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Sarilumab plus methotrexate improves patient-reported outcomes in patients with active rheumatoid arthritis and inadequate responses to methotrexate: results of a phase III trial.

ABSTRACT: Sarilumab is a human monoclonal antibody directed against the alpha subunit of the interleukin-6 receptor complex. In the MOBILITY phase III randomized controlled trial (RCT), sarilumab?+?methotrexate (MTX) treatment resulted in clinical improvements at 24 weeks that were maintained at 52 weeks in adults with rheumatoid arthritis (RA), who have inadequate response to MTX (MTX-IR). These analyses indicate the effects of sarilumab?+?MTX versus placebo on patient-reported outcomes (PROs) in this RCT.Patients (n?=?1197) were randomized to receive placebo, sarilumab 150 or 200 mg subcutaneously?+?MTX every 2 weeks for 52 weeks; after 16 weeks, patients without ?20 % improvement from baseline in swollen or tender joint counts on two consecutive assessments were offered open-label treatment. PROs included patient global assessment of disease activity (PtGA), pain, health assessment questionnaire disability index (HAQ-DI), Short Form-36 Health Survey (SF-36), and functional assessment of chronic illness therapy-fatigue (FACIT-F). Changes from baseline at weeks 24 and 52 were analyzed using a mixed model for repeated measures. Post hoc analyses included percentages of patients reporting improvements equal to or greater than minimal clinically important differences (MCID) and normative values in the FACIT-F and SF-36. Pearson correlation between observed PRO scores and clinical measures of disease activity was tested at week 24.Both doses of sarilumab?+?MTX vs placebo?+?MTX resulted in improvement from baseline by week 24 in PtGA, pain, HAQ-DI, SF-36 and FACIT-F scores (p?

SUBMITTER: Strand V

PROVIDER: S-EPMC5012017 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Sarilumab plus methotrexate improves patient-reported outcomes in patients with active rheumatoid arthritis and inadequate responses to methotrexate: results of a phase III trial.

Strand Vibeke V Kosinski Mark M Chen Chieh-I CI Joseph George G Rendas-Baum Regina R Graham Neil M H NM van Hoogstraten Hubert H Bayliss Martha M Fan Chunpeng C Huizinga Tom T Genovese Mark C MC

Arthritis research & therapy 20160906

<h4>Background</h4>Sarilumab is a human monoclonal antibody directed against the alpha subunit of the interleukin-6 receptor complex. In the MOBILITY phase III randomized controlled trial (RCT), sarilumab + methotrexate (MTX) treatment resulted in clinical improvements at 24 weeks that were maintained at 52 weeks in adults with rheumatoid arthritis (RA), who have inadequate response to MTX (MTX-IR). These analyses indicate the effects of sarilumab + MTX versus placebo on patient-reported outcome ...[more]

