Background Despite gout being the most common inflammatory arthritis, there remains an unmet need for more effective treatment. AR882 is a novel, potent, and selective uric acid transporter 1 (URAT1) inhibitor in development for the treatment of gout and tophaceous gout. AR882 was well tolerated, including patients with various degrees of renal insufficiency, and has consistently demonstrated robust sUA lowering in multiple clinical trials. Objectives This global phase 2b trial is a randomized, double-blinded, placebo-controlled, 12-week study to evaluate the safety, tolerability, and efficacy of AR882 versus placebo in patients with gout. Methods The trial recruited patients 18 to 75 years of age with eGFR >30 mL/min across 20 sites in the US, Australia, and Taiwan, who met the ACR/EULAR Gout Classification Criteria. Following gout flare prophylaxis for 10 days, patients received either once-daily AR882 50 mg, AR882 75 mg, or matching placebo for 12 weeks. Blood samples were collected every two weeks through Week 12 for laboratory tests, sUA and pharmacokinetic measurements. Efficacy endpoint was the percent of patients who reached sUA below 6, 5, 4, and 3 mg/dL. Safety including vital signs and electrocardiograms were collected throughout the study. Results A total of 140 patients were enrolled in this study. The majority of patients were male (93.6%) and white (58%), followed by Asian (28%) and Black or African (15%). The baseline sUA level was 8.6 (±1.3) mg/dL; mean age 54.3 (24-73) years; mean body weight 96.4 (±17.8) kg. Major comorbidities seen in patients included hypertension (47%), hyperlipidemia (35%), renal insufficiency (34%), arthritis (23%), diabetes (19%), cardiovascular disease (15%), lung disease (11%), and liver disease (5%). Following 12 weeks of treatment, median sUA levels were reduced from baseline 8.6 mg/dL to 3.5 mg/dL with 75 mg and 5.0 mg/dL with 50 mg. No change was observed in the placebo group. At Week 12, 89%, 82%, 63% and 29% of patients achieved < 6, <5, <4 and <3 mg/dL, respectively, in the 75 mg group. In the 50 mg group, 78%, 50%, 8% of patients achieved < 6, <5 and <4 mg/dL, respectively. The sUA lowering effect was similar for three consecutive measurements between Week 8 and 12. There were no serious adverse events in AR882 treated patients. Mild or moderate adverse events including diarrhea, headache, and upper respiratory infection were observed in this study. A total of 65 gout flare incidents were observed and evenly distributed across groups during the 12-week treatment. Conclusion The majority of patients receiving AR882 had achieved sUA levels below 5 or 4 mg/dL, which are two key thresholds for more efficient flare and tophi reductions[1][2]. AR882 was well tolerated over the 12-week treatment period and patients with comorbidities did not require any adjustments in management of the diseases while treated with AR882. This study suggests AR882 may offer improved efficacy with acceptable safety compared to existing therapies for gout and may have utility in the treatment of patients across the spectrum of gout including those with severe or refractory disease. References [1]Perez-Ruiz F, Calabozo M, Pijoan JI, et al. Arthritis Rheum. 2002;47(4):356-60[2]Richette P, Doherty M, Pascual E, et al. Ann Rheum Dis. 2017;76:29-42. Acknowledgements: NIL. Disclosure of Interests James Cheng-Chung Wei: None declared, Roy M. Fleischmann Speakers bureau: AbbVie, Pfizer Inc, Consultant of: AbbVie, Amgen Inc., Biogen, Bristol Myers Squibb, Eli Lilly and Company, Galapagos, Galvani, Gilead, GSK plc, Janssen Pharmaceuticals, Novartis AG, Union Chimique Belge (UCB), Grant/research support from: AbbVie, Amgen Inc., Biogen, Bristol Myers Squibb, Eli Lilly and Company, Flexion, Galapagos, Galvani, Genentech, Gilead, GSK plc, Horizon, Janssen Pharmaceuticals, Novartis AG, UCB, Viela, Sarah Morris Shareholder of: Arthrosi therapeutics, Employee of: Arthrosi therapeutics, Elizabeth Polvent Shareholder of: Arthrosi therapeutics, Employee of: Arthrosi therapeutics, Zancong Shen Shareholder of: Arthrosi therapeutics, Employee of: Arthrosi therapeutics, Andrea Clouser Roche Shareholder of: Arthrosi therapeutics, Employee of: Arthrosi therapeutics, Vijay Hingorani Consultant of: Arthrosi therapeutics, Shunqi Yan Shareholder of: Arthrosi therapeutics, Employee of: Arthrosi therapeutics, Li-Tain Yeh Shareholder of: Arthrosi therapeutics, Employee of: Arthrosi therapeutics, Robert Keenan Shareholder of: Arthrosi therapeutics, Employee of: Arthrosi therapeutics.Figure 1Percent of Patients with sUA at Targets following 12-week Treatment of AR882 or Placebo.

