Sarilumab Dose Research Articles

Evaluating Meaningful Changes in Patient-Reported Outcome Measurement Information System-Fatigue Scores from Three Phase 3 Clinical Trials of Sarilumab for Patients With Rheumatoid Arthritis.

The aim of this study was to evaluate changes in fatigue measured by Patient-Reported Outcome Measurement Information System (PROMIS)-Fatigue scores in patients with rheumatoid arthritis (RA) who received sarilumab and to assess the proportion of patients achieving clinically meaningful change. Data from three phase 3 randomized controlled trials of patients with RA who received sarilumab-MOBILITY, TARGET, and MONARCH-were evaluated. The 10 RA-relevant items from the 13-item Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue were scored in the PROMIS T score metric. Mean changes in 10-item PROMIS-Fatigue T score (PROMIS-Fatigue 10a) were compared, proportions of patients reporting meaningful within-person change thresholds were assessed, and results were visualized using empirical cumulative distribution function (eCDF) curves. Patients with RA reported high baseline fatigue. Using PROMIS-Fatigue 10a, at week 24, patients receiving 150 or 200 mg sarilumab every other week in MOBILITY and TARGET had rapidly and significantly improved mean levels of fatigue compared to those who received placebo. When compared to patients who received adalimumab in MONARCH, patients who received sarilumab had a trend toward increased improvement. eCDF curves showed separation between active treatment versus placebo with both sarilumab doses and across the score range for improvement. Higher proportions of patients reported three-, five-, and seven-point improvements in PROMIS-Fatigue scores in groups who received active treatment. Substantial proportions of patients with RA who received sarilumab reported meaningful change in fatigue measured by PROMIS-Fatigue 10a over time. This study demonstrates the ability to convert FACIT-Fatigue score onto the PROMIS T score metric, the rapid reduction in fatigue with biologic therapies, and the use of novel eCDF curves to show individual patient-level change.

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

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. 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. 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. Regardless of age, sarilumab therapy was well tolerated by patients with rheumatoid arthritis, with no new safety signals reported in this study.

Role of IP-10 to Predict Clinical Progression and Response to IL-6 Blockade With Sarilumab in Early COVID-19 Pneumonia. A Subanalysis of the SARICOR Clinical Trial.

The Clinical Trial of Sarilumab in Adults With COVID-19 (SARICOR) showed that patients with coronavirus disease 2019 (COVID-19) pneumonia and increased levels of interleukin (IL)-6 might benefit from blockade of the IL-6 pathway. However, the benefit from this intervention might not be uniform. In this subanalysis, we sought to determine if other immunoactivation markers, besides IL-6, could identify which subgroup of patients benefit most from this intervention. The SARICOR trial was a phase II, open-label, multicenter, controlled trial (July 2020-March 2021) in which patients were randomized to receive usual care (UC; control group), UC plus a single dose of sarilumab 200 mg (sarilumab-200 group), or UC plus a single dose of sarilumab 400 mg (sarilumab-400 group). Patients who had baseline serum samples for cytokine determination (IL-8, IL-10, monocyte chemoattractant protein-1, interferon-inducible protein [IP]-10) were included in this secondary analysis. Progression to acute respiratory distress syndrome (ARDS) according to cytokine levels and treatment received was evaluated. One hundred one (88%) of 115 patients enrolled in the SARICOR trial had serum samples (control group: n = 33; sarilumab-200: n = 33; sarilumab-400: n = 35). Among all evaluated biomarkers, IP-10 showed the strongest association with treatment outcome. Patients with IP-10 ≥2500 pg/mL treated with sarilumab-400 had a lower probability of progression (13%) compared with the control group (58%; hazard ratio, 0.19; 95% CI, 0.04-0.90; P = .04). Conversely, patients with IP-10 <2500 pg/mL did not show these differences. IP-10 may predict progression to ARDS in patients with COVID-19 pneumonia and IL-6 levels >40 pg/mL. Importantly, IP-10 value <2500 pg/mL might discriminate those individuals who might not benefit from sarilumab therapy among those with high IL-6 levels.

