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Background Recruitment rates for phase 2b/3 randomized controlled trials (RCTs) in IBD have substantially dropped over time. Several steps are required prior to successful patient randomization. Initially the physician must propose a trial to a potentially eligible patient during a pre-screening process (step 1). This is followed by patient’s acceptance or refusal (step 2). Finally, after informed consent the patient undergoes trial screening to ensure they meet all eligibility criteria (step 3). Evaluating each step separately, this study aims to assess reasons why IBD patients are not included in RCT and patients’ outcome after screen failure (SF). Methods All IOIBD member physicians (n=58) were invited to participate. To assess steps 1 and 2, consecutive IBD patients in relapse for whom a treatment change was required were prospectively included over a 4-week period. Reasons that prevented the IBD physician offering a sponsored multicenter phase 2b/3 RCT (step 1) and reasons why the patient accepted or refused to participate (step 2) were assessed through a physician and a patient survey, respectively. Reasons for SF (step 3) from the last 6 months, including the 4 weeks of steps 1-2, were collected retrospectively. Results A total of 104 (59 male, 62 CD, mean age of 37.2 years) and 102 patients (58 male, 63 CD, mean age of 40.6 years) from 12 centers were included in steps 1-2 and 3, respectively (Tables 1 and 2). Among 104 patients in relapse for whom a treatment change was required, 41 (39.4%) were offered a RCT. Of the 28 who consented to RCT, 5 failed their screening (SF rate of 17.9%) and 23 were included. Main reason that prevent IBD physicians from offering an RCT (step 1) are shown in Figure 1. After receiving information about RCT, major reasons why patients accepted or refused to participate included the trust they had in their IBD specialist and the risk of being assigned to a placebo, respectively (step 2). Regarding 102 patients included in step 3, main reasons of SF were insufficient disease activity (n=37), concurrent infection (n=15) and dropout (n=12) (Figure 2). Half of SFs could have been avoided by thorough prescreening. After SF, 51 patients were treated with commercially available therapy, 14 were rescreened for the same RCT (after resolution of the issue leading to SF), no treatment was required for 14, 10 were referred to surgery and 6 were screened for another RCT (the outcome was unknown for 7). Conclusion This first multicentric study reported a SF rate of 17.9%. Insufficient disease activity and the risk of assigning the patient to a placebo seem to be barriers to inclusion. Half of SFs could have been avoided by better pre-screening. After SF, most of patients were treated with commercially available therapy.

Background Filgotinib (FIL) is a once-daily, oral, Janus kinase 1 preferential inhibitor approved for the treatment of ulcerative colitis (UC). FIL 200 mg (FIL200) was effective in inducing and maintaining clinical remission vs placebo (PBO) and well tolerated in patients with UC in the randomized, phase 2b/3 SELECTION trial (NCT02914522).1 The efficacy and safety of continued FIL200 therapy are being assessed in the continuing SELECTION long-term extension (LTE) study. Methods The SELECTION programme comprises SELECTION and the associated LTE study (SELECTIONLTE; NCT02914535). In SELECTION, adults with moderately to severely active UC received induction (IND) FIL200, FIL 100 mg (FIL100) or PBO once daily for 11 weeks. Patients in clinical remission or with a Mayo Clinic Score (MCS) response at week 10 (responders) could enter the 47-week Maintenance (MNT) Study. SELECTIONLTE enrolled patients who completed IND and MNT (completers), patients who were not responders at IND week 10 (non-responders), and patients with disease worsening during MNT. This interim analysis assessed the efficacy and safety of open-label FIL200 through LTE week 144 in completers and LTE week 192 in non-responders, respectively, representing a total of 3.9 years of treatment each (completers: 58 + 144 weeks; non-responders 10 + 192 weeks). The cut-off date was 24 February 2022. Continuous measures of partial MCS (pMCS) and proportions of patients achieving the minimal clinically important difference (MCID) in total IBDQ score (≥16-point increase vs baseline) were assessed without imputation (as observed). Safety was assessed by the exposure-adjusted incidence rate per 100 patient-years of exposure (PYE) for treatment-emergent adverse events (TEAEs) and TEAEs of interest. Results This analysis included 148 completers and 372 non-responders (IND FIL100, n=212; IND FIL200, n=160). Among completers, the reductions in mean pMCS in SELECTION over weeks 0–10 were maintained up to LTE week 144 (Figure 1). In non-responders, mean pMCS decreased from LTE baseline to week 192 (Figure 2). High proportions of completers (>90%) and non-responders (>60%) achieved the MCID in IBDQ score; proportions were maintained over time (Table 1). Safety events among all patients treated with open-label FIL200 in the LTE study (total PYE=2055.5) are reported in Table 2. Conclusion: FIL200 was effective in maintaining symptomatic remission and health-related quality of life for up to ~4 years. No new safety signals were observed over ~4 years of treatment, and safety events were comparable with those seen in previous analyses.2 1. Feagan BG et al. Lancet 2021;397:2372–84. 2. Feagan BG et al. J Crohns Colitis 2022;16(Suppl1):i456–7.

Background The once-daily, oral, Janus kinase 1 preferential inhibitor filgotinib (FIL) is approved for the treatment of moderately to severely active rheumatoid arthritis (RA) and ulcerative colitis (UC) in the UK, the EU and Japan.1 To further understand the safety profile of FIL across indications, we evaluated the risk of major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs) in patients treated with FIL 200 mg (FIL200) or FIL 100 mg (FIL100). Methods An integrated analysis was conducted with RA data from five phase 2/3 trials and two long-term extension (LTE) trials of FIL, and UC data from two phase 2/3 trials and one LTE trial of FIL (herein termed ‘overall’ data). Subgroup analyses by age and cardiovascular (CV) risk factors (excluding age) were conducted. Real-world data were extracted from a systematic literature review. Exposure-adjusted incidence rates (EAIRs) or incidence rates per 100 patient-years of exposure and 95% confidence intervals (CIs) were estimated for MACEs and VTEs. For clinical trial data, MACEs and VTEs included positively adjudicated events only. Results In pooled data, baseline characteristics were generally similar across treatment arms for RA and UC (Tables 1 and 2). In the RA data, MACE EAIRs were 0.29 and 0.41 for the overall FIL200 and FIL100 arms, respectively (Figure 1). MACE IRs were 0.45–0.77 for the general RA population. Higher MACE EAIRs were reported in the subgroup of patients with RA aged ≥65 years vs In the UC data, MACE rates were 0.29, 0.35 and 0.87 in the overall FIL200 and FIL100 arms and in the general UC population, respectively (Figure 2). VTE rates were 0.08, 0.18 and 0.39 in the overall FIL200 and FIL100 arms and in the general UC population, respectively. For both MACE and VTE EAIRs, wide CIs were reported in patients with UC aged ≥65 years and in those with CV risk, owing to low numbers of events and/or patients in these subgroups. Conclusion No association was identified between FIL200 treatment and an increased risk of MACEs or VTEs compared with the general RA or UC population. Patients aged ≥65 years or with CV risk had slightly higher rates of MACEs and VTEs than those in other subgroups; however, overlapping CIs suggested no real difference. Further work should examine real-world data from FIL-treated patients and longer follow-up. 1. https://www.ema.europa.eu/en/medicines/human/EPAR/jyseleca

Background Tumor necrosis factor-like cytokine 1A (TL1A) is an upstream regulator of pro-inflammatory cytokines and fibrosis signals. PRA023 is an anti-TL1A monoclonal antibody in development for multiple inflammatory/fibrotic diseases using a precision medicine approach with a companion diagnostic (CDx). This Phase 2 placebo-controlled, multi-center, double-blind study aimed to assess the efficacy and safety of PRA023 for induction treatment in adults with moderately to severely active ulcerative colitis (UC). Methods Key eligibility criteria included a modified Mayo Score of 4-9, a centrally read (with adjudication) endoscopy subscore of ≥ 2, a rectal bleeding subscore of ≥ 1, and a history of insufficient response, loss of response, and/or intolerance to conventional and/or advanced (approved biologics and JAK inhibitors/S1P modulators) therapies (≤ 4 advanced agents from ≤ 3 classes). Patients were stratified by prior biologic exposure status (yes/no) and CDx status (yes/no) and randomized 1:1 to placebo or intravenous PRA023 (1000mg on Day 1, 500mg at Weeks 2, 6, and 10). The primary endpoint was clinical remission at week 12. Analyses of all ranked secondary endpoints, the first being endoscopic improvement (endoscopy score of ≤ 1), were multiplicity controlled. Results Of the 135 patients in the full analysis data set, 60/67 (89.6%) in the placebo arm and 68/68 (100%) in the PRA023 arm completed the 12-week Induction Period. Baseline characteristics were similar with minor differences in the proportion of patients with baseline endoscopy score of 3 and prior exposure to ≥ 3 advanced therapies (Table 1). A significantly greater proportion of patients who received PRA023 achieved the primary endpoint of clinical remission (26.5% PRA023 vs. 1.5% placebo, ∆25.0%, p < 0.0001) at Week 12 (Table 2). In addition, substantially more patients who received PRA023 achieved the key secondary endpoint of endoscopic improvement (36.8% PRA023 vs. 6.0% placebo, ∆30.8%, p < 0.0001). All remaining ranked secondary endpoints were met (Table 2). The rates of treatment-emergent adverse events (AEs) were similar between the two arms with no serious AEs or AEs leading to study drug discontinuation in the PRA023 arm (Table 3). There were no safety signals identified from the study. Conclusion PRA023 was effective with favorable tolerability for the induction of clinical remission and endoscopic improvement in moderately to severely active UC. A Phase 3 study will be conducted to confirm these findings. Recruitment is ongoing for the CDx+ expansion cohort of the study to assess the effectiveness of the CDx, designed to select patients with a higher probability of responding to PRA023.

Background Symptoms, endoscopy, histology, and biomarkers are used to evaluate disease activity and response to therapy in ulcerative colitis (UC). Histologic disease activity may persist in ~25% of patients with normal-appearing endoscopic mucosa, and observational studies demonstrate an association between the achievement of histologic remission (vs endoscopic remission alone) and a lower risk of complications. These findings suggest that histologic remission may be a distinct treatment target. The aim of the VERDICT trial is to determine the optimal treatment target in UC to inform clinical practice and future drug development. Methods The primary objective of the multicentre, randomised, controlled VERDICT trial (Figure 1) is to determine whether a treatment target of corticosteroid (CS)-free symptomatic + endoscopic + histologic remission is superior to CS-free symptomatic remission alone in moderately to severely active UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2). Patients are randomised to 3 treatment targets (2:3:5 ratio): CS-free symptomatic remission (Mayo RBS = 0) (Group 1); CS-free endoscopic remission (MES ≤1) + symptomatic remission (Group 2); or CS-free histologic remission (Geboes score Results The primary efficacy outcome is the time from treatment target achievement to a UC-related complication, defined as a UC-related hospitalisation, colectomy, need for rescue therapy, or treatment-related or other complication. This composite outcome will be compared among treatment target Groups 1 and 3 using the Cox proportional hazard model analysis. The trial was initiated in September 2020, and 660 patients are planned for enrolment. Of these, ~50% are currently enrolled at 55 sites across 10 North American and European countries. Prespecified interim analyses will be conducted when the first 50 patients in each group reach weeks 16, 32, and 48. Conclusion The VERDICT trial in active UC is designed to determine the optimal treatment target to inform clinical practice, drug trials, and future evidence-based recommendations.

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.

Background For patients living with inflammatory bowel diseases (IBD), the ultimate treatment goal is “normal life”. However, no patient-reported outcome measurement (PROM) exists to measure the level of life normality in IBD. We previously asked patients across the world (5 continents) to identify and rank-order items important to their “normal life”. The top-25 ranked items are being used for subsequent PROM development. In this study, we aimed to compare the perception of healthcare professionals (HCP) and patients with IBD on normal life. Methods IBD patients without an ostomy, pouch or significant comorbidities were interviewed in their mother tongue in 5 continents about “normal life” using a semi-structured interview guide. All items indicated as important were extracted from translated transcripts using directed content analysis (1) until saturation of items occurred. Categorisation was guided by the Wilson’s & Cleary’s Quality of Life model. (2) Second, in an online Delphi procedure, interviewed patients and HCP from each participating centre scored importance of each item on a 0-10 scale. Items scored 7 or higher by >75% were considered important to the respective group. Patient-ranked items were then presented to a patient focus group to clarify wording and merge similar items. Items merged in the patient focus group were merged similarly in HCP rankings. Third, HCP- and patient-rankings were compared. We compared top-25 items selected for PROM development and top-3 items per category. Results 45 CD and 40 UC patients spread over 6 countries were interviewed (median age 36, 56% male, 68% employed, median disease duration 7 years [IQR 4-15]) (table 1). Saturation occurred after 33 CD and 36 UC interviews, yielding 156 unique items. In the Delphi procedure, 54 patients considered 31 items important for normal life with IBD of which 25 remained after focus group discussion. 34 HCP (12 IBD nurses, 16 IBD gastroenterologists, 6 colorectal surgeons) considered 72 items important. Top-25 rankings overlapped in 15 items between patients and HCP, being 5 of 12 physical, 1 of 4 activities, 2 of 3 social, 4 of 11 psychological items and 3 of 5 circumstances (table 2). Top-3 rankings per category overlapped in 2 physical, 1 activities, 2 social, 1 psychological items and 2 circumstances (table 3). Conclusion We identified discrepancies in the perception of normal life with IBD between patients living with IBD and healthcare professionals (HCP). Of top-25 selected items for PROM development, 15 items overlapped between patients and HCP. Of top-3 items per category, the least overlap was seen in activities and psychological items. PROM development and international validation is ongoing.