Background Upadacitinib (UPA) is an oral reversible Janus kinase inhibitor. In patients (pts) with RA, UPA 15 mg once daily (QD) demonstrated better clinical responses at 12 weeks (wks) vs adalimumab (ADA) 40 mg every other week (EOW) in the phase 3 SELECT-COMPARE study; these were maintained through 3 years (yrs) in the ongoing long-term extension (LTE), along with an acceptable safety profile.[1,2] Objectives To assess the safety and efficacy of UPA vs ADA through 5 yrs in the SELECT-COMPARE LTE. Methods Pts receiving background methotrexate were randomized 2:2:1 to UPA 15 mg QD, placebo (PBO), or ADA 40 mg EOW. Rescue (PBO to UPA, UPA to ADA, or ADA to UPA) was mandated for lack of response (<20% improvement in tender or swollen joint counts at wks 14, 18, or 22), or failure to achieve Clinical Disease Activity Index (CDAI) low disease activity (LDA) at wk 26. All remaining PBO pts switched to UPA at wk 26. Pts who completed the 48-wk double-blind period could continue to receive open-label UPA or ADA in the LTE for up to 10 yrs total. Rates of treatment-emergent adverse events (TEAEs) and AEs of special interest were calculated per 100 pt-yrs through 5 yrs for all pts receiving UPA or ADA. Efficacy assessments at 5 yrs were performed by original randomized group for CDAI LDA (≤10) and remission (≤2.8), and disease activity score for 28-joints C-reactive protein (DAS28[CRP]) ≤3.2 and <2.6. Radiographic progression (change from baseline in modified total Sharp score [mTSS]) and proportion of pts with no radiographic progression (change from baseline in mTSS ≤0) were assessed at 192 wks (latest available timepoint; data collected at wks 96/192/520 only) by treatment sequence. No formal statistical comparisons were performed. Results Through 5 yrs, 1417 pts were exposed to UPA (4497 pt-yrs) and 579 to ADA (1472 pt-yrs). UPA was generally well tolerated, with similar rates of TEAEs, serious TEAEs, TEAEs leading to discontinuation of study drug, and COVID-related TEAEs vs ADA (Figure 1). Rates of most AEs of special interest with UPA were similar vs ADA, except for numerically higher rates of herpes zoster, creatine phosphokinase elevation, lymphopenia, and hepatic disorder (mainly transaminase elevations) with UPA. In the 651 and 327 pts originally randomized to UPA and ADA, respectively, greater proportions of pts achieved CDAI LDA and remission, and DAS28(CRP) scores ≤3.2 and <2.6, with UPA vs ADA (Table 1). Through 192 wks, similar proportions of pts treated with UPA vs ADA had no radiographic progression; mean changes from baseline in mTSS were similar, except for a numerically smaller change with continuous UPA (Table 1). Conclusion The safety profile of UPA over 5 yrs was consistent with the 3-yr results and the integrated phase 3 safety analysis.[1,2] Consistent with the 3-yr analyses,[2] UPA continued to show numerically better clinical responses than ADA at 5 yrs. Radiographic progression remained similarly low through 192 wks with UPA and ADA. References [1]Cohen SB, et al. Ann Rheum Dis 2020. doi:10.1136/annrheumdis-2020-218510[2]Fleischmann R, et al. RMD Open 2022. doi:10.1136/rmdopen-2021-002012 Acknowledgements AbbVie funded this trial and participated in the trial design, research, analysis, data collection, interpretation of data, and the review and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing support was provided by Laura Chalmers, PhD, of 2 the Nth (Cheshire, UK), and was funded by AbbVie. Disclosure of Interests Roy M. Fleischmann Consultant of: AbbVie, Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galapagos, Galvani, Gilead, GSK, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Biosplice, Bristol-Myers Squibb, Flexion, Gilead, Horizon, Eli Lilly, Galvani, Janssen, Novartis, Pfizer, Sanofi-Aventis, Selecta, Teva, UCB, Viela, and Vorso, Jerzy Swierkot Speakers bureau: AbbVie, Accord, BMS, Janssen, MSD, Pfizer, Roche, Sandoz, and UCB, Consultant of: AbbVie, Accord, BMS, Janssen, MSD, Pfizer, Roche, Sandoz, and UCB, Grant/research support from: AbbVie, Accord, BMS, Janssen, MSD, Pfizer, Roche, Sandoz, and UCB, Sara Penn Employee of: AbbVie, and may hold stock or options, Patrick Durez Speakers bureau: AbbVie, Galapagos, Lilly, Nordimed, and Thermofischer, Louis Bessette Speakers bureau: AbbVie, Amgen, Bristol-Meyers Squibb, Celgene, Eli Lilly, Fresenius Kabi, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Teva, and UCB, Consultant of: AbbVie, Amgen, Bristol-Meyers Squibb, Celgene, Eli Lilly, Fresenius Kabi, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Teva, and UCB, Grant/research support from: AbbVie, Amgen, Bristol-Meyers Squibb, Celgene, Eli Lilly, Fresenius Kabi, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Teva, and UCB, Xianwei Bu Employee of: AbbVie, and may hold stock or options, Nasser Khan Employee of: AbbVie, and may hold stock or options, Yihan Li Employee of: AbbVie, and may hold stock or options, Charles Peterfy Shareholder of: Spire Sciences, Inc, Consultant of: Daiichi Sankyo, Eli Lilly, Five Prime, Genentech, Gilead, GlaxoSmithKline, Istesso, Labcorp, Paradigm, SetPoint, Sorrento, and UCB, Employee of: Spire Sciences, Inc, Yoshiya Tanaka Speakers bureau: AbbVie, Asahi Kasei, Astellas, BMS, Chugai, Daiichi-Sankyo, Eisai, GSK, Janssen, Lilly, Mitsubishi Tanabe, MSD, Novartis, Ono, Pfizer, Sanofi, Taisho Toyama, Takeda, UCB, and YL Biologics, Grant/research support from: AbbVie, Asahi Kasei, Astellas, BMS, Chugai, Daiichi-Sankyo, Eisai, GSK, Janssen, Lilly, Mitsubishi Tanabe, MSD, Novartis, Ono, Pfizer, Sanofi, Taisho Toyama, Takeda, UCB, and YL Biologics, Eduardo Mysler Speakers bureau: AbbVie, Amgen, AZ, BMS, Janssen, Lilly, Novartis, Pfizer, Roche, Sandoz, and Sanofi, Paid instructor for: AbbVie, Amgen, AZ, BMS, Janssen, Lilly, Novartis, Pfizer, Roche, Sandoz, and Sanofi, Grant/research support from: AbbVie, Amgen, AZ, BMS, Janssen, Lilly, Novartis, Pfizer, Roche, Sandoz, and Sanofi.Table 1Efficacy endpointsAt 5 yrs, by original randomized group (non-responder imputation)UPA N=651a,bADA N=327a,cCDAI ≤1036.4 (32.7, 40.1)26.9 (22.1, 31.7)CDAI ≤2.824.6 (21.3, 27.9)18.7 (14.4, 22.9)DAS28(CRP) ≤3.234.7 (31.1, 38.4)24.8 (20.1, 29.4)DAS28(CRP) <2.631.8 (28.2, 35.4)23.2 (18.7, 27.8)At 192 wks, by treatment sequence (as observed)PBO to UPA N=442UPA N=288UPA to ADA N=150ADA N=109ADA to UPA N=111Radiographic progression (change from baseline in mTSS, mean [95% CI])1.3 (0.8, 1.7)0.5 (0.2, 0.9)1.7 (0.7, 2.8)1.2 (0.5, 1.9)0.9 (0.2, 1.5)No radiographic progression (mTSS change from baseline ≤0)77.1(73.2, 81.1)80.9(76.4, 85.4)74.0(67.0, 81.0)78.0(70.2, 85.8)77.5(69.7, 85.2)Data are % of pts (95% confidence interval) unless otherwise stated.aPts rescued at or before wk 26 were considered non-responders. b252 rescued. c159 rescued.

