Disease Control with Upadacitinib in Patients with Psoriatic Arthritis: A Post Hoc Analysis of the Randomized, Placebo-Controlled SELECT-PsA 1 and 2 Phase 3 Trials.
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ABSTRACT: Introduction
Low disease activity (LDA)/remission is the target of treatment in patients with psoriatic arthritis (PsA). We assessed the proportions of patients with PsA receiving upadacitinib who achieved LDA/remission over 1 year.Methods
This was a post hoc analysis of the double-blind, placebo-controlled SELECT-PsA 1 (also adalimumab-controlled) and SELECT-PsA 2 trials. Treatment targets assessed included LDA/remission defined by Disease Activity in Psoriatic Arthritis (≤ 14/ ≤ 4) and Psoriatic Arthritis Disease Activity Scores (≤ 3.2/ ≤ 1.9), as well as minimal disease activity (MDA)/very low disease activity (VLDA) states (5/7 and 7/7 components, respectively, of MDA criteria). Targets were assessed at 24 and 56 weeks. For binary outcomes, non-responder imputation was used for missing data. Data from patients receiving upadacitinib 30 mg was not included in the analysis.Results
Overall, 1386 patients were analyzed. Disease control (i.e., LDA/MDA) was achieved at 24 weeks in upadacitinib 15 mg-treated patients across both studies: LDA/MDA was achieved by 25-48% of patients receiving upadacitinib 15 mg versus 2-16% of patients receiving placebo, and remission/VLDA rates were 7-14% with upadacitinib 15 mg versus 0-4% with placebo. The proportions of patients achieving treatment targets were numerically similar to upadacitinib 15 mg and adalimumab. All responses were sustained at 56 weeks.Conclusions
Remission and LDA are feasible targets with upadacitinib treatment in patients with PsA.Trial registration
ClinicalTrial.gov identifiers NCT03104400 (SELECT-PsA 1) and NCT03104374 (SELECT-PsA 2).
SUBMITTER: Mease P
PROVIDER: S-EPMC9314475 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundUpadacitinib is a Janus kinase inhibitor under evaluation for the treatment of psoriatic arthritis (PsA). We evaluated upadacitinib in patients with PsA and prior inadequate response or intolerance to at least one biologic disease-modifying antirheumatic drug (DMARD).MethodsIn this 24-week randomised, placebo-controlled, double-blind, phase 3 trial, 642 patients were randomised (2:2:1:1) to once per day upadacitinib 15 mg or 30 mg, placebo followed by upadacitinib 15 mg or placebo followed by upadacitinib 30 mg at week 24. The primary endpoint was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at week 12. Achievement of minimal disease activity (MDA) was assessed at week 24. Treatment-emergent adverse events are reported for all patients who received at least one dose of trial drug.ResultsAt week 12, significantly more patients receiving upadacitinib 15 mg and 30 mg versus placebo achieved ACR20 (56.9% and 63.8% vs 24.1%; p<0.001 for both comparisons). At week 24, MDA was achieved by more upadacitinib 15 mg-treated (25.1%) and 30 mg-treated patients (28.9%) versus placebo (2.8%; p<0.001 for both comparisons). Generally, the rates of treatment-emergent adverse events were similar with placebo and upadacitinib 15 mg and higher with upadacitinib 30 mg at week 24. Rates of serious infections were 0.5%, 0.5% and 2.8% with placebo, upadacitinib 15 mg and upadacitinib 30 mg, respectively.ConclusionIn this trial of patients with active PsA who had inadequate response or intolerance to at least one biologic DMARD, upadacitinib 15 mg and 30 mg was more effective than placebo over 24 weeks in improving signs and symptoms of PsA.Clinical trial registration numberNCT03104374.
