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Abstract
Objective This randomised, double-blind, parallel-group, phase 3 study compared monotherapy with sirukumab, an anti–interleukin-6 cytokine monoclonal antibody, with adalimumab monotherapy in patients with rheumatoid arthritis (RA).
Methods Biologic-naïve patients with active RA who were inadequate responders or were intolerant to, or inappropriate for, methotrexate were randomised to subcutaneous sirukumab 100 mg every 2 weeks (n=187), sirukumab 50 mg every 4 weeks (n=186) or adalimumab 40 mg every 2 weeks (n=186). Primary endpoints at week 24 were change from baseline in Disease Activity Score in 28 joints (DAS28) using erythrocyte sedimentation rate (ESR) and proportion of patients achieving an American College of Rheumatology (ACR) 50 response; these endpoints were tested in sequential order. This study is registered at EudraCT (number: 2013-001417-32) and ClinicalTrials.gov (number: NCT02019472).
Results Significantly greater improvements from baseline in mean (SD) DAS28 (ESR) were observed at week 24 with sirukumab 100 mg every 2 weeks (−2.96 (1.580)) versus adalimumab 40 mg every 2 weeks (−2.19 (1.437); P<0.001). Sirukumab 50 mg every 4 weeks also showed significantly greater improvement from baseline at week 24 in DAS28 (ESR) (−2.58 (1.524)) compared with adalimumab (P=0.013). The ACR50 response rates with the 100 mg (35.3%) and 50 mg (26.9%) doses of sirukumab were comparable to that with adalimumab (31.7%) at week 24. The safety profile of sirukumab was consistent with that observed with anti–interleukin-6 receptor antibodies. A dose-related effect on the incidence of injection-site reactions was observed with sirukumab.
Conclusion Sirukumab monotherapy showed greater improvements in DAS28 (ESR), but similar ACR50 response rates, versus adalimumab monotherapy.
- rheumatoid arthritis
- DMARDs (biologic)
- anti-TNF
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Introduction
Currently, in the treatment of established rheumatoid arthritis (RA), a combination of biological disease-modifying antirheumatic drugs (bDMARD) with methotrexate (MTX) is superior to bDMARD monotherapy.1 2 However, a number of patients discontinue MTX, most commonly due to side effects.3 For example, in a study of 157 patients with RA who were currently or had previously used MTX, 29.3% discontinued MTX therapy, most often due to gastrointestinal or hepatic side effects.3 For patients who cannot use conventional synthetic DMARDs (csDMARD), monotherapy with interleukin (IL)-6 pathway or Janus kinase (JAK) inhibitors may have advantages compared with monotherapy with other bDMARDs.2 4
Elevated IL-6 levels are present in synovial tissue of patients with RA and correlate with disease activity.5–7 Sirukumab is a fully human monoclonal antibody that binds to IL-6 with high affinity and specificity, preventing IL-6 from binding to membrane and soluble forms of the IL-6 receptor (IL-6R).8 The two dose regimens chosen for the phase 3 pivotal studies, sirukumab 50 mg every 4 weeks and 100 mg every 2 weeks, significantly improved signs and symptoms of disease among patients with active RA refractory to csDMARDs and refractory to ≥1 anti–tumour necrosis factor (TNF) drug or intolerant to ≥2 anti-TNF drugs.9 10 The majority of patients in these trials received sirukumab in combination with csDMARDs.9 10
The objective of this phase 3 study (SIRROUND-H; EudraCT number, 2013-001417-32; ClinicalTrials.gov number, NCT02019472), the primary results of which are presented here, was to demonstrate superior efficacy of sirukumab monotherapy compared with adalimumab monotherapy (the most commonly used bDMARD for the treatment of RA11) over 52 weeks in patients with active RA who had an inadequate response to MTX or were intolerant to or inappropriate for MTX.
Methods
This phase 3, randomised, double-blind, parallel-group, active comparator study evaluated the superiority (in terms of efficacy) of subcutaneous sirukumab monotherapy compared with adalimumab monotherapy, along with safety, physical function, pharmacokinetic properties and immunogenicity, in biologic-naïve patients with active RA (online supplementary figure 1).
