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Background:Magnetic resonance imaging (MRI) was used to confirm dose selection in a phase IIb clinical trial of baricitinib in patients with active rheumatoid arthritis (RA) on background methotrexate therapy (NCT01185353).[1] MRI data were retrospectively assessed for consistency, timing of post-contrast sequences following intravenous (IV) Gadolinium (Gd), and readability. Data were re-analyzed using a novel quantitative computer-aided methodology to extract the continuous volume of inflammatory changes.[2]Objectives:The objective was to examine how image quality and timing of the post-contrast MRI sequence can impact MRI-based exploratory endpoints in RA clinical trials when using novel computer-aided analysis tools.Methods:A total of 154 patients with definitive radiographic erosion had an MRI of the hand and wrist at baseline and at weeks 12 and 24. Three-dimensional T1-w fat-suppressed MRI sequences before and after IV Gd contrast were performed with dedicated coils. Due to the limited field of view, the coils were re-positioned during the image acquisition between the metacarpophalangeal (MCP) and finger joints and the wrist, following IV Gd injection, which introduced a time delay of the post-contrast sequences in the two anatomies in all patients.Digital Imaging and Communications in Medicine (DICOM) headers of the MRIs were automatically assessed; the distribution of the time delay in minutes from Gd injection to post-contrast scan acquisition was calculated and the image quality and suitability for reading were evaluated (Figure 1). The time delays across MRI acquisitions at baseline and weeks 12 and 24 were also compared. Quality scores were assigned for each image using visual image quality assessment by an experienced reader blinded to treatment regimen, patient visits, and time after Gd. The images were categorized by quality based on total score. The reader used a proprietary software, to pre-define regions of interest (ROI) around the wrist and MCP joints (MCP-2 to MCP-5) in all three timepoints as a batch, avoiding adjacent blood vessels and possible artifacts. From these ROIs, the normalized volume of inflammation (NormI) was calculated in each joint relative to a standardized ROI in the thenar muscle. Quantitative Total Volume of Inflammation (QVI) was extracted automatically from all ROIs by counting the pixels that were enhanced two standard deviations above the intensity level of the normal muscle, allowing differentiation of areas with low-to-high inflammation.Results:The timing of post-contrast images from Gd injection was closely linked to image quality. In up to 10% of MRI data, the delay from Gd injection to scan acquisition caused significant variation in signal intensities. This led to a perceived increase in enhanced synovial volume due to the known effusion effects of the contrast media over time, which did not correspond to real size of the underlying synovial volume and pathology (Figure 2).Conclusion:The acquisition of MRIs in RA trials should be done in a methodical and systematic manner, where the quality of MRI scans and the correct timing of post-contrast sequences are optimized. The incorporation of unacceptable quality data will impact the interpretation of RA clinical trial data, especially when novel computer-assisted quantitative analysis methods for post-processing are used. Incorrect timing and inconsistency in image quality can be prevented by using coils covering the whole hand and/or a dynamic contrast-enhance (DCE)-MRI sequence immediately following IV Gd injection to ensure correct timing of the post-contrast MRI sequence.References:[1]Peterfy C, et al. J Rheumatol. 2019 46: 887–895.[2]Tripathi D, et al. IJRCI. 2014 2(S1):SR2. DOI: 10.15305/ijrci/v2iS1/89.Disclosure of Interests:Mikael Boesen Consultant of: AbbVie, AstraZeneca, Eli Lilly, Esaote, Glenmark, Novartis, Pfizer, UCB, Paid instructor for: IAG, Image Analysis Group, AbbVie, Eli Lilly, AstraZeneca, esaote, Glenmark, Novartis, Pfizer, UCB (scientific advisor)., Speakers bureau: Eli Lilly, Esaote, Novartis, Pfizer, UCB, Mark Hinton: None declared, Javier Gonzalez-Zabaleta: None declared, Scott Beattie Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Douglas Schlichting Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Terence Rooney Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Olga Kubassova Shareholder of: IAG, Image Analysis Group, Consultant of: Novartis, Takeda, Lilly, Employee of: IAG, Image Analysis Group

Background:Reducing structural damage is an important treatment goal for rheumatoid arthritis (RA). Demonstrating a clinically meaningful, statistically significant difference in radiographic progression (assessed by van der Heijde modified total Sharp score, mTSS) is a common objective in trials for RA treatments.Complete collection of radiographic data is challenging, especially in long term follow-up and pediatric studies. Therefore, scores for individual joints or entire patients are regularly missing. A frequently used analysis method for mTSS is the analysis of covariance model, in which missing data are imputed using linear extrapolation (ANCOVA+LE). However, other ways to deal with missing information have also been proposed.Objectives:To evaluate robust analysis methods for mTSS data.Methods:Simulated data were used to compare a random coefficient model (RC) without imputation, ANCOVA+LE and ANCOVA with last observation carry forward imputation (LOCF).A log-normal distribution was used to generate baseline patient level data to simulate a 2-arm clinical trial using baseline mTSS and rate of change in mTSS from recently completed trials. Changes in mTSS (12, 28 and 44 week timepoints) were generated under linear, concave quadratic (fast progression then slow progression), and convex quadratic (slow progression then fast progression) assumptions, with the proportion of change forced to be 0 (a proportion of simulated patients do not have progression). A monotone missing pattern was assumed to generate a data set with missing data (the ‘observed’ dataset).ANCOVA analyses were performed using baseline and treatment as predictors. The RC model was applied using baseline, treatment, time, and time-by-treatment interactions as fixed effect and time as a random effect. Bias (difference between average of simulation sample mean and true value, the smaller the better), root mean square error (RMSE, a measure of variation among simulation samples, the smaller the better), power and type I error rate were compared between methods.Results:The random coefficient model provided better or at least similar results in bias, RMSE, power and type I error rate as ANCOVA+LE under evaluated scenarios (Table 1).Progression assumptionSimulation parameters(Number of simulations = 500; common sample size=300, baseline mTSS=~11.7)ModelBiasPowerRMSELinearppbo= 0.6, rpbo= 0.065ptrt= 0.68 rpbo= 0.046Δwk44= −0.49ANCOVA + Full0.0020.9240.140ANCOVA + LE0.0030.8660.155ANCOVA+LOCF0.1540.8440.190RC + FULL0.0010.920.139RC + OBS−0.0020.8720.156Concaveppbo= 0.6, rpbo= −0.0009, qpbo= 0.11ptrt= 0.68, rtrt= −0.0011, qtrt= 0.093Δwk44= −0.611ANCOVA + Full0.0020.9820.141ANCOVA + LE−0.0020.9260.180ANCOVA+LOCF0.1880.940.222RC + FULL0.0020.9780.141RC + OBS−0.0050.9240.174Convexppbo=0.6, rpbo= 0.0037, qpbo=−0.09ptrt= 0.68, rtrt= 0.003, qtrt= −0.1Δwk44= −0.83ANCOVA + Full0.00310.139ANCOVA + LE0.3430.9480.368ANCOVA+LOCF0.3910.9740.405RC + FULL−0.00410.140RC + OBS0.1990.9880.249Abbreviations: FULL = complete dataset with no missing values trt = active treatment, OBS = the ‘observed’ dataset, pbo = placebo, p= proportion of patients with no progression, r = linear progression rate (mTSS units per week), q = quadratic term coefficient. Δ = active treatment progression – placebo rConclusion:RC is a robust analysis method for mTSS. We recommend its use in primary analyses, especially for long-term extension and pediatric studies with a higher likelihood of missing data. This method can also provide reference for time points when no data are collected via estimated slope. ANCOVA+LE can be used for sensitivity analysis.References:None.Disclosure of Interests:Robert B.M. Landewé Consultant of: AbbVie; AstraZeneca; Bristol-Myers Squibb; Eli Lilly & Co.; Galapagos NV; Novartis; Pfizer; UCB Pharma, Luna Sun Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Yun-Fei Chen Shareholder of: Own shares in Eli Lilly and Company., Employee of: Employee of Eli Lilly and Company, Douglas Schlichting Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead Sciences, Inc., Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma; Director of Imaging Rheumatology BV

