Efficacy and Safety of Etrasimod in Patients with Moderately to Severely Active Isolated Proctitis: Results From the Phase 3 ELEVATE UC Clinical Programme.

BACKGROUND AND AIMS: Pivotal trials in ulcerative colitis have historically excluded patients with isolated proctitis. Etrasimod is an oral, oncedaily, selective sphingosine 1phosphate1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis. This post hoc analysis assessed efficacy and safety of etrasimod 2 mg once daily in patients with isolated proctitis (centrally read) from the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials. METHODS: Patients, including those with isolated proctitis (<10 cm rectal involvement) who met all other inclusion criteria in ELEVATE UC 52 and ELEVATE UC 12, were randomised 2:1 to receive etrasimod or placebo. Primary, secondary and other identified efficacy endpoints and safety were assessed. RESULTS: We analysed data from 64 and 723 patients at Week 12 (both trials pooled), and 36 and 397 patients at Week 52 (ELEVATE UC 52 only) with isolated proctitis and more extensive colitis (≥10 cm rectal involvement), respectively. Patients with isolated proctitis receiving etrasimod demonstrated significant improvements versus placebo, including clinical remission rates at Weeks 12 (42.9% vs 13.6%) and 52 (44.4% vs 11.1%), endoscopic improvement (52.4% vs 22.7%) at Week 12 and bowel urgency numerical rating scale score at Week 12 (all p<0.01). Generally similar trends were observed in patients with more extensive colitis. Safety was consistent across subgroups, with no new findings. CONCLUSIONS: Etrasimod demonstrated significant improvements versus placebo in patients with isolated proctitis, and those with more extensive disease, in most efficacy endpoints at Week 12 and 52.

Comparing the efficacy of vedolizumab between males and females: a post-hoc analysis of GEMINI-1 and VARSITY.

Vedolizumab is a first-line treatment option for ulcerative colitis. There are differences in incidence of ulcerative colitis between males and females, but whether sex affects treatment outcomes is less clear. We examined sex-based differences in patients with ulcerative colitis initiated on vedolizumab from two major randomized controlled trials (RCTs). We conducted a post-hoc analysis on participants with ulcerative colitis from the VARSITY and GEMINI-1 RCTs who received vedolizumab. Outcomes of interest were rates of clinical improvement, clinical remission, and endoscopic improvement at weeks 6, 14, and 52 in male and female participants, as were differences in concentrations of trough vedolizumab and C-reactive protein; 1009 persons in GEMINI-1 and VARSITY trials were included. Male and female patients had similar disease characteristics aside from males being more likely to have Mayo 3 grade endoscopic severity at baseline (62.8 vs. 48.9%, P  < 0.001). At week 6, females were more likely to have endoscopic improvement (47.4 vs. 35.2%, P  = 0.001) and increased vedolizumab trough levels [34.0 (23.0-44.5) vs. 28.9 (19.0-34.6), P  < 0.001]. The probability of achieving clinical remission (28.9 vs. 34.5%, P  = 0.057) or endoscopic improvement (35.5 vs. 39.3%, P  = 0.212) at week 52 was not different between males and females. Females with ulcerative colitis treated with vedolizumab appear more likely to achieve early endoscopic improvement than males, though longer-term outcomes demonstrated no difference. Further studies are required to better understand mechanisms through which sex or sex-associated factors could influence response to therapy in ulcerative colitis.

Comparative efficacy and safety of subcutaneous infliximab and vedolizumab in patients with Crohn's disease and ulcerative colitis included in randomised controlled trials.