| S-EPMC7892371 | biostudies-literature
Project description:IntroductionThe aim of this work is to assess the effect of upadacitinib versus adalimumab and placebo on patient-reported outcomes (PROs) in psoriatic arthritis (PsA) patients with inadequate responses to ≥ 1 non-biologic disease-modifying anti-rheumatic drugs (non-bDMARD-IR) in SELECT PsA-1.MethodsIn this placebo- and active comparator, phase 3 randomized, controlled trial, patients received daily upadacitinib 15 or 30 mg, placebo, or adalimumab 40 mg every other week through 56 weeks. At week 24, placebo-assigned patients were rerandomized to upadacitinib 15 or 30 mg. 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), Short Form 36 Health Survey (SF-36), EQ-5D-5L index score, Bath Ankylosing Spondylitis Disease Activity Index, morning stiffness, Self-Assessment of Psoriasis Symptoms, and Work Productivity and Activity Impairment. Mean changes from baseline in PROs, improvements ≥ minimum clinically important differences (MCID), scores ≥ normative values, and sustained clinically meaningful responses were compared between treatment groups.ResultsAt weeks 12 and 24, upadacitinib treatment resulted in improvements from baseline versus placebo across all PROs as well as improvements versus adalimumab in HAQ-DI and SF-36 Physical Component Summary score (nominal p < 0.05). Improvements in PtGA, pain, and HAQ-DI were reported as early as week 2. At week 12, significantly (nominal p < 0.05) more upadacitinib- versus placebo-treated patients reported improvements ≥ MCID across all PROs including seven SF-36 domains. The proportions of upadacitinib-treated patients reporting clinically meaningful improvements at week 12 were similar to or greater than with adalimumab and sustained through week 56. Significantly (nominal p < 0.05) more upadacitinib-treated (both doses) patients reported scores ≥ normative values at week 12 versus placebo, and scores were generally similar to or greater than adalimumab.ConclusionsUpadacitinib treatment provides rapid, sustained, and clinically meaningful improvements in PROs in non-bDMARD-IR patients with PsA. SELECT-PsA 1 ClinicalTrials.gov number, NCT03104400.
| S-EPMC8572257 | biostudies-literature
Project description:IntroductionEfficacy and safety of the Janus kinase (JAK) inhibitor upadacitinib (UPA) was evaluated in patients with psoriatic arthritis (PsA) through week 104 of the ongoing long-term extension of the phase 3 trial SELECT-PsA 1.MethodsExploratory analyses of all primary and secondary endpoints (non-responder imputation and as observed for binary endpoints; mixed-effect model repeated measures and as observed for continuous endpoints), and summary of treatment-emergent adverse events, in patients receiving UPA 15 mg (UPA15) or 30 mg (UPA30) once daily, or adalimumab 40 mg (ADA) every other week, through week 104 are reported.ResultsOf 1704 patients, 25.4% discontinued the study drug by week 104. Proportions of patients achieving ≥ 20%/50%/70% improvement in American College of Rheumatology criteria (ACR20/50/70), ≥ 75%/90%/100% improvement in Psoriasis Area and Severity Index (PASI75/90/100), or minimal disease activity (MDA) were maintained through week 104; greater responses by nominal P value were observed with UPA15 and UPA30 versus ADA for ACR20/50/70 and MDA. Mean change from baseline in modified total Sharp/van der Heijde Score (mTSS) was similar across groups and to week 56 results. The safety profile of UPA was generally comparable to ADA and not altered from week 56 data. Rates of serious infection, herpes zoster, anemia, neutropenia, lymphopenia, and elevated creatine phosphokinase remained numerically higher with UPA15 and/or UPA30 versus ADA. Rates of malignancies excluding non-melanoma skin cancer (NMSC), major adverse cardiovascular events, and venous thromboembolism were similar across groups; rates of NMSC were higher with UPA versus ADA. Two deaths were reported with UPA15, one with UPA30, and one with ADA.ConclusionsIn PsA patients, efficacy responses were similar or greater with UPA15 or UPA30 versus ADA through week 104, and inhibition of radiographic progression was maintained. No new safety risks were identified with exposure to UPA through 2 years (week 104).Clinical trial registrationClinicalTrials.gov, NCT03104400.
