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Background:Guidelines recommend adjusting therapy in patients with rheumatoid arthritis (RA) who fail to reach and sustain low disease activity (LDA) or remission (disease control). Many factors can affect the decision to change therapy, including the potential for improvement as well as the fear of potential worsening or loss of improvement already achieved. Although data exist on response to treatment in patients who switch therapy, data addressing the likelihood of worsening are limited.Objectives:The aim of this analysis was to describe the demographic, clinical characteristics, and change in clinical outcomes in patients on biologic/targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) who had some improvement in clinical disease activity index (CDAI) but did not achieve LDA after ~ 6-12 months of treatment and then switched to a different b/tsDMARD.Methods:This study included adult inadequately responding RA patients from the CORRONA registry who: (1) started a biologic or Janus kinase inhibitor (JAKi) between January 2010 to November 2020 (V1), (2) had any CDAI improvement (i.e., decrease ≥1 unit) but were not in LDA or remission at a subsequent visit (baseline [BL]) occurring 3 to 15 months after V1; (3) had a third visit (follow-up [F/U]) 6 (±3) months after BL with a valid CDAI measure; (4) switched therapy at the BL or between BL and F/U, with the switch occurring at least 3 months prior to the F/U. CDAI >10 and ≤22 was defined as moderate disease activity (MDA) and CDAI >22 was defined as high disease activity (HDA). Two thresholds of change in CDAI (≥6 and ≥12 units) were used to define meaningful improvement and meaningful worsening after the switch. If there was no meaningful improvement or meaningful worsening, this was considered as no meaningful change (-5 to +5 for 6 units change and -11 to +11 for 12 units change). These thresholds for meaningful change were set for all switchers regardless of their pre-switch CDAI value. Descriptive statistics were generated for demographic and clinical characteristics for the switchers at BL, and the change of clinical outcomes was evaluated from BL to F/U.Results:Of the 1,224 patients fulfilling the inclusion criteria, 93 (7.6%) switched therapy and 1,131 (92.4%) did not switch therampy after not achieving an adequate response on the initial b/tsDMARD. At BL, 42.5% and 70.0% of patients had no meaningful improvement to their prior therapy based on ≥6 and ≥12-unit change, respectively; mean (SD) age was 53.1 (14.0) years; duration of RA 10.7 (10.4) years; CDAI 22.2 (10.8); 81.7% were female; 64.5% had MDA, 35.5% had HDA; 21.5 % reported being disabled, 24.7% were current smokers, and 50% were obese. In terms of prior biologic use 57.0%, 22.6%, and 20.4% had been on 1, 2, and 3+, respectively. From BL to F/U, meaningful worsening occurred in 30.1% and 12.9% using a threshold of 6 and 12, respectively, with the remaining patients experiencing meaningful improvement or no meaningful change (Figure 1).Figure 1.Meaningful Worsening, Meaningful Improvement, and No Meaningful Change Based on CDAI Change Thresholds of ≥6 and ≥12 From BL to F/U (N=93)Conclusion:In our analysis, a large proportion of patients who initiated a biologic/JAKi and experienced some improvement but failed to attain LDA or remission, did not switch therapy within approximately a year. This analysis consisted of many patients who did not have a meaningful response to their prior biologic/JAKi, patients who had received multiple prior biologics, and a large portion of patients with poor prognostic factors. Despite this, the proportion of patients with meaningful worsening was low compared with most patients who had either meaningful improvement or no meaningful change. Additional research is warranted to understand the reasons for not switching and whether the likelihood of a meaningful change correlates with prior response, poor prognosis, or other factors.Acknowledgements:Amy Praestgaard (Sanofi) contributed to the statistical analysis for this abstract. Medical writing support for this abstract was provided by Krishna Kammari (Sanofi).Disclosure of Interests:Jeffrey Curtis Grant/research support from: and personal fees from AbbVie, Amgen, BMS, CORRONA, Eli Lily, Janssen, Myriad, Pfizer, Roche, Regeneron, Radius, UCB, outside the submitted work, Stefano Fiore Shareholder of: Sanofi, Employee of: Sanofi. In addition, he has a patent EP 19306553.9; USPTO #s 62/799,698; 62/851,474; 62/935,395 issued, Kerri Ford Shareholder of: Sanofi, Employee of: Sanofi, Judson Janak: None declared, Hong Chang: None declared, Dimitrios A Pappas Employee of: CORRONA LLC. He has previously acted as a consultant for Sanofi, Abbvie, Gtech Roche Hellas, and Novartis. He has an equity interest in CORRONA LLC. and is on the Board of directors of the CORRONA research foundation, Taylor Blachley: None declared, Kelechi Emeanuru: None declared, Vivian Bykerk Grant/research support from: reports grants from Amgen, BMS, UCB, and Novartis were given to institution, that grants from the NIH, PCORI, and CIHR were given to institutions which whom she is affiliated, and that she has received personal fees from Amgen, Gilead, BMS, Pfizer, Sanofi Aventis, Roche, UCB and Regeneron, outside the submitted work.