BACKGROUND: While indirect comparison of infliximab (IFX) and vedolizumab (VDZ) in adults with Crohn's disease (CD) or ulcerative colitis (UC) shows that IFX has better effectiveness during induction, and comparable efficacy during maintenance treatment, comparative data specific to subcutaneous (SC) IFX (i.e., CT-P13 SC) versus VDZ are limited. AIM: Pooled analysis of randomised studies to compare efficacy and safety with IFX SC and VDZ in moderate-to-severe inflammatory bowel disease. METHODS: Parallel-group, randomised studies evaluating IFX SC and VDZ in patients with moderate-to-severe CD or UC were identified. Eligible studies reported ≥ 1 prespecified outcome of interest at Week 6 (reflecting treatment during the induction phase) and/or at 1 year (Weeks 50-54; reflecting treatment during the maintenance phase). Prespecified efficacy and safety outcomes considered in this pooled analysis included the proportions of patients achieving disease-specific clinical responses, clinical remission, or discontinuing due to lack of efficacy, and the proportions of patients experiencing adverse events (AEs), serious AEs, infections, serious infections, or discontinuing due to AEs. Data from multiple studies or study arms were extracted and pooled using a random-effect model; comparative analyses were performed separately for patients with CD and UC. RESULTS: We identified three eligible CD trials and four eligible UC trials that assigned over 1200 participants per disease cohort to either IFX SC or VDZ. In patients with CD, intravenous induction therapy with IFX demonstrated better efficacy (non-overlapping 95% confidence intervals [CIs]) compared with VDZ; during the maintenance phase, IFX SC showed numerically better efficacy (overlapping 95% CIs) than VDZ. A lower proportion of IFX SC-treated patients discontinued therapy due to lack of efficacy over 1 year. In patients with UC, efficacy profiles were similar with IFX SC and VDZ during the induction and maintenance phases, and a lower proportion of IFX SC-treated patients discontinued therapy due to lack of efficacy over 1 year. In both cohorts, safety profiles for IFX SC and VDZ were generally comparable during 1 year. CONCLUSION: IFX SC demonstrated better efficacy than VDZ in patients with CD, and similar efficacy to VDZ in patients with UC; 1-year safety was comparable with IFX SC and VDZ.

Defining Endoscopic Remission in Crohn's Disease: MM-SES-CD and SES-CD Thresholds Associated With Low Risk of Disease Progression.

BACKGROUND & AIMS: We assessed Modified Multiplier Simple Endoscopic Score for Crohn's Disease (MM-SES-CD) and Simple Endoscopic Score for Crohn's Disease (SES-CD) thresholds that are best associated with low likelihood of long-term disease progression. METHODS: Data from 61 patients with early Crohn's disease (CD) who participated in the CALM long-term extension study were used as the derivation cohort and validated using the McMaster inflammatory bowel disease database (n = 99). The primary outcome was disease progression (new internal fistula/abscess, stricture, perianal fistula or abscess, CD-related hospitalization or surgery) since the end of the CALM trial. Optimal MM-SES-CD and SES-CD thresholds were determined using the maximum Youden index. Receiver operating characteristic curve analyses compared threshold scores of remission definitions on disease progression. RESULTS: In the derivation cohort, based on the maximum Youden index, the optimal thresholds associated with a low likelihood of disease progression were MM-SES-CD <22.5 and SES-CD <4. A significantly greater proportion of patients with a MM-SES-CD ≥22.5 had disease progression as compared with patients in the derivation cohort with MM-SES-CD <22.5 (10/17 [58.8%] vs 3/44 [6.8%]; P < .001). Similarly, a significantly greater number of patients with SES-CD ≥ 4 had disease progression compared with those with a SES-CD <4 (11/25 [44.0%] vs 2/36 [5.6%]; P < .001). Compared with other clinical or endoscopic remission definitions, which demonstrated poor to fair accuracy, MM-SES-CD <22.5 performed the best for predicting disease progression (area under the curve = 0.81; 95% confidence interval, 0.68-0.94; P < .001). These thresholds were confirmed in the validation cohort. CONCLUSION: Achievement of MM-SES-CD <22.5 or SES-CD <4 in patients with ileocolonic or colonic CD is associated with low risk of disease progression and may be suitable targets in clinical trials and practice for endoscopic healing.

Association Between Smoking Status and the Efficacy and Safety of Tofacitinib in Patients with Ulcerative Colitis.

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). This analysis assessed the impact of cigarette smoking on tofacitinib efficacy and safety in the UC clinical program. Methods: Efficacy endpoints and adverse events (AEs) were evaluated by smoking status (ever smokers [current and ex-smokers] and never smokers) in the phase (P)2 induction study (baseline demographics and safety only), P3 studies (OCTAVE Induction 1&2, OCTAVE Sustain, OCTAVE Open), and P3/4b RIVETING study. Results: This post hoc analysis included 1156 patients (ever smokers, n = 416 [36.0%; current smokers, n = 59 (5.1%); ex-smokers, n = 357 (30.9%)]; never smokers, n = 740 [64.0%]; median [range] treatment duration 654 [1-2712] and 615.5 [1-2850] days, respectively). Similar proportions of ever smokers and never smokers achieved efficacy endpoints. AEs were reported in 88.7% of ever smokers and 83.8% of never smokers. Overall, 60.6% of ever smokers had an infection (serious infections, 5.5%; herpes zoster [nonserious and serious], 10.8%; Clostridioides difficile infection, 12.0%; lower respiratory tract infection, 19.5%: corresponding values among never smokers were 53.1%, 3.9%, 6.8%, 8.5%, and 11.4%). Major adverse cardiovascular events were reported in 1.0% of ever smokers and 0.7% of never smokers and thromboembolism events (venous and arterial) in 1.0% of ever smokers and 0.9% never smokers. Deaths, malignancies (excluding non-melanoma skin cancer [NMSC]), and NMSC occurred infrequently in ever smokers (0.5%, 2.5%, and 3.7%, respectively) and never smokers (0.1%, 1.5%, and 1.0%, respectively). Colorectal cancer was reported in 0.6% of never smokers; no cases occurred in ever smokers. Conclusions: Efficacy and safety of tofacitinib were generally similar in ever smokers and never smokers. Overall, serious AEs and, as expected, infections were more frequent in ever smokers versus never smokers. This may inform treatment selection and monitoring strategies. ClinicalTrialsgov: NCT00787202;NCT01465763;NCT01458951;NCT01458574;NCT01470612;NCT03281304.