BackgroundBaricitinib is an oral, reversible, selective Janus kinase 1 and 2 inhibitor.MethodsIn this phase III, double-blind 24-week study, 684 biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with rheumatoid arthritis and inadequate response or intolerance to ≥1 conventional synthetic DMARDs were randomly assigned 1:1:1 to placebo or baricitinib (2 or 4 mg) once daily, stratified by region and the presence of joint erosions. Endpoint measures included American College of Rheumatology 20% response (ACR20, primary endpoint), Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) score ≤3.3.ResultsMore patients achieved ACR20 response at week 12 with baricitinib 4 mg than with placebo (62% vs 39%, p≤0.001). Compared with placebo, statistically significant improvements in DAS28, SDAI remission, Health Assessment Questionnaire-Disability Index, morning joint stiffness, worst joint pain and worst tiredness were observed. In a supportive analysis, radiographic progression of structural joint damage at week 24 was reduced with baricitinib versus placebo. Rates of adverse events during the treatment period and serious adverse events (SAEs), including serious infections, were similar among groups (SAEs: 5% for baricitinib 4 mg and placebo). One patient had an adverse event of tuberculosis (baricitinib 4 mg); one patient had an adverse event of non-melanoma skin cancer (baricitinib 4 mg). Two deaths and three major adverse cardiovascular events occurred (placebo). Baricitinib was associated with a decrease in neutrophils and increases in low-density and high-density lipoprotein.ConclusionsIn patients with rheumatoid arthritis and an inadequate response or intolerance to conventional synthetic DMARDs, baricitinib was associated with clinical improvement and inhibition of progression of radiographic joint damage.Trial registration numberNCT01721057; Results.

Background:Baricitinib (bari) is an oral selective inhibitor of Janus kinase (JAK) 1 and 2, approved for the treatment of moderately to severely active rheumatoid arthritis (RA) in adults.Objectives:Here we update the drug’s safety profile with data up to 8.4 years of treatment.Methods:Long-term safety of bari was assessed from 9 completed randomized trials (5 Ph3, 3 Ph2, 1 Ph 1b) and 1 ongoing long-term extension (LTE) study. Incidence rates (IR) per 100 patient-years (PY) were calculated for all patients with RA treated with ≥1 dose of bari through 1-Sep-2019 (All-Bari-RA analysis set). IRs for deep vein thrombosis (DVT), pulmonary embolism (PE), and DVT and/or PE (DVT/PE) were also calculated for groups of patients while receiving bari 2mg or bari 4mg within All-Bari-RA. Major adverse cardiovascular events (MACE) were adjudicated in 5 phase 3 studies and the LTE.Results:3770 pts received bari for 13,148 PY, with a median and maximum exposure of 4.2 and 8.4 years, respectively. Overall IRs per 100 PY were: for any treatment-emergent adverse event (AE)(25.8); serious AE (including death)(7.2); temporary interruption due to AE (9.5); permanent discontinuation due to AE (4.8); death (0.52); serious infection (2.7); opportunistic infection (0.44) (excluding tuberculosis [TB], including multidermatomal herpes zoster [HZ]); TB (0.15); HZ (3.0); MACE (0.50); DVT (0.31); PE (0.24); DVT/PE (0.45); malignancies excluding non-melanoma skin cancer (NMSC) (0.90); NMSC (0.33); lymphoma (0.06); and gastrointestinal perforation (0.04). Incidence rates (IR)[95% confidence intervals] for patients while receiving bari 2mg (N=1077) and bari 4mg (N=3400) were DVT 2mg (0.38) [0.18, 0.73] and 4mg (0.30) [0.21, 0.43]; PE 2mg (0.26) [0.09, 0.56] and 4mg (0.25) [0.16, 0.36]; and DVT/PE 2mg (0.47) [0.23, 0.84] and 4mg (0.46) [0.34, 0.61]. IRs for death tended to increase in later time intervals (beyond 192 weeks). No particular cause of death contributed to this increase. For all other safety topics of interest, across 48-week treatment intervals, IRs remained stable over time. Across safety topics, IRs were consistent with previous analyses1,2.Conclusion:In this update with 3,021 additional PY of exposure, bari maintained a safety profile similar to that previously reported,1,2with no increase of IRs across safety topics through exposures up to 8.4 years.References:[1]Smolen JS et al. J Rheumatol. 2019 Jan;46(1):7-18[2]Genovese MC et al. Ann Rheum Dis. 2019 78(supp. 2):A308Table.n/NARIRTreatment emergent AE3391/377025.8Serious AE (including death)940/37707.2Temporary d/c due to AE1241/36479.5Permanent d/c due to AE644/37704.8Death69/37700.52Serious infection344/37702.7Opportunistic infection (excluding tuberculosis, including multidermatomal herpes zoster)59/37700.44Herpes zoster384/37703.0Tuberculosis20/37700.15Major adverse cardiovascular events*63/32510.50DVT41/37700.31PE32/37700.24DVT and/or PE60/37700.45Malignancies excluding NMSC120/37700.90NMSC44/37700.33Lymphoma8/37700.06Gastrointestinal perforation6/37700.04*studies with positive adjudication. AE=adverse event; D/C= discontinuation; DVT=deep vein thrombosis; IR=incidence rate; NAR=number of patients at risk; NMSC=non-melanoma skin cancer; PE=pulmonary embolismDisclosure of Interests:Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme, Josef S. Smolen Grant/research support from: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Consultant of: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Tsutomu Takeuchi Grant/research support from: Eisai Co., Ltd, Astellas Pharma Inc., AbbVie GK, Asahi Kasei Pharma Corporation, Nippon Kayaku Co., Ltd, Takeda Pharmaceutical Company Ltd, UCB Pharma, Shionogi & Co., Ltd., Mitsubishi-Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co. Ltd., Consultant of: Chugai Pharmaceutical Co Ltd, Astellas Pharma Inc., Eli Lilly Japan KK, Speakers bureau: AbbVie GK, Eisai Co., Ltd, Mitsubishi-Tanabe Pharma Corporation, Chugai Pharmaceutical Co Ltd, Bristol-Myers Squibb Company, AYUMI Pharmaceutical Corp., Eisai Co., Ltd, Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Novartis Pharma K.K., Pfizer Japan Inc., Sanofi K.K., Dainippon Sumitomo Co., Ltd., 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, Walter Deberdt Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Douglas Schlichting Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Hongsuk Song Employee of: Syneos Health under contract to Eli Lilly and Company, Daojun Mo Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Chad Walls Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Kevin Winthrop Grant/research support from: Bristol-Myers Squibb, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Pfizer Inc, Roche, UCB

