Efficacy and safety of brodalumab, an anti-IL17RA monoclonal antibody, in patients with axial spondyloarthritis: 16-week results from a randomised, placebo-controlled, phase 3 trial

James Cheng-Chung Wei, Tae-Hwan Kim, Mitsumasa Kishimoto, Naoki Ogusu, Haeyoun Jeong, Shigeto Kobayashi, 4827-006 study group, Kurisu Tada, Mitsumasa Kishimoto, Kou Katayama, Atsuo Taniguchi, Yohei Seto, Mitsuhiro Morita, Kazuhiro Hatta, Tetsuya Tomita, Nobuo Negoro, Hitoshi Goto, Shigeyoshi Tsuji, Norikazu Murata, Kiyoshi Matsui, Masahiro Yamamura, Hiroaki Dobashi, Junichi Fukushi, Satoshi Ikemura, Akira Maeyama, Mitsuyo Kinjo, Yukitaka Ueki, Eishi Uechi, Tatsuya Atsumi, Hideto Kameda, Yoshinori Taniguchi, Sei Muraoka, Masanobu Oishi, Seung Jae Hong, Won Park, Shin Seok Lee, Chang Hee Suh, Seong Wook Kang, Tae-Hwan Kim, Jung Yoon Choe, Ji Hyeon Ju, Jin Kyun Park, Seung-Geun Lee, Yun Jong Lee, Sang-Heon Lee, Cheng Chung Wei, Tien Tsai Cheng, Wen Chan Tsai, Chung Ming Huang, Hsin Hua Chen, Der-Yuan Chen, Meng Yu Weng, Shue Fen Luo, Kun Hung Chen, Ling Jung Yen, Cheng Han Wu, Hsiang Cheng Chen, James Cheng-Chung Wei, Tae-Hwan Kim, Mitsumasa Kishimoto, Naoki Ogusu, Haeyoun Jeong, Shigeto Kobayashi, 4827-006 study group, Kurisu Tada, Mitsumasa Kishimoto, Kou Katayama, Atsuo Taniguchi, Yohei Seto, Mitsuhiro Morita, Kazuhiro Hatta, Tetsuya Tomita, Nobuo Negoro, Hitoshi Goto, Shigeyoshi Tsuji, Norikazu Murata, Kiyoshi Matsui, Masahiro Yamamura, Hiroaki Dobashi, Junichi Fukushi, Satoshi Ikemura, Akira Maeyama, Mitsuyo Kinjo, Yukitaka Ueki, Eishi Uechi, Tatsuya Atsumi, Hideto Kameda, Yoshinori Taniguchi, Sei Muraoka, Masanobu Oishi, Seung Jae Hong, Won Park, Shin Seok Lee, Chang Hee Suh, Seong Wook Kang, Tae-Hwan Kim, Jung Yoon Choe, Ji Hyeon Ju, Jin Kyun Park, Seung-Geun Lee, Yun Jong Lee, Sang-Heon Lee, Cheng Chung Wei, Tien Tsai Cheng, Wen Chan Tsai, Chung Ming Huang, Hsin Hua Chen, Der-Yuan Chen, Meng Yu Weng, Shue Fen Luo, Kun Hung Chen, Ling Jung Yen, Cheng Han Wu, Hsiang Cheng Chen

Abstract

Objective: To investigate the efficacy and safety of brodalumab, a fully human anti-interleukin-17 receptor A monoclonal antibody, in patients with axial spondyloarthritis (axSpA).

Methods: In a multicentre, placebo-controlled phase 3 study (NCT02985983) conducted at 48 sites across Japan, Korea and Taiwan, patients with axSpA were randomised 1:1 to receive subcutaneous brodalumab 210 mg (n=80) or placebo (n=79) at baseline, weeks 1 and 2 and every 2 weeks thereafter, during the 16-week double-blind period. The primary endpoint was the proportion of patients with Assessment of SpondyloArthritis International Society (ASAS) 40 response at week 16. Secondary endpoints included the proportion of patients with ASAS 20 response and change in Ankylosing Spondylitis Disease Activity Score using C-reactive protein (ASDAS-CRP) at week 16 and safety.