Supplementary file 1
Patients/study population
Eligible patients were ≥18 years of age with active RA (≥8 of 68 tender joints and ≥6 of 66 swollen joints at screening/baseline, and C-reactive protein (CRP) levels of ≥10 mg/L or erythrocyte sedimentation rate (ESR) of ≥28 mm/hour at screening) and were considered inadequate responders to MTX (after ≥12 weeks of MTX (dose of ≥15 mg/week)) or intolerant to or inappropriate for treatment with MTX for safety reasons (including MTX-naïve patients).
Study design
This 68-week study included a 52-week treatment period and a 16-week safety follow-up period.
Patients were randomised at 102 centres in the USA, Europe, Latin America and South Africa from April 2014 to May 2015. Eligible patients were randomised 1:1:1 to subcutaneous sirukumab 100 mg every 2 weeks, subcutaneous sirukumab 50 mg every 4 weeks or subcutaneous adalimumab 40 mg every 2 weeks. Details of randomisation and masking are provided in the online supplementary methods and results. Patients with <20% improvement from baseline in both swollen joint counts (SJC)/tender joint counts (TJC) at week 16 qualified for early escape (EE): patients receiving adalimumab 40 mg every 2 weeks changed to weekly dosing; patients receiving sirukumab 50 mg every 4 weeks changed to 100 mg every 2 weeks; and patients on sirukumab 100 mg every 2 weeks remained on their randomised dose. Patients receiving sirukumab who met EE criteria received weekly placebo injections in between to maintain blinding.
Study evaluations
All analyses were prespecified in the statistical analysis plan. The two primary efficacy endpoints were change from baseline in Disease Activity Score in 28 joints (DAS28) using ESR at week 24 and proportion of patients with an American College of Rheumatology (ACR) 50 response at week 24 (see details of hierarchical statistical testing in the Statistical Methods section). Major secondary efficacy endpoints included the proportion of patients with DAS28 (ESR) remission and the proportion with an ACR20 response at week 24. Additional efficacy endpoints included ACR70 response, Clinical Disease Activity Index (CDAI), the Health Assessment Questionnaire–Disability Index (HAQ-DI), the 36-item Short Form Health Survey (SF-36) and the Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue questionnaire (online supplementary methods and results). Efficacy endpoints were assessed through week 52. Safety was monitored throughout the 68-week study and included evaluations of treatment-emergent adverse events (TEAE) and clinical laboratory tests. Serum sirukumab or adalimumab concentrations and immunogenicity to sirukumab or adalimumab were assessed (online supplementary methods and results).
Statistical methods
Based on the results of a phase 4, active-controlled study of tocilizumab monotherapy (the ADACTA study12) and assuming a treatment difference of 0.6–0.8 for the change from baseline in DAS28 at week 24 (SD of 1.6–1.8) and an ACR50 response rate at week 24 of 45%–50% with sirukumab versus 30% with adalimumab, a sample size of 170 patients per treatment arm was needed to achieve a power of ≥81% for the primary endpoints to detect a treatment difference between sirukumab and adalimumab using an α of 0.05 (two sided). The primary hypotheses to be tested in this study, in sequential order, were: (1) sirukumab 100 mg every 2 weeks demonstrates superior efficacy versus adalimumab 40 mg every 2 weeks in change from baseline in DAS28 (ESR) at week 24, and (2) sirukumab 100 mg every 2 weeks demonstrates superior efficacy versus adalimumab 40 mg every 2 weeks in the proportion of patients with an ACR50 response at week 24. The change from baseline in DAS28 (ESR) was tested using an analysis of covariance model, controlling for treatment group, reason for MTX failure and baseline value; missing values were imputed using baseline observation carried forward methodology. ACR50 response was tested using a Cochran-Mantel-Haenszel test stratified by reason for MTX failure; missing values, EE or treatment failures (see online supplementary methods and results for definition) were imputed as non-responders. As prespecified, if the first (DAS28 (ESR) endpoint) comparison of sirukumab 100 mg every 2 weeks to adalimumab 40 mg every 2 weeks was statistically significant at a two-sided α level of 0.05, the study was considered positive. Differences in the change from baseline in DAS28 (ESR) at week 24 and proportion of patients with an ACR50 response at week 24 were evaluated between the sirukumab 50 mg every 4 weeks group and the adalimumab 40 mg every 2 weeks group as major secondary analyses using methodology similar to that used for sirukumab 100 mg every 2 weeks. Online supplementary figure 2 outlines the testing procedures for primary and secondary hypotheses and how they differed for global and USA-specific regulatory requirements.
