Efficacy and safety of HLX01 in patients with moderate-to-severe rheumatoid arthritis despite methotrexate therapy: a phase 3 study

Xiaofeng Zeng, Ju Liu, Xiumei Liu, Lijun Wu, Yi Liu, Xiangping Liao, Huaxiang Liu, Jiankang Hu, Xin Lu, Linjie Chen, Jian Xu, Zhenyu Jiang, Fu-Ai Lu, Huaxiang Wu, Ying Li, Qingyu Wang, Jun Zhu, HLX01-RA03 Investigators, Lingyun Sun, Meimei Wang, Xiaoxia Yu, Pingting Yang, Qinghua Zou, Baijie Xu, Hua Zhang, Cibo Huang, Liqi Bi, Xiaoxia Li, Jianzhao Cheng, Hua Wei, Lan He, Hao Zhang, Hongsheng Sun, Zongwen Shuai, Jianhong Zhao, Yang Li, Rongbin Li, Fengju Li, Xiaomei Li, Zhuoli Zhang, Wufang Qi, Hongwei Du, Jingchun Jin, Jian Wu, Xiaofeng Zeng, Ju Liu, Xiumei Liu, Lijun Wu, Yi Liu, Xiangping Liao, Huaxiang Liu, Jiankang Hu, Xin Lu, Linjie Chen, Jian Xu, Zhenyu Jiang, Fu-Ai Lu, Huaxiang Wu, Ying Li, Qingyu Wang, Jun Zhu, HLX01-RA03 Investigators, Lingyun Sun, Meimei Wang, Xiaoxia Yu, Pingting Yang, Qinghua Zou, Baijie Xu, Hua Zhang, Cibo Huang, Liqi Bi, Xiaoxia Li, Jianzhao Cheng, Hua Wei, Lan He, Hao Zhang, Hongsheng Sun, Zongwen Shuai, Jianhong Zhao, Yang Li, Rongbin Li, Fengju Li, Xiaomei Li, Zhuoli Zhang, Wufang Qi, Hongwei Du, Jingchun Jin, Jian Wu

Abstract

Background: To evaluate the efficacy and safety of HLX01, a rituximab biosimilar, as combination therapy with methotrexate in Chinese patients with active rheumatoid arthritis who had inadequate responses to methotrexate.

Methods: In this double-blind, placebo-controlled phase 3 trial, biologic-naïve patients with moderate-to-severe active rheumatoid arthritis and inadequate responses to methotrexate were randomized 2:1 to receive 1000 mg HLX01 or placebo intravenously on days 1 and 15. On the first day of weeks 24 and 26, patients in both groups received 1000 mg HLX01 via intravenous infusion. The primary endpoint was the American College of Rheumatology (ACR) 20 response rate at week 24. Secondary endpoints including efficacy, safety, immunogenicity, pharmacokinetics and pharmacodynamics were assessed up to week 48.

Results: Between 28 May 2018 and 11 September 2020, 275 patients were randomized to the HLX01 group (n = 183) or the placebo group (n = 92). At week 24, the proportion of patients achieving ACR20 response was significantly greater in the HLX01 group compared with the placebo group in the intention-to-treat population (60.7% vs 35.9%; P < 0.001) and per-protocol set (60.3% vs 37.1%; P < 0.001). Most secondary efficacy endpoints favoured HLX01 when assessed at weeks 12, 24, 36 and 48. Incidences of treatment-emergent adverse events were similar between groups. Infusion-related reactions occurred more frequently following the initial two doses of HLX01 than the subsequent doses.

Conclusions: HLX01 plus methotrexate improved clinical outcomes compared with placebo in Chinese patients with rheumatoid arthritis who had inadequate responses to methotrexate. This treatment regimen was well tolerated, showing comparable safety profiles to placebo.

Trial registration: ClinicalTrials.gov , NCT03522415 . Registered on 11 May 2018.

Keywords: Biologic disease-modifying anti-rheumatic drug; Methotrexate; Phase 3; Rheumatoid arthritis; Rituximab.

