Search

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 in vitro, 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 200 mg (98%) and 150 mg SC every 2 weeks (94%), and tocilizumab 162 mg SC weekly (>99%) and 8 mg/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 8 mg/kg IV every 4 weeks (reductions proportionally smaller with 4 mg/kg IV every 4 weeks). Higher IL-6Rα binding affinity translated into higher RO with sarilumab vs tocilizumab 4 mg/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.

Background Diabetes is common in patients with rheumatoid arthritis (RA). Interleukin (IL)-6 is implicated in both the pathogenesis of RA and in glucose homeostasis; this post hoc analysis investigated the effects of IL-6 receptor vs. tumour necrosis factor inhibition on glycosylated haemoglobin (HbA1c) in patients with RA with or without diabetes. Methods Data were from two placebo-controlled phase III studies of subcutaneous sarilumab 150/200 mg q2w + methotrexate or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and a phase III monotherapy study of sarilumab 200 mg q2w vs. adalimumab 40 mg q2w. Patients with diabetes were identified by medical history or use of antidiabetic medication (patients with HbA1c ≥ 9% were excluded from all three studies). HbA1c was measured at baseline and weeks 12/24. Safety and efficacy were assessed in RA patients with or without diabetes. Results Patients with diabetes (n = 184) were older, weighed more and exhibited higher RA disease activity than patients without diabetes (n = 1928). Regardless of diabetes status, in patients on background csDMARDs, least squares (LS) mean difference (95% CI) in change from baseline in HbA1c for sarilumab 150 mg/200 mg vs. placebo at week 24 was − 0.28 (− 0.40, − 0.16; nominal p p p = 0.0043). Greater reduction in HbA1c than placebo or adalimumab was observed at week 24 with sarilumab in patients with diabetes and/or baseline HbA1c ≥ 7%. There was no correlation between baseline/change from baseline in HbA1c and baseline/change from baseline in C-reactive protein, 28-joint Disease Activity Score, or haemoglobin, nor between HbA1c change from baseline and baseline glucocorticoid use. Medical history of diabetes or use of diabetes treatments had limited impact on safety and efficacy of sarilumab and was consistent with overall phase III findings in patients with RA. Conclusions In post hoc analyses, sarilumab was associated with a greater reduction in HbA1c than csDMARDs or adalimumab, independent of sarilumab anti-inflammatory effects. Prospective studies are required to further assess these preliminary findings. Trial registration ClinTrials.gov NCT01061736: date of registration February 03, 2010; ClinTrials.gov NCT01709578: date of registration October 18, 2012; ClinTrials.gov NCT02332590: date of registration January 07, 2015.

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. 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. 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. 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. NCT01061736, NCT02332590, NCT01709578, NCT01768572.

CAD is a rare form of autoimmune hemolytic anemia (AIHA) that accounts for approximately 20% of all AIHA and is characterized by classical complement pathway-activated hemolysis. Clinical manifestations of CAD can include complement-mediated chronic hemolytic anemia, profound fatigue, as well as transient agglutination-mediated circulatory symptoms (Berentsen et al. Hematol Oncol Clin North Am. 2015; Swiecicki et al. Blood. 2013). Recent research has shown that patients with anemia are more likely to develop depression and anxiety (Shafi et al. J Coll Physicians Surg Pak. 2018; Vulser et al. Acta Psychiatr Scand. 2016), but this has not been previously studied in patients with CAD. We conducted a matched-cohort comparison study evaluating the risk of medically attended anxiety or depression in patients with and without CAD. All patients with CAD were identified in the Optum Claims-Clinical dataset by reviewing clinical notes for CAD terms. Patients with CAD were matched (1:10) to non-CAD patients by age (±3 years), sex, race, region of residence, and active time and season and year of entry date in the Optum health plan. Inclusion criteria included 25 years of age or older with no history of anxiety or depression. Medically attended anxiety or depression was defined using International Classification of Diseases (ICD-9 and ICD-10) codes for inpatient stays and outpatient hospital visits, medication class, and procedure codes for psychotherapy. Cox regression models were built to estimate time to hospitalizations without medications or psychotherapy, medications or psychotherapy without hospitalization, hospitalization with medication or psychotherapy, or any of these outcomes adjusted for age, sex, race, region, comorbidity score, and cluster (matched CAD and non-CAD cohorts). As patients with both primary CAD (not due to secondary causes) and secondary cold agglutinin syndrome (coexisting diagnosis of malignancy or infection) were included in the primary analysis, subset analyses also were performed for patients with primary CAD. A total of 384 patients with CAD (mean [standard deviation {SD}] age: 70.0 [13.0] years) and 2789 patients without CAD (comparisons; mean [SD] age: 69.6 [12.7] years) were identified between 2006 and 2016. The mean (SD) time to event for any hospitalization, medication use, or psychotherapy was 27.7 (24.4) months for patients with CAD and 38.2 (25.6) months for comparisons with patients with CAD being 60% more likely to have medically attended anxiety or depression (adjusted hazard ratio [aHR]: 1.6; 95% confidence interval [CI]: 1.3-2.1). Patients with CAD were almost twice as likely to be prescribed medication or psychotherapy for anxiety and depression after their CAD diagnosis (aHR: 1.8; 95% CI: 1.2-2.9) or to be hospitalized for a depression or anxiety-related event along with medication or psychotherapy (aHR: 2.0; 95% CI: 1.4-2.9). There was also a nonsignificant risk for patients with CAD being hospitalized for anxiety and depression without medication or psychotherapy (aHR: 1.2; 95% CI: 0.8-1.9). Subanalysis of patients with primary CAD also were at a statistically significant increased risk for medically attended anxiety or depression (aHR: 1.8; 95% CI: 1.4-2.4) with the largest risk for prescription medication or psychotherapy (aHR: 2.7; 95% CI: 1.6-4.6). To our knowledge, this is the first study to evaluate anxiety or depression among patients with CAD. Our study indicates that medically attended depression and anxiety manifest at a higher rate in patients with CAD compared with a matched non-CAD cohort. These findings suggest that patients with CAD may experience extra-hematologic manifestations of the disease that potentially have a broader impact on their overall mental health, physical health, and quality of life. Further investigation on this topic is warranted. Disclosures Patel: Sanofi: Current Employment. Jiang:EpidStrategies: Current Employment. Nicholson:EpidStrategies: Current Employment. Frankenfeld:EpidStrategies: Current Employment. Iglesias-Rodriguez:Sanofi: Current Employment. Fryzek:EpidStrategies: Current Employment. Su:Sanofi: Current Employment.

