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Differential activation of peroxisome proliferator-activated receptor-gamma by troglitazone and rosiglitazone. H S Camp , O Li , S C Wise , Y H Hong , C L Frankowski , X Shen , R Vanbogelen and T Leff Department of Cell Biology, Warner-Lambert Company, Ann Arbor, Michigan, USA. Abstract The antidiabetic thiazolidinediones, which include troglitazone and rosiglitazone, are ligands for the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-gamma and exert their antihyperglycemic effects by regulation of PPAR-gamma-responsive genes. We report here that PPAR-gamma activation by troglitazone depends on the experimental setting. Troglitazone acts as a partial agonist for PPAR-gamma in transfected muscle (C2C12) and kidney (HEK 293T) cells, producing a submaximal transcriptional response (1.8- to 2.5-fold activation) compared with rosiglitazone (7.4- to 13-fold activation). Additionally, troglitazone antagonizes rosiglitazone-stimulated PPAR-gamma transcriptional activity. Limited protease digestion of PPAR-gamma suggests conformational differences in the receptor bound to troglitazone versus rosiglitazone. Consistent with this finding, an in vitro coactivator association assay demonstrated that troglitazone-bound PPAR-gamma recruited the transcriptional coactivators p300 and steroid receptor coactivator 1 less efficiently than rosiglitazone-bound receptor. In contrast to these observations, troglitazone behaves as a full agonist of PPAR-gamma in 3T3L1 adipocytes. Two-dimensional protein gel electrophoresis demonstrated that troglitazone and rosiglitazone regulated distinct but overlapping sets of genes in several cell types. Thus, troglitazone may behave as a partial agonist under certain physiological circumstances and as a full agonist in others. These differences could be caused by variations in the amount of specific cofactors, differences in PPAR response elements, or the presence of different isoforms of PPAR-gamma.

Background:Upadacitinib (UPA), a selective JAK-1 inhibitor, has demonstrated efficacy in active RA among patients with an inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD-IR).1 To understand treatment effectiveness from the patients’ perspective we examined the impact of UPA on patient-reported outcomes (PROs).Objectives:To evaluate the effect of UPA vs placebo (PBO) on PROs in SELECT-NEXT (NCT02675426), a randomized controlled trial assessing the efficacy and safety of UPA in csDMARD-IR RA patients.Methods:Patients in SELECT-NEXT received UPA 15 mg or 30 mg daily or PBO for 12 weeks followed by a 5-year extension phase. PROs included physical function (Health Assessment Questionnaire Disability Index [HAQ-DI]), Patient’s Global Assessment of Disease Activity (PtGA) by visual analog scale (VAS), pain by VAS, fatigue by FACIT-F, duration and severity of morning (AM) stiffness, quality of life (QoL) by Short Form 36 Health Survey [SF-36], and Work Instability Scale for RA (RA-WIS). Changes in least square means (LSMs) from baseline (BL) to week 12 were based on mixed effect repeated measures models. Percentages of patients reporting changes in PRO scores from BL to week 12 ≥minimum clinically important differences (MCIDs) or scores ≥normative values (age- and gender-matched for SF-36 only) were determined for UPA and PBO arms; comparisons between groups used chi-square tests. For each PRO, the incremental number needed to treat (NNT) to achieve clinically meaningful improvement from BL (≥MCID) was calculated.Results:Data from 661 patients (221 in UPA 15 mg; 219 in UPA 30 mg; 221 in PBO) were analysed. Mean age was 56 years, 79% were female; 45% had RA for ≥5 years. Statistically significant LSM changes from BL to week 12 were reported with both UPA doses vs PBO for HAQ-DI, PtGA, pain, FACIT–F, duration and severity of AM stiffness, SF-36 (PCS; 6 or 7/8 domains), and RA-WIS (Table). Compared with PBO at week 12, significantly more UPA-treated (both doses) patients reported improvement ≥MCID in HAQ-DI, PtGA, pain, FACIT-F, duration and severity of AM stiffness, SF-36 (PCS; 4 or 7/8 domains), and RA-WIS as well as scores ≥normative values in HAQ-DI, PtGA, FACIT-F, SF-36 (PCS; 4 or 5/8 domains). For most PROs, NNTs with