Efficacy and safety of upadacitinib for active ankylosing spondylitis refractory to biological therapy: a double-blind, randomised, placebo-controlled phase 3 trial.

OBJECTIVES: To evaluate the efficacy and safety of upadacitinib, a Janus kinase inhibitor, in patients with active ankylosing spondylitis (AS) with an inadequate response (IR) to biological disease-modifying antirheumatic drugs (bDMARDs). METHODS: Adults with active AS who met modified New York criteria and had an IR to one or two bDMARDs (tumour necrosis factor or interleukin-17 inhibitors) were randomised 1:1 to oral upadacitinib 15 mg once daily or placebo. The primary endpoint was Assessment of SpondyloArthritis international Society 40 (ASAS40) response at week 14. Sequentially tested secondary endpoints included Ankylosing Spondylitis Disease Activity score, Spondyloarthritis Research Consortium of Canada MRI spine inflammation score, total back pain, nocturnal back pain, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Metrology Index and Maastricht Ankylosing Spondylitis Enthesitis Score. Results are reported from the 14-week double-blind treatment period. RESULTS: A total of 420 patients with active AS were randomised (upadacitinib 15 mg, n=211; placebo, n=209). Significantly more patients achieved the primary endpoint of ASAS40 at week 14 with upadacitinib vs placebo (45% vs 18%; p<0.0001). Statistically significant improvements were observed with upadacitinib vs placebo for all multiplicity-controlled secondary endpoints (p<0.0001). Adverse events were reported for 41% of upadacitinib-treated and 37% of placebo-treated patients through week 14. No events of malignancy, major adverse cardiovascular events, venous thromboembolism or deaths were reported with upadacitinib. CONCLUSION: Upadacitinib 15 mg was significantly more effective than placebo over 14 weeks of treatment in bDMARD-IR patients with active AS. No new safety risks were identified with upadacitinib. TRIAL REGISTRATION NUMBER: NCT04169373.

Upadacitinib for the treatment of active non-radiographic axial spondyloarthritis (SELECT-AXIS 2): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Upadacitinib, a Janus kinase inhibitor, has been shown to be effective in patients with ankylosing spondylitis. We aimed to assess the efficacy and safety of upadacitinib in non-radiographic axial spondyloarthritis. METHODS: The SELECT-AXIS 2 non-radiographic axial spondyloarthritis study was a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 113 sites across 23 countries (Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, China, Czech Republic, France, Germany, Hungary, Israel, Japan, Mexico, Poland, Russia, Slovakia, South Korea, Spain, Taiwan, Turkey, Ukraine, and the USA). Eligible adults had active non-radiographic axial spondyloarthritis, with objective signs of inflammation based on MRI or elevated C-reactive protein and an inadequate response to non-steroidal anti-inflammatory drugs. Patients were randomly assigned (1:1) to receive oral upadacitinib 15 mg once daily or placebo using interactive response technology. Random treatment assignment was stratified by MRI inflammation in the sacroiliac joints and screening high-sensitivity C-reactive protein status (MRI-positive and C-reactive protein-positive, MRI-positive and C-reactive protein-negative, and MRI-negative and C-reactive protein-positive) and previous exposure to biologic disease-modifying antirheumatic drugs (yes vs no). Treatment assignment was masked from patients, investigators, study site personnel, and the study sponsor. The primary endpoint was the proportion of patients with an Assessment of SpondyloArthritis international Society 40 (ASAS40) response at week 14. Analyses were performed on the full analysis set of patients, who underwent random allocation and received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04169373. FINDINGS: Between Nov 26, 2019, and May 20, 2021, 314 patients with active non-radiographic axial spondyloarthritis were enrolled into the study, and 313 received study drug (156 in the upadacitinib group and 157 in the placebo group); 295 (94%) patients (145 in the upadacitinib group and 150 in the placebo group) received treatment for the full 14 weeks. A significantly higher ASAS40 response rate was achieved with upadacitinib compared with placebo at week 14 (70 [45%] of 156 patients vs 35 [23%] of 157 patients; p<0·0001; treatment difference 22%, 95% CI 12-32). The rate of adverse events up to week 14 was similar in the upadacitinib group (75 [48%] of 156 patients) and placebo group (72 [46%] of 157 patients). Serious adverse events and adverse events leading to discontinuation of study drug occurred in four (3%) of 156 patients in the upadacitinib group and two (1%) of 157 patients in the placebo group. Few patients had serious infections or herpes zoster in either treatment group (each event occurred in two [1%] of 156 patients in the upadacitinib group and one [1%] of 157 patients in the placebo group). Five (3%) of 156 patients in the upadacitinib group had neutropenia; no events of neutropenia occurred in the placebo group. No opportunistic infections, malignancies, major adverse cardiovascular events, venous thromboembolic events, or deaths were reported with upadacitinib treatment. INTERPRETATION: Upadacitinib significantly improved the signs and symptoms of non-radiographic axial spondyloarthritis compared with placebo at week 14. These findings support the potential of upadacitinib as a new therapeutic option in patients with active non-radiographic axial spondyloarthritis. FUNDING: AbbVie.

Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials.

