 and 48. Efficacy endpoints, including mean change from baseline in Disease Activity Score using 28 joints (DAS28), safety, immunogenicity, pharmacokinetics, and pharmacodynamics were evaluated.

Results: In total, 154 patients were randomized to CT-P10 or RTX (n = 103 and 51, respectively); 137 (n = 92 and 45) completed the first course of treatment, of whom 83 (n = 60 and 23) were re-treated. Improvements from baseline in all efficacy endpoints were highly similar between the CT-P10 and RTX groups over both treatment courses. At week 24 after the second course, mean change from week 0 of the first course in DAS28 erythrocyte sedimentation rate was -2.47 and -2.04 for CT-P10 and RTX, respectively, (p = 0.1866) and in DAS28 C-reactive protein was -2.32 and -2.00, respectively (p = 0.3268). The proportion of patients positive for antidrug antibodies at week 24 after the second treatment course was 20.0% and 21.7% in the CT-P10 and RTX groups, respectively. The safety profile of CT-P10 was comparable to that of RTX, and pharmacokinetic and pharmacodynamic properties were similar.

Conclusions: In patients with RA, efficacy, safety, and other clinical data were comparable between CT-P10 and RTX after up to two courses of treatment over 72 weeks. (ClinicalTrials.gov identifier NCT01534884).

Conflict of interest statement

Funding

This work was funded by CELLTRION, Inc. (Incheon, Republic of Korea). The funding body contributed to the design of the study; the collection, analysis, and interpretation of data; and reviewed drafts and the final version of the manuscript. The final decision to submit the manuscript was taken by the authors.

Conflict of interest

DHY is a scientific consultant and on the speaker’s bureau of CELLTRION and has received research grants not related to this clinical study. PH and SR received grants from CELLTRION for conducting the clinical trial. MJL received grants from CELLTRION during the conduct of the study. SJL is an employee of, and holds stock options in, CELLTRION. SYL and SHK are employees of CELLTRION. WP received consulting fees during the conduct of the study and grants outside the submitted work from CELLTRION. C-HS, SCS, SJ, FFCM, PW, EYL, FGM-R, PS, MS, VK, DHS, LM, and J-YC have no conflicts of interest.

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. The protocol for the study was approved by regulatory authorities and the ethics committees of all participating centers, as follows. Brazil: Comitê de Ética em Pesquisa da Associação de Assistência à Criança Deficiente; Comitê de Ética em Pesquisa em Seres Humanos da Universidade Federal de Juiz de Fora; Comitê de Ética em Pesquisa do Hospital de Clínicas da Universidade Federal do Paraná. Germany: Ethics Committee of PPD Germany GmbH & Co KG. Republic of Korea: Institutional Review Board (IRB) of IN-HA University Hospital; IRB of Hanyang University Medical Center; IRB of Seoul St Mary’s Hospital, The Catholic University; SNUMC/SNUH IRB; IRB of Severance Hospital; IRB of Chonnam National University Hospital; IRB of Daegu Catholic University Medical Center; IRB of Daejeon Eulji University Hospital. Mexico: Comitê de Ética ICLE SC; Comitê de Investigación y Ética del Hospital Centro de Especialidades Médicas del Sureste SA de CV; Comitê de Bioetica de la Unidad de Investigación en Enfermedades Cronico Degenerativas; Comitê de Investigación para Estudios en Humanos del “Hospital Médica Sur” S.A.B de C.V; Comitê Bioetico para la Investigación Clínica S.C. IRB. Poland: Bioethics Committee at the Regional Medical Council of Wielkopolska Medical Chamber. Russia: Council on Ethics, Annex to the Order of the Ministry of Healthcare of the Russian Federation. Spain: Comité Etico de Investigación Clínica de Andalucia. Ukraine: Central Commission on Ethics Questions of the MoH of Ukraine.

Informed consent

All patients provided written informed consent to participate in the study.

Figures

Fig. 1

Patient disposition. DAS28 Disease Activity Score using 28 joints, EULAR European League Against Rheumatism, RTX innovator rituximab

Fig. 2

Disease activity during the first and second courses of treatment as measured by a DAS28-ESR, b DAS28-CRP, c CDAI and d SDAI (efficacy population). Efficacy population for the first course included 100 patients in the CT-P10 and 48 patients in the innovator rituximab treatment groups. Of these, 82 patients received a second course of treatment (59 and 23 patients in the CT-P10 and innovator rituximab treatment groups, respectively). CDAI Clinical Disease Activity Index, CRP C-reactive protein, DAS28 Disease Activity Score using 28 joints, ESR erythrocyte sedimentation rate, RTX innovator rituximab, SD standard deviation, SDAI Simplified Disease Activity Index

Fig. 3

Response to first and second treatment courses according to European League Against Rheumatism criteria using C-reactive protein (efficacy population). Efficacy population for the first course included 100 patients in the CT-P10 and 48 patients in the innovator rituximab treatment groups. Of these, 82 patients received a second course of treatment (59 and 23 patients in the CT-P10 and innovator rituximab treatment groups, respectively). RTX innovator rituximab