Background:Rheumatoid arthritis (RA) patients who fail therapy may be switched to any of the five classes of biological disease-modifying antirheumatic drugs (DMARDs) and targeted synthetic DMARDs, to meet treatment goals. Physicians may hesitate to switch between Janus Kinase inhibitors (JAKi) and interleukin-6 receptor inhibitors (IL-6Ri) since they both impact IL-6 signalling and due to limited data on switching between the two classes.Objectives:This retrospective, observational study based on the real-world Corrona RA registry aimed to describe the response in RA patients switching between IL-6Ri and JAKi.Methods:Adult RA patients who initiated either IL-6Ri or JAKi after November 2012 and had a six-month post-initiation follow-up visit were eligible. Patients in ‘Cohort A’ initiated an IL-6Ri following discontinuation of a JAKi and those in ‘Cohort B’ initiated a JAKi following discontinuation of an IL-6Ri. Disease activity measures and patient-reported outcomes (PROs) were evaluated at baseline and at six-month follow-up. Within each group, change from baseline was assessed for Clinical Disease Activity Index (CDAI), Health Assessment Questionnaire (HAQ), pain, fatigue, tender joint count (TJC), swollen joint count (SJC), physician global assessment (MDGA), patient global assessment (PtGA) and morning stiffness duration. Proportion of patients achieving CDAI low disease activity (LDA), CDAI remission and minimal clinically important difference (MCID) for HAQ, pain, fatigue, MDGA, PtGA were assessed. Adjusted linear and logistic regression models were performed for between-group comparisons (Cohort A vs Cohort B) excluding initiators who switched therapy prior to six-month visit.Results:Cohorts A and B included 122 and 144 initiators, respectively. Patients who switched toIL-6Ri (vs JAKi) were younger (mean [SD] age, 56.2 [11.3] vs 58.9 [12.6] years), had higher baseline CDAI (23.2 [12.9] vs 20.2 [12.8]), had higher prior use of ≥2 csDMARDs (75% vs 65%), and were less likely to initiate therapy as monotherapy (44% vs 50%).In Cohort A, significant changes from baseline were observed for all continuous outcomes except HAQ and fatigue. In Cohort B, a significant improvement was observed only for patient-reported pain (Table 1).Table 1.Unadjusted Within-Group Change from Baseline to Six Months, Mean (95% CI), nOutcomesCohort A, N = 122Cohort B, N = 144CDAI-4.7 (-7.6, -1.9), 109-2.4 (-5.2, 0.4), 116HAQ-0.0 (-0.1, 0.1), 105-0.1 (-0.1, 0.0), 118Patient-reported pain-8.2 (-13.4, -3.0), 109-5.9 (-11.5, -0.2), 120Patient-reported fatigue-4.4 (-9.0, 0.2), 109-1.7 (-6.6, 3.3), 117TJC-1.6 (-3.0, -0.1), 112-1.2 (-2.6, 0.3), 117SJC-1.5 (-2.5, -0.4), 112-0.4 (-1.3, 0.6),117MDGA-10.9 (-15.6, -6.3), 112-4.3 (-8.7, 0.2), 117PtGA-6.0 (-11.2, -0.8), 109-4.8 (-10.5, 0.8), 120Morning stiffness durationa-1.3 (-2.2, -0.5), 109-0.1 (-1.1, 0.8), 118aAmong those reporting morning stiffness at baseline.In the adjusted between-group comparison (data not shown) of change from baseline, there were no significant differences in clinical outcomes between Cohorts A and B.In both cohorts, patients achieved CDAI LDA, CDAI remission, and MCIDs across other PROs (Figure 1). In the adjusted between-group comparison (data not shown), the results were similar with the exception of achievement of CDAI LDA among patients with moderate to high disease activity at baseline.Figure 1.Rates of CDAI LDA, CDAI Remission, and MCID for PROsa at Six MonthsConclusion:In general, in both cohorts a substantial proportion of patients achieved CDAI LDA and MCID across PROs. Despite some overlap of JAKi and IL-6Ri therapies’ on the IL-6 pathway, there are some distinct mechanisms of action which may result in meaningful improvements for a subset of patients.Acknowledgements:Amy Praestgaard (Sanofi) contributed to the interpretation of the statistical analysis for this abstract. Medical writing support for this abstract was provided by Nupur Chaubey (Sanofi).Disclosure of Interests:Anisha Dua Speakers bureau: AbbVie, Consultant of: Consulting/advisory board for AbbVie, Novartis, and Chemocentryx, Employee of: Board member of Vasculitis foundation and Chicago Rheumatism Society, Kerri Ford Shareholder of: Sanofi, Employee of: Sanofi, Stefano Fiore Shareholder of: Sanofi, Employee of: Sanofi. In addition, Stefano Fiore has a patent EP 19306553.9; USPTO #s 62/799,698; 62/851,474; 62/935,395 issued, Dimitrios A Pappas Shareholder of: Corrona LLC, Consultant of: Sanofi, AbbVie, Gtech, Roche Hellas, and Novartis, Employee of: Corrona LLC. Board of directors, Corrona Research Foundation, Judson Janak: None declared, Taylor Blachley: None declared, Carla Roberts-Toler: None declared, Kelechi Emeanuru: None declared, Joel Kremer Consultant of: AbbVie, Lilly, Novartis, Pfizer, BMS, Genentech, Regeneron, Sanofi, and Corrona, Grant/research support from: AbbVie, Lilly, Novartis, and Pfizer, Alan Kivitz Shareholder of: Pfizer, Sanofi, GlaxoSmithKline, Gilead Sciences, Inc., and Novartis, Speakers bureau: Celgene, Merck, Lilly, Novartis, Pfizer, Sanofi, Flexion, and AbbVie, Consultant of: AbbVie, Boehringer Ingelheim, Flexion, Janssen, Pfizer, Sanofi, Regeneron, SUN Pharma Advanced Research, Gilead Sciences, Inc. In addition, Alan Kivitz reports other from Altoona Center for Clinical Research, PC, during the conduct of the study.