PMID: 27600829

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Project description:BACKGROUND:Sarilumab is a human immunoglobulin G1 anti-interleukin-6 (IL-6) receptor monoclonal antibody that blocks IL-6 from binding to membrane-bound and soluble IL-6 receptor α. This bridging study assessed the efficacy and safety of sarilumab + methotrexate (MTX) in Japanese patients with active rheumatoid arthritis (RA) and inadequate response to MTX (MTX-IR). METHODS:In this phase III study, 243 patients were randomized 2:2:1:1 to receive subcutaneous sarilumab 150 mg every 2 weeks (q2w), sarilumab 200 mg q2w, placebo switching to sarilumab 150 mg q2w + MTX at 24 weeks, or placebo switching to sarilumab 200 mg q2w at 24 weeks, all in combination with MTX, for a total of 52 weeks (double-blind, placebo-controlled 24-week period followed by a single-blind 28-week extension). The primary endpoint was the proportion of patients achieving American College of Rheumatology 20% improvement criteria (ACR20) responses at week 24. RESULTS:ACR20 response rates at week 24 were 67.9%, 57.5%, and 14.8% for sarilumab 150 mg, sarilumab 200 mg, and placebo, respectively. Serious treatment-emergent adverse events were reported by 9.9%, 6.3%, 0%, and 13.3% of patients in the sarilumab 150 mg, sarilumab 200 mg, placebo to sarilumab 150 mg, and placebo to sarilumab 200 mg groups, respectively. No deaths occurred. The incidence of infections ranged from 52.5 to 67.9%, with five serious infections for the sarilumab 150 mg group and one for the group switched from placebo to 200 mg sarilumab. Absolute neutrophil count < 1.0 Giga/l occurred in 13.6% and 7.5% of patients in the sarilumab 150 and 200 mg groups, respectively, and was not associated with infection. CONCLUSIONS:In Japanese MTX-IR RA patients treated with sarilumab (150 and 200 mg q2w) in combination with MTX, sustained clinical efficacy was shown by significant improvement in signs, symptoms, and physical function; bridging between this and a previous global study was achieved. At week 52, the safety profiles of both doses of sarilumab were generally similar, as previously observed and as expected based on IL-6 class. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02293902 . Registered on 19 November 2014.

Project description:BackgroundInterleukin 6 (IL-6) signaling plays a key role in the pathophysiology of rheumatoid arthritis (RA) and is inhibited by sarilumab, a human monoclonal antibody blocking the IL-6 receptor alpha (IL-6Rα). The effects of sarilumab plus methotrexate (MTX) on serum biomarkers of joint damage and bone resorption were assessed in two independent studies (phase II (part A) and phase III (part B)) of patients with RA with a history of inadequate response to MTX from the MOBILITY study (NCT01061736).MethodsSerum samples were analyzed at baseline and prespecified posttreatment time points. Biomarkers of tissue destruction, cartilage degradation, and synovial inflammation were measured in part A; assessment of these markers was repeated in part B and included additional analysis of biomarkers of bone formation and resorption (including soluble receptor activator of nuclear factor-kB ligand (sRANKL)). A mixed model for repeated measures was used to compare treatment effects on change in biomarkers. Additionally, changes from baseline in biomarkers were compared between American College of Rheumatology 50 % responders and nonresponders and between patients who achieved or did not achieve low disease activity (LDA), separately by treatment group, at week 24.ResultsIn part A, sarilumab 150 and 200 mg every 2 weeks (q2w) significantly reduced biomarkers of tissue destruction, cartilage degradation, and synovial inflammation at both 2 and 12 weeks posttreatment (p < 0.05 vs placebo). These results were replicated in part B, with markers of these damaging processes reduced at weeks 2 and 24 (p < 0.05 vs placebo). Additionally, sarilumab 200 mg q2w significantly reduced both sRANKL and sRANKL/osteoprotegerin ratio at week 24 (p < 0.01 vs placebo). Trends for reduction were noted for several biomarkers in patients who achieved LDA compared with those who did not.ConclusionsSarilumab plus MTX significantly suppressed biomarkers of bone resorption and joint damage, as compared with placebo plus MTX, in patients with RA. Additional work is needed to determine whether differences in biomarker profiles at baseline or posttreatment can identify patients who achieve improvement in disease activity.Trial registrationClinicalTrials.gov, NCT01061736 , February 2, 2010.