A comparison of the effectiveness of different doses of tocilizumab and sarilumab in the treatment of severe COVID-19: a natural experiment due to drug shortages

ObjectivesInterleukin (IL)-6 inhibitors are administered to treat patients hospitalized with COVID-19. In 2021, due to shortages, different dosing regimens of tocilizumab, and a switch to sarilumab, were consecutively implemented. Using real-world data, we compare the effectiveness of these IL-6 inhibitors. MethodsHospitalized patients with COVID-19, treated with IL-6 inhibitors, were included in this natural experiment study. Sixty-day survival, hospital- and intensive care unit (ICU) length of stay, and progression to ICU or death were compared between 8 mg/kg tocilizumab, fixed-dose tocilizumab, low-dose tocilizumab, and fixed-dose sarilumab treatment groups. ResultsA total of 5485 patients from 49 hospitals were included. After correction for confounding, increased hazard ratios (HRs) for 60-day mortality were observed for fixed-dose tocilizumab (HR 1.20, 95% confidence interval [CI] 1.04-1.39), low-dose tocilizumab (HR 1.12, 95% CI 0.97-1.31), and sarilumab (HR 1.24, 95% CI 1.08-1.42), all relative to 8 mg/kg. The 8 mg/kg dosing regimen had lower odds of progression to ICU or death. Both hospital- and ICU length of stay were shorter for low-dose tocilizumab than for the 8 mg/kg group. ConclusionWe found differences in the probability of 60-day survival and the incidence of the combined outcome of mortality or ICU admission, mostly favoring 8 mg/kg tocilizumab. Because of potential time-associated residual confounding, further clinical studies are warranted.

CLINICAL AND ECONOMIC ANALYSIS OF GENETICALLY ENGINEERED BIOLOGICS CONSUMPTION BY PATIENTS WITH COVID-19

The aim of the article is a comparative clinical and economic assessment of genetically engineered monoclonal antibodies against interleukins in infectious diseases facilities in Volgograd region, reassigned to treat COVID-19 patients.Materials and methods. ABC analysis of the drug consumption in infectious disease facilities in Volgograd region in 2020 and 2021, cost-minimization analysis, and volume of consumption (standard dose per 1000 patients) for genetically engineered monoclonal antibodies against interleukins, were performed on the basis of pharmacies dispensing drug reports on infectious diseases facilities, Russian State Register of maximum selling prices, and Russian guidelines for COVID-19 treatment.Results. Only a small proportion of COVID-19 patients (43.6 standard doses per 1000 patients in 2020 and 137.8 per 1000 patients in 2021) received genetically engineered biologics in infectious disease facilities in Volgograd Region. Ne-vertheless, in the studied facilities, medical drug expenses on them exceeded from 20% in 2020 to 40% of the total inventory value in 2021. In mild COVID-19 patients with a high comorbidity index, netaquimab was the least expensive drug therapy and levilimab was the most expensive one. For moderate COVID-19, a standart recommended dose of sarilumab was the least expensive among the drugs used in the studied facilities, and anakinra was the least expensive drug among all the recommended GEBs. In severe and extremely severe COVID-19 courses, tocilizumab and sarilumab were less the least expensive among the GEBs used in the infectious disease facilities, and anakinra was the least expensive among all the recommended GEBs.Conclusion. Accepting a possible equal effectiveness based on the currently available data, sarilumab is the least expensive for moderate COVID-19 and tocilizumab is the least expensive for severe and extremely severe COVID-19.

Sarilumab administration in patients with severe COVID‑19: A report of four cases and a literature review

Almost 2 years have passed since the World Health Organization declared a pandemic state for severe acute respiratory syndrome coronavirus 2 infection. The pathogenesis of coronavirus disease 2019 (COVID‑19) consists of an initial viral phase responsible for early symptoms followed by an inflammatory phase, which is cytokine‑mediated, responsible for late‑onset symptoms, culminating in acute respiratory distress syndrome. Considering that IL‑6 plays a key‑role in the development and maintenance of inflammation, drugs targeting both IL‑6 and IL‑6 receptors have been evaluated. The present study reports the cases of four hospitalized patients with severe respiratory COVID‑19 treated with a single dose of sarilumab, a monoclonal anti‑IL‑6 antibody, along with standard of care medications and oxygen therapy. A few days following sarilumab administration, the clinical and biochemical conditions began to improve, until the discontinuation of O₂ therapy and discharge. The present study demonstrates that sarilumab may represent a promising drug that may be used to treat the hyperinflammatory phase; however, further trials are required to determine whether it should be used combination with other drugs or alone, and to better understand the pharmacokinetics and related side‑effects.

