Artigos de revistas sobre o tema "Finch, Pruyn and Company, Inc"

Background:The oral, potent, selective JAK1 inhibitor filgotinib (FIL) showed favorable efficacy at week (W)12 and W24 of treatment for rheumatoid arthritis (RA) compared with methotrexate (MTX) monotherapy (mono) in FINCH 3 (NCT02886728) and with placebo (PBO) or adalimumab (ADA) in FINCH 1 (NCT02889796).Objectives:50% clinical improvement from baseline at W12 is a key checkpoint for RA treatment.1These post hoc analyses evaluated FIL treatment effect on improvement in ACR components at W12 and remission at W24 in FINCH 3 and FINCH 1.Methods:FINCH 3 and FINCH 1 were global, phase 3, double-blind studies in patients (pts) with active RA. In FINCH 3, MTX-naïve pts were randomised 2:1:1:2 to once-daily (QD) oral FIL 200 mg + weekly MTX, FIL 100 mg + MTX, FIL 200 mg mono + PBO, or PBO + MTX mono up to W52. In FINCH 1, pts with inadequate response to MTX (MTX-IR) on a background of stable MTX were randomised (3:3:2:3) to oral FIL 200 or 100 mg QD, subcutaneous ADA 40 mg Q2W, or PBO up to W52. Post hoc analyses evaluated proportions of pts with 50% improvement from baseline in each ACR component and in all 7 ACR components (ACR50c) at W12, and proportions of pts with ACR50c at W12 achieving clinical remission at W24. Comparisons between treatments were not adjusted for multiplicity; subgroup comparisons are descriptive.Results:Analyses included 1249 pts in FINCH 3 and 1755 pts in FINCH 1. Greater proportions of pts receiving FIL 200 mg + MTX, FIL 100 mg + MTX, or FIL mono (FINCH 3) vs MTX mono (FINCH 3) or PBO + MTX (FINCH 1)—and numerically higher proportions of pts receiving FIL 200 mg + MTX vs FIL 100 mg + MTX (both studies) or ADA + MTX (FINCH 1)—achieved ACR50c and individual components at W12 (Table). Proportions of pts achieving CDAI ≤2.8 (Figure 1) or Boolean remission (Figure 2) at W24 were higher for pts with vs without ACR50c at W12 (Figures 1–2).Table.Proportions of patients with 50% improvement in each ACR component and ACR50c at week 12ACR componentSJC66TJC68PainPGASGAHAQ-DIhsCRPACR50cFINCH 3FIL 200 mg + MTX82.2***76.9***59.2***72.8***56.5***54.9***59.1***26.2***FIL 100 mg + MTX81.2***74.4***48.5*68.1*46.9**49.5***58.5***19.3***FIL 200 mg mono82.9***75.7***47.6*66.2*47.1**47.3**59.5***22.9***MTX mono67.159.639.258.435.635.633.76.0FINCH 1FIL 200 mg + MTX83.2***,+77.9***,+50.1***,+67.4***48.2***42.1***,+67.2***,+++18.5***FIL 100 mg + MTX77.9***72.3***45.1***62.9***43.2***35.2***55.0***12.5***ADA + MTXa76.970.541.561.542.034.455.713.8PBO + MTX66.759.228.050.928.023.125.92.5aNot formally compared vs PBO + MTX.*, p <0.05;**, p <0.01;***, p <0.001 vs MTX mono (FINCH 3) or PBO + MTX (FINCH 1);+, p <0.05;+++, p <0.001 vs ADA + MTX (FINCH 1); not adjusted for multiplicity.ACR50c, 50% improvement from baseline in all ACR components; ADA, adalimumab; FIL, filgotinib; MTX, methotrexate; mono, monotherapy; PBO, placebo.Conclusion:In MTX-naïve and MTX-IR pts with RA, FIL treatment was more effective vs MTX (FINCH 3) or PBO (FINCH 1) for achieving ACR50c at W12—a potential predictor of remission at W24. Proportions of pts achieving ACR50c at W12 were numerically higher for pts receiving FIL 200 mg + MTX vs FIL 100 mg + MTX (both studies) or ADA + MTX (FINCH 1).References:[1]Smolen JS, et al.Ann Rheum Dis. 2017;76:960–77.Disclosure of Interests:Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Daniel Aletaha Grant/research support from: AbbVie, Novartis, Roche, Consultant of: AbbVie, Amgen, Celgene, Lilly, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi Genzyme, Speakers bureau: AbbVie, Celgene, Lilly, Merck, Novartis, Pfizer, Sanofi Genzyme, UCB, Janet Pope Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly & Company, Merck, Roche, Seattle Genetics, UCB, Consultant of: AbbVie, Actelion, Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eicos Sciences, Eli Lilly & Company, Emerald, Gilead Sciences, Inc., Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, UCB, Speakers bureau: UCB, Yoshiya Tanaka Grant/research support from: Asahi-kasei, Astellas, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Pfizer, and Ono, Consultant of: Abbvie, Astellas, Bristol-Myers Squibb, Eli Lilly, Pfizer, Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Sanofi, UCB, and Teijin, Patrick Durez Speakers bureau: AbbVie, Bristol-Myers Squibb, Celltrion, Eli Lilly, Pfizer, Sanofi, Antonio Gomez-Centeno: None declared, Alena Pechonkina Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Beatrix Bartok Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Franziska Matzkies Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Lei Ye Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Zhaoyu Yin Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Robin Besuyen Shareholder of: Galapagos, Employee of: Galapagos, William Rigby Grant/research support from: Bristol-Myers Squibb, Consultant of: AbbVie, Bristol-Myers Squibb, Genentech, Pfizer, Bernard Combe Grant/research support from: Novartis, Pfizer, Roche-Chugai, Consultant of: AbbVie; Gilead Sciences, Inc.; Janssen; Eli Lilly and Company; Pfizer; Roche-Chugai; Sanofi, Speakers bureau: Bristol-Myers Squibb; Gilead Sciences, Inc.; Eli Lilly and Company; Merck Sharp & Dohme; Pfizer; Roche-Chugai; UCB

Background:Filgotinib (FIL) is an oral, potent, selective JAK1 inhibitor. FINCH 1 (NCT02889796) assessed FIL efficacy and safety in patients (pts) with rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX-IR); primary outcome results at week (W)12 and W24 were previously reported.1Objectives:To present FINCH 1 W52 results.Methods:This global, phase 3, double-blind, active- and placebo (PBO)-controlled study randomised MTX-IR pts with active RA on a background of stable MTX 3:3:2:3 to oral FIL 200 mg or FIL 100 mg once daily, subcutaneous adalimumab (ADA) 40 mg every 2W, or PBO up to W52; pts receiving PBO at W24 were rerandomised to FIL 100 or 200 mg. Efficacy was assessed from clinical, radiographic, and pt-reported outcomes; W52 comparisons were not adjusted for multiplicity. Safety endpoints included adverse events (AEs) and laboratory abnormalities.Results:Of 1755 treated pts, 1417 received study drug through W52. The majority (81.8%) were female, mean (standard deviation [SD]) RA duration was 7.8 (7.6) years, and baseline mean (SD) DAS28(CRP) was 5.7 (0.9). FIL efficacy was sustained through W52; 54%, 43%, and 46% of pts receiving FIL 200 and 100 mg and ADA, respectively, had W52 DAS28(CRP) <2.6 (nominal p for FIL 200 vs ADA = 0.024) (Figures 1–2, Table 1). FIL safety profile through W52 was consistent with W24 data. AEs of interest were infrequent and balanced among treatments (Table 2); 82 pts (4.7%) discontinued treatment due to AEs.Table 1.Efficacy outcomes at week 52FIL 200 mg(n = 475)FIL 100 mg(n = 480)ADA(n = 325)ACR20/50/70, %78/62/4476/59/3874/59/39DAS28(CRP) ≤3.2, %66+5959mTSSa0.18+++0.450.61HAQ-DIb−0.93+−0.85−0.85SF-36 PCSb12.011.512.4FACIT-Fb11.912.211.7aLeast squares mean change from baseline.bMean change from baseline.+p <0.05,+++p <0.001 vs ADA; not adjusted for multiplicity.ADA, adalimumab; FIL, filgotinib; mTSS, modified van der Heijde TSS.Table 2.Treatment-emergent AEs through week 52Event, n (%)FIL 200(n = 475)FIL 100 mg(n = 480)ADA(n = 325)All AEs352 (74.1)350 (72.9)239 (73.5)Serious AEs35 (7.4)40 (8.3)22 (6.8)Infection206 (43.4)194 (40.4)129 (39.7)Serious infection13 (2.7)13 (2.7)10 (3.1)Herpes zoster6 (1.3)4 (0.8)2 (0.6)VTE1 (0.2)01 (0.3)MACE (adjudicated)02 (0.4)1 (0.3)Malignancy (excluding NMSC)2 (0.4)2 (0.4)2 (0.6)NMSC1 (0.2)1 (0.2)0Death3 (0.6)1 (0.2)1 (0.3)Data omitted for patients rerandomised from placebo to FIL.ADA, adalimumab; AE, adverse event; FIL, filgotinib; MACE, major adverse cardiovascular event; NMSC, nonmelanoma skin cancer; VTE, venous thromboembolism.Conclusion:Through W52, both FIL 200 and 100 mg showed sustained efficacy based on clinical and pt-reported outcomes and radiographic progression and were well tolerated in MTX-IR pts with RA, with faster onset and numerically greater efficacy for FIL 200 vs 100 mg.References:[1]Combe et al.,Ann Rheum Dis.2019; 78 (Suppl 2):77–8.Disclosure of Interests:Bernard Combe Grant/research support from: Novartis, Pfizer, Roche-Chugai, Consultant of: AbbVie; Gilead Sciences, Inc.; Janssen; Eli Lilly and Company; Pfizer; Roche-Chugai; Sanofi, Speakers bureau: Bristol-Myers Squibb; Gilead Sciences, Inc.; Eli Lilly and Company; Merck Sharp & Dohme; Pfizer; Roche-Chugai; UCB, Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim,,Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Yoshiya Tanaka Grant/research support from: Asahi-kasei, Astellas, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Pfizer, and Ono, Consultant of: Abbvie, Astellas, Bristol-Myers Squibb, Eli Lilly, Pfizer, Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Sanofi, UCB, and Teijin, 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, J-Abraham Simon-Campos: None declared, Herbert S.B. Baraf Grant/research support from: Horizon; Gilead Sciences, Inc.; Pfizer; Janssen; AbbVie, Consultant of: Horizon; Gilead Sciences, Inc.; Merck; AbbVie, Speakers bureau: Horizon, Uma Kumar: None declared, Franziska Matzkies Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Beatrix Bartok Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Lei Ye Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Ying Guo Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Chantal Tasset Shareholder of: Galapagos (share/warrant holder), Employee of: Galapagos, John Sundy Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Angelika Jahreis Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Neelufar Mozaffarian Shareholder of: Gilead, Employee of: Gilead, Robert B.M. Landewé Consultant of: AbbVie; AstraZeneca; Bristol-Myers Squibb; Eli Lilly & Co.; Galapagos NV; Novartis; Pfizer; UCB Pharma, Sang-Cheol Bae: None declared, Edward Keystone Grant/research support from: AbbVie; Amgen; Gilead Sciences, Inc; Lilly Pharmaceuticals; Merck; Pfizer Pharmaceuticals; PuraPharm; Sanofi, Consultant of: AbbVie; Amgen; AstraZeneca Pharma; Bristol-Myers Squibb Company; Celltrion; F. Hoffman-La Roche Ltd.; Genentech, Inc; Gilead Sciences, Inc.; Janssen, Inc; Lilly Pharmaceuticals; Merck; Myriad Autoimmune; Pfizer Pharmaceuticals, Sandoz, Sanofi-Genzyme, Samsung Bioepsis., Speakers bureau: AbbVie; Amgen; Bristol-Myers Squibb; Celltrion; F. Hoffman-La Roche Ltd, Janssen, Inc; Merck; Pfizer Pharmaceuticals; Sanofi-Genzyme; UCB, Peter Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB

Background:In the FINCH 1 study, filgotinib (FIL)—an oral, potent, selective Janus kinase 1 inhibitor—in combination with methotrexate (MTX) provided significant improvements in the signs and symptoms of rheumatoid arthritis (RA) in patients (pts) with inadequate response to MTX.1While EULAR guidelines recommend a treat-to-target approach focusing on reducing inflammation to prevent joint damage, physical disability, and mortality, pts consider control of pain and fatigue, along with maintenance of physical function and health-related quality of life (HRQoL), to be important aspects for their care.2,3Objectives:To evaluate the rate and magnitude of change in patient-reported outcomes (PROs) from FINCH 1.Methods:In the FINCH 1 study (NCT02889796), pts with active RA received oral FIL 200 mg + MTX, FIL 100 mg + MTX, PBO + MTX, or subcutaneous adalimumab (ADA) 40 mg + MTX for up to 52 weeks (W); pts receiving PBO at W24 were rerandomised 1:1 to FIL 100 or 200 mg. PROs included the HAQ-DI and VAS pain scale, SF-36, and FACIT-Fatigue questionnaire. The change from baseline (CFB) at each time point was assessed up to W52 for each treatment group. The mixed-effects model for repeated measures was used to compare each FIL group with PBO for the CFB at each time point through W24. The logistic regression model was used to compare each FIL group with PBO for the proportion of pts achieving the minimum clinically important difference (MCID) of ≥0.22 reduction in CFB in HAQ-DI at each time point through W24.Results:Of 1755 pts randomised and treated (475 FIL 200 mg + MTX; 480 FIL 100 mg + MTX; 325 ADA + MTX; and 475 PBO + MTX), 1417 (80.7%) received study drug through W52. As early as W2 through W24, pts receiving either dose of FIL experienced nominally significantly greater (p <0.001) CFB in HAQ-DI and VAS pain scale than those receiving PBO; CFB improvements were maintained through W52 (Fig 1A, B). At W2, compared with PBO (40.2%), a nominally significantly greater proportion of pts achieved the HAQ-DI MCID in both the FIL 200 (52.5%; p <0.001) and 100 mg (46.7%; p = 0.043) groups. This benefit vs PBO was maintained up to W24 and the proportion of pts who achieved a HAQ-DI reduction of ≥0.22 remained ≥75.8% in the FIL 200 mg group and ≥71.5% in the FIL 100 mg group from W12 through W52. FIL provided nominally significantly greater improvement in HRQoL vs PBO at W4 and W12 for both the CFB of the SF-36 Physical Component Summary (PCS) (p <0.001) and Mental Component Summary (MCS) (p ≤0.006); nominal significance was also seen at W24 for CFB of SF-36 PCS (Fig 2A, B). By W4, pts receiving either dose of FIL reported a nominally significantly greater mean CFB in FACIT-Fatigue scores vs PBO (p <0.001); significance was maintained through W24 and improvement in reported fatigue continued through W52 in the FIL groups (Fig 2C). In general, CFB for HAQ-DI, VAS pain scale, and FACIT-Fatigue observed for the FIL groups was higher or comparable to ADA at various time points (Fig 1, 2).Conclusion:Both doses of FIL provided rapid and sustained improvements in functional status, pain, HRQoL, and fatigue compared with PBO for pts with RA and inadequate response to MTX throughout the 52-week period.References:[1]Combe BG, et al.Ann Rheum Dis.2019;78 (Suppl 2):A77.[2]Fautrel B, et al.Rheumatol Int.2018;38:935–47.[3]Smolen JS, et al.Ann Rheum Dis.2017;76:960–77.Disclosure of Interests:Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim,,Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Yoshiya Tanaka Grant/research support from: Asahi-kasei, Astellas, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Pfizer, and Ono, Consultant of: Abbvie, Astellas, Bristol-Myers Squibb, Eli Lilly, Pfizer, Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Sanofi, UCB, and Teijin, Susan Lee Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Lei Ye Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Hao Hu Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Robin Besuyen Shareholder of: Galapagos, Employee of: Galapagos, Bernard Combe Grant/research support from: Novartis, Pfizer, Roche-Chugai, Consultant of: AbbVie; Gilead Sciences, Inc.; Janssen; Eli Lilly and Company; Pfizer; Roche-Chugai; Sanofi, Speakers bureau: Bristol-Myers Squibb; Gilead Sciences, Inc.; Eli Lilly and Company; Merck Sharp & Dohme; Pfizer; Roche-Chugai; UCB

Background:Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that affects 1% of the world’s population. Several key biological functions are dysregulated in RA, manifesting clinically as pain, fatigue, and synovitis, with articular destruction, organ-based comorbidities, and functional decline. Defining immune dysregulation in the peripheral blood of patients (pts) with RA will help inform future work to assess the extent to which immune homeostasis can be therapeutically achieved for these pts.Objectives:To identify baseline molecular characteristics of the peripheral immune system, at the level of individual immune cell subsets, in pts with RA recruited to clinical trials of the oral, selective Janus kinase 1 (JAK1) inhibitor, filgotinib.Methods:Peripheral blood mononuclear cells (PBMC) were collected from 324 pts with moderate to severely active RA, who had an inadequate response to methotrexate ([MTX], FINCH-1;NCT02889796; n=109) or who were MTX naïve (FINCH-3;NCT02886728; n=215). PBMC were also collected from 50 demographically matched healthy volunteers (HV). The Immune Profiler platform was used to sort PBMC into 24 immune cell subsets, then quantify their gene expression and chromatin accessibility using RNA-seq and the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), respectively. Differentially expressed genes (DEGs) and differentially accessible regions (DARs) were identified among immune cell subsets from pts with RA versus HV. Gene set signature scores of Molecular Signatures Database hallmark pathways were calculated using single sample gene set enrichment analysis (ssGSEA) to examine differences in pathway activity between groups.Results:A total of 14,500 sequencing datasets were generated from the pt and HV immune cell subsets. Among these, over 26,000 DEGs and 220,000 DARs were identified in RA versus HV (false discovery rate <0.05) across the 24 immune cell subsets. DEGs were identified in all immune cell subsets tested and were most pronounced in natural killer (NK) subsets; most DARs were detected in myeloid and NK subsets. ssGSEA revealed differential pathway signaling in RA versus HV across multiple functions at the immune cell subset level. Myeloid subsets from pts with RA often showed elevated pathway activities versus HV whereas B, T and NK subsets showed a general decrease. In particular, monocyte populations from pts with RA versus HV had elevated pathway activities involved in inflammatory response and interleukin-6/Janus kinase/signal transducer and activator of transcription 3 signaling. The B, T and NK subsets showed a general decrease in tumor necrosis factor-α signaling; conversely, monocyte subsets showed an increase. Prior MTX exposure did not have a notable impact on the detected molecular profile.Conclusion:Differences in gene expression, hallmark pathway activity, and chromatin accessibility were identified in RA versus HV at the immune cell subset level. Significant contributions to differences in chromatin accessibility identified in the myeloid and NK cell populations suggest that there are more active regulatory sequences in these cell types that are associated with RA. Further investigations based on these findings may increase understanding of the immune regulatory paradigm in the context of RA.Acknowledgments:This study was funded by Gilead Sciences, Inc. Editorial support was provided by Fishawack Communications Inc and funded by Gilead Sciences, Inc.Disclosure of Interests:Peter C. Taylor Grant/research support from: Celgene, Eli Lilly and Company, Galapagos, and Gilead, Consultant of: AbbVie, Biogen, Eli Lilly and Company, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Roche, and UCB, Jinfeng Liu Shareholder of: Gilead Sciences Inc., Roche, Employee of: Gilead Sciences Inc., Luting Zhuo Employee of: Gilead Sciences Inc., Yuan Tian Employee of: Gilead Sciences Inc., Thomas Snyder Employee of: Verily Life Sciences, Charlie Kim Employee of: Verily Life Sciences, Pouya Kheradpour Employee of: Verily Life Sciences, Kat Drake Employee of: Verily Life Sciences, Sam Kim Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Rachael E. Hawtin Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc.

