Toshifumi Hibi

Background: Carotegrast methyl is an oral α4-integrin antagonist used to induce remission in patients with ulcerative colitis with an inadequate response to 5-aminosalicylate (5-ASA). This multicenter, retrospective observational study evaluated the clinical usefulness of carotegrast methyl in real-world practice. Methods: Patients with an inadequate response to 5-ASA who received carotegrast methyl were included. Clinical data were collected during and after treatment for up to 52 weeks. The primary endpoint was the response rate at week 8. The remission rate at week 8, response/remission rate at end of treatment, cumulative response/remission rate, and adverse drug reactions were also assessed. Effectiveness was evaluated using the patient reported outcomes-2 measure (sum of Mayo subscores for stool frequency and rectal bleeding). Results: Data were collected from 196 patients, of whom 180 were evaluable for effectiveness. The PRO-2-defined response and remission rates at week 8 were 57.8% and 43.3%, respectively, and the rates at the end of treatment (median treatment duration: 83.5 days) were 58.9% and 50.0%, respectively. The cumulative PRO-2-defined response/remission rates increased until week 16, followed by a slight further increase. Adverse drug reactions occurred in 31 of 196 patients (15.8%, 43 events), with no serious events. Conclusions: In terms of patient-reported symptom improvement, carotegrast methyl is an effective and well-tolerated treatment for patients with ulcerative colitis who have an inadequate response to 5-ASA. A substantial proportion of patients responded to 8 weeks of treatment. Continued treatment for up to 16 weeks may improve symptoms, even in patients with insufficient response at week 8.

Background: Bowel urgency (BU) is a key symptom of ulcerative colitis (UC), often impairing the quality of life. This study aimed to identify intestinal ultrasound parameters associated with BU, given that UC may also have transmural involvement, and compare these with endoscopic activity and biomarkers. Methods: In this single‐centre prospective study, UC patients undergoing colonoscopy between January 31 and September 27, 2023 were enrolled. Transabdominal and transperineal ultrasound were performed to evaluate bowel wall thickness (BWT), including individual layers (mucosa, submucosa, and muscularis propria), and colour Doppler signal (CDS) in the sigmoid colon and rectum. BU was defined according to the Simple Clinical Colitis Activity Index urgency subscore. Results: Of 59 patients, 33 (56%) reported BU. Compared with those without BU, patients with BU had significantly higher C‐reactive protein, Mayo Endoscopic Subscore (MES), BWT (descending colon, sigmoid colon, rectum), CDS (sigmoid colon, rectum), and submucosal and muscularis propria thickness in the sigmoid colon (all p < 0.05). Mucosal thickness and faecal calprotectin were not significantly different ( p = 0.11 and p = 0.48, respectively). In MES‐adjusted logistic regression, submucosal ( p < 0.01) and muscularis propria ( p = 0.03) thickness remained associated with BU, whereas mucosal thickness did not ( p = 0.97). Receiver operating characteristic analysis showed that sigmoid submucosal thickness had greater diagnostic accuracy than mucosal thickness (AUC 0.77 vs. 0.62, p < 0.05). Conclusions: Sigmoid submucosal thickening was associated with BU and suggests that transmural inflammation may contribute to symptom pathophysiology. Trial Registration: UMIN000050099

Efficacy and safety of ozanimod in Japanese patients with moderately to severely active ulcerative colitis naive to immunomodulators or advanced therapies: post hoc analysis of the phase 2/3 J-True North study

