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 combination 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 tocilizumab, 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 system (IVRS/IWRS), with allocation (within 4 12 weeks before screening according to drug for both strata stratified by body weight (<55 kg, 55 kg). used) with glucocorticosteroids, cyclosporine, mycopheno- The monotherapy stratum was also stratified based upon late, azathioprine, cyclophosphamide, TNF antagonists or whether the patient was an inadequate responder to MTX other RA-directed biologics; new treatment or dose adjust- (MTX-IR). Investigators and site staff were blinded to study ment of nonsteroidal anti-inflammatory drugs (NSAIDs; treatment and had no access to randomization information except for low-dose acetylsalicylic acid for cardiovascular (treatment codes) during the study except under circum- disease) or cyclo-oxygenase-2 inhibitors, or treatment with > stances permitted by the protocol (e.g. emergency safety oral prednisone or equivalent 10 mg/day, within 4 weeks issues). The number of swollen and tender joints was eval- of randomization; active or incompletely treated tubercu- uated by a blinded independent assessor with no access to losis; history of or current infections; other relevant auto- patient data (including previous joint assessments). The immune, inflammatory, or malignant disease. investigator, sponsor, and patients were also blinded to post-baseline data for high-sensitivity C-reactive protein (hs- Assessments CRP), serum sarilumab, and anti-sarilumab antibody levels. After the last patient’s week 24 visit, the first database lock The primary endpoint was the long-term safety of sarilumab occurred and statistical analyses were performed. Patients treatment, either as monotherapy or in combination with MODERN RHEUMATOLOGY 241

Table 1. Demographics and patient characteristics at baseline (randomized population). Sarilumab Monotherapy stratum Combination stratum 150 mg q2w 200 mg q2w 150 mg q2w þ non-MTX 200 mg q2w þ non-MTX (n ¼ 30) (n ¼ 31) csDMARDs (n ¼ 15) csDMARDs (n ¼ 15) Age, mean (SD) years 54.4 (13.8) 52.5 (10.3) 56.3 (10.9) 63.3 (10.6) Female/male, % 90.0/10.0 83.9/16.1 80.0/20.0 86.7/13.3 Weight, mean (SD) kg 54.3 (9.8) 56.5 (12.9) 50.3 (7.2) 50.7 (9.2) Race, % Japanese 100.0 100.0 100.0 100.0 Prior biologic DMARDs use, n (%) 5 (16.7) 10 (32.3) 3 (20.0) 1 (6.7) Baseline non-MTX csDMARDs intake, n (%)a ––15 (100.0) 15 (100.0) Bucillamine ––0 2 (13.3) Bucillamine þ iguratimod ––0 1 (6.7) Bucillamine þ iguratimod þ sodium ––0 1 (6.7) aurothiomalate Bucillamine þ iguratimod þ sulfasalazine ––1 (6.7) 0 Downloaded from https://academic.oup.com/mr/article/30/2/239/6299750 by guest on 01 October 2021 Bucillamine þ sulfasalazine ––2 (13.3) 1 (6.7) Iguratimod ––1 (6.7) 1 (6.7) Iguratimod þ sulfasalazine ––2 (13.3) 0 Leflunomide ––1 (6.7) 2 (13.3) Mizoribine ––0 1 (6.7) Mizoribine þ tacrolimus ––1 (6.7) 0 Sodium urothiomalate þ sulfasalazine ––0 1 (6.7) Sulfasalazine ––4 (26.7) 4 (26.7) Tacrolimus ––3 (20.0) 1 (6.7) Duration of RA, mean (range) years 8.3 (0.5–44.3) 7.9 (0.3–32.2) 6.4 (0.3–17.8) 7.0 (0.4–13.1) Seropositive for rheumatoid factor, n (%) 22 (73.3) 22 (71.0) 10 (66.7) 10 (66.7) Anti-CCP antibody positive, n (%) 28 (93.3) 27 (87.1) 15 (100.0) 12 (80.0) DAS28-CRP, mean (SD) 5.0 (1.1) 5.1 (1.0) 5.1 (0.7) 4.5 (1.0) Tender joint count, mean (SD) 16.6 (12.2) 17.0 (13.7) 14.5 (10.3) 11.1 (6.9) Swollen joint count, mean (SD) 14.8 (9.0) 11.8 (7.2) 12.6 (5.7) 11.0 (6.5) CRP, mean (SD) mg/L 14.6 (24.9) 16.4 (20.3) 24.2 (20.7) 13.2 (21.5) HAQ-DI score, mean (SD) 0.9 (0.6) 0.8 (0.5) 0.8 (0.5) 0.8 (0.5) Anti-CCP: anti-cyclic citrullinated peptide; CRP: C-reactive protein; csDMARDs: conventional synthetic