Safety of sarilumab in a Japanese population with rheumatoid arthritis by age group: Data from an interim analysis of a post-marketing surveillance study.

OBJECTIVES: Using data from a post-marketing surveillance, this interim subgroup analysis investigated the safety of sarilumab in younger (<65 years) and older patients (≥65 and ≥75 years) with rheumatoid arthritis. METHODS: During this interim analysis, patients who were treated with sarilumab in Japan were enrolled between June 2018-2021. Data collected by 12 January 2022 were analysed, with adverse drug events monitored over 52 weeks. RESULTS: Of 972 patients with available data, proportion of patients aged <65 years, ≥65 years and ≥75 years were 40.8%, 59.2% and 27.8%, respectively. Most patients (95.5%) received the standard 200 mg dose of sarilumab as the initial dose. Adverse drug reactions were reported in 24.6% of patients, with serious events accounting for 6.4% of cases. No malignancy and low incidences of adverse drug reactions of special interest were reported across all age groups (<65 years, 7.8%; ≥65 years, 8.2%; ≥75 years, 8.5%). When stratified by absolute neutrophil count above and below the lower limit of normal, there were no numerical differences in incidences of serious and non-serious infections between age groups. CONCLUSIONS: Regardless of age, sarilumab therapy was well tolerated by patients with rheumatoid arthritis, with no new safety signals reported in this study.

Long-term safety and efficacy of sarilumab with or without background csDMARDs in rheumatoid arthritis.

OBJECTIVE: To evaluate the long-term safety and efficacy of sarilumab with/without conventional synthetic (cs)DMARDs in RA. METHODS: The analyses evaluated two open-label extensions (OLEs): EXTEND and MONARCH OLE, which included patients from six randomized trials. Patients received sarilumab 200 mg once every 2 weeks (q2w) for at least 264 weeks up to 516 weeks (EXTEND: Sarilumab Monotherapy and Sarilumab + csDMARD groups) or for 276 weeks (MONARCH OLE: Continuation and Switch groups). Primary endpoints included safety, immunogenicity and changes in laboratory parameters. Secondary endpoints included clinical signs and symptoms along with health-related quality-of-life (HRQOL) questionnaires. RESULTS: The Sarilumab Monotherapy (n = 111), Continuation (n = 165) and Switch (n = 155) groups received sarilumab monotherapy, while the Sarilumab + csDMARD group (n = 1910) received sarilumab in combination with csDMARDs. Incidence of one or more treatment-emergent adverse events was 126 (Sarilumab Monotherapy group), 169 (Sarilumab + csDMARD group), 159 (Continuation group) and 159 (Switch group) events/100 patient-years. Neutropenia was the most common adverse event. Neutropenia was not associated with an increased incidence of infections. Most neutropenia cases normalized on-treatment. Adverse events of special interests, such as malignancies, major adverse cardiovascular events, venous thromboembolism and gastrointestinal perforations, were rare. Immunogenicity was low and not associated with hypersensitivity reactions or discontinuations due to lack or loss of efficacy. Improvements in clinical signs and symptoms and HRQOL, observed during the initial blinded trials, were maintained throughout the OLE assessment period. CONCLUSIONS: Long-term sarilumab treatment with/without csDMARDs in patients with RA revealed no new safety findings. Efficacy and HRQOL were maintained or further increased over the open-label assessment period. TRIAL REGISTRATION: EXTEND, ClinicalTrials.gov, https://www.clinicaltrials.gov/ct2/show/NCT01146652, NCT01146652; MONARCH OLE, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02332590, NCT02332590.

Disproportionate articular pain is a frequent phenomenon in rheumatoid arthritis and responds to treatment with sarilumab.

OBJECTIVES: In some patients with RA, joint pain is more severe than expected based on the amount of joint swelling [referred to as disproportionate articular pain (DP)]. We assessed DP prevalence and the effects of sarilumab, an IL-6 inhibitor, on DP. METHODS: Data from RA patients treated with placebo or 200 mg sarilumab in the phase 3 randomized controlled trials (RCTs) MOBILITY and TARGET, adalimumab 40 mg or sarilumab 200 mg in the phase 3 RCT MONARCH and sarilumab 200 mg in open-label extensions (OLEs) were used. DP was defined as an excess tender 28-joint count (TJC28) over swollen 28-joint count (SJC28) of ≥7 (TJC28 - SJC28 ≥ 7). Treatment response and disease activity were determined for patients with and without DP. RESULTS: Of 1531 sarilumab 200 mg patients from RCTs, 353 (23%) had baseline DP. On average, patients with DP had higher 28-joint DAS using CRP (DAS28-CRP) and pain scores than patients without DP, whereas CRP levels were similar. After 12 and 24 weeks, patients with baseline DP treated with sarilumab were more likely to be DP-free than those treated with placebo or adalimumab. In RCTs, more sarilumab-treated patients achieved low disease activity vs comparators, regardless of baseline DP status. In OLEs, patients were more likely to lose rather than gain DP status. CONCLUSION: About one-quarter of patients with RA experienced DP, which responded well to sarilumab. These data support the concept that other mechanisms (potentially mediated via IL-6) in addition to inflammation may contribute to DP in RA. TRIAL REGISTRATIONS: NCT01061736, NCT02332590, NCT01709578, NCT01146652.