Background ORAL Surveillance ( NCT02092467 ) was a randomised, open-label, non-inferiority, Phase 3b/4 study assessing the relative risk of major adverse cardiovascular (CV) events (MACE) and malignancies with tofacitinib vs TNF inhibitors (TNFi) in patients (pts) with moderate to severe rheumatoid arthritis despite methotrexate (MTX) and a high risk of MACE (aged ≥50 yrs; ≥1 additional CV risk factor). Objectives To assess risk of venous thromboembolic events (VTE; including deep vein thrombosis [DVT] and pulmonary embolism [PE]) in ORAL Surveillance. Methods Pts on stable MTX received tofacitinib 5 or 10 mg twice daily (BID) or a TNFi (etanercept 50 mg weekly or adalimumab 40 mg once every 2 weeks). Incidence rates (IRs; pts with first events/100 pt-yrs [PY]) and 95% CIs were calculated for adjudicated VTE, DVT and PE (overall by 6-month interval and for pts with/without history of VTE). For overall VTE, DVT and PE, numbers needed to harm (NNH; tofacitinib 5 or 10 mg BID vs TNFi) were calculated post hoc. Multivariate Cox models were used post hoc to identify overall independent baseline (BL) risk factors for PE. Censoring time was a 28-day on-treatment period (minimum of last contact date or last study treatment dose date +28 days). Results Analysis included 1455, 1456 and 1451 pts receiving tofacitinib 5 mg BID, 10 mg BID and TNFi, respectively. Generally, across 6-month intervals to >54 months, VTE, DVT and PE IRs were numerically higher with both tofacitinib doses vs TNFi, and with tofacitinib 10 vs 5 mg BID; IRs were consistent across time (data not shown). Across treatments, VTE, DVT and PE IRs were higher in pts with vs without history of VTE; however, only a small number of pts per treatment had history of VTE (Figure 1). NNH for tofacitinib 5 and 10 mg BID, respectively, vs TNFi were 763 and 198 PY for VTE, 1347 and 589 PY for DVT, and 870 and 229 PY for PE, or, over 5 yrs, 153 and 40 pts for VTE, 269 and 118 pts for DVT, and 174 and 46 pts for PE. Identified BL risk factors for PE across treatments included history of VTE, antidepressant use, body mass index ≥30 kg/m 2 , corticosteroid use, male sex, age ≥65 yrs, oral contraceptives/hormone-replacement therapy (HRT) use, and history of hypertension (Table 1). Table 1. Multivariate Cox analyses to identify overall independent BL risk factors for PE across treatments HR (95% CI) p value BL covariate History of VTE 7.06 (2.46, 20.25) 0.0003 Antidepressant use a 2.94 (1.44, 6.02) 0.0032 Body mass index ≥30 kg/m 2 2.97 (1.40, 6.32) 0.0047 Corticosteroid use b 3.01 (1.40, 6.46) 0.0047 Proton pump inhibitor use 0.32 (0.15, 0.71) 0.0052 Male sex c 2.18 (1.06, 4.48) 0.0340 Age ≥65 yrs 2.00 (1.03, 3.88) 0.0401 Oral contraceptives/HRT use 3.56 (1.05, 12.10) 0.0422 History of hypertension 2.57 (0.98, 6.76) 0.0554 a BL antidepressant use was an indicator of an underlying condition of depression, and subgroup analysis did not identify the difference in HRs for depression across treatments b Proxy for elevated BL disease activity; HRs for BL corticosteroid use were similar between all tofacitinib doses combined and TNFi; includes any BL corticosteroid use c Impact of sex on PE risk considered inconclusive Multivariate Cox model using backward selection included treatment effects (not subject to model selection) and overall potential independent risk factors (those affecting PE IRs equally across treatments; subject to model selection) identified from a prior set of Cox regression analyses (which included treatment and a single candidate risk factor in each model fitting, cycling through a predetermined set of risk factors); cut-off for risk factor to stay in multivariate model was p<0.10; nominal p value and HR (95% CI) based on this model HR, hazard ratio Conclusion Generally, in ORAL Surveillance, VTE, DVT and PE IRs were numerically higher for tofacitinib (10 > 5 mg BID) vs TNFi across 6-month intervals, and for pts with vs without history of VTE. Multivariate Cox models identified BL risk factors for PE that may help support future treatment decisions. Acknowledgements Study sponsored by Pfizer Inc. Medical writing support was provided by Emma Mitchell, CMC Connect, and funded by Pfizer Inc. Disclosure of Interests Christina Charles-Schoeman Consultant of: AbbVie, Gilead Sciences, Pfizer Inc and Regeneron-Sanofi, Grant/research support from: AbbVie, Bristol-Myers Squibb and Pfizer Inc, Roy M. Fleischmann Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Galvani, Gilead Sciences, GSK, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis and UCB, Grant/research support from: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Flexion, Galapagos, Galvani, Genentech, Gilead Sciences, GSK, Horizon, Janssen, Novartis, Noven, Pfizer Inc, Samumed, Sanofi Aventis, SciSelecta, Teva Pharmaceuticals, UCB, Viela and Vorso, Eduardo Mysler Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer Inc, Roche and Sanofi, Grant/research support from: Eli Lilly, Pfizer Inc and Roche, Maria Greenwald Grant/research support from: AbbVie, Eli Lilly, Galapagos, Gilead Sciences, Novartis and Pfizer Inc, Cunshan Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, All-shine Chen Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Carol A. Connell Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, John Woolcott Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Sujatha Menon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Yan Chen Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Kristen Lee Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Zoltán Szekanecz Speakers bureau: AbbVie, Eli Lilly, Novartis, Pfizer Inc, Roche and Sanofi, Paid instructor for: AbbVie, Eli Lilly, Gedeon Richter, Novartis, Pfizer Inc and Roche, Consultant of: AbbVie, Eli Lilly, Novartis, Pfizer Inc, Roche and Sanofi, Grant/research support from: Pfizer Inc