Results: ASAS 40 response rate (n/N; 95% CI) was 43.8% (35/80; 32.7, 55.3) with brodalumab vs 24.1% (19/79; 15.1, 35.0) with placebo (rate difference, 19.7% (5.3, 34.1); p=0.018 by stratified Cochran-Mantel-Haenszel test). ASAS 20 response rate (n/N; 95% CI) was 67.5% (54/80; 56.1, 77.6) vs 41.8% (33/79; 30.8, 53.4) and least squares mean change (95% CI) from baseline (brodalumab, 2.660; placebo, 2.716) in ASDAS-CRP was -1.127 (-1.322, -0.931) with brodalumab vs -0.672 (-0.872, -0.473) with placebo at week 16. Treatment-emergent adverse events were reported in 44 (55%) and 45 (57%) patients in the brodalumab and placebo groups, respectively.

Conclusion: Brodalumab demonstrated a significant improvement at week 16 in patients with active axSpA. Safety of brodalumab was consistent with that reported in previous global/Japanese psoriasis studies.

Keywords: ankylosing; biological therapy; inflammation; spondylitis; therapeutics.

Conflict of interest statement

Competing interests: JC-CW reports grants from Kyowa Kirin for the work under consideration for publication; grants from AbbVie, BMS, Celgene and UCB Pharma; personal fees from TSH Taiwan; and grants and personal fees from Janssen, Novartis and Pfizer, outside the submitted work. T-HK reports grants from Kyowa Kirin for the work under consideration for publication. MK reports personal fees from Kyowa Kirin for the work under consideration for publication and personal fees from AbbVie, Eli Lilly, Celgene, Pfizer, Gilead, Janssen, UCB Pharma, Eisai, Novartis, Tanabe-Mitsubishi, Ayumi and Astellas, outside the submitted work. NO is an employee of Kyowa Kirin. HJ is an employee of Kyowa Kirin Korea. SK reports personal fees from Kyowa Kirin for the work under consideration for publication; personal fees from AbbVie GK, Bristol-Myers Squibb, Eisai, Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma, Teijin Pharma, Novartis Pharma K.K., Eli Lilly Japan K.K. and Asahikasei Pharma, outside the submitted work.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Patient disposition. *Did not meet the study criteria for AS or nr-axSpA, as judged by the central image readers. †Failed to meet the inclusion criteria or met one of the exclusion criteria. AS, ankylosing spondylitis; axSpA, axial spondyloarthritis; nr-axSpA, non-radiographic axSpA.
Figure 2
Figure 2
Response rates (full analysis set). (A) ASAS 40 response rate in patients with axSpA. (B) ASAS 20 response rate in patients with axSpA. (C) ASAS 40 response rate in patients with AS vs nr-axSpA. (D) ASAS 40 response rate in patients with HLA-B27 positive vs HLA-B27 negative. (E) ASAS 40 response rate in patients with CRP abnormal vs CRP normal. *Data are presented in online supplemental table S5. AS, ankylosing spondylitis; ASAS, Assessment of SpondyloArthritis International Society; axSpA, axial spondyloarthritis; CRP, C-reactive protein; HLA, human leucocyte antigen; nr-axSpA, non-radiographic axSpA; ULN, upper limit of normal.
Figure 3
Figure 3
ASDAS-CRP (full analysis set). (A) Change in ASDAS-CRP score from baseline at each efficacy timepoint over 16 weeks. *Baseline-observation-carried-forward ASAS response at week 16. (B) ASDAS-CRP response rate by disease improvement. Disease improvement was defined as clinically important and major for change from baseline in the ASDAS-CRP score of ≥1.1 and ≥2.0, respectively. (C) ASDAS-CRP response rate by disease activity state in the brodalumab (left) and placebo (right) groups. Disease activity state was defined by ASDAS-CRP score as follows: score