This final long-term extension (LTE) analysis assessed the long-term efficacy and safety of ustekinumab (UST) in the Asian patient subpopulation of the UNITI/IM-UNITI study. Patients completing safety and efficacy evaluations at Week 44 of the maintenance study were eligible to participate in the LTE and continued their UST treatment. Unblinding occurred after Week 44 analyses were completed, and patients still receiving placebo were discontinued; no placebo data were reported beyond Week 44 in this report. Efficacy assessments were performed every 12 weeks (q12w) until unblinding and at dosing visits thereafter through Week 252. Safety events (per 100 patient-years [PY]) were assessed through Week 272. Sixty-three Asian patients entered the LTE. At Week 44, clinical response/clinical remission rates in the UST 90 mg subcutaneous (SC) q12w and every 8 weeks (q8w) arms were 75.0%/58.3% and 61.5%/53.8%, respectively. At Week 252, clinical response/clinical remission rates in the UST 90 mg SC q12w and q8w arms were 58.3%/41.7% and 23.1%/15.4%, respectively. Normalized C-reactive protein levels were maintained over 252 weeks of UST treatment. Among patients who entered the LTE, the number of treatment-emergent adverse events and serious infections in the UST 90 mg SC combined group was 267.2/100 PY and 4.5/100 PY, respectively. Maintenance therapy with UST 90 mg SC was well tolerated and efficacious in maintaining clinical remission and response rates through 5 years in Asian patients with Crohn's disease, consistent with the global population. (ClinicalTrials.gov Identifier: UNITI-1 [NCT01369329], UNITI-2 [NCT01369342], and IM UNITI [NCT01369355]).

Background/Aims: Vedolizumab (VDZ), a gut-selective monoclonal antibody for ulcerative colitis (UC) treatment, has no established biomarkers or clinical features that predict long-term remission. Week 2 remission, a potential predictor of long-term remission, could inform maintenance treatment strategy. Methods: This retrospective, observational chart review included patients with UC in Japan who initiated VDZ between December 2018 and February 2020. Outcome measures included 14- and 54-week remission rates in patients with week 2 and non-week 2 remission (remission by week 14), 54-week remission rates in patients with week 14 remission and primary nonresponse, and predictive factors of week 2 and week 54 remission (logistic regression). Results: Overall, 332 patients with UC (176 biologic-naïve and 156 biologic-non-naïve) were included. Significantly more biologic-naïve than biologic-non-naïve patients achieved week 2 remission (36.9% vs. 28.2%; odds ratio [OR], 1.43; 95% confidence interval [CI], 1.05–1.94; P= 0.0224). Week 54 remission rates were significantly different between week 14 remission and primary nonresponse (both groups: P< 0.0001), and between week 2 and non-week 2 remission (all patients: OR, 2.41; 95% CI, 1.30–4.48; P= 0.0052; biologic-naïve patients: OR, 2.40; 95% CI, 1.10–5.24; P= 0.0280). Week 2 remission predictors were male sex, no anti-tumor necrosis factor alpha exposure, and normal/mild endoscopic findings. Week 54 remission was significantly associated with week 2 remission and no tacrolimus use. Conclusions: Week 2 remission with VDZ is a predictor of week 54 remission in patients with UC. Week 2 may be used as an evaluation point for UC treatment decisions. (Japanese Registry of Clinical Trials: jRCT-1080225363)

Ulcerative colitis disease severity affects the speed of symptom relief under filgotinib treatment: a post hoc analysis of the phase 2b/3 SELECTION study

Background/Aims: Previous literature suggests that the response of patients with ulcerative colitis to vedolizumab may be affected by previous biologic therapy exposure. This real-world study evaluated vedolizumab treatment effectiveness in biologicnon-naïve patients. Methods: This was a multicenter, retrospective, observational chart review of records from 16 hospitals in Japan (December 1, 2018, to February 29, 2020). Included patients who had ulcerative colitis, were aged ≥ 20 years, and received at least 1 dose of vedolizumab. Outcomes included clinical remission rates from weeks 2 to 54 according to prior biologic exposure status and factors associated with clinical remission up to week 54. Results: A total of 370 eligible patients were included. Clinical remission rates were significantly higher in biologic-naïve (n=197) than in biologic-non-naïve (n=173) patients for weeks 2 to 54 of vedolizumab treatment. Higher clinical remission rates up to week 54 were significantly associated with lower disease severity (partial Mayo score ≤ 4, P= 0.001; albumin ≥ 3.0, P= 0.019) and the duration of prior anti-tumor necrosis factor α (anti-TNFα) therapy (P= 0.026). Patients with anti-TNFα therapy durations of < 3 months, 3 to < 12 months, and ≥ 12 months had clinical remission rates of 28.1%, 32.7%, and 60.0%, respectively (P= 0.001 across groups). Conclusions: The effectiveness of vedolizumab in biologic-non-naïve patients was significantly influenced by duration of prior anti-TNFα therapy. (Japanese Registry of Clinical Trials: jRCT-1080225363)