Switching from intravenous to subcutaneous infliximab maintenance therapy in inflammatory bowel disease: Post hoc longitudinal analysis of a randomized trial.

BACKGROUND: Pharmacokinetic non-inferiority of subcutaneous (SC) to intravenous (IV) CT-P13 maintenance therapy was demonstrated in a randomized trial (NCT02883452). This post hoc analysis evaluated longitudinal clinical outcomes with the two infliximab treatment strategies. METHODS: Patients with Crohn's disease or ulcerative colitis received CT­P13 IV loading doses (5 mg/kg; Week [W] 0 and W2) before randomization (1:1) to receive CT-P13 SC (body weight-based dosing every 2 weeks [Q2W]; W6-54; 'SC maintenance group') or CT­P13 IV (5 mg/kg Q8W; W6-22) then CT-P13 SC (Q2W; W30-54; 'IV-to-SC switch group'). Paired W30/W54 patient-level data were analyzed. RESULTS: Fifty-three (IV-to-SC switch) and fifty-nine (SC maintenance) patients were analyzed. Median trough serum CT-P13 concentrations were significantly higher at W54 versus W30 in the IV-to-SC switch group (20.4 versus 2.3 µg/mL; p < 0.00001), while remaining consistent in the SC maintenance group. Statistically significant improvements in pharmacokinetics, efficacy, fecal calprotectin levels, and quality of life were seen following switch to SC administration at W30 in the IV-to-SC switch group; safety findings were similar pre- and post-switch. CONCLUSION: Formulation switching from IV to SC infliximab maintenance therapy was well tolerated and may provide additional clinical improvements. Findings require confirmation in larger prospective studies.

Efficacy and Safety of Filgotinib for the Treatment of Perianal Fistulizing Crohn's Disease [DIVERGENCE 2]: a Phase 2, Randomized, Placebo-Controlled Trial.

BACKGROUND AND AIMS: There is an unmet need for the treatment of perianal fistulizing Crohn's disease [PFCD]. This study evaluated the efficacy and safety of the Janus kinase 1 preferential inhibitor filgotinib, for the treatment of PFCD. METHODS: This phase 2, double-blind, multicentre trial enrolled adults with PFCD and prior treatment failure. Participants were randomized [2:2:1] to receive filgotinib 200 mg, filgotinib 100 mg, or placebo once-daily orally for up to 24 weeks. The primary endpoint was combined fistula response [reduction from baseline of at least one draining external opening determined by physical assessment, and no fluid collections >1 cm on pelvic magnetic resonance imaging (MRI)] at week 24. RESULTS: Between April 2017 and July 2020, 106 individuals were screened and 57 were randomized. Discontinuations were lowest in the filgotinib 200 mg group [3/17 (17.6%) versus 13/25 (52.0%) for filgotinib 100 mg and 9/15 (60.0%) for placebo]. The proportion of participants who achieved a combined fistula response at week 24 was 47.1% [8/17; 90% confidence interval (CI) 26.0, 68.9%] in the filgotinib 200 mg group, 29.2% [7/24; 90% CI 14.6, 47.9%] in the filgotinib 100 mg group, and 25.0% [3/12; 90% CI 7.2, 52.7%] in the placebo group. Serious adverse events occurred more frequently with filgotinib 200 mg [5/17 (29.4%)] than with placebo [1/15 (6.7%)]. There were no treatment-related serious adverse events or deaths. CONCLUSIONS: Filgotinib 200 mg was associated with numerical reductions in the number of draining perianal fistulas based on combined clinical and MRI findings compared with placebo, and was generally well tolerated. [NCT03077412].

Treatment persistence and switching patterns of ABP 501 in European patients with inflammatory bowel disease.