Background:EULAR guidelines recommend a treat-to-target approach focusing on reducing inflammation to prevent joint damage, physical disability, and mortality.1However, patients consider reduction in pain and fatigue, along with maintenance of physical function, and improvement in health-related quality of life (HRQoL) important areas for improvement with RA treatment.2In the FINCH 2 study, filgotinib (FIL)—a potent, selective, oral small molecule Janus kinase 1 inhibitor—in combination with conventional synthetic (cs)DMARD therapy significantly improved the signs and symptoms of rheumatoid arthritis (RA) in patients with an inadequate response to a biologic (b)DMARD compared with placebo (PBO).3In addition, patients experienced significant improvements in HAQ-DI at week (W)12 and W24 with FIL 100 mg (p <0.001, p = 0.003) or 200 mg (p <0.001 for both) compared with PBO.3Objectives:To evaluate the rate and magnitude of change in patient-reported outcomes (PROs) from FINCH 2 assessing pain, HRQoL, and fatigue.Methods:Patients in this double-blind, randomised study (NCT02873936) received FIL 200 mg, FIL 100 mg, or PBO while continuing csDMARD therapy. PROs were collected prospectively on day 1 and at the W2, W4, W8, W12, W14, W16, W20, and W24 visits for assessment of pain (VAS pain scale) and on day 1 and at W4, W12, and W24 for assessment of fatigue (FACIT-Fatigue) and HRQoL (SF-36). Changes from baseline for each PRO at each time point up to W24 were analysed longitudinally using a mixed-effects model for repeated measures. P values for the difference between each FIL arm and PBO at each time point were calculated.Results:Among the 448 patients randomised and treated (FIL 200 mg, n = 147; FIL 100 mg, n = 153; PBO, n = 148) 381 (85.0%) completed the study. Baseline mean (SD) VAS pain scale was 67 (21.0), SF-36 physical component summary (PCS) was 31.1 (7.89), SF-36 mental component summary (MCS) was 44.3 (11.6), and FACIT-Fatigue score was 24.4 (11.6); baseline values did not vary between treatment groups. Significantly greater improvements in VAS pain scores began at W2 and were maintained through W24 for patients who received either dose of FIL vs PBO (Fig 1A). FIL also significantly improved patients’ fatigue at W4, W12, and W24 compared with PBO for those receiving 200 mg doses, and at W4 and W12 for those receiving 100 mg doses (Fig 1B). HRQoL related to physical functioning (SF-36 PCS) was significantly enhanced at W4, W12, and W24 with both doses of FIL as compared with PBO (Fig 2A). Improvements to mental-health-related QoL (SF-36 MCS) were reported for FIL as early as W4 and maintained through W24, with statistically significant improvements at W4 and W12 for FIL 200 mg vs PBO (Fig 2B).Conclusion:In a patient population with refractory disease that had inadequate response to prior bDMARDs and had significant disease at baseline, FIL treatment—coadministered with csDMARD therapy—was able to provide rapid and sustained improvements in key measures of pain, HRQoL, and fatigue as reported by patients.References:[1]Smolen, et al.Ann Rheum Dis. 2017;76:960–77.[2]Fautrel, et al.Rheumatol Int.2018;38:935–47.[3]Genovese, et al.JAMA. 2019;322(4):315–25.Disclosure of Interests:David Walker Grant/research support from: Gilead, Consultant of: Gilead, Lilly, Pfizer, Roche, Speakers bureau: Lilly, Pfizer, Roche, Tsutomu Takeuchi Grant/research support from: AbbVie, Asahikasei Pharma Corp., Astellas Pharma, Inc., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi-Tanabe Pharma Corp., Nipponkayaku Co. Ltd., Shionogi & Co., Ltd., Takeda Pharmaceutical Co., Ltd., UCB Japan, Consultant of: Astellas Pharma, Inc., Chugai Pharmaceutical Co, Ltd., Eli Lilly Japan,, Speakers bureau: Abbvie, AYUMI Pharmaceutical Corp., Bristol-Myers Squibb, Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan, Gilead Sciences, Inc., Mitsubishi-Tanabe Pharma Corp., Novartis Pharma K.K., Pfizer Japan Inc., Sanofi K.K., Dainippon Sumitomo Co., Ltd, Beatrix Bartok Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Shangbang Rao Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., I-Heng Lee Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Robin Besuyen Shareholder of: Galapagos, Employee of: Galapagos, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme

Background:The once daily, oral Janus kinase (JAK)-1 preferential inhibitor filgotinib (FIL) improved signs and symptoms of rheumatoid arthritis (RA) in phase (P)3 trials.1-3 Patients (pts) with RA have increased herpes zoster (HZ) reactivation risk vs the general population. JAK inhibition is associated with increased infection incidence, including HZ.4Objectives:To assess long-term safety of FIL across the global clinical program with respect to HZ.Methods:Pts meeting 2010 ACR/EULAR RA criteria in a pooled analysis of P2 DARWIN 1–2 (D1–2), P3 FINCH 1–3 (F1–3), and long-term extension studies (D3, F4) were included. Placebo (PBO)-controlled as-randomised analysis included pts receiving FIL 100 mg (FIL100), FIL 200 mg (FIL200), or PBO up to week (W)12 (D1–2, F1–2); active-controlled as-randomised analysis included pts receiving FIL100, FIL200, adalimumab (ADA), or methotrexate (MTX) up to W52 (F1, F3). Long-term as-treated analysis included pts in all 7 studies receiving FIL100, FIL200, ADA, MTX, or PBO; data after re-randomisation were included and contributed to treatment received. Exposure-adjusted incidence rates (EAIR)/100 patient-years, calculated up to the last follow-up time or day, and differences with 95% confidence intervals (CIs) were calculated from the Poisson model. Logistic regression model was used for treatment-emergent (TE) HZ risk factor analysis and odds ratio (95% CI) and P value were provided.Results:Table 1 shows TE HZ EAIRs in a pooled analysis. Rates of HZ were lower for FIL200 vs PBO during the 12W PBO-controlled period. At 52W, HZ rates were higher for FIL200/100 vs active control. Long-term HZ rates increased for FIL200 vs FIL100.Table 1.EAIR of treatment-emergent herpes zosterNPatient-years exposureEAIR(95% CI)EAIR diff(95% CI vs PBO/active control)12W PBO-controlled FIL200777179.80.6 (0.1, 3.9)−0.56 (−2.5, 1.3) FIL100788181.61.1 (0.3, 4.4)−0.02 (−2.2, 2.2) PBO781178.41.1 (0.3, 4.5)Active-controlled, as-randomiseda FIL200475439.71.4 (0.6, 3.0)0.69 (−0.7, 2.1) FIL100480443.40.9 (0.3, 2.4)0.23 (−1.1, 1.5) ADA325297.60.7 (0.2, 2.7)Active-controlled, as-randomiseda FIL200626578.01.7 (0.9, 3.2)0.65 (−0.8, 2.2) FIL100207195.01.5 (0.5, 4.8)0.46 (−1.6, 2.5) MTX416372.21.1 (0.4, 2.9)Long-term as-treatedb FIL20022674047.71.8 (1.4, 2.3)NC FIL10016472032.91.1 (0.8, 1.7)NCaup to W52. bdata cut for LTE FINCH 4, Sept 19, 2019; DARWIN 3, April 26 2019.ADA, adalimumab; CI, confidence interval; EAIR, exposure-adjusted incidence rate; FIL, filgotinib; MTX, methotrexate; NC, not calculated; PBO, placebo; W week.Figure 1 shows multivariate logistic regression model of TE risk factors.Of 104 pts with TE HZ in long-term as-treated analysis set, 5 receiving FIL200 had history of HZ; EAIR (95% CI) was 8.7 (3.6–21.0). Of 8 pts with multiple events, 3 had events of differing severity for the same HZ episode.EAIRs (95% CI) of TE HZ in Asia were: 3.7 (1.7–8.1) FIL200, n=197; 2.8 (1.3–6.3) FIL100, n=158; 0 ADA, n=40; 2.8 (0.4–19.6) MTX, n=43; and 3.4 (0.5–23.8) PBO, n=77 in long-term as-treated population. EAIRs (95% CI) in rest of the world were: 1.6 (1.2–2.1) FIL200, n=2070; 0.9 (0.6–1.5) FIL100, n=1489; 0.8 (0.2–3.1) ADA, n=285; 0.9 (0.3–2.9) MTX, n=373; and 0.7 (0.2–2.9) PBO, n=704 for all pts as-treated.Most TE HZ infections were mild to moderate and non-serious; 6 were serious; 2 were recurrences. No visceral TE HZ occurred across the FIL RA program; there was 1 case each of genital, disseminated, and ophthalmic HZ. The disseminated HZ occurred in a pt with prior HZ history. Lymphopenia was not associated with HZ during the PBO-controlled W12 period.Conclusion:HZ was more common in both FIL groups vs ADA or MTX up to 52 weeks but comparable vs PBO during the 12-week placebo-controlled period. In multivariate analyses, prior history of HZ, Asian region, and age ≥50 years were associated with increased HZ risk.References:[1]Genovese et al. JAMA. 2019;322:315–25.[2]Westhovens et al. Ann Rheum Dis. 2021; online first.[3]Combe et al. Ann Rheum Dis. 2021; online first.[4]Higarashi and Honda. Drugs. 2020;80:1183–201.Disclosure of Interests:Kevin Winthrop Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly and Co., Galapagos NV, Gilead Sciences, GlaxoSmithKline, Pfizer, Roche, and UCB, Grant/research support from: AbbVie, Bristol-Myers Squibb, and Pfizer, Maya H Buch Speakers bureau: AbbVie; Eli Lilly and Company; Gilead Sciences, Inc.; Merck-Serono; Pfizer; Roche; Sandoz; Sanofi; and UCB, Consultant of: AbbVie; Eli Lilly and Company; Gilead Sciences, Inc.; Merck-Serono; Pfizer; Roche; Sandoz; Sanofi; and UCB, Grant/research support from: AbbVie; Eli Lilly and Company; Gilead Sciences, Inc.; Merck-Serono; Pfizer; Roche; Sandoz; Sanofi; and UCB, Jeffrey Curtis Grant/research support from: AbbVie, Amgen, BMS, Corrona, Eli Lilly, Janssen, Myriad, Pfizer, Regeneron, Roche, and UCB, Gerd Rüdiger Burmester Speakers bureau: AbbVie; Eli Lilly; Pfizer; and Gilead Sciences, Inc., Consultant of: AbbVie; Eli Lilly; Pfizer; and Gilead Sciences, Inc., Daniel Aletaha Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Medac, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sandoz, Sanofi/Genzyme, and UCB, Consultant of: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, and Sanofi/Genzyme, Grant/research support from: AbbVie, Merck Sharp & Dohme, Novartis, and Roche, Koichi Amano Speakers bureau: AbbVie GK, Astellas, Chugai Pharmaceutical Co. Ltd., Eli Lilly, GlaxoSmithKline KK, Pfizer Japan, Mitsubishi-Tanabe Pharma, Grant/research support from: Asahi Kasei Pharma, Alena Pechonkina Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Iyabode Tiamiyu Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Cianna Leatherwood Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Lei Ye Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Qi Gong Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Robin Besuyen Shareholder of: Galapagos, BV, Employee of: Galapagos, BV, James Galloway Speakers bureau: Pfizer, Bristol-Myers Squibb, UCB and Celgene