UPA ranged from 4 to 8 patients.Table 1LSM changes from baseline and percentage of responders at week 12 after UPA initiationConclusions:Treatment with UPA 15 mg or 30 mg daily for 12 weeks resulted in significant and clinically meaningful improvements in physical function, pain, fatigue, AM stiffness, QoL, and less work instability among csDMARD-IR RA patients. The NNTs to achieve these improvements were favourable.Reference[1]Burmester, et al. Arthritis Rheumatol2017:69(suppl 10), abstract 1904.Acknowledgements:Financial support for the study was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the abstract. All authors contributed to the development of the publication and maintained control over the final content. Medical writing services were provided by Joann Hettasch of Fishawack Communications and funded by AbbVie.Disclosure of Interest:V. Strand Consultant for: AbbVie, Amgen, AstraZeneca, BMS, Celgene, Genentech, GSK, Janssen, Lilly, Novartis, Pfizer, Regeneron, Sanofi, and UCB, J. Pope Consultant for: AbbVie, Amgen, BMS, Celltrion, GSK, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, Sandoz, UCB, N. Tundia Shareholder of: AbbVie, Employee of: AbbVie, A. Friedman Shareholder of: AbbVie, Employee of: AbbVie, H. Camp Shareholder of: AbbVie, Employee of: AbbVie, A. Pangan Shareholder of: AbbVie, Employee of: AbbVie, A. Ganguli Shareholder of: AbbVie, Employee of: AbbVie, M. Fuldeore Shareholder of: AbbVie, Employee of: AbbVie, D. Goldschmidt Employee of: Analysis Group, Inc., which received consulting fees from AbbVie for this study, M. Schiff Consultant for: Abbvie, BMS, Eli Lilly, JNJ, UCB, Speakers bureau: AbbVie, BMS

Background:Upadacitinib (UPA), an oral, JAK1-selective inhibitor, demonstrated efficacy through 12 and 24 weeks (wks) in phase 3 trials of patients (pts) with active rheumatoid arthritis (RA) and inadequate response (IR) to csDMARDs and bDMARDs, respectively.1,2 Efficacy evaluations at Wk 12 are an important assessment point according to T2T recommendations.3 Objectives:To assess the impact of UPA at 12 wks on individual and composite measures of RA disease activity.Methods:Pts received UPA 15 mg or 30 mg once daily (QD) or PBO for 12 wks in two phase 3 trials. SELECT NEXT1 and SELECT BEYOND2 enrolled csDMARD- and bDMARD-IR pts, respectively. For this investigation, responses at Wk 12, were defined as ≥50% improvement in ACR components. Among ACR50 responders, the proportions of pts achieving ≥50% improvement in all 7 components of the ACR response criteria [Tender Joint Count (TJC68), Swollen Joint Count (SJC66), Pt Global Assessment (PtGA), Physician Global Assessment (PhGA), Pt Pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), and high sensitive C-reactive protein (hsCRP)] were assessed. Differences in the cumulative distributions of CDAI, DAS28-CRP, and SDAI between baseline (BL) and Wk 12 were assessed. All analyses were based on observed data without imputation.Results:Pts in both studies, on average, had established, moderate to severe RA at BL, with (mean) disease durations of 7.3 and 13.2 years, CDAI of 38.2 and 40.9, in csDMARD-IR and bDMARD-IR pts, respectively; 53% of bDMARD-IR pts had exposure to ≥2 bDMARDs.1,2 In both populations, significantly more pts on UPA vs PBO achieved ≥50% improvement in each ACR component at Wk 12 (Table). Among pts who achieved ACR50 at Wk 12, approximately one-half of the csDMARD-IR and one-third of the bDMARD-IR pts achieved ≥50% improvement in all 7 ACR components. While there were no differences at BL, cumulative distributions of CDAI, DAS28-CRP, and SDAI separated by treatment at Wk 12 (p<0.001); for the lowest quartiles for UPA 15 mg and 30 mg vs PBO, CDAI levels dropped to 6.2 and 5.1 vs 12.5 in csDMARD-IR; and 7.2 and 8.2 vs 13.1 in bDMARD-IR.Conclusions:In pts with an insufficient response to either csDMARDs or bDMARDs, treatment responses at 12 wks were observed in significantly higher proportions with UPA vs PBO. Favorable effects with UPA were seen in the composite scores and the individual parameters, including PROs and acute-phase reactants.References[1]Burmester, et al., Arthritis Rheumatol2017;69:S10.[2]Genovese, et al. Arthritis Rheumatol2017;69:S10.