disease-modifying antirheumatic drugs; DAS28-CRP: Disease Activity Score in 28 joints using C-reactive protein; DMARD: disease-modifying antirheumatic drugs; HAQ-DI: Health Assessment Questionnaire-Disability Index; MTX: methotrexate; q2w: once every 2 weeks; RA: rheumatoid arthritis; SD: standard deviation. aPatients in the monotherapy stratum were not receiving non-MTX csDMARDs at baseline as per the inclusion/exclusion criteria. non-MTX csDMARDs. Safety assessments included adverse The safety population was the randomized population events (AEs; including treatment-emergent AEs (TEAEs), who received at least one dose or partial dose of study serious TEAEs, AEs of special interest and AEs leading to medication (analyzed according to treatment received) or discontinuation or death), laboratory safety variables, vital for whom it was unclear whether the study medication was signs, physical examination, and electrocardiograms. Safety taken (analyzed according to randomized group). The effi- data were collected at the time of informed consent and cacy analysis population was the modified intent-to-treat each study visit. (mITT) population, including all randomized patients who Secondary efficacy endpoints were ACR20/50/70 response received at least one dose of study medication. For ACR rates over time (assessed at screening, baseline, then at response, patients with insufficient data, completely missing weeks 2, 4, 8, 12, 24, and 52), change from baseline in ACR ACR components after imputation or who prematurely dis- components, change from baseline in DAS28 using CRP continued study treatment were considered non-responders. level (DAS28-CRP), DAS28-CRP remission at weeks 12, 24, and 52, change from baseline in physical functioning (according to HAQ-DI), and HAQ-DI response at weeks 12, Results 24, and 52 (defined as change from baseline 0.3 or Patients 0.22 [14]). Overall, 91 patients were randomized to receive sarilumab 150 mg q2w monotherapy (n ¼ 30), sarilumab 200 mg q2w Statistical analysis monotherapy (n ¼ 31), sarilumab 150 mg q2w þ csDMARDs The sample size was not based on statistical considerations (n ¼ 15), or sarilumab 200 mg q2w þ csDMARDs (n ¼ 15), but was determined to allow documentation of safety in a in 40 sites in Japan (Figure 1). Of the 91 treated patients, 79 sufficient number of patients. Approximately, 60 patients for (86.8%) completed the 52-week treatment period. The first the monotherapy stratum and 30 patients for the combin- patient was enrolled in February 2015 and the last patient ation stratum were to be enrolled. Baseline patient demo- completed the trial in November 2016. graphics and characteristics and primary and secondary Baseline demographics and disease characteristics were endpoints were summarized using descriptive statistics. generally balanced between treatment groups within the 242 H. KAMEDA ET AL. Downloaded from https://academic.oup.com/mr/article/30/2/239/6299750 by guest on 01 October 2021

Figure 1. Patient disposition. csDMARDs: conventional synthetic disease-modifying antirheumatic drugs; MTX: methotrexate; q2w: once every 2 weeks. monotherapy and combination strata considering the small similar in the monotherapy groups (340 and 352 days for sample size, except that a higher mean CRP was observed in the 150 and 200 mg dose groups, respectively). the 150 mg combination compared with the 200 mg combination group, and the mean age was higher in the 200 mg Efficacy combination group compared with the 150 mg combination group (Table 1). At baseline, 29 patients (47.5%) in the Improvements in ACR20, ACR50, and ACR70 response monotherapy stratum were receiving oral corticosteroids rates were similar between the two monotherapy groups and and 52 (85.2%) were receiving NSAIDs. All