Background:Patients with rheumatoid arthritis (RA) who have received multiple biologics or targeted therapies over time tend to have more refractory and more severe disease, which may lead to worse clinical response to treatment.Objectives:We used data from the ACR RISE registry to assess whether disease severity was greater in those who received sarilumab shortly after its FDA approval (May 2017) than in subsequent time periods and to evaluate the effectiveness of sarilumab in populations with various degrees of disease severity.Methods:Patients with RA who initiated sarilumab treatment in the period 2017-2020 were identified in the ACR RISE registry and divided into Cohort 1 (2017, year of the FDA approval) and the calendar year-based Cohorts 2-4 (2018-2020). Patient demographics, RA-related features, and comorbidities were determined using data prior to sarilumab initiation. The cohorts were compared using chi-square test (categorical variables) and a nonparametric test (continuous variables). Sarilumab effectiveness was assessed using 3 cohorts assembled based on progressively restrictive criteria: Active Disease cohort (Clinical Disease Activity Index [CDAI] >10 or Routine Assessment of Patient Index Data 3 [RAPID3] >6, and C-reactive protein, if measured, ≥8 mg/L), TARGET Eligibility cohort (patients who satisfied enrolment criteria for TARGET,1 a Phase 3 sarilumab trial in patients with RA and an inadequate response to TNF inhibitors), and TARGET Baseline cohort (patients from TARGET Eligibility cohort with characteristics weighted to match those from the TARGET trial baseline,1 using the matching-adjusted indirect comparison method2). In all 3 effectiveness cohorts, mean changes in CDAI and RAPID3 at 6 and 12 months post-initiation of sarilumab were evaluated using a model adjusted for baseline score, age, sex, race, calendar year, and seropositivity.Results:A total of 2949 patients, treated by 585 rheumatologists, initiated sarilumab treatment in the period 2017–2020. The 4 yearly cohorts were relatively similar in terms of patients’ age, sex, race, and most clinical characteristics. However, patients receiving sarilumab shortly after FDA approval (Cohort 1) had more ambulatory visits, a greater number of previously used non-TNFi biologics (particularly tocilizumab), and a higher comorbidity burden, and were more likely to be current users of glucocorticoids or opioids than sarilumab initiators in the subsequent 3 years. In the 3 cohorts used to assess sarilumab effectiveness, the greatest improvement was observed in the TARGET Baseline cohort, which also had the greatest mean baseline CDAI score (43), compared with the other two (24 both).Conclusion:In this real-world cohort, we observed modest evidence for channeling of patients with greater RA severity and greater prior exposure to non-TNFi biologics to sarilumab shortly after its FDA approval. This cohort effect did not diminish the effectiveness of sarilumab. All cohorts showed improvement, with the greatest clinical improvement observed in the cohort with the highest baseline CDAI score who most closely resembled those enrolled in a phase 3 trial of patients with an inadequate response to TNF inhibitors.References:[1]Fleischmann R, et al. Arthritis Rheumatol 2017;69:277-290.[2]Signorovitch JE et al. Value Health 2012;15:940-7.Figure 1.Adjusted improvements in CDAI and RAPID3Acknowledgements:This study was sponsored by Sanofi. Medical writing support was provided by Vojislav Pejović, PhD (Eloquent Medical Affairs, division of Envision Pharma Group) and funded by Sanofi.Disclosure of Interests:Stefano Fiore Employee of: Sanofi, Lang Chen: None declared, Cassie Clinton Consultant of: Information available in profile, Huifeng Yun Grant/research support from: Research support for Pfizer, Amy Praestgaard Employee of: Sanofi, Kerri Ford Employee of: Sanofi, Jeffrey Curtis Consultant of: Received consulting and research grants from AbbVie, Amgen, BMS, Lilly, Gilead, GSK, Janssen, Myriad, Pfizer, Roche, Samsung, Sandoz, Sanofi, UCB, Grant/research support from: Received consulting and research grants from AbbVie, Amgen, BMS, Lilly, Gilead, GSK, Janssen, Myriad, Pfizer, Roche, Samsung, Sandoz, Sanofi, UCB

