Abstract: Filgotinib (FIL) is a Janus kinase 1 preferential inhibitor for the treatment of moderate to severe rheumatoid arthritis (RA) 1 . The recommended dose for adults with RA is 200 mg (FIL200); however, a starting dose of 100 mg (FIL100) is recommended for those aged ≥75 years (y) in view of limited clinical experience 1 . An important consideration is the generally higher incidence of adverse events (AEs) in the elderly due to comorbidities. Objectives To evaluate the efficacy and safety of FIL100 and FIL200 in patients with RA aged ≥75 y. Methods FINCH 4 ( NCT03025308 ) is an ongoing phase 3 open-label LTE study of FIL100 and FIL200 for RA. Eligible patients completed a prior phase 3 randomized double-blind study of FIL lasting 52 weeks (FINCH 1 or 3) or 24 weeks (FINCH 2). In this post hoc analysis, safety and efficacy were assessed in patients aged 〈 75 and ≥75 y in FINCH 4. Efficacy measures were American College of Rheumatology (ACR)20/50/70 responses, clinical disease activity index (CDAI) ≤10/≤2.8, disease activity score (DAS)28 〈 2.6/≤3.2 and health assessment questionnaire-disability index (HAQ-DI). Results At LTE Week 48, 52% and 44% of patients aged 〈 75 and ≥75 y, respectively, were on methotrexate. In both age groups, response rates for key efficacy measures at LTE Week 48 were generally maintained from LTE baseline (Figure 1) in patients with and without prior FIL exposure in FINCH 1–3, and were numerically higher with FIL200 vs FIL100. Mean change from baseline in HAQ-DI with FIL200 and FIL100 was 0.61 and 0.74 in those aged 〈 75 y and 1.04 and 0.98 in those aged ≥75 y, respectively. Figure 1. The exposure-adjusted incidence rate (EAIR) of serious AEs and AEs of special interest (AESI) was generally higher in patients aged ≥75 y than 〈 75 y. In those aged ≥75 y, the EAIR of AEs leading to premature study discontinuation, treatment-emergent AEs (TEAEs), and serious TEAEs was higher with FIL200 vs FIL100; the incidence of major adverse cardiovascular events, venous thrombotic and embolic events, serious infections, herpes zoster and malignancies was low in both dose groups (Table 1). Three patients died, all from the FIL200 group; each had a medical history relevant to the cause of death. Table 1. Exposure-adjusted incidence rate (95% CI) of AEs at Week 48 as events per 100 years of exposure FIL200 FIL100 Age, years 〈 75 ≥75 〈 75 ≥75 n=1469 n=61 n=1136 n=63 (PYE 2253.9) (PYE 92.2) (PYE 1753.7) (PYE 98.4) With prior FIL exposure, n (%) 1142 (77.7) 53 (86.9) 830 (73.1) 33 (52.4) TEAE 48.3 (45.5, 51.3) 55.3 (42.1, 72.8) 48.7 (45.5, 52.1) 42.7 (31.6, 57.8) Serious TEAE 6.8 (5.8, 8.0) 17.4 (10.6, 28.3) 7.4 (6.2, 8.7) 14.2 (8.4, 24.0) AE leading to premature study discontinuation 2.9 (2.3, 3.7) 9.8 (5.1, 18.8) 3.9 (3.1, 5.0) 4.1 (1.5, 10.8) AE leading to death 0.5 (0.3, 0.9) 3.3 (0.7, 9.5)* 0.3 (0.2, 0.8) 0.0 (0.0, 3.8) Infections 28.8 (26.6, 31.1) 29.3 (20.1, 42.7) 27.4 (25.0, 29.9) 26.4 (18.0, 38.8) Serious infections 1.6 (1.2, 2.2) 2.2 (0.5, 8.7) 1.7 (1.1, 2.4) 3.1 (1.0, 9.5) Herpes zoster 1.6 (1.2, 2.3) 2.2 (0.5, 8.7) 1.0 (0.6, 1.6) 3.1 (1.0, 9.5) Adjudicated major adverse cardiovascular event 0.4 (0.2, 0.7) 2.2 (0.5, 8.7) 0.5 (0.2, 0.9) 1.0 (0.1, 7.2) Venous thrombotic and embolic events 0.3 (0.1, 0.6) 2.2 (0.5, 8.7) 0.2 (0.1, 0.5) 1.0 (0.1, 7.2) Malignancy excluding NMSC 0.7 (0.4, 1.2) 4.3 (1.6, 11.6) 0.7 (0.4, 1.2) 3.1 (1.0, 9.5) NMSC 0.4 (0.2, 0.8) 1.1 (0.0, 6.0) 0.2 (0.1, 0.6) 0.0 (0.0, 3.8) *Cause of death: esophageal carcinoma; cardiovascular; unknown. FIL(100/200), filgotinib (100/200 mg); NMSC, nonmelanoma skin cancer; PYE, patient years of exposure; (TE)AE, (treatment-emergent) adverse event Conclusion In the ≥75 y group, response rates for key efficacy measures remained stable to Week 48 and were generally higher with FIL200 vs FIL100. The incidence of serious AEs and AESI was higher in those aged ≥75 than 〈 75 y. Patient numbers/exposure time may have been insufficient to show potential between-group differences in safety/efficacy outcomes. References [1]Filgotinib SmPC Acknowledgements The FINCH studies were funded by Gilead Sciences (Foster City, CA, United States). We thank the physicians and patients who participated in the studies. Medical writing support was provided by Debbie Sherwood, BSc (Aspire Scientific Ltd, Bollington, UK) and funded by Galapagos NV (Mechelen, Belgium). Disclosure of Interests Daniel Aletaha Speakers bureau: AbbVie, Amgen, Lilly, Janssen, Merck, Novartis, Pfizer, Roche, and Sandoz, Consultant of: AbbVie, Amgen, Lilly, Janssen, Merck, Novartis, Pfizer, Roche, and Sandoz, Grant/research support from: AbbVie, Amgen, Lilly, Novartis, Roche, SoBi, and Sanofi, Rene Westhovens Speakers bureau: Celltrion, Galapagos, and Gilead, Consultant of: Celltrion, Galapagos, and Gilead, Bernard Combe Speakers bureau: AbbVie, BMS, Celltrion, Eli Lilly, Gilead-Galapagos, Janssen, MSD, Novartis, Pfizer, and Roche-Chugai, Consultant of: AbbVie, Celltrion, Eli Lilly, Gilead-Galapagos, Janssen, and Roche-Chugai, Jacques-Eric Gottenberg Consultant of: AbbVie, BMS, Galapagos, Gilead, Lilly, and Pfizer, Grant/research support from: BMS and Pfizer, Maya H Buch Speakers bureau: AbbVie, Consultant of: AbbVie, Galapagos, Gilead, and Pfizer, Grant/research support from: Gilead and Pfizer, Roberto Caporali Speakers bureau: AbbVie, Amgen, BMS, Celltrion, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Sandoz, and UCB, Consultant of: AbbVie, Amgen, BMS, Celltrion, Fresenius-Kabi, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sandoz, and UCB, José A Gómez-Puerta Speakers bureau: AbbVie, BMS, Galapagos, GSK, Lilly, MSD, Novartis, Pfizer, Roche, and Sanofi, Consultant of: GSK, Roche, and Sanofi, Paul Van Hoek Employee of: Galapagos, Vijay Rajendran Employee of: Galapagos, Pieter-Jan Stiers Shareholder of: Galapagos, Employee of: Galapagos, Thijs Hendrikx Employee of: Galapagos, Gerd Rüdiger Burmester Consultant of: AbbVie, Amgen, BMS, Galapagos, Lilly, MSD, Pfizer, Roche, and Sanofi, Yoshiya Tanaka Speakers bureau: AbbVie, Amgen, Astellas, Astra-Zeneca, Boehringer-Ingelheim, BMS, Chugai, Eisai, Eli Lilly, Gilead, Mitsubishi-Tanabe, and YL Biologics, Consultant of: AbbVie, Ayumi, Daiichi-Sankyo, Eli Lilly, GSK, Sanofi, and Taisho, Grant/research support from: AbbVie, Asahi-Kasei, Boehringer-Ingelheim, Chugai, Corrona, Daiichi-Sankyo, Eisai, Kowa, Mitsubishi-Tanabe, and Takeda

Abstract: The preferential Janus kinase-1 inhibitor FIL is approved for treatment of moderate to severe active RA in Europe and Japan. Objectives In this post hoc, exploratory analysis, efficacy and safety of long-term treatment with FIL (± MTX) were assessed in MTX-naïve pts treated with FIL or MTX in the Phase 3 PS ( NCT02886728 ). 1 Methods Pts received FIL 200 mg (FIL200)+MTX, FIL 100 mg (FIL100)+MTX, FIL200 alone, or MTX alone up to 52 W in PS. 1 Those completing PS on study drug could enter LTE ( NCT03025308 ; data cutoff: June 1, 2020). MTX completers were rerandomized, blinded, to FIL200 or FIL100; pts on FIL in PS remained on the same dose in LTE. MTX was washed out for 4 W at LTE baseline (BL); pts could (re)start MTX and/or other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) ≥4 W after LTE first dosing. 1 Efficacy data to LTE W48 and safety data are reported. Results As of June 1, 2020, 439/492 (89%) and 144/169 (85%) pts who entered LTE from PS FIL200 and PS FIL100 groups, respectively, remained on LTE study treatment; of those rerandomized from MTX, 131/148 (89%) FIL200 and 133/151 (88%) FIL100 pts remained on study treatment. LTE BL characteristics were similar between FIL200 and FIL100 groups. After MTX washout, 17% of FIL200 and 23% of FIL100 pts (re)started MTX (at clinical judgment). ACR20/50/70 response rates among pts from PS FIL arms decreased modestly from LTE BL to W12 then stabilized. Among pts who switched from PS MTX to LTE FIL, response rates remained stable or improved to approach those of PS FIL pts by W48 (Figure 1). Similar trends were seen in DAS28(CRP) and CDAI. Treatment-emergent adverse events (TEAEs), Grade ≥3 AEs, serious AEs, and infections were largely comparable across groups and did not increase after MTX to FIL switch. There were 6 deaths, all among PS FIL200 pts (Table 1). Table 1. EAIRs of TEAEs through June 2020 EAIR (95% CI) FIL200+MTX → FIL200 → FIL100+MTX → MTX → MTX → FIL200 LTE FIL200 LTE FIL100 LTE FIL200 LTE FIL100 LTE n=325 n=167 n=169 n=148 n=151 PYE=474.4 PYE=232.5 PYE=236.4 PYE=213.4 PYE=215.4 TEAE 49.7 (43.8, 56.5) 46.9 (38.9, 56.6) 49.9 (41.7, 59.8) 50.6 (41.9, 61.1) 46.4 (38.2, 56.5) TEAE Grade ≥3 7.2 (5.1, 10.0) 6.5 (3.9, 10.7) 10.2 (6.8, 15.1) 7.0 (4.2, 11.7) 7.0 (4.2, 11.6) TE serious AE 5.9 (4.1, 8.5) 6.0 (3.6, 10.2) 8.9 (5.8, 13.6) 6.6 (3.9, 11.1) 6.5 (3.9, 11.0) Death 1.1 (0.3, 2.5) 0.4 (0.1, 3.1) 0 (0, 1.6) 0 (0, 1.7) 0 (0, 1.7) Infections 28.5 (24.0, 33.7) 29.7 (23.4, 37.6) 27.5 (21.6, 35.1) 28.6 (22.2, 36.7) 27.4 (21.2, 35.4) Serious infections 1.1 (0.4, 2.5) 3.0 (1.4, 6.3) 2.5 (1.1, 5.7) 1.9 (0.7, 5.0) 1.9 (0.7, 4.9) Opportunistic infections 0.2 (0, 1.5) 0 (0, 1.6) 0.8 (0.2, 3.4) 0 (0, 1.7) 0 (0, 1.7) Herpes zoster 0.8 (0.3, 2.2) 1.7 (0.6, 4.6) 0.8 (0.2, 3.4) 1.9 (0.7, 5.0) 0.9 (0.2, 3.7) MACE (adjudicated) 0.6 (0.1, 1.8) 0.9 (0.2, 3.4) 0 (0, 1.6) 0 (0, 1.7) 0 (0, 1.7) VTE (adjudicated