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: Filgotinib (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. 1 Objectives To assess the effect of FIL on lymphocyte levels and lymphopenia in the FINCH 4 long-term extension (LTE) study in RA. Methods Safety 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. Results The 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 lymphocytes Prior FIL exposure No prior FIL exposure Overall Total FIL200 FIL100 FIL200 FIL100 FIL200 FIL100 (N=2729) (n=1195) (n=863) (n=335) (n=336) (n=1530) (n=1199) Decreased lymphocytes 228 (19.1) 125 (14.5) 41 (12.3) 40 (12.0) 269 (17.6) 165 (13.8) 434 (16.0) (any grade), n (% ) Grade 1 48 (4.0) 35 (4.1) 14 (4.2) 7 (2.1) 62 (4.1) 42 (3.5) 104 (3.8) Grade 2 159 (13.3) 82 (9.5) 21 (6.3) 26 (7.8) 180 (11.8) 108 (9.1) 288 (10.6) Grade 3 21 (1.8) 8 (0.9) 6 (1.8) 7 (2.1) 27 (1.8) 15 (1.3) 42 (1.5) Grade 4 0 0 0 0 0 0 0 A 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 × 10 9 /L [Grade 1]; 〈 0.8–0.5 × 10 9 /L [2]; 〈 0.5–0.2 × 10 9 /L [3]; 〈 0.2 × 10 9 /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. Conclusion In 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/en Acknowledgements The 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 Interests Jacques-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.