Citations

Abstract 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.

Abstract Background Improvement in clinical outcomes and normalisation of objective markers of inflammation, high-sensitivity C-reactive protein (hs-CRP) and faecal calprotectin (FCP), are considered treatment targets per STRIDE-II guidelines.1 We evaluated the effect of the oral selective Janus kinase inhibitor upadacitinib (UPA) on changes in hs-CRP, FCP, and clinical outcomes in patients with Crohn’s disease (CD). Methods In 2 phase 3, randomized, double-blind, placebo-controlled induction studies (U-EXCEL, NCT03345849; U-EXCEED, NCT03345836), patients with moderate-to-severe CD received 12-week treatment with UPA 45 mg (UPA45) once daily (QD) or placebo (PBO). Patients with clinical response to UPA45 were rerandomised in U-ENDURE (NCT03345823) to receive 52-week maintenance treatment with UPA 30 mg QD (UPA30), UPA 15 mg QD (UPA15), or PBO. Endpoints included marker normalisation (hs-CRP ≤ 5 mg/L, FCP ≤ 250 µg/g) in patients with elevated baseline marker levels, normal marker and clinical remission by Crohn’s Disease Activity Index (CDAI < 150) or very soft/liquid stool frequency (SF)/abdominal pain score (APS) (average daily SF ≤ 2.8 and average daily APS ≤ 1, neither greater than baseline), and ≥ 50% reduction from baseline in marker values with a decrease of at least 100 points in CDAI from baseline. Median changes from baseline in marker levels were also evaluated. Non-responder imputation with no special data handling for missing data due to COVID-19 was used. Results Of 1021 enrolled patients, 645 (63.2%) had elevated hs-CRP (> 5 mg/L) and 750 (73.5%) had elevated FCP (> 250 µg/g) levels at baseline. Significantly greater proportions of patients with elevated baseline marker levels achieved normalisation with UPA compared with PBO at week 12 (Fig 1A/B) and week 52 (Fig 2A/B; nominal P < .001 for all). Decreases in marker levels from baseline with UPA were observed as early as week 2 and were significantly greater than with PBO through week 12 (Fig 1C) and week 52 (Fig 2C; nominal P < .001 for all). Patients achieved clinical endpoints and improvements in markers at significantly higher rates with UPA45 vs PBO at week 12 (Fig 1D–F) and with UPA15 and UPA30 vs PBO at week 52 (Fig 2D–F; P < .001 for all). The safety profile of UPA in CD was previously reported and no new safety concerns were identified. Conclusion Improvements in clinical endpoints and normalisation of objective markers of inflammation were achieved as early as week 2 with UPA45 induction and sustained with UPA15 and UPA30 maintenance therapy in patients with CD. Median changes in hs-CRP and FCP with UPA support continued improvement of inflammation up to week 52. 1. Turner D., et al. Gastroenterology. 2021;160(5):1570–1583.

Abstract 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.

Abstract Background Corticosteroids (CS) may be used for induction of remission in Crohn’s disease (CD); however, side effects, toxicities, and low rates of mucosal healing may limit their long-term use. Safety and efficacy of upadacitinib (UPA), an oral selective Janus kinase inhibitor, were evaluated among patients with CD receiving UPA with CS at baseline in phase 3 clinical trials. Methods In 2 phase 3 studies (U-EXCEL, NCT03345849; U-EXCEED, NCT03345836), patients with moderate-to-severe CD were randomized to 12-week induction with UPA 45 mg once daily (QD) or placebo (PBO). Patients who achieved clinical response to UPA 45 mg were rerandomized in U-ENDURE (NCT03345823) to UPA 30 mg QD, UPA 15 mg QD, or PBO for a 52-week maintenance period. Patients taking CS at baseline or week 0 of maintenance (end of induction) were included. A CS taper began at induction week 4 and continued during maintenance. Endpoints included the proportion of patients who discontinued CS use (CS-free) at week 12 or for ≥ 90 days prior to week 52, and achieved clinical remission by stool frequency/abdominal pain score or by Crohn’s Disease Activity Index (CDAI), enhanced clinical response, decrease of at least 100 points in CDAI from baseline, endoscopic remission, and endoscopic response at week 12 and week 52. CS daily dose (in prednisone equivalent doses) was recorded. Safety was assessed through induction and maintenance. Results Of 1021 patients evaluated, 358 (35.1%) were taking CS at baseline (mean daily prednisone equivalent dose, 23.0 mg). Greater changes from baseline in mean CS daily dose were observed with UPA vs PBO at induction week 12 (−17.3 mg vs −10.7 mg); these changes were sustained at maintenance week 52 (UPA 30 mg, −16.4 mg; UPA 15 mg, −17.4 mg; PBO, −14.7 mg). The proportion of patients who achieved a ≥ 50% reduction in CS daily dose was higher with UPA vs PBO at induction week 12 among patients taking CS at baseline (72.6% vs 48.4%) and at week 52 among patients taking CS at baseline or week 0 of maintenance (UPA 30 mg, 49.2%; UPA 15 mg, 44.4%; PBO, 11.1%). A significantly higher proportion of patients taking UPA vs PBO were CS-free and achieved clinical remission, clinical response, endoscopic response, and endoscopic remission at week 12 (Fig 1A) and week 52 (Fig 1B). Rates of adverse events (AEs), serious AEs, and discontinuation were comparable between groups (Table 1). Serious infections, opportunistic infections, and herpes zoster events were numerically higher with UPA vs PBO (Table 1). Conclusion Patients with CD taking CS were able to taper and discontinue their CS regimen and experience clinical and endoscopic improvements with UPA treatment during the induction and maintenance periods.

Abstract 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].