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Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P2,3, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these two phase 3 trials, we aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis. In two independent randomised, multicentre, double-blind, placebo-controlled, phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12, adults with active moderate-to-severe ulcerative colitis and an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients in ELEVATE UC 52 were enrolled from 315 centres in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centres in 37 countries. Randomisation was stratified by previous exposure to biologicals or Janus kinase inhibitor therapy (yes vs no), baseline corticosteroid use (yes vs no), and baseline disease activity (modified Mayo score [MMS]; 4–6 vs 7–9). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 independently assessed induction at week 12. The primary efficacy endpoints were the proportion of patients with clinical remission at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. Safety was evaluated in both trials. ELEVATE UC 52 and ELEVATE UC 12 were registered with ClinicalTrials.gov, NCT03945188 and NCT03996369, respectively. Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and Jan 28, 2021. Patients in ELEVATE UC 12 were enrolled between Sept 15, 2020, and Aug 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment. The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo. In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74 [27%] of 274 patients vs ten [7%] of 135 patients; p<0·0001) and at week 52 (88 [32%] of 274 patients vs nine [7%] of 135 patients; p<0·0001). In ELEVATE UC 12, 55 (25%) of 222 patients in the etrasimod group had clinical remission compared with 17 (15%) of 112 patients in the placebo group at the end of the 12-week induction period (p=0·026). Adverse events were reported in 206 (71%) of 289 patients in the etrasimod group and 81 (56%) of 144 patients in the placebo group in ELEVATE UC 52 and 112 (47%) of 238 patients in the etrasimod group and 54 (47%) of 116 patients in the placebo group in ELEVATE UC 12. No deaths or malignancies were reported. Etrasimod was effective and well tolerated as an induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Etrasimod is a treatment option with a unique combination of attributes that might address the persistent unmet needs of patients with ulcerative colitis. Arena Pharmaceuticals.

Background/objectivesUlcerative colitis (UC) is an immune-mediated disease that causes inflammation in the gastrointestinal tract. Diet has an important role in the treatment of UC. This study aimed to compare the effects of extra virgin olive oil (EVOO), as a functional food, with canola oil in the treatment of UC.Subjects/methodsForty patients were participating in this crossover clinical trial. Thirty two patients completed two intervention rounds. Blood samples were taken before and after 20 days intervention. Disease activity score and gastrointestinal symptoms were evaluated using the Mayo score and gastrointestinal symptom rating scale (GSRS) respectively.ResultsErythrocyte sedimentation rate (p = 0.03) and high-sensitivity C-reactive protein (p < 0.001) were decreased significantly after EVOO consumption. Bloating, constipation, fecal urgency, incomplete defecation, and final GSRS were reduced significantly after EVOO consumption (p < 0.05).ConclusionsIntake of EVOO decreased the inflammatory markers and improved gastrointestinal symptoms in UC patients. It seems this functional food can be beneficial in the treatment of UC as a complementary medicine.