Conflict of interest statement

Ying Li, Qingyu Wang and Jun Zhu are employees of Shanghai Henlius Biotech, Inc. All other authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Study design and patient flow chart. a Study design. b Patient flow chart. ITT intention-to-treat, MTX methotrexate, PKS pharmacokinetic set, PPS per-protocol set, R randomized, SS1 safety set 1, SS2 safety set 2
Fig. 2
Fig. 2
ACR20, ACR50 and ACR70 responses. a Proportion of patients with an ACR20 response in the ITT population and the PPS population at week 24, and proportion of patients achieving a clinical response according to b ACR20, c ACR50 and d ACR70 in the ITT population over time. Error bars represent standard error. ACR American College of Rheumatology, ITT intention-to-treat, PPS per-protocol set
Fig. 3
Fig. 3
Change in disease activity based on DAS28-CRP and DAS28-ESR. a DAS28-CRP and b DAS28-ESR adjusted mean change from baseline in the ITT population. c Proportion of patients with remission (DAS28 ≤2.6) or low disease activity (DAS28 ≤3.2) at week 24 in the ITT population. Error bars represent standard error. CRP C-reactive protein, DAS28 disease activity score of 28 joints, ESR erythrocyte sedimentation rate, ITT intention-to-treat

References

    1. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365:2205–2219. doi: 10.1056/NEJMra1004965.
    1. Smolen JS, Landewe RBM, Bijlsma JWJ, Burmester GR, Dougados M, Kerschbaumer A, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79:685–699. doi: 10.1136/annrheumdis-2019-216655.
    1. Mease PJ, Stryker S, Liu M, Salim B, Rebello S, Gharaibeh M, et al. Treatment patterns in rheumatoid arthritis patients newly initiated on biologic and conventional synthetic disease-modifying antirheumatic drug therapy and enrolled in a North American clinical registry. Arthritis Res Ther. 2021;23:236. doi: 10.1186/s13075-021-02599-4.
    1. Singh JA, Saag KG, Bridges SL, Jr, Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 2016;68:1–25. doi: 10.1002/acr.22783.
    1. Aletaha D, Stamm T, Kapral T, Eberl G, Grisar J, Machold KP, et al. Survival and effectiveness of leflunomide compared with methotrexate and sulfasalazine in rheumatoid arthritis: a matched observational study. Ann Rheum Dis. 2003;62:944–951. doi: 10.1136/ard.62.10.944.
    1. Chinese Rheumatology Association 2018 Chinese guideline for the diagnosis and treatment of rheumatoid arthritis. Zhonghua Nei Ke Za Zhi. 2018;57:242–251.
    1. RITUXAN® prescribing information [Internet]. U.S. Food and Drug Administration [cited 8 February 2022]. Available from: .
    1. Giacomelli R, Afeltra A, Alunno A, Baldini C, Bartoloni-Bocci E, Berardicurti O, et al. International consensus: what else can we do to improve diagnosis and therapeutic strategies in patients affected by autoimmune rheumatic diseases (rheumatoid arthritis, spondyloarthritides, systemic sclerosis, systemic lupus erythematosus, antiphospholipid syndrome and Sjogren’s syndrome)?: the unmet needs and the clinical grey zone in autoimmune disease management. Autoimmun Rev. 2017;16:911–924. doi: 10.1016/j.autrev.2017.07.012.
    1. MabThera product information [Internet]. European Medicines Agency [cited 17 March 2021]. Available from: .
    1. Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 2006;54:2793–2806. doi: 10.1002/art.22025.
    1. Mease PJ, Cohen S, Gaylis NB, Chubick A, Kaell AT, Greenwald M, et al. Efficacy and safety of retreatment in patients with rheumatoid arthritis with previous inadequate response to tumor necrosis factor inhibitors: results from the SUNRISE trial. J Rheumatol. 2010;37:917–927. doi: 10.3899/jrheum.090442.
    1. Cohen SB, Keystone E, Genovese MC, Emery P, Peterfy C, Tak PP, et al. Continued inhibition of structural damage over 2 years in patients with rheumatoid arthritis treated with rituximab in combination with methotrexate. Ann Rheum Dis. 2010;69:1158–1161. doi: 10.1136/ard.2009.119222.
    1. Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004;350:2572–2581. doi: 10.1056/NEJMoa032534.
    1. Emery P, Deodhar A, Rigby WF, Isaacs JD, Combe B, Racewicz AJ, et al. Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab’s Efficacy in MTX iNadequate rEsponders (SERENE)) Ann Rheum Dis. 2010;69:1629–1635. doi: 10.1136/ard.2009.119933.