OBJECTIVES: To investigate baricitinib (LY3009104, formerly INCB028050), a novel, oral inhibitor of JAK1/JAK2 in patients with moderate to severe rheumatoid arthritis (RA) despite treatment with methotrexate. METHODS: In this phase IIb study, 301 patients were randomised 2:1:1:1:1 to receive once daily doses of placebo or 1, 2, 4 or 8 mg baricitinib for 12 weeks. Patients assigned to 2, 4 and 8 mg baricitinib continued blinded treatment for an additional 12 weeks. Patients assigned to placebo or 1 mg baricitinib were reassigned to 2 mg twice daily or 4 mg once daily baricitinib between weeks 12-24. The primary endpoint was the proportion of patients in the combined 4 and 8 mg groups achieving an American College of Rheumatology 20% (ACR20) response versus placebo at week 12. RESULTS: Significantly more patients in the combined baricitinib 4 and 8 mg groups compared with placebo achieved an ACR20 response at week 12 (76% vs 41%, p

Background Baricitinib (bari), a JAK1 and JAK2 inhibitor, was efficacious in a 24-week (wk) Ph 3 study in patients (pts) with active RA and an inadequate response (IR) to conventional synthetic DMARDs (csDMARDs) (RA-BUILD) 1 . Objectives To evaluate radiographic progression of structural joint damage in RA-BUILD pts with IR or intolerance to ≥1 csDMARD over 48 wks of bari treatment in the long-term extension study, RA-BEYOND. Methods In the 24-wk RA-BUILD study, pts were randomized to placebo (PBO; N=228), bari 2mg (N=229) or bari 4mg (N=227) once daily (QD), with rescue possible from Wk16. Pts completing RA-BUILD and entering RA-BEYOND continued to receive the bari dose received at the end of RA-BUILD. Pts receiving PBO at the end of RA-BUILD were switched to bari 4mg in RA-BEYOND. Pt and investigator blinding was maintained in RA-BEYOND. Joint damage was measured using the van der Heijde modified total Sharp score (mTSS). To account for missing scores and scores obtained after rescue or discontinuation of study drug, data were analyzed using 1) linear extrapolation (LE), and 2) last observation carried forward (LOCF). The observed/LOCF method used all available observed data, including after rescue or switch, with pts analyzed according to original treatment assignment. Results Using LE, progression of mTSS, bone erosion, and joint space narrowing (JSN) at 24 and 48 wks was statistically significantly lower for both bari 2 or 4mg compared to PBO (Table). Only bari 4mg demonstrated statistically significant inhibition of progressive radiographic joint damage compared to PBO using observed/LOCF at Wk 48 or based on categorical measures. Conclusions Once daily oral bari inhibited radiographic progression of structural joint damage in pts with an IR or intolerance to csDMARDs over 48 wks of treatment. The most robust benefit across measures of radiographic progression was seen for the 4mg dose. References Dougados M et al. Ann Rheum Dis 2015;74(S2):79. Abstract LB0001. Disclosure of Interest D. van der Heijde Consultant for: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Celgene, Daiichi, Eli Lilly & Company, Galapagos, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, UCB, Employee of: Director Imaging Rheumatology BV, M. Dougados Grant/research support from: Eli Lilly & Company, Pfizer, Roche, UCB, Merck, BMS, AbbVie, Consultant for: Eli Lilly & Company, Pfizer, Roche, UCB, Merck, BMS, AbbVie, Y.-C. Chen Grant/research support from: Eli Lilly & Company, Speakers bureau: Eli Lilly & Company, M. Greenwald Grant/research support from: Eli Lilly & Company, E. Drescher: None declared, R. Klar Employee of: Quintiles Transnational, Inc, L. Xie Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, I. de la Torre Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, T. Rooney Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, S. Witt Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, D. Schlichting Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, S. DeBono Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, P. Emery Consultant for: Pfizer Inc, MSD, AbbVie, BMS, UCB, Roche, Novartis, Samsung, Eli Lilly & Company, Takeda

Background Baricitinib (bari), a JAK1 and JAK2 inhibitor, was efficacious compared to placebo (PBO) and adalimumab (ADA) in a 52-week (Wk) Ph 3 study in patients (pts) with active rheumatoid arthritis (RA) and an inadequate response (IR) to methotrexate (MTX) 1 . Objectives To evaluate changes in lipid and lipoprotein profile over 52 wks of treatment with bari or ADA compared with PBO in the aforesaid study. Methods MTX-IR pts with active RA were randomized 3:3:2 to bari 4mg once daily (QD), PBO, or ADA 40mg biweekly. Lipid profile was evaluated at baseline and at Wks 12, 24, and 52 and nuclear magnetic resonance (NMR)-measured lipoprotein particle size and number at baseline and Wk 12. Results Treatment with both bari and ADA resulted in significant mean increases from baseline to Wk 12 in total cholesterol (PBO -0.2%, bari 15%, ADA 7%), triglycerides (PBO 1%, bari 17%, ADA 12%), LDL-C (PBO -0.6%, bari 16%, ADA 9%), and HDL-C (PBO 0.8%, bari 17%, ADA 8%). These increases persisted through Wk 52. The NMR lipoprotein profile revealed similar changes for bari and ADA relative to PBO regarding an increase in large LDL, a decrease of all types of small LDL, and increases in IDL, VLDL and subfractions, and total HDL as well as large and small HDL particles (Table 1). Significant increases in total LDL particle numbers were not observed with either bari or ADA. Conclusions The increase in LDL-C and HDL-C with both bari and ADA is accompanied by an increase in large LDL, total HDL particles and a decrease in small LDL. The nature of these changes may potentially indicate a more atheroprotective profile than that of the PBO group. References Taylor et al. Arthritis Rheumatol 2015;67(suppl10). Abstract 2L. Disclosure of Interest P. Taylor Grant/research support from: UCB, GlaxoSmithKline, Celgene, Consultant for: UCB, Eli Lilly & Company, Pfizer, Galapagos, Merck, GSK, AbbVie, Takeda, BMS, E. Keystone Grant/research support from: Abbott, Amgen, AstraZeneca, BMS, F. Hoffman-La Roche Inc, Janssen, Eli Lilly & Company, Novartis, Pfizer, Sanofi-Aventis, Consultant for: Abbott, AstraZeneca, Biotest, BMS, F. Hoffmann-La Roche, Genentech, Janssen, Eli Lilly & Company, Merck, Pfizer, UCB, Speakers bureau: Abbott, Amgen, AstraZeneca, BMS Canada, F. Hoffmann-La Roche, Janssen, Pfizer, UCB, Y. Tanaka Grant/research support from: Mistubishi-Tanabe, Takeda, Chugai, Astellas, Eisai, Taisho-Toyama, Kyowa-Kirin, Abbvie, Bristol-Myers, Speakers bureau: Abbvie, Daiichi-Sankyo, Chugai, Takeda, Mitsubishi-Tanabe, Bristol-Myers, Astellas, Eisai, Janssen, Pfizer, Asahi-kasei, Eli Lilly, GlaxoSmithKline, UCB, Teijin, MSD, Santen, D. van der Heijde Consultant for: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Celgene, Daiichi, Eli Lilly & Company, Galapagos, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, UCB, Employee of: Director Imaging Rheumatology BV, J. Zhong Employee of: Quintiles Transnational, Inc, S. Thanabalasundrum Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, G. Ruotolo Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, D. Schlichting Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, T. Rooney Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, W. Macias Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, S. Zuckerman Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, S. de Bono Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, M. Weinblatt Grant/research support from: Crescendo Bioscience, Consultant for: Eli Lilly & Company, Crescendo Bioscience, Pfizer, AbbVie