Background Biologic therapies are used to treat moderate-to-severe Crohn’s Disease (CD), but many patients eventually lose response to them. With new potential therapies for CD, understanding their efficacy after patients undergo biologic treatment is important for clinical decision-making. This post hoc analysis assessed the outcomes of upadacitinib (UPA), an oral selective Janus kinase inhibitor, in patients with CD who had failed a biologic, by the number and type of prior biologic therapies. Methods In the 2 induction studies, U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836), patients with moderate-to-severe CD received oral UPA 45 mg once daily (QD) therapy or placebo (PBO) for 12 weeks. Patients achieving clinical response to UPA induction were re-randomised in the maintenance study, U-ENDURE (NCT03345823), to receive UPA 15 mg QD, UPA 30 mg QD, or PBO for 52 weeks. This analysis assessed clinical, endoscopic, and safety outcomes in patients with inadequate response or intolerance to biologic therapy by number and type of biologics failed. Data from the U-EXCEL and U-EXCEED studies were pooled. Results At baseline, patient (n=733) characteristics were similar for UPA vs PBO within each subgroup by number of prior biologics (1, n=279; 2, n=223; >2, n=231); patients who received ≥ 2 prior biologics had longer disease duration (median, years: 1, 6.2; 2, 9.4; >2, 12.9) and were more likely to have used steroids (1, 27.7%; 2, 40.4%; >2, 45.0%). Across subgroups, greater proportions of patients receiving UPA vs PBO achieved clinical remission (Figure 1) and endoscopic response and remission (Figure 2) at week 12 of induction and week 52 of maintenance; response rates were generally higher for patients who had failed fewer biologics. When analyzed by type of prior biologic (tumor necrosis factor inhibitor [yes/no], n=704/29; ustekinumab [yes/no], n=272/461; vedolizumab or natalizumab [yes/no], n=220/513), the proportion of patients achieving clinical and endoscopic outcomes was slightly higher for those without prior exposure to each biologic. Adverse events (AEs) occurred at numerically higher rates for patients who had failed multiple biologics in the induction and maintenance studies across both PBO and UPA treatment arms. AEs of special interest occurred at similar rates across subgroups. No non-melanoma skin cancers, major adverse cardiovascular events, or venous thromboembolic events were reported. Conclusion Clinical and endoscopic improvements were observed with UPA induction and maintenance therapy in patients with moderate-to-severe CD, regardless of number and type of prior biologics failed; greater benefits and fewer AEs were observed in patients who failed fewer biologic therapies.

Background The unmet need in Crohn’s disease (CD) exists for new medications with an optimized risk-benefit ratio with avoidance of systemic side effects. This Phase 2 study evaluated the efficacy and safety of the oral, once-daily, gut-selective pan-Janus kinase inhibitor izencitinib as an induction therapy for CD. Methods This trial was a multicentre, randomized, double-blind, Phase 2 study of adults with moderately-to-severely active CD (≥220 and ≤ 450 CDAI with SES-CD score of ≥6 [or ≥4 if isolated ileal disease]) who were corticosteroid-dependent or had demonstrated failure to aminosalicylates, corticosteroids, immunosuppressive agents, and/or biologic therapies. Patients were randomised 2:3:3 to receive placebo or izencitinib, 80, or 200 mg once daily for 12 weeks. The primary endpoint was change in CDAI score from baseline to week 12 and was analysed using a mixed-model repeated measures analysis. Change from baseline in SES-CD was analysed with an analysis of covariance model and binary endpoints were analyzed using a stratified Cochran-Mantel-Haenszel chi-square test. Results 159 and 145 patients were included in the safety and modified ITT populations, respectively. At week 12, the LS mean change in CDAI was -105.6 (SE: 12.7) and -117.9 (12.4) points for patients randomized to izencitinib 80 and 200 mg, respectively, vs -104.86 (SE: 15.496) for those randomized to placebo. There were no improvements observed in change from baseline in SES-CD. There were non-significant numerical improvements in clinical and endoscopic response between placebo and the highest dose 200mg. No improvements were observed in CDAI-based clinical remission or PRO2 (SF/AP)-based remission at any dose of izencitinib relative to placebo. As expected, plasma izencitinib exposure was low. Serious adverse events (AEs; n = 13) were well balanced among the treatment groups and not considered related to study treatment; no deaths were observed. Exacerbation of Crohn’s Disease, headache, rash, abdominal pain and nausea were the most common treatment-emergent AEs observed with izencitinib treatment. No clinically important changes in laboratory values, electrocardiography parameters, or vital signs were noted in patients treated with izencitinib compared with placebo, and no drug-related AEs of special interest were observed. Conclusion In patients with moderately-to-severely active Crohn’s Disease, izencitinib treatment for 12 weeks did not demonstrate a statistically significant reduction in CDAI or endoscopic severity. Izencitinib at both doses was well tolerated without a new safety signal.

Background In the risankizumab (RZB) phase 3 clinical programme, Crohn’s disease (CD) patients who responded to RZB intravenous (IV) induction were re-randomised to RZB or placebo (PBO) (withdrawal PBO subcutaneous [SC] in maintenance (FORTIFY), while responders to PBO induction continued receiving PBO. Patients in the withdrawal (PBO SC) arm of FORTIFY who received IV RZB induction achieved high rates of clinical response/remission at Week (Wk) 52 likely due to the prolonged PK/PD effect of RZB and robust efficacy during induction.1 Here, we describe disease activity outcomes in non-randomised patients who received PBO during both induction and maintenance. Methods: This post-hoc analysis included patients who received PBO IV in the induction study (ADVANCE or MOTIVATE), achieved clinical response (definition in Figure footnote) at Wk 12, and continued on PBO SC during FORTIFY.1,2 Subjective measures of disease activity (clinical remission [per CD Activity Index (CDAI)] and per stool frequency [SF] and abdominal pain score [APS], CDAI clinical response, and SF/APS enhanced clinical response), as well as objective measures of biomarkers (high sensitivity C-Reactive Protein and faecal calprotectin) levels and endoscopic outcomes (response, remission, and ulcer-free endoscopy), during FORTIFY were evaluated (endpoint definitions in Figure footnotes) at Wk 52. Biomarkers were additionally evaluated at induction baseline. For reference only, previously reported data from patients who were clinical responders to RZB IV induction and were re-randomised in FORTIFY are presented alongside data from the continuous PBO patients subgroup.1,2 Results In the 104 patients who received PBO during both induction and maintenance, clinical response and remission rates decreased steadily during FORTIFY (Figure), while biomarker levels were relatively unchanged from induction baseline to FORTIFY Wk 52. In contrast, a slower rate of loss of response per clinical response/remission and lower biomarker levels over time were observed in RZB IV induction responders re-randomised to PBO in FORTIFY. Although already low, endoscopic response rates in the continuous PBO group decreased from FORTIFY Wk 0 to Wk 52, whereas endoscopic remission and ulcer-free endoscopy rates remained unchanged. Conclusion The symptomatic improvement achieved in patients clinically responding to PBO during induction was not maintained with continued PBO treatment in maintenance, unlike that observed in patients withdrawn from RZB, underscoring the durability of RZB induction response.1 Most objective measures of disease activity in patients receiving continuous PBO were relatively unchanged over time, with biomarkers remaining elevated and endoscopic rates of response low.

Background Network meta-analysis (NMA) using randomised controlled trial (RCT) data can provide indirect evidence on comparative efficacy of various treatments.1 The NMA reported herein was conducted to evaluate infliximab (IFX) and vedolizumab (VDZ) comparative efficacy during maintenance treatment of moderate-to-severe Crohn’s disease (CD) and ulcerative colitis (UC), covering various dosing regimens and administration routes for each biologic. Methods Studies were identified by literature searches that included publications up to 1 November 2022. Parallel-group RCTs evaluating IFX or VDZ (intravenous [IV] or subcutaneous [SC]) for maintenance treatment of adult patients with moderate-to-severe CD or UC that reported clinical remission rates were included. Eligible studies treated patients for a minimum of 22 weeks, with follow-up of 30–60 weeks for maintenance. Clinical remission rates in tumour necrosis factor inhibitor (TNFi)-naïve patients from each study were analysed in a Bayesian NMA fixed-effect model. Results Overall, 13 RCTs were identified and included in the analysis (Table 1 for CD and Table 2 for UC). The difference in study design between IFX (treat-through) and VDZ (re-randomisation of induction responders only) was noted. A connected network of evidence could be generated using CD and UC studies (Figures 1A and 1B, respectively). In both CD and UC, IFX SC 120 mg had the highest odds ratio (95% confidence interval [CI]) vs. placebo for clinical remission during the maintenance phase (CD: 5.90 [1.90–18.2]; UC: 5.45 [1.94–15.3]), albeit with the CIs overlapping with the CIs of the other tested regimens (Figures 2A and 2B). In both CD and UC, IFX SC 120 mg ranked highest for clinical remission among the biological agents, dosing regimens, and routes of administration tested. Conclusion In both CD and UC, IFX SC showed a favourable efficacy profile for achieving clinical remission during maintenance treatment of TNFi-naïve adult patients, when compared with the other IFX IV or VDZ IV/SC regimens tested. References: 1 Rouse B et al., Intern Emerg Med 2017;12(1):103-111.

Background Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). Although ≈30% of UC patients initially present with isolated proctitis, most phase 3 trials of systemic therapies in UC excluded this subgroup. We report the efficacy and safety of etrasimod in subjects with isolated proctitis enrolled in the ELEVATE UC programme. Methods In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), subjects (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 comprised a 12-week induction period. Both trials allowed inclusion of subjects with isolated proctitis ( Results This analysis included 64 pooled subjects with isolated proctitis at week 12 (42 etrasimod, 22 PBO) and 36 subjects from UC 52 at week 52 (27 etrasimod, 9 PBO). Greater proportions (P Conclusion Efficacy and safety of etrasimod in subjects with isolated proctitis was consistent with the overall population of the ELEVATE programme.1 The analysis was performed on a small dataset and should be interpreted with caution but informs on the efficacy of etrasimod in a subpopulation of UC subjects commonly excluded from drug development trials. Reference: 1. Sandborn WJ, et al. Presented at: DDW 2022; May 24, 2022. Abstract 968a.

Background Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). First-dose, transient heart rate (HR) reduction and cardiac conduction aberrations are a known, on-target effect of S1P receptor modulators. Here, we report characteristics of patients for whom adverse events (AEs) of bradycardia or atrioventricular (AV) block were reported in the phase 3 ELEVATE programme. Methods In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), patients (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo on study day 1 with no dose titration regimen. Cardiac conduction was evaluated in all patients with a 12-lead ECG during the screening period, prior to randomisation on day 1 (baseline), and 4-hours post-dose. Bradycardia was considered an AE of special interest if the HR was 230 ms, or if associated with clinical symptoms. Results A total of 9 events of bradycardia were reported in patients receiving etrasimod across both trials (Table 1). All but 1 event (8/9) were first reported on day 1 of treatment, with the remaining first reported on day 2 (none reported after day 2). Seven of 9 events were asymptomatic; the 2 symptomatic events (moderate dizziness; mild dizziness, palpitations) led to therapy discontinuation and resolved without additional intervention. No serious or severe events of bradycardia or hemodynamic changes were reported. Three AEs of AV block were reported in patients on etrasimod across both trials. All events occurred on day 1 during in-clinic ECG monitoring per study protocol and were nonserious, asymptomatic, and resolved without interventional treatment. Two events were first degree, one of which was pre-existing (treatment was discontinued); the other patient continued treatment and completed the study. The third event was second-degree (Mobitz Type I) (treatment was discontinued). Among the small sample size of 11 patients who experienced ≥1 AE of bradycardia or AV block, there were no baseline characteristics that could be used to predict these events (Table 2). Conclusion Cardiac AEs with etrasimod were generally rare, mild, asymptomatic, and occurred on day 1 in association with the first dose. This is consistent with other S1P receptor modulators. Data from the ongoing 5-year open-label extension will further characterize the etrasimod safety profile.