patients in the between the two combination groups, with the exception of combination stratum were receiving non-MTX csDMARDs the combination group comparison at week 52 where there (detailed in Table 1), 13 (43.3%) were receiving oral cortico- was a lower proportion of responders in the 200 mg group steroids, and 19 (63.3%) were receiving NSAIDs. Non-MTX compared with the 150 mg group for all ACR measures; this csDMARDs received included bucillamine (a D-penicill- was mainly due to the small sample size and the proportion amine derivative csDMARD [15]), iguratimod (a csDMARD of patients who discontinued from the study (Figure 2; suppressing production of Igs and inflammatory cytokines, Table 2). Similar to observations at week 24, all ACR com- and inhibiting activation of nuclear factor-kappa B [16]), ponents in patients treated with sarilumab in both strata and mizoribine (an inhibitor of inosine monophosphate were generally improved relative to baseline at week 52 dehydrogenase in the purine synthesis cycle like mycophe- (Table 2). nolate mofetil [17]). Improvements of DAS28-CRP from baseline were The median duration of study treatment was 364 days observed through the 52-week treatment period in both across all treatment groups; however, the mean duration treatment groups within each strata (Figure 2). By week 12, was 337 compared with 262 days in the 150 mg and 200 mg over 35% of patients in the monotherapy strata had combination groups, respectively. This difference was due to achieved DAS28-CRP remission (Table 2), and the propor- more patients in the 200 mg combination group not com- tions of patients who achieved DAS28-CRP remission at pleting the 52-week treatment period; in the 200 mg com- week 24 (>45%) were maintained at week 52. More than bination group, six patients discontinued by week 52 (five half of the patients in the combination groups had achieved before week 24), and in the 150 mg combination group, two DAS28-CRP remission by week 12. The incidence of discontinued by week 52 (one before week 24), mostly due patients with DAS28-CRP remission at week 52 was gener- to AEs (Figure 1). The mean duration of treatment was ally comparable with week 24. For both definitions of a OENRHEUMATOLOGY MODERN

Figure 2. ACR response rates over time (ACR20/ACR50/ACR70) and disease activity (DAS28-CRP) over time. Apparent differences in ACR response rates between weeks 24 and 52 in the combination 200 mg group were mainly due to the small sample size and the high proportion of patients who discontinued early from the study. ACR20/50/70: American College of Rheumatology 20%/50%/70% responses; BL: baseline; csDMARDs: conventional synthetic disease-modifying antirheumatic drugs; DAS28-CRP: Disease Activity Score in 28 joints using C-reactive protein; MTX: methotrexate; q2w: once every 2 weeks; RA: rheumatoid arthritis; SE: standard error.

243 Downloaded from https://academic.oup.com/mr/article/30/2/239/6299750 by guest on 01 October 2021 October 01 on guest by https://academic.oup.com/mr/article/30/2/239/6299750 from Downloaded 244 H. KAMEDA ET AL.

Table 2. Efficacy results (mITT population)a. Sarilumab 150 mg q2w 200 mg q2w 150 mg q2w þ non-MTX 200 mg q2w þ non-MTX (n¼ 30) (n¼ 31) csDMARDs (n¼ 15) csDMARDs (n¼ 15)b Signs and symptoms ACR20 response, n (%) At week 24 22 (73.3) 20 (64.5) 12 (80.0) 11 (73.3) At week 52 23 (76.7) 23 (74.2) 11 (73.3) 6 (40.0) ACR50 response, n (%) At week 24 14 (46.7) 14 (45.2) 10 (66.7) 8 (53.3) At week 52 17 (56.7) 17 (54.8) 9 (60.0) 5 (33.3) ACR70 response, n (%) At week 24 9 (30.0) 8 (25.8) 6 (40.0) 5 (33.3) At week 52 8 (26.7) 8 (25.8) 8 (53.3) 4 (26.7) ACR components, mean (SD) change from baseline at week 24 Tender joint count 11.8 (10.1) 9.5 (9.2) 9.9 (9.9) 8.3 (5.5) Swollen