Background:The Janus kinase-1 preferential inhibitor filgotinib (FIL) improved signs and symptoms of rheumatoid arthritis (RA) in the FIL clinical program.1–3Objectives:To assess FIL safety across regions.Methods:This was an analysis of patients (pts) meeting 2010 ACR/EULAR RA criteria in pooled phase (P)2 DARWIN 1–2 (D1–2), P3 FINCH 1–3 (F1–3), and long-term extension studies (DARWIN 3, FINCH 4). Data were analyzed by region: North America, South and Central America, Western Europe, Eastern Europe, Asia, South East (SE) Asia, and Other. Week (W)12 placebo (PBO)-controlled analysis included data from pts receiving once-daily FIL 100 mg (FIL100), FIL 200 mg (FIL200), or PBO for ≤12W (D1–2, F1–2); long-term as-treated data included pts from all 7 studies receiving FIL100 or FIL200; data after rerandomization were included and contributed to treatment received. Data presented as exposure-adjusted incidence rates (EAIRs)/100 patient-years of exposure (PYE) of treatment-emergent (TE) adverse events (TEAEs).Results:Table 1 shows EAIRs of TEAEs in PBO-controlled analysis. EAIRs/100 PYE of all TEAEs in Western Europe, Asia, and Other were higher than in remaining regions and for PBO vs FIL arms; EAIRs for FIL200/FIL100 in North America and SE Asia were higher vs PBO. EAIRs/100 PYE of TE serious AEs were higher in SE Asia for FIL100 and for FIL200/FIL100 in Other, with high PBO EAIRs in Western Europe. EAIRs/100 PYE of TEAEs leading to study discontinuation were higher in FIL arms vs PBO in Western Europe and Other (FIL200); in Asia and SE Asia, EAIRs were higher for PBO vs FIL200/FIL100.Table 1.EAIR of TEAEs (placebo-controlled)North AmericaN = 481South and Central AmericaN = 350Western EuropeN = 141Eastern EuropeN = 933AsiaN = 236South East AsiaN= 135OtherN = 70TEAEFIL200a216.9 (162.5, 289.5)205.6 (155.1, 272.6)285.0 (188.6, 430.8)150.3 (119.3, 189.4)248.9 (180.6, 343.1)165.1 (104.0, 262.1)298.4 (150.3, 592.5)FIL100b182.2 (136.8, 242.7)159.2 (117.3, 216.1)285.7 (183.7, 444.3)146.4 (115.9, 185.0)246.9 (180.3, 338.1)153.7 (94.2, 251.0)263.5 (113.9, 609.2)PBOC174.5 (130.3, 233.7)162.1 (118.8, 221.2)314.9 (200.7, 493.9)148.4 (117.6, 187.4)259.0 (188.0, 356.8)81.6 (40.8, 163.3)306.0 (142.8, 655.7)TE serious AEFIL200a14.3 (6.0, 34.4)11.4 (3.7, 35.5)8.3 (1.2, 59.0)12.2 (5.2, 28.7)5.5 (0.8, 38.9)0.0 (0.0, ∞)49.6 (10.2, 144.9)FIL100b10.6 (4.0, 28.3)7.2 (1.8, 28.7)19.9 (5.0, 79.7)15.1 (6.8, 33.7)16.2 (5.2, 50.2)28.8 (9.3, 89.4)20.5 (0.5, 114.0)PBOC16.1 (7.2, 35.9)7.5 (1.9, 30.0)29.6 (9.5, 91.7)4.6 (1.3, 15.8)11.4 (2.8, 45.5)10.2 (1.4, 72.4)0.0 (0.0, 69.2)TEAE leading to discontinuationFIL200a8.6 (2.8, 26.6)3.8 (0.1, 21.2)16.6 (4.2, 66.5)12.9 (5.5, 30.5)0.0 (0.0, 20.2)9.2 (1.3, 65.1)16.5 (0.4, 92.1)FIL100b10.6 (4.0, 28.3)7.2 (0.9, 26.0)19.9 (5.0, 79.7)1.9 (0.2, 13.8)5.4 (0.1, 30.1)9.6 (1.4, 68.2)0.0 (0.0, 75.5)PBOC5.4 (1.3, 21.5)0.0 (0.0, 13.8)9.9 (1.4, 70.0)12.9 (5.4, 30.7)17.1 (3.5, 49.9)20.4 (5.1, 81.6)0.0 (0.0, 69.2)Data presented as EAIR (95% CI)/100 patient-yearsaN = 777, 179.8 PYE bN = 788, 181.6 PYE cN = 781, 178.4 PYEA subject may contribute to more than one treatment group if they received more than one treatment of interest.EAIR and corresponding 95% CI were estimated using Poisson regression model by treatment, including study and treatment with an offset of natural log of exposure time, except when 0 events occurred; Poisson model was not adjusted by study.AE, adverse event; CI, confidence interval; EAIR, exposure-adjusted incidence rate; FIL, filgotinib; PBO, placebo; PYE, patient-years of exposure; TE, treatment-emergentFigure shows serious infections (SI), venous thromboembolism (VTE) and herpes zoster (HZ) EAIRs.EAIRs for SI were highest in Other for FIL200 and SE Asia for FIL100. While VTE EAIRs were low, pts in 5/7 regions had VTE. HZ EAIRs were highest in Asia.Conclusion:Although EAIR of TEAEs varied between regions, no consistent trend was reflected in any particular region.References:[1]Genovese et al. JAMA. 2019;322:315–25.[2]Westhovens et al. Ann Rheum Dis. 2021; online first.[3]Combe et al. Ann Rheum Dis. 2021; online first.Disclosure of Interests:Bernard Combe Speakers bureau: BMS; Eli Lilly & Co.; Gilead Sciences, Inc.; MSD; Pfizer; Roche-Chugai; and UCB, Consultant of: AbbVie; Eli Lilly & Co.; Gilead Sciences, Inc.; Janssen; Pfizer; Roche-Chugai; and Sanofi, Grant/research support from: Novartis, Pfizer, and Roche-Chugai, Tsukasa Matsubara Speakers bureau: Pfizer Japan, Nichi-Iko, Astellas, Meiji Seika, Bristol-Myers Squibb, AbbVie GK, Janssen, Chugai, Eisai, AYUMI, Alena Pechonkina Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., YingMeei Tan Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Zhaoyu Yin Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Jaehyung Hong Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Robin Besuyen Shareholder of: Galapagos, BV, Employee of: Galapagos, BV, Antonio Gomez-Centeno Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly & Co., Gebro, Janssen, Menarini, Merck Sharp & Dohme, Pfizer, Roche, Rubio, Sanofi, and UC, Consultant of: AbbVie, Biogen, Bristol-Myers Squibb, Celgene, Eli Lilly & Co., Gebro, Gilead Sciences, Inc., Hospira, Merck Sharp & Dohme, Pfizer, Roche, Rubio, Sandoz, Sanofi, Grant/research support from: Boehringer Ingelheim, Celltrion, Eli Lilly & Co., Galapagos NV, Gilead Sciences, Inc., Novartis, Pfizer, Roche, Sanofi, UCB, YL Biologics, Maya H Buch Speakers bureau: AbbVie; Eli Lilly and Company; Gilead Sciences, Inc.; Merck-Serono; Pfizer; Roche; Sandoz; Sanofi; and UCB, Consultant of: AbbVie; Eli Lilly and Company; Gilead Sciences, Inc.; Merck-Serono; Pfizer; Roche; Sandoz; Sanofi; and UCB, Grant/research support from: AbbVie; Eli Lilly and Company; Gilead Sciences, Inc.; Merck-Serono; Pfizer; Roche; Sandoz; Sanofi; and UCB

Background:Filgotinib (FIL), an oral, potent, selective JAK-1 inhibitor, provided statistically significant and clinically meaningful improvement in rheumatoid arthritis (RA) signs and symptoms, physical function, radiographic progression, and quality of life in a comprehensive clinical program of 4 phase 3 (FINCH 1–4;NCT02889796,NCT02873936,NCT02886728,NCT03025308) and 3 phase 2 (DARWIN 1–3;NCT01668641,NCT01894516,NCT02065700) trials in patients (pts) with early and biologic-refractory RA.1–3Objectives:To assess long-term safety of FIL.Methods:Treatment-emergent adverse events (TEAEs) from the FIL clinical program were integrated and presented for pts receiving FIL 200 mg or FIL 100 mg QD (including pts who transitioned to FIL from placebo [PBO], methotrexate [MTX], adalimumab [ADA], or another dose of FIL) as well as pts receiving PBO, MTX, and ADA across all 7 studies. Exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY) were calculated for adverse events (AEs) of interest per treatment. Incidence was total number of pts with events, and PY exposure was time between first and last doses. Major adverse cardiovascular events (MACE) and venous thromboembolism (VTE) were centrally adjudicated by an independent committee.Results:Across the 7 trials, 4057 pts with RA (2227 pts FIL 200 mg; 1600 pts FIL 100 mg) received >1 dose of treatment for 5493 total PY of exposure (3079.2 PY FIL 200 mg; 1465.3 PY FIL 100 mg) (Table). EAIRs of serious AEs and TEAEs leading to death in pts receiving FIL were comparable to those for PBO, ADA, or MTX, with no dose-dependent effect (Figure 1). EAIR for herpes zoster (HZ), serious, and opportunistic infections are shown in Figure 2. EAIR for HZ were low overall, but numerically slightly higher for FIL relative to PBO, ADA, and similar to MTX. Serious infection EAIRs were comparable between pts receiving FIL 100 mg and ADA, and numerically slightly lower for FIL 200 mg and MTX. Rates of opportunistic infections (including active tuberculosis) were low overall; EAIR for FIL doses were comparable to placebo and numerically lower than ADA or MTX. Rates of MACE and VTE were numerically lower for FIL relative to PBO (Figure 1). Malignancies, including nonmelanoma skin cancer, were rare overall, and rates were low in pts receiving FIL (Figure 1).Table.Total exposure to study treatments pooled from 7 studiesNumber of patientsPatient-years of exposureFIL 200 mg22273079.2FIL 100 mg16001465.3ADA325290.1MTX416356.2PBO781302.4Patients could contribute to >1 treatment group.ADA, adalimumab; FIL, filgotinib; MTX, methotrexate; PBO, placebo.Conclusion:In this integrated analysis, FIL was well-tolerated, and no new safety concerns were identified. No clinically meaningful dose-dependent safety effects were observed. MACE and VTE were uncommon. Serious infections rates were low; HZ reactivation was infrequent. Safety results were consistent with selective JAK-1 inhibition and highlight the favourable safety and tolerability of FIL in patients with RA.References:[1]Genovese, et al.JAMA2019;322(4):315–25.[2]Westhovens, et al.Ann Rheum Dis2017;76:998–1008.[3]Kavanaugh, et al.Ann Rheum Dis2017;76:1009–19.Disclosure of Interests:Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme, Kevin Winthrop Grant/research support from: Bristol-Myers Squibb, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, GSK, Pfizer Inc, Roche, UCB, Yoshiya Tanaka Grant/research support from: Asahi-kasei, Astellas, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Pfizer, and Ono, Consultant of: Abbvie, Astellas, Bristol-Myers Squibb, Eli Lilly, Pfizer, Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Sanofi, UCB, and Teijin, 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., Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim,,Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Franziska Matzkies Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Lei Ye Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Deyuan Jiang Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Ying Guo Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Beatrix Bartok Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Robin Besuyen Shareholder of: Galapagos, Employee of: Galapagos, 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, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB

Background:Despite effective treatments, many patients (pts) with rheumatoid arthritis (RA) have inadequate responses to biologic DMARDs (bDMARD-IR), highlighting an unmet need. It is unclear whether prior bDMARD use affects efficacy of the oral, selective JAK-1 inhibitor filgotinib (FIL).Objectives:To explore clinical response to FIL in bDMARD-IR pts stratified by mode of action (MOA) and number of prior bDMARDs.Methods:The global, phase 3 FINCH-2 (NCT02873936) study treated 448 bDMARD-IR pts with active RA.1Pts were randomised 1:1:1 to once-daily FIL 200 mg, FIL 100 mg, or placebo (PBO) for 24 weeks. Efficacy was assessed by percent of pts achieving low disease activity (LDA) or remission at week (W)24 as measured by CDAI and DAS28(CRP) stratified by number and MOA of prior bDMARDs. Comparisons were not adjusted for multiplicity. Nonresponder imputation was used.Results:In total, 448 bDMARD-IR pts were included, 105 with prior experience with ≥3 bDMARDs (Table). At W24, pts receiving FIL were in LDA at a higher proportion vs PBO, irrespective of number of prior bDMARDs or MOA (Figure 1). For pts receiving FIL 200 vs PBO, DAS28(CRP) ≤3.2 was achieved at W24 by 52% vs 26%, 51% vs 22%, and 38% vs 9% of pts with 1, 2, or ≥3 prior bDMARDs, respectively, and 49% vs 21% and 50% vs 13% of pts exposed to TNF or IL-6 inhibitors; for all subgroups, rates were significantly higher vs PBO (Figure 1). Delta between FIL 200 mg and PBO was maintained irrespective of number or type of prior bDMARDs. At W24, pts receiving FIL achieved remission at numerically higher rates vs PBO (Figure 2). For pts receiving FIL 200 mg vs PBO, DAS28(CRP) <2.6 was achieved at W24 by 36% vs 14%, 30% vs 14%, and 22% vs 6% of pts with 1, 2, and ≥3 prior bDMARDs, respectively, and 31% vs 14% and 29% vs 9% of pts exposed to TNF or IL-6 inhibitors (Figure 2). Delta between FIL 200 mg and PBO was maintained irrespective of number or type of prior bDMARDs. Treatment-emergent adverse events across subgroups were consistent with overall study population.Table.Number and MOA of prior bDMARDsFIL 200 mgn = 147FIL 100 mgn = 153PBOn = 148TotalN = 448Prior bDMARDs 173 (49.7)86 (56.2)77 (52.0)236 (52.7) 237 (25.2)33 (21.6)36 (24.3)106 (23.7) ≥337 (25.2)34 (22.2)34 (23.0)105 (23.4)LOE ≥1 bDMARD125 (85.0)129 (84.3)126 (85.1)380 (84.8)Intolerance ≥1 bDMARD36 (24.5)34 (22.2)32 (21.6)102 (22.8)Prior TNFi121 (82.3)134 (87.6)124 (83.8)379 (84.6) LOE ≥1 TNFi97 (66.0)113 (73.9)103 (69.6)313 (69.9) Intolerance ≥1 TNFi25 (17.0)24 (15.7)24 (16.2)73 (16.3)Prior non-TNFi73 (49.7)62 (40.5)75 (50.7)210 (46.9) LOE ≥1 non-TNFi52 (35.4)43 (28.1)56 (37.8)151 (33.7) Intolerance ≥1 non-TNFi13 (8.8)13 (8.5)11 (7.4)37 (8.3)Prior IL-6i34 (23.1)35 (22.9)32 (21.6)101 (22.5) LOE ≥1 IL-6i25 (17.0)22 (14.4)21 (14.2)68 (15.2) Intolerance ≥1 IL-6i5 (3.4)10 (6.5)5 (3.4)20 (4.5)Data presented as n (%).i, inhibitor; LOE, lack of efficacy.Conclusion:Treatment with FIL vs PBO led to higher rates of LDA and remission in pts with IR to IL-6 or TNF inhibition, or to 1, 2, or ≥3 prior bDMARDs, with a similar safety profile to the overall study population. A significantly higher proportion of pts overall receiving FIL 200 mg vs PBO were in LDA at W24. Improved efficacy of FIL vs PBO in pts who previously failed multiple bDMARDs indicates distinct benefits of selective JAK-1 inhibition with FIL.References:[1]Genovese, et al.JAMA2019;322(4):315–25.Disclosure of Interests: :Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Maya H Buch Grant/research support from: Pfizer, Roche, and UCB, Consultant of: Pfizer; AbbVie; Eli Lilly; Gilead Sciences, Inc.; Merck-Serono; Sandoz; and Sanofi, Roberto Caporali Consultant of: AbbVie; Gilead Sciences, Inc.; Lilly; Merck Sharp & Dohme; Celgene; Bristol-Myers Squibb; Pfizer; UCB, Speakers bureau: Abbvie; Bristol-Myers Squibb; Celgene; Lilly; Gilead Sciences, Inc; MSD; Pfizer; Roche; UCB, Grace C. Wright Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Exagen, Eli Lilly, Myriad Autoimmune, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi Genzyme, UCB, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Exagen, Eli Lilly, Myriad Autoimmune, Novartis, Regeneron Pharmaceuticals, Inc., Sanofi Genzyme, UCB, 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., Kenneth Kalunian Grant/research support from: Pfizer, Lupus Research Alliance, Sanford Consortium, Consultant of: Genentech, Nektar, BMS, Janssen, AstraZeneca, Biogen, Vielabio, Equillium, Eli Lilly, ILTOO, Abbvie, Amgen, Roche, Gilead, Alena Pechonkina Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Ying Guo Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Shangbang Rao Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., YingMeei Tan Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Robin Besuyen Shareholder of: Galapagos, Employee of: Galapagos, Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme

Background:The Janus kinase-1 preferential inhibitor filgotinib (FIL) improved signs and symptoms of rheumatoid arthritis (RA) across the FIL clinical program.1–3Objectives:To assess FIL efficacy across geographic regions.Methods:Pooled data from patients (pts) meeting 2010 ACR/EULAR RA criteria randomised to once-daily FIL 200 mg (FIL200), FIL100 mg (FIL100), or placebo (PBO) with background conventional synthetic disease-modifying antirheumatic drugs in DARWIN 1 (P2; up to week [W]12) and FINCH 1–2 (P3; up to W24) studies were evaluated. Data were analysed by region: North America, South and Central America, Western Europe, Eastern Europe, Asia, South East (SE) Asia, and Other. W12 American College of Rheumatology 20% improvement (ACR20) and W24 Disease Activity Score in 28 joints (C-reactive protein) (DAS28[CRP]) <2.6 and ≤3.2 response rates were analysed by a logistic regression model. Change from baseline (CFB) in Health Assessment Questionnaire-Disability Index (HAQ-DI) at W12 was analysed by a mixed-effects model for repeated measures. Analyses were exploratory and not adjusted for multiplicity.Results:Despite high PBO response rates in Eastern Europe and South and Central America, greater proportions of pts receiving FIL200 or FIL100 vs PBO achieved ACR20 at W12 (P <0.05) in all regions, except Other (with lowest sample size, n = 69), where both FIL doses were numerically greater than PBO (Table 1). At W12, least-squares mean CFB in HAQ-DI improved for pts receiving FIL200 or FIL100. vs PBO (P <0.05) in all regions, except SE Asia, where improvement was numeric (Table 1).Table 1.Proportion of pts achieving ACR20 and LSM change from baseline HAQ-DI at week 1ACR20HAQ-DIFIL200FIL100FIL200FIL100FIL200FIL100North America64.8*58.3*33.8−0.63*−0.58*−0.34n = 455(56.7, 72.9)(50.3, 66.4)(26.0, 41.6)(−0.70, −0.56)(−0.65, −0.51)(−0.41, −0.27)South and Central America77.277.357.4−0.77*−0.67*−0.43n = 283(68.1, 86.3)†(65.8, 86.2)†(46.9, 68.0)(−0.85, −0.68)(−0.75, −0.59)(−0.52, −0.35)Western Europe69.4*68.3*24.4−0.69*−0.61*−0.28n = 135(55.5, 83.3)(52.8, 83.8)(10.8. 38.1)(−0.80, −0.58)(−0.73, −0.49)(−0.40, −0.17)Eastern Europe77.1*69.1*54.6−0.62*−0.51*−0.34n = 822(71.9, 82.3)(63.5, 74.7)(48.5, 60.7)(−0.68, −0.56)(−0.57, −0.45)(−0.40, −0.28)Asia81.0*60.0†37.7−0.83*−0.61†−0.42n = 236(71.7, 90.3)(48.6, 71.4)(26.2, 49.1)(−0.92, −0.73)(−0.70, −0.52)(−0.52, −0.33)South East Asia70.2†71.1†39.5−0.61−0.57−0.45n = 135(56.1, 84.4)(56.8, 85.5)(23.8, 55.3)(−0.73, −0.49)(−0.69, −0.45)(−0.58, −0.33)Other60.052.439.1−0.56‡−0.60‡−0.33n = 69(38.8, 81.2)(28.6, 76.1)(17.0, 61.2)(−0.72, −41)(−0.76, −0.43)(−0.49, −0.17)Overall73.4*66.4*45.3−0.71*−0.61*−0.40N = 2135(70.1, 76.8)(62.9, 70.0)(41.5, 49.0)(−0.76, −0.66)(−0.66, −0.56)(−0.45, −0.35)Includes only patients initially randomised to the treatment groups in each study for the comparison of interest. ACR20 presented as percentage (95% CI); 95% CI was based on normal approximation method with a continuity correction; P values calculated from the logistic regression.HAQ-DI presented as LSM (95% CI); LSM, 95% CI, and P value calculated from a mixed-effects model for repeated measures.*P <0.001, †P <0.01, ‡P <0.05; not adjusted for multiplicity.ACR20, American College of Rheumatology 20% improvement; CI, confidence interval; FIL, filgotinib; HAQ-DI, Health Assessment Questionnaire-Disability Index; LSM, least square mean; PBO, placebo.At W24, DAS28(CRP) <2.6 and ≤3.2 response rates were higher for both doses of FIL vs PBO (P <0.05) in all regions, with the exception of Other, where PBO was higher than FIL100 for DAS28(CRP) <2.6 (Figure 1).Conclusion:In exploratory analyses, ACR20, DAS28(CRP) <2.6 and ≤3.2 response rates and HAQ-DI scores varied between regions; however, no stable trend was shown in any particular region. Small pt numbers in some subgroups may confound statistical analysis.References:[1]Genovese et al. JAMA. 2019;322:315–25.[2]Westhovens et al. Ann Rheum Dis. 2021; online first.[3]Combe et al. Ann Rheum Dis. 2021; online first.Disclosure of Interests:Maya H Buch Speakers bureau: AbbVie; Eli Lilly and Company; Gilead Sciences, Inc.; Merck-Serono; Pfizer; Roche; Sandoz; Sanofi; and UCB, Consultant of: AbbVie; Eli Lilly and Company; Gilead Sciences, Inc.; Merck-Serono; Pfizer; Roche; Sandoz; Sanofi; and UCB., Grant/research support from: AbbVie; Eli Lilly and Company; Gilead Sciences, Inc.; Merck-Serono; Pfizer; Roche; Sandoz; Sanofi; and UCB., Tsukasa Matsubara Speakers bureau: Pfizer Japan, Nichi-Iko, Astellas, Meiji Seika, Bristol-Myers Squibb, AbbVie GK, Janssen, Chugai, Eisai, AYUMI, Bernard Combe Speakers bureau: BMS; Eli Lilly & Co.; Gilead Sciences, Inc.; MSD; Pfizer; Roche-Chugai; and UCB, Consultant of: AbbVie; Eli Lilly & Co.; Gilead Sciences, Inc.; Janssen; Pfizer; Roche-Chugai; and Sanofi, Grant/research support from: Novartis, Pfizer, and Roche-Chugai, Alena Pechonkina Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., YingMeei Tan Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Zhaoyu Yin Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Jaehyung Hong Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Robin Besuyen Shareholder of: Galapagos, BV, Employee of: Galapagos, BV, Antonio Gomez-Centeno Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly & Co., Gebro, Janssen, Menarini, Merck Sharp & Dohme, Pfizer, Roche, Rubio, Sanofi, and UCB, Consultant of: AbbVie, Biogen, Bristol-Myers Squibb, Celgene, Eli Lilly & Co., Gebro, Gilead Sciences, Inc., Hospira, Merck Sharp & Dohme, Pfizer, Roche, Rubio, Sandoz, Sanofi, Grant/research support from: Boehringer Ingelheim, Celltrion, Eli Lilly & Co., Galapagos NV, Gilead Sciences, Inc., Novartis, Pfizer, Roche, Sanofi, UCB, YL Biologics

BackgroundFilgotinib (FIL) is a Janus kinase 1 preferential inhibitor approved for the treatment of moderate to severe rheumatoid arthritis (RA) in patients (pts) with an inadequate response to disease-modifying antirheumatic drugs.1 In a pooled analysis of Phase 3 FINCH 1–3 studies of FIL in RA, median lymphocyte levels were relatively stable over 1 year with lymphocyte decreases observed in individual FIL-treated pts. Lymphocyte levels should be monitored.1ObjectivesTo assess the effect of FIL on lymphocyte levels and lymphopenia in the FINCH 4 long-term extension (LTE) study in RA.MethodsSafety data of FIL 100 mg (FIL100) and 200 mg (FIL200) from LTE baseline to data cut off (01 June 2020) are reported overall and by prior FIL exposure for pts who received ≥1 FIL dose in FINCH 4 (NCT03025308; adults with RA who had completed FINCH 1/2/3). Adverse events (AEs) of lymphopenia were graded based on clinical severity; laboratory abnormalities (decreased lymphocytes) were graded per Common Terminology Criteria for Adverse Events v4.03 (CTCAE). Frequencies of both measures and exposure-adjusted incidence rates (EAIRs) of AEs are reported. Median lymphocyte levels are reported to LTE Week 48.ResultsThe safety analysis set included 2729 pts (FIL200: n=1530; FIL100: n=1199). Of these, 75.4% (n=2058) had prior FIL exposure in FINCH 1/2/3. Median FIL exposure to LTE Week 48 was 600 (FIL200: 696; FIL100: 533) days.In both treatment groups, median laboratory lymphocyte levels remained relatively stable to LTE Week 48 for pts with prior FIL exposure. Pts without prior exposure had numerically higher median lymphocyte levels at LTE baseline vs pts with prior exposure (Figure 1). These decreased over time, but medians remained within normal range. The frequency and EAIR of graded decreases in laboratory lymphocyte levels were higher with FIL200 vs FIL100 (Table 1); incidence was slightly higher in pts with vs without prior FIL exposure, with the difference most apparent for Grade 2 decreases.Table 1.Frequencies of treatment-emergent laboratory decreases in lymphocytesPrior FIL exposureNo prior FIL exposureOverallTotalFIL200FIL100FIL200FIL100FIL200FIL100(N=2729)(n=1195)(n=863)(n=335)(n=336)(n=1530)(n=1199)Decreased lymphocytes228 (19.1)125 (14.5)41 (12.3)40 (12.0)269 (17.6)165 (13.8)434 (16.0)(any grade), n (%)Grade 148 (4.0)35 (4.1)14 (4.2)7 (2.1)62 (4.1)42 (3.5)104 (3.8)Grade 2159 (13.3)82 (9.5)21 (6.3)26 (7.8)180 (11.8)108 (9.1)288 (10.6)Grade 321 (1.8)8 (0.9)6 (1.8)7 (2.1)27 (1.8)15 (1.3)42 (1.5)Grade 40000000A treatment-emergent laboratory decrease in lymphocytes was defined as an increase of ≥1 toxicity grade from baseline at any time post-baseline up to and including the date of last study drug dose + 30 days. Severity grades were defined per CTCAE (lower limit of normal: <0.8 × 109/L [Grade 1]; <0.8–0.5 × 109/L [2]; <0.5–0.2 × 109/L [3]; <0.2 × 109/L [4]).Figure 1.Of all pts receiving FIL, 43 (1.6%) reported a lymphopenia AE; frequencies and EAIRs of lymphopenia AEs were slightly higher with FIL200 (1.9%; EAIR [95% CI]: 1.2 [0.9–1.8]) vs FIL100 (1.2%; 0.8 [0.4–1.3]). Most were Grade 1 or 2 in severity. Grade 3 lymphopenia AEs occurred in 4 (0.3%) vs 1 (<0.1%) pts receiving FIL200 vs FIL100. There were no Grade 4 AEs in either group.No serious AEs of lymphopenia or treatment discontinuations due to lymphopenia were reported. In total, 8 (0.3%) pts interrupted study treatment due to lymphopenia. Infection rates, but not serious infections, were slightly higher for pts with lymphopenia, however no relationship between lymphopenia severity and infection AE grade was seen.ConclusionIn FINCH 4, lymphopenia AEs were infrequent but numerically greater with FIL200 vs FIL100, suggesting a dose–response relationship. While exposure at either dose may be associated with decreased lymphocytes, median lymphocyte levels were comparable in both groups and all remained within normal range at LTE Week 48, similar to observations in FINCH 1–3.References[1]Filgotinib SmPC and Jyseleca EPAR, 2020. Available at: https://www.ema.europa.eu/enAcknowledgementsThe authors would like to acknowledge Nadia Verbruggen and Pieter-Jan Stiers for providing statistical analysis support. This study was co-funded by Galapagos NV (Mechelen, Belgium) and Gilead Sciences, Inc. (Foster City, CA, USA). Medical writing support was provided by Kristian Clausen, MPH, CMPP (Aspire Scientific Ltd, Bollington, UK), and funded by Galapagos NV.Disclosure of InterestsJacques-Eric Gottenberg Consultant of: AbbVie, Bristol Myers Squibb, Galapagos, Gilead, Lilly, and Pfizer, Grant/research support from: Bristol Myers Squibb, and Pfizer, Gerd Rüdiger Burmester Consultant of: AbbVie, Amgen, Bristol Myers Squibb, Galapagos, Lilly, MSD, Pfizer, Roche, and Sanofi, Katrien Van Beneden Shareholder of: Galapagos NV, Employee of: Galapagos NV, Chris Watson Shareholder of: Galapagos Biotech Ltd, Employee of: Galapagos Biotech Ltd, Ineke Seghers Employee of: Galapagos NV, Vijay Rajendran Employee of: Galapagos NV, Lorenzo Dagna Consultant of: AbbVie, Amgen, AstraZeneca, Biogen, Boehringer-Ingelheim, Bristol Myers Squibb, Celltrion, Eli Lilly and Company, Galapagos, GlaxoSmithKline, Janssen, Kiniksa Pharmaceuticals, Novartis, Pfizer, Roche, Sanofi-Genzyme, and Swedish Orphan Biovitrium (SOBI), Grant/research support from: Bristol Myers Squibb, Celltrion, Kiniksa Pharmaceuticals, Pfizer, and Swedish Orphan Biovitrium (SOBI), Maya H Buch Speakers bureau: Speaker fees paid to host institution by AbbVie, Consultant of: Consultant honoraria paid to host institution by AbbVie, Galapagos, Gilead, and Pfizer, Grant/research support from: Gilead and Pfizer.

BackgroundFilgotinib (FIL) is an oral Janus kinase 1 preferential inhibitor, approved for the treatment of moderate to severe active rheumatoid arthritis (RA). In previous analyses, comparable incidence of selected adverse events (AEs) occurred in FIL 200 mg (FIL200) and 100 mg (FIL100) dose groups, except for herpes zoster.[1]ObjectivesTo provide an update on FIL selected AEs up to a median (max) exposure of 3.8 (8.3) years.MethodsIntegrated FIL RA data from 7 clinical trials are reported: phase 2 (NCT01888874,NCT01894516), phase 3 (NCT02889796,NCT02873936,NCT02886728), and the long-term extension studies DARWIN 3 phase 2 (NCT02065700) and FINCH 4 phase 3 (NCT03025308). Exposure-adjusted incidence rates (EAIRs)/100 patient-years of exposure (PYE), censored at time of first event, were determined for major adverse cardiovascular event (MACE), venous thromboembolism (VTE), arterial systemic thromboembolism, non-melanoma skin cancer (NMSC), malignancies excluding NMSC, herpes zoster, serious infections and deaths. Data were as of May 2, 2022 (DARWIN 3) and May 6, 2022 (FINCH 4). MACE and VTE only include positively adjudicated events with a data cutoff of April 3, 2022.ResultsThe as-treated population included 3691 patients with 12,541 PYE. Median (max) exposure was 3.8 (8.3) in the pooled FIL group; 3.8 (8.3) years for FIL200 and 3.3 (7.8) years for FIL100. Baseline demographics and disease characteristics were balanced between groups.[2]Small numerical differences were observed between FIL doses for EAIRs of selected AEs. Numerically higher incidences of NMSC, herpes zoster and all-cause mortality were reported with FIL200 vs FIL100; incidences of MACE and serious infections were numerically lower with FIL200 vs FIL100, with overlapping confidence intervals (Table 1). Over 240 weeks, the risks of MACE and VTE were comparable for FIL100 vs FIL200; low event numbers make interpretation difficult. The risk of herpes zoster was higher with FIL200 vs FIL100, and generally similar for serious infection or all-cause mortality (Figure 1).ConclusionOver a maximum of 8.3 years, FIL200 and FIL100 continued to show small numerical differences in EAIRs of selected AEs between dose groups in the overall RA population. Slightly higher incidence rates for NMSC, herpes zoster and all-cause mortality were reported in the FIL200 than FIL100 group, with a higher incidence of MACE and serious infections with the lower dose; confidence intervals overlapped between the dose groups.References[1]Winthrop KL, et al. Arthritis Rheumatol 2022;74(S9): abstract 0273[2]Winthrop KL, et al. Ann Rheum Dis 2022;81:184–92Table 1.Frequencies and EAIRs of selected AEs in parent and ongoing long-term extension RA clinical trialsFIL100 (PYE= 4532.4)(n=1647)FIL200 (PYE= 8008.6)(n=2267)n (%), EAIR per 100 PYE (95% CI)MACE*22 (1.3),0.49 (0.3, 0.7)27 (1.2),0.34 (0.2, 0.5)VTE*9 (0.5),0.20 (0.1, 0.4)15 (0.7),0.19 (0.1, 0.3)ASTE1 (<0.1),0.02 (0.0, 0.1)1 (<0.1),0.01 (0.0, 0.1)NMSC9 (0.5),0.20 (0.1, 0.4)27 (1.2),0.34 (0.2, 0.5)Malignancies (excluding NMSC)30 (1.8),0.66 (0.4, 0.9)57 (2.5),0.71 (0.5, 0.9)Herpes zoster49 (3.0),1.10 (0.8, 1.5)114 (5.0),1.48 (1.2, 1.8)Serious infections97 (5.9),2.18 (1.8, 2.2)149 (6.6),1.88 (1.6, 2.2)All-cause mortality26 (1.6),0.57 (0.4, 0.8)57 (2.5),0.71 (0.5, 0.9)*Positively adjudicated MACE/VTE.AE, adverse event; ASTE, arterial systemic thromboembolism; CI, confidence interval; EAIR, exposure-adjusted incidence rate; FIL100/200, filgotinib 100/200 mg; MACE, major adverse cardiovascular event; NMSC, non-melanoma skin cancer; PYE, patient-years of exposure; RA, rheumatoid arthritis; VTE, venous thromboembolism.AcknowledgementsFunding: The FINCH and DARWIN studies were co-funded by Gilead Sciences Inc. (Foster City, CA, USA) and Galapagos NV (Mechelen, Belgium). Publication coordination was provided by Fabien Debailleul, PhD, of Galapagos NV. Medical writing support was provided by Iain Haslam, PhD, CMPP (Aspire Scientific Ltd, Bollington, UK), and funded by Galapagos NV.Disclosure of InterestsKevin Winthrop Consultant of: Pfizer, AbbVie, UCB, Eli Lilly & Company, Galapagos, GSK, Roche, Gilead, BMS, Regeneron, Sanofi, AstraZeneca, Novartis, Grant/research support from: BMS, Pfizer, Daniel Aletaha Speakers bureau: AbbVie, Gilead, Galapagos, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Sandoz, Sanofi, Consultant of: AbbVie, Gilead, Galapagos, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Sandoz, Sanofi, Grant/research support from: AbbVie, Gilead, Galapagos, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Sandoz, Sanofi, Roberto Caporali Speakers bureau: AbbVie, Galapagos, Lilly, Pfizer, UCB, BMS, Fresenius, Novartis, Celltrion, Janssen, Amgen, Consultant of: AbbVie, Galapagos, Lilly, Pfizer, UCB, Fresenius, Novartis, Yoshiya Tanaka Speakers bureau: Boehringer Ingelheim, Eli Lilly, AbbVie, Gilead, AstraZeneca, BMS, Chugai, Daiichi-Sankyo, Eisai, Pfizer, Mitsubishi-Tanabe, GSK, Grant/research support from: Asahi-Kasei, AbbVie, Chugai, Eisai, Takeda, Daiichi-Sankyo, Boehringer Ingelheim, Tsutomu Takeuchi Speakers bureau: AbbVie GK, AYUMI, BMS, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Gilead Sciences Inc., Janssen Pharm K.K., Mitsubishi-Tanabe, Pfizer Japan, Sanofi K.K., Consultant of: AbbVie GK, Astellas, Chugai, Eli Lilly Japan, Gilead Sciences Inc., Janssen Pharm K.K, Mitsubishi Tanabe, Pfizer Japan, Grant/research support from: Astellas, AYUMI, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, AbbVie GK, Asahi Kasei Pharma, Mitsubishi Tanabe, Nippon Kayaku, UCB Japan, Paul Van Hoek Consultant of: AOP Health, Aspen, Astellas, Galapagos, Sanofi-Genzyme, Employee of: Janssen, MSD, Schering-Plough, Pieter-Jan Stiers Employee of: Galapagos, Vijay Rajendran Shareholder of: Galapagos, Employee of: Galapagos, Katrien Van Beneden Shareholder of: Galapagos, Employee of: Galapagos, Jacques-Eric Gottenberg Consultant of: AbbVie, BMS, Galapagos, Gilead, Lilly, MSD, Novartis, Pfizer, Grant/research support from: BMS, Pfizer, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Amgen, BMS, Chugai, Galapagos, Lilly, Pfizer, Sanofi, Consultant of: AbbVie, Amgen, BMS, Galapagos, Lilly, Pfizer, Sanofi.

Abstract Background Filgotinib (FIL) is an oral, selective janus kinase 1 inhibitor under development for the treatment of rheumatoid arthritis (RA) and other inflammatory diseases. Safety and efficacy of FIL was investigated in the FINCH clinical program, which includes three Phase 3, summarized, summarized studies in patients with moderate to severely active RA. FINCH1: patients with inadequate response to MTX (NCT02889796); FINCH2: patients receiving conventional disease-modifying antirheumatic drugs (csDMARDs) with inadequate response to biological DMARDs (NCT02873936); FINCH3: MTX-naïve patients initiating MTX ± FIL, or receiving FIL monotherapy (NCT02886728). We present pooled safety data up to 24 weeks (W24). Methods The FINCH studies enrolled patients with RA (2010 ACR/EULAR criteria), ≥6 swollen joints and ≥6 tender joints at screening and Day 1. Safety analyses included patients receiving ≥1 dose of study drug. Patients in FINCH 1 and 2 who did not experience at least a 20% improvement in both swollen joint count and tender joint count by W14 discontinued study drug and switched to standard of care. W24 safety data from all studies were aggregated and ummarized. Key safety endpoints were treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs of interest, deaths and treatment-emergent laboratory abnormalities. Results 3,452 patients were evaluated; 2,088 received FIL. At W24, the frequency of TEAEs and TEAEs of interest were similar for those who received FIL and those in the control groups (Table 1). Most TEAEs were infections. Laboratory abnormality rates were similar between FIL and control groups, and were mild to moderate (grades 1 and 2). Overall, the frequency of major adverse cardiac events, herpes zoster virus, deep vein thrombosis and pulmonary embolism was low, and similar across groups. Conclusion Pooled data from this large database highlights the favourable safety and tolerability profile of FIL in patients with RA both as monotherapy and in combination with MTX/csDMARD. Disclosures D. Walker: Other; Received support from Lilly, Pfizer, Novartis and Roche. K. Winthrop: Grants/research support; Received grants for clinical research from Bristol-Myers Squibb Company and Insmed Incorporated. Other; Received support from AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Eli Lilly & Co., MSD, Novartis, Pfizer, Roche-Chugai, Sanofi, and UCB. M.C. Genovese: Other; Gilead Sciences Inc., Galapagos NV, AbbVie Inc. Eli Lilly and Company, Pfizer. B.G. Combe: Honoraria; Honoraria from AbbVie, BMS, Gilead, Janssen, Eli Lilly and Co., MSD, Novartis, Pfizer, Roche-Chugai, Sanofi and UCB. Y. Tanaka: Honoraria; Received from Daiichi-Sankyo, Astellas, Chugai, Eli Lilly and Co., Pfizer, AbbVie, YL Biologics, BMS, Takeda, Misubishi-Tanabe, Novartis, Eisai, Janssen, Teijin. Grants/research support; Received grant support from Asahi-Kasei, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, BMS, UCB, Daiichi-Sankyo, Eisai, and Ono. A. Kivitiz: Consultancies; Consultant for AbbVie, Celgene, Horizon, Janssen, Merck, Novartis, Pfizer, UCB, Genzyme,Sanofi, Regeneron, SUN Pharma Advanced Research, Boehringer Ingelheim and Flexion. Shareholder/stock ownership; Shareholder of Novartis. F. Matzkies: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. B. Bartok: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. L. Ye: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. Y. Guo: Corporate appointments; Gilead Sciences, Inc. Shareholder/stock ownership; Gilead Sciences, Inc. C. Tasset: Corporate appointments; Employee of Galapagos NV. J.S. Sundy: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. E. Keystone: Consultancies; AbbVie, Amgen, AstraZeneca Pharma, Biotest, BMS Canada, Celltrion, Crescendo, Bioscience, F.Hoffman-La Roche Inc., Genentech, Janssen, Eli Lilly and Co., Merck, Pfizer, PuraPharm, Sandoz,, Sanofi-Aventis, Sanofi- Genzyme Samsung Bioepsis, and UCB. Other; AbbVie, Amgen, AstraZeneca Pharma, Biotest, BMS Canada, Celltrion, Crescendo, Bioscience, F.Hoffman-La Roche Inc., Genentech, Janssen, Eli Lilly and Co., Merck, Pfizer, PuraPharm, Sandoz,, Sanofi-Aventis, Sanofi-Genzyme, Samsumg Bioepsis, and UCB. R. Westhovens: Corporate appointments; An investigator and advisor for Celltrion and Galapagos/Gilead. W. Rigby: Consultancies; Consultancy for Gilead. G.R. Burmester: Consultancies; Consultancy from AbbVie, Gilead, Eli Lilly, and Pfizer. Honoraria; Honoraria from AbbVie, Gilead, Eli Lilly, and Pfizer.