Background For patients with RA who are refractory to biologic DMARDs (bDMARDs), such as tumor necrosis factor inhibitors (TNFis), optimal disease control is less likely to be achieved with subsequent therapy. 1 In line with recommendations from EULAR and ACR, switching to a treatment with a different mechanism of action is appropriate for these patients. Objectives To describe the efficacy and safety of upadacitinib (UPA) 15 mg once daily in patients with RA and an inadequate response or intolerance to TNFis (TNFi-IR). Methods A post hoc subgroup analysis was conducted in TNFi-IR patients who were treated with UPA 15 mg once daily in three Phase 3 clinical trials: SELECT-BEYOND, 2 -CHOICE, 3 and -COMPARE. 4 For COMPARE, only patients treated with adalimumab and switched to UPA as rescue therapy were included. ≥20/50/70% improvement in ACR criteria, DAS28(CRP), CDAI, and SDAI, as well as change from baseline in HAQ-DI and other patient-reported outcomes (PROs) were reported through 24 weeks. Non-responder imputation was used for all missing categorical outcomes; as observed (COMPARE) or multiple imputation (CHOICE, BEYOND) were used for missing continuous outcomes. Pooled safety results were presented as exposure-adjusted event rates (EAERs) with a cut-off of June 30, 2021. Results 568 TNFi-IR patients were included: 146 from BEYOND, 263 from CHOICE, and 159 from COMPARE. Mean duration since RA diagnosis was longer for BEYOND and CHOICE versus COMPARE; cardiovascular (CV) risk factors were common among this refractory population (Table 1). ACR20/50/70 and disease activity outcomes observed in the TNFi-IR population were generally consistent with the overall BEYOND 2 and CHOICE 3 bDMARD-IR populations, and consistent across the three studies in the TNFi-IR subgroups (Figure 1). Improvements in PROs including HAQ-DI, fatigue, pain, and morning stiffness over 24 weeks were observed (data not shown). Pooled safety results reporting 1574.8 patient-years (PY) of exposure in the TNFi-IR subgroup showed similar results to the overall BEYOND 2 and CHOICE 3 bDMARD-IR study populations, with EAERs of 3.1 events/100 PY for herpes zoster and 0.8 events/100 PY for adjudicated major adverse CV events, adjudicated venous thromboembolism (VTE), and malignancy excluding non-melanoma skin cancer. The EAER of any AE leading to death was 1.4 events/100 PY. Table 1. Baseline characteristics of TNFi-IR patients treated with UPA 15 mg n (%), unless specified SELECT-BEYOND (n=146) SELECT-CHOICE (n=263) SELECT-COMPARE (ADA → UPA) (n=159) Female 122 (83.6) 219 (83.3) 133 (83.6) Mean (SD) age, years 56.6 (11.0) 55.5 (11.1) 53.9 (10.6) Mean (SD) duration of RA diagnosis, years 13.2 (9.5) 12.5 (9.4) 8.2 (8.5) Concomitant csDMARDs MTX alone 100 (70.4) 195 (74.1) 159 (100.0) MTX and other csDMARDs 20 (14.1) 25 (9.5) 0 csDMARDs other than MTX 22 (15.5) 38 (14.4) 0 Concomitant oral steroids 73 (50.0) 140 (53.2) 98 (61.6) 1 prior bDMARD 68 (46.6) 172 (65.4) 142 (89.3) 2 prior bDMARDs 40 (27.4) 62 (23.6) 17 (10.7) a ≥3 prior bDMARDs 38 (26.0) 29 (11.0) 0 Failed ≥1 prior TNFi due to lack of efficacy b 131 (89.7) 223 (84.8) 159 (100.0) History of VTE / CV event 3 (2.1) / 28 (19.2) 6 (2.3) / 20 (7.6) 4 (2.5) / 14 (8.8) CV risk factors Hypertension 72 (49.3) 109 (41.4) 68 (42.8) Diabetes mellitus 22 (15.1) 34 (12.9) 17 (10.7) Smoking (current former past) 68 (46.6) 109 (41.5) 55 (34.6) Elevated LDL-C (≥3.36 mmol/L) 38 (26.0) 52 (20.0) 48 (30.2) Low HDL-C (≤1.55 mmol/L) 80 (54.8) 171 (65.0) 88 (55.3) a These patients received one bDMARD before entry into SELECT-COMPARE. b Remaining patients were intolerant to ≥1 prior TNFi. Conclusion In this post hoc subgroup analysis, TNFi-IR patients treated with UPA 15 mg achieved clinically meaningful efficacy responses over 24 weeks, with safety consistent with the overall bDMARD-IR patient population in the Phase 3 program. References [1]Rendas-Baum R, et al. Arthritis Res Ther 2011;13:R25; [2]Genovese C, et al. Lancet 2018;391:2513–24; [3]Rubbert-Roth A, et al. NEJM 2020;383:1511–21; [4]Fleischmann R, et al. Ann Rheum Dis 2019;78:1454–62. Acknowledgements AbbVie funded this study; contributed to its design; participated in data collection, analysis, and interpretation of the data; and participated in the writing, review, and approval of the abstract. AbbVie and the authors thank all study investigators for their contributions and the patients who participated in this study. No honoraria or payments were made for authorship. Medical writing support was provided by Amy Wilson, MSc, of 2 the Nth (Cheshire, UK), and was funded by AbbVie. Disclosure of Interests Roy M. Fleischmann Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Galvani, Gilead, GSK, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Biosplice, Bristol-Myers Squibb, Flexion, Gilead, Horizon, Eli Lilly, Galvani, Janssen, Novartis, Pfizer, Sanofi-Aventis, Selecta, Teva, UCB, Viela, and Vorso, Louis Bessette Speakers bureau: AbbVie, Amgen, Bristol-Meyers Squibb, Celgene, Eli Lilly, Fresenius Kabi, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Teva, and UCB, Consultant of: AbbVie, Amgen, Bristol-Meyers Squibb, Celgene, Eli Lilly, Fresenius Kabi, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Teva, and UCB, Grant/research support from: AbbVie, Amgen, Bristol-Meyers Squibb, Celgene, Eli Lilly, Fresenius Kabi, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Teva, and UCB, Jeffrey Sparks Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer, Stephen Hall Consultant of: AbbVie, Amgen, Bristol-Meyers Sqibb, Eli Lilly, Gilead, Janssen, Merck, Novartis, and UCB, Grant/research support from: AbbVie, Amgen, Bristol-Meyers Sqibb, Eli Lilly, Gilead, Janssen, Merck, Novartis, and UCB, Manish Jain Consultant of: AbbVie, Amgen, Eli Lilly, Novartis, and Pfizer, Grant/research support from: AbbVie, Amgen, Eli Lilly, Novartis, and Pfizer, Adriana Kakehasi Speakers bureau: AbbVie, Amgen, Eli Lilly, Fresenius Kabi, Janssen, Novartis, Pfizer, Sandoz, and UCB, Consultant of: AbbVie, Amgen, Eli Lilly, Fresenius Kabi, Janssen, Novartis, Pfizer, Sandoz, and UCB, Grant/research support from: AbbVie, Amgen, Eli Lilly, Fresenius Kabi, Janssen, Novartis, Pfizer, Sandoz, and UCB, Yanna Song Shareholder of: AbbVie (may own stock or options), Employee of: AbbVie, Sebastian Meerwein Shareholder of: AbbVie (may own stock or options), Employee of: AbbVie, Ryan DeMasi Shareholder of: AbbVie (may own stock or options), Employee of: AbbVie, Jessica Suboticki Shareholder of: AbbVie (may own stock or options), Employee of: AbbVie, Andrea Rubbert-Roth Consultant of: AbbVie, AbbVie Deutschland, Amgen, Bristol-Myers Squibb, Chugai Pharmaceuticals, Eli Lilly, F. Hoffman-La Roche, Gilead Sciences, Janssen Global Services, Novartis, and Sanofi Pasteur