Background:Due to strict inclusion/exclusion criteria, randomized controlled trials (RCTs) may not represent the heterogeneous rheumatoid arthritis (RA) population encountered in routine clinical practice; longitudinal observational studies are needed to complement learnings from RCTs. The PROspective sarilumab (preFILled syringe/pen) multinational, obsErvational Study (PROFILE) is collecting information on treatment strategies and sarilumab usage patterns and adherence in routine clinical practice for up to 52 weeks in patients with moderate-to-severe RA.Objectives:In this planned interim analysis, we report baseline characteristics of patients prescribed sarilumab in routine clinical practice and the efficacy and safety of sarilumab after 12 weeks of treatment.Methods:Adults with RA (2010 ACR/EULAR criteria) can enroll in this multinational, open-label, single-arm, Phase 4 study if, per their treating physicians’ judgment, they are to initiate treatment with sarilumab as mono- or combination (with csDMARD) therapy, in accordance with local labeling/prescribing information, ≤4 weeks prior to or ≤8 weeks after study Visit 1 (signed informed consent and disease characteristics documented); 1000 patients are planned for enrollment. Concomitant use of biologic or targeted synthetic DMARDs (b/tsDMARDs) is not permitted. Primary endpoint is change from baseline in Clinical Disease Activity Index (CDAI) score at Weeks 24 and 52. Statistical analyses are descriptive.Results:This analysis included 291 patients who reached, or discontinued before, the Week 12 visit, of whom 108 (37%) received sarilumab mono- and 183 (63%) received combination therapy. At baseline (BL), the monotherapy group had longer disease duration and a smaller proportion of b/tsDMARD-naïve patients than the combination therapy group (9.7 vs 8.7 years and 39% vs 53%). Baseline and week 12 CDAI values were available in 132 patients. Mean (SD) BL CDAI scores for the monotherapy and combination groups were 26.7 (13.1) and 27.0 (14.4). At Week 12, CDAI scores were improved by −9.1 (17.5) and −10.5 (13.9), and 37% (19/51) of patients receiving monotherapy and 48% (45/93) of those receiving combination therapy had achieved low disease activity (CDAI ≤10). Remission (CDAI ≤2.8) was achieved by 12% (6/51) of monotherapy and 20% (19/93) of combination-therapy patients. Overall, 55 (19%) discontinued sarilumab: 27 (9%) for an adverse event (AE), 19 (7%) for insufficient response, 4 (1%) for noncompliance, 5 (2%) for other reasons. Severe AEs leading to treatment discontinuation were leukopenia and neutropenia (n=1 patient), peripheral swelling (1), lung cancer (1), and fatigue (1). Ten patients (3%) had a treatment-emergent serious AE.Conclusion:In this planned interim analysis, sarilumab mono- or combination therapy resulted in improved disease outcomes, assessed by CDAI, at Week 12, an important treat-to-target time point. Safety and efficacy were consistent with Phase 3 trial findings, with no new safety signals, although interim results must be interpreted with caution. Future analyses will evaluate efficacy and safety after 24 and 52 weeks of treatment in routine clinical practice.Acknowledgments:Study funding and medical writing support (Laura George, Adelphi Communications Ltd, Macclesfield, UK) were provided by Sanofi Genzyme (Cambridge, USA) and Regeneron Pharmaceuticals, Inc. (Tarrytown, USA) in accordance with Good Publication Practice (GPP3) guidelines.Disclosure of Interests:Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim,,Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Jacques-Eric Gottenberg Grant/research support from: Bristol-Myers Squibb, Pfizer, Roche, Consultant of: AbbVie, Bristol-Myers Squibb, Janssen, Lilly, MSD, Pfizer, Roche, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Lilly, MSD, Pfizer, Roche, UCB, Martin Bergman Shareholder of: Johnson & Johnson – stockholder, Consultant of: AbbVie, BMS, Celgene Corporation, Genentech, Janssen, Merck, Novartis, Pfizer, Sanofi – consultant, Speakers bureau: AbbVie, Celgene Corporation, Novartis, Pfizer, Sanofi – speakers bureau, Melitza Iglesias-Rodriguez Shareholder of: Sanofi Genzyme, Employee of: Sanofi Genzyme, Gregory St John Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., Chunfu Qiu Shareholder of: Sanofi Genzyme, Employee of: Sanofi Genzyme, Hubert van Hoogstraten Shareholder of: Sanofi, Employee of: Sanofi, Louis Bessette Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, UCB Pharma, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, UCB Pharma, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Sanofi