Abstract Background Mirikizumab, a p19-directed interleukin-23 monoclonal antibody, has demonstrated induction of clinical remission at week 12 with maintenance through week 104 in patients with moderately-to-severely active ulcerative colitis (UC). Results are presented from the LUCENT-3 open-label extension study through week 152. Methods Of 868 LUCENT clinical trial program mirikizumab-treated induction patients, 544 were responders of whom 365 were rerandomized to mirikizumab maintenance. Of these, 324 completed week 52 and 316 entered extension treatment (286 week 52 responders; 179 week 52 remitters). Efficacy and safety outcomes are reported for mirikizumab-treated LUCENT-3 participants, including biologic-failed patients, with data for week 52 maintenance responders/remitters. Discontinuations or missing data were handled by nonresponder imputation, modified nonresponder imputation (mNRI), and observed cases. Results Using mNRI, 81.6% of week 52 responders demonstrated clinical response at week 152. Week 152 remission rates for week 52 responders included clinical (56.1%), corticosteroid-free (CSF; 54.5%), endoscopic (61.0%), histologic-endoscopic mucosal remission (HEMR; 52.6%), symptomatic (74.9%), and bowel urgency (BU; 58.6%). At week 152, 53.3% of week 52 responders achieved histologic-endoscopic mucosal improvement (HEMI) and 74.3% achieved BU clinically meaningful improvement (CMI). Among week 52 remitters, 85.4% showed a clinical response at week 152, with clinical (70.1%), CSF (68.9%), endoscopic (72.0%), HEMR (63.4%), symptomatic (81.4%), and BU (60.8%) remission. At week 152, among week 52 remitters, 64.0% of patients achieved HEMI and 75.6% achieved BU CMI. Stool frequency, rectal bleeding, BU, and abdominal pain score reductions from induction baseline to maintenance week 52 were sustained through week 152 for week 52 completers. Overall, in the safety population, 7.4% of patients reported severe adverse events (AEs); 5.3% discontinued treatment due to AEs. AEs of special interest included opportunistic infection (1.8%), hepatic disorders (3.2%), cerebrocardiovascular events (1.5%), and malignancy (0.3%). Patients with antidrug antibodies reduced over time from 23.6% in year 1 to 3.2% in year 3. Conclusions Symptomatic, clinical, endoscopic, histologic, and quality-of-life outcomes support long-term sustained benefit of mirikizumab treatment up to 152 weeks in patients with UC, including biologic-failed patients, with no new safety concerns. Clinical Trial Registry ClinicalTrials.gov: NCT03518086; NCT03524092; NCT03519945. Lay Summary Long-term symptomatic, clinical response/remission, endoscopic, and histologic data from an open-label study of patients with moderately-to-severely active ulcerative colitis demonstrate that 3-year continuous treatment with mirikizumab maintained clinical remission in most induction clinical responders, regardless of previous biologic failure status.

BackgroundThe interleukin-22 cytokine (IL-22) has demonstrated efficacy in preclinical colitis models with non-immunosuppressive mechanism of action. Efmarodocokin alfa (UTTR1147A) is a fusion protein agonist that links IL-22 to the crystallisable fragment (Fc) of human IgG4 for improved pharmacokinetic characteristics, but with a mutation to minimise Fc effector functions.MethodsThis randomised, phase 1b study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of repeat intravenous dosing of efmarodocokin alfa in healthy volunteers (HVs; n=32) and patients with ulcerative colitis (n=24) at 30–90 µg/kg doses given once every 2 weeks or monthly (every 4 weeks) for 12 weeks (6:2 active:placebo per cohort).ResultsThe most common adverse events (AEs) were on-target, reversible, dermatological effects (dry skin, erythema and pruritus). Dose-limiting non-serious dermatological AEs (severe dry skin, erythema, exfoliation and discomfort) were seen at 90 μg/kg once every 2 weeks (HVs, n=2; patients, n=1). Pharmacokinetics were generally dose-proportional across the dose levels, but patients demonstrated lower drug exposures relative to HVs at the same dose. IL-22 serum biomarkers and IL-22-responsive genes in colon biopsies were induced with active treatment, and microbiota composition changed consistent with a reversal in baseline dysbiosis. As a phase 1b study, efficacy endpoints were exploratory only. Clinical response was observed in 7/18 active-treated and 1/6 placebo-treated patients; clinical remission was observed in 5/18 active-treated and 0/6 placebo-treated patients.ConclusionEfmarodocokin alfa had an adequate safety and pharmacokinetic profile in HVs and patients. Biomarker data confirmed IL-22R pathway activation in the colonic epithelium. Results support further investigation of this non-immunosuppressive potential inflammatory bowel disease therapeutic.Trial registration number NCT02749630.

