Efficacy and Safety of Switching From Rituximab to Biosimilar CT-P10 in Rheumatoid Arthritis

72-Week Data From a Randomized Phase 3 Trial

Seung Cheol Shim; Ljubinka Božić-Majstorović; Alfredo Berrocal Kasay; Elias Chalouhi El-Khouri; Fedra Irazoque-Palazuelos; Francisco Fidencio Cons Molina; Francisco G. Medina-Rodriguez; Pedro Miranda; Pavel Shesternya; Jose Chavez-Corrales; Piotr Wiland; Slawomir Jeka; Olena Garmish; Pawel Hrycaj; Natalia Fomina; Won Park; Chang-Hee Suh; Sang Joon Lee; Sung Young Lee; Yun Ju Bae; Dae Hyun Yoo

Disclosures

Rheumatology. 2019;58(12):2193-2202. 

In This Article

Abstract and Introduction

Abstract

Objective: To evaluate the efficacy and safety of CT-P10, a rituximab biosimilar after a single switch, during a multinational, randomized, double-blind Phase 3 trial involving patients with RA.

Methods: Patients received 48 weeks' treatment with CT-P10 or United States- or European Union-sourced reference rituximab (US-RTX and EU-RTX, respectively). Patients entering the extension period (weeks 48–72) remained on CT-P10 (CT-P10/CT-P10; n = 122) or US-RTX (US-RTX/US-RTX; n = 64), or switched to CT-P10 from US-RTX (US-RTX/CT-P10; n = 62) or EU-RTX (EU-RTX/CT-P10; n = 47) for an additional course. Efficacy endpoints included Disease Activity Score using 28 joints (DAS28), American College of Rheumatology (ACR) response rates, and quality of life-related parameters. Pharmacodynamics, immunogenicity and safety were also assessed.

Results: At week 72, similar improvements were observed by disease activity parameters including DAS28 and ACR response rate in the four extension period treatment groups. Quality of life improvements at week 72 vs baseline were similarly shown during the extension period in all groups. Newly developed anti-drug antibodies were detected in two patients following study drug infusion in the extension period. Similar pharmacodynamic and safety profiles were observed across groups.

Conclusion: Long-term use of CT-P10 up to 72 weeks was effective and well tolerated. Furthermore, switching from reference rituximab to CT-P10 in RA was well tolerated and did not result in any clinically meaningful differences in terms of efficacy, pharmacodynamics, immunogenicity and safety.

Introduction

B cells play a fundamental role in the pathogenesis of RA, through autoantibody-dependent and -independent mechanisms.[1,2] Rituximab, a monoclonal antibody against the B-cell surface-antigen CD20, exerts its therapeutic effects via immune-mediated cytotoxicity, direct induction of apoptosis, and subsequent depletion of CD20-positive B cells.[3] Rituximab, in combination with MTX, can reduce clinical symptoms and signs of RA[4–6] and is approved for patients with moderate-to-severe RA who show an inadequate response or intolerance to anti-TNF agents.[7,8] Available from the original manufacturer, Roche (Welwyn Garden City, UK) in Europe and Genentech, Inc. (South San Francisco, CA, USA) in the USA, rituximab is also approved in non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukaemia, granulomatosis with polyangiitis and microscopic polyangiitis.[7,8] CT-P10 (CELLTRION, Incheon, Republic of Korea) is a rituximab biosimilar approved in several regions or countries.[9,10] To gain regulatory approval, a biosimilar must demonstrate that it exhibits no clinically meaningful differences from its reference product, in terms of quality, safety and efficacy.[11,12] A comprehensive, stepwise approach is recommended, starting with analytical, in vitro and/or non-clinical in vivo studies, and concluding with clinical studies evaluating pharmacokinetics (PK), pharmacodynamics (PD), efficacy, immunogenicity and safety.[13] Comparisons with the reference product at each of these steps inform the type and extent of data required at the next step. Overall, it is the 'totality of evidence' that informs regulatory decisions, although approval usually requires proof of statistical equivalence of the biosimilar and reference product in terms of PK and efficacy, as well as a demonstration of comparable safety profiles.[11,12] For CT-P10, a Phase 1 study in patients with active RA demonstrated equivalent PK to European-sourced rituximab (EU-RTX) with no substantial differences in efficacy, PD, immunogenicity or safety.[14] Two Phase 3 studies in patients with NHL also showed no clinically meaningful differences between CT-P10 and US-sourced rituximab (US-RTX).[15,16]

Here, and in two previous reports,[17,18] we present the results of a multinational, double-blind, active-controlled Phase 3 study involving patients with active RA initially randomized to CT-P10, US-RTX, or EU-RTX (ClinicalTrials.gov identifier: NCT02149121). This study consisted of two periods: a main period of two treatment courses and an extension period of one additional course. For the first course of study treatment, PK and efficacy equivalence of CT-P10 and US-RTX or EU-RTX were demonstrated by achieving predefined endpoints at week 24.[17] Follow-up of patients eligible for a second course of their allocated study treatment (administered on weeks 24 and 26) until week 48 showed that CT-P10 and RTX were similar in terms of efficacy, PK, PD, immunogenicity and safety.[18] On completion of this main period, patients could enter an extension period from week 48 to week 72. Here we report results of the extension period, which evaluated the efficacy, PD, immunogenicity and safety of CT-P10 after a single switch from either US-RTX or EU-RTX, and in patients maintained on CT-P10 or US-RTX.

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