Background Baricitinib (bari), a JAK1 and JAK2 inhibitor, showed significant improvements across multiple measures of disease activity as early as week (wk) 1 that were maintained through wk 52 in ph 3 studies of patients (pts) with active RA.1,2 Objectives To determine if, in bari-treated pts, early changes in disease activity predicted later achievement of low disease activity (LDA) or remission. Methods 1305 pts with inadequate response to methotrexate (MTX) were randomized in RA-BEAM (3:3:2, oral PBO/4 mg bari QD/SC injection adalimumab [ADA] Q2W, 52 wks); 584 MTX-naive pts were randomized in RA-BEGIN (4:3:4, oral MTX QW/4 mg bari QD/4 mg bari QD+MTX QW, 52 wks). Improvement from baseline (BL) to wk 4 was used to predict LDA or remission defined by Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) at wks 12/24 (bari 4 mg arm, both studies). Early responder and early nonresponder were predefined as Clinical Disease Activity Index (CDAI) improvement ≥6 and Results Compared to PBO or ADA (RA-BEAM) or MTX (RA-BEGIN), treatment with bari was associated with rapid decrease in DAS28 and CDAI from wk 1.1,2 By wk 4, 86% (RA-BEAM) and 85% (RA-BEGIN) of bari pts had a CDAI decrease ≥6. In both studies, LDA/remission rates at wks 12/24 were higher in pts with CDAI improvement ≥6 compared to pts with CDAI improvement Conclusions In RA-BEAM/RA-BEGIN, lack of early clinical response to bari 4 mg (failure to achieve CDAI improvement ≥6 at 4 wks) was associated with low rates of LDA/remission at wks 12/24. These results are consistent with similar analyses from previous ph 3 studies of bari.3 The majority of bari pts had improvement in CDAI ≥6 at wk 4; these decreases were associated with improved clinical responses at wks 12/24. Early identification of pts (4 wks) who are not likely to achieve LDA/remission may be useful in tailoring therapy to individual pts. References Taylor PC et al. Arthritis Rheumatol. 2015; 67 (suppl 10). Fleischmann R et al. Arthritis Rheumatol. 2015; 67 (suppl 10). Kremer J et al. Arthritis Rheumatol. 2015; 67 (suppl 10). Disclosure of Interest M. Weinblatt Grant/research support from: Crescendo Bioscience, Consultant for: Eli Lilly and Company, Pfizer, AbbVie, Crescendo Bioscience, P. Taylor Grant/research support from: UCB, GlaxoSmithKline, Celgene, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly and Company, Galapagos, GlaxoSmithKline, Merck, Pfizer, Takeda, USB, Y. Tanaka Grant/research support from: Mistubishi-Tanabe, Takeda, Chugai, Astellas, Eisai, Taisho-Toyama, Kyowa-Kirin, Abbvie, Bristol-Myers, Speakers bureau: Abbvie, Daiichi-Sankyo, Chugai, Takeda, Mitsubishi-Tanabe, Bristol-Myers, Astellas, Eisai, Janssen, Pfizer, Asahi-kasei, Eli Lilly, GlaxoSmithKline, UCB, Teijin, MSD, Santen, E. Keystone Grant/research support from: Abbott Laboratories, Amgen Inc., AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, Eli Lilly and Company, F. Hoffmann-La Roche Inc, Janssen Inc, Novartis Pharmaceuticals, Pfizer Pharmaceuticals, Sanofi-Aventis, UCB, Consultant for: Abbott Laboratories, AstraZeneca Pharma, Biotest, Bristol-Myers Squibb Company, Eli Lilly and Company, F. Hoffmann-La Roche Inc, Genentech Inc, Janssen Inc, Merck, Pfizer Pharmaceuticals, UCB, Speakers bureau: Abbott Laboratories, Astrazeneca LP, Bristol-Myers Squibb Canada, F. Hoffmann-La Roche Inc., Janssen Inc., Pfizer Pharmaceuticals, UCB, Amgen, M. Schiff Grant/research support from: Eli Lilly and Company, Consultant for: Eli Lilly and Company, R. Fleischmann Grant/research support from: Eli Lilly and Company, Pfizer, Consultant for: Eli Lilly and Company, Pfizer, L. Yang Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, V. Arora Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, S. de Bono Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, T. Holzkaemper Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, D. Schlichting Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, T. Takeuchi Grant/research support from: Eli Lilly and Company, Chugai Pharmaceutical Co,. Ltd, Consultant for: Eli Lilly and Company