Severe Neutropenia after Sarilumab Administration in Two COVID-19 Patients: Case Reports and Literature Review

BACKGROUND: Two years have passed since the WHO declared a pandemic state for SARS-CoV2 infection. COVID-19 pathogenesis consists of a first viral phase responsible for early symptoms followed by an inflammatory phase, which is cytokine-mediated, responsible for late-onset signs up to acute respiratory distress syndrome. Considering that interleukin (IL)6 plays a key role in the development and maintenance of inflammation, drugs targeting both IL6 and IL6 receptors have been evaluated. CASE REPORTS: The present study reports the cases of two hospitalized patients with severe respiratory COVID-19 treated with a single dose of intravenous sarilumab, a monoclonal anti-IL6 antibody, along with standard of care medications and high-flow oxygen therapy. Although a few days following sarilumab administration, clinical and biochemical conditions started ameliorating, these patients developed severe and self-limiting neutropenia. CONCLUSION: Sarilumab may represent a promising weapon to treat the fearsome hyperinflammatory phase; however, more trials are needed to decide whether to use it in combination with other drugs or alone, and to better understand pharmacokinetics and side effects.

Subcutaneous sarilumab for the treatment of hospitalized patients with moderate to severe COVID19 disease: A pragmatic, embedded randomized clinical trial.

The aim of this pragmatic, embedded, adaptive trial was to measure the effectiveness of the subcutaneous anti-IL-6R antibody sarilumab, when added to an evolving standard of care (SOC), for clinical management of inpatients with moderate to severe COVID-19 disease. Two-arm, randomized, open-label controlled trial comparing SOC alone to SOC plus sarilumab. The trial used a randomized play-the-winner design and was fully embedded within the electronic health record (EHR) system. 5 VA Medical Centers. Hospitalized patients with clinical criteria for moderate to severe COVID-19 but not requiring mechanical ventilation, and a diagnostic test positive for SARS-CoV-2. Sarilumab, 200 or 400 mg subcutaneous injection. SOC was not pre-specified and could vary over time, e.g., to include antiviral or other anti-inflammatory drugs. The primary outcome was intubation or death within 14 days of randomization. All data were extracted remotely from the EHR. Among 162 eligible patients, 53 consented, and 50 were evaluated for the primary endpoint of intubation or death. This occurred in 5/20 and 1/30 of participants in the sarilumab and SOC arms respectively, with the majority occurring in the initial 9 participants (3/4 in the sarilumab and 1/5 in the SOC) before the sarilumab dose was increased to 400 mg and before remdesivir and dexamethasone were widely adopted. After interim review, the unblinded Data Monitoring Committee recommended that the study be stopped due to concern for safety: a high probability that rates of intubation or death were higher with addition of sarilumab to SOC (92.6%), and a very low probability (3.4%) that sarilumab would be found to be superior. This randomized trial of patients hospitalized due to respiratory compromise from COVID-19 but not mechanical ventilation found no benefit from subcutaneous sarilumab when added to an evolving SOC. The numbers of patients and events were too low to allow definitive conclusions to be drawn, but this study contributes valuable information about the role of subcutaneous IL-6R inhibition in the treatment of hospitalized COVID-19 patients. Methods developed and piloted during this trial will be useful in conducting future studies more efficiently. Clinicaltrials.gov-NCT04359901; https://clinicaltrials.gov/ct2/show/NCT04359901?cond=NCT04359901&draw=2&rank=1.