Haemoglobin changes and disease activity in Japanese patients with rheumatoid arthritis treated with sarilumab.

OBJECTIVES: Anaemia is a frequent extra-articular manifestation in rheumatoid arthritis (RA); haemoglobin level changes are associated with changes in disease activity. This post-hoc analysis assessed potential relationships between haemoglobin and disease activity in Japanese patients with RA, enrolled in the KAKEHASI study (NCT02293902). METHODS: In this study, adult patients with moderate-to-severe active RA, who had an inadequate response to methotrexate, were randomised to subcutaneous sarilumab 150 mg every 2 weeks (q2w) or 200 mg q2w or placebo for 24 weeks. Post-hoc analyses were conducted on changes in haemoglobin and proportion of anaemic patients, using a mixed-effects model for repeated measures assuming an unstructured covariance. Relationships between haemoglobin and efficacy measures were explored. RESULTS: At baseline, nearly half of patients had anaemia, defined by World Health Organization criteria (haemoglobin <12 g/dL, female; or <13 g/dL, male). At Week 24, the least squares mean change in haemoglobin levels was greater in sarilumab groups than for placebo (150 mg: 1.23 g/dL, 200 mg: 1.19 g/dL, placebo: 0.17 g/dL; p=0.0002 for both doses vs. placebo). By Week 24, the proportion of patients with anaemia was 17.8%, 22.9%, and 30.1% for sarilumab 150 mg, 200 mg, and placebo, respectively. CONCLUSIONS: In Japanese patients with RA, both doses of sarilumab were associated with greater improvement in haemoglobin levels and reduction in proportion of patients with anaemia, compared with placebo. Sarilumab may be a suitable treatment for patients with RA and anaemia.

Improvement or Worsening of Disease Activity After Switch to Sarilumab in Patients With Rheumatoid Arthritis With a Partial Response to Adalimumab.

OBJECTIVE: The aim of this study was to assess the effect of switching from adalimumab to sarilumab monotherapy in partial responders with rheumatoid arthritis from the MONARCH randomized trial and its open-label extension (OLE). METHODS: Partial response was defined as improvement in Clinical Disease Activity Index (CDAI) of 12 or 6 units (baseline score: >22 or >10 and ≤22, respectively). Proportions of adalimumab partial responders with meaningful worsening or improvement at OLE weeks 12 and 24 were evaluated using 2 CDAI thresholds (≥6 and ≥12 points), 28-joint Disease Activity Score using erythrocyte sedimentation rate (≥0.6 and ≥1.2 points), Health Assessment Questionnaire Disability Index (≥0.22 and ≥0.30 points), Simple Disease Activity Index (≥7 and ≥13 points), physician and patient global assessments (≥10 and ≥20), and 28-joint swollen and tender joint counts (≥1 and ≥2 joints). Outcomes were analyzed using mixed-effect models with repeated measures for observed cases. The p values were produced using Wilcoxon tests. RESULTS: Of 369 enrolled patients, 320 (87%) entered the OLE and 155 switched from adalimumab to sarilumab; 59% (91/155) were partial responders. At week 24, 4%-17% and 2%-12% of partial responders experienced a worsening using the lower and higher thresholds, respectively, whereas 47%-78% and 27%-66% experienced improvement. CONCLUSIONS: Partial responders to adalimumab who switched to sarilumab had a low likelihood of experiencing meaningful worsening, with most patients showing meaningful improvement or no change in disease activity. This may help alleviate patients' fears of worsening when considering switching to a treatment with a different mechanism of action.

Effect of sarilumab on unacceptable pain and inflammation control in Japanese patients with moderately-to-severely active rheumatoid arthritis: Post hoc analysis of a Phase III study (KAKEHASI).

