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Background Abdominal pain (AP), bowel urgency (BU), stool frequency (SF), rectal bleeding (RB) and fatigue are debilitating symptoms that reduce quality of life in patients with ulcerative colitis (UC). Results from two Phase 3 induction trials and one maintenance trial (U-ACHIEVE [NCT02819635] and U-ACCOMPLISH [NCT03653026]) showed significant and clinically meaningful improvements in these symptoms following induction and maintenance treatment with upadacitinib (UPA) in patients with moderately to severely active UC. We evaluated the effects of 8-week UPA induction and 52-week UPA maintenance treatment on UC symptom resolution, defined as no BU, no AP, and symptomatic remission (no RB, SF≤1), and normalization of fatigue, defined as achievement of a Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT–F) score ≥ 40.1. Methods A total of 988 patients were randomized in the U-ACHIEVE and U-ACCOMPLISH induction studies to receive UPA 45 mg once daily (QD; n=660) or placebo (PBO) QD (n=328). Patients who achieved a clinical response after 8 weeks of induction (n=451) were enrolled in the U-ACHIEVE maintenance study and re-randomised 1:1:1 to UPA 15 mg QD (n=148), UPA 30 mg QD (n=154), or PBO QD (n=149). Symptom resolution was assessed at induction Weeks 0, 2, 4, 6, 8 and maintenance Weeks 0, 4, 8, 12, 20, 28, 36, 44, and 52. A more stringent assessment of symptom resolution and normalization of fatigue was conducted at Weeks 0, 2, and 8 of induction and Weeks 0 and 52 of maintenance. Results A higher percentage of patients achieved symptom resolution during induction treatment as early as Week 2 with UPA 45 mg vs PBO (11.1% vs 0.9%, p Conclusion Patients with moderately to severely active UC were more likely to achieve symptom resolution and normalization of fatigue during induction treatment with UPA compared to PBO, and these benefits were sustained during maintenance therapy.

Background Upadacitinib (UPA) demonstrated efficacy and safety in the phase 3 U-EXCEED (NCT03345836) and U-EXCEL (NCT03345849) induction, and U-ENDURE (NCT03345823) maintenance trials in patients (pts) with moderately to severely active Crohn’s disease (CD). We evaluated the impact of UPA on health-related quality of life (QoL) in pts with CD. Methods Clinical responders to UPA 45 mg (UPA45) in U-EXCEED and U-EXCEL induction trials were re-randomised at Week 12 (1:1:1) to UPA 15 mg (UPA15), UPA 30 mg (UPA30), or placebo (PBO) for 52 weeks of maintenance treatment in U-ENDURE; data from these induction and maintenance trials were included in this analysis. Endpoints included the percentage of pts who achieved an Inflammatory Bowel Disease Questionnaire (IBDQ) response (≥16 points), IBDQ remission (≥170 points), a meaningful within-person change (MWPC) from baseline of ≥9 points on the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F), and of ≥4.1 and ≥3.9 points on the 36-item Short-Form Health Survey (SF-36) physical (PCS) and mental (MCS) component summary scores, respectively, at Weeks 4/12 of induction and Week 52 of maintenance. Adjusted risk differences compared to PBO, 95% confidence intervals, and p-values were calculated based on the Cochran-Mantel-Haenszel test. Results In U-EXCEED (n=324 UPA; 171 PBO) and U-EXCEL (n=350 UPA; 176 PBO), a greater proportion of UPA45- vs PBO-treated pts had an IBDQ response at Weeks 4 (U-EXCEED: 71.6% vs 47.6%; U-EXCEL: 71.0% vs 50.2%; p≤0.001) and 12 (U-EXCEED: 63.9% vs 44.4%; U-EXCEL: 68.4% vs 46.5%; p≤0.001; Figure 1). In UPA- vs PBO-treated pts, a greater proportion achieved IBDQ remission at Weeks 4 (U-EXCEED: 41.4% vs 22.4%; U-EXCEL: 44.2% vs 23.7%; p≤0.001) and 12 (all p≤0.001; Figure 1). At Week 12, a significantly greater proportion of UPA-treated pts vs PBO demonstrated a MWPC in FACIT-F, and SF-36 PCS and MCS from baseline (p≤0.001; Figure 1). Similar results for UPA45 vs PBO were achieved as early as Week 4 in FACIT-F (U-EXCEED: 42.3% vs 20.0%; U-EXCEL: 42.0% vs 27.0%), SF-36 PCS (U-EXCEED: 56.6% vs 37.2%; U-EXCEL: 53.0% vs 37.5%; p≤0.001) and MCS (p≤0.05). In the maintenance study U-ENDURE (n=168 UPA30; 169 UPA15; 165 PBO), a greater proportion of pts receiving UPA15 and UPA30 vs PBO achieved an IBDQ response (39.1%, 53.5% vs 20.4%), IBDQ remission (36.1%, 45.2% vs 13.5%), and a meaningful improvement from baseline in FACIT-F, SF-36 PCS and MCS through 52 weeks (p≤0.01; Figure 2). Conclusion In pts with moderately to severely active CD, UPA treatment significantly improved fatigue, disease-specific and generic QoL, compared with PBO, as early as Week 4 of induction. The effects were sustained through 52 weeks of maintenance treatment.