Project description:BackgroundDespite a substantial number of treatment options in rheumatoid arthritis (RA) following tumor necrosis factor inhibitor (TNFi) inadequate response or intolerance (TNF-IR), a lack of clarity on the optimal approach remains. Sarilumab, a human monoclonal anti-interleukin-6 receptor alpha antibody, can be used as monotherapy or in combination with methotrexate or other conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) in TNF-IR patients.ObjectiveTo conduct a cost-utility analysis from a U.S. health care system perspective for sarilumab subcutaneous 200 mg + methotrexate versus abatacept + methotrexate or a bundle of TNFi + methotrexate for treatment of adult patients with moderately to severely active RA and TNF-IR.MethodsAnalysis was conducted via individual patient simulation based on patient profiles from the TARGET trial (NCT01709578); a 6-month decision tree was followed by lifetime semi-Markov model with 6-month cycles. Treatment response at 6 months, informed by network meta-analysis, was based on American College of Rheumatology (ACR) 20/50/70 criteria; patients achieving ≥ ACR20 continued with current therapy, and other patients moved to the next line of biologic DMARD therapy or conventional synthetic DMARD palliative treatment. Direct costs included wholesale acquisition drug costs and administration and routine care costs. Routine care costs and quality-adjusted life-years (QALYs) were estimated by predicting the Health Assessment Questionnaire Disability Index score based on treatment response and were imputed from published equations.ResultsSarilumab + methotrexate dominated the TNFi bundle + methotrexate, achieving lower costs ($319,324 vs. $356,096) and greater effectiveness (4.27 vs. 4.15 QALYs), and was on the cost-efficiency frontier with abatacept + methotrexate ($360,211 and 4.29 QALYs). Abatacept + methotrexate was not cost-effective versus sarilumab + methotrexate. Scenario analyses indicated the results were robust; sarilumab + methotrexate became dominant against abatacept + methotrexate after reduced model horizon, minimum response based on ACR50 or ACR70, or time to discontinuation per treatment class. Sarilumab + methotrexate was also dominant versus the TNFi bundle; when class-specific time to treatment discontinuation was specified, sarilumab remained cost-effective with an incremental cost-effectiveness ratio of $36,894.ConclusionsSarilumab + methotrexate can be considered an economically dominant (more effective, less costly) option versus a second TNFi + methotrexate; compared with abatacept + methotrexate, it is a less costly but less effective option for patients with moderately to severely active RA who have previously failed TNFi.DisclosuresThis study was funded by Sanofi and Regeneron Pharmaceuticals. Kiss and Gal are employees of Evidera, which received consulting fees from Sanofi/Regeneron for conducting this study. Muszbek was employed by Evidera at the time of this study. Kuznik and Chen are current employees of and stockholders in Regeneron Pharmaceuticals. Fournier is an employee of and stockholder in Sanofi. Proudfoot is a former employee of and current stockholder in Sanofi and current employee and stockholder in ViiV Healthcare/GlaxoSmithKline. Michaud has received grant funding from Pfizer and the Rheumatology Research Foundation. The sponsors were involved in the study design, collection, analysis, and interpretation of data as well as data checking of information provided in the manuscript. The authors had unrestricted access to study data, were responsible for all content and editorial decisions, and received no honoraria related to the development of this publication.