OBJECTIVE: The aim of this study is to investigate the effects of sarilumab on unacceptable pain [UP; visual analogue scale (VAS) >40 mm] and inflammation in patients with moderately-to-severely active rheumatoid arthritis. METHODS: In this post hoc analysis of the KAKEHASI study, 243 patients received methotrexate with sarilumab 150 or 200 mg or placebo every other week, over 52 weeks. The proportion of patients with UP and correlations of changes in pain VAS from baseline with uncontrolled inflammation (C-reactive protein ≥1 mg/dl) and disease activity indices were assessed. RESULTS: Almost 80% of patients (192/243) had UP at baseline, including ∼60% of patients with uncontrolled inflammation. Among patients receiving sarilumab, inflammation decreased rapidly, with 90% of patients achieving controlled inflammation by Week 2, while 63.1% continued to have UP. The proportion of patients with UP further decreased by Week 16 (28.5%, sarilumab vs. 64.0%, placebo). By Week 52, only ∼10% of patients had UP. Changes in pain VAS correlated with most disease activity indices and patient-reported outcomes. However, marked correlations between changes in pain VAS and C-reactive protein were observed only at Week 16. CONCLUSION: Sarilumab treatment reduced UP and inflammation in Japanese patients with rheumatoid arthritis.

Pharmacokinetics, pharmacodynamics, and safety of single-dose subcutaneous sarilumab with or without methotrexate in Japanese patients with rheumatoid arthritis: Two single-dose studies.

OBJECTIVES: To assess the safety and pharmacokinetics (PK) of single-dose subcutaneous (SC) sarilumab or tocilizumab SC ± methotrexate (MTX) and to assess the pharmacodynamics (PD) of sarilumab SC or tocilizumab SC monotherapy in Japanese rheumatoid arthritis (RA) patients. METHODS: TDU13402 was a randomized, double-blind, placebo-controlled, single-ascending dose Phase 1 study (NCT01850680). Twenty-four patients (6 per treatment group) received sarilumab 50, 100, or 200 mg plus MTX or placebo (2 per cohort) on Day (D) 1; PK and safety were assessed through D57. PDY14191 was a randomized, open-label, single-dose study (NCT02404558). Thirty patients (15 per arm) received sarilumab 150 mg or tocilizumab 162 mg on D1; PK, PD, and safety were assessed through D43. RESULTS: TDU13402: mean serum sarilumab exposure increased in a greater than dose proportional manner from 50 to 200 mg dose with no clinically meaningful increase in treatment-emergent adverse events (TEAEs). PDY14191: PK profiles of single-dose sarilumab 150 mg or tocilizumab 162 mg were similar; some numerical differences in PD profiles and TEAEs were observed. Neutrophil count decrease/neutropenia was the most frequently reported TEAE with sarilumab treatment in both studies. CONCLUSIONS: PK, PD, and safety profiles of single-dose sarilumab SC with/without MTX were consistent with results anticipated in Japanese patients with RA.

Sarilumab monotherapy vs sarilumab and methotrexate combination therapy in patients with rheumatoid arthritis.

OBJECTIVE: Sarilumab, as monotherapy or in combination with conventional synthetic DMARDs, such as MTX, has demonstrated improvement in clinical outcomes in patients with RA. The primary objective of this post hoc analysis was to compare the efficacy of sarilumab (200 mg every 2 weeks) monotherapy (MONARCH study) with that of sarilumab and MTX combination therapy (MOBILITY study) at week 24. METHODS: The endpoints assessed were mean change from baseline in the Clinical Disease Activity Index (CDAI), 28-joint Disease Activity using CRP (DAS28-CRP), CRP, haemoglobin (Hb), pain visual analogue scale (VAS) and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue. Least square (LS) mean change from baseline (95% CI) at week 24 for all endpoints was compared between the treatment arms for adjusted comparisons. RESULTS: This analysis included 184 patients on sarilumab monotherapy and 399 patients on sarilumab plus MTX. Differences (P < 0.05) were observed in ethnicity, region, body mass index group, rheumatoid factor, anti-cyclic citrullinated peptide antibodies, swollen joint count, CRP, CDAI and oral glucocorticoid use between these treatment groups. After adjusting for these differences in a mixed-effect model repeated measure, LS mean change from baseline for all assessments was similar between the treatment groups with overlapping CIs: CDAI, -28.79 vs -26.21; DAS28-CRP, -2.95 vs -2.81; CRP, -18.31 vs -16.46; Hb, 6.59 vs 8.09; Pain VAS, -33.62 vs -31.66; FACIT-Fatigue, 9.90 vs 10.24. CONCLUSION: This analysis demonstrated that the efficacy of sarilumab monotherapy was similar to that of sarilumab and MTX combination therapy.

Immunogenicity of sarilumab and impact on safety and efficacy in Japanese patients with rheumatoid arthritis: analysis of two Phase 3 randomised clinical trials.