| S-EPMC9569172 | biostudies-literature
Project description:IntroductionUpadacitinib is a Janus kinase inhibitor under investigation in patients with psoriatic arthritis (PsA). This study assessed the 56-week efficacy and safety of upadacitinib in patients with PsA and an inadequate response or intolerance to biologic therapy.MethodsIn the phase 3 SELECT-PsA 2 study, patients were randomized to 56 weeks of blinded treatment with oral upadacitinib 15 or 30 mg once daily, or placebo switched to upadacitinib 15 or 30 mg once daily at week 24. Efficacy endpoints included the proportion of patients achieving 20/50/70% improvement in American College of Rheumatology criteria (ACR20/50/70), 75/90/100% improvement in Psoriasis Area and Severity Index (PASI75/90/100), and minimal disease activity. Safety was assessed throughout the study.ResultsOf 641 patients who received ≥ 1 dose of study drug, 479 (74.7%) completed 56 weeks of treatment. Improvements in the proportion of patients achieving ACR20/50/70, PASI75/90/100, and minimal disease activity were maintained with both doses of upadacitinib through 56 weeks. Week 56 results for patients who switched from placebo to upadacitinib at week 24 were similar to those for patients originally randomized to the upadacitinib groups. The exposure-adjusted event rate for serious infections was 2.6 and 6.1 events/100 patient-years in the upadacitinib 15 and 30 mg groups, respectively. Herpes zoster occurred more frequently with upadacitinib 30 versus 15 mg; most cases were non-serious.ConclusionIn patients with PsA who had an inadequate response or intolerance to biologic therapy, the efficacy of upadacitinib was maintained over 56 weeks with no new significant safety signals observed.Trial registrationNCT03104374.
| S-EPMC8217417 | biostudies-literature
Project description:ObjectiveIncreased risk of serious adverse events (AEs) was reported for tofacitinib relative to tumour necrosis factor inhibitor therapy in patients with rheumatoid arthritis (RA) aged ≥50 years enriched for cardiovascular (CV) risk (ORAL Surveillance). We assessed post hoc the potential risk of upadacitinib in a similar RA population.MethodsPooled safety data from six phase III trials were evaluated post hoc for AEs in patients receiving upadacitinib 15 mg once a day (with or without conventional synthetic disease-modifying antirheumatic drugs), adalimumab 40 mg every other week with concomitant methotrexate (MTX), or MTX monotherapy in the overall trial population and in a subset of patients with higher CV risk (aged ≥50 years, ≥1 CV risk factor). Higher-risk patients from a head-to-head study of upadacitinib 15 mg versus adalimumab (SELECT-COMPARE) were assessed in parallel. Exposure-adjusted incidence rates for treatment-emergent AEs were summarised based on exposure to upadacitinib or comparators.ResultsA total of 3209 patients received upadacitinib 15 mg, 579 received adalimumab and 314 received MTX monotherapy; ~54% of the patients were included in the overall and SELECT-COMPARE higher-risk populations. Major adverse cardiovascular events (MACE), malignancy (excluding non-melanoma skin cancer (NMSC)) and venous thromboembolism (VTE) were more frequent in the higher-risk cohorts versus the overall population but were generally similar across treatment groups. Rates of serious infections in higher-risk populations and herpes zoster (HZ) and NMSC in all populations were higher with upadacitinib 15 mg than comparators.ConclusionsAn increased risk of MACE, malignancy (excluding NMSC) and VTE was observed in higher-risk populations with RA, yet risk was comparable between upadacitinib-treated and adalimumab-treated patients. Higher rates of NMSC and HZ were observed with upadacitinib versus comparators across all populations, and increased rates of serious infections were detected in upadacitinib-treated patients at higher CV risk.Trial registration numbersNCT02706873, NCT02675426, NCT02629159, NCT02706951, NCT02706847 and NCT03086343.
