A randomised, double-blind, phase III study comparing SB2, an infliximab biosimilar, to the infliximab reference product Remicade in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy

Abstract

Objectives: To compare the efficacy, safety, immunogenicity and pharmacokinetics (PK) of SB2 to the infliximab reference product (INF) in patients with moderate to severe rheumatoid arthritis (RA) despite methotrexate therapy.

Methods: This is a phase III, randomised, double-blind, multinational, multicentre parallel group study. Patients with moderate to severe RA despite methotrexate therapy were randomised in a 1:1 ratio to receive either SB2 or INF of 3 mg/kg. The primary end point was the American College of Rheumatology 20% (ACR20) response at week 30. Inclusion of the 95% CI of the ACR20 response difference within a ±15% margin was required for equivalence.

Results: 584 subjects were randomised into SB2 (N=291; 290 analysed) or INF (N=293). The ACR20 response at week 30 in the per-protocol set was 64.1% in SB2 versus 66.0% in INF. The adjusted rate difference was -1.88% (95% CI -10.26% to 6.51%), which was within the predefined equivalence margin. Other efficacy outcomes such as ACR50/70, disease activity score measured by 28 joints and European League against Rheumatism response were similar between SB2 and INF. The incidence of treatment-emergent adverse events was comparable (57.6% in SB2 vs 58.0% in INF) as well as the incidence of antidrug antibodies (ADA) to infliximab up to week 30 (55.1% in SB2 vs 49.7% in INF). The PK profile was similar between SB2 and INF. Efficacy, safety and PK by ADA subgroup were comparable between SB2 and INF.

Conclusions: SB2 was equivalent to INF in terms of ACR20 response at week 30. SB2 was well tolerated with a comparable safety profile, immunogenicity and PK to INF.

Trial registration number: NCT01936181.

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

Figure 1

Disposition flow chart of the study population. Among the 584 randomised, one patient from the SB2 treatment group withdrew before taking the first dose of SB2. Accordingly, the full analysis set (FAS) for SB2 is N=290 and infliximab reference product (INF) N=293 (same with the safety population (SAF)). The per-protocol set (PPS) for SB2 is N=231 and INF N=247. The pharmacokinetics population for SB2 is N=165 and INF N=160 (approximately 50% of the FAS).

Figure 2

American College of Rheumatology (ACR) response rates at week 30. (A) ACR20, 50 and 70 responses for SB2 and infliximab reference product (INF) in the per-protocol set (PPS). (B) ACR20, 50 and 70 responses for SB2 and INF in the full analysis set (FAS). Rate differences were calculated by non-parametrical analysis of covariance adjusted for baseline C reactive protein and region.

Figure 3

ACR20 response pattern over time. Dots are actual ACR20 response rates for SB2 and infliximab reference product (INF) at each visit (per-protocol set, PPS) and the curve is fitted by non-linear mixed models employing an exponential time-response model. The upper limit of the 95% CI for the 2-norm was 35.8, which was below the prespecified equivalence margin of 61.8. For details about determining equivalence between the two time-response curves, please refer to the text.

Figure 4

DAS28, SDAI and CDAI responses. (A) Mean DAS28 scores by visit for SB2 and infliximab reference product (INF). (B–D) Disease activity classification by DAS28, SDAI and CDAI. Remission is defined as DAS28<2.6, SDAI≤3.3 or CDAI≤2.8 and LDA is defined as DAS28 2.6≤to<3.2, SDAI 3.3