BACKGROUND: There is a great unmet need for advanced therapies that provide rapid, robust, and sustained disease control for patients with ulcerative colitis. We assessed the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. METHODS: This phase 3, multicentre, randomised, double-blind, placebo-controlled clinical programme consisted of two replicate induction studies (U-ACHIEVE induction [UC1] and U-ACCOMPLISH [UC2]) and a single maintenance study (U-ACHIEVE maintenance [UC3]). The studies were conducted across Europe, North and South America, Australasia, Africa, and the Asia-Pacific region at 199 clinical centres in 39 countries (UC1), 204 clinical centres in 40 countries (UC2), and 195 clinical centres in 35 countries (UC3). Patients aged 16-75 years with moderately to severely active ulcerative colitis (Adapted Mayo score 5-9; endoscopic subscore 2 or 3) for at least 90 days were randomly assigned (2:1) to oral upadacitinib 45 mg once daily or placebo for 8 weeks (induction studies). Patients who achieved clinical response following 8-week upadacitinib induction were re-randomly assigned (1:1:1) to upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 52 weeks (maintenance study). All patients were randomly assigned using web-based interactive response technology. The primary endpoints were clinical remission per Adapted Mayo score at week 8 (induction) and week 52 (maintenance). The efficacy analyses in the two induction studies were based on the intent-to-treat population, which included all randomised patients who received at least one dose of treatment. In the maintenance study, the primary efficacy analyses reported in this manuscript were based on the first 450 (planned) clinical responders to 8-week induction therapy with upadacitinib 45 mg once daily. The safety analysis population in the induction studies consisted of all randomised patients who received at least one dose of treatment; in the maintenance study, this population included all patients who received at least one dose of treatment as part of the primary analysis population. These studies are registered at ClinicalTrials.gov, NCT02819635 (U-ACHIEVE) and NCT03653026 (U-ACCOMPLISH). FINDINGS: Between Oct 23, 2018, and Sept 7, 2020, 474 patients were randomly assigned to upadacitinib 45 mg once daily (n=319) or placebo (n=155) in UC1. Between Dec 6, 2018, and Jan 14, 2021, 522 patients were randomly assigned to upadacitinib 45 mg once daily (n=345) or placebo (n=177) in UC2. In UC3, a total of 451 patients (21 from the phase 2b study, 278 from UC1, and 152 from UC2) who achieved a clinical response after 8 weeks of upadacitinib induction treatment were randomly assigned again to upadacitinib 15 mg (n=148), upadacitinib 30 mg (n=154), and placebo (n=149) in the primary analysis population. Statistically significantly more patients achieved clinical remission with upadacitinib 45 mg (83 [26%] of 319 patients in UC1 and 114 [34%] of 341 patients in UC2) than in the placebo group (seven [5%] of 154 patients in UC1 and seven [4%] of 174 patients; p<0·0001; adjusted treatment difference 21·6% [95% CI 15·8-27·4] for UC1 and 29·0% [23·2-34·7] for UC2). In the maintenance study, clinical remission was achieved by statistically significantly more patients receiving upadacitinib (15 mg 63 [42%] of 148; 30 mg 80 [52%] of 154) than those receiving placebo (18 [12%] of 149; p<0·0001; adjusted treatment difference 30·7% [21·7-39·8] for upadacitinib 15 mg vs placebo and 39·0% [29·7-48·2] for upadacitinib 30 mg vs placebo). The most commonly reported adverse events in UC1 were nasopharyngitis (15 [5%] of 319 in the upadacitinib 45 mg group vs six [4%] of 155 in the placebo group), creatine phosphokinase elevation (15 [4%] vs three [2%]), and acne (15 [5%] vs one [1%]). In UC2, the most frequently reported adverse event was acne (24 [7%] of 344 in the upadacitinib 45 mg group vs three [2%] of 177 in the placebo group). In both induction studies, serious adverse events and adverse events leading to discontinuation of treatment were less frequent in the upadacitinib 45 mg group than in the placebo group (serious adverse events eight [3%] vs nine (6%) in UC1 and 11 [3%] vs eight [5%] in UC2; adverse events leading to discontinuation six [2%] vs 14 [9%] in UC1 and six [2%] vs nine [5%] in UC2). In UC3, the most frequently reported adverse events (≥5%) were worsening of ulcerative colitis (19 [13%] of 148 in the upadacitinib 15 mg group vs 11 [7%] of 154 in the upadacitinib 30 mg group vs 45 [30%] of 149 in the placebo group), nasopharyngitis (18 [12%] vs 22 [14%] vs 15 [10%]), creatine phosphokinase elevation (nine [6%] vs 13 [8%] vs three [2%]), arthralgia (nine [6%] vs five [3%] vs 15 [10%]), and upper respiratory tract infection (seven [5%] vs nine [6%] vs six [4%]). The proportion of serious adverse events (ten [7%] vs nine [6%] vs 19 [13%]) and adverse events leading to discontinuation (six [4%] vs ten [6%] vs 17 [11%]) was lower in both upadacitinib groups than in the placebo group. Events of cancer, adjudicated major adverse cardiac events, or venous thromboembolism were reported infrequently. There were no treatment-related deaths. INTERPRETATION: Upadacitinib demonstrated a positive efficacy and safety profile and could be an effective treatment option for patients with moderately to severely active ulcerative colitis. FUNDING: AbbVie.

Performance and Predictors of Minimal Disease Activity Response in Patients With Peripheral Spondyloarthritis Treated With Adalimumab.