Background: Approval of the adalimumab (ADA) biosimilar ABP 501 for inflammatory bowel disease (IBD) indications was based on the principle of extrapolation, without indication-specific clinical trial data. Objectives: To evaluate the real-world treatment patterns of ABP 501 in patients with IBD. Design: Retrospective analysis of pharmacy claims data from Germany and France. Methods: Continuously insured adult IBD patients who initiated ABP 501 between October 2018 and March 2020 were included. Treatment persistence, adherence, and post-ABP 501 switching patterns were evaluated for two mutually exclusive groups: ADA-naïve patients (i.e. no baseline use of ADA products) and ADA-experienced patients (i.e. previously treated with ADA products). Results: A total of 3362 German patients and 733 French patients were included, with 54.4% and 65.3% being ADA-naïve patients, respectively. Median persistence (95% CI) on ABP 501 was 10.9 months (9.8-11.6) in ADA-naïve patients and 14.2 months (12.7-15.2) in ADA-experienced patients in Germany; for the French cohort, ADA-naïve and -experienced patients had median persistence of 12.8 months (10.2-14.7) and 11.5 months (8.8-14.4), respectively. During the first 12 months of ABP 501 initiation, 53.7% of German patients and 51.0% of French patients were adherent to the therapy. About 20% of patients in both countries switched from ABP 501 to another targeted therapy. In the German cohort, ADA-naïve patients most frequently switched to non-tumor necrosis factor inhibitor biologics, but ADA-experienced patients most commonly switched to reference product (RP); in the French cohort, patients most often switched to RP regardless of prior exposure to ADA products. Conclusion: About 50% of patients persisted on and were adherent to ABP 501 therapy during the first 12 months after treatment initiation in two large European countries. Post-ABP 501, switching patterns varied between countries, indicating diversified treatment practices warranting further research on reason(s) for switching and potential overall treatment outcomes.

Delayed Ustekinumab and Adalimumab Responders Have Similar Outcomes as Early Responders in Biologic-Naïve Crohn's Disease.

INTRODUCTION: Differences in 1-year outcomes among early and delayed responders have been demonstrated with some therapies in ulcerative colitis. However, it is unclear whether similar differences exist in patients with Crohn's disease (CD) treated with biologic therapies. METHODS: This was a post hoc analysis of patient-level data from the SEAVUE clinical trial program. Ustekinumab-treated and adalimumab-treated patients with clinical response at week 8, defined as a reduction in Crohn's Disease Activity Index (CDAI) score of at least 100 points from baseline or CDAI score <150, were deemed early responders and their outcomes were compared with delayed responders (week 8 nonresponders who subsequently responded at week 16) and nonresponders (no response at week 8 or 16). The primary outcome assessed was clinical remission at week 56, defined as CDAI <150. RESULTS: A total of 373 participants (187 treated with ustekinumab and 186 treated with adalimumab) were included in this analysis. The overall rate of delayed clinical response was low in the SEAVUE clinical trial program (13.1%). No differences were observed for week 56 clinical remission among early vs delayed responders to ustekinumab or adalimumab nor were there significant differences for secondary outcomes assessed. Delayed responders to ustekinumab and adalimumab had a significant decline in C-reactive protein by week 8 when compared with nonresponders. DISCUSSION: Among patients with moderate-to-severe CD, early and delayed responders to adalimumab and ustekinumab have similar 1-year clinical outcomes. Biomarker decline can be observed through the initial 8 weeks of therapy in patients who will eventually be delayed responders, which may help differentiate from nonresponders.

Predicting Endoscopic Improvement in Ulcerative Colitis Using the Ulcerative Colitis Severity Index.

