Efficacy and safety of CT-P47 versus reference tocilizumab: 32-week results of a randomised, active-controlled, double-blind, phase III study in patients with rheumatoid arthritis, including 8 weeks of switching data from reference tocilizumab to CT-P47

Abstract

Objectives: To demonstrate efficacy equivalence of CT-P47 and EU-approved reference tocilizumab (r-TCZ) in patients with rheumatoid arthritis (RA).

Methods: This double-blind, phase III study randomised (1:1) patients to receive CT-P47 or r-TCZ (8 mg/kg) every 4 weeks until week 20 during treatment period (TP) 1. Prior to week 24 dosing, patients receiving r-TCZ were randomised (1:1) to continue r-TCZ or switch to CT-P47; patients receiving CT-P47 continued CT-P47 (TP2, 8 mg/kg every 4 weeks until week 48). The dual primary endpoints (for different regulatory requirements) were mean changes from baseline in Disease Activity Score in 28 joints (DAS28; erythrocyte sedimentation rate (ESR)) at week 12 and week 24. Efficacy equivalence was determined if CIs for the treatment difference were within predefined equivalence margins: (95% CI -0.6, 0.6 (analysis of covariance (ANCOVA)) at week 12 or 90% CI -0.6, 0.5 (ANCOVA with multiple imputation) at week 24). Additional efficacy, pharmacokinetic (PK) and safety endpoints, including immunogenicity, were investigated. Findings up to week 32 are presented.

Results: In TP1, 471 patients were randomised (234 CT-P47; 237 r-TCZ). The 95% and 90% CIs for the estimated treatment differences were contained within the predefined equivalence margins; the estimated difference in DAS28-ESR at week 12 was -0.01 (95% CI -0.26, 0.24) and at week 24 was -0.10 (90% CI -0.30, 0.10). Secondary efficacy endpoints, PKs and overall safety were comparable between groups up to week 32.

Conclusions: Efficacy equivalence, alongside comparable PK, safety and immunogenicity profiles, was determined between CT-P47 and r-TCZ in adults with RA, including after switching from r-TCZ to CT-P47.

Keywords: arthritis, rheumatoid; autoimmune diseases; biosimilar pharmaceuticals.

Figure 1. Study design. *Dual primary endpoints included the mean change from baseline in DAS28-ESR at week 12 and week 24 (for different regulatory requirements). ^†Prior to dosing at week 24, patients in the r-TCZ group were randomly assigned (1:1) to either continue r-TCZ (r-TCZ maintenance) or switch to CT-P47 (CT–P47 switched). ^‡Findings up to week 32 are presented in this manuscript. ^§The EOS assessments were performed at week 52 for all patients who completed or discontinued study drug. The patients who discontinued early from the study drug also visited the study centre until week 52 by regular scheduled time interval for efficacy and safety assessments, even if they changed their RA medication (including those prohibited by the protocol). ^¶An independent joint count assessor was assigned to each study centre. Where possible, the joint count assessments were performed independently by the same person at each study centre throughout the study period. DAS28, Disease Activity Score in 28 joints; EOS, end-of-study; ESR, erythrocyte sedimentation rate; IV, intravenous; Q4W, every 4 weeks; RA, rheumatoid arthritis; r-TCZ, reference tocilizumab.

Figure 2. Patient disposition (ITT set). *The numerical difference between patients who discontinued the study drug due to adverse events in the patient disposition summary and the summary of TEAEs leading to study drug discontinuation is due to the fact that the patient disposition summary was based on the number of patients who discontinued in each treatment period (and a week 32 cut-off date was also applied) while the summary of TEAEs leading to discontinuation was based on the start date of TEAEs. ^†Prior to dosing at week 24, patients in the r-TCZ group were randomly assigned (1:1) to either continue r-TCZ (r-TCZ maintenance) or switch to CT-P47 (CT-P47 switched). Patients in the CT-P47 group continued to receive CT-P47. ITT, intention to treat; r-TCZ, reference tocilizumab; TEAE, treatment-emergent adverse event; TP, treatment period.

Figure 3. Secondary efficacy results in the overall period up to week 32 (ITT set). Mean change from baseline in ESR (A).Mean change from baseline in CRP (B).ACR20, ACR50 and ACR70 response rates at week 12 and week 24 (C).Mean change from baseline in SDAI (D).Mean change from baseline in CDAI (E).SDAI, CDAI and DAS28-ESR remission rates at week 12 and week 24 (F).SDAI, CDAI and DAS28-ESR LDA rates at week 12 and week 24 (G).ACR/EULAR remission (Boolean 1.0 and 2.0 definitions) at week 12 and week 24 (H).*SDAI score categorised as remission (0.0≤×≤3.3) and LDA (3.3<×≤11.0). ^†CDAI score categorised as remission (0.0≤×≤2.8) and LDA (2.8<×≤10.0). ACR, American College of Rheumatology; ACR20, 20% improvement according to ACR criteria; ACR50, 50% improvement according to ACR criteria; ACR70, 70% improvement according to ACR criteria; CDAI, Clinical Disease Activity Index; CRP, C reactive protein; DAS28, Disease Activity Score in 28 joints; ESR, erythrocyte sedimentation rate; EULAR, European Alliance of Associations for Rheumatology; ITT, intention to treat; LDA, low disease activity; r-TCZ, reference tocilizumab; SDAI, Simplified Disease Activity Index; TP, treatment period.