OBJECTIVE: To examine the concurrent validity and discrimination of criteria for modified minimal disease activity (MDA) in peripheral spondyloarthritis (SpA) following filter principles of Outcome Measures in Rheumatology (OMERACT) and to determine predictors of modified MDA response. METHODS: Four modified MDA versions were derived in the ABILITY-2 study using the Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index or the Leeds Enthesitis Index (LEI) while excluding psoriasis. To assess concurrent validity, modified MDA versions were correlated with Peripheral Spondyloarthritis Response Criteria (PSpARC) remission, Ankylosing Spondylitis Disease Activity Score showing inactive disease (ASDAS ID), and physician global assessment of disease activity. Treatment discrimination was assessed between adalimumab and placebo at week 12. Multiple logistic regression was used to determine baseline predictors of long-term modified MDA responses and sustained modified MDA. RESULTS: The 4 modified MDA versions showed a stronger positive correlation with PSpARC remission (rtet > 0.95) versus ASDAS ID (rtet > 0.75) at week 12 and years 1-3 and were able to show discrimination (P < 0.001). Responsiveness was shown at week 12; significantly more patients receiving adalimumab versus placebo achieved all 4 versions of modified MDA. Approximately 40-60% of patients treated with adalimumab achieved modified MDA using the LEI or SPARCC enthesitis index at years 1-3. Achieving modified MDA response after 12 weeks of adalimumab treatment was a robust positive predictor of attaining long-term modified MDA through 3 years (odds ratio [OR] 11.38-27.13 for modified MDA using the LEI; OR 17.98-37.85 for modified MDA using the SPARCC enthesitis index). CONCLUSION: All 4 versions of modified MDA showed concurrent validity and discriminated well between adalimumab and placebo treatment groups. Early modified MDA response is a more consistent predictor of long-term modified MDA achievement than baseline characteristics. The 5 of 6 versions of modified MDA could be an appropriate treatment target in patients with peripheral SpA.

Association Between Proposed Definitions of Clinical Remission/Response and Well-Being in Patients With Crohn's Disease.

BACKGROUND AND AIMS: Patient-reported outcomes are recommended endpoints in Crohn's disease [CD] trials. The association between patient-reported general well-being relative to symptoms of diarrhoea and abdominal pain [AP] in patients with moderate to severe CD was explored. METHODS: Patients from three randomized, placebo-controlled, double-blind adalimumab or upadacitinib studies with average daily very soft/liquid stool frequency [SF] ≥4 and/or AP score ≥2 at baseline were included. Using electronic diaries, patients reported general well-being [seven-point Likert scale; 1 = worst; 7 = best] in item 10 of the Inflammatory Bowel Disease Questionnaire [IBDQ]. Changes in well-being and clinical outcomes of SF and AP from baseline to week 12 or 16, and the relationship between well-being and clinical outcomes were evaluated using cumulative distribution function and probability density function curves. RESULTS: In total, 858 patients with CD were included [adalimumab, n = 695; upadacitinib, n = 163]. Patients who achieved clinical remission [SF ≤2.8, AP score ≤1.0, neither worse than baseline] were more likely than those not in clinical remission to report IBDQ item 10 response in the 6-7 group category but not IBDQ categories ≤5. Higher IBDQ score for item 10 [6-7] was associated with lower SF and AP score. Greater point increases in IBDQ item 10 were associated with a greater percentage decrease in clinical parameters; a ≥25-30% decrease in SF or AP was associated with a ≥1-point improvement in IBDQ. CONCLUSIONS: An association between improvements in patient-reported general well-being and clinical remission/response was observed using outcomes of SF and AP, supporting the clinical remission/response endpoint definitions used in clinical studies of CD. Clinical Trial Registrations [ClinicalTrials.gov]: NCT00077779 [CHARM]; NCT00348283 [EXTEND]; NCT02365649 [CELEST].

Upadacitinib in patients with psoriatic arthritis and an inadequate response to non-biological therapy: 56-week data from the phase 3 SELECT-PsA 1 study.

BACKGROUND: In SELECT-PsA 1, a randomised double-blind phase 3 study, upadacitinib 15 mg and 30 mg were superior to placebo and non-inferior to adalimumab in ≥20% improvement in American College of Rheumatology (ACR) criteria at 12 weeks in patients with psoriatic arthritis (PsA). Here, we report 56-week efficacy and safety in patients from SELECT-PsA 1. METHODS: Patients received upadacitinib 15 mg or 30 mg once daily, adalimumab 40 mg every other week for 56 weeks or placebo through week 24 switched thereafter to upadacitinib 15 mg or 30 mg until week 56. Efficacy endpoints included the proportion of patients achieving ≥20%/50%/70% improvement in ACR criteria (ACR20/50/70), ≥75%/90%/100% improvement in Psoriasis Area and Severity Index (PASI75/90/100), minimal disease activity (MDA) and change from baseline in modified total Sharp/van der Heijde Score. Treatment-emergent adverse events per 100 patient years (PY) were summarised. RESULTS: Consistent with results through week 24, ACR20/50/70, PASI75/90/100 and MDA responses were maintained with upadacitinib through week 56 and were generally numerically higher than with adalimumab; inhibition of radiographic progression was also maintained. Patients who switched from placebo to upadacitinib exhibited comparable improvements at week 56 as patients originally randomised to upadacitinib. The rates of serious adverse events were 9.1 events/100 PY with upadacitinib 15 mg and 12.3 events/100 PY with upadacitinib 30 mg. Two deaths were reported in each of the upadacitinib groups. CONCLUSION: Efficacy across various domains of PsA were maintained with upadacitinib 15 mg and 30 mg through week 56 with no new safety signals observed.

Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials.