[3]Smolen, et al. 2015. doi:10.1136/annrheumdis-2015-207524Acknowledgements:AbbVie Inc was the study sponsor, contributed to study design, data collection, analysis & interpretation, and to writing, reviewing, and approval of final version. Medical writing support was provided by Naina Barretto, PhD, of AbbVie, Inc.Disclosure of Interest:R. van Vollenhoven Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche, and UCB, Consultant for: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Crescendo, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, and Vertex, Speakers bureau: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Crescendo, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, and Vertex, R. Dore: None declared, K. Chen Shareholder of: AbbVie, Employee of: AbbVie, H. Camp Shareholder of: AbbVie, Employee of: AbbVie, J. Enejosa Shareholder of: AbbVie, Employee of: AbbVie, T. Shaw Shareholder of: AbbVie, Employee of: AbbVie, J. Suboticki Shareholder of: AbbVie, Employee of: AbbVie, S. Hall: None declared

Upadacitinib, an oral Janus kinase (JAK)1-selective inhibitor, showed efficacy in combination with stable background conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with rheumatoid arthritis who had an inadequate response to DMARDs. We aimed to evaluate the safety and efficacy of upadacitinib monotherapy after switching from methotrexate versus continuing methotrexate in patients with inadequate response to methotrexate. SELECT-MONOTHERAPY was conducted at 138 sites in 24 countries. The study enrolled adults (≥18 years) who fulfilled the 2010 American College of Rheumatology (ACR)–European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis. Patients with active rheumatoid arthritis despite stable methotrexate were randomly assigned 2:2:1:1 to switch to once-daily monotherapy of upadacitinib 15 mg or 30 mg or to continue methotrexate at their existing dose as blinded study drug; starting from week 14, patients assigned to continue methotrexate were switched to 15 mg or 30 mg once-daily upadacitinib per prespecified random assignment at baseline. The primary endpoints in this report are proportion of patients achieving 20% improvement in the ACR criteria (ACR20) at week 14, and proportion achieving low disease activity defined as 28-joint Disease Activity Score using C-reactive protein (DAS28[CRP]) of 3·2 or lower, both with non-responder imputation at week 14. Outcomes were assessed in patients who received at least one dose of study drug. This study is active but not recruiting and is registered with ClinicalTrials.gov, number NCT02706951. Patients were screened between Feb 23, 2016, and May 19, 2017 and 648 were randomly assigned to treatment. 598 (92%) completed week 14. At week 14, an ACR20 response was achieved by 89 (41%) of 216 patients (95% CI 35–48) in the continued methotrexate group, 147 (68%) of 217 patients (62–74) receiving upadacitinib 15 mg, and 153 (71%) of 215 patients (65–77) receiving upadacitinib 30 mg (p<0·0001 for both doses vs continued methotrexate). DAS28(CRP) 3·2 or lower was met by 42 (19%) of 216 (95% CI 14–25) in the continued methotrexate group, 97 (45%) of 217 (38–51) receiving upadacitinib 15 mg, and 114 (53%) of 215 (46–60) receiving upadacitinib 30 mg (p<0·0001 for both doses vs continued methotrexate). Adverse events were reported in 102 patients (47%) on continued methotrexate, 103 (47%) on upadacitinib 15 mg, and 105 (49%) on upadacitinib 30 mg. Herpes zoster was reported by one (<1%) patient on continued methotrexate, three (1%) on upadacitinib 15 mg, and six (3%) on upadacitinib 30 mg. Three malignancies (one [<1%] on continued methotrexate, two [1%] on upadacitinib 15 mg), three adjudicated major adverse cardiovascular events (one [<1%] on upadacitinib 15 mg, two [<1%] on upadacitinib 30 mg), one adjudicated pulmonary embolism (<1%; upadacitinib 15 mg), and one death (<1%; upadacitinib 15 mg, haemorrhagic stroke [ruptured aneurysm]) were reported in the study. Upadacitinib monotherapy showed statistically significant improvements in clinical and functional outcomes versus continuing methotrexate in this methotrexate inadequate-responder population. Safety observations were similar to those in previous upadacitinib rheumatoid arthritis studies. AbbVie Inc, USA.