OBJECTIVES: To describe the immunogenicity profile of sarilumab in Japanese patients with rheumatoid arthritis (RA). METHODS: Patients enrolled in the KAKEHASI and HARUKA studies were included in our analysis. In these studies, patients received sarilumab 150 mg or 200 mg every 2 weeks for 52 or 28 weeks in combination with methotrexate (MTX) (KAKEHASI), or for 52 weeks as monotherapy or in combination with non-MTX conventional synthetic disease-modifying anti-rheumatic drugs (HARUKA). Anti-drug antibodies (ADAs) and neutralising antibodies (NAbs) were assessed in the pooled population. RESULTS: Positive ADA assay responses occurred in 10/149 (7.1%) patients treated with sarilumab 150 mg and 13/185 (7.0%) patients treated with sarilumab 200 mg, with persistent responses in 2 (1.4%) and 4 (2.2%) patients, respectively. Peak ADA titre was 30. No patients treated with the 150 mg dose and one patient (0.5%) treated with the 200 mg dose exhibited NAbs. There was no evidence of an association between ADA formation and hypersensitivity reactions or reduced efficacy. CONCLUSIONS: ADAs, which occurred at a low frequency and titre, did not affect the safety or efficacy of sarilumab 150 or 200 mg administered as monotherapy or combination therapy in Japanese patients with RA in the KAKEHASI or HARUKA studies.

Sarilumab monotherapy or in combination with non-methotrexate disease-modifying antirheumatic drugs in active rheumatoid arthritis: A Japan phase 3 trial (HARUKA).

Objectives: To determine long-term safety and efficacy of sarilumab as monotherapy or with non-methotrexate (MTX) conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in Japanese patients with active rheumatoid arthritis (RA).Methods: In this double-blind, randomized study (NCT02373202), patients received subcutaneous sarilumab 150 mg q2w (S150) or 200 mg q2w (S200) as monotherapy or with non-MTX csDMARDs for 52 weeks. The primary endpoint was safety.Results: Sixty-one patients received monotherapy (S150, n = 30; S200, n = 31) and 30 received combination therapy (S150 + csDMARDs, n = 15; S200 + csDMARDs, n = 15). Rates of treatment-emergent adverse events (TEAEs) were 83.3%/90.3%/93.3%/86.7% for S150/S200/S150 + csDMARDs/S200 + csDMARDs, respectively. Nasopharyngitis and neutropenia were the most frequently reported TEAEs. One serious infection was reported in each monotherapy group and in the S200 + 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.

Safety and tolerability of subcutaneous sarilumab and intravenous tocilizumab in patients with rheumatoid arthritis.

OBJECTIVE: Safety and efficacy of mAbs blocking the IL-6 receptor have been established in RA. This is the first analysis examining safety and tolerability of sarilumab and tocilizumab administered as single or multiple doses in patients with RA within the same study. METHODS: In ASCERTAIN, patients were randomized 1: 1: 2 to 24 weeks' double-blind sarilumab 150 or 200 mg every 2 weeks s.c. or tocilizumab 4 mg/kg every 4 weeks i.v., increased to 8 mg/kg if clinically indicated. In Study 1309, patients were randomized 1: 1: 1: 1 to single-dose open-label sarilumab 150 or 200 mg s.c. or tocilizumab 4 or 8 mg/kg i.v. RESULTS: In ASCERTAIN, incidence of treatment-emergent adverse events was similar between sarilumab and tocilizumab. The most common treatment-emergent adverse events were the following: sarilumab: neutropenia [6 patients (12.2%) in the 150 mg group and 8 (15.7%) in the 200 mg group], nasopharyngitis [6 (12.2%) and 3 (5.9%)], and injection-site erythema [4 (8.2%) and 4 (7.8%)]; tocilizumab: accidental overdose [9 (8.8%)], upper respiratory tract infection [7 (6.9%)] and nausea [7 (6.9%)]. Laboratory changes in both studies included decreased neutrophils and platelets and increased transaminases and lipids. In Study 1309, incidence of absolute neutrophil count <1.0 giga/l was similar between sarilumab and tocilizumab, and occurred more frequently in the higher dose groups. No association between decrease in absolute neutrophil count and increased incidence of infection was observed in either study. CONCLUSION: No clinically meaningful differences in treatment-emergent adverse events were observed between sarilumab and tocilizumab. Laboratory changes with sarilumab were within the same range as those with tocilizumab. TRIAL REGISTRATION NUMBERS: ASCERTAIN (NCT01768572); Study 1309 (NCT02097524).

Two years of sarilumab in patients with rheumatoid arthritis and an inadequate response to MTX: safety, efficacy and radiographic outcomes.