BackgroundSustained clinical remission (REM) is the primary treatment goal for patients with rheumatoid arthritis (RA), with low disease activity (LDA) being an appropriate target for treatment-refractory patients.1,2ObjectivesTo evaluate the sustainability of response to the JAK inhibitor, upadacitinib (UPA) 15 mg once daily (QD), among patients with prior inadequate response or intolerance to biologic DMARDs.MethodsData come from the 12-week, phase 3 randomized, placebo (PBO)-controlled SELECT-BEYOND trial of UPA 15 mg or 30 mg QD in patients with moderate to severe RA on stable background conventional synthetic (cs) DMARDs. Initiation, change, or discontinuation of background RA medications, including ≤2 csDMARDs, was allowed starting at Week 24. Patients completing the 12-week trial were able to enter a long-term extension of up to 5 yrs with all PBO patients switching to UPA.3 This post hoc analysis evaluated REM (CDAI ≤2.8; SDAI ≤3.3), LDA (CDAI≤10; SDAI≤11), and DAS28(CRP) <2.6/≤3.2 at first occurrence of response before Week 60, as well as at 3, 6, and 12 months following initial response in patients randomized to UPA 15 mg. For those patients who achieved REM/LDA, Kaplan-Meier was used to define the time from when the response was first achieved to the earliest date at which the response was lost at two consecutive visits or discontinuation of study drug. The predictive ability of time to REM/LDA was evaluated using Harrell’s concordance (c)-index (range: 0 to 1, where 0.5 indicates a model that is no better at predicting an outcome than random chance). The date of the last follow up was 16 April 2018, when all patients had reached the Week 60 visit. Non-responder imputation was used for missing data. Only data from the approved 15 mg dosage are reported here.ResultsIn patients with active RA despite prior treatment with at least one bDMARD, 34% and 79% of those receiving UPA 15 mg + background csDMARD(s) achieved CDAI REM or LDA through Week 60, respectively. Sustained CDAI REM was attained by 30%, 26%, and 16% of patients randomized to UPA at 3, 6, and 12 months post initial response, while CDAI LDA was achieved by 68%, 61%, and 50% of patients during the same time points (Figure 1). Time to initial clinical response weakly predicted sustained REM but did not predict sustained LDA, with a c-index (95% CI) of 0.62 (0.49, 0.74) and 0.52 (0.44, 0.61), respectively. Through the last follow-up visit at Week 60, 39/61% of patients on UPA remained in CDAI REM/LDA (Figure 2). Of those who lost CDAI REM, 58% remained in CDAI LDA, and 22% recaptured REM by the cut-off date; 18% of patients who lost CDAI LDA recaptured response. Similar results were observed for REM and LDA based on SDAI and for DAS28(CRP) <2.6/≤3.2.ConclusionAmong patients with inadequate response or intolerance to bDMARDs, over three-quarters on UPA 15 mg achieved CDAI LDA, a relevant therapeutic target for these treatment-refractory patients, and nearly two-thirds of those maintained this response through 60 weeks. Additionally, about one-third of UPA-treated patients attained CDAI REM and maintained that response over 60 weeks.References[1]Smolen et al. Ann Rheum Dis 2020;79:685–99.[2]Singh et al. Arthritis Rheumatol 2016;68:1–26.[3]Genovese, et al. Lancet 2018;391:2513–24.AcknowledgementsAbbVie funded these studies and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. No honoraria or payments were made for authorship. Medical writing support was provided by Matthew Eckwahl, PhD, of AbbVie.Disclosure of InterestsRonald van Vollenhoven Consultant of: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Eli Lilly, GSK, Janssen, Medac, MSD, Novartis, Pfizer, Roche, and UCB, Grant/research support from: AbbVie, Arthrogen, Bristol-Myers Squibb, Eli Lilly, GSK, Pfizer, and UCB, Stephen Hall Consultant of: AbbVie, BMS, Lilly, Janssen, Pfizer, UCB, and Novartis., Grant/research support from: AbbVie, BMS, Lilly, Janssen, Pfizer, UCB, and Novartis., Alvin F. Wells Consultant of: AbbVie, Sebastian Meerwein Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Yanna Song Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Jessica Suboticki Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Roy M. Fleischmann Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, GSK, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, and UCB, Grant/research support from: AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, Janssen, Novartis, Pfizer Inc, Regeneron, Roche, Sanofi-Aventis and UCB

Background Wnt signaling pathway plays a central role in joint tissue formation and altered Wnt signaling has been associated with cartilage loss in preclinical/clinical studies.1 SM04690 is an IA small molecule inhibitor of the Wnt pathway. Objectives To report safety, clinical and imaging efficacy results from a 24 week phase 1 randomized, double-blind, placebo-controlled, dose-escalation clinical trial of a small molecule Wnt pathway inhibitor, SM04690, in knee OA. Methods Subjects with symptomatic, radiographic knee OA were randomized to receive a single IA injection in the target knee with either 0.03, 0.07, 0.23 mg SM04690 or vehicle (volume 2mLs) in a 4:1 SM04690 (N=16): vehicle (N=4) ratio. Safety, pharmacokinetics, WOMAC Total, Function, Pain subscales and strict OARSI responses2, and radiographs were collected at baseline and during the 24 week trial. Analyses of efficacy outcomes were conducted using a modified Intention-To-Treat (mITT) baseline-adjusted analysis of covariance (ANCOVA) and logistic regression. Results A total of 61 subjects (female N=41, mean age 62.6 yrs, BMI 30.4 kg/m2) were enrolled. Serum levels of SM04690 in all subjects were below limits of detection at all time points. Two dose limiting toxicities (DLTs), paroxysmal tachycardia, (also an SAE), and increased pain were reported in 0.07 mg cohort. A total of 72 AEs were reported in 28 (46%) subjects; 16 AEs in 8 subjects were considered possibly or probably related to study drug. At Week 24, improved WOMAC Total Score was seen for both 0.03 mg and 0.07 mg cohorts (change from baseline, -27.4 and -26.6 respectively) compared to placebo (-21.7) (Figure 1). Odds of having an OMERACT-OARSI strict response in 0.07 mg cohort were higher than in the placebo cohort at week 12 (odds ratio=5.7, 95% CI: 1.1, 30.0, P=0.04); odds of an OMERACT-OARSI strict response in 0.03 mg cohort were higher than in the placebo cohort at week 24 (odds ratio=4.8, 95% CI: 0.9, 25.8, P=0.07) (Figure 2). Joint space width by radiographs showed no change from baseline to Week 24 in the 0.03 mg cohort (0.00 mm), an increase in the 0.07 mg cohort (0.49 mm), and a decrease in the 0.23 mg cohort (-0.15 mm), with the placebo cohort exhibiting a larger decrease (-0.33 mm). Compared to placebo, the change in joint space width seen in 0.07 mg cohort was statistically significant (P=0.02). Conclusions These phase 1 data suggested that an intra-articular injection with a novel Wnt inhibitor SM04690 into the knee of OA patients was safe and well-tolerated. SM04690 appeared to potentially improve function, pain and knee joint space width. Additional studies are underway to further evaluate safety, tolerability, efficacy and potential DMOAD properties. References Gelse K. Osteoarthr Cartil 2002; 20(2): 162–71. Pham T, et al. J Rheumatol. 2003;30(7):1648–1654 Disclosure of Interest Y. Yazici Employee of: Samumed, LLC, T. McAlindon Consultant for: Pfizer, Regeneron, Flexion, Fidia, R. Fleischmann Grant/research support from: Samumed, LLC, A. Gibofsky Shareholder of: AbbVie, Amgen, J&J, GSK, Regeneron, Consultant for: AbbVie, Pfizer, Horizon, Iroko, Celgene, Novartis/Sandoz, Speakers bureau: AbbVie, Amgen, Celgene, Pfizer, N. Lane Consultant for: Samumed, LLC, A. Kivitz Grant/research support from: Samumed, LLC, Consultant for: Samumed, LLC, S. Majumdar Consultant for: Samumed, LLC, V. Strand Consultant for: Abbvie, Afferent, Bioventus, Carbylan, Eupraxia, Iroko, Pfizer, Regeneron, SKK, C. Swearingen Employee of: Samumed, LLC, A. DiFrancesco Employee of: Samumed, LLC, J. Tambiah Employee of: Samumed, LLC, J. Hood Employee of: Samumed, LLC, M. Hochberg Consultant for: Bioiberica, EMD Serono, Novartis Pharma AG, Plexxikon, Regeneron, Samumed, Theralogix LLC