Background: Sarilumab is a human mAb blocking IL-6Rα. In Phase 3 MONARCH (NCT02332590), sarilumab (200 mg subcutaneously [SC] every 2 wks [q2w] for 24 wks) was superior to adalimumab monotherapy (40 mg SC q2w) in reducing disease activity and improving physical function in RA patients (pts) with an inadequate response or intolerance to methotrexate. Objectives: To assess whether pts who achieved clinical response on sarilumab during MONARCH sustained this response in the OLE and to evaluate efficacy and safety of switching from adalimumab to sarilumab vs continuous sarilumab treatment. Methods: Pts completing the double-blind phase of MONARCH were eligible for the ongoing OLE, in which all pts receive sarilumab (200 mg SC q2w) for a maximum duration of 276 wks. Disease activity, physical function, and safety were assessed regularly. Results: 320/369 Pts enrolled in MONARCH entered the OLE; pts either switched from adalimumab to sarilumab (n=155) or continued on sarilumab (n=165). At OLE entry (Wk 24 of the double-blind phase), the mean x from baseline DAS28-ESR was –2.28 in the switch group vs -3.36 in the continuation group, and by Wk 48 was -4.06 vs -4.18, respectively. By Wk 48 of the OLE, the proportion of pts in the switch and continuation groups who achieved DAS28–ESR≤3.2 was 61.3% vs 61.2%, DAS28–ESR Figure 1 Mean V from baseline in DAS28-ESR (OLE population; as observed). Conclusions: Switching from adalimumab (40 mg q2w) to sarilumab monotherapy (200 mg q2w) improved the signs and symptoms of RA to a similar level as continuous sarilumab treatment, and was associated with a lower HAQ-DI score, which may have resulted in numerical differences in ACR responses between the two groups. Acknowledgements: Study funding and medical writing support (Vicki Cronin, Adelphi) provided by Sanofi and Regeneron Pharmaceuticals, Inc. Disclosure of Interest: G. R. Burmester Grant/research support from: AbbVie, Pfizer, UCB, Roche, Consultant for: AbbVie, Lilly, Merck Sharpe & Dohme, Pfizer, Sanofi, Roche, UCB, Speakers bureau: AbbVie, Lilly, Merck Sharpe & Dohme, Pfizer, Sanofi, Roche, UCB, G. St John Shareholder of: Regeneron, Employee of: Regeneron, M. Iglesias-Rodriguez Employee of: Sanofi, C.-C. Hu Shareholder of: Sanofi, Consultant for: Astellas, Employee of: Sanofi, Quintiles, T. Raskina: None declared, H. Amital Grant/research support from: Pfizer, Abbvie, Yansen, Consultant for: Pfizer, Merck Sharpe & Dohme, Speakers bureau: Pfizer, Merck Sharpe & Dohme, Yansen, Sanofi, Bristol-Myers Squibb, A. Gomez Centeno Grant/research support from: Boehringer Ingelheim, Celltrion, Galapagos-Gilead, Lilly, Novartis, Pfizer, Roche, Sanofi, UCB, YL Biologics, Consultant for: Abbvie, Biogen, Bristol-Myers Squibb, Celgene, Gebro, Hospira, Lilly, Merck Sharpe & Dohme, Pfizer, Roche, Rubio, Sandoz, Sanofi, Speakers bureau: Abbvie, Bristol-Myers Squibb, Gebro, Janssen, Lilly, Menarini, Merck Sharpe & Dohme, Pfizer, Roche, Rubio, UCB, Sanofi, A. Rubbert-Roth Consultant for: Abbvie, Bristol-Myers Squibb, Chugai, Roche, Merck Sharpe & Dohme, Pfizer, Lilly, Hexal/Novartis, Janssen, Sanofi, Speakers bureau: Roche, Chugai, Sanofi, Lilly