Clinical characteristics and outcomes of critically ill mechanically ventilated COVID-19 patients receiving interleukin-6 receptor antagonists and corticosteroid therapy: a preliminary report from a multinational registry

BackgroundInterleukin-6 receptor antagonists (IL-6RAs) and steroids are emerging immunomodulatory therapies for severe and critical coronavirus disease (COVID-19). In this preliminary report, we aim to describe the epidemiology, clinical characteristics, and outcomes of adult critically ill COVID-19 patients, requiring invasive mechanical ventilation (iMV), and receiving IL-6RA and steroids therapy over the last 11 months.Materials and methodsInternational, multicenter, cohort study derived from Viral Infection and Respiratory Illness University Study registry and conducted through Discovery Network, Society of Critical Care Medicine. Data were collected between March 01, 2020, and January 10, 2021.ResultsOf 860 patients who met eligibility criteria, 589 received steroids, 170 IL-6RAs, and 101 combinations. Patients who received IL-6RAs were younger (median age of 57.5 years vs. 61.1 and 61.8 years in the steroids and combination groups, respectively). The median C-reactive protein level was > 75 mg/L, indicating a hyperinflammatory phenotype. The median daily steroid dose was 7.5 mg dexamethasone or equivalent (interquartile range: 6–14 mg); 80.8% and 19.2% received low-dose and high-dose steroids, respectively. Of the patients who received IL-6RAs, the majority received one dose of tocilizumab and sarilumab (dose range of 600–800 mg for tocilizumab and 200–400 mg for sarilumab). Regarding the timing of administration, we observed that steroid and IL-6RA administration on day 0 of ICU admission was only 55.6% and 39.5%, respectively. By day 28, when compared with steroid use alone, IL-6RA use was associated with an adjusted incidence rate ratio (aIRR) of 1.12 (95% confidence interval [CI] 0.88, 1.4) for ventilator-free days, while combination therapy was associated with an aIRR of 0.83 (95% CI 0.6, 1.14). IL-6RA use was associated with an adjusted odds ratio (aOR) of 0.68 (95% CI 0.44, 1.07) for the 28-day mortality rate, while combination therapy was associated with an aOR of 1.07 (95% CI 0.67, 1.70). Liver dysfunction was higher in IL-6RA group (p = 0.04), while the bacteremia rate did not differ among groups.ConclusionsDiscordance was observed between the registry utilization patterns (i.e., timing of steroids and IL-6RA administration) and new evidence from the recent randomized controlled trials and guideline recommendations. These data will help us to identify areas of improvement in prescribing patterns and enhance our understanding of IL-6RA safety with different steroid regimens. Further studies are needed to evaluate the drivers of hospital-level variation and their impact on clinical outcomes.Trial registration ClinicalTrials.gov: NCT04486521. Registered on July 2020

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

IntroductionIn 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.MethodsThe 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.ResultsIn 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.ConclusionsWell-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 RegistrationNCT01061736, NCT02332590, NCT01709578, NCT01768572.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-021-00361-5.

Differential Binding of Sarilumab and Tocilizumab to IL-6Rα and Effects of Receptor Occupancy on Clinical Parameters.

We evaluated interleukin-6 (IL-6) receptor-α subunit (IL-6Rα) signaling inhibition with sarilumab and tocilizumab, the association between IL-6Rα receptor occupancy (RO) and C-reactive protein (CRP), and the potential clinical relevance of any differences. For this, we measured IL-6Rα binding and signaling inhibition with sarilumab and tocilizumab invitro, simulated soluble IL-6Rα RO over time for approved sarilumab subcutaneous (SC) and tocilizumab intravenous (IV) and SC doses, and assessed associations between calculated RO and CRP reduction, 28-joint Disease Activity Score based on CRP, and 20%/50%/70% improvement in American College of Rheumatology responses from clinical data. Sarilumab binds IL-6Rα in vitro with 15- to 22-fold higher affinity than tocilizumab, and inhibits IL-6-mediated classical and trans signaling via membrane-bound and soluble IL-6Rα. Sarilumab 200 and 150 mg SC every 2 weeks achieved >90% RO after first and second doses, respectively, maintained throughout the treatment period. At steady-state trough, RO was greater with sarilumab 200mg (98%) and 150 mg SC every 2 weeks (94%), and tocilizumab 162 mg SC weekly (>99%) and 8mg/kg IV every 4 weeks (99%), vs tocilizumab 162 mg SC every 2 weeks (84%) and 4 mg/kg IV every 4 weeks (60%). Higher RO was associated with greater CRP reduction and 28-joint Disease Activity Score based on CRP reduction, and more sarilumab patients achieving 20%/50%/70% improvement in American College of Rheumatology responses. The greatest reduction in CRP levels was observed with sarilumab (both doses) and tocilizumab 8mg/kg IV every 4 weeks (reductions proportionally smaller with 4mg/kg IV every 4 weeks). Higher IL-6Rα binding affinity translated into higher RO with sarilumab vs tocilizumab 4mg/kg every 4 weeks or 162 mg every 2 weeks; tocilizumab required the higher dose or increased frequency to maintain the same degree of RO and CRP reduction. Higher RO was associated with clinical parameter improvements.