BACKGROUND: Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, and tyrosine kinase 2. We aimed to assess the efficacy and safety of upadacitinib compared with placebo for the treatment of moderate-to-severe atopic dermatitis. METHODS: Measure Up 1 and Measure Up 2 were replicate multicentre, randomised, double-blind, placebo-controlled, phase 3 trials; Measure Up 1 was done at 151 clinical centres in 24 countries across Europe, North and South America, Oceania, and the Asia-Pacific region; and Measure Up 2 was done at 154 clinical centres in 23 countries across Europe, North America, Oceania, and the Asia-Pacific region. Eligible patients were adolescents (aged 12-17 years) and adults (aged 18-75 years) with moderate-to-severe atopic dermatitis (≥10% of body surface area affected by atopic dermatitis, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for Atopic Dermatitis [vIGA-AD] score of ≥3, and Worst Pruritus Numerical Rating Scale score of ≥4). Patients were randomly assigned (1:1:1) using an interactive response technology system to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily for 16 weeks, stratified by baseline disease severity, geographical region, and age. Coprimary endpoints were the proportion of patients who had achieved at least a 75% improvement in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 [clear] or 1 [almost clear] with ≥2 grades of reduction from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all randomly assigned patients who received at least one dose of study drug. These trials are registered with ClinicalTrials.gov, NCT03569293 (Measure Up 1) and NCT03607422 (Measure Up 2), and are both active but not recruiting. FINDINGS: Between Aug 13, 2018, and Dec 23, 2019, 847 patients were randomly assigned to upadacitinib 15 mg (n=281), upadacitinib 30 mg (n=285), or placebo (n=281) in the Measure Up 1 study. Between July 27, 2018, and Jan 17, 2020, 836 patients were randomly assigned to upadacitinib 15 mg (n=276), upadacitinib 30 mg (n=282), or placebo (n=278) in the Measure Up 2 study. At week 16, the coprimary endpoints were met in both studies (all p<0·0001). The proportion of patients who had achieved EASI-75 at week 16 was significantly higher in the upadacitinib 15 mg (196 [70%] of 281 patients) and upadacitinib 30 mg (227 [80%] of 285 patients) groups than the placebo group (46 [16%] of 281 patients) in Measure Up 1 (adjusted difference in EASI-75 response rate vs placebo, 53·3% [95% CI 46·4-60·2] for the upadacitinib 15 mg group; 63·4% [57·1-69·8] for the upadacitinib 30 mg group) and Measure Up 2 (166 [60%] of 276 patients in the upadacitinib 15 mg group and 206 [73%] of 282 patients in the upadacitinib 30 mg group vs 37 [13%] of 278 patients in the placebo group; adjusted difference in EASI-75 response rate vs placebo, 46·9% [39·9-53·9] for the upadacitinib 15 mg group; 59·6% [53·1-66·2] for the upadacitinib 30 mg group). The proportion of patients who achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg (135 [48%] patients) and upadacitinib 30 mg (177 [62%] patients) groups than the placebo group (24 [8%] patients) in Measure Up 1 (adjusted difference in vIGA-AD response rate vs placebo, 39·8% [33·2-46·4] for the upadacitinib 15 mg group; 53·6% [47·2-60·0] for the upadacitinib 30 mg group) and Measure Up 2 (107 [39%] patients in the upadacitinib 15 mg group and 147 [52%] patients in the upadacitinib 30 mg group vs 13 [5%] patients in the placebo group; adjusted difference in vIGA-AD response rate vs placebo, 34·0% [27·8-40·2] for the upadacitinib 15 mg group; 47·4% [41·0-53·7] for the upadacitinib 30 mg group). Both upadacitinib doses were well tolerated. The incidence of serious adverse events and adverse events leading to study drug discontinuation were similar among groups. The most frequently reported treatment-emergent adverse events were acne (19 [7%] of 281 patients in the upadacitinib 15 mg group, 49 [17%] of 285 patients in the upadacitinib 30 mg group, and six [2%] of 281 patients in the placebo group in Measure Up 1; 35 [13%] of 276 patients in the upadacitinib 15 mg group, 41 [15%] of 282 patients in the upadacitinib 30 mg group, and six [2%] of 278 patients in the placebo group in Measure Up 2), upper respiratory tract infection (25 [9%] patients, 38 [13%] patients, and 20 [7%] patients; 19 [7%] patients, 17 [16%] patients, and 12 [4%] patients), nasopharyngitis (22 [8%] patients, 33 [12%] patients, and 16 [6%] patients; 16 [6%] patients, 18 [6%] patients, and 13 [5%] patients), headache (14 [5%] patients, 19 [7%] patients, and 12 [4%] patients; 18 [7%] patients, 20 [7%] patients, and 11 [4%] patients), elevation in creatine phosphokinase levels (16 [6%] patients, 16 [6%] patients, and seven [3%] patients; nine [3%] patients, 12 [4%] patients, and five [2%] patients), and atopic dermatitis (nine [3%] patients, four [1%] patients, and 26 [9%] patients; eight [3%] patients, four [1%] patients, and 26 [9%] patients). INTERPRETATION: Monotherapy with upadacitinib might be an effective treatment option and had a positive benefit-risk profile in adolescents and adults with moderate-to-severe atopic dermatitis. FUNDING: AbbVie.

Upadacitinib in Patients with Psoriatic Arthritis and Inadequate Response to Biologics: 56-Week Data from the Randomized Controlled Phase 3 SELECT-PsA 2 Study.

INTRODUCTION: Upadacitinib 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. METHODS: In 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. RESULTS: Of 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. CONCLUSION: In 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 REGISTRATION: NCT03104374.

Trial of Upadacitinib and Adalimumab for Psoriatic Arthritis.