Results
Study population
Of 776 patients screened, 559 were randomised (figure 1). Demographic and baseline disease characteristics were well balanced across treatment groups (table 1). Among randomised patients, 57.1% (n=319) and 42.9% (n=240) failed MTX for efficacy and safety/tolerability reasons, respectively (online supplementary table 1). Overall, 97.9% (547/559) of patients had prior MTX use (online supplementary table 1). Treatment compliance was >95% and >93% across all groups through weeks 24 and 52, respectively. Through week 52, 131 patients discontinued study drug, most often due to adverse events (AE) (figure 1; online supplementary table 2).
Patient distribution and disposition through week 52. EE, early escape.
Baseline and demographic characteristics
Efficacy
For the first primary endpoint, the improvement from baseline in DAS28 (ESR) was significantly greater at week 24 for sirukumab 100 mg compared with adalimumab (P<0.001; table 2). For the second primary endpoint, the difference in ACR50 response rate at week 24 between patients receiving sirukumab 100 mg and those receiving adalimumab was not statistically significant (P=0.464; table 2). Following the prespecified testing procedure, the change from baseline in DAS28 (ESR) at week 24 was significantly greater for sirukumab 50 mg compared with adalimumab (P=0.013; table 2). The difference in ACR50 response rate at week 24 between patients receiving sirukumab 50 mg and those receiving adalimumab was not statistically significant (P=0.306; table 2). Based on the testing hierarchy, no further hypothesis testing was performed. Results from sensitivity analyses to explore the impact of handling missing data on the primary endpoints were similar to the primary analysis (data not shown). For both doses of sirukumab and adalimumab, decreases (improvements) from baseline in DAS28 (ESR) were observed from as early as week 2 through week 52 (figure 2A). Across all three treatment groups, a clinically relevant proportion of patients achieved an ACR50 response through week 52 (figure 2B). At week 52, improvements from baseline in DAS28 (ESR) and the proportion of patients achieving ACR50 response were comparable to those at week 24 (online supplementary table 3). Improvements from baseline at week 24 in individual ACR components were similar for adalimumab and sirukumab 100 mg, and slightly lower for sirukumab 50 mg for some parameters (online supplementary table 4).
Primary endpoints: (A) Change from baseline in DAS28 (ESR)a and (B) proportion of patients achieving an ACR50 response by visit through week 52.b,c aObserved values; patients with missing baseline values were excluded from analysis. bImputed values. cData for A and B are included in online supplementary tables 9 and 10, respectively. ACR, American College of Rheumatology; DAS28 (ESR), Disease Activity Score in 28 joints, using erythrocyte sedimentation rate; q2w, every 2 weeks; q4w, every 4 weeks.
Primary, major secondary and other endpoints at week 24
Major secondary endpoints and other efficacy endpoint analyses showed similar clinically meaningful improvements for both sirukumab groups and the adalimumab group and are summarised in table 2 for week 24 and online supplementary table 3 for week 52. Changes from baseline in the SJC, TJC, patient’s global assessment of disease activity and ESR at week 24 are also summarised in table 2. DAS28 (ESR) remission rates were numerically higher across all treatment groups at week 52 compared with week 24; a numerically higher remission rate was observed in the sirukumab groups compared with the adalimumab group at weeks 24 and 52. ACR20 response rates at week 24 were similar across groups and remained generally comparable at week 52, while ACR70 response rates increased slightly from week 24 to week 52 across all groups. For the primary efficacy endpoints and major secondary endpoints, there was a trend for numerically greater improvements in patients randomised to sirukumab who had failed MTX for safety reasons compared with those who failed for efficacy reasons; however, this finding was not consistent for both doses of sirukumab across multiple endpoints and timepoints (online supplementary table 5).