Efficacy and safety of early treatment with sarilumab in hospitalised adults with COVID-19 presenting cytokine release syndrome (SARICOR STUDY): protocol of a phase II, open-label, randomised, multicentre, controlled clinical trial

IntroductionAbout 25% of patients with COVID-19 develop acute respiratory distress syndrome (ARDS) associated with a high release of pro-inflammatory cytokines such as interleukin-6 (IL-6). The aim of the SARICOR study...

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.

THU0167 ASSOCIATIONS BETWEEN RHEUMATOID ARTHRITIS DISEASE ACTIVITY AND PATIENT-REPORTED OUTCOMES IN SARILUMAB CLINICAL TRIALS

Background:Sarilumab is a human interleukin (IL)-6 receptor inhibitor approved for the treatment of adults with moderately to severely active rheumatoid arthritis (RA). The relationship between disease activity (DA), sarilumab treatment, and improvements in patient-reported outcomes (PROs) has not been well-studied.Objectives:Assess the association between DA and PROs in three sarilumab Phase 3 trials.Methods:This post hoc analysis included patients from three trials: two placebo-controlled trials (MOBILITY;NCT01061736and TARGET;NCT01709578) with sarilumab dose groups 150 mg and 200 mg q2w that were combined for this analysis; and MONARCH (NCT02332590) with sarilumab 200 mg versus adalimumab 40 mg q2w. Associations between PROs and DA were tested at Week 24. All statistics are descriptive.Results:Sarilumab was generally associated with larger PRO improvement than placebo both in patients who did and patients who did not achieve DA thresholds (Table). Improvement was less pronounced in patients who did not achieve DA thresholds. In the active-comparator trial, PROs improved in both treatment groups, across all DA levels. There was no clear difference between sarilumab and adalimumab in PRO response. There was a consistent trend of positive but reduced PRO responses with increased DA level using multiple cut-points (data not shown).Table.Median (interquartile range) change from baseline in PROsFACIT-fatigue (0–52)Pain (VAS 0–100)Sleep (VAS 0–100)MOBILITYaPlaceboSarilumabPlaceboSarilumabPlaceboSarilumabDAS28-CRP &lt;3.27.3 (14.0)9.0 (13.0)–36.0 (33.0)–41.0 (37.0)–17.0 (47.0)–26.0 (46.0)DAS28-CRP ≥3.24.3 (10.0)7.5 (12.0)–14.0 (35.0)–18.5 (33.0)–12.0 (35.0)–14.5 (35.0)CDAI ≤107.3 (13.0)9.0 (13.0)–37.0 (35.0)–41.0 (39.0)–17.0 (45.0)–26.0 (44.0)CDAI &gt;104.3 (10.0)8.0 (11.3)–12.5 (34.0)–22.0 (35.0)–12.0 (33.5)–14.0 (36.0)SDAI ≤118.0 (13.0)9.0 (13.0)–37.0 (32.0)–40.0 (38.0)–24.0 (47.0)–26.0 (45.0)SDAI &gt;114.0 (9.0)8.0 (11.0)–12.0 (34.0)–22.0 (36.0)–10.0 (34.0)–16.0 (36.0)TARGETbPlaceboSarilumabPlaceboSarilumabDAS28-CRP &lt;3.216.0 (13.0)14.0 (16.0)–44.5 (28.5)–53.0 (35.0)DAS28-CRP ≥3.27.0 (13.0)8.5 (13.5)–18.0 (38.0)–27.5 (34.0)CDAI ≤1014.0 (13.4)14.0 (15.0)–42.0 (32.0)–52.0 (34.0)CDAI &gt;106.0 (13.0)9.0 (15.0)–18.0 (38.0)–28.0 (37.0)SDAI ≤1115.0 (12.0)14.0 (15.3)–45.0 (30.0)–52.5 (33.0)SDAI &gt;116.0 (14.0)8.9 (15.0)–17.5 (38.0)–27.0 (37.0)MONARCHcAdalimumabSarilumabAdalimumabSarilumabDAS28-CRP &lt;3.210.0 (13.0)11.0 (15.0)–45.0 (23.0)–42.0 (39.0)DAS28-CRP ≥3.27.0 (13.0)5.0 (12.5)–21.0 (30.0)–20.5 (32.5)CDAI ≤1010.0 (14.0)11.0 (14.0)–44.0 (25.0)–42.0 (41.0)CDAI &gt;107.0 (13.0)7.0 (14.3)–21.0 (31.0)–28.5 (36.0)DA thresholds per trial protocols.aPlacebo n = 398; sarilumab n = 799.bPlacebo n = 181; sarilumab n = 365; sleep not assessed.cAdalimumab n = 185; sarilumab n = 184; SDAI and sleep not assessed.Conclusion:Achieving lower DA was associated with increased PRO improvements. In patients who did not achieve DA thresholds, the improvements were more favorable with sarilumab than placebo. This may support the emerging concept that mechanisms other than inflammation may contribute to improvements in PROs, potentially mediated via IL-6 signaling.Acknowledgments:Study funding and medical writing support (Matt Lewis, Adelphi Communications Ltd) were provided by Sanofi and Regeneron Pharmaceuticals, Inc.Disclosure of Interests:Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme, Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Laure Gossec Grant/research support from: Lilly, Mylan, Pfizer, Sandoz, Consultant of: AbbVie, Amgen, Biogen, Celgene, Janssen, Lilly, Novartis, Pfizer, Sandoz, Sanofi-Aventis, UCB, Hubert van Hoogstraten Shareholder of: Sanofi, Employee of: Sanofi, Amy Praestgaard Employee of: Sanofi Genzyme, Gregory St John Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., Thomas Huizinga Grant/research support from: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Consultant of: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Daniel Aletaha Grant/research support from: AbbVie, Novartis, Roche, Consultant of: AbbVie, Amgen, Celgene, Lilly, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi Genzyme, Speakers bureau: AbbVie, Celgene, Lilly, Merck, Novartis, Pfizer, Sanofi Genzyme, UCB, Roy Fleischmann Grant/research support from: AbbVie, Akros, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer, IngelhCentrexion, Eli Lilly, EMD Serono, Genentech, Gilead, Janssen, Merck, Nektar, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, Samsung, Sandoz, Sanofi Genzyme, Selecta, Taiho, UCB, Consultant of: AbbVie, ACEA, Amgen, Bristol-Myers Squibb, Eli Lilly, Gilead, GlaxoSmithKline, Novartis, Pfizer, Sanofi Genzyme, UCB