joint count 10.3 (7.5) 8.4 (7.5) 8.1 (4.2) 6.6 (3.8) Downloaded from https://academic.oup.com/mr/article/30/2/239/6299750 by guest on 01 October 2021 Pain VAS 35.8 (25.0) 37.5 (30.5) 37.2 (21.0) 31.2 (28.6) Physician global VAS 45.1 (19.7) 39.1 (22.1) 36.6 (21.5) 32.9 (16.7) Patient global VAS 32.7 (25.9) 34.8 (27.1) 29.9 (20.4) 32.9 (25.2) HAQ-DI 0.4 (0.6) 0.3 (0.3) 0.5 (0.3) 0.4 (0.5) CRP, mg/L 14.4 (25.4) 16.5 (20.3) 24.4 (21.4) 13.5 (21.9) ACR components, mean (SD) change from baseline at week 52 Tender joint count 12.8 (11.2) 11.0 (9.5) 10.8 (9.5) 9.1 (6.9) Swollen joint count 11.5 (7.1) 8.3 (7.2) 9.4 (4.6) 6.0 (4.9) Pain VAS 35.0 (26.3) 40.8 (32.7) 45.2 (19.6) 33.1 (26.7) Physician global VAS 48.4 (23.5) 38.5 (24.5) 38.1 (18.7) 33.2 (8.9) Patient global VAS 32.9 (24.2) 36.1 (25.7) 40.8 (25.0) 27.2 (37.9) HAQ-DI 0.5 (0.6) 0.4 (0.3) 0.5 (0.5) 0.3 (0.6) CRP, mg/L 13.0 (24.4) 16.3 (20.5) 24.4 (21.4) 7.9 (9.5) DAS28-CRP remission (<2.6), n (%) At week 12 13 (43.3) 11 (35.5) 8 (53.3) 10 (66.7) At week 24 15 (50.0) 14 (45.2) 9 (60.0) 11 (73.3) At week 52 15 (50.0) 16 (51.6) 10 (66.7) 9 (60.0) Physical function HAQ-DI response (MCID 0.3), n (%) At week 12 16 (53.3) 13 (41.9) 10 (66.7) 5 (33.3) At week 24 16 (53.3) 13 (41.9) 9 (60.0) 7 (46.7) At week 52 17 (56.7) 17 (54.8) 10 (66.7) 6 (40.0) HAQ-DI response (MCID 0.22), n (%) At week 12 19 (63.3) 17 (54.8) 11 (73.3) 7 (46.7) At week 24 17 (56.7) 19 (61.3) 10 (66.7) 8 (53.3) At week 52 18 (60.0) 20 (64.5) 10 (66.7) 7 (46.7) ACR: American College of Rheumatology; ACR 20/50/70: ACR 20%, 50%, and 70% response rates; csDMARDs: conventional synthetic disease-modifying antirheumatic drugs; DAS28-CRP: Disease Activity Score in 28 joints using C-reactive protein; HAQ-DI: Health Assessment Questionnaire-Disability Index; mITT: modified intent-to-treat; MCID: minimal clinically important difference; MTX: methotrexate; q2w: once every 2 weeks; SD: standard deviation; VAS: visual analog scale. aOther efficacy data are illustrated in Figure 2. bApparent differences in ACR response rates between weeks 24 and 52 in the 200 mg combination group were mainly due to the small sample size and the high proportion of patients who discontinued early from the study.

clinically meaningful HAQ-DI response (0.3 and 0.22 Serious AEs were reported by one, two, zero, and three units of improvement from baseline), HAQ-DI response patients in the 150 mg monotherapy, 200 mg monotherapy, rates were generally comparable at weeks 24 and 52 in both 150 mg combination, and 200 mg combination groups, treatment groups within each strata (Table 2). respectively. Serious infections (requiring hospitalization) were the most frequently reported serious AE, reported by one patient in each of the monotherapy groups; one patient Safety in the 150 mg monotherapy group had herpes zoster oticus and one patient in the 200 mg monotherapy group had bac- A summary of AEs and the most common TEAEs is shown terial pneumonia. One patient in the 200 mg combination in Table 3. The most frequently reported TEAEs by system group was hospitalized with concurrent chronic sinusitis organ class were infections and infestations for both mono- and periorbital abscess. No opportunistic infections were therapy groups and for the 200 mg combination group, and reported in either of the combination groups. AEs led to musculoskeletal and connective tissue disorders for the permanent discontinuation of treatment in one patient in 150 mg combination group. The most frequently reported the monotherapy stratum (150 mg group, herpes zoster oti- TEAEs by preferred term were nasopharyngitis (both mono- cus) and seven patients in the combination stratum (two therapy groups and the 200 mg combination group) and patients [13.3%] in the 150 mg group [hepatic function neutropenia (150 mg combination group). abnormal and ALT increased] and five patients [33.3%] in MODERN RHEUMATOLOGY 245