Background Sarilumab (150 or 200 mg subcutaneously [SC] every 2 wks [q2w])+csDMARDs demonstrated efficacy in adults with moderate–to-severely active rheumatoid arthritis (RA) with intolerance or inadequate response to prior TNFi treatment in TARGET (NCT01709578). Patients with an initial refractory response (1° failure) to TNFi may respond differently to subsequent treatment vs those who initially respond but lose TNFi effectiveness (2° failure). Objectives This post hoc analysis examined efficacy and safety of sarilumab +csDMARDS in patients who had previously demonstrated 1° vs 2° TNFi failure. Methods TNFi failure (1° vs 2°) was investigator-determined on enrolment to TARGET. Patients who experienced 1° or 2° failure were randomised to placebo (pbo; n=75 and n=99), sarilumab 150 mg (n=72; n=91), or sarilumab 200 mg q2w (n=64; n=103), respectively. Disease activity, physical function (HAQ-DI), and safety were assessed at Wk 24. Results By Wk 24, ACR20/50/70 response rates and improvements in LS mean HAQ-DI were similar in both sarilumab dose groups and superior to pbo, irrespective of 1° vs 2° TNFi failure (table 1). Odds ratios for the benefit of sarilumab over pbo according to ACR response rates, HAQ-DI, DAS28-CRP, CDAI and SDAI (figure 1) showed no differences between patients with 1° vs 2° failures. No significant treatment by subgroup (1° vs 2° failure) interactions were observed. In the 1° failure group, treatment emergent adverse events (TEAEs; table 1) occurred in 59.7%, 65.6% vs 45.3% (sarilumab 150, 200 mg vs pbo, respectively) of patients; and in 73.6% and 63.1% vs 52.5% with sarilumab 150, 200 mg vs pbo, respectively, in the 2° failure group. There was only one TEAE leading to death (pbo group) and one case each of venous thrombosis (200 mg sarilumab q2w, 2°) and pulmonary embolism (150 mg sarilumab q2w, 2°). Conclusions Key efficacy and safety measures were similar in patients treated with sarilumab +csDMARDs, regardless of previous 1° or 2° failure with TNFis. Acknowledgements Study funding and medical writing support (Vicki Cronin, Adelphi) provided by Sanofi and Regeneron Pharmaceuticals, Inc. Disclosure of Interest R. Fleischmann Grant/research support from: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, EMD-Serono, Eli Lilly, Merck, Novartis, Pfizer, Roche, Sanofi-Genzyme, UCB, Consultant for: AbbVie, ACEA, Amgen, Bristol-Myers Squibb, GSK, Eli Lilly, Novartis, Pfizer, Sanofi-Genzyme, UCB, A. Spindler: None declared, A. Kivitz Shareholder of: Novartis, Consultant for: AbbVie, Janssen, Pfizer, UCB, Genzyme, Sanofi, Regeneron, Boehringer Ingelheim, Sun Pharma, Speakers bureau: Celgene, Genentech, Merck, Novartis, Pfizer, Genzyme, Sanofi, Regeneron, Horizon, D. Ching Grant/research support from: Sanofi, Lilly, Celgene, Pfizer, Galapagos, Gilead and Abbvie, Consultant for: Abbvie, E. Mangan Shareholder of: Regeneron, Pfizer, Employee of: Regeneron, T. Kimura Shareholder of: Regeneron, Employee of: Regeneron, M. Iglesias-Rodriguez Employee of: Sanofi, G. Burmester Grant/research support from: AbbVie, Pfizer, UCB, Roche, Consultant for: AbbVie, Lilly, Merck Sharpe and Dohme, Pfizer, Sanofi, Roche, UCB, Speakers bureau: AbbVie, Lilly, Merck Sharpe and Dohme, Pfizer, Sanofi, Roche, UCB