Sat0151 efficacy and Safety of Upadacitinib Versus Abatacept in Patients With Active Rheumatoid Arthritis and Prior Inadequate Response or Intolerance to Biologic Disease-Modifying Anti-Rheumatic Drugs (Select-Choice): A Double-Blind, Randomized Controlled Phase 3 Trial

Abstract

Background:Upadacitinib (UPA) is an oral, reversible, selective JAK 1 inhibitor approved for the treatment of moderate to severe rheumatoid arthritis (RA). The efficacy/safety of UPA has been demonstrated in phase 3 studies, including superiority to adalimumab in patients (pts) with prior inadequate response (IR) to methotrexate.1-4Objectives:To assess the efficacy/safety of UPA vs abatacept (ABA) in pts with prior IR or intolerance to biologic DMARDs (bDMARDs).Methods:Pts were randomized to once daily UPA 15 mg or intravenous ABA (at Day 1, Weeks [Wks] 2, 4, 8, 12, 16 and 20 [< 60 kg: 500 mg; 60-100 kg: 750 mg; >100 kg: 1,000 mg]), with all pts continuing background stable csDMARDs. The study was double-blind for 24 wks. Starting at Wk 12, pts who did not achieve ≥20% improvement from baseline (BL) in both tender and swollen joint counts at two consecutive visits, had background medication(s) adjusted or initiated. The primary endpoint was change from BL in DAS28(CRP) at Wk 12 (non-inferiority). The non-inferiority of UPA vs ABA was tested using the 95% CI of treatment difference against a non-inferiority margin of 0.6. The two key secondary endpoints at Wk 12 were change from BL in DAS28(CRP) and the proportion of pts achieving clinical remission (CR) based on DAS28(CRP), defined as DAS28(CRP) <2.6. Both endpoints were to demonstrate the superiority of UPA vs. ABA. Treatment-emergent adverse events (TEAEs) are reported up to Wk 24 for all pts who received at least one dose of study drug.Results:Of 612 pts treated; 67% of pts had received 1 prior bDMARD, 22% received 2 prior bDMARDs, and 10% received ≥ 3 prior bDMARDs. 549 (90%) completed 24 wks of treatment. Common reasons for study drug discontinuation were AEs (UPA, 3.6%; ABA, 2.6%) and withdrawal of consent (UPA, 1.7%; ABA, 2.6%).Non-inferiority and superiority were met for UPA vs ABA at Wk 12 for change from BL in DAS28(CRP) (-2.52 vs -2.00; -0.52 [-0.69, -0.35]; p <0.001 for UPA vs ABA). UPA also demonstrated superiority to ABA in achieving DAS28(CRP) <2.6 (30.0% vs 13.3%; p <0.001 for UPA vs ABA; Figure 1). Improvements in disease activity and remission rates were maintained through Wk 24. The proportions of pts achieving low disease activity (defined as DAS28(CRP) ≤3.2), ACR20, ACR50, and ACR70 responses were greater with UPA compared with ABA at Wk 12 (nominal p <0.05). More stringent outcome measures – CR, ACR50, and ACR70 responses - remained higher with UPA than ABA through Wk 24 (nominal p <0.05). Incidence of serious TEAEs, AEs leading to discontinuation, hepatic disorders, and CPK elevations were numerically higher with UPA versus ABA (Figure 2). Eight cases of herpes zoster were reported (4 in each treatment arm). No malignancies were reported. One case of adjudicated MACE, two adjudicated cases of VTE (1 pt with DVT and 1 pt with PE; both pts had at least one risk factor for VTE), and one treatment-emergent death were reported with UPA.Conclusion:In RA pts with a prior IR or intolerance to bDMARDs, UPA demonstrated superior improvement in signs and symptoms vs ABA based on change in DAS28(CRP) and in achieving CR at Wk 12. The safety profile of UPA was consistent with the phase 3 RA studies with no new risks identified.References:[1]Burmester GR, et al. Lancet. 2018;391(10139):2503-12[2]Fleischmann R, et al. Arthritis Rheumatol. 2019;71(11):1788-800[3]Genovese MC, et al. Lancet. 2018;391(10139):2513-24[4]Smolen JS, et al. Lancet. 2019;393(10188):2303-11Disclosure of Interests:Andrea Rubbert-Roth Consultant of: Abbvie, BMS, Chugai, Pfizer, Roche, Janssen, Lilly, Sanofi, Amgen, Novartis, Jeffrey Enejosa Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Aileen Pangan Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Ricardo Xavier Consultant of: AbbVie, Pfizer, Novartis, Janssen, Eli Lilly, Roche, Boulos Haraoui Grant/research support from: Abbvie, Amgen, Pfizer, UCB, Grant/research support from: AbbVie, Amgen, BMS, Janssen, Pfizer, Roche, and UCB, Consultant of: Abbvie, Amgen, Lilly, Pfizer, Sandoz, UCB, Consultant of: AbbVie, Amgen, BMS, Celgene, Eli Lilly, Janssen, Merck, Pfizer, Roche, and UCB, Speakers bureau: Pfizer, Speakers bureau: Amgen, BMS, Janssen, Pfizer, and UCB, Maureen Rischmueller Consultant of: Abbvie, Bristol-Meyer-Squibb, Celgene, Glaxo Smith Kline, Hospira, Janssen Cilag, MSD, Novartis, Pfizer, Roche, Sanofi, UCB, Nasser Khan Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Ying Zhang Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Naomi Martin Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme

Upadacitinib in Rheumatoid Arthritis: A Benefit–Risk Assessment Across a Phase III Program

“…4). While not included in this integrated analysis, the safety profile of upadacitinib reported in SELECT-CHOICE was consistent with that from the five pivotal trials, with no new risks identified [38].…”

“…2). Similarly, upadacitinib 15 mg demonstrated superior improvement in disease activity and remission compared with abatacept in bDMARD-IR patients [38].…”

“…The SELECT phase III clinical development program evaluated the efficacy and safety of upadacitinib with background csDMARDs in both csDMARD-IR and bDMARD-IR patient populations and as a monotherapy in patients who were naïve to methotrexate or methotrexate-IR across five pivotal randomized, multicenter, double-blind, parallelgroup, placebo or active comparator-controlled studies (Table 1 in the Electronic Supplementary Material [ESM]). Two additional studies were included in the SELECT program: SELECT-CHOICE, which evaluated the safety and efficacy of upadacitinib versus abatacept in bDMARD-IR patients [38], and SELECT-SUNRISE, which evaluated upadacitinib in Japanese patients [39]. Each phase III study had separate primary endpoints to meet different requirements from the European Medicines Agency (EMA), the US Food and Drug Administration (FDA), and the Japan Pharmaceuticals and Medical Devices Agency (Table 1).…”

Cost per responder for upadacitinib vs abatacept in patients with moderate-to-severe Rheumatoid Arthritis in Italy

“…Upadacitinib ha recentemente ottenuto dall’Agenzia Europea per i Medicinali ( European Medicines Agency , EMA) l’approvazione in Europa per diverse indicazioni, tra cui il trattamento dell’AR da moderata a grave in pazienti adulti che hanno avuto una risposta inadeguata o che sono intolleranti a uno o più farmaci antireumatici modificanti la malattia ( 24 ). L’efficacia e la sicurezza di upadacitinib sono state valutate in un ampio programma di studi clinici randomizzati ( 25 , 26 , 27 , 28 , 29 ), tra cui lo studio di fase III SELECT-CHOICE ( 30 , 31 ). In riferimento a quest’ultimo studio, l’efficacia e la sicurezza di upadacitinib sono state confrontate rispetto a quelle di abatacept ( 30 , 31 ).…”

JAK inhibitors in rheumatoid arthritis: new opportunities and perspectives

“…Упадацитиниб -это пероральный селективный ингибитор JAK1 с удобной схемой приема -1 таблетка (15 мг) в сутки. Установлено, что упадацитиниб в дозе 15 мг не уступает по эффективности дозе 30 мг, но вызывает меньше нежелательных лекарственных реакций (НЛР) [4][5][6][7][8][9][10][11].…”