References

    1. Rudwaleit M, van der Heijde D, Landewé R, et al. . The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis 2009;68:777–83. 10.1136/ard.2009.108233
    1. Sieper J, Rudwaleit M, Baraliakos X, et al. . The Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis 2009;68 Suppl 2:ii1–44. 10.1136/ard.2008.104018
    1. van der Heijde D, Ramiro S, Landewé R, et al. . 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis 2017;76:978–91. 10.1136/annrheumdis-2016-210770
    1. Corbett M, Soares M, Jhuti G, et al. . Tumour necrosis factor-α inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis: a systematic review and economic evaluation. Health Technol Assess 2016;20:1–334. 10.3310/hta20090
    1. López-Medina C, Moltó A. Update on the epidemiology, risk factors, and disease outcomes of axial spondyloarthritis. Best Pract Res Clin Rheumatol 2018;32:241–53. 10.1016/j.berh.2018.10.006
    1. Stolwijk C, van Onna M, Boonen A, et al. . Global prevalence of spondyloarthritis: a systematic review and meta-regression analysis. Arthritis Care Res 2016;68:1320–31. 10.1002/acr.22831
    1. Wang R, Ward MM. Epidemiology of axial spondyloarthritis: an update. Curr Opin Rheumatol 2018;30:137–43. 10.1097/BOR.0000000000000475
    1. Ankylosing spondylitis (designated intractable disease 271). Japan Intractable Diseases Information Center. Available: [Accessed 11 Sep 2019].
    1. Hsieh M-Y, Kuo C-F. FRI0428 Epidemiology of ankylosing spondylitis in Taiwan: a nationwide population study. Ann Rheum Dis 2016;75:590–1. 10.1136/annrheumdis-2016-eular.5595
    1. Park J-S, Hong J-Y, Park Y-S, et al. . Trends in the prevalence and incidence of ankylosing spondylitis in South Korea, 2010-2015 and estimated differences according to income status. Sci Rep 2018;8:7694. 10.1038/s41598-018-25933-4
    1. Bohn R, Cooney M, Deodhar A, et al. . Incidence and prevalence of axial spondyloarthritis: methodologic challenges and gaps in the literature. Clin Exp Rheumatol 2018;36:263–74.
    1. Paine A, Ritchlin CT. Targeting the interleukin-23/17 axis in axial spondyloarthritis. Curr Opin Rheumatol 2016;28:359–67. 10.1097/BOR.0000000000000301
    1. Deodhar A, Poddubnyy D, Pacheco-Tena C, et al. . Efficacy and safety of ixekizumab in the treatment of radiographic axial spondyloarthritis: sixteen-week results from a phase III randomized, double-blind, placebo-controlled trial in patients with prior inadequate response to or intolerance of tumor necrosis factor inhibitors. Arthritis Rheumatol 2019;71:599–611. 10.1002/art.40753
    1. Pavelka K, Kivitz A, Dokoupilova E, et al. . Efficacy, safety, and tolerability of secukinumab in patients with active ankylosing spondylitis: a randomized, double-blind phase 3 study, MEASURE 3. Arthritis Res Ther 2017;19:285. 10.1186/s13075-017-1490-y
    1. Baeten D, Sieper J, Braun J, et al. . Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis. N Engl J Med 2015;373:2534–48. 10.1056/NEJMoa1505066
    1. Baraliakos X, Kivitz AJ, Deodhar AA, et al. . Long-term effects of interleukin-17A inhibition with secukinumab in active ankylosing spondylitis: 3-year efficacy and safety results from an extension of the phase 3 MEASURE 1 trial. Clin Exp Rheumatol 2018;36:50–5.
    1. Wei JC-C, Baeten D, Sieper J, et al. . Efficacy and safety of secukinumab in Asian patients with active ankylosing spondylitis: 52-week pooled results from two phase 3 studies. Int J Rheum Dis 2017;20:589–96. 10.1111/1756-185X.13094
    1. Kivitz AJ, Wagner U, Dokoupilova E, et al. . Efficacy and safety of secukinumab 150 mg with and without loading regimen in ankylosing spondylitis: 104-week results from MEASURE 4 study. Rheumatol Ther 2018;5:447–62. 10.1007/s40744-018-0123-5
    1. Kishimoto M, Taniguchi A, Fujishige A, et al. . Efficacy and safety of secukinumab in Japanese patients with active ankylosing spondylitis: 24-week results from an open-label phase 3 study (MEASURE 2-J). Mod Rheumatol 2020;30:132–40. 10.1080/14397595.2018.1538004