| S-EPMC10423494 | biostudies-literature
Project description:IntroductionEmerging evidence suggests psoriatic arthritis (PsA) with axial involvement (axPsA) and radiographic axial spondyloarthritis (r-axSpA) may possibly represent distinct disorders, with some differing clinical manifestations, genetic associations, and radiographic findings. Moreover, axPsA and r-axSpA may respond differently to therapies: guselkumab (interleukin [IL]-23p19 subunit inhibitor [i]) and ustekinumab (IL-12/23p40i) demonstrated improvements in axial symptoms in patients with PsA; however, neither risankizumab (IL-23p19i) nor ustekinumab demonstrated efficacy versus placebo in patients with r-axSpA. Current analyses aim to further understand potential molecular distinctions between axPsA and r-axSpA and examine the pharmacodynamic effects of guselkumab in patients with axPsA and those with PsA without axial involvement (non-axPsA).MethodsPost hoc analyses utilized biomarker data from blood and serum samples collected from a subset of participants in phase 3 studies of ustekinumab in r-axSpA and guselkumab in PsA (DISCOVER-1 and DISCOVER-2). Participants with axPsA were identified by investigator-verified sacroiliitis (imaging-confirmed) and axial symptoms. HLA mapping, serum cytokine analysis, and whole-blood RNA sequencing were conducted.ResultsRelative to r-axSpA, patients with axPsA had a lower prevalence of HLA-B27, HLA-C01, and HLA-C02 alleles and a higher prevalence of HLA-B13, HLA-B38, HLA-B57, HLA-C06, and HLA-C12 alleles. Compared with r-axSpA, patients with axPsA had elevated baseline levels of serum IL-17A and IL-17F cytokines, enrichment of IL-17 and IL-10 pathway-associated genes, and neutrophil gene markers. Across axPsA and non-axPsA cohorts, reductions in cytokine levels and normalization of pathway-associated gene expression with guselkumab treatment were comparable.ConclusionThe differences in HLA genetic associations, serum cytokines, and enrichment scores support the concept that axPsA and r-axSpA may be distinct disorders. The comparable pharmacodynamic effects of guselkumab on cytokine levels and pathway-associated genes observed in patients with axPsA and non-axPsA are consistent with demonstrated clinical improvements across PsA cohorts. These findings contribute to the understanding of potential genetic and molecular distinctions between axPsA and r-axSpA.Trial registrationClinicalTrials.gov identifiers, NCT03162796, NCT0315828, NCT02437162, and NCT02438787.
| S-EPMC10129963 | biostudies-literature
Project description:ObjectiveAnalyze tofacitinib efficacy and safety by background methotrexate (MTX) dose in patients with psoriatic arthritis (PsA).MethodsThis post hoc analysis pooled data from two phase III, double-blind trials (OPAL Broaden, NCT01877668; OPAL Beyond, NCT01882439) including patients receiving tofacitinib 5 or 10 mg twice daily (BID), or placebo, with stable MTX. Efficacy outcomes at month 3 stratified by MTX dose (≤ 15 month 3 stratified by MTX dose vs > 15 mg/week) were American College of Rheumatology (ACR)20/50/70, Health Assessment Questionnaire-Disability Index (HAQ-DI); Psoriasis Area and Severity Index (PASI)50/75; change from baseline in HAQ-DI; physician's global assessment of PsA (PGA-PsA-visual analog scale [VAS]); patient's global joint and skin assessment (PGJS-VAS), Leeds Enthesitis Index (LEI); and Dactylitis Severity Score (DSS). Safety assessments included adverse events and laboratory parameters.ResultsFive hundred fifty-six patients received tofacitinib 5 mg BID (n = 186), 10 mg BID (n = 178), or placebo (n = 192), plus MTX (≤ 15 mg/week, n = 371; > 15 mg/week, n = 185). At month 3, tofacitinib efficacy was generally