SAT0219 Upadacitinib in patients with active rheumatoid arthritis and inadequate response or intolerance to biological dmards: a phase 3 randomized, placebo-controlled, double-blind study of a selective jak1 inhibitor

Background: Upadacitinib (UPA), an oral, selective JAK1 inhibitor was effective in ph 2 trials in rheumatoid arthritis (RA) pts with inadequate response (IR)/intolerance to csDMARDs and bDMARDs. Objectives: To evaluate safety and efficacy of UPA in bDMARD-IR pts on stable background csDMARDs. Methods: Pts with active RA (TJC≥6, SJC≥6; hsCRP≥3 mg/L) were randomized 2:2:1:1 to receive UPA 15 mg or 30 mg once daily (QD) or PBO for 12 wks followed by UPA 15 mg or 30 mg QD starting at Wk 12. The primary endpoints were the proportion of pts achieving ACR20 (for FDA) and the proportion achieving DAS28CRP≤3.2 (for EMA) at Wk 12 (NRI). Results: Of 499 randomized pts, 498 received study drug; 451 (90.6%) and 419 (84.1%) completed Wks 12 and 24 respectively. BL disease characteristics indicated long-standing severe, refractory disease: (means) duration since diagnosis 13 yrs; DAS28CRP, 5.8; TJC68, 27.9; SJC66, 16.8; 53% experienced ≥2 prior bDMARDs. At Wk 12, more pts (p Table) . Among pts with IR to multiple bDMARDs/MOAs, and pts with lack of efficacy for α-IL-6, the proportions achieving ACR20 on UPA vs PBO were comparable to the overall treated population. By Wk 1, more pts achieved ACR20 on UPA 15 and 30 vs PBO (27.4% and 24.8% vs 10.7%, p Up to wk 12, the frequency of AEs was comparable for PBO and UPA 15, but higher for UPA 30 (table 1) . Overall AE rates (E/100 PY) through Wk 24 for UPA 30 were similar or slightly higher vs UPA 15; more AEs led to study drug discontinuation in UPA 30. Occurrence of infections was similar in all arms, but there were more serious infections and herpes zoster cases in UPA 30. Malignancies were reported in 3 pts over 12 wks with 1 additional case through Wk 24. Through Wk 12, pulmonary embolism (PE) was reported in 2 pts (1 each on UPA 15 and 30), none with DVT; through Wk 24, PE were reported in 4 more pts (UPA 15: 3, 1 of whom also had a DVT; UPA 30:1). All had risk factors for DVT/PE. 2 deaths were reported (UPA30: 1 before Wk 12; UPA 15:1 after Wk12). Conclusions: In this treatment-refractory, bDMARD-IR RA population, rapid, significant improvements were observed with UPA at both doses vs PBO during 12 wks of treatment, and maintained through 24 wks. Overall safety was consistent with ph2 and other ph3 studies with UPA. The rates of PE and DVT observed in this study have not been reported for the other ph3 studies that have been unblinded to date. Overall data from the ph3 program will allow a comprehensive evaluation of the benefit:risk profile of UPA in RA. Acknowledgements: AbbVie sponsored study design, data collection, analysis & interpretation, writing, review, approval of final. Med writing:Naina Barretto of AbbVie Disclosure of Interest: M. Genovese Grant/research support from: AbbVie, Lilly, Pfizer, Galapagos, Gilead, Consultant for: AbbVie, Lilly, Pfizer, Galapagos, Gilead, R. Fleischmann Grant/research support from: AbbVie, Consultant for: AbbVie, B. Combe Consultant for: Abbvie, BMS, Jansen, Lilly, MSD, Pfizer, Roche Chugai, UCB, S. Hall: None declared, Y. Zhang Shareholder of: AbbVie, Employee of: AbbVie, Y. Zhou Shareholder of: AbbVie, Employee of: AbbVie, M. Mohamed Shareholder of: AbbVie, Employee of: AbbVie, S. Meerwein Shareholder of: AbbVie, Employee of: AbbVie, A. Pangan Shareholder of: AbbVie, Employee of: AbbVie