Abstract Background Urinary tract infections while common in the general population are frequently overdiagnosed in patients with asymptomatic bacteriuria. Overtreatment of asymptomatic bacteriuria leads to increasing levels of antibiotic resistance. Demographic factors including age and sex are associated with increased antibiotic resistance. There has been little to no prior research on the association of race or ethnicity with antibiotic resistance. Here we report the results of a retrospective analysis of urine cultures and the associations of race, ethnicity, age, and sex with the presence of extended spectrum beta-lactamases (ESBLs). Methods All urine cultures within the electronic medical record of Corewell Health East were screened for adult outpatients who live in the 3 counties within the main catchment area in southeast Michigan (Wayne, Macomb, and Oakland counties) with positive urine cultures for the year 2019. We identified 22,169 positive urine cultures, of which 1,571 were ESBLs. Demographics for each patient with an ESBL were analyzed including race, ethnicity, sex, age, and zip code. Zip codes were used to determine median annual household income using the 2020 United States Census records and 2019 Internal Revenue Service reports. Logistic regression estimated the association between race, ethnicity, sex, age, and income and presence of an ESBL in the urine. A stepwise regression was also performed to determine the strongest predictors of ESBL. Results Asian race (OR=3.06, 95% CI 2.41 – 3.89), Arabic/Middle Eastern ethnicity (OR= 2.48, 95% CI 1.99 – 3.09) and male sex (OR=2.02, 95% CI 1.76-2.31) were associated with ESBLs. Age showed an increase in the odds ratio of 1.014 for every year over the age of 18 (95% CI 1.012-1.017). No association was found with median annual household income and ESBL. Conclusion These findings show a clear relationship between race, ethnicity, sex, and age and ESBL which appears to be independent of economic status. This serves as proof of concept that social determinants of health are associated with antibiotic resistance. Future work should expand on these relationships in other types of infections which can then be utilized in predictive models of antibiotic resistance geared at improving empiric antibiotic selection in diverse populations. Disclosures Matthew Sims, MD, PhD, Astra-Zeneca: Investigator for company-sponsored studies|ContraFect: Investigator for company-sponsored studies|Crestone: Investigator for company-sponsored studies|Finch: Investigator for company-sponsored studies|Janssen: Investigator for company-sponsored studies|Leonard-Meron: Investigator for company-sponsored studies|Merck and Co: Investigator for company-sponsored studies|OpGen Inc: Advisor/Consultant|OpGen Inc: Investigator for company-sponsored studies|Pfizer: Investigator for company-sponsored studies|Prenosis: Advisor/Consultant|Prenosis: Investigator for company-sponsored studies|QIAGEN Sciences LLC: Investigator for company-sponsored studies|Roche: Investigator for company-sponsored studies|Seres Therapeutics: Investigator for company-sponsored studies

Abstract Background Escherichia coli is a common Gram-negative bacterium that can infect normally sterile body sites and cause invasive E. coli disease (IED) including bacteremia, sepsis and septic shock. E. coli surface O-antigens are important virulence factors that contribute to pathogenicity, making them promising targets for the development of multivalent conjugate vaccines to protect against IED. Here, we describe the prevalence of O-serotypes and O-genotypes of clinical E. coli isolates across a multinational cohort of patients with IED. Methods This was a retrospective, multicenter, noninterventional study across 17 tertiary care hospitals in Europe, North America and Asia. Patients with an IED diagnosis in the 12 months prior to data collection were included. IED was defined as E. coli presence in cultures from any normally sterile body site or urine in patients exhibiting clinical criteria of invasive disease (i.e., systemic inflammatory response syndrome [SIRS], sepsis, or septic shock) and no other identifiable site of infection. O-serotyping (agglutination) and O-genotyping (whole genome sequencing [WGS]) were conducted. Subgroup analyses were performed in isolates from patients with bacteremic vs nonbacteremic IED and in patients ≥60 years old. Results 902 patients with IED were identified (median age at initial IED diagnosis, 71.0 years; 51.6% male). The most common O-serotypes (prevalence ≥5%) based on O-genotyping were O25 (17.3% [95% CI, 14.82–20.06%]), O2 (11.7% [95% CI, 9.61–14.08%]), O6 (9.3% [95% CI, 7.44–11.49%]), O1 (6.3% [95% CI, 4.78–8.20%]), O15 (5.3% [95% CI, 3.85– 6.99%]) and O75 (5.0% [95% CI, 3.64–6.72%]) (Table 1). Collectively, these 6 most prevalent serotypes accounted for 55.0% of total isolates. A similar pattern of O-serotypes was observed in the subgroup of patients ≥60 years old (Table 2), with serotypes O25, O2 and O6 most common in both bacteremic and nonbacteremic IED isolates. Conclusion The most predominant O-serotype among IED isolates from hospitalized patients with IED was O25, followed by O2, O6, O1, O15 and O75. Such epidemiological data could inform the development of an effective prophylactic vaccine against IED. Disclosures Jeroen Geurtsen, PhD, Janssen: Employee|Janssen: Stocks/Bonds Joachim Doua, MD, MPH, Janssen: Employee|Janssen: Stocks/Bonds Patricia Ibarra de Palacios, MD, Janssen: Employee at the time of analysis Matthew Sims, MD, PhD, Astra-Zeneca: Investigator for company-sponsored studies|ContraFect: Investigator for company-sponsored studies|Crestone: Investigator for company-sponsored studies|Finch: Investigator for company-sponsored studies|Janssen: Investigator for company-sponsored studies|Leonard-Meron: Investigator for company-sponsored studies|Merck and Co: Investigator for company-sponsored studies|OpGen Inc: Advisor/Consultant|OpGen Inc: Investigator for company-sponsored studies|Pfizer: Investigator for company-sponsored studies|Prenosis: Advisor/Consultant|Prenosis: Investigator for company-sponsored studies|QIAGEN Sciences LLC: Investigator for company-sponsored studies|Roche: Investigator for company-sponsored studies|Seres Therapeutics: Investigator for company-sponsored studies Peter Hermans, PhD, Janssen: Employee at the time of analysis Joshua T. Thaden, MD, PhD, Resonantia Diagnostics, Inc: Advisor/Consultant Oscar Go, PhD, Janssen: Employee|Janssen: Stocks/Bonds Bart Spiessens, PhD, Janssen: Employee|Janssen: Stocks/Bonds Darren Abbanat, PhD, Janssen: Employee at the time of analysis Florian Wagenlehner, MD, Achaogen: Advisory Board member, study participation|Astellas: Honoraria|AstraZeneca: Honoraria|AstraZeneca: Advisory Board member|Biomedical Advanced Research and Development Authority (BARDA): Grant/Research Support|Bionorica: Honoraria|Bionorica: Meeting/travel support, study participation|Deutsches Zentrum für Infektionsforschung (DZIF): Study participation|Enteris BioPharma: Study participation|Everest Medicines: Grant/Research Support|German S3 guideline Urinary tract infections: Board Member|Glaxo Smith Kline: Advisor/Consultant|Glaxo Smith Kline: Honoraria|Glaxo Smith Kline: Consulting fees, meeting/travel support, advisory board member, principal investigator in a GSK-sponsored study|Global Antibiotic Research and Development Partnership (GARDP Foundation): Grant/Research Support|Guidelines European Association of Urology: Infections in Urology: Board Member|Helperby Therapeutics: Study participation|Janssen: Honoraria|Janssen: Advisory Board member|Klosterfrau: Honoraria|LeoPharma: Advisory Board member|MerLion: Advisory Board member|MIP Pharma: Honoraria|MSD: Advisory Board member|OM Pharma/Vifor Pharma: Advisory Board member, study participation|OM-Pharma: Honoraria|Pfizer: Honoraria|Pfizer: Advisory Board member|RosenPharma: Advisory Board member|Shionogi: Advisory Board member, study participation|Speaker research group German research foundation (DFG) Bacterial Renal Infections and Defense (FOR 5427): Study participation|Spero Therapeutics: Advisor/Consultant|Spero Therapeutics: Consulting fees|University Hospital Giessen and Marburg GmbH, and Justus Liebig University, Germany: Employee|Venatorx Pharmaceuticals, Inc.: Advisor/Consultant|Venatorx Pharmaceuticals, Inc.: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Consulting fees, Advisory Board member Tetsuya Matsumoto, MD; PhD, member of the international study steering committee for the E.mbrace study and reports payment: Board Member Marc Bonten, MD, PhD, chair of the international study steering committee for the E.mbrace study (Janssen Vaccines), with payments made to UMC Utrecht: Board Member Michal Sarnecki, MD, Janssen: Employee|Janssen: Stocks/Bonds Jan Poolman, PhD, Janssen: Employee|Janssen: Stocks/Bonds