Upadacitinib is a selective inhibitor of Janus kinase 1 and was efficacious in phase 2 studies in patients with moderate-to-severe rheumatoid arthritis. We aimed to assess the efficacy of upadacitinib in patients with inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). This study is a double-blind, placebo-controlled trial at 150 sites in 35 countries. We enrolled patients aged 18 years or older with active rheumatoid arthritis for 3 months or longer, who had received csDMARDs for at least 3 months with a stable dose for at least 4 weeks before study entry, and had an inadequate response to at least one of the following csDMARDs: methotrexate, sulfasalazine, or leflunomide. Using interactive response technology, we randomly assigned patients receiving stable background csDMARDs (2:2:1:1) to receive a once-daily extended-release formulation of upadacitinib 15 mg or 30 mg, or placebo, for 12 weeks. Patients, investigators, and the funder were masked to allocation. After 12 weeks, patients taking placebo received 15 mg or 30 mg of upadacitinib once daily, according to the prespecified randomisation assignment. The primary endpoints were the proportion of patients at week 12 who achieved 20% improvement in American College of Rheumatology criteria (ACR20), and a 28-joint disease activity score using C-reactive protein (DAS28[CRP]) of 3·2 or less. We did efficacy analyses in the full analysis set of all randomly assigned patients who received at least one dose of study drug, and used non-responder imputation for assessment of the primary outcomes. This study is registered with ClinicalTrials.gov, number NCT02675426. Between Dec 17, 2015, and Dec 22, 2016, 1083 patients were assessed for eligibility, of whom 661 were recruited and randomly assigned to receive upadacitinib 15 mg (n=221), upadacitinib 30 mg (n=219), or placebo (n=221). All patients received at least one dose of study drug, and 618 (93%) completed 12 weeks of treatment. At week 12, ACR20 was achieved by 141 (64%; 95% CI 58–70) of 221 patients receiving upadacitinib 15 mg and 145 (66%; 60–73) of 219 patients receiving upadacitinib 30 mg, compared with 79 (36%; 29–42) of 221 patients receiving placebo (p<0·0001 for each dose vs placebo). DAS28(CRP) of 3·2 or less was met by 107 (48%; 95% CI 42–55) patients receiving upadacitinib 15 mg and 105 (48%; 41–55) patients receiving upadacitinib 30 mg, compared with 38 (17%; 12–22) patients receiving placebo (p<0·0001 for each dose vs placebo). Adverse events were reported in 125 (57%) of 221 patients receiving upadacitinib 15 mg, 118 (54%) of 219 patients receiving upadacitinib 30 mg, and 108 (49%) of 221 patients receiving placebo. The most frequently reported adverse events (≥5% of patients in any group) were nausea (16 [7%] of 221 in the upadacitinib 15 mg group; three [1%] of 219 in the upadacitinib 30 mg group; and seven [3%] of 221 in the placebo group), nasopharyngitis (12 [5%]; 13 [6%]; and nine [4%]), upper respiratory tract infection (12 [5%]; 12 [5%]; and nine [4%]), and headache (nine [4%]; seven [3%]; and 12 [5%]). More infections were reported for upadacitinib (64 [29%] of 221 patients receiving 15 mg and 69 [32%] of 219 patients receiving 30 mg) versus placebo (47 [21%] of 221 patients). There were three herpes zoster infections (one [<1%] in the placebo group, one [<1%] in the upadacitinib 15 mg group, and one [<1%] in the upadacitinib 30 mg group) and one primary varicella zoster virus infection (one [<1%] in the upadacitinib 30 mg group), two malignancies (both in the upadacitinib 30 mg group), one adjudicated major adverse cardiovascular event (in the upadacitinib 30 mg group), and five serious infections (one [<1%] in the placebo group, one [<1%] in the upadacitinib 15 mg group, three [1%] in the upadacitinib 30 mg group). No deaths were reported during the trial. Patients with moderately to severely active rheumatoid arthritis who received upadacitinib (15 mg or 30 mg) in combination with csDMARDs showed significant improvements in clinical signs and symptoms. AbbVie Inc.