Background Baricitinib (bari; an oral JAK 1/JAK 2 inhibitor) is in development for patients (pts) with active RA. In healthy subjects, absolute lymphocyte counts (ALC) increased after bari administration, returning to baseline (BL) by 24 hrs. 1 Objectives To examine changes in ALC and lymphocyte (LYM) subsets in pts with active RA treated with bari (4 mg QD), placebo (PBO), or adalimumab (ADA, 40 mg Q2W). Methods 1305 pts with active RA despite MTX treatment were randomized 3:3:2 to PBO, bari, or ADA. ALC, T, and B cell subsets (T: Th1, Th17, CD4, CD8, T reg, CD3+CD4+CD127-/loCD25+; B: switched/nonswitched memory, mature naive, immature transitional), and natural killer (NK) cells were quantified by flow cytometry at BL and wks 4, 12, and 24. Wk 4 phlebotomy was postdose bari or PBO; wks 12 and 24 were predose. Results ALC and T cells/subsets increased with bari and ADA at wk 4 (generally within normal ranges), returning to near BL at wks 12 and 24 in bari but remaining elevated in ADA (Table). B cells/subsets increased at wks 4 in bari and ADA and remained elevated through wk 24. NK cells were increased at wk 4 in bari and were below BL but within the normal range at wks 12 and 24; NK cells were increased at wks 12 and 24 in ADA. The percentages of pts with ≥1 low NK cell count were 20.5%, 32.6%, and 20.6% in PBO, bari, and ADA, respectively; percentage of pts with ALC CTCAE grade ≥2 were 14.1%, 9.9%, and 10.0%. Through wk 24, serious infection rates were 1.4%, 1.0%, and 0.6% for PBO, bari, and ADA; rates were 1.0%, 1.3%, and 0%, respectively, in pts with ≥1 low NK cell count and 2.9%, 4.2%, and 0% in pts with ≥1 ALC CTCAE Grade ≥2 value. Rates of herpes zoster (HZ) were 0.4%, 1.4%, and 1.2% for PBO, bari, and ADA; rates were 0%, 0.6%, and 0%, respectively, in pts with ≥1 low NK cell count and 1.4%, 2.1%, and 0% in pts with ≥1 ALC CTCAE Grade ≥2 value (no statistically significant differences between treatment groups). Conclusions Changes in ALC and subpopulations with bari in RA-BEAM were largely within normal ranges and are consistent with previous data. 2 Sustained increases in B cells were observed in bari and ADA. Sustained increases in ALC/T cells were only seen in ADA. A modest reduction in NK cells at wks 12 and 24 with bari was not associated with serious infection or HZ. References Shi JG, et al. J Clin Pharmacol. 2014;54:1354–61 Emery P, et al. Arthritis Rheumatol. 2015;67 (suppl 10) Disclosure of Interest Y. Tanaka Grant/research support from: Mistubishi-Tanabe, Takeda, Chugai, Astellas, Eisai, Taisho-Toyama, Kyowa-Kirin, Abbvie, Bristol-Myers, Speakers bureau: Abbvie, Daiichi-Sankyo, Chugai, Takeda, Mitsubishi-Tanabe, Bristol-Myers, Astellas, Eisai, Janssen, Pfizer, Asahi-kasei, Eli Lilly, GlaxoSmithKline, UCB, Teijin, MSD, Santen, R. Fleischmann Grant/research support from: Pfizer, Inc, Eli Lilly and Company, Consultant for: Eli Lilly and Company, Pfizer, M. Schiff Grant/research support from: Eli Lilly and Company, Consultant for: Eli Lilly and Company, T. Takeuchi Grant/research support from: Chugai Pharmaceutical Co., Ltd, Eli Lilly and Company, Consultant for: Eli Lilly and Company, E. Keystone Grant/research support from: Abbott Laboratories, Amgen Inc., AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, Eli Lilly and Company, F. Hoffmann-La Roche Inc, Janssen Inc, Novartis Pharmaceuticals, Pfizer Pharmaceuticals, Sanofi-Aventis, UCB., Consultant for: Abbott Laboratories, AstraZeneca Pharma, Biotest, Bristol-Myers Squibb Company, Eli Lilly and Company, F. Hoffmann-La Roche Inc, Genentech Inc, Janssen Inc, Merck, Pfizer Pharmaceuticals, UCB, Speakers bureau: Abbott Laboratories, Astrazeneca LP, Bristol-Myers Squibb Canada, F. Hoffmann-La Roche Inc., Janssen Inc., Pfizer Pharmaceuticals, UCB, Amgen, M. Weinblatt Grant/research support from: Crescendo Bioscience, Consultant for: Eli Lilly and Company, Pfizer, AbbVie, Crescendo Bioscience, S. Zuckerman Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, M. Issa Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, S. Thanabalasundrum Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, B. Augendre-Ferrante Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, S. de Bono Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, D. Schlichting Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, T. Rooney Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, W. Macias Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, P. Taylor Grant/research support from: Eli Lilly and Company, UCB, Consultant for: UCB, Eli Lilly and Company, Pfizer, Galapagos, Merck, GlaxoSmithKline, AbbVie, Takeda, Bristol-Myers Squibb

Background Regular disease activity assessment should be a key component of rheumatoid arthritis (RA) care. In patients with moderate-to-severe RA and inadequate response to methotrexate (MTX-IR) treated with baricitinib (bari) 1, 2, 4, or 8 mg in a Phase 2b double-blind study, bari demonstrated clinically and statistically significant improvements at 12 wks including DAS28-CRP 1 (Elevated high-sensitivity C-reactive protein (hsCRP) >1.2xULN or erythrocyte sedimentation rate (ESR) >28 mm/h was required at study entry. 1 ) In the same study, only modest, statistically significant improvements in a multi-biomarker disease activity score (MBDA) 2 were observed. 3 Objectives To investigate how MBDA correlates with clinical endpoints in the previously reported study. 3 Methods Post-hoc statistical analysis was conducted on combined bari 1, 2, 4, and 8 mg (n=189) and paired low (1, 2 mg; n=91) and high (4, 8 mg; n=98) doses using partial correlation analyses, which controls for effects of association with other variables, to assess the relationship between MBDA and absolute change from baseline in 13 disease activity measures. Results Mean MBDA improved from baseline to Wk 12 for each dose versus PBO, 3 but the two highest correlations were only of moderate strength: hsCRP [a component of MBDA] (r=0.60) and DAS28-CRP (r=0.43). For all other measures, associations with MBDA were significant (p Conclusions In MTX-IR patients treated with bari for 12 wks, significant changes in clinical response measures were seen but were not strongly correlated with MBDA. The highest correlations, although statistically significant, were of moderate strength. MBDA score changes did not have a strong correlation to clinical measures with bari. If these observations are corroborated they would suggest that caution is required when assessing clinical response to bari using the MBDA. References Keystone E et al. Ann Rheum Dis 2015;74(2):333–340. Segurado OG, Sasso EH. Clin Exp Rheumatol 2014;32(85):S29-S34. Taylor P et al. Ann Rheum Dis 2015;74(Suppl 2):257–258 as presented at EULAR 2015. Disclosure of Interest R. Fleischmann Grant/research support from: Eli Lilly and Company, Pfizer, Consultant for: Eli Lilly and Company, Pfizer, M. Genovese Grant/research support from: AbbVie, Astellas, Eli Lilly and Company, Galapagos, Pfizer, Vertex, Consultant for: AbbVie, Astellas, Crescendo Bioscience, Eli Lilly and Company, Galapagos, Pfizer, Vertex, E. Keystone Grant/research support from: Abbott Laboratories, Amgen Inc., AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, Eli Lilly and Company, F. Hoffmann-La Roche Inc, Janssen Inc, Novartis Pharmaceuticals, Pfizer Pharmaceuticals, Sanofi-Aventis, UCB, Consultant for: Abbott Laboratories, AstraZeneca Pharma, Biotest, Bristol-Myers Squibb Company, Eli Lilly and Company, F. Hoffmann-La Roche Inc, Genentech Inc, Janssen Inc, Merck, Pfizer Pharmaceuticals, UCB, Speakers bureau: Abbott Laboratories, Astrazeneca LP, Bristol-Myers Squibb Canada, F. Hoffmann-La Roche Inc., Janssen Inc., Pfizer Pharmaceuticals, UCB, Amgen, M. Weinblatt Grant/research support from: Crescendo Bioscience, Consultant for: Eli Lilly and Company, Pfizer, AbbVie, Crescendo Bioscience, J. Rancourt Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, E. Nantz Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, D. Schlichting Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, S. Zuckerman Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, W. Macias Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, P. Taylor Grant/research support from: Celgene, GlaxoSmithKline, UCB, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly and Company, Galapagos, GlaxoSmithKline, Merck, Pfizer, Takeda, USB