Objective Interleukin 13 (IL-13) is thought to play a key role as an effector cytokine in UC. Anrukinzumab, a humanised antibody that inhibits human IL-13, was evaluated for the treatment of UC. Design In a multicentre, randomised, double-blind, placebo-controlled study, patients with active UC (Mayo score ≥4 and <10) were randomised to anrukinzumab 200, 400 or 600 mg or placebo. Patients received five intravenous administrations over 14 weeks. The primary endpoint was fold change from baseline in faecal calprotectin (FC) at Week 14. Secondary endpoints included safety, pharmacokinetics and IL-13 levels. Results The modified intention-to-treat population included 84 patients (21 patients/arm). Fold change of FC from baseline at Week 14 was not significantly different for any treatment groups compared with the placebo. The study had a high dropout rate, in part, related to lack of efficacy. The exploratory comparisons of each dose were not significantly different from placebo in terms of change from baseline in total Mayo score, clinical response, clinical remission and proportion of subjects with mucosal healing. An increase in serum total IL-13 (free and bound to anrukinzumab) was observed for all anrukinzumab groups but not with placebo. This suggests significant binding of anrukinzumab to IL-13. The safety profile was not different between the anrukinzumab and placebo groups. Conclusions A statistically significant therapeutic effect of anrukinzumab could not be demonstrated in patients with active UC in spite of binding of anrukinzumab to IL-13. Trial registration number ClinicalTrials.gov number NCT01284062.

PF-00547659 is a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) to selectively reduce lymphocyte homing to the intestinal tract. We aimed to assess the efficacy and safety of PF-00547659 in patients with moderate to severe ulcerative colitis. This phase 2, randomised, double-blind, placebo-controlled clinical trial recruited patients aged 18–65 years from 105 centres in 21 countries, with a history (≥3 months) of active ulcerative colitis extending more than 15 cm beyond the anal verge (with a total Mayo score ≥6 and a Mayo endoscopic subscore ≥2) who had failed or were intolerant to at least one conventional therapy. Patients were stratified by previous anti-TNFα treatment, and randomly assigned by a computer-generated randomisation schedule to receive a subcutaneous injection of 7·5 mg, 22·5 mg, 75 mg, or 225 mg PF-00547659 or placebo at baseline, then every 4 weeks. Patients, investigators, and sponsors were blinded to the treatment. The primary endpoint was the proportion of patients achieving remission (total Mayo score ≤2 with no individual subscore >1 and rectal bleeding subscore ≤1) at week 12. The efficacy analysis included all patients who received at least one dose of the randomised treatment; the safety analysis was done according to treatment received. All p values were one-sided and multiplicity-adjusted. This study is registered with ClinicalTrials.gov, number NCT01620255. Between Nov 2, 2012, and Feb 4, 2016, we screened 587 patients; 357 were eligible and randomly assigned to receive placebo (n=73) or PF-00547659 at doses of 7·5 mg (n=71), 22·5 mg (n=72), 75 mg (n=71), or 225 mg (n=70). Remission rates at week 12 were significantly greater in three of four active-treatment groups than in the placebo group (2·7% [two of 73]): 7·5 mg (11·3% [eight of 71]), 22·5 mg (16·7% [12 of 72]), 75 mg (15·5% [11 of 71]), and 225 mg (5·7% [four of 70]). These rates corresponded to a stratum-adjusted (anti-TNFα-naive and anti-TNFα-experienced) risk difference versus placebo of 8·0% for 7·5 mg (90% CI 1·9 to 14, p=0·0425), 12·8% for 22·5 mg (5·6 to 19·9, p=0·0099), 11·8% for 75 mg (4·8 to 18·8, p=0·0119), and 2·6% for 225 mg (−1·2 to 6·4, p=0·1803). Four of 73 (5·5%) patients had a serious adverse event in the placebo group, 11 of 71 (15·5%) in the 7·5 mg group, one of 70 (1·4%) in the 22·5 mg group, three of 73 (4·1%) in the 75 mg group, and three of 70 (4·3%) in the 225 mg group. No safety signal was observed for the study drug. PF-00547659 was safe and well tolerated in this patient population, and better than placebo for induction of remission in patients with moderate to severe ulcerative colitis. The greatest clinical effects were observed with the 22·5 mg and 75 mg doses. Pfizer.

