A phase III randomised, double-blind, parallel-group study comparing SB4 with etanercept reference product in patients with active rheumatoid arthritis despite methotrexate therapy

Abstract

Objectives: To compare the efficacy and safety of SB4 (an etanercept biosimilar) with reference product etanercept (ETN) in patients with moderate to severe rheumatoid arthritis (RA) despite methotrexate (MTX) therapy.

Methods: This is a phase III, randomised, double-blind, parallel-group, multicentre study with a 24-week primary endpoint. Patients with moderate to severe RA despite MTX treatment were randomised to receive weekly dose of 50 mg of subcutaneous SB4 or ETN. The primary endpoint was the American College of Rheumatology 20% (ACR20) response at week 24. Other efficacy endpoints as well as safety, immunogenicity and pharmacokinetic parameters were also measured.

Results: 596 patients were randomised to either SB4 (N=299) or ETN (N=297). The ACR20 response rate at week 24 in the per-protocol set was 78.1% for SB4 and 80.3% for ETN. The 95% CI of the adjusted treatment difference was -9.41% to 4.98%, which is completely contained within the predefined equivalence margin of -15% to 15%, indicating therapeutic equivalence between SB4 and ETN. Other efficacy endpoints and pharmacokinetic endpoints were comparable. The incidence of treatment-emergent adverse events was comparable (55.2% vs 58.2%), and the incidence of antidrug antibody development up to week 24 was lower in SB4 compared with ETN (0.7% vs 13.1%).

Conclusions: SB4 was shown to be equivalent with ETN in terms of efficacy at week 24. SB4 was well tolerated with a lower immunogenicity profile. The safety profile of SB4 was comparable with that of ETN.

Trial registration numbers: NCT01895309, EudraCT 2012-005026-30.

Keywords: Anti-TNF; DMARDs (biologic); Rheumatoid Arthritis.

Figure 1

Summary of patient disposition. A total of 777 patients were screened and 181 patients were excluded mainly due to meeting the exclusion criteria. Multiple screening failure reasons were possible. All patients randomised were included in the full analysis set and the safety set. Of the 551 patients who completed 24 weeks of treatment, 481 patients were included in the per-protocol set. ETN, reference product etanercept.

Figure 2

American College of Rheumatology (ACR) response rates at week 24. The adjusted treatment difference and its 95% CI were analysed with baseline C reactive protein as a covariate and stratified by region. (A) ACR 20% (ACR20) response rates of SB4 and etanercept (ETN) in the per-protocol set and full analysis set. (B) ACR50 response rates of SB4 and ETN in the per-protocol set and full analysis set. (C) ACR70 response rates of SB4 and ETN in the per-protocol set and full analysis set. *One patient from the SB4 group was excluded from the FAS due to missing efficacy data at baseline.

Figure 3

Estimated time–response curves of American College of Rheumatology 20% (ACR20) response rate up to week 24 in the per-protocol set. For details of the estimation process, please refer to the main text. ETN, reference product etanercept.

Figure 4

Changes over time in the disease activity score in 28 joints (DAS28) and European League Against Rheumatism (EULAR) responses at week 24 in the full analysis set. (A) Change in DAS28 up to week 24. (B) EULAR response based on DAS28. (C) Proportion of patients achieving low-disease activity score (LDAS) defined as DAS28 ≤3.2 and remission defined as DAS28 ≤2.6. ETN, reference product etanercept.