Long-term safety and efficacy of sarilumab plus methotrexate on disease activity, physical function and radiographic progression: 5 years of sarilumab plus methotrexate treatment

ObjectiveIn MOBILITY (NCT01061736), sarilumab significantly reduced disease activity, improved physical function and inhibited radiographic progression at week 52 versus placebo in patients with rheumatoid arthritis (RA) and an inadequate response...

Long-term safety of sarilumab in rheumatoid arthritis: an integrated analysis with up to 7 years’ follow-up

ObjectiveSarilumab is a human monoclonal antibody that blocks IL-6 from binding to membrane-bound and soluble IL-6 receptor-α. We assessed the long-term safety of sarilumab in patients from eight clinical trials and their open-label extensions.MethodsData were pooled from patients with rheumatoid arthritis who received at least one dose of sarilumab in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs; combination group) or as monotherapy (monotherapy group). Treatment-emergent adverse events (AEs) and AEs and laboratory values of special interest were assessed.Results2887 patients received sarilumab in combination with csDMARDs and 471 patients received sarilumab monotherapy, with mean exposure of 2.8 years and 1.7 years, maximum exposure 7.3 and 3.5 years, and cumulative AE observation period of 8188 and 812 patient-years, respectively. Incidence rates per 100 patient-years in the combination and monotherapy groups, respectively, were 9.4 and 6.7 for serious AEs, 3.7 and 1.0 for serious infections, 0.6 and 0.5 for herpes zoster (no cases were disseminated), 0.1 and 0 for gastrointestinal perforations, 0.5 and 0.2 for major adverse cardiovascular events, and 0.7 and 0.6 for malignancy. Absolute neutrophil counts <1000 cells/mm3 were recorded in 13% and 15% of patients, respectively. Neutropenia was not associated with increased risk of infection or serious infection. Analysis by 6-month interval showed no signal for increased rate of any AE over time.ConclusionThe long-term safety profile of sarilumab, either in combination with csDMARDs or as monotherapy, remained stable and consistent with the anticipated profile of a molecule that inhibits IL6 signalling.