greater than placebo. Patients receiving tofacitinib 5 mg BID demonstrated greater numerical improvements in efficacy outcomes at month 3 with MTX > 15 mg/week vs MTX ≤ 15 mg/week; patients receiving tofacitinib 10 mg BID displayed the opposite. The safety profile was generally consistent between groups; headache was associated with MTX > 15 mg/week; decreased hemoglobin levels were observed in patients receiving tofacitinib 10 mg BID and MTX ≤ 15 mg/week.ConclusionEfficacy of tofacitinib was generally numerically greater than placebo, regardless of MTX dose. Tofacitinib 5 mg BID was generally more efficacious with MTX > 15 mg/week vs ≤ 15 mg/week; the opposite was observed for tofacitinib 10 mg BID. Headache was more frequent with MTX > 15 mg/week.Trial registrationClinicalTrials.gov . Identifier: NCT01877668 (registration: June 14, 2013) and NCT01882439 (registration: June 20, 2013). Key Points • Methotrexate is widely used in the treatment of psoriatic arthritis; however, there are limited data on the impact of varying background methotrexate doses on the efficacy and safety of Janus kinase inhibitors in patients with psoriatic arthritis. • This post hoc analysis assessed the impact of background methotrexate dose (≤ 15 or > 15 mg/week) on tofacitinib efficacy and safety in patients with psoriatic arthritis. • Results indicated that tofacitinib efficacy was generally numerically greater than placebo, regardless of methotrexate dose. Tofacitinib 5 mg twice daily, in combination with a higher dose of background methotrexate, was more efficacious compared with a lower dose of background methotrexate; the opposite was observed for tofacitinib 10 mg twice daily. • Headache was more frequent with the higher methotrexate dose. Data should be interpreted with caution due to the small sample sizes.
| S-EPMC8782818 | biostudies-literature
Project description:ObjectiveTo evaluate upadacitinib efficacy and safety dose response in Japanese patients with active RA and an inadequate response to conventional synthetic DMARDs (csDMARDs).MethodsThis was a multicentre, phase IIb/III, dose-ranging study conducted in Japan, in which patients on previously stable csDMARDs were randomized to receive upadacitinib 7.5, 15 or 30 mg once daily or matching placebo for a 12-week double-blind period. The primary endpoint was a 20% improvement in ACR criteria (ACR20) response at week 12 using non-responder imputation. Key secondary endpoints included ACR50, ACR70 and 28-joint DAS with CRP (DAS28-CRP) remission and low disease activity. Adverse events were also assessed.ResultsOf 197 patients treated, 187 completed the double-blind period. At week 12, more patients receiving upadacitinib 7.5, 15 or 30 mg vs placebo met the ACR20 response (75.5%, 83.7%, 80.0% vs 42.9%; P < 0.001), with significant differences observed as early as week 1. Stringent responses, including ACR50, ACR70 and DAS28-CRP <2.6, were achieved by significantly higher proportions of patients on upadacitinib than placebo and by numerically higher proportions on upadacitinib 15 or 30 mg vs upadacitinib 7.5 mg. Adverse events and infections (serious infections, opportunistic infections and herpes zoster) were more common with upadacitinib vs placebo and numerically highest with upadacitinib 30 mg. There were no venous thromboembolic events reported.ConclusionEfficacy of upadacitinib was demonstrated in this population of Japanese patients with RA and an inadequate response to csDMARDs. Safety and tolerability were consistent with other upadacitinib RA studies. The 15 mg dose of upadacitinib showed the most favourable benefit-risk profile.Trial registrationClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02720523.