Table 3. Summary of treatment-emergent AEs and most common treatment-emergent AEs (safety population)a. Sarilumab 150 mg q2w þ non-MTX 200 mg q2w þ non-MTX 150 mg q2w (n¼ 30) 200 mg q2w (n¼ 31) csDMARDs (n¼ 15) csDMARDs (n¼ 15) AEs 25 (83.3) 28 (90.3) 14 (93.3) 13 (86.7) Serious AEs 1 (3.3) 2 (6.5) 0 3 (20.0) AEs leading to permanent 1 (3.3) 0 2 (13.3) 5 (33.3) treatment discontinuation AEs leading to death 0 0 0 0 Most frequent AEs by system organ class and preferred term Infections and infestations 21 (70.0) 16 (51.6) 5 (33.3) 6 (40.0) Nasopharyngitis 13 (43.3) 14 (45.2) 4 (26.7) 5 (33.3) Gastroenteritis 1 (3.3) 1 (3.2) 2 (13.3) 0 Blood and lymphatic disorders 2 (6.7) 5 (16.1) 5 (33.3) 4 (26.7) Neutropenia 1 (3.3) 3 (9.7) 5 (33.3) 3 (20.0) Nervous system disorders 4 (13.3) 3 (9.7) 1 (6.7) 3 (20.0)

Dizziness 2 (6.7) 1 (3.2) 0 2 (13.3) Downloaded from https://academic.oup.com/mr/article/30/2/239/6299750 by guest on 01 October 2021 Respiratory, thoracic and 7 (23.3) 4 (12.9) 0 2 (13.3) mediastinal disorders Oropharyngeal pain 3 (10.0) 2 (6.5) 0 0 Gastrointestinal disorders 9 (30.0) 10 (32.3) 3 (20.0) 5 (33.3) Stomatitis 3 (10.0) 4 (12.9) 3 (20.0) 4 (26.7) Hepatobiliary disorders 1 (3.3) 5 (16.1) 1 (6.7) 0 Hepatic function abnormal 1 (3.3) 4 (12.9) 1 (6.7) 0 Musculoskeletal and connective 6 (20.0) 5 (16.1) 6 (40.0) 1 (6.7) tissue disorders RA 4 (13.3) 2 (6.5) 1 (6.7) 0 General disorders and 3 (10.0) 9 (29.0) 3 (20.0) 1 (6.7) administration site conditions Injection site erythema 1 (3.3) 6 (19.4) 0 1 (6.7) Injury, poisoning and 6 (20.0) 4 (12.9) 4 (26.7) 3 (20.0) procedural complications Contusion 2 (6.7) 0 3 (20.0) 0 AE: adverse event; csDMARDs: conventional synthetic disease-modifying antirheumatic drugs; MTX: methotrexate; q2w: once every 2 weeks; RA: rheumatoid arthritis. aValues are the number (%) of patients with investigator-reported AEs overall or by system organ class and preferred term (10% of patients in any treatment group by preferred term).

Table 4. Laboratory assessments (safety population)a. Sarilumab 150 mg q2w þ non-MTX 200 mg q2w þ non-MTX 150 mg q2w (n¼ 30) 200 mg q2w (n¼ 31) csDMARDs (n¼ 15) csDMARDs (n¼ 15) Absolute neutrophil count, n (%) Grade 1: 1.5 Giga/L to < LLN 8 (26.7) 8 (25.8) 0 1 (6.7) Grade 2: 1to<1.5 Giga/L 6 (20.0) 9 (29.0) 3 (20.0) 8 (53.3) Grade 3: 0.5 to <1 Giga/L 2 (6.7) 4 (12.9) 5 (33.3) 3 (20.0) Grade 4: <0.5 Giga/L 0 0 0 0 Hepatic enzyme levels, n (%) ALT >1 ULN and 3 ULN 10 (33.3) 8 (25.8) 5 (33.3) 5 (33.3) >3 ULN and 10 ULN 1 (3.3) 4 (12.9) 2 (13.3) 0 >10 ULN 0 0 0 0 AST >1 ULN and 3 ULN 10 (33.3) 7 (22.6) 7 (46.7) 5 (33.3) >3 ULN and 5 ULN 0 1 (3.2) 1 (6.7) 0 >5 ULN 0 0 0 0 ALT: alanine aminotransferase; AST: aspartate aminotransferase; csDMARDs: conventional synthetic disease-modifying antirheumatic drugs; LLN: lower limit of normal; MTX: methotrexate; q2w: once every 2 weeks; ULN: upper limit of normal. aValues are the number (%) of patients with laboratory findings.

the 200 mg combination group [chronic sinusitis, breast can- 200 mg monotherapy group. In the combination stratum, cer female, gastric cancer, thrombocytopenia, and both neutropenia was reported for five patients (33.3%) in the white blood cell count decreased and stomatitis]). No deaths 150 mg group and three patients (20.0%) in the 200 mg occurred during the study. group. Most cases of decreases in absolute neutrophil counts Neutropenia was reported for one patient (3.3%) in the (ANCs) were 1.0 Giga/L to < the lower limit of normal 150 mg monotherapy group and three patients (9.7%) in the (LLN; grades 1–2 neutropenia) (occurring in 14 [46.7%] and 246 H. KAMEDA ET AL.