Although chromoendoscopy is currently the recommended mode of surveillance in patients with long-standing ulcerative colitis, it is technically challenging and requires a long procedure time. The aim of this study was to compare the dysplasia detection rate of high-definition white light endoscopy with random biopsy (HDWL-R) vs high-definition chromoendoscopy with targeted biopsy (HDCE-T). This was a multicenter, prospective randomized controlled trial involving 9 tertiary teaching hospitals in South Korea. A total of 210 patients with long-standing ulcerative colitis were randomized to undergo either the HDWL-R group (n = 102) or HDCE-T group (n = 108). The detection rates of colitis-associated dysplasia (CAD) or all colorectal neoplasia from each trial arm were compared. There was no significant difference in the CAD detection rate between HDCE-T and HDWL-R groups (4/102, 3.9% vs 6/108, 5.6%, P = 0.749). However, HDCE-T showed a trend toward improved colorectal neoplasia detection compared with HDWL-R (21/102, 20.6% vs 13/108, 12.0%, P = 0.093). The median (range) time for colonoscopy withdrawal between the 2 groups was similar (17.6 [7.0-43.3] minutes vs 16.5 [6.3-38.1] minutes; P=0.212; for HDWL-R and HDCE-T, respectively). The total number of biopsies was significantly larger in the HDWL-R group (34 [12-72]) compared with the HDCE-T group (9 [1-20]; P < 0.001). On the basis of our prospective randomized controlled trial, HDCE-T was not superior to HDWL-R for detecting CADs.

The long-term goal of our ongoing studies is to determine if, and to what extent, a multi-mineral product (Aquamin) could benefit individuals with ulcerative colitis (UC). As a step toward achieving that goal, we carried out a pilot 180-day biomarker trial (clinicaltrials.gov ID: NCT03869905) in patients with UC in remission or with mild disease. A total of 28 subjects participated in the study. Each subject was randomly assigned to receive either Aquamin for 180 days or placebo for 90 days. At Day-90, placebo subjects crossed over to Aquamin for the final 90 days. At Day-0, -90 and -180, serum samples were analyzed for C-reactive protein (CRP), alkaline phosphatase (ALP), intestine-specific ALP (ALPI), and for biomarkers of bone turnover (osteocalcin, TRAP5b and bone-specific ALP [BALP]). Stool specimens were assessed for fecal calprotectin (fCAL) and colon biopsies were examined histologically by Geboes scoring at the same time points. Each subject underwent DEXA scanning (at Day-0 and Day-180 only). In addition, mass spectrometry-based proteomic assessment was performed using colon biopsies obtained at each time point. Subjects who received Aquamin for the complete 180-day period (a total of 12) demonstrated improvements in all biomarkers (CRP, fCAL, ALP, ALPI, and Geboes scoring); this was not observed in the placebo group (16 subjects). When cumulative pre-post differences were compared between the Aquamin and placebo groups, Aquamin treatment significantly decreased these differences (a 24% decrease as compared to a 38% increase with placebo, p = 0.0284). Subjects who received Aquamin for 90-days showed intermediary responses. Subjects receiving Aquamin for 180 days also demonstrated increases in bone mineral density (BMD) and bone mineral content (BMC), resulting in a statistically significant increase (7.3%, p = 0.0324) in the hip strength index over the treatment period. This was accompanied by increases in osteocalcin and TRAP5b and a decrease in BALP. The proteomic screen demonstrated upregulation of multiple gut barrier proteins, cell surface transporter molecules and certain proteins with anti-inflammatory potential in response to Aquamin. Aquamin treatment also led to downregulation of several proteins associated with the pro-inflammatory state. The results presented here suggest that the use of a multi-mineral intervention improves disease-related biomarkers in patients with UC. These studies suggest the potential value of the mineral intervention as a low-cost, non-toxic adjuvant therapy for mild UC or for individuals with UC in remission.