OBJECTIVES:Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. This post-hoc pooled analysis assessed commonalities and differences in tofacitinib efficacy and safety for US versus rest of the world (ROW) populations. METHODS:Pooled phase (P) III data from patients receiving tofacitinib 5 or 10 mg twice daily (BID) or placebo were assessed for efficacy at Month 3 and for safety outcomes over 12 months. For adverse events of special interest, data on tofacitinib 5 or 10 mg BID or placebo were pooled from six PII and five PIII randomised studies. RESULTS:PIII data were available for 664 vs. 2447 and PII/PIII data for 943 vs. 3567 US vs. ROW patients, respectively. The US population had a higher proportion of Caucasians (81.5% vs. 54.4%), lower proportion of Asians (1.0% vs. 34.6%), and higher mean body weight (85.7 vs. 66.2 kg) and body mass index (31.5 vs. 25.6 kg/m2) compared with ROW. At Month 3, PIII efficacy was similar between US and ROW as assessed by ACR 20/50/70 response rates, remission rates (DAS 28-4[ESR]<2.6), and HAQ-DI scores. Diarrhoea, peripheral oedema, and upper respiratory tract infection occurred in >5% of PIII patients in the US population. Incidence rates for adverse events of special interest were similar between the US and ROW PII/PIII populations. CONCLUSIONS:Patients in the US achieved similar efficacy and safety with tofacitinib 5 and 10 mg BID compared with patients in ROW.

Background TNF and IL-17 independently contribute to the pathophysiology of RA, synergistically inducing inflammatory mediators and joint destruction. Selective dual neutralization of TNF and IL-17 confers superior protection vs inhibition of either alone in mouse RA models. ABT-122 is a novel dual variable domain immunoglobulin (DVD-Ig™) targeting both human TNF and IL-17A and hypothesized to provide greater clinical responses in RA patients (pts). Objectives Investigate safety, tolerability, and exploratory pharmacodynamics of multiple doses of ABT-122 in pts with stable RA Methods Two phase 1, placebo (PBO)-controlled, multiple-dose studies randomized 43 pts with stable RA receiving stable methotrexate (7.5–25 mg/wk). Pts received subcutaneous PBO, ABT-122 1 mg/kg every other wk (4 doses), or ABT-122 0.5, 1.5, or 3 mg/kg weekly (8 doses), and were evaluated through 45 d after last dose. Serum for inflammation markers and chemokines, based on preclinical studies with dual TNF and IL-17 neutralization, was collected at baseline (BL) through d 92 and analyzed by multiplex assays. Results No clinically significant safety findings were observed. Rates of treatment-emergent AEs were similar in the ABT-122 and PBO groups, with no evidence of a dose response. There were no AE or serious AE trends, systemic hypersensitivity reactions, or dose-limiting toxicities with ABT-122. Infections were reported, as expected in RA, with no apparent patterns related to etiology, type, or dose with ABT-122 vs PBO, and no pt discontinued the study owing to infection. There were no clinically significant laboratory, vital sign, or ECG abnormalities. CXCL9 and CXCL10 decreased within 3 d of ABT-122 administration (−25% and −30% vs BL, respectively) relative to PBO. Maximal decreases occurred by d 15 (−60% and −45% for CXCL9 and CXCL10, respectively) and persisted through 14 d after last dose. CCL23 decreased following ABT-122, with maximal decreases (−30%) at d 64, and continued through d 92. Consistent with TNF inhibition, soluble E-selectin decreased following ABT-122, persisting through d 92 for the 3 mg/kg group. Conclusions ABT-122 demonstrated a well-tolerated safety profile in RA pts through 8 wk of dosing up to 3 mg/kg, consistent with the prior first-in-human study in healthy subjects. Because CXCL9, CXCL10, and CCL23 are involved in lymphocyte and myeloid cell recruitment into inflamed tissues, decreases in these chemokines indicate that ABT-122 rapidly modulates potential pathophysiologic pathways in RA pts, with evidence for persistent effects after cessation of dosing. These results suggest that dual neutralization of TNF and IL-17 may provide an opportunity to control inflammation and its clinical manifestations in RA and other immune-mediated inflammatory diseases. Acknowledgement The design, study conduct, analysis, and financial support of the clinical trials were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the content. All authors had access to all relevant data. Katherine Groschwitz and John Fincke of Complete Publication Solutions, LLC, provided medical writing support. ABT-122 is an investigational product. Disclosure of Interest R. Fleischmann Grant/research support from: AbbVie, Consultant for: AbbVie, F. Wagner: None declared, A. Kivitz Grant/research support from: AbbVie, H. Mansikka Shareholder of: AbbVie, Employee of: AbbVie, N. Khan Shareholder of: AbbVie, Employee of: AbbVie, J. Liu Shareholder of: AbbVie, Employee of: AbbVie, F. Hong Shareholder of: AbbVie, Employee of: AbbVie, M. Ruzek Shareholder of: AbbVie, Employee of: AbbVie, R. Padley Shareholder of: AbbVie, Employee of: AbbVie

Background Clinical response remains difficult to predict in patients with rheumatoid arthritis (RA). Acute phase reactants (APRs) C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are regularly measured in standard care, and abnormal CRP and ESR are frequently used as inclusion criteria for RA clinical trials. Alone or in combination with demographic, clinical, and imaging parameters, these APRs are often considered important in treatment decisions in RA. However, results of these tests for inflammation are discordant in a substantial proportion of patients,1–3 and the clinical implications of discordant CRP:ESR findings have not been well studied. Objectives To explore the relationship between clinical response and baseline CRP:ESR discordance in RA. Methods Randomized patients with moderate-severe RA who participated in 3 etanercept (ETN) clinical trials4–6 and had both APR measurements were included in these post hoc analyses. To allow comparison, baseline CRP and ESR were standardized to the same scale by subtracting the respective means and dividing by the respective standard deviations for each patient. Standardized CRP was subtracted from standardized ESR and differences categorized by quartile (cutoffs: Q1, –0.5; median, 0; Q3, 0.5). DAS28 (ESR) low disease activity (LDA) and remission after 16 or 52 weeks of treatment with