INTRODUCTION: We developed and internally validated a prognostic scoring index for ulcerative colitis (UC) patients that includes baseline patient-reported outcomes (PROs), biomarkers, endoscopy, and histology for achieving 1-year endoscopic improvement (EI). METHODS: This post hoc analysis included 644 patients treated with ustekinumab induction therapy. Data were randomly split to obtain a 70% training and 30% testing cohort. Multivariate analyses assessed baseline variables and those with P < .05 were assigned weights based on their relative prognostic value from logistic regression modeling for predicting 1-year EI (Mayo endoscopic score ≤1). A cutoff was obtained by calculating the maximum Youden index and validated in the testing cohort. RESULTS: Prior biologic failure, albumin <40 g/L, C-reactive protein >5 mg/L, Mayo stool frequency subscore, endoscopic erosions/ulcerations, and chronic histologic structural/architectural changes demonstrated significant associations with 1-year EI and were included in the final model. The Ulcerative Colitis Severity Index (UCSI) had acceptable discriminative ability for 1-year EI in the training (area under the curve [AUC], 0.78; 95% confidence interval, 0.70-0.86) and testing cohort (AUC, 0.76; 95% CI, 0.68-0.85). Compared with the UCSI, the Mayo Clinic score demonstrated poor accuracy (AUC, 0.49; 95% CI, 0.40-0.58) for predicting 1-year EI (P = .0006). The UCSI predicted 1-year endoscopic healing (Mayo endoscopic score = 0), clinical remission (total Mayo Clinic score ≤2 and no subscore >1), partial Mayo score remission <2, and 2-item Patient-Reported Outcome score (Mayo stool frequency and rectal bleeding subscore = 0) with significantly greater accuracy compared with the Mayo Clinic score. DISCUSSION: The UCSI is an internally validated prognostic scoring tool that accurately predicts 1-year EI at baseline among moderate-to-severe UC patients initiating therapy. Further validation with additional datasets is needed.

Modified-Release Phosphatidylcholine (LT-02) for Ulcerative Colitis: Two Double-Blind, Randomized, Placebo-Controlled Trials.

BACKGROUND & AIMS: The aim of this study was to evaluate the efficacy of LT-02, a novel modified-release phosphatidylcholine (PC) formulation, for induction and maintenance of remission in patients with mild to moderate ulcerative colitis (UC) and inadequate response to mesalamine. METHODS: LT-02 was evaluated in a multicenter double-blind, randomized, placebo-controlled study comprising a 12-week induction trial (PCG-2), followed by a 48-week maintenance trial (PCG-4). In PCG-2, patients were randomized 1:1:1 to treatment with 0.8 g LT-02 4 times daily (QID), 1.6 g LT-02 twice daily (BID), or placebo, respectively. All patients continued to take a standard dose of oral mesalamine (≥2.4 g/day). The primary end point in PCG-2 was deep remission. Patients achieving remission at week 12 were randomly assigned 2:1:1 to 1.6 g LT-02 BID, placebo, or 500 mg mesalamine (3 times daily), respectively, in PCG-4; the primary end point was remission at 48 weeks. RESULTS: PCG-2 was terminated early for futility after a prespecified interim analysis; 466 patients (of 762 planned) were randomized. There was no statistically significant difference in deep remission at week 12 (placebo, 13.5%; LT-02 BID, 14.2%; LT-02 QID, 9.7%). In PCG-4, 150 patients (of approximately 400 planned) were randomized. There was no statistically significant difference in remission rates at week 48 (LT-02 BID, 49.3%; mesalamine, 50.0%; placebo, 43.2%). LT-02 was safe. CONCLUSIONS: Despite prior evidence of beneficial effects of PC in phase 2 trials, our induction study with LT-02 in patients with mild to moderate UC was terminated prematurely for futility. Signals of efficacy in maintenance therapy require confirmation in an adequately powered maintenance trial. LT-02 was safe and well-tolerated. CLINICALTRIALS: gov: NCT02280629, NCT02142725.

Washout Periods in Inflammatory Bowel Disease Trials: A Systematic Literature Review and Proposed Solutions.

Inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD), impose a substantial burden. Despite many effective molecules, significant numbers of patients do not achieve clinical remission at 1 year1 and undergo surgery during their lives, revealing an important unmet need and therapeutic gap. Multiple randomized controlled trials (RCTs) are ongoing or planned to develop more effective and tolerable therapies. In parallel, a dramatic decline in recruitment rates has been observed. A multitude of factors have contributed to poor recruitment rates, including a long washout period between the investigational drug and prior advanced therapies (ie, biologic or small molecule drug).2,3 This study aims to review the different washout periods with prior advanced therapies or immunosuppressants in phase 3 RCTs for UC and CD and to propose potential solutions to ultimately improve the design of clinical studies and patient enrollment in future trials.

Prediction of Response to Systemic Corticosteroids in Active UC by Microbial Composition-A Prospective Multicenter Study.