Environmental and lifestyle factors play an important role in the natural history of Crohn's disease and ulcerative colitis. A group of international experts from the International Organization for the Study of Inflammatory Bowel Diseases voted on a series of consensus statements to inform the management of inflammatory bowel disease (IBD). The recommendations include avoiding traditional cigarette smoking in patients with Crohn's disease or ulcerative colitis, screening for symptoms of depression, anxiety, and psychosocial stressors at diagnosis and during flares (with referral to mental health professionals when appropriate), and encouraging regular physical activity as tolerated. Patients using dietary approaches for treatment of their IBD should be encouraged to adopt diets that are best supported by evidence and involve monitoring for the objective resolution of inflammation. We recommend formal assessment for obesity and nutritional deficiencies, and patients should be encouraged to maintain a normal body-mass index. A shared decision-making approach to contraception should include the consideration of IBD-related factors, and risk factors for venous thromboembolism. Long-term or frequent use of high-dose non-steroidal anti-inflammatory drugs should be avoided. For primary prevention of disease in the offspring of patients with IBD, we recommend avoiding passive exposure to tobacco, using antibiotics judiciously, and considering breastfeeding when able.

Background An association between shorter disease duration and improved clinical efficacy has been shown in post hoc analyses of clinical trial data with biological therapies in Crohn’s disease (CD). The efficacy and safety of risankizumab (RZB) as induction and maintenance therapy have been recently reported. Here, the efficacy of RZB stratified by baseline CD duration is reported. Methods In ADVANCE (NCT03105128) and MOTIVATE (NCT03104413), patients with moderately to severely active CD received intravenous (IV) RZB induction therapy or placebo (PBO) for 12 weeks. Patients with clinical response to RZB IV induction were re-randomised in a 52-week maintenance study (FORTIFY, NCT03105102) to receive subcutaneous (SC) RZB or PBO (ie, withdrawal). For this post-hoc analysis, patient subgroups were stratified by years of CD duration at baseline (< 2, 2–5, > 5–10, and > 10 years). Induction analyses focused on patients who received RZB 600 mg IV or PBO for 12 weeks. As all patients who entered maintenance responded to RZB IV induction, maintenance analyses were limited to those patients who responded to induction and then received RZB 360 mg SC for 52 weeks. Clinical and endoscopic outcomes were evaluated using nonresponder imputation incorporating multiple imputation to handle missing data due to impact of the COVID-19 pandemic. Safety was assessed throughout the studies. Results The induction and maintenance analyses included 527 patients who received RZB 600 mg IV and 141 patients who received RZB 360 mg SC, respectively. At the end of induction (week 12), patients with CD duration of < 2 years achieved higher rates of endoscopic outcomes with IV RZB induction vs patients with longer durations of disease (Figure 1), and regardless of baseline CD duration, greater proportions of RZB-treated patients achieved clinical remission (defined by stool frequency and abdominal pain), endoscopic response, endoscopic remission, and ulcer-free endoscopy vs PBO (P ≤ .05). Clinical remission rates at week 12 were numerically higher in patients with CD duration of < 5 years vs > 5 years (Figure 1). Similar results for improved clinical and endoscopic outcomes associated with shorter disease duration were observed at week 52 with RZB 360 mg SC maintenance treatment (Figure 2). RZB was well tolerated with lower rates of serious adverse events and serious infections vs PBO in induction, across CD duration subgroups. Conclusion RZB induction and maintenance therapy was effective and well tolerated with a safety profile generally similar across CD duration subgroups. Achievement of clinical and endoscopic endpoints were higher in patients with shorter duration of CD, suggesting that earlier introduction of RZB therapy may lead to improved outcomes.

Background Ulcerative colitis (UC) can result in a high prevalence of bowel movement urgency (BU), significantly reducing patient quality of life. Purpose Early BU improvement association with later clinical endpoint improvements was examined in moderately-to-severely active UC patients (pts) treated with mirikizumab (miri). Method BU was evaluated in Phase 3 randomized placebo (PBO)-controlled 12-week induction (LUCENT-1, NCT03518086) and 40-week maintenance (LUCENT-2, NCT03524092) trials with miri. Pts received IV miri 300mg or PBO during induction. Week (W)12 miri responders were rerandomized at LUCENT-2 baseline (BL) to subcutaneous miri 200mg or PBO. BU was measured with 11-point Urgency Numeric Rating Scale (UNRS) from 0 (no urgency) to 10 (worst possible). Pts’ UNRS scores were an average from 7 consecutive days prior to visit. Association of pts with BU Clinically Meaningful Improvement (CMI) or BU remission between BL and W4 with the proportion of pts achieving clinical response, and clinical, endoscopic, or symptomatic remission at end of W12 was assessed. For pts who achieved clinical response at W12, the analyses were repeated for the end of maintenance based on W12 BU status. Logistic regression models with treatment, urgency (BU CMI or BU Remission), treatment-by-urgency group interaction, and stratification factors were fitted to examine the association between early urgency improvement and later clinical endpoints. Result(s) Treatment-by-urgency group interactions were not statistically significant across clinical outcomes for induction and maintenance. For induction, treatment and urgency status were statistically significant. Pts experiencing BU CMI or BU remission at W4 were consistently more likely to achieve clinical response, and clinical, endoscopic, or symptomatic remission at W12 for both treatment groups. For remission, only treatment main effect was statistically significant. Among miri induction clinical responders (an enriched population), BU CMI or BU Remission at end of induction (W12) was not associated with later maintenance efficacy outcomes (W52). Miri-treated pts achieved higher rates of clinical response, and clinical, endoscopic, or symptomatic remission at W52 than with PBO regardless of BU CMI or BU Remission at W12 (Table). Image Conclusion(s) Early BU Improvement, CMI or Remission, was associated with better clinical outcomes during induction for miri and PBO pts, showing BU is a sensitive predictor of early clinical outcomes. Among miri induction responders, miri consistently provided better maintenance of response and remission rates than PBO. Please acknowledge all funding agencies by checking the applicable boxes below Other Please indicate your source of funding; Eli Lilly and Company Disclosure of Interest D. Clemow Employee of: Eli Lilly and Company, C. Sapin Employee of: Eli Lilly and Company, T. Hibi Grant / Research support from: AbbVie, ActivAid, Alfresa Pharma, Bristol Myers Squibb, Eli Lilly Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen Pharmaceutical K.K., JMDC, Mochida Pharmaceutical, Nippon Kayaku, Pfizer Japan, and Takeda, Consultant of: AbbVie, Apo Plus Station, Bristol Myers Squibb, Celltrion, EA Pharma, Eli Lilly and Company, Gilead Sciences, Janssen, Kyorin, Mitsubishi Tanabe Pharma, Nichi-Iko Pharmaceutical, Pfizer, Takeda, and Zeria Pharmaceutical, Speakers bureau of: AbbVie, Aspen Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen, JIMRO, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, and Takeda, M. Dubinsky Shareholder of: Trellus Health, Grant / Research support from: AbbVie, Janssen, Pfizer, and Prometheus Biosciences, Consultant of: AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, F. Hoffmann-La Roche, Genentech, Gilead Sciences, Janssen, Pfizer, Prometheus Therapeutics and Diagnostics, Takeda, and UCB Pharma, S. Vermeire Consultant of: AbbVie, Arena Pharmaceuticals, Avaxia Biologics, Boehringer Ingelheim, Celgene, Dr. Falk Pharma, Ferring Pharmaceuticals, Galapagos NV, Genentech/Roche, Gilead Sciences, Hospira, Janssen, Mundipharma, Merck Sharp & Dohme, Pfizer, ProDigest, Progenity, Prometheus Therapeutics and Diagnostics, Robarts Clinical Trials, Second Genome, Shire, Takeda, Theravance Biopharma, and Tillots Pharma AG, Speakers bureau of: AbbVie, Dr. Falk Pharma, Ferring Pharmaceuticals, Galapagos NV, Genentech/Roche, Gilead Sciences, Janssen, Pfizer, Robarts Clinical Trials, and Takeda, S. Schreiber Grant / Research support from: personal fees and/or travel support from: AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Dr. Falk Pharma, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Gilead Sciences, I-MAB Biopharma, Janssen, Merck Sharp & Dohme, Mylan, Novartis, Pfizer, Protagonist Therapeutics, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Theravance Biopharma, and UCB Pharma, T. Gibble Employee of: Eli Lilly and Company, L. Peyrin-Biroulet Grant / Research support from: AbbVie, Fresenius Kabi, Merck Sharp & Dohme, and Takeda, Consultant of: AbbVie, Alimentiv, Allergan, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Enthera, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Genentech, Gilead Sciences, Gossamer Bio, InDex Pharmaceuticals, Inotrem, Janssen, Merck Sharp & Dohme, Mylan, Norgine, Ono Pharmaceutical, OSE Immunotherapeutics, Pandion Therapeutics, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, Theravance Biopharma, Thermo Fisher Scientific, Tillots Pharma AG, Viatris, and Vifor Pharma, M. Watanabe Grant / Research support from: AbbVie, Alfresa Pharma, EA Pharma, Kissei, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Takeda, and Zeria Pharmaceutical, Consultant of: AbbVie, Boehringer Ingelheim, EA Pharma, Eli Lilly Japan K.K., Gilead Sciences, Nippon, and Takeda, Speakers bureau of: EA Pharma, Eli Lilly Japan K.K., Gilead Sciences, Janssen, JIMRO, Kissei, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer Japan, Takeda, and Zeria Pharmaceutical, R. Panaccione Grant / Research support from: AbbVie, Ferring Pharmaceuticals, Janssen, Pfizer, and Takeda, Consultant of: Abbott, AbbVie, Alimentiv, Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmo Pharmaceuticals, Eisai, Elan Pharma, Eli Lilly and Company, Ferring Pharmaceuticals, Galapagos NV, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Mylan, Oppilan Pharma, Pandion Therapeutics, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, and UCB Pharma, J. Jones: None Declared

Background Risankizumab (RZB), an anti-IL-23 p19 inhibitor, was well-tolerated and superior to placebo (PBO) in inducing clinical remission and endoscopic response in patients (pts) with moderate-to-severe Crohn’s disease (CD) in two phase 3 studies at 12 weeks. Aims FORTIFY (NCT03105102), was a 52-week (wk) phase 3 double-blind, re-randomized responder withdrawal study that evaluated the efficacy and safety of continuing RZB as subcutaneous (SC) maintenance therapy versus withdrawal to placebo in pts achieving induction response to RZB Methods Week 12 IV RZB responders were re-randomized 1:1:1 to: RZB SC 360mg (N=141), RZB 180mg (N=157), or PBO (withdrawal from IV RZB; N=164) every 8wks for 52wks. Co-primary endpoints were clinical remission (per CD Activity Index [CDAI] (US); or stool frequency/abdominal pain score [SF/APS] (OUS) and endoscopic response at wk52. Other clinical and endoscopic endpoints, inflammatory biomarkers, RZB serum levels, and safety were assessed over time. Results Rates of clinical remission (CDAI, SF/APS) and clinical response were similar for RZB and PBO groups through wk24, with rates lower for PBO thereafter. At wk52, clinical remission (CDAI, SF/APS) and endoscopic response rates were significantly higher with RZB 360mg than PBO ( P Conclusions In pts with moderate-to-severe CD, a robust pharmacodynamic effect on the IL-23 pathway after 12wks RZB IV induction was maintained with RZB SC maintenance therapy. The durability of RZB was demonstrated with high rates of efficacy over the 52-wk study. RZB was superior to PBO for achieving clinical remission and endoscopic response at wk52. Results for the more stringent endpoints (endoscopic remission\deep remission) and persistent improvements in inflammatory biomarkers are consistent with a dose response relationship. Continued RZB SC maintenance treatment was generally safe and well-tolerated. Funding Agencies AbbVie

Background STARDUST is a phase 3b randomized trial comparing two therapeutic strategies with ustekinumab (UST) in patients (pts) with Crohn’s disease (CD): treat-to-target (T2T) using early endoscopic assessment vs standard of care (SoC). Results from the Week (W)48 and long-term extension (LTE) (W48 to W104) were published previously.1,2 Here we explore the efficacy of the T2T approach in modifying disease course with UST by analyzing time-to-disease modifying (DM) event up to W104. Methods Adult pts with moderate–severe active CD, received iv, weight-based UST ~6mg/kg at W0; then sc UST 90mg at W8. At W16, pts with ≥70-point reduction in CD Activity Index were randomized 1:1 to either T2T or SoC and received sc UST 90mg, every 12W/8W (up to 4W in the T2T arm), as per the protocol. From W48, eligible pts could continue to receive sc UST up to W104 with further protocol-guided dose adjustment. DM events were recorded through W48 and W104 starting at randomization, and time-to-event analysis was performed for pts in both arms. DM events are represented by combined bowel damage events (defined as the development of new strictures/fistulae or the occurrence of an intra-abdominal abscess) or CD-related hospitalizations or surgeries based on the adverse event analysis. Time-to-first bowel damage event, CD-related surgery, hospitalization, hospitalization or surgery was analyzed separately; Kaplan–Meier (K–M) curves with corresponding hazard ratios (HRs) and 95% confidence intervals (CIs) are shown here. Results Of 440 pts randomized to either T2T or SoC at W16, 74 discontinued before W48. Of the remaining 366 pts completing W48, 43 discontinued and did not enter LTE. At W48, 323 pts entered LTE; 20.1% of these pts discontinued before completing W104. HRs (95% CI) for time-to-first DM event from randomization through W48 and W104 are shown in Table 1, suggesting a numeric benefit in favour of the T2T arm. The separation of the K–M curves for time-to-first DM event between the two arms was apparent at W48 and continued up to W104, without significant difference (Figure 1a and b). Conclusion In STARDUST, with UST, starting at W48, numerically less DM events were observed in the T2T arm, mainly driven by the lower number of CD-related hospitalizations and bowel damage events, potentially linked to numerically higher proportion of endoscopic responders at W48.1 These results advocate for an optimized T2T approach using strictly defined targets like endoscopic response, on top of clinical and biomarkers, to facilitate decision making in clinical practice. References 1. Danese S, et al. United European Gastroenterol J. 2020;8:1264–1265 (Abstract LB11). 2. Peyrin-Biroulet L, et al. United European Gastroenterol J. 2021;9 (Suppl 1).