Objectives: To examine 2-year safety, efficacy and radiographic outcomes of sarilumab in adults with RA and inadequate response to MTX (MTX-IR). Methods: In the randomized, placebo-controlled MOBILITY trial, MTX-IR patients received subcutaneous sarilumab (150 or 200 mg) or placebo every 2 weeks (q2w) plus MTX for up to 1 year. Upon study completion, patients could enrol in the open-label, long-term extension study (EXTEND, NCT011046652), in which all patients received sarilumab 200 mg q2w plus MTX. Dose reduction to 150 mg q2w was allowed for abnormal laboratory findings and per investigator's discretion. Results: Of 1197 patients participating in MOBILITY, 901 entered EXTEND. Over the 2-year period, treatment-emergent adverse events (TEAEs) and serious AEs occurred at rates of 279.6 events per 100 patient-years and 16.6 events per 100 patient-years, respectively. The most common TEAEs were neutropenia, injection site erythema, increased alanine aminotransferase and upper respiratory tract infections. After 1 year in the open-label, long-term extension, disease activity reached similar levels regardless of initial treatment. Modified total Sharp scores at year 1 were maintained through year 2. Best radiographic outcomes were observed in patients initially randomized to sarilumab 200 mg q2w. After dose reduction, 89.4% of patients continued the study through 2 years. Conclusion: Sarilumab safety through year 2 was consistent with IL-6 receptor blockade. Clinical response was similar irrespective of initial treatment, and radiographic progression stabilized. Patients initiated on sarilumab 200 mg q2w had the best radiographic outcomes. Dose reduction allowed most patients to continue with the study.

Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial.

OBJECTIVES: To compare efficacy and safety of sarilumab monotherapy with adalimumab monotherapy in patients with active rheumatoid arthritis (RA) who should not continue treatment with methotrexate (MTX) due to intolerance or inadequate response. METHODS: MONARCH was a randomised, active-controlled, double-blind, double-dummy, phase III superiority trial. Patients received sarilumab (200 mg every 2 weeks (q2w)) or adalimumab (40 mg q2w) monotherapy for 24 weeks. The primary end point was change from baseline in 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) at week 24. RESULTS: Sarilumab was superior to adalimumab in the primary end point of change from baseline in DAS28-ESR (-3.28 vs -2.20; p<0.0001). Sarilumab-treated patients achieved significantly higher American College of Rheumatology 20/50/70 response rates (sarilumab: 71.7%/45.7%/23.4%; adalimumab: 58.4%/29.7%/11.9%; all p≤0.0074) and had significantly greater improvement in Health Assessment Questionnaire-Disability Index (p=0.0037). Importantly, at week 24, more patients receiving sarilumab compared with adalimumab achieved Clinical Disease Activity Index remission (7.1% vs 2.7%; nominal p=0.0468) and low disease activity (41.8% vs 24.9%; nominal p=0.0005, supplemental analysis). Adverse events occurred in 63.6% (adalimumab) and 64.1% (sarilumab) of patients, the most common being neutropenia and injection site reactions (sarilumab) and headache and worsening RA (adalimumab). Incidences of infections (sarilumab: 28.8%; adalimumab: 27.7%) and serious infections (1.1%, both groups) were similar, despite neutropenia differences. CONCLUSIONS: Sarilumab monotherapy demonstrated superiority to adalimumab monotherapy by improving the signs and symptoms and physical functions in patients with RA who were unable to continue MTX treatment. The safety profiles of both therapies were consistent with anticipated class effects. TRIAL REGISTRATION NUMBER: NCT02332590.

Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis.

BACKGROUND & AIMS: The comparative efficacy and safety of infliximab and azathioprine therapy alone or in combination for ulcerative colitis (UC) have not been evaluated previously. METHODS: This randomized, double-blind trial evaluated the efficacy and safety of 16 weeks of treatment with infliximab monotherapy, azathioprine monotherapy, or the 2 drugs combined in tumor necrosis factor-a antagonist-naive adults with moderate to severe UC. Patients were assigned randomly to receive intravenous infusions of infliximab 5 mg/kg at weeks 0, 2, 6, and 14 plus daily oral placebo capsules; oral azathioprine 2.5 mg/kg daily plus placebo infusions on the infliximab schedule; or combination therapy with the 2 drugs. Corticosteroid-free clinical remission (primary end point, week 16) was evaluated at weeks 8 and 16. The study was terminated before the enrollment target was reached. RESULTS: A total of 239 patients were included in efficacy analyses. Baseline characteristics were similar between treatment groups. Corticosteroid-free remission at week 16 was achieved by 39.7% (31 of 78) of patients receiving infliximab/azathioprine,compared with 22.1% (17 of 77) receiving infliximab alone(P =.017) and 23.7% (18 of 76) receiving azathioprine alone(P =.032). Mucosal healing at week 16 occurred in 62.8% (49 of 78) of patients receiving infliximab/azathioprine, compared with 54.6% (42 of 77) receiving infliximab (P = .295) and 36.8% (28 of 76) receiving azathioprine (P =.001). Serious infections occurred in 2 patients (1 patient receiving infliximab,and 1 patient receiving azathioprine). CONCLUSIONS: Anti­tumor necrosis factor-a­naive patients with moderate to severe UC treated with infliximab plus azathioprine were more likely to achieve corticosteroid-free remission at 16 weeks than those receiving either monotherapy. Combination therapy led to significantly better mucosal healing than azathioprine monotherapy. ClinicalTrials.gov number, NCT00537316.