BACKGROUND: The Janus kinase inhibitor upadacitinib is a potential treatment for psoriatic arthritis. The efficacy and safety of upadacitinib as compared with adalimumab, a tumor necrosis factor α inhibitor, in patients who have an inadequate response to nonbiologic disease-modifying antirheumatic drugs are unclear. METHODS: In a 24-week, phase 3 trial, we randomly assigned patients in a 1:1:1:1 ratio to receive oral upadacitinib at a dose of 15 mg or 30 mg once daily, placebo, or subcutaneous adalimumab (40 mg every other week). The primary end point was an American College of Rheumatology 20 (ACR20) response (≥20% decrease in the number of tender and swollen joints and ≥20% improvement in at least three of five other domains) at week 12 with upadacitinib as compared with placebo. Secondary end points included comparisons of upadacitinib with adalimumab. RESULTS: A total of 1704 patients received an active drug or placebo. The percentage of patients who had an ACR20 response at week 12 was 70.6% with 15-mg upadacitinib, 78.5% with 30-mg upadacitinib, 36.2% with placebo (P<0.001 for both upadacitinib doses vs. placebo), and 65.0% with adalimumab. The difference between groups for 15-mg upadacitinib as compared with adalimumab was 5.6 percentage points (95% confidence interval [CI], -0.6 to 11.8) and for 30-mg upadacitinib as compared with adalimumab was 13.5 percentage points (95% CI, 7.5 to 19.4). Both upadacitinib doses were noninferior to adalimumab for the ACR20 response at week 12; the 30-mg dose but not the 15-mg dose was superior to adalimumab. The incidence of adverse events through week 24 was 66.9% with 15-mg upadacitinib, 72.3% with 30-mg upadacitinib, 59.6% with placebo, and 64.8% with adalimumab. There were serious infections in 1.2%, 2.6%, 0.9%, and 0.7% of the patients, respectively. Hepatic disorders occurred in 9.1% of patients in the 15-mg upadacitinib group and 12.3% in the 30-mg upadacitinib group, but grade 3 increases in aminotransferase levels occurred in 2% of patients or fewer in all groups. CONCLUSIONS: The percentage of patients with psoriatic arthritis who had an ACR20 response at week 12 was significantly higher with 15-mg or 30-mg upadacitinib than with placebo. The 30-mg dose but not the 15-mg dose was superior to adalimumab. Adverse events were more frequent with upadacitinib than with placebo. (Funded by AbbVie; SELECT-PsA 1 ClinicalTrials.gov number, NCT03104400.).

Efficacy and safety of upadacitinib over 84 weeks in Japanese patients with rheumatoid arthritis (SELECT-SUNRISE).

BACKGROUND: The objective of the study was to evaluate the efficacy and safety of upadacitinib over 84 weeks in Japanese patients with active rheumatoid arthritis (RA) and an inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs. METHODS: All patients completing a 12-week, randomized, double-blind treatment period entered a blinded extension and continued upadacitinib 7.5, 15, or 30 mg once daily (QD), or were switched from placebo to upadacitinib 7.5, 15, or 30 mg QD. Efficacy and safety were assessed over 84 weeks. RESULTS: Of 197 randomized patients, 187 (94.9%) completed the 12-week period and entered the blinded extension; 152 (77.2%) patients were ongoing at week 84. At week 84, the proportions of patients achieving a 20% improvement in American College of Rheumatology criteria (ACR20) were 85.7%, 77.6%, and 58.0% with continued upadacitinib 7.5, 15, and 30 mg, respectively (nonresponder imputation), and were similar in patients who had switched from placebo. Favorable response rates were also observed for more stringent measures of response (ACR50/70) and remission (defined by the Disease Activity Score of 28 joints with C-reactive protein, Clinical Disease Activity Index, or Simplified Disease Activity Index). The 15 mg and 30 mg doses of upadacitinib were associated with more rapid and numerically higher initial responses for some measures of disease activity and remission compared with the 7.5 mg dose. Rates of adverse events, infection, opportunistic infection, serious infection, and herpes zoster were lower with upadacitinib 7.5 and 15 mg versus 30 mg. CONCLUSIONS: Upadacitinib demonstrated sustained efficacy and was well tolerated over 84 weeks in Japanese patients with RA, with upadacitinib 15 mg offering the most favorable benefit-risk profile. TRIAL REGISTRATION: ClinicalTrials.gov NCT02720523 . Registered on March 22, 2016.

Upadacitinib for psoriatic arthritis refractory to biologics: SELECT-PsA 2.

BACKGROUND: Upadacitinib 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). METHODS: In 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. RESULTS: At 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. CONCLUSION: In 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 NUMBER: NCT03104374.

Upadacitinib monotherapy versus methotrexate monotherapy in methotrexate-naïve Japanese patients with rheumatoid arthritis: a sub-analysis of the Phase 3 SELECT-EARLY study.

OBJECTIVE: To assess upadacitinib monotherapy versus methotrexate (MTX) in MTX-naïve Japanese patients with rheumatoid arthritis (RA) from the Phase 3 SELECT-EARLY study. METHODS: Japanese patients were randomized 2:1:1:1 to upadacitinib 7.5, 15, or 30 mg daily or MTX 7.5 mg/week (titrated to ≤15 mg/week). Efficacy endpoints included the proportion of patients reporting 20% improvement in American College of Rheumatology criteria (ACR20) at week 12 and change from baseline in modified Total Sharp Score (mTSS) at week 24. Other efficacy outcomes were also assessed at weeks 12 and/or 24. Safety was assessed over 24 weeks. RESULTS: Of 138 Japanese patients enrolled, significantly more patients treated with upadacitinib 7.5 and 15 mg, but not 30 mg, reported ACR20 responses versus MTX at week 12. Significantly smaller changes from baseline in mTSS were observed with upadacitinib 15 and 30 mg, but not 7.5 mg, versus MTX at week 24. Upadacitinib demonstrated an acceptable safety profile; herpes zoster occurred in 3.6%, 7.4%, and 7.1% of patients treated with upadacitinib 7.5, 15, and 30 mg, respectively. CONCLUSION: Similar to the global study population, upadacitinib demonstrated clinical efficacy superior to placebo in the Japanese subpopulation. Among upadacitinib-treated patients, herpes zoster was least common with 7.5 mg.

