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

Jung-Yoon Choe, Nenad Prodanovic, Jaroslaw Niebrzydowski, Ivan Staykov, Eva Dokoupilova, Asta Baranauskaite, Roman Yatsyshyn, Mevludin Mekic, Wieskawa Porawska, Hana Ciferska, Krystyna Jedrychowicz-Rosiak, Agnieszka Zielinska, Jasmine Choi, Young Hee Rho, Josef S Smolen, Jung-Yoon Choe, Nenad Prodanovic, Jaroslaw Niebrzydowski, Ivan Staykov, Eva Dokoupilova, Asta Baranauskaite, Roman Yatsyshyn, Mevludin Mekic, Wieskawa Porawska, Hana Ciferska, Krystyna Jedrychowicz-Rosiak, Agnieszka Zielinska, Jasmine Choi, Young Hee Rho, Josef S Smolen

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.

Conflict of interest statement

J-YC reports receiving grant/research support and consultant fees from Samsung Bioepis. JSS reports receiving grant/research support from AbbVie, Jassen, MSD, Pfizer, Roche, UCB, Consultant for: AbbVie, Amgen, AstraZeneca, Astro-Pharma, Celgene, GSK, Jassen, Lilly, Medimmune, MSD, Norvartis-Sandoz, Novo Nordisk, Pfizer, Roche, Samsung Bioepis, Sanofi, UCB. AB reports receiving grant/research support from AbbVie and Samsung Bioepis. NP, JN, IS, ED, RY, MM, WP, HC, KJ-R and AZ report receiving grant/research support from Samsung Bioepis. JC and YHR are employees of Samsung Bioepis.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Figures

Figure 1
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
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
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
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