Real-World Sarilumab Use and Rule Testing to Predict Treatment Response in Patients with Rheumatoid Arthritis: Findings from the RISE Registry.

INTRODUCTION: Clinical trial findings may not be generalizable to routine practice. This study evaluated sarilumab effectiveness in patients with rheumatoid arthritis (RA) and tested the real-world applicability of a response prediction rule, derived from trial data using machine learning (based on C-reactive protein [CRP] > 12.3 mg/l and seropositivity [anticyclic citrullinated peptide antibodies, ACPA +]). METHODS: Sarilumab initiators from the ACR-RISE Registry, with ≥ 1 prescription on/after its FDA approval (2017-2020), were divided into three cohorts based on progressively restrictive criteria: Cohort A (had active disease), Cohort B (met eligibility criteria of a phase 3 trial in RA patients with inadequate response/intolerance to tumor necrosis factor inhibitors [TNFi]), and Cohort C (characteristics matched to the phase 3 trial baseline). Mean changes in Clinical Disease Activity Index (CDAI) and Routine Assessment of Patient Index Data 3 (RAPID3) were evaluated at 6 and 12 months. In a separate cohort, predictive rule was tested based on CRP levels and seropositive status (ACPA and/or rheumatoid factor); patients were categorized into rule-positive (seropositive with CRP > 12.3 mg/l) and rule-negative groups to compare the odds of achieving CDAI low disease activity (LDA)/remission and minimal clinically important difference (MCID) over 24 weeks. RESULTS: Among sarilumab initiators (N = 2949), treatment effectiveness was noted across cohorts, with greater improvement noted for Cohort C at 6 and 12 months. Among the predictive rule cohort (N = 205), rule-positive (vs. rule-negative) patients were more likely to reach LDA (odds ratio: 1.5 [0.7, 3.2]) and MCID (1.1 [0.5, 2.4]). Sensitivity analyses (CRP > 5 mg/l) showed better response to sarilumab in rule-positive patients. CONCLUSIONS: In real-world setting, sarilumab demonstrated treatment effectiveness, with greater improvements in the most selective population, mirroring phase 3 TNFi-refractory and rule-positive RA patients. Seropositivity appeared a stronger driver for treatment response than CRP, although optimization of the rule in routine practice requires further data.

Rheumatoid arthritis (RA) is a condition that may cause joint damage, if untreated. Sarilumab is an advanced medication, approved for treating moderate-to-severe RA in patients not responding to initial standard medicines. Clinical trials have shown that sarilumab improves RA symptoms; however, some people do not respond. This is a common problem in RA treatment. Physicians measure proteins in people's blood (called biomarkers; e.g., anticyclic citrullinated peptide antibodies [ACPA], C-reactive protein [CRP], and rheumatoid factor [RF]) to predict a medicine's response. A previous study showed that people with positive blood tests for ACPA and CRP (> 12.3 mg/l) responded well to sarilumab; this study was based on machine learning (a branch of science using computers) and identified factors that could be linked to treatment benefits. The present study analyzed routine data of 2949 people from the ACR-RISE Registry and showed an improvement in RA symptoms after 6 and 12 months of sarilumab, with a greater improvement noted in patients previously treated with other medicines. Biomarkers were tested in 205 people to check whether they could predict treatment response in day-to-day life. People were called rule-positive if they tested positive for RF and/or ACPA with CRP > 12.3 mg/l, and otherwise rule-negative. After 24 weeks of treatment, rule-positive people had a greater chance of disease improvement than rule-negative people. These results showed the benefits of sarilumab in RA in routine care and suggested the usefulness of machine learning in identifying biomarkers that physicians can use to make treatment decisions.

Clinical Efficacy of Sarilumab Versus Upadacitinib Over 12 weeks: An Indirect Treatment Comparison.