Background ABT-494 is a potent and selective Janus kinase (JAK) 1 inhibitor being developed for the treatment of several autoimmune disorders, with potential for an improved safety profile compared with non-selective JAK inhibitors. This work characterized the pharmacokinetics, safety, and tolerability of ABT-494 following single and multiple dosing of the immediate-release formulation. Methods ABT-494 single (1–48 mg or placebo; n  = 56) and multiple (3–24 mg or placebo twice daily for 14 days; n  = 44) doses in healthy subjects, as well as multiple doses (3–24 mg or placebo twice daily for 27 days; n  = 14) in subjects with rheumatoid arthritis (RA) on a background of methotrexate were evaluated. Pharmacokinetic samples were collected and safety and tolerability were assessed. Results ABT-494 followed bi-exponential disposition, with a terminal elimination half-life of 6–16 h and a functional half-life, calculated from maximum observed plasma concentration ( C max ) to trough plasma concentration ( C trough ) ratio at steady state, of 3–4 h. ABT-494 exposure was approximately dose proportional over the 3–36 mg dose range, with no significant accumulation with repeated dosing. In subjects with RA, no pharmacokinetic interaction between ABT-494 and methotrexate was observed. The fraction of ABT-494 dose eliminated in urine as unchanged ABT-494 was 14–25 %. All treatment-emergent adverse events (TEAEs) were mild or moderate in severity, with headache being the most frequently observed TEAE (15.6 % for ABT-494 vs. 16.7 % for placebo) after multiple twice-daily administration to healthy subjects. No clinically significant changes in laboratory parameters, vital signs, or electrocardiogram findings in healthy or RA subjects were observed. Conclusions The favorable pharmacokinetics, safety, and tolerability results from these studies supported further evaluations of ABT-494 in phase IIb dose-ranging trials in RA and Crohn’s disease. Trial Registration ClinicalTrials.gov ( https://clinicaltrials.gov/ ) identifier: NCT01741493.

Background To evaluate the efficacy and safety of upadacitinib monotherapy versus methotrexate (MTX) monotherapy over 5 years among MTX-naïve patients with moderately to severely active rheumatoid arthritis (RA) in the long-term extension (LTE) of the phase 3 SELECT-EARLY trial. Methods Patients were randomized to receive upadacitinib 15 mg or 30 mg or MTX. Patients who did not achieve CDAI remission and had < 20% improvement in tender and swollen joint counts at week 26 received rescue therapy (addition of MTX in the upadacitinib group and addition of upadacitinib in the MTX group). Efficacy assessments were evaluated over 5 years and are reported as observed (AO) for patients who received continuous monotherapy with upadacitinib 15/30 mg or MTX and by randomized group applying non-responder imputation (NRI). Treatment-emergent adverse events (TEAEs) per 100 patient-years were summarized over 5 years. Results Of 945 patients randomized and treated, 775 (82%) completed week 48 and entered the LTE on study drug. Higher proportions of patients consistently achieved disease activity targets over 5 years with upadacitinib than MTX. In AO analyses, 53%/59% of patients attained CDAI remission with upadacitinib 15/30 mg versus 43% with MTX at week 260. NRI analyses showed better CDAI, DAS28(CRP), and ACR responses with upadacitinib relative to MTX at week 260 (all comparisons, nominal P  < .001). Upadacitinib treatment also resulted in numerically greater inhibition of structural joint progression through week 260 compared to MTX. Most TEAEs, serious AEs, and AEs leading to discontinuation were numerically higher in patients receiving upadacitinib 30 mg. Rates of serious infections, herpes zoster, creatine phosphokinase elevation, nonmelanoma skin cancer, and neutropenia were numerically higher with upadacitinib than MTX. The observed safety profile of upadacitinib over 5 years was consistent with earlier trial results and integrated phase 3 safety analyses. Conclusions Upadacitinib showed better clinical responses versus MTX in patients with RA throughout the 5-year trial. Higher rates of several AEs were observed with upadacitinib, especially in the 30 mg group, compared to MTX. When used as monotherapy in MTX-naïve patients, the approved upadacitinib 15 mg dose showed better long-term efficacy versus MTX and an overall favorable benefit-risk profile. Trial registration NCT02706873.