Background:Anemia is a common comorbidity in patients with rheumatoid arthritis (RA).Objectives:Assess whether low hemoglobin (Hb) identifies a subgroup of patients at increased risk of joint damage progression, and investigate whether sarilumab modulates this risk.Methods:The 52-week, double-blind, Phase 3 MOBILITY trial (NCT01061736) in patients with active RA and inadequate response to methotrexate (n = 1197) demonstrated the tolerability and efficacy (clinical and radiographic) of subcutaneous sarilumab 150 and 200 mg every 2 weeks versus placebo, both in combination with methotrexate (MTX). In thispost hocanalysis, baseline characteristics and radiographic outcomes in MOBILITY were analyzed by baseline Hb category (low or normal) according to World Health Organization criteria, with low Hb defined as Pvalues are presented.Results:A total of 414 patients (35%) had low Hb at baseline. Patients with low Hb were more likely than patients with normal Hb to be female (86% vs 79%, respectively), Asian (14% vs 5%), younger (mean age 49 vs 51 years), and to have lower body weight (mean 69 vs 77 kg); all nominalPPTable.Mean change from baseline (SD) in radiographic measures of joint damagePlacebo+ MTXSarilumab 150 mg+ MTXSarilumab 200 mg+ MTXLow Hb (n = 140)Normal Hb (n = 258)Low Hb (n = 145)Normal Hb (n = 255)Low Hb (n = 129)Normal Hb (n = 270)mTSS3.75 (9.00)2.29 (6.98)1.20*** (5.58)0.73** (4.07)0.60*** (4.13)0.08*** (4.83)Joint space narrowing1.52 (3.71)1.22 (3.92)0.79* (3.17)0.30** (2.70)0.50** (2.93)0.06*** (3.33)Erosion score2.24 (6.24)1.07 (3.91)0.41*** (3.18)0.44* (2.05)0.10*** (2.13)0.02*** (2.19)NominalP*Conclusion:Overall, sarilumab slowed joint damage progression in patients with RA. Additionally, in those patients with low Hb, who may suffer greater damage than those with normal Hb, sarilumab also increased Hb.Acknowledgments:Study funding and medical writing support (Matt Lewis, PhD, of Adelphi Communications Ltd, Macclesfield, UK) were provided by Sanofi Genzyme (Cambridge, MA, USA) and Regeneron Pharmaceuticals, Inc. (Tarrytown, NY, USA) in accordance with Good Publication Practice (GPP3) guidelines.Disclosure of Interests: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, Jean-Pierre Morello Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., Owen Hagino Shareholder of: Sanofi, Employee of: Sanofi, Amy Praestgaard Employee of: Sanofi Genzyme, Stefano Fiore Shareholder of: Sanofi, Employee of: Sanofi, 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

Background The efficacy and safety of sarilumab, a fully human monoclonal antibody directed against IL-6R, has been shown in patients with moderate-to-severe rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX) in the randomized, double-blind, placebo (Pbo)-controlled, phase 3 part of the MOBILITY study (NCT01061736).1 Approximately 20% of patients were exposed to biologic DMARDs (bDMARDs), defined as prior use of a non-investigational biologic DMARD for RA. Of these, 50% had received prior anti-TNF therapy and none had stopped bDMARD treatment due to lack of efficacy. The clinical efficacy and safety of sarilumab in bDMARD-experienced and -naive MOBILITY patients was previously reported.2 Objectives To compare the clinical and radiographic efficacy and safety of sarilumab vs Pbo at 52 weeks in RA patients who were bDMARD-experienced (including prior anti-TNF therapy) and bDMARD-naive in MOBILITY. Methods This post hoc analysis of MOBILITY evaluates sarilumab clinical and radiographic efficacy and safety over 52 weeks in the intention-to-treat population, categorized according to prior bDMARD exposure, including a subset of patients with prior anti-TNF therapy. Results Compared with placebo, smaller numerical mean increases in mTSS, including erosion (ES) and joint space narrowing (JSN), were observed with sarilumab (150 mg + MTX and 200 mg q2w + MTX), at Wks 24 and 52, irrespective of prior bDMARD use (including the prior anti-TNF therapy subgroup). For each group, a