Project description:BACKGROUND:The phase III MONARCH randomized controlled trial (NCT02332590) demonstrated that in patients with rheumatoid arthritis (RA), sarilumab (anti-interleukin-6 receptor monoclonal antibody) monotherapy is superior to adalimumab monotherapy in reducing disease activity and signs and symptoms of RA, as well as in improving physical function, with similar rates of adverse and serious adverse events. We report the effects of sarilumab versus adalimumab on patient-reported outcomes (PROs). METHODS:Patients with active RA intolerant of, or inadequate responders to, methotrexate were randomized to sarilumab 200 mg plus placebo every 2 weeks (q2w; n?=?184) or adalimumab 40 mg plus placebo q2w (n?=?185). Dose escalation to weekly administration of adalimumab or matching placebo was permitted at week 16. PROs assessed at baseline and weeks 12 and 24 included patient global assessment of disease activity (PtGA), pain and morning stiffness visual analogue scales (VASs), Health Assessment Questionnaire Disability Index (HAQ-DI), 36-item Short Form Health Survey (SF-36), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Rheumatoid Arthritis Impact of Disease (RAID), and rheumatoid arthritis-specific Work Productivity Survey (WPS-RA). Between-group differences in least-squares mean (LSM) changes from baseline were analyzed. p?<?0.05 was considered significant for PROs in a predefined hierarchy. For PROs not in the hierarchy, nominal p values are provided. Proportions of patients reporting improvements greater than or equal to the minimal clinically important difference (MCID) and achieving normative values were assessed. RESULTS:At week 24, sarilumab treatment resulted in significantly greater LSM changes from baseline than adalimumab monotherapy in HAQ-DI (p?<?0.005), PtGA (p?<?0.001), pain VAS (p?<?0.001), and SF-36 Physical Component Summary (PCS) (p?<?0.001). Greater LSM changes were reported for sarilumab than for adalimumab in RAID (nominal p?<?0.001), morning stiffness VAS (nominal p?<?0.05), and WPS-RA (nominal p?<?0.005). Between-group differences in FACIT-F and SF-36 Mental Component Summary (MCS) were not significant. More patients reported improvements greater than or equal to the MCID in HAQ-DI (nominal p?<?0.01), RAID (nominal p?<?0.01), SF-36 PCS (nominal p?<?0.005), and morning stiffness (nominal p?<?0.05), as well as greater than or equal to the normative values in HAQ-DI (p?<?0.05), with sarilumab versus adalimumab. CONCLUSIONS:In parallel with the clinical efficacy profile previously reported, sarilumab monotherapy resulted in greater improvements across multiple PROs than adalimumab monotherapy. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02332590 . Registered on 5 January 2015.

Project description:ObjectiveTo evaluate the efficacy and safety of sarilumab plus conventional synthetic disease-modifying antirheumatic drugs (DMARDs) in patients with active moderate-to-severe rheumatoid arthritis (RA) who had an inadequate response or intolerance to anti-tumor necrosis factor (anti-TNF) therapy.MethodsPatients were randomly allocated to receive sarilumab 150 mg, sarilumab 200 mg, or placebo every 2 weeks for 24 weeks with background conventional synthetic DMARDs. The co-primary end points were the proportion of patients achieving a response according to the American College of Rheumatology 20% criteria for improvement (ACR20) at week 24, and change from baseline in the Health Assessment Questionnaire disability index (HAQ DI) at week 12. Each sarilumab dose was evaluated against placebo; differences between the 2 sarilumab doses were not assessed.ResultsThe baseline characteristics of the treatment groups were similar. The ACR20 response rate at week 24 was significantly higher with sarilumab 150 mg and sarilumab 200 mg every 2 weeks compared with placebo (55.8%, 60.9%, and 33.7%, respectively; P < 0.0001). The mean change from baseline in the HAQ DI score at week 12 was significantly greater for sarilumab (least squares mean change: for 150 mg, -0.46 [P = 0.0007]; for 200 mg, -0.47 [P = 0.0004]) versus placebo (-0.26). Infections were the most frequently reported treatment-emergent adverse events. Serious infections occurred in 1.1%, 0.6%, and 1.1% of patients receiving placebo, sarilumab 150 mg, and sarilumab 200 mg, respectively. Laboratory abnormalities included decreased absolute neutrophil count and increased transaminase levels in both sarilumab groups compared with placebo. In this study, reductions in the absolute neutrophil count were not associated with an increased incidence of infections or serious infections.ConclusionSarilumab 150 mg and sarilumab 200 mg every 2 weeks plus conventional synthetic DMARDs improved the signs and symptoms of RA and physical function in patients with an inadequate response or intolerance to anti-TNF agents. Safety data were consistent with interleukin-6 receptor blockade and the known safety profile of sarilumab.

Dataset Information

Sarilumab plus methotrexate improves patient-reported outcomes in patients with active rheumatoid arthritis and inadequate responses to methotrexate: results of a phase III trial.

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Sarilumab plus methotrexate improves patient-reported outcomes in patients with active rheumatoid arthritis and inadequate responses to methotrexate: results of a phase III trial.

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