References

    1. Birnbaum H, Pike C, Kaufman R, et al. . Societal cost of rheumatoid arthritis patients in the US. Curr Med Res Opin 2010;26:77–90. 10.1185/03007990903422307
    1. Cross M, Smith E, Hoy D, et al. . The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 2014;73:1316–22. 10.1136/annrheumdis-2013-204627
    1. Smolen JS, Landewe R, Breedveld FC, et al. . EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014;73:492–509. 10.1136/annrheumdis-2013-204573
    1. Maini R, St Clair EW, Breedveld F, et al. . Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999;354:1932–9.
    1. Modena V, Bianchi G, Roccatello D. Cost-effectiveness of biologic treatment for rheumatoid arthritis in clinical practice: an achievable target? Autoimmun Rev 2013;12:835–8. 10.1016/j.autrev.2012.11.009
    1. EMA/CHMP. Guideline on similar biological medicinal products 2015. (accessed 6 Mar 2015).
    1. Dorner T, Strand V, Castaneda-Hernandez G, et al. . The role of biosimilars in the treatment of rheumatic diseases. Ann Rheum Dis 2013;72:322–8. 10.1136/annrheumdis-2012-202715
    1. EMA/CHMP. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues 2014. (accessed 6 Mar 2015).
    1. Jung SK, Lee KH, Jeon JW, et al. . Physicochemical characterization of Remsima. MAbs 2014;6:1163–77. 10.4161/mabs.32221
    1. Park W, Hrycaj P, Jeka S, et al. . A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis 2013;72:1605–12. 10.1136/annrheumdis-2012-203091
    1. Yoo DH, Hrycaj P, Miranda P, et al. . A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis 2013;72:1613–20. 10.1136/annrheumdis-2012-203090
    1. EMA/CHMP. CHMP summary of positive opinion for Remsima 2013. (accessed 6 Mar 2015).
    1. Hirsch BR, Lyman GH. Biosimilars: a cure to the U.S. health care cost conundrum? Blood Rev 2014;28:263–8. 10.1016/j.blre.2014.08.003
    1. Shin DH, Kim Y, Kim YS, et al. . A phase I pharmacokinetic study comparing SB2, an Infliximab biosimilar, and Infliximab Reference Product (Remicade(R)) in healthy subjects. Rome, Italy: EULAR Congress, SAT0144, 2015.
    1. Anderson J, Caplan L, Yazdany J, et al. . Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care Res (Hoboken) 2012;64:640–7. 10.1002/acr.21649
    1. Felson DT, Smolen JS, Wells G, et al. . American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis 2011;70:404–13. 10.1136/ard.2011.149765
    1. Shankar G, Arkin S, Cocea L, et al. . Assessment and reporting of the clinical immunogenicity of therapeutic proteins and peptides-harmonized terminology and tactical recommendations. AAPS J 2014;16:658–73. 10.1208/s12248-014-9599-2
    1. Abe T, Takeuchi T, Miyasaka N, et al. . A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. J Rheumatol 2006;33:37–44.
    1. Westhovens R, Yocum D, Han J, et al. . The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial. Arthritis Rheum 2006;54:1075–86. 10.1002/art.21734
    1. EMA/CHMP. Guideline on the choice of the non-inferiority margin 2005. (accessed 6 Mar 2015).
    1. US FDA. Guidance for Industry: non-inferiority clinical trials 2010. (accessed 6 Mar 2015).
    1. International_Conference_on_Harmonisation. Statistical Principles for Clinical Trials E9 1998. (accessed 6 Mar 2015).
    1. Koch GG, Tangen CM, Jung JW, et al. . Issues for covariance analysis of dichotomous and ordered categorical data from randomized clinical trials and non-parametric strategies for addressing them. Stat Med 1998;17:1863–92. 10.1002/(SICI)1097-0258(19980815/30)17:15/16<1863::AID-SIM989>;2-M
    1. Tangen CM, Koch GG. Complementary nonparametric analysis of covariance for logistic regression in a randomized clinical trial setting. J Biopharm Stat 1999;9:45–66. 10.1081/BIP-100100999
    1. Zink RC, Koch GG. SAS macro NParCov, version 2, non-parametric analysis of covariance. USA: Biometric Consulting Laboratory, Department of Biostatistics, University of North Carolina at Chapel Hill, 2002.
    1. Reeve R, Pang L, Ferguson B, et al. . Rheumatoid arthritis disease progression modeling. Ther Innov Regul Sci 2013;47:641–50. 10.1177/2168479013499571
    1. Kay J, Smolen JS. Biosimilars to treat inflammatory arthritis: the challenge of proving identity. Ann Rheum Dis 2013;72:1589–93. 10.1136/annrheumdis-2012-203198
    1. Curtis JR, Xi J, Patkar N, et al. . Drug-specific and time-dependent risks of bacterial infection among patients with rheumatoid arthritis who were exposed to tumor necrosis factor alpha antagonists. Arthritis Rheum 2007;56:4226–7. 10.1002/art.23050
    1. Galloway JB, Hyrich KL, Mercer LK, et al. . Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. Rheumatology (Oxford) 2011;50:124–31. 10.1093/rheumatology/keq242
    1. EMA. Remicade: EPAR—Product Information (SmPC) 2014. (accessed 6 Mar 2015).
    1. Krintel SB, Grunert VP, Hetland ML, et al. . The frequency of anti-infliximab antibodies in patients with rheumatoid arthritis treated in routine care and the associations with adverse drug reactions and treatment failure. Rheumatology (Oxford) 2013;52:1245–53. 10.1093/rheumatology/ket017
    1. Wolbink GJ, Vis M, Lems W, et al. . Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum 2006;54:711–15. 10.1002/art.21671
    1. Brodszky V, Baji P, Balogh O, et al. . Budget impact analysis of biosimilar infliximab (CT-P13) for the treatment of rheumatoid arthritis in six Central and Eastern European countries. Eur J Health Econ 2014;15(Suppl 1):S65–71. 10.1007/s10198-014-0595-3

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner