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 Efficacy and safety of FIL were assessed in patients (pts) with IR to bDMARDs in a LTE trial ( NCT03025308 ) enrolled from a Phase 3 PS ( NCT02873936 ). 1 Methods bDMARD-IR pts received FIL 200 mg (FIL200), FIL 100 mg (FIL100), or placebo (PBO), all with stable conventional synthetic (cs)DMARDs up to 24 weeks (W). At W14 of the PS, pts with IR to FIL or PBO ( 〈 20% improvement in swollen [66] and tender [68] joint counts) switched to standard of care (SOC; investigator’s choice of treatment). Pts completing the PS on FIL, PBO, or SOC could enter the LTE. PS FIL pts were maintained, blinded, on their FIL dose; PS PBO and PS SOC pts were rerandomized, blinded, to FIL200 or FIL100. Efficacy data to LTE W48 and safety data to data cutoff (June 1, 2020) are reported. Results The PS included 147, 153, and 148 pts on FIL200, FIL100, and PBO. Pts continuing on LTE FIL200 and FIL100 at data cutoff: 80/121 (66%) and 76/110 (69%) from PS FIL200 and FIL100; 35/47 (75%) and 32/46 (70%) from PS PBO, and 13/23 (57%) and 13/22 (59%) from PS SOC. LTE baseline (BL) characteristics were similar in FIL200 and FIL100 pts. During LTE, PS FIL ACR20/50/70 response rates decreased modestly by W48 (Figure 1). Among PS PBO pts, response rates were lower at LTE BL, reaching similar levels to PS FIL pts by W48; rates increased to W48 in PS SOC pts on either FIL dose but not to levels of other groups. Percentages of pts attaining DAS28(CRP) ≤3.2, DAS28(CRP) 〈 2.6, CDAI ≤10, and CDAI ≤2.8 were maintained up to W48 for FIL/FIL pts. PBO/FIL and SOC/FIL pts showed similar patterns to ACR responses (Figure 1). Exposure-adjusted incidence rates (EAIRs)/100 pt-years of exposure for treatment-emergent adverse events (TEAE), serious AEs, and serious infection were higher in SOC/FIL pts vs FIL/FIL or PBO/FIL pts, but samples were small and confidence intervals overlapped. There were 5 deaths (Table 1). Table 1. EAIRs of TEAEs in LTE, as of June 1, 2020 EAIR (95% CI) FIL200+csD → FIL200+csD n=121PYE 228.4 PBO+csD → FIL200+csD n=47PYE 98.1 SOC+csD → FIL200+csD n=23PYE 42.1 FIL100+csD → FIL100+csD n=110PYE 223.3 PBO+csD → FIL100+csD n=46PYE 91.1 SOC+csD → FIL100+csD n=22PYE 38.2 TEAE 46.9 (38.8, 56.6) 38.7 (28.2, 53.2) 52.2 (34.4, 79.3) 40.3 (32.8, 49.5) 40.6 (29.4, 56.1) 49.8 (31.8, 78.0) TEAE Grade ≥3 10.5 (7.0, 15.7) 10.2 (5.5, 18.9) 19.0 (9.5, 38.0) 10.3 (6.8, 15.5) 13.2 (7.5, 23.2) 18.3 (8.7, 38.5) TE serious AE 12.3 (8.5, 17.8) 12.2 (6.9, 21.5) 21.4 (11.1, 41.1) 8.1 (5.1, 12.8) 13.2 (7.5, 23.2) 21.0 (10.5, 41.9) Death 1.3 (0.4, 4.1) 1.0 (0, 5.7) 0 (0, 8.8) 0.4 (0.1, 3.2) 0 (0, 4.0) 0 (0, 9.7) TE infections 34.2 (27.4, 42.6) 22.4 (14.8, 34.1) 35.6 (21.5, 59.1) 22.4 (17.0, 29.5) 26.3 (17.7, 39.3) 39.3 (23.7, 65.2) TE serious infections 3.5 (1.8, 7.0) 2.0 (0.5, 8.2) 7.1 (2.3, 22.1) 0.9 (0.2, 3.6) 2.2 (0.5, 8.8) 7.9 (2.5, 24.4) Opportunistic infections 0 (0, 1.6) 0 (0, 3.8) 0 (0, 8.8) 0 (0, 1.7) 0 (0, 4.0) 0 (0, 9.7) TE herpes zoster 2.2 (0.7, 5.1) 1.0 (0.1, 7.2) 0 (0, 8.8) 0 (0, 1.7) 2.2 (0.5, 8.8) 2.6 (0.1, 14.6) TE MACE (adjudicated) 1.3 (0.4, 4.1) 1.0 (0.1, 7.2) 0 (0, 8.8) 0.9 (0.2, 3.6) 1.1 (0.2, 7.8) 0 (0, 9.7) TE DVT/PE (adjudicated) 0.9 (0.2, 3.5) 0 (0, 3.8) 2.4 (0.1, 13.2) 0.4 (0.1, 3.2) 0 (0, 4.0) 0 (0, 9.7) Malignancies (excluding NMSC) 1.3 (0.4, 4.1) 3.1 (1.0, 9.5) 4.7 (0.6, 17.2) 1.8 (0.7, 4.8) 3.3 (1.1, 10.2) 0 (0, 9.7) NMSC 0 (0, 1.6) 0 (0, 3.8) 4.7 (0.6, 17.2) 0 (0, 1.7) 0 (0, 4.0) 0 (0, 9.7) DVT, deep vein thrombosis; MACE, major adverse cardiovascular event; NMSC, nonmelanoma skin cancer; PE, pulmonary embolism; TE, treatment-emergent Conclusion Efficacy was mostly maintained in PS FIL pts up to W48. Response among PS PBO and SOC pts increased from BL to W48, but response in PS SOC pts continued to be lower than in other groups; these pts may represent a refractory population. FIL safety was largely consistent between PS and LTE. References [1]Genovese MC et al. JAMA 2019;322:315–25. Acknowledgements This study was funded by Gilead Sciences, Inc., Foster City, CA. Medical writing support was provided by Claudine Bitel, PhD, of AlphaScientia, LLC, San Francisco, CA; and funded by Gilead Sciences, Inc., Foster City, CA. Disclosure of Interests Maya H Buch Speakers bureau: AbbVie, Consultant of: AbbVie, Galapagos, Gilead, and Pfizer, Grant/research support from: Gilead and Pfizer, Tsutomu Takeuchi Speakers bureau: AbbVie, AYUMI, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Eli Lilly Japan, Gilead Sciences, Mitsubishi-Tanabe, Novartis, Pfizer Japan, and Sanofi, Consultant of: Astellas, Chugai, and Eli Lilly Japan, Grant/research support from: AbbVie, Asahi Kasei, Astellas, Chugai, Daiichi Sankyo, Eisai, Mitsubishi-Tanabe, Shionogi, Takeda, and UCB Japan, Vijay Rajendran Shareholder of: Galapagos, Employee of: Galapagos, Jacques-Eric Gottenberg Speakers bureau: AbbVie, Eli Lilly and Co., Galapagos, Gilead Sciences, Inc., Roche, Sanofi Genzyme, and UCB, Consultant of: Bristol Myers Squibb, Sanofi Genzyme, and UCB, Grant/research support from: Bristol Myers Squibb and Pfizer, Alena Pechonkina Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., YingMeei Tan Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Qi Gong Shareholder of: Gilead Sciences, Inc., Employee of: Gilead Sciences, Inc., Katrien Van Beneden Shareholder of: Galapagos, Employee of: Galapagos, Roberto Caporali Speakers bureau: AbbVie, Amgen, BMS, Celltrion, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Sandoz, and UCB, Consultant of: AbbVie, Amgen, BMS, Celltrion, Galapagos, Janssen, Lilly, Fresenius-Kabi, MSD, Novartis, Pfizer, Roche, Sandoz, and UCB

Abstract: FIL is a Janus kinase (JAK) 1 preferential inhibitor approved for the treatment (tx) of moderate to severe RA. Weight gain has been reported with other JAK inhibitors 1–3 ; it is important to describe the effect of FIL on BW/BMI for physicians to correctly inform and appropriately treat patients. Objectives Our primary aim was to assess the effect of FIL on BW/BMI using data from the FINCH 1–3 studies. Secondary aims were to assess the efficacy and safety of FIL according to baseline BMI. Methods FINCH 1–3 ( NCT02889796 , NCT02873936 , NCT02886728 ) were phase 3, randomised, double-blind, active/placebo (PBO)-controlled studies of FIL 100/200 mg (FIL100/FIL200) ± methotrexate (MTX) in patients with active RA who had an inadequate response to MTX (FINCH 1) or biologic DMARD (FINCH 2), or were MTX naïve (FINCH 3). We assessed changes from baseline (CFB) in BW and BMI by tx group and baseline BMI, and the efficacy and safety of FIL by baseline BMI ( 〈 25, 25– 〈 30 or ≥30 kg/m 2 ). Efficacy measures included American College of Rheumatology (ACR)20/50/70 response, Disease Activity Score 28 with C-reactive protein (DAS28-CRP) and health assessment questionnaire disability index (HAQ-DI). Safety data were from 7 RA clinical trials (FINCH 1–4, DARWIN 1–3) 4 . Results In FINCH 1–3, baseline disease characteristics such as HAQ-DI, DAS28-CRP and clinical disease activity index were similar across BMI subgroups for each tx group. There were no clinically relevant CFB in median BW or BMI in any tx group or differences between tx groups. Mean CFB in BMI (kg/m 2 ) were 0.4 with FIL200 and FIL100 and 0.3 with adalimumab (ADA) at Week 52 in FINCH 1; 0.2, 0.6 and −0.1 with FIL200, FIL100 and PBO, respectively, at Week 24 in FINCH 2; and 0.5, 0.6, 1.1 and 0.3 with FIL200+MTX, FIL100+MTX, FIL200 and MTX, respectively, at Week 52 in FINCH 3. CFB in BMI did not appear dependent on baseline BMI. FIL200±MTX was efficacious vs controls regardless of baseline BMI for most measures at each timepoint. In FINCH 1, in the 〈 25, 25– 〈 30 and ≥30 kg/m 2 BMI subgroups, DAS28-CRP 〈 2.6 was achieved by 38%, 29% and 33% of the FIL200 group, 29%, 19% and 21% of the ADA group, and 7%, 10% and 11% of the PBO group at Week 12, respectively. Figure 1 shows ACR20 responders by baseline BMI in FINCH 1–3. Integrated safety data across baseline BMI subgroups are summarised in Table 1. VTE rate was numerically higher with FIL200 in the ≥30 than 25– 〈 30 or 〈 25 kg/m 2 BMI subgroups; serious infection rate was numerically higher with FIL100 in the 〈 25 mg/m 2 subgroup vs other BMI subgroups. Table 1. Exposure-adjusted incidence rate (95% CI) of AEs per 100 PYE by baseline BMI FIL dose (mg) BMI (kg/m 2 ) 〈 25 25– 〈 30 ≥30 PYE 3062.8 PYE 2640.1 PYE 2382.2 TEAEs 200 34.5 (32.0, 37.1) 35.7 (33.0, 38.6) 36.6 (33.7, 39.8) 100 44.3 (40.4, 48.6) 43.0 (38.9, 47.5) 45.3 (41.1, 50.0) Serious TEAEs 200 5.3 (4.4, 6.4) 5.8 (4.8, 7.1) 7.1 (5.8, 8.5) 100 7.6 (6.0, 9.4) 6.5 (5.0, 8.4) 8.1 (6.4, 10.2) Deaths 200 0.3 (0.2, 0.7) 0.5 (0.3, 1.0) 0.5 (0.2, 1.0) 100 0.4 (0.1, 1.0) 0.3 (0.1, 1.0) 0.2 (0.1, 0.9) Venous thrombotic and embolic events 200 0.1 (0.0, 0.4) 0.1 (0.0, 0.5) 0.5 (0.2, 1.0) 100 0.1 (0.0, 0.7) 0.1 (0.0, 0.8) 0.2 (0.1, 0.9) Major adverse cardiovascular events 200 0.3 (0.2, 0.7) 0.3 (0.1, 0.7) 0.5 (0.2, 1.0) 100 0.6 (0.3, 1.3) 0.3 (0.1, 1.0) 0.6 (0.2, 1.4) Serious infections 200 1.1 (0.7, 1.7) 1.7 (1.2, 2.5) 1.8 (1.2, 2.6) 100 2.6 (1.8, 3.9) 1.2 (0.7, 2.2) 2.2 (1.4, 3.4) Herpes zoster 200 1.6 (1.1, 2.2) 1.4 (1.0, 2.1) 1.8 (1.2, 2.6) 100 1.0 (0.5, 1.8) 1.2 (0.7, 2.2) 1.0 (0.5, 2.0) Malignancy excluding nonmelanoma skin cancer 200 0.5 (0.3, 1.0) 0.7 (0.4, 1.3) 0.5 (0.3, 1.1) 100 0.6 (0.3, 1.3) 0.4 (0.2, 1.2) 0.8 (0.4, 1.7) BMI, body mass index; FIL, filgotinib; PYE, patient years of exposure; (TE)AE, (treatment-emergent) adverse event Conclusion FIL did not substantially affect CFB in BW or BMI. FIL200±MTX was generally more efficacious vs controls regardless of baseline BMI, and the rate of TEAEs was similar across baseline BMI subgroups. References [1]Tofacitinib SmPC [2]Baracitinib SmPC [3]Upadacitinib SmPC [4]Winthrop K, et al. ACR 2021. Abstract 1698 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 Alejandro Balsa Speakers bureau: AbbVie, Galapagos, Gilead, Lilly, Nordic, Pfizer, Sandoz, and UCB, Consultant of: AbbVie, Galapagos, Lilly, Nordic, Pfizer, and UCB, Grant/research support from: AbbVie, Pfizer, UCB, Siegfried Wassenberg Speakers bureau: AbbVie, MSD, Pfizer, and Sanofi, Consultant of: AbbVie, Gilead, Lilly, Nichi-Iko, Pfizer, and UCB, Grant/research support from: Pfizer, Anne Tournadre Speakers bureau: Fresenius-Kabi and Sanofi, Paid instructor for: Fresenius-Kabi, Consultant of: AbbVie, Fresenius-Kabi, Lilly, Novartis, and Sanofi, Grant/research support from: Novartis, Pfizer, and UCB, Hans-Dieter Orzechowski Employee of: Galapagos, Katrien Van Beneden Shareholder of: Galapagos, Employee of: Galapagos, Vijay Rajendran Employee of: Galapagos, Udo Lendl Employee of: Galapagos, Pieter-Jan Stiers Shareholder of: Galapagos, Employee of: Galapagos, Chris Watson Shareholder of: Galapagos, Employee of: Galapagos, Roberto Caporali Speakers bureau: AbbVie, Accord, BMS, Celltrion, Fresenius-Kabi, Galapagos, Lilly, MSD, Novartis, Pfizer, Sandoz, and UCB, Consultant of: AbbVie, Accord, BMS, Celltrion, Fresenius-Kabi, Galapagos, Lilly, MSD, Novartis, Pfizer, Sandoz, and UCB, Patrick Verschueren Speakers bureau: Eli Lilly, Galapagos, MSD, and Roularta, Consultant of: AbbVie, BMS, Celltrion, Eli Lilly, Galapagos, Gilead, Nordic Pharma, Pfizer, Sidekick Health, and UCB, Grant/research support from: Pfizer Chair Management of Early Rheumatoid Arthritis at KU Leuven Belgium.