Background Ulcerative colitis (UC) is a chronic inflammatory disorder with an unknown etiology1. Over recent years, a growing body of evidence has been pinpointing gut virome dysbiosis as a fundamental component in its progression2, although its role during the early phases of chronic inflammation is far from being fully defined. Therefore, we sought to investigate the role of a virome-associated protein encoded by the Orthohepadnavirus genus, the Hepatitis B virus X protein (HBx)3, during UC aetiopathogenesis. Methods HBx positivity of UC patient-derived blood and gut mucosa was assessed by RT-PCR and Sanger sequencing correlated with clinical characteristics by multivariate analysis. Transcriptomics was performed on HBx-overexpressing endoscopic biopsies from healthy donors. C57BL/6 mice underwent intramucosal injections of liposome-conjugated HBx-encoding plasmids or the control. Multidimensional flow cytometry analysis was performed on colonic samples from HBx-treated and control animals. Transepithelial electrical resistance measurement, proliferation assay, ChIP-Seq, and RNA-Seq were performed on in vitro models of the gut barrier. Results HBx was detected in about 45% of patients with UC (Figure 1) and found to induce colonic inflammation in mice (Figure 2A-2D), while its silencing reverted the colitis phenotype in vivo (Figure 2E-2H). HBx acts as a transcriptional regulator in epithelial cells (Figure 3), provoking barrier leakage and altering inflammatory response (Figures 3 and 4). Conclusion This study paves the way for the understanding of the aetiopathogenesis of UC and provides a brand-new standpoint that looks at the virome as a target for tailored treatments, possibly leading to an entirely new approach to therapeutic intervention. References: 1. Massimino L, Lamparelli LA, Houshyar Y, et al. The Inflammatory Bowel Disease Transcriptome and Metatranscriptome Meta-Analysis (IBD TaMMA) framework. Nat Comput Sci 2021;1:511–5. doi:10.1038/s43588-021-00114-y 2. Ungaro F, Massimino L, D’Alessio S, et al. The gut virome in inflammatory bowel disease pathogenesis: From metagenomics to novel therapeutic approaches. United European Gastroenterol J 2019;7:999–1007. doi:10.1177/2050640619876787 3. Ungaro F, Massimino L, Furfaro F, et al. Metagenomic analysis of intestinal mucosa revealed a specific eukaryotic gut virome signature in early-diagnosed inflammatory bowel disease. Gut Microbes 2019;10:149–58. doi:10.1080/19490976.2018.1511664

Background Infliximab (IFX) is used to treat patients with acute severe ulcerative colitis (ASUC) who fail to respond to intravenous corticosteroid therapy. Yet, a significant proportion of patients does not respond adequately and requires colectomy. Our aim was to explore baseline predictors of colectomy-free survival during IFX rescue therapy in patients with steroid-refractory ASUC. Methods We performed an individual patient data meta-analysis (IPDMA) with data retrospectively collected from hospitalised, corticosteroid-refractory patients diagnosed with ASUC (based on Truelove and Witts’ criteria) who received IFX rescue therapy. Baseline characteristics including sex, smoking status, disease extent, disease duration, Mayo endoscopic subscore, serum albumin, C-reactive protein, haemoglobin, and white blood count were evaluated as predictors of colectomy-free survival at three and twelve months after start of IFX therapy. Data were analysed using R software (v4.2.0). Results Data were collected from six centres contributing a total of 140 patients (Table 1). Fifteen patients (10.7%) required colectomy within three months and another eight patients underwent colectomy by one year (total colectomy rate after one year 16.4%) (Figure 1). No baseline predictors of colectomy-free survival were identified (log-rank P>0.05). Patients who received intensified IFX induction therapy (n=64, >5 mg/kg), in contrast to patients on regular induction doses of 5 mg/kg at weeks 0-2-6 (n=49), did not have lower rates of colectomy. A total of 53 IFX serum trough concentrations (TC) were measured in 31 patients. The median IFX TC during weeks (w)1-2 of therapy was 13.5 mg/L (interquartile range [IQR] 9.3-16.3 mg/L), and 7.0 (IQR 1.9-12.0) mg/L during w3-6. Target attainment rates were 8.3% (1/12 patients) and 18.2% (2/11 patients), respectively, towards the previously reported IFX TC targets of 28.3 mg/L at w2 and 15.0 mg/L at w6 for achieving endoscopic remission at w12.1 IFX TCs during induction were not significantly different between patients who received standard and intensified induction therapy. Conclusion Colectomy rates remain a significant burden of ASUC even for patients receiving IFX. In our interim IPDMA, we did not identify baseline predictors of colectomy-free survival. Poor target attainments of the previously established concentration targets demand dose optimisation. Pharmacometrics modelling of the IFX dose-exposure-biomarker/measure-response relationship within the spECTRUM consortium (DEFINE study) will facilitate dose-finding simulations to demonstrate the value of model-informed therapeutic drug monitoring. References: 1. Papamichael et al. Clin Gastroenterol Hepatol. 2016.

Background In ulcerative colitis (UC), persistent histological activity is associated with higher rates of relapse and long-term complications, even when endoscopic remission is achieved; therefore, histological healing is a potentially important treatment target. Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator for the treatment of moderately to severely active UC. This post hoc analysis of the phase 3 ELEVATE programme evaluated the efficacy of etrasimod according to different histologic and composite endpoints. Methods In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), subjects (16-80 years) with moderately to severely active UC were randomised 2:1 to once-daily etrasimod 2 mg or placebo (PBO). ELEVATE UC 52 utilized a treat-through design comprising a 12-week induction period followed by a 40-week maintenance period. ELEVATE UC 12 comprised a 12-week induction period. A key secondary endpoint was the achievement of endoscopic improvement-histologic remission (EIHR). In this post hoc analysis (baseline MMS 5-9), efficacy of etrasimod was compared to PBO at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12 using additional histologic and composite endpoints defined in Table 1. Results At week 12 and at week 52, significant improvements with etrasimod were observed in histologic outcomes, including EIHR (with and without eosinophils), histologic remission, histologic-endoscopic mucosal improvement (HEMI), endoscopic normalization-histologic remission (with and without eosinophils), and disease clearance (Figure 1). In both studies, etrasimod was superior to PBO in achievement of HEMI at week 12 (ELEVATE UC 52 and UC 12: 27.7% vs 8.9%, and 25.7% vs 10.7%, both P Conclusion In this post hoc analysis, etrasimod was superior to PBO for achievement of stringent composite endpoints including EIHR, endoscopic normalization-histologic remission, and disease clearance in both ELEVATE UC 52 and ELEVATE UC 12.

Background The optimal treatment target for ulcerative colitis (UC) is uncertain. The VERDICT trial in moderate to severe UC aims to determine if a treatment target of corticosteroid (CS)-free symptomatic + endoscopic + histologic remission is superior to CS-free symptomatic remission alone. Trial progress and the study cohort to date are described herein. Methods Our aim is to enrol 660 patients with moderately to severely active UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2). Patients are randomised to 3 treatment targets (2:3:5 ratio): CS-free symptomatic remission (Mayo RBS = 0) (Group 1); CS-free endoscopic remission (MES ≤1) + symptomatic remission (Group 2); or CS-free histologic remission (Geboes score Results As of 2 November 2022, 331 patients were enrolled at 55 sites across 10 North American and European countries. Mean (SD) baseline characteristics (Table) include a UC duration of 8.6 (8.3) years, Mayo Clinic score of 8.7 (1.7), C-reactive protein level of 13.3 (15.6) mg/dL, and a faecal calprotectin level of 1462.3 (1481.3) mg/kg. At baseline, 52% (172/331) and 11% (37/331) of patients were receiving concomitant CS and immunosuppressives, respectively, and 14% (47/331) had current/prior exposure to tumour necrosis factor antagonists. Most patients (85%) were receiving nonbiologic therapy. Of all randomised patients, 43/69 (Group 1), 65/98 (Group 2), and 115/164 patients (Group 3) have reached week 16; and 28 (65%), 25 (39%), and 42 (37%) met their target, respectively. After a median of 35 weeks (IQR 18-53), a total of 30 (Group 1), 32 (Group 2), and 50 patients (Group 3) have met their target and will be followed to relapse or study termination. The serious adverse event rate (8%; 36/483) was similar across groups. Conclusion VERDICT has randomised ~50% of its target enrolment. Enrolled patients represent a typical moderate to severe UC population and are primarily bionaive and receiving early VDZ initiation. Early results suggest the feasibility of achieving each treatment target, specifically histologic remission, and are consistent with expected values. No new VDZ safety signals were identified. Completion of enrolment is anticipated in late 2023.

Background Intestinal ultrasound (IUS) is accurate to assess endoscopic activity in ulcerative colitis (UC). The Milan ultrasound criteria (MUC) is a validated scoring system to assess and grade endoscopic activity in UC. The most accurate cutoff value for MUC was > 6.2 for endoscopic activity (defined as a Mayo endoscopic score, MES ≥ 2). The aim of this study was to assess the predictive value of IUS and MUC for treatment response in a longitudinal cohort, using colonoscopy (CS) as reference standard. Methods Consecutive active UC patients starting biologic therapy were included. All patients underwent CS, IUS, clinical and faecal calprotectin (FC) evaluations prior commencing a biological therapy, and within one year (mean 9.4 months). In addition, patients were evaluated by IUS, clinical and FC assessments at week 12. The primary objective was to evaluate whether ultrasound improvement (defined as MUC ≤ 6.2) at week 12 predicted endoscopic improvement at reassessment (defined as MES ≤ 1). Endoscopic remission was defined as MES = 0. Results Forty-nine patients were included (59% under infliximab, 29% under vedolizumab, 8% under adalimumab, 4% under ustekinumab). MUC and MES correlated at reassessment (r= 0.767, p < 0.001). Ultrasound improvement at week 12 was the only independent predictor for MES ≤ 1 and MES = 0 at reassessment (OR 5.80, p = 0.010; OR 10.41, p = 0.041; respectively). Ultrasound improvement at week 12 showed NPV of 96% for detecting MES = 0. A ≥ 2 reduction of the MUC score predicted MES=0 (area under the curve, AUC 0.816). MUC ≤ 4.3 was the most accurate cut-off value for MES = 0 (AUC 0.876). The responsiveness ratio of Guyatt for the MUC was 1.73 and the standardized effect size ratio was 1.6. Both these values > 0.8 indicate a large effect of responsiveness for the MUC. Conclusion MUC is highly accurate to monitor treatment response. Ultrasound improvement after the induction period may predict long-term endoscopic response. The MUC may be used both in clinical trials and routine practice.