INTRODUCTION: The efficacy of sarilumab and upadacitinib, in combination with disease-modifying antirheumatic drugs (DMARDs), was demonstrated in phase 3 clinical trials of patients with rheumatoid arthritis (RA) refractive to previous biologic DMARDs. In the absence of head-to-head clinical trials, the matching-adjusted indirect comparison (MAIC) and simulated treatment comparison (STC) estimate the relative efficacy of sarilumab and upadacitinib in patients with RA who had an inadequate response to previous biologic DMARDs. METHODS: Patient-level data for sarilumab were obtained from the TARGET trial (NCT01709578) and published aggregate data for upadacitinib were obtained from the SELECT-BEYOND trial (NCT02706847). For the MAIC, individual patient data from the TARGET trial were assigned weights such that weighted mean baseline characteristics of the treatment effect modifiers matched those from SELECT-BEYOND. For the STC, the TARGET patient-level data and mean baseline values from SELECT-BEYOND were used to simulate sarilumab treatment effects for a SELECT-BEYOND population. Endpoints evaluated included the American College of Rheumatology (ACR) response criteria ACR20/50/70, Disease Activity Score-28 for Rheumatoid Arthritis with C-reactive protein (DAS28-CRP) < 3.2, DAS28-CRP < 2.6, Simple Disease Activity Index (SDAI) < 3.3, and Clinical Disease Activity Index (CDAI) < 2.8 at 12 weeks. RESULTS: The analysis included 365 patients from TARGET and aggregated data of 333 patients from SELECT-BEYOND. Matching for potential treatment effect baseline modifiers (i.e., age, oral glucocorticoid use, tender joint count of 68 counts, swollen joint count of 66 counts, serum CRP level, and patient global assessment of disease activity) resulted in a reduction of the effective sample size of TARGET population to 166. Following MAIC and STC analysis, the odds of achieving all aforementioned clinical outcomes versus placebo at week 12 were similar for sarilumab and upadacitinib. CONCLUSION: In the MAIC and STC analyses from TARGET and SELECT-BEYOND trials, the efficacy of sarilumab and upadacitinib were comparable.

Pharmacokinetics and Pharmacodynamics of Subcutaneous Sarilumab and Intravenous Tocilizumab Following Single-Dose Administration in Patients With Active Rheumatoid Arthritis on Stable Methotrexate.

We assessed pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships of interleukin-6 (IL-6), soluble IL-6 receptor, and C-reactive protein (CRP) in serum, and absolute neutrophil count (ANC) in blood following single doses of subcutaneous sarilumab versus intravenous tocilizumab (NCT02097524) from patients with rheumatoid arthritis (RA) who are inadequate responders to methotrexate (MTX) and on a stable dose of MTX. Patients with RA randomized (1:1:1:1) to single-dose sarilumab (150 or 200 mg subcutaneously) or tocilizumab (4 or 8 mg/kg intravenously) were included (n = 101), and PK, PD, and PK/PD relationships and safety were assessed over 6 weeks postdose. PK profiles for both drugs are described by parallel linear and nonlinear target-mediated clearance pathways. PD markers showed similar onset of effect during the first week postdose, regardless of dose or route of administration. CRP and ANC decreased, with median postdose nadirs at 7-15 days for CRP and 3-5 days for ANC. Both drugs at low and high doses achieved the same nadir for ANC and a similar return toward baseline within 2 weeks postdose, suggesting a saturation of effect. Safety profiles of sarilumab and tocilizumab were generally similar. In conclusion, despite differences in PK, the onset of the decrease in CRP (efficacy) and ANC (safety) after a single dose were similar for subcutaneous sarilumab and intravenous tocilizumab. PD effects and safety were consistent with previous studies.

Identification of a Rule to Predict Response to Sarilumab in Patients with Rheumatoid Arthritis Using Machine Learning and Clinical Trial Data.

INTRODUCTION: In rheumatoid arthritis, time spent using ineffective medications may lead to irreversible disease progression. Despite availability of targeted treatments, only a minority of patients achieve sustained remission, and little evidence exists to direct the choice of biologic disease-modifying antirheumatic drugs in individual patients. Machine learning was used to identify a rule to predict the response to sarilumab and discriminate between responses to sarilumab versus adalimumab, with a focus on clinically feasible blood biomarkers. METHODS: The decision tree model GUIDE was trained using a data subset from the sarilumab trial with the most biomarker data, MOBILITY, to identify a rule to predict disease activity after sarilumab 200 mg. The training set comprised 18 categorical and 24 continuous baseline variables; some data were omitted from training and used for validation by the algorithm (cross-validation). The rule was tested using full datasets from four trials (MOBILITY, MONARCH, TARGET, and ASCERTAIN), focusing on the recommended sarilumab dose of 200 mg. RESULTS: In the training set, the presence of anti-cyclic citrullinated peptide antibodies, combined with C-reactive protein > 12.3 mg/l, was identified as the "rule" that predicts American College of Rheumatology 20% response (ACR20) to sarilumab. In testing, the rule reliably predicted response to sarilumab in MOBILITY, MONARCH, and ASCERTAIN for many efficacy parameters (e.g., ACR70 and the 28-joint disease activity score using CRP [DAS28-CRP] remission). The rule applied less to TARGET, which recruited individuals refractory to tumor necrosis factor inhibitors. The potential clinical benefit of the rule was highlighted in a clinical scenario based on MONARCH data, which found that increased ACR70 rates could be achieved by treating either rule-positive patients with sarilumab or rule-negative patients with adalimumab. CONCLUSIONS: Well-established and clinically feasible blood biomarkers can guide individual treatment choice. Real-world validation of the rule identified in this post hoc analysis is merited. CLINICAL TRIAL REGISTRATION: NCT01061736, NCT02332590, NCT01709578, NCT01768572.