17 [54.8%] of patients in the 150 and 200 mg monotherapy No cases of diverticulitis, gastrointestinal perforation, or groups, respectively, and three [20.0%] and nine [60.0%] of gastrointestinal ulceration were reported. patients in the 150 and 200 mg combination groups, respect- None of the vital signs or electrocardiograms that met ively) (Table 4). ANC <1.0 Giga/L occurred in six patients criteria for potentially clinically significant abnormalities in the monotherapy stratum (two [6.7%] in the 150 mg were associated with clinically relevant manifestations. group; four [12.9%] in the 200 mg group) and eight patients in the combination stratum (five [33.3%] in the 150 mg Discussion group; three [20.0%] in the 200 mg group). There were no cases of ANC <0.5 Giga/L (grade 4 neutropenia) and no This study showed that both 150 mg and 200 mg of sarilu- patients with grade 3 neutropenia experienced associated mab as monotherapy or in combination with non-MTX serious infections in either stratum. csDMARDs had similar safety profiles in Japanese patients Thrombocytopenia was reported for one patient in each with active moderate to severe RA. The AE profile was as group in both strata (leading to discontinuation for one expected and as previously reported [4–6]. Patients in both patient in the 200 mg combination group); none were asso- the monotherapy and combination strata showed improve- Downloaded from https://academic.oup.com/mr/article/30/2/239/6299750 by guest on 01 October 2021 ciated with bleeding event; mean platelet counts remained ments in clinical signs and symptoms, and phys- within the normal range. ical function. Hepatic AEs affected eight patients in the monotherapy Infections and infestations were the most common stratum (two patients [6.7%] in the 150 mg monotherapy TEAEs by system organ class for both the monotherapy and group [hepatic function abnormal and ALT increased], six the 200 mg combination groups; musculoskeletal disorder patients [19.4%] in the 200 mg monotherapy group [four and connective tissue disorder (followed by infections and hepatic function abnormal, one ALT increased, one hepatic infestations) were the most frequent TEAEs by system organ steatosis]; none of whom discontinued) and two patients class for the 150 mg combination group. Nasopharyngitis (13.3%) in the 150 mg combination group (ALT increased and neutropenia were the most frequently reported TEAEs and hepatic function abnormal), in both cases leading to by preferred term at week 52. There were no cases of grade treatment discontinuation. Most patients across all groups 4 neutropenia (ANC <0.5 Giga/L) and no patients with had ALT and aspartate aminotransferase (AST) values grade 3 neutropenia experienced associated serious infection 3 the upper limit of normal (ULN) and there were no in either stratum, confirming previous findings that neutro- ALT values >10 ULN or AST values >5 ULN (Table 4). penia is not associated with risk of infection following sari- Elevations in lipids were reported in one patient (3.3%) lumab treatment [4–6]; notably in MONARCH, infection in the 150 mg monotherapy group, three patients (9.7%) in rates were similar between patients treated with sarilumab the 200 mg monotherapy group, and one patient (6.7%) in versus adalimumab despite a higher incidence of neutro- the 200 mg combination group. No serious lipid elevations penia with sarilumab [5]. The lack of an association between or elevations in lipids leading to discontinuation were neutropenia and infection in patients treated with IL-6 reported. No major adverse cardiovascular events were inhibitors has also been observed with tocilizumab, where reported in either stratum. transient neutropenia was suggested to be due to margin- Hypersensitivity events were reported for approximately ation of neutrophils [9,18]. Laboratory abnormalities in the one-quarter of patients in the monotherapy stratum (eight current study were also consistent with the anticipated patients [26.7%] in the 150 mg group; seven patients [22.6%] effects of IL-6 inhibition, and no clinically significant vital in the 200 mg group) and by two patients (13.3%) in each signs or electrocardiograms were reported. of the combination groups. Hypersensitivity AEs of rash, Efficacy data showed that treatment with sarilumab eczema, eczema nummular, and injection site rash were monotherapy or added to non-MTX csDMARDs provided reported in the combination stratum; the most frequently sustained clinical benefit through 52 weeks for the majority reported hypersensitivity AEs in the monotherapy stratum of Japanese patients with active RA who were intolerant, were eczema and dermatitis contact (each reported by three inappropriate, or inadequate-responders to MTX (the patients across both groups). There were no cases of monotherapy stratum), or who were inadequate responders