Similar decreases (improvements) in CDAI (a disease activity index that includes clinical parameters and no acute phase reactants) and HAQ-DI scores from baseline were observed with sirukumab (both doses) and adalimumab treatment at weeks 24 and 52 (online supplementary table 6). Approximately 50%–60% of the patients in each treatment group achieved clinically meaningful improvements from baseline (≥5-point increase) in SF-36 physical component summary and mental component summary scores at weeks 24 and 52 (online supplementary table 6). High proportions of patients (≥60%) achieved clinically meaningful improvements from baseline (≥4-point increase) in FACIT-Fatigue score across all groups (online supplementary table 6).
Safety
All reported safety assessments are for the entire 68-week study, unless otherwise specified. Overall incidences of TEAEs for patients randomised to adalimumab, sirukumab 50 mg and sirukumab 100 mg were 69.9% (130/186), 74.7% (139/186) and 71.7% (134/187), respectively (table 3). The most frequently reported (>5%) individual TEAEs for sirukumab and adalimumab are summarised in table 3. TEAEs leading to treatment discontinuation and serious TEAEs occurred in more patients with sirukumab 50 mg compared with sirukumab 100 mg or adalimumab treatment (table 3); detailed listings of these TEAEs are provided in online supplementary tables 7 and 8.
Overall summary of safety through week 68
The percentage of patients with injection-site reactions was approximately two-fold greater with sirukumab 100 mg compared with sirukumab 50 mg and adalimumab; none were considered serious (table 3). One patient each in the sirukumab 100 mg group (injection-site swelling) and adalimumab group (injection-site induration) discontinued treatment due to injection-site reactions. Rates of hypersensitivity reactions were low for all groups; no cases of anaphylaxis occurred (table 3).
The rate of infections was similar with sirukumab compared with adalimumab, with nasopharyngitis, upper respiratory tract infections and bronchitis being the most frequently reported (table 3). Among patients receiving adalimumab, sirukumab 50 mg and sirukumab 100 mg, rates of serious infections were 2.2% (4/186), 7.5% (14/186) and 2.7% (5/187), respectively. Two cases of reactivated pulmonary tuberculosis, one case of opportunistic infection, three major adverse cardiovascular events, six malignancies, seven pregnancies, two gastrointestinal perforations and four deaths were reported. Details of these events are summarised in the online supplementary methods and results.
Laboratory abnormalities of interest (associated with IL-6 inhibition) were more common with both sirukumab doses compared with adalimumab through week 52. All treatments were associated with liver enzyme increases; lipid level elevations and neutrophil count reductions were more frequently associated with sirukumab treatment (table 4). Additional details about laboratory abnormalities are included in the online supplementary methods and results.
Number of patients with NCI-CTCAE toxicity grades 3 and 4 postbaseline laboratory abnormalities through week 68*
Immunogenicity
The incidence of antibodies to sirukumab through week 68 was low (sirukumab 100 mg, 4.9% (9/183); sirukumab 50 mg, 3.8% (7/182)), while the incidence of antibodies to adalimumab was 91.9% (171/186). The presence of antibodies to sirukumab or adalimumab did not appear to markedly reduce response rates. More detailed pharmacokinetic and immunogenicity results are summarised in the online supplementary methods and results.
Discussion
Some patients are unable to use csDMARDs, possibly due to tolerability issues.3 For these patients, there may be advantages to using monotherapy with agents targeting the IL-6 pathway or JAK inhibitors.2 4 Thus, the efficacy of sirukumab monotherapy was compared with that of adalimumab monotherapy, the most commonly used bDMARD for the treatment of RA.11 For the first primary endpoint in this study, monotherapy with sirukumab 100 mg was superior to monotherapy with adalimumab 40 mg in biologic-naïve patients with active RA in terms of improvements in DAS28 (ESR) from baseline to week 24. However, for the second primary endpoint, ACR50 response rates were comparable for sirukumab 100 mg and adalimumab. It should be noted, however, that the proportion of patients achieving ACR50 response in the adalimumab group in this study (31.7%) was slightly higher than that reported for adalimumab monotherapy in other RA studies (22.1%–29.7%).12–17 Similar results were observed for sirukumab 50 mg. Sirukumab’s direct and greater effect on acute phase reactants (ESR and CRP) compared with adalimumab, coupled with the finding that sirukumab and adalimumab produced comparable improvements in the CDAI measure, may account for the superiority of sirukumab on the DAS28 (ESR) endpoint, but non-superiority on the ACR50 response endpoint in this study. The acute phase reactant component is weighted more heavily in the DAS28 (ESR) formula than in the ACR50 criteria, and not at all in the CDAI.18–20 Both sirukumab and adalimumab showed early efficacy, with improvements in RA signs and symptoms as early as week 2. Overall, improvements in measures of signs and symptoms, physical function and patient-reported outcomes were generally similar across the sirukumab and adalimumab groups.
