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Modifying Antirheumatic Drugs in Active Rheumatoid Arthritis: a Japan Phase 3 Trial (HARUKA)

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Modifying Antirheumatic Drugs in Active Rheumatoid Arthritis: a Japan Phase 3 Trial (HARUKA) MODERN RHEUMATOLOGY 2020, VOL. 30, NO. 2, 239–248 https://doi.org/10.1080/14397595.2019.1639939 ORIGINAL ARTICLE Sarilumab monotherapy or in combination with non-methotrexate disease- modifying antirheumatic drugs in active rheumatoid arthritis: A Japan phase 3 trial (HARUKA) Hideto Kamedaa, Kazuteru Wadab, Yoshinori Takahashib, Owen Haginoc, Hubert van Hoogstratend, Neil Grahame and Yoshiya Tanakaf aDivision of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Toho University (Ohashi Medical Center), Tokyo, Japan; bSanofi K.K., Tokyo, Japan; cSanofi, Bridgewater, NJ, USA; dSanofi-Genzyme, Cambridge, MA, USA; eRegeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; fFirst Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Downloaded from https://academic.oup.com/mr/article/30/2/239/6299750 by guest on 01 October 2021 Japan, Kitakyushu, Japan ABSTRACT ARTICLE HISTORY Objectives: To determine long-term safety and efficacy of sarilumab as monotherapy or with non- Received 13 March 2019 methotrexate (MTX) conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in Accepted 1 July 2019 Japanese patients with active rheumatoid arthritis (RA). KEYWORDS Methods: In this double-blind, randomized study (NCT02373202), patients received subcutaneous sari- Rheumatoid arthritis; lumab 150 mg q2w (S150) or 200 mg q2w (S200) as monotherapy or with non-MTX csDMARDs for 52 sarilumab; Japan; phase III; weeks. The primary endpoint was safety. anti-IL-6 receptor Results: Sixty-one patients received monotherapy (S150, n ¼ 30; S200, n ¼ 31) and 30 received combin- ation therapy (S150 þ csDMARDs, n ¼ 15; S200 þ csDMARDs, n ¼ 15). Rates of treatment-emergent adverse events (TEAEs) were 83.3%/90.3%/93.3%/86.7% for S150/S200/S150 þ csDMARDs/ S200 þ csDMARDs, respectively. Nasopharyngitis and neutropenia were the most frequently reported TEAEs. One serious infection was reported in each monotherapy group and in the S200 þ csDMARDs group. There were no cases of grade 4 neutropenia; no patients with grade 3 neutropenia experienced associated serious infection. Improvements in ACR20/50/70 response rates were generally similar between the two monotherapy groups and between the two combination groups; improvements in physical function (Health Assessment Questionnaire-Disability Index, HAQ-DI) and DAS28-CRP were observed at weeks 24 and 52 (all groups). Conclusion: The safety profile of sarilumab was consistent with known class effects of interleukin-6 signaling blockade therapeutics. Sarilumab as mono- or combination therapy improved clinical signs/ symptoms and physical function in Japanese RA patients. Introduction intolerance to anti-tumor necrosis factor (TNF) therapy (TARGET) [6]. Sarilumab as monotherapy or combination Interleukin (IL)-6 is a key cytokine in the pathogenesis of therapy improved signs and symptoms and physical func- rheumatoid arthritis (RA) linked to joint inflammation and destruction [1,2]. Inhibition of the IL-6 signaling pathway tion in patients with RA. Safety profiles were consistent through blockade of the IL-6 receptor (IL-6R) is being with previous studies [7,8] and anticipated class effects. explored as a therapeutic option for patients with RA. Known effects of IL-6 signaling blockade include a higher Sarilumab is a human immunoglobulin (Ig)G1 monoclonal incidence of infections, elevations in alanine aminotransfer- antibody against the IL-6R [3]. The efficacy and safety of ase (ALT) and total serum cholesterol, and lower neutrophil sarilumab in patients with active RA has been investigated count [7–10]. in phase 3 global trials: in combination with methotrexate In MOBILITY, treatment with sarilumab 200 mg or (MTX) in patients with inadequate response to MTX (the 150 mg once every 2 weeks (q2w) plus MTX (versus placebo MOBILITY study) [4]; as monotherapy versus adalimumab plus MTX) was associated with significantly higher propor- in patients with intolerance or inadequate response to MTX tions of patients achieving American College of (MONARCH) [5]; and in combination with conventional Rheumatology 20% (ACR20) improvement responses at synthetic disease-modifying antirheumatic drugs week 24, significantly greater improvements from baseline (csDMARDs) in patients with an inadequate response or in the Health Assessment Questionnaire-Disability Index CONTACT Hideto Kameda [email protected] Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Toho University (Ohashi Medical Center), 2-22-36 Ohashi, Meguro-ku, Tokyo 153-8515, Japan Supplemental data for this article can be accessed here. ß 2019 Japan College of Rheumatology. Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. 240 H. KAMEDA ET AL. (HAQ-DI) at week 16, and significantly reduced radio- and all individuals who had contact with patients were to graphic progression of structural damage (modified Sharp/ remain blinded until the end of study. Post-screening visits van der Heijde score (SHS)) at week 52 [4]. Although the took place at baseline and weeks 2, 4, 6, 8, 10, 12, 16, 20, study was not powered to detect differences between the 24, 28, 36, 44, and 52, followed by a post-treatment follow- two doses of sarilumab, the 200 mg q2w dose provided bet- up at week 58. ter inhibition of radiographic progression than 150 mg q2w The study was performed in accordance with applicable (mean SHS change from baseline at week 52, 0.25 and 0.90, laws and guidelines, including the Declaration of Helsinki respectively, versus 2.78 for placebo plus MTX, p<.0001) and the International Council for Harmonisation guidelines [4]. Efficacy results in TARGET for sarilumab 150 mg q2w for Good Clinical Practice. The protocol and amendments and 200 mg q2w versus placebo (all plus csDMARDs) were were approved by the institutional/central review boards for similar to those in MOBILITY; radiographic progression all 40 sites that enrolled patients (a further four sites gained was not assessed [6]. In MONARCH, in patients with inad- approvals but did not enroll any patients). Details of the equate response or intolerance to MTX, sarilumab 200 mg sites involved in the study including Principal Investigator q2w was clinically superior to adalimumab, as assessed by names, site numbers and the name of the institutional/cen- Downloaded from https://academic.oup.com/mr/article/30/2/239/6299750 by guest on 01 October 2021 change from baseline in Disease Activity Score in 28 joints tral review board can be found in Supplemental Table S1. using erythrocyte sedimentation rate (DAS28-ESR) and Written informed consent was obtained from all participants HAQ-DI, with similar safety profiles, including infection (or legally acceptable representative) prior to the conduct of rates, despite a higher incidence of neutropenia in the sari- any study-related procedures. lumab group [5]. In addition to the anti-IL-6R biological DMARD tocilizu- mab, some csDMARDs have been developed and widely Patient population used in Japan [11]. It is therefore important to assess the Included in the study were Japanese patients (aged 20 use of sarilumab in such clinical settings. This manuscript years) with moderate to severe RA, defined as: RA diagnosis reports results from the Phase 3 HARUKA study, performed according to ACR/European League Against Rheumatism to evaluate the long-term safety and efficacy of sarilumab as (EULAR) 2010 criteria with 3 months disease duration; monotherapy or in combination with non-MTX csDMARDs ACR Class I–III functional status (1991 revised criteria [13]); in Japanese patients with active RA. A second study in at least four of 68 tender joints and four of 66 swollen joints Japan evaluated the efficacy and safety of sarilumab plus at screening; and hs-CRP 4 mg/L or erythrocyte sedimenta- MTX in patients with RA with inadequate response to MTX tion rate (ESR) 28 mm/h. Patients in the monotherapy stra- (KAKEHASI) [12]. tum were: inappropriate for MTX treatment per investigator judgment; or intolerant to MTX, with or without other Materials and methods DMARDs, per investigator judgment; or MTX-IR. Up to 12 patients who were MTX-IR (with or without other Study design DMARDs) were allowed; these patients had to have received The HARUKA trial (NCT02373202) was a multicenter, treatment for 12 weeks before randomization and have randomized, double-blind, 52-week study. Patients were been on a stable dose for 6 weeks before screening (current randomized (2:2:1:1) to receive subcutaneous (SC) injections treatment to be discontinued before randomization). Patients of sarilumab in either the monotherapy stratum (sarilumab in the combination stratum had to have received continuous 150 mg or sarilumab 200 mg q2w) or combination stratum treatment with non-MTX csDMARDs (as monotherapy or (sarilumab 150 mg or sarilumab 200 mg q2w, plus current combination) for 12 weeks before randomization and have background non-MTX csDMARDs). been on a stable dose for 6 weeks prior to screening. Randomization was performed centrally via an interactive The main exclusion criteria were: recent treatment – voice or web response
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