Background Baricitinib (bari), an oral JAK1 and JAK2 inhibitor, was efficacious in a Ph 3 study (RA-BEGIN) in RA patients (pts) who had limited or no exposure to methotrexate (MTX) and who were naive to other csDMARDs and bDMARDs. 1 Objectives To evaluate patient-reported outcomes (PROs) from RA-BEGIN. Methods Pts were randomized to MTX QW, bari 4 mg QD, or bari 4 mg QD+MTX QW. PROs listed in the table and the Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA) questionnaire were collected on electronic tablets during study visits. Bari vs. MTX and bari+MTX vs. MTX were assessed with ANCOVA and logistic regression models. Results 584 pts were randomized. Mean baseline PROs for MTX, bari, and bari+MTX, respectively, were HAQ-DI:1.67, 1.64, 1.58; Pt9s Global Assessment of Disease Activity (PtGDA):65.6, 65.0, 63.1; pt assessment of pain:65.2, 64.1, 62.6. Compared to MTX, bari and bari+MTX were superior in physical function, PtGDA, pain, and fatigue at Wks 24 and 52. Statistically significant improvements in all components of the WPAI-RA (absenteeism, presenteeism, work productivity loss and activity impairment) were seen in the bari and bari+MTX pts vs. MTX at Wk 24; statistically significant improvements were seen for work loss for bari+MTX vs. MTX at Wk 52 and for activity impairment for bari and bari+MTX vs MTX at Wk 52. Conclusions In this Ph 3 study of pts with early active RA, bari alone or with MTX was associated with significant improvements at 24 and 52 wks compared to MTX in most PROs. References Fleischmann et al. Arthritis Rheumatol 2015;67(S10) Disclosure of Interest M. Schiff Consultant for: AbbVie, Amgen, BMS, Eli Lilly & Company, JNJ, UCB, T. Takeuchi Consultant for: AbbVie GK; Asahi Kasei Medical K.K., Astellas Pharma, Astra Zeneca K.K., Bristol–Myers K.K., Celtrion, Chugai Pharmaceutical Co. Ltd, Daiichi Sankyo Co. Ltd, Eisai Co. Ltd, Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Nipponkayaku Co. Ltd, Novartis Pharma K.K., Pfizer Japan Inc, Santen Pharmaceutical Co. Ltd, SymBio Pharmaceuticals Ltd, Taisho Toyama Pharmaceutical Co. Ltd, Takeda Pharmaceutical Co. Ltd, Teijin Pharma Ltd, C. Gaich Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, A. DeLozier Employee of: Eli Lilly and Company, D. Schlichting Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, W.-L. Kuo Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, P. Durez Consultant for: Eli Lilly and Company, T. Carmack: None declared, J.-E. Won Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, R. Fleischmann Grant/research support from: AbbVie, Akros, Amgen, Ardea, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Genentech, Janssen, Eli Lilly & Company, Novartis, Pfizer, Regeneron, Resolve, Roche, Sanofi-Aventis, UCB, Consultant for: AbbVie, Akros, Amgen, Ardea, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Genentech, Janssen, Eli Lilly & Company, Novartis, Pfizer, Regeneron, Resolve, Roche, Sanofi-Aventis, UCB

Background and objectives Baricitinib is an oral, reversible inhibitor of Janus kinase (JAK)1/JAK2 being developed as treatment for patients with RA. Previous studies have shown transient increases in total lymphocyte count within hours of dosing and return to baseline prior to the next dose. We examined changes over time in lymphocyte subsets in RA patients treated with baricitinib or placebo in the phase 3 RA-BUILD and RA-BEACON studies. Materials and methods Patients had active RA with insufficient response (IR) to conventional synthetic DMARDs (csDMARDs) (RA-BUILD; N=684) or TNF inhibitors (TNFi) (RA-BEACON; N=527). Patients were randomised 1:1:1 to placebo or 2 or 4mg baricitinib QD for 24 weeks. Lymphocyte subsets and natural killer (NK) cells were quantified by flow cytometry at baseline and Week (wk) 4, wk12, and wk24. Total lymphocyte count was measured at each visit. Results Significant improvements in disease activity were seen for baricitinib versus placebo in both studies. Total lymphocyte increases at wk4 for baricitinib were generally within normal ranges. Change in total lymphocyte count was similar at wk12 and wk24 for baricitinib versus placebo. In RA-BUILD/RA-BEACON, increased T-cells/µL (158.3/22.6 and 124.1/170.7 for 2mg and 4mg,p ≤ 0.05), B-cells/µL (66.7/36.8 and 82.9/74.3 for 2mg and 4mg,p ≤ 0.001), and NK-cells/µL (59.5/36.8 and 46.2/77.0 for 2mg and 4mg,p ≤ 0.01) versus placebo were seen at wk4. Decreased T-cells/µL (wk12= -20.9/0.7 and -87.6/-33.1 for 2mg and 4mg; wk24 = -117.2/-128.1 and -83.4/-53.8 for 2mg and 4mg,p ≤ 0.05) and NK-cells/µL (wk12 = -36.7/-22.0 and -57.0/-22.7 for 2mg and 4mg,p ≤ 0.001 in RA-BEACON; wk24 = -41.2/-45.0 and -53.4/-40.9 for 2mg and 4mg, p ≤ 0.05 in RA-BEACON) and increased B-cells/µL (wk12 = 65.0/49.3 and 75.1/70.2 for 2mg and 4mg, p ≤ 0.001; wk24= 24.3/22.6 and 55.2/65.0 for 2mg and 4mg,p ≤ 0.001 for 4mg) were seen later for baricitinib groups. Changes in other T- and B-cell populations were variable, but generally reflected these patterns. Decreased NK-cell count did not appear to be associated with an increased incidence of infection. Conclusions Baricitinib produced significant clinical improvements in disease activity in csDMARD-IR and TNFi-IR RA patients. Improvements were accompanied by a variety of changes in lymphocyte counts, predominantly within normal ranges. Similar lymphocyte subset assessments will be available in a long-term extension study.

Background Baricitinib, an oral inhibitor of JAK1 and JAK2 signaling, improved the signs and symptoms in patients with active rheumatoid arthritis (RA) who were methotrexate inadequate responders (MTX-IR) in a double-blind, placebo (PBO) controlled study1. Objectives To investigate how a quantitative, multibiomarker disease activity score (MBDA) and its individual components are affected by treatment with baricitinib 4 mg (n=50) once daily compared to PBO (n=79) during a 12 week treatment period in moderate-to-severe RA patients. Methods Serum samples collected at baseline and Weeks 4 and 12 from patients in the study1 were shipped frozen to Crescendo Biosciences for analysis2. MBDA scores and changes in individual MBDA components were subjected to post-hoc statistical analyses. Results At baseline, the proportion of patients with low, moderate, and high MBDA scores were similar in the 2 groups, as were median MBDA scores (PBO=44 vs. baricitinib 4 mg=47). Unlike PBO-treated patients, baricitinib 4 mg patients had decreased MBDA scores at 4 and 12 weeks compared to baseline (baricitinib 4 mg =35.5 and 37.0 (p 0.05) changes for baricitinib-treated patients at either timepoint for epidermal growth factor (EGF), MMP-1, or vascular endothelial growth factor-A (VEGF-A). For baricitinib-treated patients versus PBO, at 4 but not 12 weeks, Interleukin-6 (IL-6) and resistin were significantly decreased and at 12 but not 4 weeks, leptin was significantly increased. Conclusions Consistent with other indices of disease activity1, the treatment of MTX-IR patients with baricitinib 4 mg once daily resulted in a reduction in the MBDA scores, apparent by 4 weeks. Decreases in MBDA scores and the components were present at both 4 and 12 weeks. Reduction in the levels of inflammatory markers beyond those associated with an acute phase response is apparent in these patients. References Keystone E et al., Ann Rheum Dis 2015;74(2):333-340. Curtis JR et al., Art Care Res 2012:64(12):1794-1803. Disclosure of Interest P. Taylor Consultant for: Pfizer, Eli Lilly & Company, M. Genovese Grant/research support from: Abbvie, Astellas, Eli Lilly & Company, Galapagos, Pfizer, Vertex, Consultant for: Abbvie, Astellas, Eli Lilly & Company, Galapagos, Pfizer, Vertex, E. Keystone Grant/research support from: Abbott Laboratories, Amgen Inc., AstraZeneca Pharmaceuticals LP, Bristol-Meyers Squibb, F. Hoffman-La Roche Inc., Janssen Inc., Eli Lilly & Company, Novartis Pharmaceuticals, Pfizer Pharmaceuticals, Sanofi-Aventis, UCB, Consultant for: Abbott Laboratories, AstraZeneca Pharmaceuticals LP, Biotest, Bristol-Meyers Squibb, F. Hoffman-La Roche Inc., Genentech, Janssen Inc., Eli Lilly & Company, Merck, Pfizer Pharmaceuticals, UCB, Speakers bureau: Abbott Laboratories, Astrazeneca LP, Bristol-Meyers Squibb Canada, F. Hoffman-La Roche Inc., Janssen Inc., Pfizer Pharmaceuticals, UCB, Amgen, M. Weinblatt Grant/research support from: Bristol-Meyers Squibb, Crescendo Bioscience, UCB, Consultant for: Abbvie, Amgen, Astra Zeneca, Bristol-Meyers Squibb, Crescendo Bioscience, Eli Lilly & Company, Pfizer, Roche, UCB, J. Rancourt Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, E. Nantz Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, D. Schlichting Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, S. Zuckerman Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, W. Macias Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company