For certain endpoints that are generally harder to achieve (DAS28 remission, ACR50), a numerically greater treatment response was observed for sirukumab 100 mg compared with sirukumab 50 mg, suggesting a possible dose–response relationship for sirukumab monotherapy, although the study was not designed to compare the two doses. In contrast, no efficacy-related dose response was identified when sirukumab was administered in combination with csDMARDs.9 10
In the ADACTA and MONARCH studies, both of which were direct comparative studies versus adalimumab, tocilizumab and sarilumab demonstrated significant improvements compared with adalimumab in CDAI and other measures, including ACR response and various patient-reported outcomes, when administered as monotherapy in patients with RA who were intolerant or inadequate responders to MTX.12 17 In this study, improvements from baseline in signs and symptoms and patient-reported outcomes were generally comparable between sirukumab and adalimumab groups. There is no clear evidence-based mechanistic or scientific reason why the two anti–IL-6R antibody monotherapy regimens would be more efficacious than adalimumab, while sirukumab, which inhibits IL-6, and adalimumab were comparable in efficacy in the SIRROUND-H trial. In addition to the targeted mechanism of action, the studies differed in study design (eg, 52-week double-blind treatment period in this study vs 24 weeks in ADACTA and MONARCH), the geographical distribution of the study population (eg, >60% of patients were from Eastern Europe in this study, higher than ADACTA and MONARCH), as well as blinding and analysis methods.12 17 The response rate in the adalimumab comparator groups varied across the three studies.12 17
The strengths of the study were that it was the only large study of sirukumab in bionaïve patients, and was a randomised, blinded, controlled monotherapy trial of 52 weeks’ duration with an active comparator, which evaluated two doses of the investigational agent. The limitations were that adalimumab monotherapy control treatment yielded responses that were higher than in other adalimumab studies,12–17 rendering indirect comparisons to other studies challenging. A direct comparative study of sirukumab against an anti–IL-6R antibody would be of interest but, at the time of study design, such a trial was not feasible for reasons of uncertain effect size, blinding and compound availability. Due to the effects of sirukumab on acute phase reactants, the use of DAS28 (ESR) as one of the two primary objectives may also have presented challenges for comparing efficacy between sirukumab and adalimumab, as discussed above. MTX carry-over effects may also have been present and differed between treatment groups; an MTX washout period of more than 2 weeks and/or balancing treatment groups based on this variable could have been useful.
The safety profile of sirukumab was generally consistent with the known safety profile of anti–IL-6R antibody treatment and previous sirukumab RA studies.9 12 17 21 22 In this study, the rate of serious infections was numerically higher with sirukumab 50 mg than with adalimumab or sirukumab 100 mg. Two sirukumab-treated patients had gastrointestinal perforations, while none occurred with adalimumab. Four sirukumab-treated patients died, while no deaths were reported in the adalimumab group. All deaths occurred after week 24, lacked dose dependence, and the causes of death were diverse and typical of patients with RA. In the 24-week ADACTA and MONARCH studies, of the two deaths and one death reported, respectively, none occurred in the adalimumab groups.12 17 Through week 68, no dose response was observed in AE or serious AE rates, except for injection-site reactions. Laboratory abnormalities commonly observed with sirukumab were liver transaminase increases, lipid level elevations and neutrophil count reductions. The safety and tolerability of adalimumab in this study were consistent with published data of adalimumab monotherapy in RA.12 13 15 23 24 When determining which bDMARD monotherapy to use, individual patient comorbidities and risk profiles in relation to anti-TNF or IL-6 pathway inhibitor class effects should be taken into account.