anaphylaxis. to non-MTX csDMARDs (the combination stratum), and Five patients (16.7%) in the 150 mg monotherapy group were generally consistent with the results achieved at week and two patients (6.5%) in the 200 mg monotherapy group 24. The exceptions were differences in ACR response rates developed anti-drug antibodies (ADAs) during the TEAE between weeks 24 and 52 in the 200 mg combination group period; median peak titers were 30.0 in both groups. No and between the 150 mg and 200 mg combination groups at patients developed neutralizing antibodies. None of the week 52; these results were mainly due to the small sample patients in the combination stratum were ADA positive. size and the proportion of patients who discontinued from There was no evidence of a relationship between ADA for- the study. mation and hypersensitivity or lack of efficacy. Based on the results of the large MOBILITY study [4], No malignancies were reported for the monotherapy stra- the KAKEHASI bridging study in Japanese patients [12], tum. Two cases of malignancy (13.3%) were reported in the and the strategy of recent RA treatment guidelines in aiming 200 mg combination group (breast cancer female and gas- for early clinical remission [19], a dose of 200 mg sarilumab tric cancer). q2w is recommended. In the MOBILITY study, both 150 mg MODERN RHEUMATOLOGY 247 and 200 mg q2w doses provided sustained clinical efficacy, Yoshiya Tanaka has received speaking fees from Daiichi Sankyo, with radiographic results after 1 year of follow-up suggesting Inc.; Astellas Pharma Inc.; Pfizer Inc; Mitsubishi Tanabe Pharma; that the 200 mg q2w dose of sarilumab provided substan- Bristol-Myers Squibb; Chugai Pharmaceutical Co., Ltd.; YL Biologics Ltd.; Eli Lilly and Company; Sanofi K.K.; Janssen Pharmaceutical K.K.; tially better inhibition of radiographic progression than the UCB Japan Co. Ltd.; and has received research grants from Mitsubishi 150 mg q2w dose [4]. In the current study and other global Tanabe Pharma; Takeda Pharmaceutical Company; Bristol-Myers studies, there were no major problems with tolerance in the Squibb; Chugai Pharmaceutical Co., Ltd.; Astellas Pharma Inc.; AbbVie 200 mg q2w groups reported [4–6]. G.K.; MSD K.K.; Daiichi Sankyo, Inc.; Pfizer Inc; Kyowa Kirin, Inc.; Eisai Co., Ltd.; and Ono Pharmaceutical Co., Ltd. The tolerability and efficacy results for Japanese patients in this study are consistent with the results of the KAKEHASI study in Japanese MTX-IR patients [12] and of Funding global sarilumab studies in non-Japanese populations [4–6], This study was sponsored by Sanofi and Regeneron supporting the use of sarilumab in Japan. In the Pharmaceuticals, Inc. KAKEHASI study, sarilumab plus MTX showed sustained clinical efficacy, and a safety profile consistent with the Downloaded from https://academic.oup.com/mr/article/30/2/239/6299750 by guest on 01 October 2021 anticipated effects of an IL-6 inhibitor [10], as previously observed in the MOBILITY study [4]. The positive results References achieved with sarilumab without the use of MTX in the cur- 1. Narazaki M, Tanaka T, Kishimoto T. The role and therapeutic rent study will be of importance to the Japanese population, targeting of IL-6 in rheumatoid arthritis. Expert Rev Clin where the use of csDMARDs, including MTX, has devel- Immunol. 2017;13(6):535–51. oped in a unique manner. The safety profiles of sarilumab 2. Tanaka Y, Martin Mola E. IL-6 targeting compared to TNF tar- in combination with non-MTX csDMARDs, which included geting in rheumatoid arthritis: studies of olokizumab, sarilumab and sirukumab. Ann Rheum Dis. 2014;73(9):1595–7. bucillamine, iguratimod, and mizoribine, and of sarilumab 3. June RR, Olsen NJ. Room for more IL-6 blockade? Sarilumab monotherapy, were acceptable. for the treatment of rheumatoid arthritis. Expert Opin Biol A limitation of this study was the small sample size Ther. 2016;16(10):1303–9. (especially in the combination therapy groups); this study 4. Genovese MC, Fleischmann R, Kivitz AJ, Rell-Bakalarska M, was conducted to evaluate the safety and efficacy of sarilu- Martincova R, Fiore S, et al. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate mab monotherapy and combination therapy for treatment response to methotrexate: results of a phase III study. Arthritis of RA specifically in Japanese patients. Rheumatol. 2015;67(6):1424–37. In conclusion, sarilumab 150 mg q2w or 200 mg q2w, both 5. Burmester GR, Lin Y, Patel R, van Adelsberg J, Mangan EK, as monotherapy or in combination with non-MTX Graham NM, et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of csDMARDs, has an acceptable safety profile consistent with patients with active rheumatoid arthritis (MONARCH): a rando- IL-6-signaling blockade, and improves the signs and symptoms mised, double-blind, parallel-group phase III trial. Ann Rheum of RA and physical function in Japanese patients with active Dis. 2017;76(5):840–7. RA. The safety and efficacy profiles were consistent with those 6. Fleischmann R, van Adelsberg J, Lin Y, Castelar-Pinheiro GD, seen in sarilumab studies in non-Japanese populations. Brzezicki J, Hrycaj P, et al. Sarilumab and nonbiologic disease- modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis – Acknowledgements factor inhibitors. Arthritis Rheumatol. 