Background Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). The safety and efficacy of etrasimod for the treatment of moderate to severe UC has been evaluated in the OASIS phase 2 and ELEVATE phase 3 placebo (PBO)-controlled trials. Long-term safety and efficacy of etrasimod for UC are being evaluated in an ongoing, open-label extension (OLE) study. We report an integrated analysis of the cumulative safety profile observed during the clinical development programme. Methods Safety outcomes included adverse event (AE) frequency and exposure-adjusted incidence rates (EAIRs) of AEs of interest determined based on safety data from PBO-controlled trials and OLE trials. Patients who received PBO or etrasimod (1 or 2 mg) were analysed as two cohorts: patients who received either PBO or etrasimod as part of one phase 2 study (etrasimod 1 or 2 mg for 12 weeks; NCT02447302) or two phase 3 studies (etrasimod 2 mg for 12 or 52 weeks; NCT03945188 and NCT03996369) were reported as the PBO-controlled cohort, and all patients who received ≥1 dose of etrasimod in the all UC cohort (studies above, NCT02536404, NCT03950232, and open-label period of NCT04176588; data cut-off January 31, 2022). Patients may have participated in >1 study. Results Overall, 956 patients received ≥1 dose of etrasimod with 769.3 patient years (PY) of exposure with demographics for both cohorts reported in Table 1. In the PBO-controlled cohort, a total of 629 and 314 patients received etrasimod and PBO, respectively, with 288.1 and 115.1 PY of exposure. Mean (SD) exposure per patient was 23.9 (18.5) and 19.1 (15.1) weeks for etrasimod and PBO, respectively. Of the 956 patients who received etrasimod in the all UC cohort, mean (SD) exposure was 42.0 (27.5) weeks. Rates for AEs, serious AEs, and infections (including serious infections, opportunistic infections, and herpes zoster) were similar between treatment arms and between the PBO-controlled and all UC cohorts (Table 2). Eleven (1.8%) etrasimod-treated patients reported events of bradycardia (EAIR=0.04) in the PBO-controlled cohort (9 of 11 events were asymptomatic); no events were reported in PBO-treated patients. Other AEs of special interest including hypertension and macular oedema were similar between treatment arms and with the all UC cohort. Conclusion Etrasimod in patients with moderately to severely active UC was overall well tolerated and had an acceptable safety profile that did not appear to change with longer-term treatment of up to 2.5 years. In the PBO-controlled cohort, serious infections and herpes zoster were more commonly reported among PBO patients.

Background Vedolizumab (VDZ) is a gut-selective humanised monoclonal anti-α4β7 integrin antibody for treatment of UC and CD. This post-authorization safety study (PASS) compared long-term safety in patients (pts) treated with VDZ or other biologics for UC or CD. Methods This was a prospective, observational, multicentre, cohort study in pts with UC or CD starting treatment with VDZ or other biologics (NCT02674308, EUPAS6469). Pts were biologic naïve (VDZ=35%, Other biologic=65%) or had prior exposure to biologics other than VDZ and were followed for up to 7 yrs. Pts were treated under usual standard of care as directed by their physician with no discontinuation from the study due to physician-directed treatment changes. The primary safety outcome was serious infections and was compared between cohorts using a Cox proportional hazards model adjusted by propensity score (with other biologics as reference). Secondary safety outcomes were adverse events (AE) of special interest (AESI) as listed in Tables 2 and 3. Results In total, 5208 patients were enrolled across 21 countries between Mar 2015 and Jul 2019. The full analysis set comprised 5008 pts (VDZ=2502; other biologic=2506) and mean (SD) study duration was 37.4 (14.1) months. Consistent with the observational nature of the study and the current standard of care, the baseline characteristics in the two cohorts were imbalanced (Table 1). The overall treatment-emergent Adverse Event (AE) rate was 61.3% (VDZ) and 59.5% (other biologic), with serious AEs in 27.5% (VDZ) and 25.7% (other biologic), respectively. In UC pts, the incidence rate (IR) of serious infections were: 0.014 (95% CI: 0.010, 0.019) [VDZ] and 0.015 (0.010, 0.023) [other biologic], with a hazard ratio (HR) of 1.018 (0.931, 1.114), p=0.70 (Table 2). In CD pts, corresponding findings were 0.012 (95% CI: 0.008, 0.017) [VDZ] and 0.006 (95% CI: 0.004, 0.009) [other biologic] with HR of 1.035 (0.959, 1.117), p=0.38 (Table 3). The incidence of primary and secondary safety outcomes is reported in Table 2 for UC and Table 3 for CD. There were no safety issues relating to pregnancy and no cases of PML observed. There were 19 deaths in the VDZ cohort (1 case of pneumonia deemed as treatment-related); and 13 deaths in the other biologic cohort, 2 cases deemed treatment-related (one case septic shock and pneumonia; one case non-small cell lung cancer). Clinical outcomes and quality of life (QoL) measures were comparable between cohorts. Conclusion In this long-term, prospective, real-world observational study of a large multinational population under routine standard of care there was no new safety signal identified in relation to VDZ. Results are consistent with the known safety profile of VDZ.

Background The efficacy and safety of mirikizumab (miri) for moderately to severely active ulcerative colitis (UC) was demonstrated in the Phase 3 LUCENT trials (LUCENT-1 and -2; NCT03518086, NCT03524092).1,2 Some patients may improve more slowly and require a prolonged course of induction before achieving clinical response. Therefore, we evaluated clinical response in patients who had not responded by the end of the 12-week(W) induction period and who received extended induction treatment for an additional 12W. Methods Patients not responding to intravenous (IV) administration of 300 mg miri every 4 weeks (Q4W) (n=272) at W12 (LUCENT-1), received extended 12-W induction treatment of open label 300 mg miri IV Q4W for 3 additional doses (LUCENT-2). Patients responding at W24 (n=144) of continuous IV treatment, entered open label maintenance and received 200 mg miri Q4W subcutaneously (SC) until W52. Key outcomes through 52W are reported (Definitions in Table). Results Among the 272 patients who failed to achieve a clinical response after 12W of induction treatment, 72.4% had a Mayo endoscopic subscore of 3, indicating severe disease. Of these patients, 146 (53.7%) achieved a clinical response and 31 (11.4%) achieved clinical remission at W24. Of the 144 responders at 24W entering the open label maintenance study, 52 (36.1%) patients achieved clinical remission, 104 (72.2%) achieved clinical response, 62 (43.1%) achieved endoscopic remission and 60 (41.7%) patients achieved histologic improvement at W52. Furthermore, for these patients, there was a 3.8 (±2.7) point reduction from baseline in bowel urgency (BU) severity and 58.8% achieved clinically meaningful improvement in BU (Table). Among these patients, 38.3% demonstrated treatment-emergent adverse events (TEAEs). Most TEAEs were mild (21.4%), while only 5.4% were serious. Overall, there was a 3.2% of discontinuation due to TEAEs. No new safety signals or deaths were reported. Conclusion Among patients who did not initially respond to induction treatment with miri at 12W, 3 additional miri induction doses induced clinical response and remission in patients, highlighting the potential benefit of extended induction treatment with miri in those patients with more severe inflammation at baseline. 1.D’Haens et al., OP26: Efficacy and safety of mirikizumab as induction therapy in patients with moderately to severely active Ulcerative Colitis: Results from the Phase 3 LUCENT-1 study, Crohn's and Colitis, Vol. 16, Iss. Supplement_1, Jan. 2022, i028–i029 2.Dubinsky et al., 867e: Efficacy and safety of mirikizumab as maintenance therapy in patients with moderately to severely active Ulcerative Colitis: Results from the Phase 3 Lucent-2 study, Gastroenterology, Vol. 162, Iss. 7, S-1393-94

Background Inflammatory bowel diseases (IBD) affect patients during their childbearing years. Literature evidence is scarce regarding the level of knowledge among health care professionals (HCPs) and patients out the impact of IBD on fertility. The aim of this survey was to investigate HCPs' and patients' knowledge on fertility, pregnancy, and sexual function, to evaluate how HCPs approach this topic and to report patients’ reproductive outcomes. Methods Subjects were invited to anonymously complete an online questionnaire collecting data on demographics, patients' disease characteristics, Crohn's and colitis pregnancy-specific disease-related knowledge (CCPKnow), family planning, reason of childlessness, pregnancy outcomes, need for assisted reproductive technology, impact on sexual function, and availability of patients’ information regarding IBD and pregnancy. Results A total of 257 HCPs from 40 countries and 793 patients (615 females, 176 males and 2 who preferred not to disclose their gender; 396 (50%) with ulcerative colitis, 381 (48%) with Crohn’s disease, 14 (1.8%) with undetermined IBD) from 4 countries completed the survey. The characteristics of participants are listed in Table 1. In total, 98.4% of HCPs had good or very good pregnancy-specific knowledge according to CCPKnow score, compared to only 29.3% of patients. Of the women surveyed, 56.3% had no children (14.1% due to a voluntary choice). A total of 427 pregnancies and 401 live births were reported in 266 women. Twenty-four pregnancies (5.6%) in 22 women required assisted reproductive technologies (ART). There were no more complications in pregnancies resulting from ART compared with spontaneous conception (5/24; 20.8% vs 211/401; 52.6%). Three quarters of IBD patients (75.6%) had breastfed. An impaired sexual function was found in one-fifth (21.9%) of men with IBD, while two-thirds (66.1%) of the women reported sexual function impairment. Surprisingly, 63% of patients reported not having received any information about IBD and pregnancy, and only 10% of patients had received information from their IBD specialist. In addition, 42.1% and 36% of HCPs had already referred a patients to a medically assisted reproduction centre to receive general information about their reproductive health and about options of fertility preservation (e.g., cryopreservation), respectively. Conclusion IBD patients have a poor knowledge about the impact of IBD on fertility and pregnancy and HCPs does not sufficiently inform their patients. More information on these topics is needed for IBD patients.

Background We report the results of TOFAST, a French ongoing prospective observational multicenter study, evaluating the clinical benefit of tofacitinib for the treatment of moderate to severe UC. Methods In this descriptive interim analysis, effectiveness and safety were assessed at the end of induction therapy (up to 4 months after tofacitinib initiation). Clinical response was defined as a decrease in partial Mayo score (PMS) (≥ 3 points and ≥ 30%) from inclusion with a concomitant decrease in rectal bleeding (RB) subscore ≥ 1 point (absolute subscore of 0 or 1). Clinical remission was defined as PMS ≤2 with no subscore >1. Change in daily PRO2 scores [RB and stool frequency (SF)] during the first 14 days and the median time to patient relief were also analyzed. Results Among the 102 patients included, 86 had available data at the first follow-up visit, corresponding to the end of induction period. At inclusion, 53.9% of patients were male with a mean (± SD) age of 37.1 ±13.6 years, a median disease duration of 6.1 years [Q1; Q3: 2.8; 10.8]. 48% of patients had pancolitis and 24.5% an extraintestinal manifestation; mean PMS was 6 ±1.8 with median SF and RB scores of 3.0 [Q1; Q3: 2.0; 3.0] and 2.0 [1.0; 2.0], respectively. Regarding prior drug exposure, 92.2% of patients had received at least one anti-TNF agent, 62.7% vedolizumab and 34.3% ustekinumab. Tofacitinib was initiated at 10 mg b.i.d, in combination with 5-ASA and corticosteroids for 19.6% and 33.3% of patients, respectively. At the first follow-up visit (median 1.9 months after treatment initiation), tofacitinib was ongoing in 87.2%, mostly (73.3%) at 10 mg b.i.d. Corticosteroids were ongoing in 29.1% of patients. At the end of induction period, rates of clinical response and remission were 52.3% and 43%, respectively. Median changes in RB and SF scores were identical at days 7 and 14, -1 point [Q1; Q3: -1.0; 0.0] and -1 point [Q1; Q3: -2.0 - 0.0], respectively. For patients who reported improvement (68.6%), the median time to relief was 7 days [Q1-Q3: 4.0-15.0]. PRO2 scores normalisation during the first 14 days is shown in the figure. RRegarding safety, 73.5% of patients reported at least one adverse event (AE) and 12.6% reported at least one serious AE. Ten (9.8%) infections (none considered as serious) and 2 (1.9%) Herpes Zoster were reported. No major cardiovascular or venous thromboembolic event, nor malignancy or death were observed (Table). Conclusion The interim results of TOFAST study show that at the end of induction therapy with tofacitinib, 52.3% of patients achieved clinical response and >40% achieved remission. Rapid improvement in SF and RB scores was observed within 2 weeks. AEs were consistent with the known tofacitinib safety profile.