BACKGROUND: Corticosteroids are used for induction of remission in patients with moderately to severely active ulcerative colitis. However, up to one-third of patients fail to this therapy. We investigated if fecal microbial composition or its metabolic capacity are associated with response to systemic corticosteroids. METHODS: In this prospective, multicenter study, patients with active ulcerative colitis (Lichtiger score ≥4) receiving systemic corticosteroids were eligible. Data were assessed and fecal samples collected before and after 4 weeks of treatment. Patients were divided into responders (decrease of Lichtiger Score ≥50%) and nonresponders. The fecal microbiome was assessed by the 16S rRNA gene marker and analyzed with QIIME 2. Microbial metabolic pathways were predicted using parsimonious flux balance analysis. RESULTS: Among 93 included patients, 69 (74%) patients responded to corticosteroids after 4 weeks. At baseline, responders could not be distinguished from nonresponders by microbial diversity and composition, except for a subgroup of biologic-naïve patients. Within 4 weeks of treatment, responders experienced changes in beta diversity with enrichment of ascribed beneficial taxa, including Blautia, Anaerostipes, and Bifidobacterium, as well as an increase in predicted butyrate synthesis. Nonresponders had only minor longitudinal taxonomic changes with a significant increase of Streptococcus salivarius and a microbial composition shifting away from responders. CONCLUSION: Baseline microbial diversity and composition seem to be of limited use to predict response to systemic corticosteroids in active ulcerative colitis. Response is longitudinally associated with restoration of microbial composition and its metabolic capacity.

Alternative Endoscopy Reading Paradigms Determine Score Reliability and Effect Size in Ulcerative Colitis.

OBJECTIVE: Central reading of endoscopy is advocated by regulatory agencies for clinical trials in ulcerative colitis [UC]. It is uncertain whether the local/site reader should be included in the reading paradigm. We explore whether using locally- and centrally-determined endoscopic Mayo subscores [eMS] provide a reliable final assessment and whether the paradigm used has an impact on effect size. METHODS: eMS data from the TURANDOT [NCT01620255] study were used to retrospectively examine seven different reading paradigms (using the scores of local readers [LR], first central readers [CR1], second central readers [CR2], and various consensus reads [ConCR]) by assessing inter-rater reliabilities and their impact on the key study endpoint, endoscopic improvement. RESULTS: More than 40% of eMS scores between two trained central readers were discordant. Central readers had wide variability in scorings at baseline (intraclass correlation coefficient [ICC] of 0.475 [0.339, 0.610] for CR1 vs CR2). Centrally-read scores had variable concordance with LR (LR vs CR1 ICC 0.682 [0.575, 0.788], and LR vs CR2 ICC 0.526 [0.399, 0.653]). Reading paradigms with LR and CR which included a consensus, enhanced ICC estimates to >0.8. At Week 12, without the consensus reads, the CR1 vs CR2 ICC estimates were 0.775 [0.710, 0.841], and with consensus reads the ICC estimates were >0.9. Consensus-based approaches were most favourable to detect a treatment difference. CONCLUSION: The ICC between the eMS of two trained and experienced central readers is unexpectedly low, which reinforces that currently used central reading processes are still associated with several weaknesses.

Efficacy and safety of 48 weeks of guselkumab for patients with Crohn's disease: maintenance results from the phase 2, randomised, double-blind GALAXI-1 trial.