Background In ph 2 studies, baricitinib (bari) improved disease activity with an acceptable safety profile in patients (pts) with active RA and inadequate response (IR) to conventional DMARDs (cDMARDs). Objectives To report results from a 24-week (Wk) global ph 3 study of bari in pts with active RA and an IR or intolerance to ≥1 cDMARD. Methods Pts with active RA (TJC & SJC≥6 & hsCRP≥3.6 mg/L) with stable background treatment were randomized 1:1:1 to placebo (PBO) or bari (2 or 4 mg) QD, stratified by region and baseline joint erosion status, with rescue from Wk 16 for nonresponders. Primary endpoint was ACR20 response at Wk 12 for bari 4 mg vs. PBO. Results Of 684 randomized pts, 81% were seropositive with mean baseline DAS28 of 5.55 (-hsCRP) and 6.22 (-ESR). Rescue rates were 9%, 7%, and 24% for bari 2 mg, 4 mg, PBO, respectively. ACR20 response at Wk 12 was 62% with bari 4 mg vs. 40% with PBO (p≤0.001). Improvements in ACR50, ACR70, DAS28, CDAI, SDAI, and HAQ-DI were seen (Table), many as early as Wk 1. Change in mTSS at Wk 24 was lower with bari 2 or 4 mg vs. PBO (p≤0.05, p≤0.01, respectively). TEAE and SAE rates, including serious infections, were similar among pts receiving bari 2 or 4 mg or PBO (SAEs: 3%, 5%, 5%, respectively). There were no GI perforations or opportunistic infections. In the bari 4 mg group, 1 TB case and 1 NMSC case occurred. In the PBO group, 2 deaths and 2 MACE occurred. Lab findings were similar to ph 2; few abnormalities led to discontinuation. Conclusions Once daily oral bari was associated with rapid and sustained clinical improvement and inhibition of radiographic joint damage, with an acceptable safety and tolerability profile. The most robust benefit across measures was seen with the 4 mg dose. Disclosure of Interest M. Dougados Grant/research support from: Eli Lilly and Company, AbbVie, Pfizer, UCB, Bristol-Myers Squibb, Novartis, Sanofi, and Roche, Consultant for: Eli Lilly and Company, AbbVie, Pfizer, UCB, Bristol-Myers Squibb, Novartis, Sanofi, and Roche, D. van der Heijde Consultant for: AbbVie, Amgen, AstraZeneca, Augurex, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli Lilly and Company, Galapagos, GSK, Janssen Biologics, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB, and Vertex, Y.-C. Chen Grant/research support from: Eli Lilly and Company, Speakers bureau: Eli Lilly and Company, AbbVie, Pfizer, and Bristol-Myers Squibb, M. Greenwald Grant/research support from: Eli Lilly and Company, E. Drescher: None declared, J. Liu Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, S. Beattie Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, I. de la Torre Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, T. Rooney Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, D. Schlichting Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, S. de Bono Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, P. Emery Consultant for: Abbott/AbbVie, Bristol-Myers Squibb, Pfizer, UCB, MSD, Roche, Novartis, Samsung, Takeda, and Eli Lilly and Company

Background In ph 2 studies, baricitinib (bari) improved disease activity with an acceptable safety profile in pts with active RA naive to biologic DMARDs (bDMARDs). 1,2 Objectives To report patient-reported outcomes (PRO) from a ph 3 study of bari in pts with active RA on 1 or 2 conventional DMARDs (cDMARDs) and an inadequate response or intolerance to ≥1 TNF inhibitors. Methods Pts were randomized 1:1:1 to placebo (PBO) or bari (2 or 4 mg) QD for 24 wks. PROs are listed in the table. Analyses included ANCOVA, logistic regression, and nonparametric methods and compared bari 2 or 4 mg vs. PBO. Results 527 pts were randomized. Assessment of PROs at baseline revealed severe impairment of physical function (HAQ-DI: 1.7-1.8) and QoL. Bari 2 and 4 mg resulted in statistically significant improvements from baseline vs. PBO in most PROs at 24 wks (Table). Conclusions In this ph 3 study of pts with active RA on cDMARDs and an inadequate response to bDMARDs, bari was associated with significant improvement in most PROs through 24 wks compared to PBO. References Keystone et al. Ann Rheum Dis 2015;74:333-340. Tanaka et al. Arthritis Rheum 2013;65(S10):S765. Disclosure of Interest J. Smolen Grant/research support from: Abbvie, Janssen, MSD, Pfizer, Roche, UCB, Consultant for: Abbvie, Amgen, Astra-Zeneca, Astro, Celgene, Glaxo, Janssen, Lilly, Medimmune, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB, J. Kremer Grant/research support from: Abbvie, Amgen, BMS, Genentech, Lilly, Pfizer and UCB, Employee of: Part time employment with Corrona, C. Gaich Employee of: Eli Lilly and Company, A. DeLozier Employee of: Eli Lilly and Company, D. Schlichting Employee of: Eli Lilly and Company, L. Xie Employee of: Eli Lilly and Company, M. Genovese Grant/research support from: Abbvie, Astellas, Eli Lilly and Company, Galapagos, Pfizer, and Vertex

Background Baricitinib, a novel oral JAK1/2-inhibitor, was evaluated in a Phase 2b study in patients with moderate-to-severe RA. The primary ACR20 12-week-endpoint was met, and maintained through 24 weeks. 1 Objective To evaluate changes in serum LDL, HDL, and total cholesterol over 24 weeks of baricitinib treatment compared with placebo. Methods Patients were randomised to QD dosing with placebo (n = 98) or 1, 2, 4, or 8 mg of baricitinib with ˜50 patients per treatment arm. Serum lipids were determined at screening, baseline and at Weeks 2, 4, 8, 12, 14, 16, 20, 24, and particle size and number were determined by Nuclear Magnetic Resonance (NMR) at baseline, Weeks 12/24. Results Baricitinib treatment resulted in dose- and time-dependent increase relative to placebo in LDL, HDL and total cholesterol detectable by Week-2. The mean percent increase in total cholesterol in the combined baricitinib arms was 9.5% (p Conclusions The increase in LDL-cholesterol with baricitinib treatment is attributed to a shift towards larger particles rather than an overall increase in LDL-particle number at Week-12 and persisting through 24 weeks, while changes observed in HDL-cholesterol were associated with an increase in total number of HDL-particles. 1 Reference Genovese MC, Keystone E, Taylor P, et al . Arthritis Rheum 2012; 64 :2487.