ETN + methotrexate (MTX) were analyzed by quartile of CRP:ESR discordance. Results Across clinical trials, 693 patients received ETN+MTX and had CRP and ESR measured. After 16 or 52 weeks of ETN+MTX treatment, significantly higher proportions of patients achieved DAS28 LDA and remission in the group with higher CRP than ESR at baseline (lower ESR/higher CRP); lower proportions of responders were seen in the group with similar CRP and ESR (ESR$≈ $CRP), and the lowest proportion in the group with lower CRP than ESR (higher ESR/lower CRP) (Table). Conclusions In clinical trials, elevated CRP relative to ESR at baseline was a significantly better predictor of the ability of active treatment to show clinical response after 4 months or 1 year of combination etanercept-methotrexate therapy than similar CRP and ESR or lower CRP vs higher ESR. These findings underscore the importance of incorporating this readily available biomarker (CRP) into clinical trial settings; whether this is true in clinical practice cannot be determined from this data set but should be investigated prospectively. References Costenbader KH, et al. Clin Exp Rheumatol. 2007;25:746–9. Feldman M, et al. Transl Res. 2013;161:37–43. Kay J, et al. Arthritis Res Ther. 2014:16:R40. Klareskog L, et al. Lancet. 2004;363:675–81. Emery P, et al. Lancet. 2008;372:375–82. Kim HY, et al. Int J Rheum Dis. 2012;15:188–96. Disclosure of Interest R. Fleischmann Consultant for: Pfizer, A. Szumski Employee of: inVentiv Health, H. Jones Shareholder of: Pfizer, Employee of: Pfizer

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 <1000/μL. 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

Objectives Final 5yr safety and efficacy results of subcutaneous golimumab (GLM)+/-MTX evaluated in a phase 3 trial (GO-BEFORE) of MTX-naïve pts with rheumatoid arthritis (RA) are reported. Methods Pts were randomized to PBO+MTX, GLM 100mg+PBO, GLM 50mg+MTX, or GLM 100mg+MTX q4w. PBO+MTX pts crossed over to GLM+MTX at wks 28 (blinded early escape) or 52 (pts with ≥1 swollen/tender joint). Pts continued treatment at wk52 (start of long-term extension). After the last pt completed wk52 and unblinding occurred, PBO+MTX pts could switch to GLM 50mg+MTX, MTX and corticosteroid use could be adjusted, and a one-time GLM dose change (50 → 100mg or 100 → 50mg) was permitted at investigator’s discretion. The last GLM injection was at wk252. Observed efficacy results (ACR20/50/70, DAS28-CRP, HAQ-DI, radiographic) by randomized treatment group and cumulative safety data are reported through wks 256 and 268, respectively. Results Of 637 randomized pts, 3 were never treated; 419 continued treatment through wk252, and 215 withdrew (111 for AE, 23 for lack of efficacy, 20 lost to follow-up, 53 for other reasons, 8 deaths). 402 completed the safety follow-up through wk268. Efficacy results are presented in the table. At wk 256, 84.3% of all pts had an ACR20, 93.9% had DAS28-CRP EULAR response, and 80.6% had improvement in HAQ-DI ≥0.25. Mean changes from baseline in total vdH-S score were small and 64% of pts randomized to GLM+MTX had no radiographic progression (ΔvdH-S≤0). The most common AEs were upper respiratory tract infection(29.4%), nausea(19.6%), bronchitis(16.6%), and increased alanine aminotransferase(16.1%); 11.9% of pts had an injection-site reaction. Through wk268, 204/616(33.1%) pts had an SAE; 17.5% of pts discontinued study agent due to AEs. Overall rates of serious infections, malignancies, and death were 12.2%, 3.4%, and 1.9%, resp. Of 595 pts with available samples, 58(9.7%) were positive for antibodies to GLM. Image/graph Conclusions The retention rate was high(66.1%) through 5yrs. GLM+MTX therapy resulted in maintained improvements in signs/symptoms of RA and in physical function, and inhibited structural damage progression long-term. No new safety signals were detected through 5years in MTX-naïve RA pts. Disclosure of Interest P. Emery Grant/research support from: Janssen R&D, LLC, R. Fleischmann Grant/research support from: Janssen R&D, LLC, I. Strusberg Grant/research support from: Janssen R&D, LLC, P. Durez Grant/research support from: Janssen R&D, LLC, P. Nash Grant/research support from: Janssen R&D, LLC, E. Amante Grant/research support from: Janssen R&D, LLC, M. Churchill Grant/research support from: Janssen R&D, LLC, W. Park Grant/research support from: Janssen R&D, LLC, B. Pons-Estel Grant/research support from: Janssen R&D, LLC, C. Han Shareholder of: Johnson & Johnson, Employee of: Janssen Global Services, LLC, T. Gathany Shareholder of: Johnson & Johnson, Employee of: Janssen Global Services, LLC, Y. Zhou Shareholder of: Johnson & Johnson, Employee of: Janssen R&D, LLC, S. Xu Shareholder of: Johnson & Johnson, Employee of: Janssen R&D, LLC, E. Hsia Shareholder of: Johnson & Johnson, Employee of: Janssen R&D, LLC

To examine physical function, health-related quality of life(HRQOL) and work productivity in patients enrolled from Latin American countries (Argentina,Chile and Mexico) in Phase III clinical trials for golimumab(GLM) in rheumatoid arthritis(RA). Active RA patients not previously treated with methotrexate(MTX)(GO-BEFORE,N=637) or with inadequate response to MTX(GO-FORWARD,N=444) were randomized to SC GLM(50 or 100mg)+MTX or PBO+MTX, q4wks.At wk24(GO-FORWARD) or wk52(GO-BEFORE), PBO+MTX group switched to GLM 50mg+MTX. Physical function was assessed using HAQ(0-3). HRQOL was assessed using SF-36 PCS(0-100) and SF-36 MCS(0-100). Impact of disease on work productivity was assessed using a productivity VAS (0-10). Clinically meaningful improvement was defined as improvement of ≥0.25 point in HAQ, or ≥5 points in SF-36 PCS and MCS. At baseline, both MTX naive (N=96) and MTX experienced (N=56) RA patients enrolled in Latin American region experienced moderate to severe physical disability (mean HAQ score of 1.60 to 1.75) and impaired HRQOL (mean PCS of 30.0 to 30.3 and mean MCS of 9.4 to 42.6). The impact of RA on productivity was severe (mean VAS score of 6.3-6.7). Patients treated with GLM (50 or 100 mg)+MTX had significantly greater mean improvement than PBO+MTX group in HAQ (0.87 vs. 0.56, p=0.01), PCS (12.44 vs. 6.93, p<0.01) and work productivity (-3.69 vs. -2.25, p<0.01) at wk 24, and greater proportions of patients in GLM+MTX group than PBO+MTX achieved clinically meaningful improvement in HAQ (84.04% vs. 65.45%, p=0.01), PCS (74.47% vs. 49.09%, p<0.01) and MCS (45.74% vs. 41.82%, p=0.73). Similar results were observed in patients who were MTX naïve and experienced although the magnitudes of improvements were greater in MTX naïve patients than MTX-experienced patients. The improvements were sustained over wk52 and 104. MTX naïve and MTX experienced RA patients from Latin America treated with GLM demonstrated improved physical function, HRQOL, and work productivity.