Background Subcutaneous infliximab (IFX-SC) was launched in France for the treatment of patients with inflammatory bowel disease (IBD) in 2021. Real-life and pharmacokinetic (PK) data after switching from intravenous infliximab (IFX-IV) to IFX-SC are needed. The PEREM study is a French multicenter prospective cohort aiming to describe the persistence of IFX-SC after switch from IFX-IV. Methods IBD patients in steroid-free clinical remission [Harvey Bradshaw Index (HBI) ≤ 4 for Crohn's disease (CD) and partial Mayo score (PMS) ≤ 2 with each subscore ≤ 1 for UC] for at least 6 months on IFX-IV therapy were proposed to switch to IFX-SC as part of routine care. Patients were included in 40 centers between Oct 2021 and May 2022. Clinical scores (HBI, PMS), biological samples (CRP and fecal calprotectin - FC), PK and anti IFX antibodies (ATI) were evaluated 3, 6, 12 and 24 months after switch. In case of IFX-SC discontinuation, time and reason for withdrawal were documented. Safety and adverse events of interest were recorded. The primary endpoint was IFX-SC persistence at 12 months. As not all patients met this primary endpoint at the time of writing this abstract, we present here the results at 6 months (M6). Results Among the 444 patients included [44% female, median age: 37 years (Min, Max: 18-88), 72% Crohn's], 71% were receiving IFX-IV at a dose of 5 mg/kg every 8 weeks and 84% were treated on monotherapy. Among the 417 patients analyzed, five withdrew their consent before the M6 visit and 324 were assessed at M6; 25/324 (7.7%) discontinued IFX-SC before M6 (seven for relapse, twelve for intolerance, two for pregnancy, four for unknown reasons) including one (0.3%) switch back to IFX-IV. Rate of survival without IFX-SC discontinuation at M6 was 92.6% (95% CI 89.3-95.1). Among the patients evaluated at M6, median clinical scores did not vary between inclusion and M6: HBI from 0 (IQR: 0-1) to 0 (IQR: 0-1), PMS from 0 (IQR: 0-0) to 0 (IQR: 0-0), respectively. The median CF and CRP levels were respectively 52 μg/g (IQR: 19-142) at inclusion and 37 μg/g (IQR: 14-129) at M6, and 1 mg/L (IQR: 1-4) at inclusion and 1 mg/L (IQR 0-4) at 6 months. At baseline, median infliximab levels were 6.6 μg/mL (min, max: 0-29) and 20 μg/mL (min, max: 0.3- 79.2) at M6. No major safety signals were recorded. Conclusion In a national real-life multicenter cohort, rate of persistence of IFX-SC after 6 months was 92.6% in IBD patients switched in remission, without significant clinical or biological changes. Treatment switch was associated with an increase in IFX levels. These data are confirming the good efficacy and safety of IFX-SC after switch.

Background There is a need to identify Crohn’s Disease (CD) patients who will obtain most clinical benefit from treatment with vedolizumab (VDZ), an anti-α4β7 integrin inhibitor for the treatment of ulcerative colitis and Crohn’s Disease (CD). Previously, a clinical decision support tool (CDST) has been developed and validated to guide treatment decisions in CD patients (pts) treated with intravenous VDZ.1 In this study, we aimed to test the ability of the CDST to predict clinical outcomes in CD pts receiving maintenance treatment with the subcutaneous (SC) formulation of VDZ. Methods Pts with moderate to severe CD receiving maintenance treatment with VDZ SC in the VISIBLE 2 study were categorized using the CDST into low (≤13 points), intermediate (>13 and ≤19 points) and high response probability groups (>19 points) based on the scoring system detailed in Table 1. Clinical outcomes evaluated included clinical remission: CD Activity Index (CDAI) ≤ 150 at Week 6, 14, 30, and 52, and enhanced clinical response: decrease from baseline in CDAI score ≥ 100 points at Week 52. All outcomes were evaluated as observed. Results There were 275 pts who completed induction treatment with VDZ 300 mg IV and continued into maintenance treatment with VDZ 108 mg SC until Week 52. Using the CDST, at baseline, 14 pts (5.1%) had a low, 98 (35.6%) had an intermediate, and 163 (59.3%) had a high probability of treatment response with VDZ. Due to the low number of pts in the low probability group, the low and intermediate groups were combined. At Week 6, 99 pts (61.1%) in the high probability group had achieved clinical remission vs 38 pts (33.9%) in the low/intermediate probability group (Fig 1). Rates of clinical remission in the high probability group continued to exceed those of the low/intermediate group through until Week 52 when 89 pts (86.4%) in the high probability group were in clinical remission vs 43 pts (79.6%) in the low/intermediate probability group (Fig 1). In the high probability group, 97 pts (94.2%) had an enhanced clinical response at Week 52 compared with 46 pts (85.2%) in the low/intermediate group. Conclusion Compared with the low/intermediate group, pts categorized by the CDST as having the highest probability of treatment response to VDZ achieved clinical remission sooner, as early as Week 6. These findings provide further confirmation of the CDST as a means of identifying pts with CD likely to benefit from treatment with VDZ in either IV or SC formulations. References: 1. Dulai PS et al. (2018) Gastroenterology 155:687-695.e10.

Background Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development to treat immune-mediated inflammatory disorders. CULTIVATE (NCT04173273) is a seamless phase 2/3 trial comprising 5 substudies designed to evaluate the efficacy, safety, and tolerability of etrasimod in subjects with moderately to severely active Crohn’s disease (CD). Here, we report the induction data from the first substudy (Substudy A). Methods Substudy A was a phase 2, randomised, double-blind study using a 14-week induction period followed by a 52-week extension period. Adults (18-80 years) with moderately to severely active CD and an inadequate response, loss of response to, or intolerance to ≥1 conventional or advanced treatments for CD were randomised 1:1 to once-daily etrasimod 2 mg or 3 mg. Subjects were stratified by baseline biologic failure status and oral corticosteroid use. The primary efficacy endpoint was achievement of endoscopic response (defined as endoscopic remission [SES-CD ≤4 and ≥2-point reduction from baseline with no subscore >1] or ≥50% decrease in SES-CD score) at week 14. Secondary/exploratory endpoints included achievement of endoscopic remission, clinical remission (CDAI Results Of 83 subjects randomised to etrasimod 2 mg or 3 mg, respectively, 32/42 (76.2%) and 36/41 (87.8%) completed week 14 (Table 1). Overall, 21.4% and 9.8% of subjects in the 2-mg and 3-mg groups, respectively, achieved the primary endpoint of endoscopic response, 14.3% and 7.3% achieved endoscopic remission, 31.0% and 43.9% achieved clinical remission, and 33.3% and 40.0% achieved IBDQ remission at week 14 (Figure 1). Most treatment-emergent AEs were mild or moderate, with more AEs reported in the 3-mg vs 2-mg group. The incidence of serious AEs (4.8% and 2.4%) and AEs leading to discontinuation (4.8% and 7.3%) was low in the 2-mg and 3-mg groups, respectively (Table 2). Two subjects in the 3-mg group experienced second degree atrioventricular block type 1 TEAEs (during 2-mg titration). Conclusion Data from this substudy of subjects with moderately to severely active CD suggest endoscopic and clinical improvement with both etrasimod 2 mg and 3 mg. However, the small sample size and lack of placebo arm limit the ability to draw conclusions about efficacy including comparison between the 2-mg vs 3-mg groups. Both doses were well tolerated and safety was consistent with other etrasimod clinical programmes. Data from the extension phase of Substudy A and the placebo-controlled, dose-ranging phase 2b Substudy 1 are forthcoming.

Background NLRX1 is a mitochondrial membrane protein whose activation reduces oxidative stress and decreases effector cell differentiation and cytokine release. NX-13 is a first-in-class, orally active, gut selective NLRX1 agonist with low systemic exposure. In preclinical studies of IBD, NX-13 effectively reduced inflammatory responses and disease severity. A phase 1a study (healthy subjects) showed NX-13 to be well tolerated with low systemic drug exposure suggesting a gut-selective drug delivery. We report the results of a phase 1b study in patients with Ulcerative colitis (UC) on the safety, target engagement and clinical efficacy of NX-13. Methods In this double-blind trial, 36 patients with active UC (Total Mayo Score [MCS] 4-10; Mayo endoscopic subscore [MES] 2-3) were randomly assigned to NX-13 250mg Immediate Release (IR), 500mg IR, 500mg Modified Release (MR) or Placebo to be taken QD for 4 weeks (safety visit at week 5). Biologic exposed patients, stable 5’ASAs dose and corticosteroids (oral ≤20mg/day prednisone or equivalent) were permitted. IV or topical corticosteroids use was prohibited. Primary endpoints were safety and pharmacokinetic (PK) analysis. The study was not powered for clinical efficacy, however MCS, histopathologic Geboes score, and NLRX1, cytokine, and gene expression were obtained at baseline and day 28 in exploratory analyses (Table 1). Results During the 5-week observation period, no serious adverse events (AEs) were reported. All AEs were classified as mild or moderate and were most common in the 500mg MR group. One patient was withdrawn before week 5 due to a flare of UC. IR dose plasma PK levels peaked at 1hour, while the MR dose was absorbed later and maintained a low exposure longer. Qualitative immunohistochemical analysis showed target engagement as indicated by increase of NLRX1 at all doses. Symptomatic efficacy was seen in 8/11 patients in the 250mg group with a PRO (RB+SF) score of 0 at week 4. The decrease in MCS was 2.1-3.4 in the NX-13 arms vs 1 point with placebo (Fig 1A) while clinical response rates ranged from 27-72% amongst the active arms with no placebo responders, though no dose-response relationship was observed (Fig 1B). Endoscopic response ranged from 27-40% (Fig 1C), with 5/32 dosed patients being in endoscopic remission. Histologic remission largely paralleled endoscopic response and cytokine and mRNA levels support target engagement. Conclusion In patients with active UC, NX-13 was well-tolerated and target engagement was achieved. The exploratory efficacy endpoints indicated rapid clinical, endoscopic, and histologic improvement at week 4, relative to placebo. This novel mechanism of action will be further evaluated in a phase 2 study.

Background Histological remission is an important target for Ulcerative Colitis (UC) treatment; however, scoring of histological images is time-consuming and prone to inter and intra-observer variability. Thus, a need exists for an accurate, reproducible, and reliable automated method. Previously, we demonstrated an Artificial Intelligence (AI) Tool using image processing and machine learning algorithms to measure histological disease activity using the Nancy index consistently and accurately.1 Here, we aim to enhance the capabilities of the AI Tool, by adding substantially more population-diversified training data while maintaining accuracy and robustness of results. Methods Eight global sites submitted 600 UC histological images. These were added to the 200 images previously used to train and validate the AI Tool. The 800-image dataset was divided into 2 groups: 90% used for training, 10% for testing. The novel AI algorithms were trained using state-of-the-art image processing and machine learning techniques based on deep learning and feature extraction. Cell and tissue regions of each training image were manually annotated, measured, and assigned a Nancy Index independently by 3 histopathologists, and used to further train the AI using over 43,000 characterisations. The AI Tool fully characterises histological images, identifying tissue types, cell types, cell numbers and locations, and automatically measures the Nancy Index for each image. Intra Class Correlation (ICC) and Confusion Matrix analyses were performed to evaluate the AI Tool and assess accuracy. Results The average ICC was 92.1% among the histopathologists and 91.1% between histopathologists and AI Tool, compared with 88.3% and 87.2% in the previous study.1 Confusion matrix analysis (Table 1) demonstrated the strongest correlation at the extremes of the Nancy Index, with 80% correlation between predicted and true labels for Nancy Scores of 0 or 4. When 2 adjacent scores were combined, correlations were stronger: 96% for a true Nancy score of 0 being predicted as 0 or 1, and 100% for a true Nancy score of 2 being predicted as 2 or 3. Conclusion By adding a larger number of images to the AI Tool training data, the robustness of the AI Tool was substantially improved while maintaining accuracy. The continued high correlation of AI Tool performance with the histopathologists reinforces the potential role for the AI Tool for IBD clinical applications. Fully characterising whole slides could standardise and validate an AI-driven scoring system for histology slides in IBD, eliminating the subjectivity of the human pathologist in assessment of disease activity. References: 1. Peyrin-Biroulet L, et al. J Crohn's and Colitis. 2022;16(Suppl 1):i105.