Assessing endoscopic disease severity in ulcerative colitis (UC) is a key element in determining therapeutic response, but its use in clinical practice is limited by the requirement for experienced human reviewers. To determine whether deep learning models can grade the endoscopic severity of UC as well as experienced human reviewers. In this diagnostic study, retrospective grading of endoscopic images using the 4-level Mayo subscore was performed by 2 independent reviewers with score discrepancies adjudicated by a third reviewer. Using 16 514 images from 3082 patients with UC who underwent colonoscopy at a single tertiary care referral center in the United States between January 1, 2007, and December 31, 2017, a 159-layer convolutional neural network (CNN) was constructed as a deep learning model to train and categorize images into 2 clinically relevant groups: remission (Mayo subscore 0 or 1) and moderate to severe disease (Mayo subscore, 2 or 3). Ninety percent of the cohort was used to build the model and 10% was used to test it; the process was repeated 10 times. A set of 30 full-motion colonoscopy videos, unseen by the model, was then used for external validation to mimic real-world application. Model performance was assessed using area under the receiver operating curve (AUROC), sensitivity and specificity, positive predictive value (PPV), and negative predictive value (NPV). Kappa statistics (κ) were used to measure agreement of the CNN relative to adjudicated human reference cores. The authors included 16 514 images from 3082 unique patients (median [IQR] age, 41.3 [26.1-61.8] years, 1678 [54.4%] female), with 3980 images (24.1%) classified as moderate-to-severe disease by the adjudicated reference score. The CNN was excellent for distinguishing endoscopic remission from moderate-to-severe disease with an AUROC of 0.966 (95% CI, 0.967-0.972); a PPV of 0.87 (95% CI, 0.85-0.88) with a sensitivity of 83.0% (95% CI, 80.8%-85.4%) and specificty of 96.0% (95% CI, 95.1%-97.1%); and NPV of 0.94 (95% CI, 0.93-0.95). Weighted κ agreement between the CNN and the adjudicated reference score was also good for identifying exact Mayo subscores (κ = 0.84; 95% CI, 0.83-0.86) and was similar to the agreement between experienced reviewers (κ = 0.86; 95% CI, 0.85-0.87). Applying the CNN to entire colonoscopy videos had similar accuracy for identifying moderate to severe disease (AUROC, 0.97; 95% CI, 0.963-0.969). This study found that deep learning model performance was similar to experienced human reviewers in grading endoscopic severity of UC. Given its scalability, this approach could improve the use of colonoscopy for UC in both research and routine practice.

Several probiotic compounds have shown promise in the therapy of ulcerative colitis (UC). However, a strong sustained benefit remains to be seen. Uncontrolled pilot studies suggest that a probiotic preparation (VSL#3) maintains remission in mild to moderate UC and reduces active inflammation in adult patients. Aims of our prospective, 1-year, placebo-controlled, double-blind study were to assess the efficacy of VSL#3 on induction and maintenance of remission and to evaluate the safety and tolerability of the probiotic preparation therapy in children with active UC. A total of 29 consecutive patients (mean age: 9.8 years; range: 1.7-16.1 years; female/male: 13/16) with newly diagnosed UC were randomized to receive either VSL#3 (weight-based dose, range: 450-1,800 billion bacteria/day; n=14) or an identical placebo (n=15) in conjunction with concomitant steroid induction and mesalamine maintenance treatment. Children were prospectively evaluated at four time points: within 1 month, 2 months, 6 months, and 1 year after diagnosis or at the time of relapse. Lichtiger colitis activity index and a physician's global assessment were used to measure disease activity. At baseline, within 6 months and 12 months or at the time of relapse, all patients were assessed endoscopically and histologically. All 29 patients responded to the inflammatory bowel disease (IBD) induction therapy. Remission was achieved in 13 patients (92.8%) treated with VSL#3 and IBD therapy and in 4 patients (36.4%) treated with placebo and IBD therapy (P<0.001). Overall, 3 of 14 (21.4%) patients treated with VSL#3 and IBD therapy and 11 of 15 (73.3%) patients treated with placebo and IBD therapy relapsed within 1 year of follow-up (P=0.014; RR=0.32; CI=0.025-0.773; NNT=2). All 3 patients treated with VSL#3 and 6 of 11 (54.5%) patients treated with placebo relapsed within 6 months of diagnosis. At 6 months, 12 months, or at time of relapse, endoscopic and histological scores were significantly lower in the VSL#3 group than in the placebo group (P<0.05). There were no biochemical or clinical adverse events related to VSL#3. This is the first pediatric, randomized, placebo-controlled trial that suggests the efficacy and safety of a highly concentrated mixture of probiotic bacterial strains (VSL#3) in active UC and demonstrates its role in maintenance of remission.