Immunogenicity of Sarilumab Monotherapy in Patients with Rheumatoid Arthritis Who Were Inadequate Responders or Intolerant to Disease-Modifying Antirheumatic Drugs.

IntroductionThis open-label study evaluated the immunogenicity, safety, and efficacy of sarilumab monotherapy in patients with active, moderate-to-severe rheumatoid arthritis (RA) and inadequate response or intolerance to prior conventional synthetic disease-modifying antirheumatic drugs.MethodsAdults with RA (n = 132) were randomized to receive subcutaneous sarilumab (150 [n = 65] or 200 mg [n = 67]) every 2 weeks (q2w) for 24 weeks. Endpoints included incidence of antidrug antibodies (ADAs) at week 24, safety, and efficacy.ResultsPersistent ADAs occurred in eight patients (12.3%) receiving sarilumab 150 mg q2w, seven of whom (10.8%) had neutralizing antibodies (NAbs), and in four patients (6.1%) receiving sarilumab 200 mg q2w, two of whom (3.0%) had NAbs; all exhibited low antibody titers. Infections and neutropenia were the most common adverse events (AEs). There were three serious AEs, no reports of anaphylaxis, and few hypersensitivity reactions (e.g., rash) with no notable differences in hypersensitivity reactions in ADA-positive patients relative to ADA-negative patients. Changes in absolute neutrophil count, alanine aminotransferase level, and platelet count were consistent with interleukin-6 signaling blockade and in agreement with previous observations. At week 24, overall American College of Rheumatology 20%/50%/70% improvement criteria responses were 73.8%/53.8%/29.2%, respectively, with sarilumab 150 mg q2w and 71.6%/50.7%/29.9% with sarilumab 200 mg q2w. No patients with an ADA-positive response showed loss of efficacy.ConclusionsADA titers were low and persistent ADAs and NAbs occurred relatively infrequently in both sarilumab dose groups. ADA did not meaningfully impact the safety or efficacy of either dose of sarilumab over 24 weeks.Trial RegistrationClinicalTrials.gov, identifier NCT02121210.FundingSanofi Genzyme and Regeneron Pharmaceuticals, Inc.Plain Language SummaryPlain language summary available for this article.Electronic Supplementary MaterialThe online version of this article (10.1007/s40744-019-0157-3) contains supplementary material, which is available to authorized users.

Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a randomized, placebo-controlled phase III trial in Japan

BackgroundSarilumab 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).MethodsIn 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.ResultsACR20 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.ConclusionsIn 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 registrationClinicalTrials.gov, NCT02293902. Registered on 19 November 2014.

OP0028 Effects of Sarilumab plus MTX on Clinical, Radiographic, and Functional Endpoints in Patients with Moderate-To-Severe Rheumatoid Arthritis: Results of A Phase 3, Randomized, Double-Blind, Placebo-Controlled, International Study

BackgroundSarilumab, a fully human mAb directed against IL-6R, demonstrated efficacy in phase 2 of SARIL-RA-MOBILITY in rheumatoid arthritis (RA) patients (pts) with inadequate response to methotrexate (MTX) and was generally...

Sarilumab for the treatment of ankylosing spondylitis: results of a Phase II, randomised, double-blind, placebo-controlled study (ALIGN)

ObjectivesThe ALIGN study (NCT01061723) evaluated the efficacy and safety of sarilumab, the first fully human monoclonal antibody against interleukin-6 receptor-α (IL-6Rα), in patients with ankylosing spondylitis (AS).MethodsPatients with active AS...