significantly greater percentage of patients receiving sarilumab had no radiographic progression at Wk 52 vs Pbo and, for patients with radiographic progression, the cumulative probability distribution plots for ΔTSS, ΔES and ΔJSN (from baseline) showed a frequency distribution favorable to sarilumab (both doses). In both bDMARD-experienced and -naive RA patients, each of the sarilumab doses + MTX resulted in clinically meaningful and statistically significant ACR20, ACR50, ACR70, CDAI and DAS28-CRP responses vs Pbo at Wk 24; similar results were observed for the prior anti-TNF therapy subset. ACR20, 50 and 70 responses were maintained in bDMARD-experienced and -naive subgroups up to Wk 52. The most common treatment-emergent adverse events with sarilumab + MTX included infections, neutropenia, injection site reactions and increased transaminases, irrespective of prior bDMARD experience. Conclusions These results suggest that, irrespective of prior bDMARD experience, sarilumab improved signs and symptoms of RA and inhibited progression of structural damage in patients with active RA and inadequate response to MTX. References Genovese M et al. Abstr. No. EULAR14-SCIE-3001 presented at EULAR 2014, Paris, France Fleischmann R et al. Arthritis Rheumatol 2014; 66(11) Abstr 2823:S1232–3 Acknowledgements The study was sponsored by Sanofi and Regeneron Pharmaceuticals Inc. Editorial support was provided by Diane Davies of Envision Scientific Solutions and was funded by Sanofi and Regeneron Pharmaceuticals Inc. Disclosure of Interest D. van der Heijde: None declared, M. Genovese Grant/research support from: Sanofi, Regeneron, Eli Lilly, Consultant for: Sanofi, Regeneron, Eli Lilly, C. Fan Shareholder of: Sanofi, Employee of: Sanofi, S. Fiore Shareholder of: Sanofi, Employee of: Sanofi, D. Decktor Shareholder of: Johnson & Johnson, Employee of: Regeneron, R. Fleischmann Grant/research support from: AbbVie, Amgen, Ardea, AstraZeneca, BMS, Celgene, GSK, Janssen, Eli Lilly, Merck, Pfizer, Resolve, Roche, Sanofi, UCB, Consultant for: AbbVie, Akros, Amgen, Antares, Ardea, AstraZeneca, Augurex, BMS, Celgene, Covagen, Five Prime, GSK, Iroko, Janssen, Eli Lilly, McNeil, Merck, Pfizer, Plexxicon, Resolve, Roche, Sanofi, Teva, UCB, Vertex

Background Sarilumab is the first fully-human monoclonal antibody directed against the IL-6R and is being investigated for the treatment of RA. Patients with RA have elevated tissue turnover at sites of inflammation, resulting from increased activity of proteases, including matrix metalloproteinase (MMP). MMP-cleaved fragments of collagen type 1 (C1M), collagen type 2 (C2M), collagen type 3 (C3M), and C-reactive protein (CRPM) are elevated in sera from patients with RA and reductions may be associated with treatment response. Indeed, the C1M neo-epitope has been recently identified as a potentially prognostic biomarker of bone erosion. Objectives The objective of this study was to determine whether sarilumab reduces the levels of serum biomarkers related to synovial inflammation and joint damage in patients with RA. Methods MOBILITY part A was the dose-ranging phase 2 portion of the MOBILITY trial of subcutaneous sarilumab in patients with active RA treated with concomitant methotrexate (MTX). Sera were collected at baseline, 2 weeks, and 12 weeks from patients randomized to treatment with MTX+placebo (Pbo), MTX+sarilumab 150 mg q2w, or MTX+sarilumab 200 mg q2w. C1M, C2M, C3M and CRPM were analyzed by ELISA. Results Baseline levels of each biomarker were similar among treatment groups. Sarilumab treatment at both doses resulted in marked reduction in levels of C1M, C2M, C3M and CRPM from baseline at 2 weeks (Table, percent change from baseline ± SE) and suppression of each marker was maintained at 12 weeks (data not shown). In contrast, in the MTX+Pbo group there was no significant decrease in these biomarkers at both 2 and 12 weeks. Observed AEs were similar to those reported with other IL-6 inhibitors. Conclusions Sarilumab treatment in patients with RA resulted in significant dose-dependent reduction in MMP-generated neo-epitope biomarkers