Treatment with baricitinib (bari), an oral inhibitor of JAK1/JAK2, demonstrated improvements in signs and symptoms of RA through 52 wks in a Phase 2b study, 1 and also in dose- and time-dependent changes in serum lipids, LDL particle size and HDL and VLDL particle numbers. 2 Increases in HDL, but not LDL cholesterol, correlated with decreases in CRP at Wk 12. Changes in serum cholesterol, in apolipoprotein content of LDL, VLDL, and HDL particles were evaluated. Patients (pts) with RA were randomised to QD doses of placebo (PBO) (n = 98) or bari 1 mg (n = 49), 2 mg (n = 52), 4 mg (n = 52), or 8 mg (n = 50) for 12 wks. Pts assigned to 2-, 4-, or 8-mg bari continued blinded treatment for an additional 12 wks. Serum samples were collected through 52 wks for conventional lipid determinations (total cholesterol, LDL, HDL, and triglycerides). Apolipoprotein content was assessed at Wks 4 and 12 for PBO, 4-, and 8-mg bari groups. Pts treated with bari through 52 wks maintained a stable cholesterol and triglyceride profile with no further changes beyond Wks 12 and 24. Increases in apolipoprotein A-I, apolipoprotein B, and total apolipoprotein CIII were observed with 4- and 8-mg bari with no increase in LDL-associated apolipoprotein CIII. Bari treatment also demonstrated a significant reduction in HDL-associated SAA at the 4- and 8-mg doses compared to PBO while a significant reduction in Lp (a) was observed only in the 8-mg bari group (all p In addition to increases in serum cholesterol and lipoprotein particle number (HDL and VLDL) and size (LDL), there were changes in apolipoprotein content of these particles in pts treated with bari. The increase in HDL cholesterol with bari treatment correlated with an improvement in DAS28-CRP. References Taylor P, Genovese MC, Keystone E, et al . Ann Rheum Dis 2013; 72 :A65–A66. Kremer J, Genovese M, Keystone E, et al . Baricitinib effects on serum cholesterol and circulating lipid particles in a Phase 2b study in patients with rheumatoid arthritis [abstract]. Ann Rheum Dis 2013; 72 (Suppl 3):241.

Background Baricitinib, a novel, oral inhibitor of JAK1/JAK2 in the JAK-STAT signaling pathway, was evaluated in a blinded Phase 2b study in Japanese patients (pts) with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX). Objectives The primary objective was to evaluate the efficacy of baricitinib as determined by the combined proportion of pts in the 4- and 8-mg dose groups who achieved an ACR20 response compared to placebo at Week 12. Methods Pts were randomized 2:1:1:1:1 to receive placebo (PBO) or 1 of 4 once-daily baricitinib doses (1, 2, 4, or 8 mg, respectively) for 12 weeks. Results Of the 145 pts randomized, 77% of the combined 4- and 8-mg (67% of the 4-mg and 88% of the 8-mg dose) groups achieved ACR20 responses compared with 31% of PBO-treated pts (p≤0.001) at Week 12. Significant differences versus PBO (p 9 /L) from baseline at 12 weeks were -0.25, -0.32, -0.60, -1.12, and -0.48 for PBO, 1-, 2-, 4-, and 8-mg groups, respectively. Dose-related increases from baseline (median) in serum creatinine and both HDL- and LDL-cholesterol were observed at 12 weeks, with the largest changes observed for the 8-mg group. Dose-dependent changes in several bone metabolic markers were also observed. Conclusions Clinical efficacy was demonstrated in this Phase 2b study of baricitinib in combination with background MTX in Japanese RA pts through 12 weeks. Safety signals observed through 12 weeks were consistent with a previous study of baricitinib in non-Japanese pts with RA. 1 References Keystone et al. Ann Rheum Dis 2012; 71(Suppl3):152 Acknowledgements Study sponsored by Eli Lilly Japan K.K. Disclosure of Interest : Y. Tanaka Grant/research support: Bristol-Meyers Squibb, Mitsubishi Tanabe Pharma, AbbVie, MSD, Chugai Pharmaceutical, Astellas Pharma, Daiichi Sankyo, Consultant for: Mitsubishi Tanabe Pharma, Eisai, Chugai Pharmaceutical, Abbott Japan, Astellas Pharma, Daiichi Sankyo, AbbVie, Janssen Pharmaceuticals, Pfizer Japan, Takeda Pharmaceutical Company Limited, AstraZeneca, Eli Lilly Japan, GlaxoSmithKline, Quintiles, MSD, and Asahi Kasei Pharma, K. Emoto Shareholder of: Eli Lilly Japan K.K., Employee of: Eli Lilly Japan K.K., M. Tsujimoto Employee of: Eli Lilly Japan K.K., D. Schlichting Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, W. Macias Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company DOI 10.1136/annrheumdis-2014-eular.1366

Background Baricitinib (formerly LY3009104/INCB028050) is a novel, oral inhibitor of JAK1 and JAK2 in the JAK-STAT signalling pathway being investigated as a treatment for rheumatoid arthritis (RA). Objectives To report 52 week safety and efficacy findings of an open label extension of the phase 2b study. Methods Patients (Pts) were initially randomised to placebo (PBO) or 1of 4 once-daily (QD) baricitinib doses (1, 2, 4, or 8 mg) for 12 wks. Pts assigned to 2 mg, 4 mg or 8 mg continued assigned treatment and pts assigned to placebo or 1 mg were reassigned to 4 mg QD or 2 mg BID for an additional 12 weeks of blinded treatment. In the open label portion of the study, patients in 8 mg group continued to receive 8 mg QD and all other patients received 4 mg QD. Doses could be escalated to 8 mg QD at 28 or 32 weeks at the investigator’s discretion when >6 tender and swollen joints were present. Analyses reported here include data through 52 weeks for patients treated in the open-label extension (non-responder imputation used for discontinued patients). Results Of the 212 pts eligible to participate, 201(95%) pts entered the open label extension, 184 patients completed 52 weeks of treatment, 15 pts discontinued, and 2 pts had not yet completed 52 weeks. Among pts who remained on 4 mg (n = 108), TEAEs occurred in 57 (53%), SAEs in 14 (13%), infections in 34 (31%) and serious infections in 4 (4%). Among pts who received 8 mg at any time (n = 93), TEAEs occurred in 59 (63%), SAEs in 8 (9%), infections in 37 (40%) and serious infections in 2 (2%). No opportunistic infections or TB cases were observed. There was one death due to myocardial infarction in the 8 mg group. Among all patients combined in the open label extension, the proportions of pts achieving ACR20, ACR50, ACR70, CDAI Remission, SDAI Remission, DAS28CRP ≤3.2, DAS28CRP Conclusions Among pts completing 52 weeks of a phase 2b study, clinical improvements observed at week 24 were maintained or improved during the open label extension. Safety signals observed over the open label extension were consistent with previously reported results of baricitinib. Reference 1.1. EULAR 2013, Ann Rheum Dis 2013;72 Supplement 3:65, Genovese et al.