for DVT/PE) 0.2 (0, 1.2) 0.4 (0.1, 3.1) 0 (0, 1.6) 0 (0, 1.7) 0 (0, 1.7) Malignancies (excluding NMSC) 0.6 (0.2, 2.0) 0 (0, 1.6) 1.7 (0.6, 4.5) 0.5 (0, 2.6) 0 (0, 1.7) NMSC 0.6 (0.2, 2.0) 0.4 (0.1, 3.1) 0.8 (0.2, 3.4) 0.5 (0, 2.6) 0 (0, 1.7) DVT, deep vein thrombosis; EAIRs, exposure-adjusted incidence rates (per 100 patient-years of exposure); MACE, major adverse cardiovascular event; NMSC, nonmelanoma skin cancer; PE, pulmonary embolism; VTE, venous thromboembolism Figure 1. Conclusion Overall, response rates improved from LTE BL to W48 for pts switched from PS MTX to FIL and decreased modestly for PS FIL pts. Rates of AEs of special interest were generally low and tended to be higher in pts maintained on FIL from PS. Safety findings in this subpopulation were comparable with the PS through W52 1 and with a 7-trial integrated safety analysis. 2 Limitations: the LTE was not formally randomized at BL, the groups were of unequal size, and the switch from MTX to FIL for LTE was by design rather than based on disease activity. References [1]Westhovens R et al. Ann Rheum Dis 2021;80:727–38. [2]Winthrop K et al. Arthritis Rheumatol 2020;72(suppl 10): abstract 0229. Acknowledgements Funding for the trials was provided by Galapagos NV and Gilead Sciences, Inc. The sponsors participated in the planning, execution, and interpretation of the research. This study was funded by Gilead Sciences, Inc., Foster City, CA. Medical writing support was provided by Gregory Bezkorovainy, MA, of AlphaScientia, LLC, San Francisco, CA; and funded by Gilead Sciences, Inc., Foster City, CA. Funding for this analysis was provided by Gilead Sciences, Inc. Disclosure of Interests 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, Rene Westhovens Consultant of: Celltrion, Galapagos, and Gilead Sciences, Inc., Grant/research support from: Celltrion, Galapagos, and Gilead Sciences, Inc., Tatsuya Atsumi Speakers bureau: AbbVie Inc., Astellas Pharma Inc., Bristol Myers Squibb Co., Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd, Eisai Co. Ltd, Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma Co., Otsuka Pharmaceutical Co., Ltd, Pfizer Inc., Takeda Pharmaceutical Co., Ltd, UCB Japan Co. Ltd, Consultant of: AbbVie Inc., Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd, Eli Lilly Japan K.K., Gilead Sciences, Inc., Pfizer Inc., UCB Japan Co. Ltd, Grant/research support from: AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Bristol Myers Squibb Co., Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd, Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma Co., Pfizer Inc., YingMeei Tan Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Alena Pechonkina Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Qi Gong Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Vijay Rajendran Shareholder of: Galapagos NV, Employee of: Galapagos NV, Sander Strengholt Shareholder of: Galapagos BV, Employee of: Galapagos BV, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Eli Lilly, Gilead Sciences, Inc. and Pfizer, Consultant of: AbbVie, Eli Lilly, Gilead Sciences, Inc. and Pfizer