BACKGROUND: Many patients with moderately to severely active Crohn's disease do not respond to available therapies or lose response over time. The GALAXI-1 study previously found that three intravenous guselkumab dosages showed superior clinical and endoscopic outcomes over placebo at week 12 in patients with moderately to severely active Crohn's disease. We report the safety and efficacy of subcutaneous guselkumab maintenance regimens to week 48 in the GALAXI-1 study. METHODS: We did a phase 2, randomised, multicentre, double-blind trial. Adult patients with moderately to severely active Crohn's disease were randomly allocated with a computer-generated randomisation schedule to receive one of five treatment groups, with regimens consisting of an intravenous induction phase transitioning to a subcutaneous maintenance phase starting at week 12 in a treat-through design: (1) guselkumab 200→100 mg group (200 mg intravenous at weeks 0, 4, and 8, then 100 mg subcutaneous every 8 weeks; (2) guselkumab 600→200 mg group (600 mg intravenous at weeks 0, 4, and 8, then 200 mg subcutaneous every 4 weeks); (3) guselkumab 1200→200 mg group (1200 mg intravenous at weeks 0, 4, and 8, then 200 mg subcutaneous every 4 weeks); (4) ustekinumab group (approximately 6 mg/kg intravenous at week 0, then 90 mg subcutaneous every 8 weeks); or (5) placebo group (placebo induction followed by either placebo maintenance [for those with CDAI clinical response at week 12] or crossover to ustekinumab [for those without CDAI clinical response at week 12]). Endpoints assessed at week 48 included CDAI remission (CDAI score <150), endoscopic response (≥50% improvement from baseline in SES-CD or SES-CD score ≤2), and endoscopic remission (SES-CD score ≤2) in the primary efficacy analysis population of all randomised patients who received at least one dose of study drug, excluding those discontinued during a temporary study pause. Safety analyses included all randomised patients who received at least one study drug dose. This trial is registered at Clinical Trials.gov (NCT03466411) and is active but not recruiting. FINDINGS: Among 700 patients screened, 309 (112 biologic-naive; 197 biologic-experienced) were included in the primary efficacy analysis population: 61 in the guselkumab 200→100 mg group, 63 in the guselkumab 600→200 mg group, 61 in the guselkumab 1200→200 mg group, 63 in the ustekinumab group, and 61 in the placebo group. 126 (41%) women and 183 (59%) men were included, with median age 36·0 years (IQR 28·0-49·0). At week 48, the numbers of patients with CDAI clinical remission were 39 (64%) in the guselkumab 200→100 mg group, 46 (73%) in the guselkumab 600→200 mg group, 35 (57%) in the guselkumab 1200→200 mg group, and 37 (59%) in the ustekinumab group. The corresponding numbers of patients with endoscopic response were 27 (44%), 29 (46%), 27 (44%), and 19 (30%), respectively, and endoscopic remission was seen in 11 (18%), 11 (17%), 20 (33%), and four (6%) patients, respectively. In the placebo group, 15 patients were in CDAI clinical response at week 12 and continued placebo; of these, nine (60%) were in clinical remission at week 48. 44 patients in the placebo group were not in CDAI clinical response at week 12 and crossed over to ustekinumab; of these, 26 (59%) were in clinical remission at week 48. Up to week 48, adverse events frequencies in the safety population (n=360) were 46 (66%) of 70 patients (464·9 events per 100 patient-years of follow-up) in the placebo group, 163 (74%) of 220 patients (353·1 per 100 patient-years) in the three guselkumab groups combined, and 60 (85%) of 71 patients (350·7 per 100 patient-years) in the ustekinumab group. Among patients treated with guselkumab or ustekinumab, the most frequently reported infections up to week 48 were nasopharyngitis (25 [11%] of 220 guselkumab recipients, 12 [11%] of 114 ustekinumab recipients) and upper respiratory infections (13 [6%] guselkumab recipients, eight [7%] ustekinumab recipients). After week 12, one patient who responded to placebo induction and two guselkumab-treated patients had serious infections. No active tuberculosis, opportunistic infections, or deaths occurred. INTERPRETATION: Patients receiving guselkumab intravenous induction and subcutaneous maintenance treatment achieved high rates of clinical and endoscopic efficacy up to week 48. No new safety concerns were identified. FUNDING: Janssen Research & Development.

Efficacy and Safety of the Anti-Mucosal Addressin Cell Adhesion Molecule-1 Antibody Ontamalimab in Patients with Moderate-to-Severe Ulcerative Colitis or Crohn's Disease.

BACKGROUND AND AIMS: Ontamalimab is a fully human immunoglobulin G2 monoclonal antibody against mucosal addressin cell adhesion molecule-1 developed as treatment for inflammatory bowel disease. METHODS: Six phase 3, multicentre, randomised, double-blind, placebo-controlled clinical trials compared efficacy and safety of ontamalimab [25 mg and 75 mg once every 4 weeks] with placebo in patients with moderate-to-severe ulcerative colitis or Crohn's disease [two induction studies and one re-randomised maintenance study per condition]. This clinical trial programme was discontinued in 2020 for reasons unrelated to drug safety/efficacy; Crohn's disease studies are described in the supplementary materials. RESULTS: The induction [12-week] and maintenance [52-week] studies included 659 and 366 randomised patients, respectively. More patients who received ontamalimab induction than placebo achieved the primary endpoint of clinical remission at week 12 [25 mg, 18.5% vs 15.8% (p = 0.617), 27.0% vs 12.5% (p = 0.027); 75 mg, 29.8% vs 15.8% (p = 0.018), 29.5% vs 12.5% (p = 0.014)]; significantly more patients who received ontamalimab maintenance therapy than placebo achieved week 52 clinical remission [25 mg, 53.5% vs 8.2%, p < 0.001; 75 mg, 40.2% vs 12.8%, p < 0.001]. Endoscopic improvement was generally significantly different vs placebo [induction: 25 mg, 27.8% vs 21.1 (p = 0.253), 35.1% vs 12.5% (p = 0.001); 75 mg, 41.1% vs 21.1 (p = 0.002), 33.9% vs 12.5% (p = 0.003); maintenance: 25 mg, 56.3% vs 9.6% (p < 0.001); 75 mg, 48.8% vs 15.1% (p < 0.001)]. Adverse event rates were similar between ontamalimab and placebo groups. CONCLUSIONS: Ontamalimab 75 mg was effective with no safety concerns as induction and maintenance therapy for patients with moderate-to-severe ulcerative colitis.