Background To evaluate the effect of upadacitinib on patient-reported outcomes (PROs) in patients with RA who had an inadequate response to csDMARDs. Methods Patients in SELECT-NEXT, a randomised controlled trial, were on a background of csDMARDs and received upadacitinib 15 mg and 30 mg or placebo daily for 12 weeks. PROs included Patient Global Assessment of Disease Activity (PtGA), pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), duration and severity of morning (AM) joint stiffness, Short Form 36 Health Survey (SF-36), and Work Instability Scale for RA (RA-WIS). Least squares mean (LSM) changes were based on mixed-effect repeated measure models. Percentages of patients reporting improvements ≥ minimum clinically important differences (MCIDs) and scores ≥ normative values and number needed to treat (NNT) were determined; group comparisons used chi-square tests. Results Data from 661 patients were analysed. Compared with placebo, patients receiving upadacitinib reported statistically significant improvements (both doses, P  < 0.05) in PtGA, pain, HAQ-DI, FACIT-F, duration and severity of AM stiffness, SF-36 (PCS and 6/8 domains), and RA-WIS at week 12. Significantly, more upadacitinib-treated patients (both doses, P  < 0.05) reported improvements ≥ MCID in PtGA, pain, HAQ-DI, FACIT-F, AM stiffness, SF-36 (PCS and 4 or 7/8 domains), and RA-WIS and scores ≥ normative values in HAQ-DI, FACIT-F, and SF-36 (PCS and 4 or 5/8 domains). For most PROs, the incremental NNT with upadacitinib to report clinically meaningful improvement from baseline ranged from 4 to 8 patients. Conclusions Upadacitinib 15 mg or 30 mg daily for 12 weeks resulted in significant and clinically meaningful improvements in global disease activity, pain, physical function, fatigue, duration and severity of AM stiffness, HRQOL, and work instability among csDMARD-IR patients with RA. Trial registration Clinicaltrials.gov, NCT02675426 . Retrospectively registered 5 February 2016.