| S-EPMC7590414 | biostudies-literature
Project description:Upadacitinib is an oral Janus kinase inhibitor approved for the treatment of rheumatoid arthritis (RA) and recently approved by the European Medicines Agency for the treatment of psoriatic arthritis (PsA). The efficacy and safety profile of upadacitinib in PsA have been established in the SELECT-PsA program in two global phase III studies, which evaluated upadacitinib 15 and 30 mg q.d. The analyses described here characterized upadacitinib pharmacokinetics and exposure-response relationships for efficacy and safety endpoints using data from the SELECT-PsA studies. Upadacitinib pharmacokinetics in patients with PsA were characterized through a Bayesian population analysis approach and were comparable to pharmacokinetics in patients with RA. Exposure-response relationships for key efficacy and safety endpoints were characterized using data from 1916 patients with PsA. The percentage of patients achieving efficacy endpoints at week 12 (American College of Rheumatology [ACR]50 and ACR70), 16 and 24 (sIGA0/1) increased with increasing upadacitinib average plasma concentration over a dosing interval, whereas no clear exposure-response trend was observed for ACR20 at week 12 or ACR20/50/70 at week 24 within the range of plasma exposures evaluated in the phase III PsA studies. No clear trends for exposure-response relationships were identified for experiencing pneumonia, herpes zoster infection, hemoglobin less than 8 g/dl, lymphopenia (grade ≥ 3), or neutropenia (grade ≥ 3) after 24 weeks of treatment. Shallow relationships with plasma exposures were observed for serious infections and hemoglobin decrease greater than 2 g/dl from baseline at week 24. Based on exposure-response analyses, the upadacitinib 15 mg q.d. regimen is predicted to achieve robust efficacy in patients with PsA and to be associated with limited incidences of reductions in hemoglobin or occurrence of serious infections.
| S-EPMC8742648 | biostudies-literature
Project description:IntroductionThis integrated analysis describes the safety profile of upadacitinib, an oral Janus kinase inhibitor, at 15 and 30 mg once daily for up to 3 years of exposure in patients with active psoriatic arthritis (PsA) who had a prior inadequate response or intolerance to ≥ 1 non-biologic or biologic disease-modifying antirheumatic drug.MethodsSafety data were pooled and analyzed from two randomized, placebo-controlled phase 3 trials. Both trials evaluated upadacitinib 15 mg and 30 mg once daily, and one trial also evaluated adalimumab 40 mg every other week. Treatment-emergent adverse events (TEAEs) and laboratory data were summarized for four groups: pooled placebo, pooled upadacitinib 15 mg, pooled upadacitinib 30 mg, and adalimumab. TEAEs were reported as exposure-adjusted event rates (events per 100 patient-years [E/100 PY]) up to a data cut-off of June 29, 2020.ResultsA total of 2257 patients received ≥ 1 dose of upadacitinib 15 mg (N = 907) or 30 mg (N = 921) for 2504.6 PY of exposure or adalimumab (N = 429) for 549.7 PY of exposure. Upper respiratory tract infection, nasopharyngitis, and increased creatine phosphokinase (CPK) were the most common TEAEs with upadacitinib. Rates of malignancies, adjudicated major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs), and deaths were similar across treatment groups. Rates of herpes zoster (HZ) and opportunistic infections (OI; excluding tuberculosis, HZ, and oral candidiasis) were higher with upadacitinib versus adalimumab. Serious infection, anemia, and CPK elevations were most frequent with upadacitinib 30 mg. Potentially clinically significant laboratory abnormalities were uncommon.ConclusionsUpadacitinib 15 mg and adalimumab had similar safety profiles with the exception of HZ and OIs, consistent with what was observed in rheumatoid arthritis. Rates of malignancies, MACEs, VTEs, and deaths were comparable among patients receiving upadacitinib and adalimumab. No new safety risks emerged with longer-term exposure to upadacitinib.Trial registration numbersSELECT-PsA 1: NCT03104400; SELECT-PsA 2: NCT03104374.
| S-EPMC8717827 | biostudies-literature