Background Real-world treatment of ulcerative colitis (UC) requires a patient-centric, holistic definition of ‘comprehensive remission' that goes beyond standard regulatory definitions. In an international initiative, we reviewed aspects of UC that affect patients and attempted to achieve consensus on which aspects should be considered in a definition of ‘comprehensive remission’, using a modified Delphi process. This initiative summarized expert consensus recommendations on aspects of UC that are important to patients and that affect their lives, how to measure and score these aspects, and objective markers of mucosal inflammation that are relevant to evaluate in remission, such as endoscopic and histological activity and inflammatory biomarkers. Methods The Delphi consensus panel comprised 10 physicians with expertise in UC and one patient advocate, and two additional physicians chaired the process. To inform the Delphi statements, we asked 18 patients about their experiences of living with UC in remission, asked panel members about their experience of treating patients and systematically reviewed associations between outcome measures in UC. Panel members voted on a 6-point Likert scale in three rounds of anonymous voting, the final round of which was preceded by a live discussion. Consensus was met if ≥ 67% of the panel agreed with the statement (4–6 on the 6-point Likert scale). Statements not meeting consensus in voting rounds 1 and 2 were revised and any not meeting consensus by the end of voting round 3 were discarded (Figure 1). Results The panel agreed that a definition of comprehensive remission should include aspects of UC that are currently measured in clinical trials (blood in stools, stool frequency, disease-related quality of life [QoL], endoscopic remission, histological inflammatory activity, inflammatory biomarkers and discontinuation of corticosteroids), but also additional patient-reported symptoms should be added. These were bowel urgency, abdominal pain, extra-intestinal manifestations, fatigue and sleep disturbance (Table 1). Suggestions for how the severity could be measured and thresholds for remission were agreed for each aspect, with the exception of extra-intestinal manifestations. Disease activity evaluated using ultrasound was voted as important to consider but was not recommended to be included in a measure of comprehensive remission at this stage. Conclusion We used a robust methodology to reach agreement and provide recommendations on the aspects of UC that can be used to define comprehensive remission and assessed in clinical practice. We plan to develop this as a combined measure which may also have applicability in clinical trials.

Background Treat-to-target (T2T) strategy may optimise IBD disease management. We describe interim clinical and endoscopic results of the STARDUST trial in Crohn’s disease (CD) patients, following 16 weeks (W) of ustekinumab (UST) induction. Methods STARDUST, an ongoing phase 3b randomised strategy trial, enrolled adults with moderate–severely active CD (CD activity index [CDAI] 220–450) and simple endoscopic index for CD [SES-CD] ≥3) who failed conventional therapy ±1 biologic. At W0, patients received intravenous, weight-based UST of ~6mg/kg (approved label) and at W8, subcutaneous UST 90mg. At W16, patients with CDAI reduction ≥70 points were randomised (1:1) to T2T or standard of care. Key endpoints (intention-to-treat [ITT] set, as observed) were analysed at W8 and W16: % patients in clinical remission (CDAI score Results The ITT full set included 500 patients with BL mean (SD) CDAI score 282.3 (65.8), SES-CD 13.1 (8.1), CRP 15.7 (23.4) mg/l, FCal 1741.9 (2932.1) mg/g and disease duration 9.4 (8.7) years; 58.4% previously failed 1 biologic. At W16, 79.4% of patients had a clinical response and 66.6% were in clinical remission. About half of the patients showed ≥50% improvement in FCal and CRP levels, which normalised in about 1/3 of patients. Results were similar irrespective of previous biologic (Table 1); 84% of patients in response at W16 were in clinical remission. Statistically significant changes from BL in CDAI, FCal, and CRP were observed at W8, and in IBDQ scores at W16 (Table 2). In the T2T set (n = 220; CDAI 70 responders), BL characteristics were similar to the full analysis set; SES-CD score was 13.4 (8.8). At W16, 36.8% and 11.4% of patients in the T2T set achieved endoscopic response and remission, respectively. The endoscopic response was independent of BL SES-CD score and disease duration, but numerically better for colonic vs. ileal disease. No new safety signals were reported. Conclusion STARDUST is the first T2T trial in CD patients. After 16 W following induction with UST, 2/3 of patients achieved clinical remission. Thirty-seven per cent of those randomised to the T2T arm (CDAI 70 responders) showed endoscopic response by central reading at W16. Results were similar irrespective of being bio-naïve or failing 1 biologic.

In inflammatory bowel disease [IBD], mucosal healing is a major therapeutic target and a reliable predictor of clinical course. However, endoscopic mucosal healing is not synonymous with histological healing, and the additional benefits of including histological remission as a target are unclear. In Crohn´s disease [CD], there are few studies highlighting the value of histological remission as a therapeutic target. Histological activity can persist in CD patients who are in endoscopic remission, and the absence of histological activity may be associated with lower relapse rates. Therefore, standardisation of procedures to evaluate CD histological activity is desirable. Topics that would benefit from standardisation and harmonisation include biopsy procedures, biopsy processing techniques, the content of histological scores, and the definitions of histological remission, histological response, and histological activity. In line with these needs, the European Crohn's and Colitis Organisation [ECCO] assembled a consensus group with the objective of developing position statements on CD histology based on published evidence and expert consensus. There was agreement that definitions of histological remission should include absence of erosion, ulceration, and mucosal neutrophils; that the absence of neutrophilic inflammation is an appropriate histological target in CD; that CD histological scores, such as the Global Histological Disease Activity Score, lack formal validation; and that histological scoring systems for ulcerative colitis, including the Geboes Score, Robarts Histopathology Index, and Nancy Histological Index, can be used for scoring intestinal biopsies in CD patients. ispartof: J Crohns Colitis vol:16 issue:6 pages:876-883 ispartof: location:England status: published

Background Intestinal ultrasound (IUS) is accurate and non-invasive to detect and monitor disease activity in Crohn’s disease (CD). The Bowel Ultrasound Score (BUSS= 0.75 × bowel wall thickness + 1.65 × presence (1) or absence (0) of bowel wall flow) demonstrated high accuracy in detecting therapy-related changes, and good correlation with the Simple Endoscopic Score for CD (SES-CD). The most accurate cutoff value for BUSS was 3.52 for endoscopic remission (SES-CD ≤ 2).This study aimed to prospectively evaluate ultrasound remission as a relevant treatment target. Methods Consecutive patients with active CD (SES-CD > 2) starting biologic treatments were included. Patients underwent colonoscopy and IUS at baseline and after 1 year of treatment. Clinical, biochemical and ultrasound assessments were additionaly performed at week 12. Primary outcome was to evaluate whether ultrasound remission at week 12 could predict endoscopic remission at week 54. Endoscopic remission was defined as SES-CD ≤ 2, ultrasound remission was defined by BUSS ≤ 3.52, clinical remission was defined by HBI (Harvey-Bradshaw Index) < 5, and biochemical remission was defined by normalization of C-reactive protein (< 5 mg/L) and fecal calprotectin (three different thresholds were assessed: < 250 µg/g, < 100 µg/g, < 50 µg/g). Results Ninety-three patients were included (8 under infliximab, 40 under adalimumab, 5 under vedolizumab and 40 under ustekinumab). Eighteen patients (19%) and 36 patients (39%) achieved endoscopic remission and ultrasound remission at week 54, respectively. CD patients with ultrasound remission at week 12 were more likely to achieve endoscopic remission (odds ratio [OR] 6.88 [2.14–22.04]; p = 0.001) and ultrasound remission (OR 4.26 [1.61–11.24]; p = 0.003) at week 54. Calprotectin value < 50 µg/g at week 12 predicted endoscopic remission at univariable (OR 3.14 [1.04–9.45]; p = 0.041), but not at multivariable analysis. No other clinical or biochemical variables at week 12 predicted endoscopic and/or ultrasound remission at week 54. Conclusion Ultrasound remission achieved at week 12 may predict long-term endoscopic remission and may be a strategic treatment target, both in clinical practice and in clinical trials.

Background Early flare prediction is essential for the timely management of Crohn’s disease (CD) patients, allowing to optimize the available therapeutic toolbox and to decrease the disease burden. We aimed to evaluate the performance of readily available biomarkers (when evaluated at least once or more frequently during follow-up) and to develop risk matrices to predict CD progression. Methods CD patients receiving infliximab (IFX) as maintenance therapy (n=289) were followed up for 24 months; those patients were enrolled in DIRECT, a prospective, multicenter real-world study. Disease progression was evaluated using two composite outcomes incorporating clinical and drug-related factors, the first including also IFX dose and/or frequency adjustments. Univariate and multivariable logistic regressions were used to calculate the odds ratios (OR) and to develop risk matrices. Results The isolated presence of anemia at least once during follow-up was a significant predictor of disease progression (OR 2.436 and 3.396 [p≤0.001] for composite outcomes 1 and 2, respectively), regardless of confounding factors. Levels of C-reactive protein (CRP) above 10.0 mg/L or fecal calprotectin (FC) above 500.0 µg/g, in at least one visit, were also significant predictors, while milder elevations (3.1-10.0 mg/L and 250.1-500.0 µg/g) were only relevant when found in at least two visits (consecutive or not). The risk matrices combining the different non-invasive biomarkers had a good ability to predict CD progression. Indeed, patients simultaneously presenting anemia, CRP>10 mg/dL and FC>500.0 µg/g at least once had a probability of disease progression that ranged between 42 and 63%. Conclusion The combined evaluation of FC, hemoglobin, and CRP in at least one time point and their incorporation into risk matrices seems to be the optimal strategy for CD management, as data from additional visits did not meaningfully influence the predictions and may delay decision-making. This is one of the first studies developing risk matrices to predict the occurrence of composite outcomes in CD patients, providing an easily applicable tool for CD clinical management.

Background Treatment choices for patients with inflammatory bowel disease (IBD) are based on the balance between risks and benefits. To date, there are no globally accepted methods for assessing the risk-benefit ratio. Our aim was to compare the perspectives of patients and physicians in evaluating the risks and benefits before initiating therapy for IBD. Methods An anonymous survey was conducted between March and August 2022. Multiple choice questions, similar for physicians and patients, were formulated. The questionnaire was developed in English and was later translated in Italian and French by native speakers. All patients with a confirmed diagnosis of IBD who were followed up at the IRCCS San Raffaele Hospital (Italy), Nancy University Hospital (France), and University Hospital CHU of Liège (Belgium) were invited to participate. All physicians who attended an IBDscope webinar were invited to participate by email. Results In total, 367 patients and 146 physicians participated in the survey from 34 countries worldwide (Tables 1 and 2). For most patients (71.4%) and physicians (89.0%), efficacy and safety were equally important in choosing a therapy. Clinical improvement and clinical remission were the most relevant outcomes for patients (90.9 and 88.4 Likert scales), while clinical remission and endoscopic remission were for physicians (90.0 and 87.6 Likert scales). The main factors in the benefit-risk assessment for patients were quality of life (95.1%), disease activity (87.5%), and presence of comorbidities (84.5%). The main factors for physicians were presence of comorbidities (99.3%), disease activity (97.9%), prior failure to biologics or small molecules (96.6%). Disease duration, family history of IBD, administration interval, therapy duration, and administration route had a limited role for both physicians and patients. Based on patients' and physicians’ opinions, the risk of serious infections (90.5% and 98.6%), malignancies (90.5% and 100.0%), cardiovascular events (88.8% and 98.6%), death (86.4% and 91.8%), relapse (86.1% and 94.5%), all infections (86.1% and 100.0%), surgery (83.1% and 93.1%), and hospitalization (76.6% and 88.4%) should be included in the benefit-risk assessment. The risk percentages considered acceptable by patients and physicians are reported in Figures 1 and 2. Infliximab was the most effective drug for physicians in inducing and maintaining disease remission in both Crohn’s disease and ulcerative colitis, while ustekinumab and vedolizumab were equally considered the safest drugs. Conclusion Physicians and patients have different priorities in evaluating the benefit-risk balance of a new therapy. Treatment decisions should be discussed and shared with patients.

Background Crohn’s disease (CD) is a chronic, immune-mediated inflammatory condition of the intestine, for which the majority of patients still needs to undergo surgical resection. Following the most common intervention ileocolonic resection, the vast majority of patients suffers from recurrence of CD in the neoterminal ileum. Endoscopic lesions usually precede symptoms in the first months after resection and predict the severity of the further disease course. No treatments have been approved for recurrence-prevention of CD. REPREVIO is a prospective placebo-controlled randomized trial investigating the preventive effect of vedolizumab, an anti-integrin antibody, on recurrence of CD. Methods Following ileocolonic resection, patients were treated with vedolizumab (300 mg IV at week 0,8,16 and 24) or PLC (1:1) at 12 sites in the Netherlands, France, Italy and Spain. Treatment was initiated within 4 weeks following ileocolonic resection with anastomosis. Six months following surgery, patients underwent ileocolonoscopy for assessment of recurrent lesions. Video recordings were centrally scored using the modified Rutgeerts’ score by 2 readers with adjudication in case of disagreement. The primary endpoint was endoscopic recurrence (ER) of CD (non-parametric); secondary endpoints were the proportion of patients with ER >i2a and clinical recurrence. Adverse events were recorded. Results 95 pts were screened and 80 randomized. All patients have reached month 6 and the videos are being analysed. We will receive the results of all statistical analysis in December, 2022. Conclusion The efficacy of vedolizumab postoperative recurrence-prevention treatment was studied in the REPREVIO study.