2017;69(2):277 90. 7. Radin AR, Mellis SJ, Jasson M, Nadler D, Belomestnov P, Wu R, The authors would like to thank the study participants and study et al. REGN88/SAR153191, a fully-human interleukin-6 receptor investigators. The authors thank Ms Mariko Sumi’s contribution as a monoclonal antibody, reduces acute phase reactants in patients biological statistician on this study. Medical writing assistance, under with rheumatoid arthritis: preliminary observations from Phase the direction of the authors, was provided by Annette Smith, PhD, of 1 studies. Arthritis Rheum. 2010;62(Suppl. 10):1121. CMC AFFINITY, a division of Complete Medical Communications 8. Sieper J, Braun J, Kay J, Badalamenti S, Radin AR, Jiao L, et al. Ltd, Macclesfield, UK, and Claire Lavin, PhD, on behalf of CMC Sarilumab for the treatment of ankylosing spondylitis: results of AFFINITY, funded by Sanofi and Asahi Kasei Pharma Corporation. a Phase II, randomised, double-blind, placebo-controlled study (ALIGN). Ann Rheum Dis. 2015;74(6):1051–7. 9. Koike R, Harigai M, Atsumi T, Amano K, Kawai S, Saito K, et al. Conflict of interest Japan College of Rheumatology 2009 guidelines for the use of tocilizumab, a humanized anti-interleukin-6 receptor monoclonal anti- Hideto Kameda has received consulting fees, speaking fees, and/or hono- body, in rheumatoid arthritis. Mod Rheumatol. 2009;19(4):351–7. raria from AbbVie G.K.; Asahi Kasei Pharma Corporation; Bristol- 10. Scott LJ. Tocilizumab: a review in rheumatoid arthritis. Drugs. Myers Squibb; Chugai Pharmaceutical Co., Ltd.; Eli Lilly Japan K.K.; 2017;77(17):1865–79. Janssen Pharmaceutical K.K.; Mitsubishi Tanabe Pharma; Novartis 11. Ogasawara M, Kageyama M, Kusaoi M, Onuma S, Kon T, Pharma K.K.; and Sanofi K.K.; and has received research grants from Sekiya F, et al. Recent trends in use of nonbiologic DMARDs AbbVie G.K.; Asahi Kasei Pharma Corporation; Astellas Pharma Inc.; and evaluation of their continuation rates in single and dual Bristol-Myers Squibb; Chugai Pharmaceutical Co., Ltd.; Eisai Co., Ltd.; combination therapies in rheumatoid arthritis patients in Japan. Mitsubishi Tanabe Pharma; Novartis Pharma K.K. and Sanofi K.K. Mod Rheumatol. 2012;22(6):831–6. Kazuteru Wada, Yoshinori Takahashi, Owen Hagino, and Hubert 12. Tanaka Y, Wada K, Takahashi Y, Hagino O, van Hoogstraten H, van Hoogstraten are employees of Sanofi and may hold stock and/or Graham NMH, et al. Sarilumab plus methotrexate in patients stock options in the company. with active rheumatoid arthritis and inadequate response to Neil M. H. Graham is an employee of Regeneron and may hold methotrexate: results of a randomized, placebo-controlled phase stock and/or stock options in the company. III trial in Japan. Arthritis Res Ther. 2019;21(1):79. 248 H. KAMEDA ET AL.

13. Hochberg MC, Chang RW, Dwosh I, Lindsey S, Pincus T, Wolfe rheumatoid arthritis: interim analysis of a post-marketing surveillance F. The American College of Rheumatology 1991 revised criteria study of 2679 patients in Japan. Mod Rheumatol. 2017;27(5):755–65. for the classification of global functional status in rheumatoid 17. Ishikawa H. Mizoribine and mycophenolate mofetil. Curr Med – arthritis. Arthritis Rheum. 1992;35(5):498–502. Chem. 1999;6(7):575 97. 14. Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of 18. MainiRN,TaylorPC,SzechinskiJ,PavelkaK,BrollJ,Balint patient outcome in arthritis. Arthritis Rheum. 1980;23(2):137–45. G, et al. Double-blind randomized controlled clinical trial of 15. Ichikawa Y, Saito T, Yamanaka H, Akizuki M, Kondo H, the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete Kobayashi S, et al. Therapeutic effects of the combination of response to methotrexate. Arthritis Rheum. 2006;54(9): methotrexate and bucillamine in early rheumatoid arthritis: a 2817–29. multicenter, double-blind, randomized controlled study. Mod 19. Smolen JS, Landewe R, Bijlsma J, Burmester G, Chatzidionysiou Rheumatol. 2005;15(5):323–8. K, Dougados M, et al. EULAR recommendations for the man- 16. MimoriT,HarigaiM,AtsumiT,FujiiT,KuwanaM,MatsunoH, agement of rheumatoid arthritis with synthetic and biological et al. Safety and effectiveness of 24-week treatment with iguratimod, disease-modifying antirheumatic drugs: 2016 update. Ann a new oral disease-modifying antirheumatic drug, for patients with Rheum Dis. 2017;76(6):960–77. Downloaded from https://academic.oup.com/mr/article/30/2/239/6299750 by guest on 01 October 2021