related to joint and tissue turnover. The most dramatic reduction associated with sarilumab treatment was observed with the C1M neo-epitope, a potentially prognostic biomarker of structural damage (ref). Additional studies are needed to determine if reduction of MMP-cleaved fragments, such as C1M or CRPM, predict clinical and/or radiographic responses (bone erosion and/or joint space narrowing) in patients treated with sarilumab. References AS Siebuhr et al. Serological identification of fast progressors of structural damage with rheumatoid arthritis. Arthritis Research & Therapy 2013, 15:R86 doi:10.1186/ar4266. Acknowledgements Sponsored by Sanofi and Regeneron Pharmaceuticals Inc. (NCT01061736). Disclosure of Interest : S. Fiore Shareholder of: Sanofi US, Employee of: Sanofi US, A. Boyapati Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., S. Hamon Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., J. van Adelsberg Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., M. Liu Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., J. Hamilton Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc. DOI 10.1136/annrheumdis-2014-eular.3852

Background Sarilumab, 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 well tolerated when dosed every other week (q2w). Two doses were chosen for phase 3. Objectives To evaluate the clinical efficacy, radiographic and functional improvement, and safety profile of subcutaneous dose regimens of sarilumab+MTX for the treatment of RA. Methods In phase 3 of the SARIL-RA-MOBILITY study, adults with active, moderate-to-severe RA who had an inadequate response to MTX were randomized to placebo (Pbo), sarilumab 150 mg q2w, or sarilumab 200 mg q2w (1:1:1) plus background MTX. The co-primary endpoints were: 1) proportion of pts achieving ACR20 response at Week (Wk) 24; 2) change from baseline in HAQ-DI at Wk 16 and; 3) change from baseline in van der Heijde modified total Sharp score (mTSS) at Wk 52. Results Baseline demographic and disease characteristics (efficacy population, n=1197) were similar across groups: 82% female; mean age 51 yrs; disease duration 9 yrs; RF+ 85%; tender joint count 26; swollen joint count 17; hsCRP 2.2 mg/dL. Both doses of sarilumab provided statistically significant, clinically meaningful improvement, relative to Pbo, in all three co-primary endpoints (Table). The key secondary endpoint, major clinical response, during the 52-wk study period, and all secondary clinical response endpoints, including proportion of ACR50 and ACR70 responses, reduction in DAS28CRP, and CDAI scores, were statistically significant with both sarilumab doses at Wk 24 and Wk 52. Treatment-emergent adverse events (AE) (safety population, n=1282) were observed in 62% of pts in Pbo and 75% to 78% in sarilumab groups. Forty serious AEs were reported in Pbo and 62 and 68 events in sarilumab 150 and 200 mg arms, respectively. The most frequently reported serious AEs were infections in 10, 11, and 17 pts in the Pbo, sarilumab 150 and 200 mg groups (3.9, 3.8 and 6.0 events/100 patient-years), respectively. Seven deaths occurred during the study with an onset of the fatal event during the double-blind period in 5 pts (2 Pbo, 2 150 mg, 1 200 mg) and during open label sarilumab rescue in 2 pts. Lab abnormalities included increases in lipids and transaminases and decreases in neutrophils. No serious infections occurred in pts with neutrophils Conclusions In this phase 3 study, both sarilumab doses (150 mg and 200 mg q2w), in combination with MTX, demonstrated efficacy in pts with active RA who had inadequate response to MTX. Both sarilumab doses met clinical, radiographic, and functional endpoints. Clinical response was maintained throughout the 52-wk study period. Infection SAEs and laboratory abnormalities with sarilumab are consistent with IL-6 signaling blockade. Acknowledgements Sponsored by Sanofi and Regeneron Pharmaceuticals Inc. (NCT01061736) Disclosure of Interest M. Genovese Grant/research support: Sanofi, Consultant for: Sanofi, R. Fleischmann Grant/research support: Sanofi, Regeneron Pharmaceuticals, Inc., Consultant