Trial of Upadacitinib or Abatacept in Rheumatoid Arthritis.

BACKGROUND: Upadacitinib is an oral selective Janus kinase inhibitor to treat rheumatoid arthritis. The efficacy and safety of upadacitinib as compared with abatacept, a T-cell costimulation modulator, in patients with rheumatoid arthritis refractory to biologic disease-modifying antirheumatic drugs (DMARDs) are unclear. METHODS: In this 24-week, phase 3, double-blind, controlled trial, we randomly assigned patients in a 1:1 ratio to receive oral upadacitinib (15 mg once daily) or intravenous abatacept, each in combination with stable synthetic DMARDs. The primary end point was the change from baseline in the composite Disease Activity Score for 28 joints based on the C-reactive protein level (DAS28-CRP; range, 0 to 9.4, with higher scores indicating more disease activity) at week 12, assessed for noninferiority. Key secondary end points at week 12 were the superiority of upadacitinib over abatacept in the change from baseline in the DAS28-CRP and the percentage of patients having clinical remission according to a DAS28-CRP of less than 2.6. RESULTS: A total of 303 patients received upadacitinib, and 309 patients received abatacept. From baseline DAS28-CRP values of 5.70 in the upadacitinib group and 5.88 in the abatacept group, the mean change at week 12 was -2.52 and -2.00, respectively (difference, -0.52 points; 95% confidence interval [CI], -0.69 to -0.35; P<0.001 for noninferiority; P<0.001 for superiority). The percentage of patients having remission was 30.0% with upadacitinib and 13.3% with abatacept (difference, 16.8 percentage points; 95% CI, 10.4 to 23.2; P<0.001 for superiority). During the treatment period, one death, one nonfatal stroke, and two venous thromboembolic events occurred in the upadacitinib group, and more patients in the upadacitinib group than in the abatacept group had elevated hepatic aminotransferase levels. CONCLUSIONS: In patients with rheumatoid arthritis refractory to biologic DMARDs, upadacitinib was superior to abatacept in the change from baseline in the DAS28-CRP and the achievement of remission at week 12 but was associated with more serious adverse events. Longer and larger trials are required in order to determine the effect and safety of upadacitinib in patients with rheumatoid arthritis. (Funded by AbbVie; SELECT-CHOICE Clinicaltrials.gov number, NCT03086343.).

Efficacy and Safety of Upadacitinib Monotherapy in Methotrexate-Naive Patients With Moderately-to-Severely Active Rheumatoid Arthritis (SELECT-EARLY): A Multicenter, Multi-Country, Randomized, Double-Blind, Active Comparator-Controlled Trial.

OBJECTIVE: The SELECT-EARLY trial was undertaken to study the effect of upadacitinib, an oral, reversible Janus kinase 1-selective inhibitor, as monotherapy in patients with predominantly early rheumatoid arthritis who were naive for or had limited exposure to methotrexate (MTX). METHODS: Patients (n = 947) were randomized 1:1:1 to receive once-daily doses of upadacitinib 15 mg or 30 mg or weekly MTX (7.5-20 mg/week) for 24 weeks. The primary end points were the proportion of patients who met the American College of Rheumatology 50% (ACR50) improvement criteria at week 12, and the proportion in whom a Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) of <2.6 was achieved at week 24. Data are presented through week 24. RESULTS: At baseline, the median disease duration was 0.5 years (range 0-44 years). A total of 840 patients (89%) completed 24 weeks of treatment. The study met both primary end points for upadacitinib 15 mg and 30 mg versus MTX (ACR50 was achieved at week 12 in 52% and 56% of patients, respectively, versus 28% [P < 0.001], and DAS28-CRP <2.6 was achieved at week 24 in 48% and 50% of patients, respectively, versus 19% [P < 0.001]). Statistically significant and clinically meaningful improvements in multiple patient-reported outcomes (PROs) were recorded for both upadacitinib doses versus MTX. Overall, 88% of patients receiving upadacitinib 15 mg and 89% of patients receiving 30 mg, respectively, had no radiographic progression (modified total Sharp score ≤0) compared to 78% of those receiving MTX (P < 0.01). Through week 24, the frequency of treatment-emergent adverse events was similar between the MTX arm (65%) and upadacitinib 15 mg arm (64%), but was slightly higher in the upadacitinib 30 mg arm (71%). Six deaths were reported (2 in the upadacitinib 15 mg arm, 3 in the upadacitinib 30 mg arm, and 1 in the MTX arm). CONCLUSION: Our findings indicate that patients receiving either dose of upadacitinib monotherapy experienced significant improvements in clinical, radiographic, and PROs compared to patients receiving MTX.

Efficacy and safety of upadacitinib in Japanese patients with rheumatoid arthritis (SELECT-SUNRISE): a placebo-controlled phase IIb/III study.

OBJECTIVE: To evaluate upadacitinib efficacy and safety dose response in Japanese patients with active RA and an inadequate response to conventional synthetic DMARDs (csDMARDs). METHODS: This 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. RESULTS: Of 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. CONCLUSION: Efficacy 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 REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02720523.