Background Upadacitinib (UPA) demonstrated efficacy and safety as induction and maintenance therapy for ulcerative colitis (UC) in Phase 3 trials U-ACHIEVE (NCT02819635) and U-ACCOMPLISH (NCT03653026). This post-hoc analysis aims to characterise the benefit-risk profile of UPA induction and maintenance therapy vs placebo (PBO) in patients (pts) with moderately to severely active UC based on a number needed to treat/harm (NNT/NNH) analysis. Methods Efficacy and safety data from the pooled intention-to-treat population of U-ACHIEVE and U-ACCOMPLISH trials were included. Pts received UPA 45 mg (UPA45) once daily (QD) or PBO for 8 weeks (induction trials). Clinical responders (per Adapted Mayo score) at Week 8 of induction were re-randomised to receive UPA 15 mg (UPA15) or 30 mg (UPA30) QD, or PBO in the 52-week maintenance study. The primary efficacy endpoint was clinical remission per Adapted Mayo score. Secondary outcomes are listed in Table 1 and safety outcomes are listed in Table 2. N, percentages, and outcome differences compared by Z test were reported. NNT/NNH was calculated as the inverse of the difference in proportions achieving efficacy/safety outcomes for UPA vs PBO. Positive NNT values indicate greater efficacy and negative NNH values imply lower safety risk for UPA vs PBO. Results A significantly greater proportion of pts achieved clinical remission at induction (UPA45 29.9% vs PBO 4.4%) and maintenance (UPA15 40.4%, UPA30 53.6% vs PBO 10.8%) with UPA vs PBO, as well as all secondary endpoints (all p Conclusion This post-hoc Phase 3 analysis demonstrates greater efficacy and generally comparable safety of UPA vs PBO, indicating a favourable benefit-risk profile for UPA in pts with moderately to severely active UC.

Background Patients with Crohn’s disease (CD) experience reduced quality of life (QoL), and disease-related impact on work productivity, contributing to a high disease burden. This study evaluated the association of achieving endoscopic outcomes at week 12 and associated QoL at week 52 in patients with CD treated with upadacitinib (UPA). Methods This post-hoc analysis evaluated data from two Phase 3 UPA induction (U-EXCEED and U-EXCEL) trials and one maintenance (U-ENDURE) trial in patients with moderate to severe CD. Patients who responded to 12-week induction therapy with UPA (45 mg per day [QD]) in U-EXCEED or U-EXCEL and received maintenance therapy with UPA (15 or 30 mg QD) up to 52 weeks in U-ENDURE were included. Meaningful improvement in QoL outcomes (Inflammatory Bowel Disease Questionnaire [IBDQ] remission ≥170, IBDQ response increase ≥16, Functional Assessment of Chronic Illness Therapy – Fatigue [FACIT-F] response increase ≥9, Short Form 36 [SF-36] Physical Component Score [PCS] and Mental Component Score [MCS] change ≥5, and Work Productivity and Activity Impairment Questionnaire [WPAI] change ≥7%) was evaluated at week 52 and compared between patients who achieved endoscopic response, endoscopic remission and ulcer-free endoscopy (absence of ulceration) at week 12 and those who did not using Chi-square test. Results Of 337 clinical responders included in the analyses, 152 (45.1%), 87 (25.8%), and 75 (22.2%) patients achieved endoscopic response, endoscopic remission, and ulcer-free endoscopy, respectively, at the end of induction. Significantly more patients who achieved an endoscopic response at end of induction (vs those who did not) attained a meaningful improvement in PROs by week 52 (IBDQ remission, 52.6% vs 30.3%; IBDQ response, 56.6% vs 36.8%; FACIT-F response, 46.7% vs 25.9%; SF-36 PCS 49.3% vs 30.8% and MCS 39.5% vs 25.9%; all P≤0.01, Table 1). Additionally, patients who achieved endoscopic response (vs those who did not) at the end of induction were more likely to attain meaningful improvement in WPAI overall work impairment by week 52 (47.1% vs 26.5%, P≤0.01, Table 1). Similar findings were observed in patients who achieved endoscopic remission (P≤0.01, Table 1) and ulcer-free endoscopy (P≤0.05, Table 1) vs those who did not at end of induction. Conclusion Achieving endoscopic outcomes at end of induction treatment was associated with meaningful improvement in quality of life and overall work productivity at 52 weeks for patients with CD receiving UPA. Endoscopic remission and ulcer-free endoscopy were associated with very similar long-term benefit.