Outcomes and endpoints of postoperative recurrence in Crohn's Disease: systematic review and consensus conference.

BACKGROUND: Outcomes after ileocolonic resection in Crohn's Disease (CD) are heterogeneous and a clear definition of postoperative recurrence remains to be determined. Our Endpoints Working Group of the International Organization for the study of Inflammatory Bowel Disease (IOIBD) aimed to standardize postoperative outcomes, to discuss which endpoints should be used for postoperative clinical trials and to define those which could be used in trials or registries. METHODS: Based on a systematic review of the literature, recommendations and statements were drafted and sent to all IOIBD members for a first round of voting. Recommendations and statements were revised based on the voters' comments during a consensus hybrid conference open to all IOIBD members. If no agreement was reached after 2 rounds of voting, the statement was excluded. RESULTS: In the systematic review, 3,071 manuscripts were screened, of which 434 were included. Sixteen recommendations were identified, of which 11 were endorsed. Recommendations and statements include that endoscopy remains the gold standard and should be used as a short-term primary endpoint in both observational cohorts and randomized controlled trials. Clinical symptoms classically used in clinical trials for luminal CD are not reliable in this specific situation. For that reason, longer term endpoints should be based on the evidence of macroscopic inflammation assessed by imaging techniques, endoscopy or reflected by the presence of complications. CONCLUSIONS: Agencies recommend the use of clinical evaluations, as in the case of luminal CD, and do not recognize primary endpoints based solely on endoscopy. This consensus has led to agreement on the need to define postoperative endoscopy- and/or imaging-based endpoints.

Effects of Mirikizumab on Histologic Resolution of Crohn's Disease in a Randomized Controlled Phase 2 Trial.

BACKGROUND & AIMS: Histologic evaluation of mucosal healing in Crohn's disease is an evolving treatment target. We evaluated histologic outcomes for mirikizumab efficacy and associations with endoscopic and 1-year outcomes. METHODS: Biopsy specimens from 1 ileal and 4 colonic segments were evaluated at weeks 0, 12, and 52 from each of the 170 SERENITY participants. Criteria for the weeks 12 and 52 histologic response were no epithelial neutrophils or epithelial damage, or >50% decrease in either the Robarts Histopathology Index or the active Global Histologic Disease Activity Score, and remission (no mucosal neutrophils and no epithelial damage) had to be met in all biopsy specimens. Agreement was evaluated between histologic and endoscopic end points. Associations between 1-year outcomes and week 12 histologic and endoscopic response were evaluated. RESULTS: At week 12, 1000 mg mirikizumab resulted in greater rates of histologic response (66% vs 27%; P < .001) and remission (26% vs 6%; P < .01) than placebo. Rates were numerically similar at 1 year (mirikizumab pooled response, 46%-69%; remission, 13%-31%). Agreement between week 12 histologic and endoscopic response was 69% (Cohen's kappa coefficient [κ] = 0.40) and remission was 83% (κ = 0.38) in all pooled arms, including placebo. At 1 year, the percentage of participants who received any dose of mirikizumab and achieved endoscopic remission differed by their week 12 response: histologic (20%), endoscopic (25%), combined histology-endoscopy (45%), or neither (4%) (P = .003). CONCLUSIONS: In a post hoc analysis of phase 2 data, mirikizumab induced and sustained histologic response and remission in Crohn's disease over 52 weeks. Early combined histologic-endoscopic response was associated with endoscopic remission after 1 year of treatment with mirikizumab (ClinicalTrials.gov NCT02891226).

[Use of subcutaneous Vedolizumab: A position paper issued by the Inflammatory Bowel Disease Working Group of the Austrian Society of Gastroenterology and Hepatology (ÖGGH)]. / Positionspapier der Arbeitsgruppe Chronisch Entzündliche Darmerkrankungen der ÖGGH zum Einsatz von Vedolizumab subkutan.

The humanized monoclonal anti-α4ß7-integrin-antibody vedolizumab is one of several biologic therapeutic options in moderate-to-severe ulcerative colitis and Crohn's disease. Within the VISIBLE trial program, a novel subcutaneous application route was evaluated in addition to the already established intravenous form. In this position statement, the working group "Inflammatory Bowel Diseases" of the Austrian Society for Gastroenterology and Hepatology (OEGGH) summarizes the evidence regarding the subcutaneous application of vedolizumab. This work supplements a position paper on the value of vedolizumab as a first-line biologic that has already been published and offers useful recommendations for clinical practice.