Efficacy and Safety of Upadacitinib in a Randomized Trial of Patients With Crohn's Disease.

BACKGROUND & AIMS: We evaluated the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, in a randomized trial of patients with Crohn's disease (CD). METHODS: We performed a double-blind, phase 2 trial in adults with moderate to severe CD and inadequate response or intolerance to immunosuppressants or tumor necrosis factor antagonists. Patients were randomly assigned (1:1:1:1:1:1) to groups given placebo; or 3 mg, 6 mg, 12 mg, or 24 mg upadacitinib twice daily; or 24 mg upadacitinib once daily and were evaluated by ileocolonoscopy at weeks 12 or 16 of the induction period. Patients who completed week 16 were re-randomized to a 36-week period of maintenance therapy with upadacitinib. The primary endpoints were clinical remission at week 16 and endoscopic remission at week 12 or 16 using the multiple comparison procedure and modeling and the Cochran-Mantel-Haenszel test, with a 2-sided level of 10%. RESULTS: Among the 220 patients in the study, clinical remission was achieved by 13% of patients receiving 3 mg upadacitinib, 27% of patients receiving 6 mg upadacitinib (P < .1 vs placebo), 11% of patients receiving 12 mg upadacitinib, and 22% of patients receiving 24 mg upadacitinib twice daily, and by 14% of patients receiving 24 mg upadacitinib once daily, vs 11% of patients receiving placebo. Endoscopic remission was achieved by 10% (P < .1 vs placebo), 8%, 8% (P < .1 vs placebo), 22% (P < .01 vs placebo), and 14% (P < .05 vs placebo) of patients receiving upadacitinib, respectively, vs none of the patients receiving placebo. Endoscopic but not clinical remission increased with dose during the induction period. Efficacy was maintained for most endpoints through week 52. During the induction period, patients in the upadacitinib groups had higher incidences of infections and serious infections vs placebo. Patients in the twice-daily 12 mg and 24 mg upadacitinib groups had significant increases in total, high-density lipoprotein, and low-density lipoprotein cholesterol levels compared with patients in the placebo group. CONCLUSIONS: In a phase 2 trial of patients with CD, upadacitinib induced endoscopic remission in a significant proportion of patients compared with placebo. Upadacitinib's benefit/risk profile supports further development for treatment of CD. (Clinicaltrials.gov, Number: NCT02365649).

Exposure-Response Analyses of Upadacitinib Efficacy and Safety in Phase II and III Studies to Support Benefit-Risk Assessment in Rheumatoid Arthritis.

Exposure-response analyses of upadacitinib (UPA) key efficacy and safety end points (3,685 and 4,577 subjects for efficacy and safety, respectively) using data from phase II and phase III rheumatoid arthritis (RA) studies were conducted to support benefit-risk assessment. Percentage of subjects achieving American College of Rheumatology (ACR)20/50/70, disease activity score 28 (C-reactive protein) (DAS28-CRP) ≤ 3.2, and DAS28-CRP < 2.6 increased with increasing UPA plasma exposures. With the small number of observed safety events, no clear trends for exposure-response relationships were identified for pneumonia, herpes zoster infection, changes in platelet count, lymphopenia (Grade ≥ 4), or neutropenia (Grade ≥ 3) up to Week 26. Shallow exposure-response relationships were observed for > 2 g/dL decrease in hemoglobin, lymphopenia Grade ≥ 3 at Week 12/14, and serious infections at Week 24/26. Exposure-efficacy analyses demonstrate that UPA 15 mg q.d. (once daily) dose provided the optimal benefit-risk in RA through maximizing efficacy with only small incremental benefit with 30 mg q.d.; and with consistency across RA subpopulations and with UPA monotherapy or combination with conventional synthetic disease-modifying antirheumatic drugs.

Upadacitinib in adults with moderate to severe atopic dermatitis: 16-week results from a randomized, placebo-controlled trial.

BACKGROUND: Atopic dermatitis is a chronic inflammatory skin disease characterized by pruritic skin lesions. OBJECTIVE: We sought to evaluate the safety and efficacy of multiple doses of the selective Janus kinase 1 inhibitor upadacitinib in patients with moderate to severe atopic dermatitis. METHODS: In the 16-week, double-blind, placebo-controlled, parallel-group, dose-ranging portion of this 88-week trial in 8 countries (ClinicalTrials.gov, NCT02925117; ongoing, not recruiting), adults with moderate to severe disease and inadequate control by topical treatment were randomized 1:1:1:1, using an interactive response system and stratified geographically, to once-daily upadacitinib oral monotherapy 7.5, 15, or 30 mg or placebo. The primary end point was percentage improvement in Eczema Area and Severity Index from baseline at week 16. Efficacy was analyzed by intention-to-treat in all randomized patients. Safety was analyzed in all randomized patients who received study medication, based on actual treatment. RESULTS: Patients (N = 167) enrolled from November 21, 2016, to April 20, 2017. All were randomized and analyzed for efficacy (each upadacitinib group, n = 42; placebo, n = 41); 166 were analyzed for safety (each upadacitinib group, n = 42; placebo, n = 40). The mean (SE) primary efficacy end point was 39% (6.2%), 62% (6.1%), and 74% (6.1%) for the upadacitinib 7.5-, 15-, and 30-mg groups, respectively, versus 23% (6.4%) for placebo (P = .03, <.001, and <.001). Serious adverse events occurred in 4.8% (2 of 42), 2.4% (1 of 42), and 0% (0 of 42) of upadacitinib groups (vs 2.5% [1 of 40] for placebo). CONCLUSIONS: A dose-response relationship was observed for upadacitinib efficacy; the 30-mg once-daily dose showed the greatest clinical benefit. Dose-limiting toxicity was not observed.

Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis (SELECT-AXIS 1): a multicentre, randomised, double-blind, placebo-controlled, phase 2/3 trial.

BACKGROUND: The JAK pathway is a potential therapeutic target in ankylosing spondylitis. This study assessed the efficacy and safety of upadacitinib, a selective JAK1 inhibitor, in patients with ankylosing spondylitis. METHODS: This multicentre, randomised, double-blind, placebo-controlled, two-period, parallel-group, phase 2/3 study, SELECT-AXIS 1, enrolled adults in 62 sites in 20 countries. Eligible patients had active ankylosing spondylitis, fulfilled modified New York criteria, were previously untreated with biological disease-modifying antirheumatic drugs, and had inadequate response to at least two or intolerance or contraindication to non-steroidal anti-inflammatory drugs. Patients were randomly assigned 1:1 using interactive response technology to take oral upadacitinib 15 mg once daily or oral placebo for the 14-week period 1; only period 1 data are reported here. The primary endpoint was the composite outcome measure of the Assessment of SpondyloArthritis international Society 40 response at week 14. Analyses were done in the full analysis set of patients who were randomly assigned and received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03178487. FINDINGS: Between Nov 30, 2017, and Oct 15, 2018, 187 patients were randomly assigned to upadacitinib 15 mg (93 patients) or to placebo (94 patients), and 178 (95%) patients (89 in the upadacitinib group and 89 in the placebo group) completed period 1 on study drug (by the completion date of Jan 21, 2019). Significantly more patients had an Assessment of SpondyloArthritis international Society 40 response in the upadacitinib group versus in the placebo group at week 14 (48 [52%] of 93 patients vs 24 [26%] of 94 patients; p=0·0003; treatment difference 26% [95% CI 13-40]). Adverse events were reported in 58 (62%) of 93 patients in the upadacitinib group versus 52 (55%) of 94 in the placebo group. The most common adverse event in the upadacitinib group was increased creatine phosphokinase (eight [9%] of 93 patients in the upadacitinib group vs two [2%] of 94 patients with placebo). No serious infections, herpes zoster, malignancy, venous thromboembolic events, or deaths were reported; one serious adverse event was reported in each group. INTERPRETATION: Upadacitinib 15 mg was efficacious and well tolerated in patients with active ankylosing spondylitis who had an inadequate response or contraindication to non-steroidal anti-inflammatory drugs. These data support the further investigation of upadacitinib for the treatment of axial spondyloarthritis. FUNDING: AbbVie.

Upadacitinib Versus Placebo or Adalimumab in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase III, Double-Blind, Randomized Controlled Trial.

OBJECTIVE: To evaluate the efficacy, including capacity for inhibition of radiographic progression, and safety of upadacitinib, a JAK1-selective inhibitor, as compared to placebo or adalimumab in patients with rheumatoid arthritis (RA) who have experienced an inadequate response to methotrexate (MTX). METHODS: In total, 1,629 RA patients with an inadequate response to MTX were randomized (2:2:1) to receive upadacitinib (15 mg once daily), placebo, or adalimumab (40 mg every other week) while continuing to take a stable background dose of MTX. The primary end points were achievement of an American College of Rheumatology 20% (ACR20) improvement response and a Disease Activity Score in 28 joints using C-reactive protein level (DAS28-CRP) of <2.6 in the upadacitinib group compared to the placebo group at week 12; inhibition of radiographic progression was evaluated at week 26. The study was also designed and powered to test for the noninferiority and superiority of upadacitinib compared to adalimumab, as measured both clinically and functionally. RESULTS: At week 12, both primary end points were met in patients receiving upadacitinib compared to those receiving placebo (P ≤ 0.001). An ACR20 improvement response was achieved by 71% of patients in the upadacitinib group compared to 36% in the placebo group, and a DAS28-CRP score of <2.6 was observed in 29% of patients receiving upadacitinib compared to 6% of patients receiving placebo. Upadacitinib was superior to adalimumab based on the ACR50 response rate, achievement of a DAS28-CRP score of ≤3.2, change in pain severity score, and change in the Health Assessment Questionnaire disability index. At week 26, more patients receiving upadacitinib than those receiving placebo or adalimumab achieved low disease activity or remission (P ≤ 0.001). Radiographic progression was significantly inhibited in patients receiving upadacitinib and was observed in fewer upadacitinib-treated patients than placebo-treated patients (P ≤ 0.001). Up to week 26, adverse events (AEs), including serious infections, were comparable between the upadacitinib and adalimumab groups. The proportions of patients with serious AEs and AEs leading to discontinuation were highest in the adalimumab group; the proportions of patients with herpes zoster and those with creatine phosphokinase (CPK) elevations were highest in the upadacitinib group. Three malignancies, 5 major adverse cardiovascular events, and 4 deaths were reported among the groups, but none occurred in patients receiving upadacitinib. Six venous thromboembolic events were reported (1 in the placebo group, 2 in the upadacitinib group, and 3 in the adalimumab group). CONCLUSION: Upadacitinib was superior to placebo and adalimumab for improving signs, symptoms, and physical function in RA patients who were receiving background MTX. In addition, radiographic progression was significantly inhibited by upadacitinib as compared to placebo. The overall safety profile of upadacitinib was generally similar to that of adalimumab, except for higher rates of herpes zoster and CPK elevations in patients receiving upadacitinib.