Objectives To assess wk24 remission rates from GO-BEFORE and GO-FORWARD using new, “provisional” criteria proposed by the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) (Felson et al).1 Methods This is a retrospective analysis from GO-BEFORE (methotrexate (MTX)-naïve RA pts) and GO-FORWARD (RA pts with inadequate response to MTX) through wk24. In GO-BEFORE (N=637) MTX-naïve pts and in GO-FORWARD (N=444) pts with active RA despite MTX were randomized to PBO+MTX, GLM100mg+PBO, GLM50mg+MTX, or GLM100mg+MTX, grps 1-4, respectively. In GO-FORWARD, pts with <20% improvement in SJC/TJC at wk16 entered early escape: PBO+MTX$→ $GLM50mg+MTX, GLM 100mg+PBO$→ $GLM100mg+MTX, GLM 50mg+MTX$→ $GLM100mg+MTX. GLM/PBO was injected q4wks. New ACR/EULAR remission was defined as follows: Definition A [Def A]-(TJC/SJC [28 joints], CRP mg/dL, and pt global assessment, each score ≤1) and Definition B [Def B]-SDAI score is the sum of (TJC/SJC [28 joints], pt global assessment, physician global assessment, and CRP mg/dL), scoring ≤3.3. Data handling rules were applied to wk24 analysis of data (Table). Results Using new ACR/EULAR remission criteria (Def A and B), a significantly greater proportion of pts achieved remission in the combined GLM+MTX treatment grps vs grp 1 in GO-BEFORE and GO-FORWARD. A comparison between new criteria and previously published DAS28 remission criteria for the combined GLM+MTX treatment grps show: GO-BEFORE (13.2% (Def A)/15.4% (Def B) vs 26.7% (prev pub’d) and GO-FORWARD (11.2% (Def A)/12.9% (Def B) vs 28.7% (prev pub’d). As expected, the new, more stringent criteria resulted in lower remission rates vs DAS28 remission criteria. Def A and B had generally similar remission rates in both studies, with slightly lower numbers for Def A vs B. A comparison between individual treatment grps using the new criteria show: GO-BEFORE remission rates significantly greater in grp 3 for Def A and grp 4 for Def B, with grp 3 approaching statistical significance (p=0.052) (Def B) vs grp 1. In GO-FORWARD, significantly greater remission rates using Def A were achieved in grps 3 and 4, with grp 2 approaching statistical significance (p=0.053) vs grp 1, while significantly greater proportions of pts achieved remission in all GLM treatment grps vs grp 1 using Def B. Conclusions Significantly greater remission rates were achieved in the combined GLM grp vs grp 1 in GO-BEFORE and GO-FORWARD through wk24 based on new, more stringent ACR/EULAR criteria. Remission rates were generally slightly lower using Def A vs Def B. References Felson D, Smolen J, Wells G, et al. Arthritis & Rheumatism 2011:63 (3)573-586. Disclosure of Interest P. Emery Grant/Research support from: Investigators for Janssen Research & Development, LLC sponsored clinical study, E. Keystone Grant/Research support from: Investigators for Janssen Research & Development, LLC sponsored clinical study, R. Fleischmann Grant/Research support from: Investigators for Janssen Research & Development, LLC sponsored clinical study, M. Genovese Grant/Research support from: Investigators for Janssen Research & Development, LLC sponsored clinical study, L. Klareskog Grant/Research support from: Investigators for Janssen Research & Development, LLC sponsored clinical study, S. Xu Employee of: Janssen Research & Development, LLC, C. Han Employee of: Janssen Research & Development, LLC, E. Hsia Employee of: Janssen Research & Development, LLC

Objectives To assess golimumab (GLM) treatment effect in patients with rheumatoid arthritis (RA) naïve to methotrexate (MTX) therapy with severe, active and progressive disease. Methods The GO-BEFORE trial studied GLM 50mg and 100mg + MTX in MTX-naïve patients. In the overall GO-BEFORE study population, patients exhibited lower disease activity (baseline ACR components and DAS28) than was observed in previous studies of biologic agents in MTX-naive patients1. This is a retrospective analysis of GO-BEFORE wk 52 data which compares efficacy outcomes in subsets of RA patients with severe, active disease to the overall study population. 637 MTX-naïve pts were randomized to PBO+MTX (Grp 1), GLM 100mg+PBO (Grp 2), GLM 50mg+MTX (Grp 3), or GLM 100mg+MTX (Grp 4). GLM/PBO received injections q4wks. Pts with 5.1, and CRP ≥3 mg/dL. Treatment effect for each subset and the overall population was defined as the differences between GLM 50mg or 100mg +MTX and MTX-alone in ACR50, DAS28 (CRP) remission, change in HAQ ≥0.25 and total vdHS score ≤0. Differences in the treatment effect between each subset of severe, active and progressive RA and the overall population was examined. Results Greater proportions of patients achieved the efficacy endpoints in the GLM+MTX groups versus MTX-alone and the difference between the treatment groups (tx effect) was generally larger in the severe, active and progressive subsets compared with the overall population (Table). Conclusions Overall, treatment effect in the efficacy parameters between GLM 50mg +MTX and GLM 100mg +MTX versus MTX-alone was greater for the severe, active and progressive subsets versus the overall population. References Emery et al. Arthritis & Rheumatism 2009;60(8):2272-2283. Disclosure of Interest P. Emery Grant/Research support from: Investigators for Janssen Research & Development, LLC sponsored clinical study, R. Fleischmann Grant/Research support from: Investigators for Janssen Research & Development, LLC sponsored clinical study, E. Hsia Employee of: Janssen Research & Development, LLC, S. Xu Employee of: Janssen Research & Development, LLC, W. Xu Employee of: Janssen Research & Development, LLC, D. Baker Employee of: Janssen Research & Development, LLC