Background Breast cancer is the most common malignancy observed in patients with inflammatory bowel diseases (IBD) unrelated to the disease or its treatment (Poullenot F et al. JCC 2022). The main aim of our study was to assess the risk of incident cancer according to the IBD treatment given in patients with prior breast cancer. Methods Consecutive IBD patients with prior breast cancer diagnosis were included in a multicenter retrospective cohort from 25 tertiary centres. Inclusion date corresponded to the diagnosis of index cancer. Follow up was calculated from the first administration of immunomodulator after cancer diagnosis (or cancer diagnosis date in absence of treatment) to the occurrence of incident cancer, corresponding to recurrence of breast cancer or de novo cancer, or to the last follow-up visit. Patients were categorized according to the use or not of immunomodulator after cancer diagnosis: thiopurines, methotrexate, anti-TNF, vedolizumab, ustekinumab. Crude incidence rates were compared between patients receiving at least one immunomodulator and those without immunomodulator before and after matching on age, lymph node, and metastasis extension and tumor’s grade, using a propensity-score analysis with a 1:1 ratio. Results Among the 151 identified patients, 80 patients with full available data were analyzed: 76 (95%) women; mean age at index cancer diagnosis: 51.5 years [standard deviation (SD): 11.5 years]; 44 (55%) with Crohn’s disease, 35 (44 %) ulcerative colitis and 1 (1 %) indeterminate colitis; median IBD duration at inclusion was 13 years [interquartile range (IQR) 6-21]. After a median follow up of 84 months [IQR 49-154], 16 (20%) incident cancers were observed: 12 (15%) recurrences and 4 (5%) cancer de novo. Three (4%) patients died from cancer related cause during the follow up. 39 (49%) patients received no immunomodulator and, 11 (14%) were treated with thiopurines, 6 (7.5%) with methotrexate, 18 (22.5%) with anti-TNF, 5 (6%) with vedolizumab and one (1%) with ustekinumab. Those treatments were initiated with a median interval of 24 months [IQR 7-48] after cancer diagnosis. Crude incidence rate per 1000 person-years were 47.97 for patients not exposed to any immunomodulator and 12.61 for the others (p=0.0248). After matching, adjusted crude incidence rates per 1000 person-years were 50 and 27.27, respectively (p=0.3798). Rates of survival without incident cancer were not different between the two groups after matching on age, lymph node, metastasis extension, and tumor’s grade (p=0.17) (Figure 1). Conclusion In the present multicenter retrospective cohort, incident cancer risk among patient with IBD and prior breast cancer was not increased in patients subsequently exposed to immunomodulators.

Background Responses to ulcerative colitis (UC) treatments vary considerably between individuals, and factors associated with a stable response are not well defined. Filgotinib (FIL) is an oral, Janus kinase 1 preferential inhibitor approved in the EU and the UK as a UC therapy. We aimed to identify factors associated with partial Mayo Clinic Score (pMCS) over time in FIL-treated patients with UC in the phase 2b/3 SELECTION trial (NCT02914522). Methods In SELECTION, adults with moderately to severely active UC received FIL 200 mg (FIL200), FIL 100 mg (FIL100) or placebo once daily for 11 weeks in Induction (IND) Study A (biologic-naive) or B (biologic-experienced).1 Patients in clinical remission or with a Mayo Clinic Score (MCS) response at week 10 could enter the 47-week Maintenance (MNT) Study. To evaluate factors associated with pMCS during MNT this post hoc analysis used a mixed model for repeated measures (MMRM), which included fixed effects of time, IND dose (FIL200 or FIL100), the factor of interest and pMCS at IND baseline, and correlated patient residual errors. For categorical factors, the least-squares mean difference with 95% confidence interval (CI) and the overall type III p value were calculated. For continuous factors, the difference in pMCS for a one-unit change in the factor of interest was estimated with 95% CI. Multiplicity adjustment of p values was not performed. Results Data from 371 patients treated with FIL200 (n=199) or FIL100 (n=172) were included. Previous use of at least one biologic therapy or a tumour necrosis factor antagonist/vedolizumab, and week 10 MCS subscores of ≤1 were associated with higher pMCS over time than their respective reference categories (p170 were associated with lower pMCS over time than their respective reference categories (p≤0.0001). Change from baseline in pMCS at week 10 and faecal calprotectin levels at week 10 were positively associated with pMCS over time (p Conclusion History of previous biologic therapy, and week 10 assessments (endoscopic, clinical, biomarker and PRO) were among the factors influencing pMCS over the course of 1 year of FIL treatment, consistent with previous findings from trajectory modeling.2 Further MMRM analyses may help to identify patients who benefit most from FIL treatment. 1. Feagan BG et al. Lancet 2021;397:2372–84. 2. Schreiber S et al. MP443 [abstract]. UEGJ 2022;10:459.

Background and Aims Optimal management of patients with inflammatory bowel disease [IBD] after anti-tumour necrosis factor [TNF] discontinuation due to severe induced skin lesions is unclear. Our study aimed to describe dermatological and IBD evolution after anti-TNF discontinuation for this side effect. Methods We conducted a multicentre retrospective study including consecutive IBD patients who discontinued anti-TNF due to severe induced skin lesions. Our objectives were to determine factors associated with dermatological remission [complete disappearance of skin lesions] and with IBD relapse in patients with inactive disease at inclusion, notably the impact of an early switch to another biological agent within 3 months of anti-TNF discontinuation. Results Among the 181 patients [134 women, 160 Crohn’s disease] included in the 13 participating centres, dermatological remission occurred in 110 [62%] patients with a median [interquartile range, IQR] interval of 8.0 [6.8–11.0] months. Scalp location was independently associated with less remission of skin lesions (hazard ratio [HR] = 0.64 [95% CI 0.43–0.94], p = 0.02) while early switch was independently associated with a higher probability of remission of skin lesions (HR = 1.64 [95% CI 1.1–2.5], p = 0.02). Among the 148 patients with inactive IBD at inclusion, disease relapse occurred in 75 [51%] patients with a median [IQR] interval of 26.0 [23.0–39.1] months. Survival rates without IBD relapse at 1 year were 85.8% [95% CI 77.5–94.9] in the early switch group and 59.3% [95% CI 48.9–71.9] in the other group [p Conclusions Early switch to a new biological is associated with a higher probability of healing of anti-TNF-induced skin lesions and significantly reduces the risk of IBD relapse.

Background Patients with ulcerative colitis (UC) often do not respond to treatment or lose response over time, and thus switch between therapies with various mechanisms of action (MoAs).1 Filgotinib (FIL) is a once-daily, oral, Janus kinase 1 preferential inhibitor in development as a UC treatment. We assessed the efficacy of FIL in biologic (bio)-naïve and bio-experienced patients with UC, and in bio-experienced patients with failure of 1 or ≥2 biologics or 1 or 2 MoAs. Methods SELECTION (NCT02914522) was a phase 2b/3 double-blind, randomised, placebo-controlled trial comprising two induction studies and a maintenance study. Adults (18–75 years) with moderately to severely active UC were randomised 2:2:1 to FIL 200 mg, FIL 100 mg or placebo (PBO) once daily for 11 weeks in Induction Study A (bio-naïve) and B (bio-experienced). Patients in either clinical remission or Mayo Clinic Score (MCS) response at week 10 (responders) could enter the Maintenance Study. Responders who received induction FIL were re-randomised 2:1 to continue their induction regimen or PBO through week 58. Responders who received induction PBO continued PBO. We assessed clinical remission and MCS response at weeks 10 and 58 in bio-naïve patients and bio-experienced patients with failure of 1 or ≥2 biologics and 1 or 2 MoAs (TNF antagonists and vedolizumab). All p values for subgroup analyses are nominal. Results At week 10, clinical remission was achieved by a significantly higher proportion of bio-naïve and -experienced patients treated with FIL 200 mg than PBO (Figure 1a). A higher proportion of bio-experienced patients with 1 biologic or MoA failure treated with FIL 200 mg than PBO achieved clinical remission at week 10 (p Conclusion FIL 200 mg was effective in inducing and maintaining clinical remission in bio-naïve and -experienced patients. Induction results suggest FIL 200 mg is most effective in bio-naïve patients, and those who switch after failure of 1 biologic or MoA. Interpretation of week 58 data is limited by low patient numbers. Reference

Background Ustekinumab (UST) is an IL-12/23p40 antagonist used to treat pts with moderate-to-severe ulcerative colitis (UC). The ongoing UNIFI long-term extension (LTE) evaluates subcutaneous (SC) 90mg UST maintenance therapy, with efficacy (wk152) and safety (wk156) results reported here. Methods 523 intravenous UST induction responders were randomized to SC maintenance therapy (175 SC placebo [PBO]; 172 UST 90mg every 12 weeks [q12w]; 176 UST 90mg q8w). 284 UST pts who completed wk44 entered the LTE. PBO pts were discontinued after wk44 unblinding. Starting at wk56, randomized pts with UC worsening could adjust to q8w. Symptomatic remission (Mayo stool frequency subscore of 0 or 1 and a rectal bleeding subscore of 0) was evaluated in randomized pts. Safety was evaluated for all 588 pts treated in the LTE, including the randomized and nonrandomized populations; 188 received PBO and 457 received UST. The nonrandomized population included responders to PBO induction and UST induction nonresponders at wk8 who received SC UST, responded 8 wks later and received UST 90mg q8w. Results Among all pts randomized to UST at maintenance baseline (intent-to-treat population with nonresponder imputation for missing data and treatment failure criteria), 55.2% were in symptomatic remission at wk152 (biologic naïve, 66.1%; biologic failures, 43.5%; Table 1); 96.4% (185/192) of pts in symptomatic remission at wk152 were corticosteroid-free. Overall, 20.1% (39/149 biologic failure, 16/149 biologic naïve) of pts who were randomized to UST and treated in the LTE discontinued treatment between wks44 and 156. Among randomized pts treated with UST in the LTE, 67.6% were in symptomatic remission at wk152; 76.4% of those in clinical remission at wk44 were in symptomatic remission at wk152; and 84.1% of pts with observed data at wk152 were in symptomatic remission. From maintenance wk0-156, combined UST and PBO pts had 1281.6 and 425.0 pt-years of follow-up, respectively; and safety events per 100 pt-years of follow-up for combined UST vs PBO were AEs: 235.81 vs 204.48, SAEs: 7.73 vs 7.53, and serious infections: 2.34 vs 2.35 (Table 2). From wks96-156, there were no reported deaths or major adverse cardiovascular events. One UST-treated pt with fair skin and a prior history of basal cell carcinoma (BCC) reported 2 BCC. One 90 mg q8w UST pt receiving concomitant 6-MP reported SAEs of neutropenic sepsis and oral herpes SAE; the latter events were considered potential opportunistic infections. The dose of 6-MP was reduced, pt recovered and continued UST. Conclusion The efficacy of UST in pts with UC was sustained through 3 years. No new safety signals were observed.

Background Risankizumab (RZB), an IL-23 inhibitor, is being investigated for Crohn’s disease (CD). MOTIVATE (NCT03105128) and ADVANCE (NCT03104413) were two double-blind, randomised, placebo (PBO)-controlled phase 3 trials evaluating the efficacy and safety of RZB as induction therapy for CD after inadequate response or intolerance to biologic treatment, or conventional or biologic treatment. We investigated the effect of RZB on patient-reported outcomes (PROs) in these two trials. Methods Patients with moderately to severely active CD (CD activity index of 220–450, Simple Endoscopic Score for CD excluding the narrowing component ≥ 6 or ≥ 4 for isolated ileal disease, and average daily stool frequency ≥ 4 and/or average daily abdominal pain score ≥ 2) were randomised 1:1:1 (MOTIVATE; N=569) or 2:2:1 (ADVANCE; N=850) to intravenous RZB 600 mg, RZB 1200 mg or PBO at Weeks 0, 4 and 8. PROs assessed were Inflammatory Bowel Disease Questionnaire (IBDQ), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and 36-Item Short Form Health Survey (SF 36). Least-squares mean change from baseline to Week 4 and 12 were assessed for each PRO. Additionally, the proportion of patients achieving IBDQ remission (IBDQ total score ≥ 170 points) was evaluated. Comparisons between RZB dosage groups and PBO were based on Cochran-Mantel-Haenszel or chi-square/Fisher’s exact tests; missing data were reported using non-responder imputation. Results In the MOTIVATE (100% biologic inadequate responder [bio-IR]) and ADVANCE (57% bio-IR) trials, significant (P Conclusion Patients with active CD and an inadequate response to conventional or biologic treatment who received RZB (600 mg or 1200 mg) induction therapy reported significant improvements in disease-specific (IBDQ) and general health-related PROs (FACIT and SF-36) compared with PBO, with improvements seen as early as Week 4. Funding statement: Study was funded by AbbVie. Acknowledgement: Medical writing support was provided by Joann Hettasch of Fishawack Facilitate Ltd, and was funded by AbbVie.