    1. van der Heijde D, Gensler LS, Deodhar A, et al. . Dual neutralisation of interleukin-17A and interleukin-17F with bimekizumab in patients with active ankylosing spondylitis: results from a 48-week phase IIb, randomised, double-blind, placebo-controlled, dose-ranging study. Ann Rheum Dis 2020;79:595–604. 10.1136/annrheumdis-2020-216980
    1. van der Heijde D, Wei JC-C, Dougados M, et al. . Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial. Lancet 2018;392:2441–51. 10.1016/S0140-6736(18)31946-9
    1. Baraliakos X, Braun J, Deodhar A, et al. . Long-term efficacy and safety of secukinumab 150 mg in ankylosing spondylitis: 5-year results from the phase III MEASURE 1 extension study. RMD Open 2019;5:e001005. 10.1136/rmdopen-2019-001005
    1. Pavelka K, Kivitz AJ, Dokoupilova E, et al. . Secukinumab 150/300 mg provides sustained improvements in the signs and symptoms of active ankylosing spondylitis: 3-year results from the phase 3 MEASURE 3 study. ACR Open Rheumatol 2020;2:119–27. 10.1002/acr2.11102
    1. Deodhar A, van der Heijde D, Gensler LS, et al. . Ixekizumab for patients with non-radiographic axial spondyloarthritis (COAST-X): a randomised, placebo-controlled trial. Lancet 2020;395:53–64. 10.1016/S0140-6736(19)32971-X
    1. van Tok MN, van Duivenvoorde LM, Kramer I, et al. . Interleukin-17A inhibition diminishes inflammation and new bone formation in experimental spondyloarthritis. Arthritis Rheumatol 2019;71:612–25. 10.1002/art.40770
    1. Shah M, Maroof A, Gikas P, et al. . Dual neutralisation of IL-17F and IL-17A with bimekizumab blocks inflammation-driven osteogenic differentiation of human periosteal cells. RMD Open 2020;6:e001306. 10.1136/rmdopen-2020-001306
    1. Nirula A, Nilsen J, Klekotka P, et al. . Effect of IL-17 receptor A blockade with brodalumab in inflammatory diseases. Rheumatology 2016;55:ii43–55. 10.1093/rheumatology/kew346
    1. Foulkes AC, Warren RB. Brodalumab in psoriasis: evidence to date and clinical potential. Drugs Context 2019;8:212570 10.7573/dic.212570
    1. CADTH common drug review: CADTH Canadian Drug Expert Committee Recommendation (Final), 2018. Available: [Accessed 25 Oct 2019].
    1. New drugs approved in FY 2016. Pharmaceuticals and Medical Devices Agency, Japan, 2016. Available: [Accessed 12 Sep 2019].
    1. SILIQ™ (brodalumab) injection, for subcutaneous use. Valeant Pharmaceuticals North America LLC, Bridgewater, NJ 08807, USA, 2017. Available: [Accessed 17 Sep 2019].
    1. Bisson-Vaivre A, Alcaix D, Zarnitsky C, et al. . Efficacy of anti-TNF in patients with spondyloarthritis in absence of any imaging sign. Joint Bone Spine 2013;80:280–6. 10.1016/j.jbspin.2012.08.003
    1. Polo Y La Borda J, Campos J, Sanz J, et al. . Predictive clinical-genetic model of long-term non-response to tumor necrosis factor-alpha inhibitor therapy in spondyloarthritis. Int J Rheum Dis 2019;22:1529–37. 10.1111/1756-185X.13607
    1. Rudwaleit M, Claudepierre P, Wordsworth P, et al. . Effectiveness, safety, and predictors of good clinical response in 1250 patients treated with adalimumab for active ankylosing spondylitis. J Rheumatol 2009;36:801–8. 10.3899/jrheum.081048
    1. Weiß A, Song I-H, Haibel H, et al. . Good correlation between changes in objective and subjective signs of inflammation in patients with short- but not long duration of axial spondyloarthritis treated with tumor necrosis factor-blockers. Arthritis Res Ther 2014;16:R35. 10.1186/ar4464
    1. Nakagawa H, Niiro H, Ootaki K, et al. . Brodalumab, a human anti-interleukin-17-receptor antibody in the treatment of Japanese patients with moderate-to-severe plaque psoriasis: efficacy and safety results from a phase II randomized controlled study. J Dermatol Sci 2016;81:44–52. 10.1016/j.jdermsci.2015.10.009
    1. Papp KA, Reich K, Paul C, et al. . A prospective phase III, randomized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. Br J Dermatol 2016;175:273–86. 10.1111/bjd.14493

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