Background STRIDE-II guidelines recommend endoscopic healing as an important treatment goal in Crohn’s disease (CD). This study evaluated the association of achieving endoscopic outcomes at week 12 and clinical outcomes at week 52 of maintenance treatment in patients with CD treated with upadacitinib (UPA). Methods This post-hoc analysis evaluated data from two Phase 3 UPA induction (U-EXCEED and U-EXCEL) trials and the maintenance (U-ENDURE) trial in patients with moderate to severe CD. Patients who responded to 12-week induction therapy with UPA (45 mg per day [QD]) in U-EXCEED or U-EXCEL and received maintenance therapy with UPA (15 or 30 mg QD) up to 52 weeks in U-ENDURE were included. Clinical outcomes (CD activity index [CDAI] remission, CDAI response, steroid-free CDAI remission, high sensitivity C-reactive protein [hs-CRP] level ≤5 mg/L, and fecal calprotectin level [F-cal] ≤250 mcg/g), were evaluated at week 52 and compared between patients who achieved endoscopic response, endoscopic remission and ulcer-free endoscopy (absence of ulceration) at week 12 and those who did not using Chi-square test. Results Of 337 clinical responders included in the analyses, 152 (45.1%), 87 (25.8%), and 75 (22.3%) patients achieved endoscopic response, endoscopic remission, and ulcer-free endoscopy, respectively, at the end of induction. Significantly more patients who achieved an endoscopic response at end of induction (vs those who did not) attained clinical outcomes at week 52 (CDAI remission, 52.0% vs 34.6%; CDAI response, 54.6% vs 39.5%; hsCRP ≤5 mg/L, 52.0% vs 30.8%; and F-cal ≤250 mcg/g, 42.1% vs 21.6%; P≤0.01, Table 1). Patients who achieved an endoscopic response vs those who did not at end of induction were also more likely to attain steroid-free CDAI remission (50.0% vs 30.9%) at week 52, (P≤0.05, Table 1). Similar findings were observed in patients who achieved endoscopic remission vs those who did not at end of induction (P≤0.01, Table 1). Significantly more patients attained CDAI remission (58.7% vs 37.7%), CDAI response (58.7% vs 42.7%), hsCRP ≤5 mg/L (58.7% vs 35.0%) and F-cal ≤250 mcg/g (50.7% vs 25.0%) at week 52, among patients who achieved ulcer-free endoscopy vs those who did not at end of induction (P≤0.05, Table 1). Conclusion Achieving endoscopic outcomes at end of induction is associated with meaningful improvement in symptoms and inflammatory biomarkers at 52 weeks for patients with CD receiving UPA therapy. Endoscopic remission and ulcer-free endoscopy are associated with very similar long-term benefits.

Background Upadacitinib (UPA), an oral Janus kinase inhibitor, and ustekinumab (UST), a parenteral IL-12/23 inhibitor, are approved therapies for patients (pts) with moderately to severely active Ulcerative Colitis (UC). In the absence of head-to-head data, we conducted a placebo (PBO)-anchored matching-adjusted indirect comparison (MAIC) to compare efficacy and safety of UPA vs UST during induction. Methods Pts received UPA 45 mg oral, once daily for 8 weeks or PBO in the phase 3 studies U-ACHIEVE (NCT02819635) and U-ACCOMPLISH (NCT03653026), and UST 6 mg/kg IV at week 0 with 8-week follow up or PBO in the phase 3 study UNIFI (NCT02407236). Efficacy outcomes were stratified by previous biologic exposure (ie, no prior exposure [bio-naïve] or inadequate response, loss of response, or intolerance to biologics [bio-failed]). Baseline characteristics for age, gender, extent and duration of disease, total Inflammatory Bowel Disease Questionnaire score, total Mayo score, high-sensitivity CRP, faecal calprotectin levels, weight, and UC medication use from the UPA trials were weighted to match the UNIFI trial. Efficacy outcomes at Week 8 were clinical remission per full Mayo score (FMS; FMS ≤2 with no subscore >1), clinical response (decrease in FMS ≥3 points and ≥30%, plus a decrease in rectal bleeding score [RBS] of ≥1 or an absolute RBS of 0 or 1), endoscopic improvement (endoscopic subscore 0 or 1), and histologic-endoscopic mucosal improvement (HEMI). Safety outcomes evaluated in the overall population were adverse events (AEs) and serious AEs (SAEs), comprising the only safety assessments consistently collected across trials. Numbers needed to treat/harm (NNT/NNH) were calculated as the inverse of the difference in proportions achieving efficacy/safety outcomes between UPA and UST. Results The MAIC included 824 UPA and 625 UST pts with efficacy data and 839 UPA and 639 UST pts with safety data. A greater proportion of pts receiving UPA vs UST in bio-naïve and bio-failed groups achieved clinical remission, endoscopic improvement, and HEMI after weighting (p≤0.01, Table 1) with NNTs Conclusion During induction, greater efficacy with similar safety was observed with UPA vs UST for pts with moderately to severely active UC based on MAIC. Potential bias due to unobserved confounders may exist with MAIC methodology. Further analyses to assess longer-term outcomes are warranted.