    1. Wu B, Wilson A, Wang FF, Wang SL, Wallace DJ, Weisman MH, et al. Cost effectiveness of different treatment strategies in the treatment of patients with moderate to severe rheumatoid arthritis in China. PLoS One. 2012;7:e47373. doi: 10.1371/journal.pone.0047373.
    1. Frisell T, Dehlin M, Di Giuseppe D, Feltelius N, Turesson C, Askling J et al. Comparative effectiveness of abatacept, rituximab, tocilizumab and TNFi biologics in RA: results from the nationwide Swedish register. Rheumatology (Oxford). 2019;58(8):1367–77.
    1. Xu Y, Xie L, Zhang E, Gao W, Wang L, Cao Y, et al. Physicochemical and functional assessments demonstrating analytical similarity between rituximab biosimilar HLX01 and the MabThera®. MAbs. 2019;11:606–620. doi: 10.1080/19420862.2019.1578147.
    1. Zeng X, Wang Y, Jiang Z, Zhang Z, He L, Zhang X et al. SAT0139 A multicentre, randomised, double-blind, parallel active-controlled clinical trial comparing pharmacokinetics, pharmacodynamics, safety and exploratory efficacy between HLX01 and Europe-sourced rituximab as a new indication in Chinese moderate to severe patients with rheumatoid arthritis. Ann Rheum Dis. 2019;78(Suppl 2):1140.
    1. Shi Y, Song Y, Qin Y, Zhang Q, Han X, Hong X, et al. A phase 3 study of rituximab biosimilar HLX01 in patients with diffuse large B-cell lymphoma. J Hematol Oncol. 2020;13:38. doi: 10.1186/s13045-020-00871-9.
    1. Rituximab injection (HLX01) product insert [Internet]. National Medical Products Administration [cited 02 July 2021]. Available from: .
    1. Henlius receives NMPA approval for its first product HLX01 –the beginning of a new era for biosimilar [Internet] [cited 10 June 2021]. Available from: .
    1. Statistical principles for clinical trails of chemical and biological agents [Internet]. National Medical Products Administration [cited 25 January 2021]. Available from: .
    1. Guidelines on Development and Evaluation of Biosimilars (drafting) [Internet]. National Medical Products Administration [cited 28 February 2021]. Available from: .
    1. Provisions for drug registration [Internet]. National Medical Products Administration [cited 25 January 2021]. Available from: .
    1. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–324. doi: 10.1002/art.1780310302.
    1. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995;38:727–735. doi: 10.1002/art.1780380602.
    1. Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003;48:35–45. doi: 10.1002/art.10697.
    1. Genovese MC, Glover J, Greenwald M, Porawska W, El Khouri EC, Dokoupilova E, et al. FKB327, an adalimumab biosimilar, versus the reference product: results of a randomized, Phase III, double-blind study, and its open-label extension. Arthritis Res Ther. 2019;21:281. doi: 10.1186/s13075-019-2046-0.
    1. Ward MM, Guthrie LC, Alba MI. Brief report: rheumatoid arthritis response criteria and patient-reported improvement in arthritis activity: is an American College of Rheumatology twenty percent response meaningful to patients? Arthritis Rheumatol. 2014;66:2339–2343. doi: 10.1002/art.38705.
    1. Buch MH, Smolen JS, Betteridge N, Breedveld FC, Burmester G, Dorner T, et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis. 2011;70:909–920. doi: 10.1136/ard.2010.144998.
    1. Listing J, Gerhold K, Zink A. The risk of infections associated with rheumatoid arthritis, with its comorbidity and treatment. Rheumatology (Oxford) 2013;52:53–61. doi: 10.1093/rheumatology/kes305.
    1. Global tuberculosis reports [Internet]. World Health Organization [cited 28 Feburary 2021]. Available from: .
    1. Rutherford AI, Patarata E, Subesinghe S, Hyrich KL, Galloway JB. Opportunistic infections in rheumatoid arthritis patients exposed to biologic therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Rheumatology (Oxford) 2018;57:997–1001. doi: 10.1093/rheumatology/key023.
    1. Garcia-Montoya L, Villota-Eraso C, Yusof MYM, Vital EM, Emery P. Lessons for rituximab therapy in patients with rheumatoid arthritis. Lancet Rheumatol. 2020;2:e497–e509. doi: 10.1016/S2665-9913(20)30033-3.

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