for: Sanofi, Regeneron Pharmaceuticals, Inc., A. Kivitz Grant/research support: Sanofi, Regeneron Pharmaceuticals, Inc., M. Rell-Bakalarska: None declared, R. Martincova Shareholder of: Sanofi, Employee of: Sanofi, S. Fiore Shareholder of: Sanofi, Employee of: Sanofi, P. Rohane Shareholder of: Sanofi, Employee of: Sanofi, H. van Hoogstraten Shareholder of: Sanofi, Employee of: Sanofi, C. Fan Shareholder of: Sanofi, Employee of: Sanofi, J. van Adelsberg Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., S. Weinstein Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., N. Graham Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., N. Stahl Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., G. Yancopoulos Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., T. Huizinga Consultant for: Sanofi, D. van der Heijde Consultant for: AbbVie, Amgen, AstraZeneca, Augurex, BMS, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, GSK, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB, Vertex, Employee of: Imaging Rheumatology bv DOI 10.1136/annrheumdis-2014-eular.3001

Background Modification of signs and symptoms and improvement in quality of life are key goals for clinical management of RA patients (pts). Sarilumab (SAR) is the first fully human monoclonal antibody directed against the alpha subunit of the IL-6 receptor (IL-6Rα). In the phase 2 MOBILITY Part A trial, SAR administered SC in combination with MTX achieved its primary endpoint of ACR20 at week 12 and guided selection of 2 doses (150 and 200 mg q2w) studied in Phase 3. Objectives This post hoc analyis evaluates the relationship between EULAR responses at week 12 and change from baseline of 2 clinical and 2 laboratory parameters (sleep [VAS], FACIT, Hb and hsCRP). Methods Patients were randomized to 6 groups: placebo, SAR 100, 150, 200 mg every other week (q2w) and 100, 150 mg weekly (qw). Disease characteristics, including those for anemia (Hb), systemic inflammation (hsCRP), fatigue (FACIT) and sleep (VAS) scores, were collected at baseline and then every 2 weeks. Results Baseline characteristics were similar across all groups (n=306): mean age 52.2±12.3 yrs; 79% women; mean disease duration 7.8±8.1 yrs; RF+ 79.7%; mean hsCRP 2.8±3.0 mg/dL. The proportion of patients achieving improved PROs, Hb, hsCRP and a EULAR good response was higher in the 2 Phase 3 dose groups vs placebo. Table 1 shows improvement at week 12 in pt reported outcomes (PROs), Hb and hsCRP for pts achieving a EULAR good response; similar findings were seen with SAR vs placebo (data not shown). Only FACIT and sleep VAS improvements were significantly better in the evaluation by EULAR good response vs. other responses (p =0.0010 [FACIT], p=0.0151 [VAS]). The most common TEAEs reported in all SAR arms were infections (non-serious) 12-26%, neutropenia 0-20%, and ALT increase 0-6%. Eight patients (none in the 2 Phase 3 doses, 2 on placebo) experienced at least 1 treatment emergent SAE (1 death due to respiratory distress syndrome/cerebrovascular accident in 100mg q2w); of these 6 led to permanent treatment discontinuation. There were no infection-related SAEs in patients with grade 3 or 4 neutropenia. Image/graph Conclusions Sarilumab doses studied in Phase 3 resulted in a significantly higher proportion of RA patients with improved Hb, hsCRP and EULAR good responses compared to placebo. This preliminary evaluation of a subset of PROs in MOBILITY Part A shows improvements in FACIT and sleep VAS scores that correlated with achievement of a EULAR good response. Acknowledgements MOBILITY Part A trial (NCT01061736) was funded by Sanofi and Regeneron Disclosure of Interest M. Genovese Grant/research support from: Sanofi, Regeneron, Consultant for: Sanofi, Regeneron, R. Fleischmann Grant/research support from: Sanofi, Regeneron, Consultant for: Sanofi, Regeneron, S. Fiore Shareholder of: Sanofi, Employee of: Sanofi, A. Radin Shareholder of: Regeneron, Employee of: Regeneron, C. Fan Shareholder of: Sanofi, Employee of: Sanofi, T. Huizinga Grant/research support from: Sanofi, Regeneron, Consultant for: Sanofi, Regeneron