Exploratory analysis of filgotinib safety data in patients with moderately to severely active rheumatoid arthritis and an increased risk of cardiovascular events: data from phase 2 and 3 clinical trials

Abstract Background/Aims The safety profile of filgotinib (FIL), a second-generation oral Janus kinase (JAK) 1 preferential inhibitor approved in Europe, Japan, and the UK for treatment of rheumatoid arthritis (RA) has been reported. In patients (pts) with active RA aged ≥50y with ≥1 cardiovascular (CV) risk factor, treated with the pan-JAK inhibitor tofacitinib, data from an interventional post-marketing study (NCT02092467) suggested a higher risk of major adverse cardiovascular events (MACE) and malignancies compared with TNF inhibitors. No data are available from a similar prospective study with FIL. This post hoc exploratory analysis aimed to describe the incidence of MACE and malignancies in a subgroup of pts with RA from the FINCH and DARWIN clinical trials, receiving FIL 200 mg (FIL200) and FIL 100 mg (FIL100). Methods Exploratory analysis of adverse events of special interest are reported using integrated FIL RA data from phase 2 (NCT01668641, NCT01894516), phase 3 (NCT02889796, NCT02873936, NCT02886728), and the long-term extension (LTE) studies DARWIN 3 (NCT02065700) and FINCH 4 (NCT03025308), in a pt population at higher risk of CV events similar to ORAL-SURVEILLANCE,1 namely, aged ≥50y with ≥1 CV risk factor (history of dyslipidemia, diabetes or CV disease; hypertension, ischemic vascular conditions, peripheral vascular disease, extra-articular manifestations of RA; or current smokers). All pts met ACR criteria for functional class I-III. Censored exposure-adjusted incidence rates (EAIRs)/100 pt-years of exposure for MACE, venous thromboembolism (VTE), malignancies excluding nonmelanoma skin cancer (NMSC), NMSC, (serious) infections, and deaths were determined. Data were as of Jan 11, 2022 (DARWIN 3) and Jan 31, 2022 (FINCH 4). Analyses were performed on an ad hoc interim analysis data set without additional cleaning. Results The higher-risk population included 1484 pts: mean age 62.1y (536 [36.1%] aged ≥65y), 291 (22.5%) current smokers, and 904 (60.9%) received background MTX; baseline (BL) MTX use was higher in the FIL100 vs FIL200 group (66.6% vs 54.6%); other BL demographics were balanced. Numerically higher EAIRs for malignancies (excluding NMSC), NMSC, serious infections, and deaths were observed for pts receiving FIL200 vs FIL100; 95% confidence intervals overlapped. For MACE and VTE, incidence is considered similar for both doses. The risk of experiencing MACE, malignancies excluding NMSC, and NMSC over time with FIL100 or FIL200 will be described. Conclusion In this RA population at higher risk of CV events, the incidence of MACE and VTE was similar for both doses. A numerically higher incidence of malignancies (excluding NMSC), NMSC, serious infections, and deaths was observed in the high- vs low-dose group. Limitations included population selection bias, low event numbers, and the post hoc nature of the analysis. The ongoing LTE and real-world studies in RA will continue to investigate the safety of FIL in these populations. Disclosure M.H. Buch: Honoraria; MHB has recieved funding (Paid to her host institution) fromAbbVie, Galapagos, Gilead, Pfizer, Eli Lilly, Merck-Serono, Roche, UCB. G.R. Burmester: Honoraria; AbbVie, Galapagos, Lilly, MSD, Pfizer, Roche, UCB, Janssen, Gilead Sciences, Inc. X. Mariette: Honoraria; AstraZeneca, Bristol Myers Squibb, Galapagos, GSK, Novartis, Pfizer. C. Charles-Schoeman: Honoraria; AbbVie, Bristol Myers Squibb (BMS), Pfizer, Regeneron-Sanofi, Gilead. V. Rajendran: Other; Employee of Galapagos NV. P. Stiers: Other; Employee of Galapagos NV. A. Cerani: Other; Employee of Galapagos NV. P. Van Hoek: Other; Employee of Galapagos NV. K. Van Beneden: Other; Employee of Galapagos NV. Y. Tanaka: Honoraria; Lilly, AbbVie, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Pfizer, Mitsubishi Tanabe, GlaxoSmithKline, Asahi Kasei, Takeda, Astellas, Janssen, Novartis, Sanofi, UCB, YL Biologics, MSD, Ono, T. H. Schulze-Koops: Honoraria; AbbVie, Galapagos, Lilly, Pfizer. R. Westhovens: Honoraria; Celltrion, Galapagos, Gilead. E. Favalli: Honoraria; AbbVie, BMS, Celltrion, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, UCB.