Subcutaneous Sarilumab in Patients With Rheumatoid Arthritis who Previously Received Subcutaneous Sarilumab or Intravenous Tocilizumab: An Open-Label Extension of a Randomized Clinical Trial.

OBJECTIVE: This post hoc analysis evaluated the safety and efficacy of open-label sarilumab in patients with rheumatoid arthritis (RA) who completed the phase III double-blind ASCERTAIN study (NCT01768572) and switched from intravenous (IV) tocilizumab to subcutaneous (SC) sarilumab, or who continued SC sarilumab in the open-label extension (OLE) study EXTEND (NCT01146652). METHODS: Patients who completed ASCERTAIN were eligible to enroll in EXTEND to receive sarilumab 200 mg SC every 2 weeks (Q2W). Safety and efficacy were reported through 96 weeks in the OLE in patients who switched from tocilizumab IV to sarilumab 200 mg SC Q2W, who switched from sarilumab 150 mg SC Q2W to sarilumab 200 mg SC Q2W, or who continued sarilumab 200 mg SC Q2W. RESULTS: Of 175 patients who completed ASCERTAIN, 168 (96%) enrolled in EXTEND, and 38 of these patients (23%) discontinued the OLE. Cumulative sarilumab exposure during follow-up was 273.7 patient-years. No new safety signals were identified, infections occurred at a rate of 59.9/100 patient-years, and there were no cases of grade 4 neutropenia. Efficacy-as assessed by Disease Activity Score (28 joints) based on C-reactive protein, Clinical Disease Activity Index, and Health Assessment Questionnaire-Disability Index scores-was sustained over 96 weeks of follow-up when switching to, or continuing, sarilumab 200 mg SC Q2W. CONCLUSION: Switching from IV to SC interleukin-6 receptor inhibitor therapy produced no new safety concerns, and clinical efficacy was sustained over 96 weeks of follow-up. These findings alleviate potential concerns over switching route of administration with interleukin-6 receptor inhibitor therapy for RA.

Sarilumab and adalimumab differential effects on bone remodelling and cardiovascular risk biomarkers, and predictions of treatment outcomes.

BACKGROUND: Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a key role in the pathogenesis of rheumatoid arthritis. Sarilumab is a human monoclonal antibody that binds membrane-bound and soluble IL-6 receptor-α to inhibit IL-6 signalling. The aim of this study was to compare the effects of sarilumab and adalimumab (a tumour necrosis factor alpha inhibitor) monotherapy on levels of circulating biomarkers associated with the acute-phase response, bone remodelling, atherothrombosis, anaemia of chronic disease and markers purported to reflect synovial lymphoid and myeloid cell infiltrates, as well as the potential of these biomarkers to differentially predict clinical and patient-reported outcomes with sarilumab vs. adalimumab. METHODS: In this post hoc analysis, serum samples were analysed at baseline and prespecified post-treatment timepoints up to week 24 in adults with moderate-to-severe active rheumatoid arthritis intolerant of or inadequate responders to methotrexate from the MONARCH trial (NCT02332590). RESULTS: Greater reductions in C-reactive protein (CRP; - 94.0% vs. -24.0%), serum amyloid A (SAA; - 83.2% vs. -17.4%), total receptor activator of nuclear factor-κB ligand (RANKL; - 18.3% vs. 10.5%) and lipoprotein (a) (- 41.0% vs. -2.8%) were observed at week 24 with sarilumab vs. adalimumab, respectively (adjusted p < 0.0001). Greater increases in procollagen type 1 N-terminal propeptide (P1NP) were observed with sarilumab vs. adalimumab at week 24 (22.8% vs. 6.2%, p = 0.027). Patients with high baseline SAA, CRP and matrix metalloproteinase-3 (MMP-3) were more likely to achieve clinical efficacy, including American College of Rheumatology 20% improvement criteria and Disease Activity Score (28 joints)-CRP < 3.2, and report improvements in patient-reported outcomes, including Health Assessment Questionnaire-Disability Index and pain visual analogue scale, with sarilumab than adalimumab. CONCLUSION: Sarilumab was associated with greater positive effects on bone remodelling and decreases in biomarkers of the acute-phase response, synovial inflammation and cardiovascular risk vs. adalimumab. High baseline concentrations of SAA, CRP and MMP-3 are predictive of clinical and patient-reported outcome responses to sarilumab treatment and prospective validation is warranted to confirm these results. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02332590. Registered on 5 January 2015.