Background/Aims: Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). However, its efficacy, safety, and the appropriate dosage have not been extensively investigated in the Japanese population. Methods: This phase 2, multicenter, randomized, double-blind, placebo-controlled dose-ranging, 12-week trial was carried out among Japanese patients with moderately to severely active UC. Patients were randomized 1:1:1 to receive etrasimod 1 mg once daily (QD), etrasimod 2 mg QD, or placebo. The primary efficacy endpoint was the proportion of patients achieving clinical remission at week 12. Secondary efficacy endpoints and treatmentemergent adverse events (TEAEs) were also investigated. Efficacy endpoints were presented as proportions of patients achieving each outcome. Results: Overall, 17, 19, and 18 patients received etrasimod 1 mg QD, etrasimod 2 mg QD, and placebo, respectively. One patient receiving etrasimod 1 mg (6.7%), 5 patients receiving etrasimod 2 mg (26.3%), and no patients receiving placebo (0%) achieved clinical remission. More patients receiving etrasimod versus placebo achieved secondary endpoints, except endoscopic normalization, at week 12. TEAEs were experienced by 9 patients receiving etrasimod 1 mg (52.9%), 13 patients receiving etrasimod 2 mg (68.4%), and 10 patients receiving placebo (55.6%). None of the TEAEs were serious and none experienced by patients receiving etrasimod led to treatment discontinuation. Conclusions: Overall, etrasimod 2 mg QD for up to 12 weeks appeared efficacious and safe in these Japanese patients with moderately to severely active UC. All TEAEs were mild to moderate in severity. (ClinicalTrials.gov: NCT05061446)

Impact of filgotinib on health-related quality of life over 3 years in Japanese patients with ulcerative colitis: a post hoc analysis of the SELECTION and SELECTION long-term extension trials

INTRODUCTION: Anti-integrin αvβ6 (anti-αvβ6) autoantibodies serve as a diagnostic biomarker and are associated with poor prognosis in ulcerative colitis (UC). We aimed to investigate whether anti-αvβ6 autoantibody levels predict treatment outcomes of advanced therapies in patients with moderately to severely active UC. METHODS: Anti-αvβ6 autoantibody levels were measured using prospectively collected serum samples at the initiation of advanced therapies. The primary outcome was treatment persistence up to 1 year; secondary outcomes included clinical remission rates at weeks 2, 6, 14, 24, and 48, comparing low-level and high-level groups stratified by an optimal cutoff from receiver operating characteristic analysis. RESULTS: A total of 144 patients were analyzed (121 [84.0%] with extensive colitis and 87 [60.4%] with prior exposure to advanced therapies). The median observation period was 10 months, and treatment discontinuation occurred in 70 patients (48.6%). Treatment persistence was significantly higher in the low-level group (log-rank test, P = 0.002), and multivariable Cox analysis identified low antibody levels as the only independent predictor (hazard ratio, 1.90; 95% CI, 1.09–3.32). Clinical remission rates were consistently higher in the low-level group throughout all time points, with the greatest difference at week 6 (47.5% vs 20.0%; χ ² test, P = 0.003). Low antibody levels remained an independent predictor of remission at all time points. DISCUSSION: Anti-αvβ6 autoantibodies predicted both treatment persistence and clinical remission after advanced therapies, highlighting their potential as a predictive biomarker in patients with active UC.