Introduction The safety and efficacy of upadacitinib 15 mg (UPA15) through week 216 was evaluated in patients with rheumatoid arthritis (RA) from the long-term extension (LTE) of the phase 3 SELECT-CHOICE study. Methods Patients with RA refractory to biologic disease-modifying antirheumatic drugs (bDMARDs) were randomized to UPA15 or abatacept (ABA) for 24 weeks. During the open-label LTE, patients on ABA switched to UPA15 at week 24, and those on UPA15 continued treatment. The safety and efficacy of continuous UPA15, and ABA to UPA15, are summarized through week 216. Results The LTE was comprised of 91.4% ( n  = 277/303) of patients that initially received UPA15, and 89.6% ( n  = 277/309) that initially received ABA. Of patients on UPA15 in the LTE ( n  = 547), 28.3% ( n  = 155/547) discontinued the study drug by week 216. Relative to other adverse events of special interest, and largely consistent with previous findings at week 24, higher rates of serious infection, COVID-19, herpes zoster, and elevated creatine phosphokinase were reported, while rates of malignancy excluding nonmelanoma skin cancer (NMSC), NMSC, major adverse cardiovascular event (MACE), and venous thromboembolism (VTE) were low. Long-term safety data with UPA through week 216 aligned with previous observations and no new safety risks were identified, including in patients who switched from ABA to UPA15. Proportions of patients achieving 28-joint disease activity score based on C-reactive protein (DAS28[CRP]) < 2.6/ ≤ 3.2, clinical disease activity index (CDAI) and simple disease activity index (SDAI) low disease activity/remission, ≥ 20%/50%/70% improvement in the American College of Rheumatology (ACR20/50/70) response criteria, and Boolean remission were maintained or improved with UPA15 through week 216. Improvements in the Health Assessment Questionnaire-Disability Index (HAQ-DI), patient’s assessment of pain, and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were also maintained or improved with UPA15 through week 216. Across all efficacy endpoints, similar results were observed in patients who switched from ABA to UPA15 versus continuous UPA15. Patients with an inadequate response to ≥ 1 prior tumor necrosis factor (TNF) inhibitor (UPA15: n  = 263/303, 86.8%; ABA to UPA15: n  = 273/309, 88.3%) showed similar responses to the total population. Conclusions The long-term safety profile of UPA was consistent with previous findings and the broader RA clinical program. Compared to the primary analyses at week 24, efficacy responses were maintained or further improved with UPA15 through week 216 in patients with RA. Trial registration, ClinicalTrials.gov identifier: NCT03086343. Plain Language Summary A long-term study looked at a drug named upadacitinib to treat people with rheumatoid arthritis (RA), a disease that causes joint pain and damage. The study included patients whose RA was not improved by other injectable medicines. The study compared upadacitinib with another drug called abatacept. After 24 weeks, patients who were taking abatacept switched to upadacitinib, and patients taking upadacitinib continued on upadacitinib treatment for over 4 years. The researchers looked at how well the treatments worked over the long-term and if there were any side effects. The side effects with upadacitinib treatment in this long-term study were similar to side effects reported in previous studies with upadacitinib. The researchers also found that upadacitinib helped to lessen the symptoms of RA over time and helped patients complete their daily activities and reduced their pain and tiredness. This was true for patients who switched from abatacept to upadacitinib after 24 weeks and for patients who took upadacitinib from the start of the study. Patients who had not responded to other medicines also had similar improvements with upadacitinib. In conclusion, upadacitinib can help people with RA over the long term and no new safety risks were found.

ObjectiveTo evaluate the efficacy and safety of upadacitinib over 5 years among patients with rheumatoid arthritis (RA) in a long-term extension (LTE) of the SELECT-BEYOND phase 3 trial.MethodsPatients refractory to ≥1 biological disease-modifying antirheumatic drug (DMARD) received upadacitinib 15 mg or 30 mg once daily or placebo, in combination with background conventional synthetic DMARD(s). At week 12, patients randomised to placebo were switched to upadacitinib 15 mg or 30 mg. All patients who completed the week 24 visit could enter the LTE for up to 5 years. Efficacy was analysed as observed and by non-responder imputation through week 260. Treatment-emergent adverse events per 100 patient-years were summarised over 5 years.ResultsOf the 498 patients randomised, 418 (84%) completed week 24 and entered the LTE. Of those who remained in the trial (n=80, upadacitinib 15 mg; n=81, upadacitinib 30 mg), 36%/36% and 81%/77% randomised to upadacitinib 15/30 mg were in Clinical Disease Activity Index (CDAI) remission or low disease activity at week 260, respectively (as observed). Approximately 47% of all patients who began in high disease activity demonstrated a CDAI improvement >12 at week 260 with upadacitinib 15/30 mg. Functional and pain-related outcomes also showed comparable improvements with both doses. Numerically higher rates of anaemia, herpes zoster and creatine phosphokinase elevation were observed with upadacitinib 30 mg vs 15 mg. No new safety issues were identified.ConclusionsUpadacitinib 15/30 mg continued to be effective in treating clinical and functional outcomes in patients with RA. The safety profile observed over 5 years was consistent with earlier study-specific and integrated assessments of upadacitinib treatment.