The immunogenicity rate was low for sirukumab monotherapy (4.4%) through week 68, similar to that observed for sirukumab combined with csDMARD treatment in other studies.9 10 The immunogenicity rate for adalimumab monotherapy through week 68 was high (91.9%) in this study, which could be related to the use of a validated, sensitive immunoassay and to administration of adalimumab as monotherapy. In this study, the presence of antibodies to either sirukumab or adalimumab did not appear to be associated with a notable reduction in efficacy. However, previous studies have shown that rates of anti-adalimumab antibodies are higher when adalimumab is used as monotherapy and appear to be associated with loss of response after prolonged treatment.25–27
In conclusion, treatment with sirukumab monotherapy demonstrated rapid and sustained improvement in signs and symptoms of RA, comparable to those achieved with adalimumab monotherapy, in a population of biologic-naïve patients with an inadequate response or intolerance to/inappropriateness for MTX. Unfortunately, because health authorities requested additional clinical data, which would have significantly delayed access to sirukumab in parts of the world, the sponsor company made the strategic decision to prioritise other therapies in development and to terminate the sirukumab RA programme.
Acknowledgments
The authors thank all investigators and participating patients in the SIRROUND-H study. Writing and editorial support were provided by Lauren Fink, PhD, of MedErgy, and were funded by Janssen Global Services and GlaxoSmithKline.
References
Footnotes
PPT and BH contributed equally.
Handling editor Josef S Smolen
Contributors PCT, YZ, RK, RR and PPT contributed to the design of the study and analysis and interpretation of the data. MHS, YJ and SD contributed to the analysis and interpretation of the data. QW contributed to the design and conduct of the study, recruitment and treatment of patients, and collection, analysis and interpretation of the data. BH contributed to the design and conduct of the study and the analysis and interpretation of the data. All authors contributed to drafting the work or revising it critically for important intellectual content, provided final approval of the version published and agreed to be accountable for all aspects of the work.
Funding This study was sponsored by Janssen Research & Development in collaboration with GlaxoSmithKline. PCT was supported in part by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC).
Disclaimer The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
Competing interests PCT has served as a consultant to AbbVie, Biogen, Bristol-Myers Squibb, Eli Lilly, Galapagos, GlaxoSmithKline, Janssen, Novartis, Pfizer, Roche, Sandoz and UCB Pharma, and has received research grant funding from Celgene, GlaxoSmithKline, Janssen and UCB Pharma. MHS has served as a consultant to AbbVie, Bristol-Myers Squibb, Johnson & Johnson, Eli Lilly and UCB Pharma, and as a speaker for AbbVie and Bristol-Myers Squibb. QW, YZ and BH are employees and shareholders of Janssen Research & Development. YJ is a contractor of Janssen Research & Development. RK, SD, RR and PPT are employees and shareholders of GlaxoSmithKline.
Patient consent Obtained.
Ethics approval The study protocol and amendments were reviewed by an Independent Ethics Committee or Institutional Review Board. This study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practices and applicable regulatory requirements.
Provenance and peer review Not commissioned; externally peer reviewed.
Author note Portions of the data in this manuscript have been previously presented as an oral presentation at the 2016 ACR/ARHP Annual Meeting (Taylor PC, Schiff M, Wang Q, Jiang Y, Kurrasch R, Daga S, Rao R, Hsu B, Tak PP. Efficacy and safety of monotherapy with sirukumab, an anti–IL-6 cytokine monoclonal antibody, compared with adalimumab monotherapy in biologic-naïve patients with active rheumatoid arthritis: results of a global, randomized, double-blind, parallel-group, phase 3 study [abstract]. Arthritis Rheumatol. 2016;68[suppl 10]. Available at: http://acrabstracts.org/abstract/efficacy-and-safety-of-monotherapy-with-sirukumab-an-anti-il-6-cytokine-monoclonal-antibody-compared-with-adalimumab-monotherapy-in-biologic-naive-patients-with-active-rheumatoid-arthritis/. Accessed August 2, 2017).