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Abstract Background Upadacitinib (UPA), an oral, reversible JAK inhibitor engineered for increased selectivity for JAK1 over JAK2, JAK3, or tyrosine kinase 2 (TYK2), demonstrated significantly greater efficacy compared with placebo (PBO) for induction of remission in patients with moderately to severely active ulcerative colitis (UC) in two phase 3 trials, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026). This analysis evaluated the efficacy of UPA on early symptomatic improvement for the first 14 days, using pooled data from U-ACHIEVE Induction and U-ACCOMPLISH. Methods U-ACHIEVE and U-ACCOMPLISH were multicentre, double-blind, PBO-controlled trials that enrolled patients who have had moderately to severely UC with an Adapted Mayo Score of 5 to 9 points and centrally reviewed endoscopy subscore of 2 to 3. A total of 998 patients were randomized to receive UPA 45mg once daily (QD) (n=658) or PBO (n=328) for 8 weeks (wks) in a 2:1 ratio. First dose of study drug was administered on Day 0. Improvement in symptoms including stool frequency subscore (SFS), rectal bleeding subscore (RBS), abdominal pain, and bowel urgency were analysed from daily symptom diary data. Multivariate regression analysis was used to determine if early changes in UC symptoms could be used to evaluate a potential correlation with patients’ likelihood of achieving clinical response or clinical remission per Adapted Mayo score at the end of induction. Results Baseline characteristics were similar between both treatment groups. Patients treated with UPA 45 mg QD experienced significant improvement in daily symptoms, with significantly more subjects achieving SFS≤1 (p<0.001), RBS of 0 (p<0.05), and SFS of 0 (p<0.05) as early as day 1 and maintained through day 14 (Figure 1). A significantly higher percentage of patients who received UPA 45 mg QD compared to PBO, achieved abdominal pain=0 and the absence of bowel urgency within 3 days of beginning treatment through day 14 (p<0.05). Multivariate analysis revealed that patients who achieved day 7 SFS≤1 (OR 2.42, 95% CI, 1.53–3.82) were more likely to attain clinical response (Table). Patients who attained day 7 SFS≤1 (OR 2.53, 95% CI 1.59–4.00) or day 7 bowel urgency absent (OR 2.40, 95% CI 1.52–3.79) were more likely to achieve clinical remission at week 8. Conclusion UPA 45 mg QD significantly improved UC symptoms as early as day 1, providing patients with rapid symptom relief. Patients who achieved early symptom improvement were more likely to attain clinical remission or clinical response at week 8. [Clinicaltrials.gov, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026)]

Background: Fecal microbiota transplantation (FMT) is a safe and effective therapy for recurrent Clostridioides difficile infection (CDI). Data on FMT for CDI in patients with underlying inflammatory bowel disease (IBD) are emerging but conflicting. We performed a systematic review and meta-analysis to describe the efficacy and safety of FMT for CDI in IBD and its impact on IBD outcomes. Methods: A systematic search of multiple databases including Embase, Scopus, and Web of Science was performed. Our primary analysis focused on pooled rate of CDI resolution after single and multiple FMTs in IBD patients. Additional analyses included rates of IBD-associated outcomes (flare, surgery, symptom improvement) after FMT. The random-effects model was used to calculate pooled rates. Results: Among 457 adult patients, 363 had CDI resolution after first FMT with a pooled cure rate of 78% [95% confidence interval (CI): 73%-83%; I 2=39%]. Overall pooled rate cure rate with single and multiple FMTs was 88% (95% CI: 81%-94%; I 2=73%). The pooled rate of an IBD flare after FMT was 26.8% (95% CI: 22.5%-31.6%; I 2=9%) and of colectomy was 7.3% (95% CI: 4.7%-10.5%; I 2=56%). Among 141 pediatric patients, 106 had CDI resolution after first FMT with pooled cure rate of 78% (95% CI: 58%-93%; I 2=59%). Overall pooled cure rate with single and multiple FMTs was 77% (95% CI: 50%-96%; I 2=63%). The pooled rate of an IBD flare after FMT was 10.8% (95% CI: 5.7%-18.5% I 2=43%), and of colectomy was 10.3% (95% CI: 2.1%-30.2% I 2=23%). Conclusions: FMT appears to be a highly effective therapy for preventing recurrent CDI in patients with IBD. Patients who fail a single FMT may benefit from multiple FMTs.

SummaryBackgroundTofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. We present final data from OCTAVE Open, an open‐label, long‐term extension study.AimsThe primary objective of OCTAVE Open was to assess the safety and tolerability of long‐term tofacitinib in patients with ulcerative colitis; evaluating efficacy was a secondary objective.MethodsEligible patients included OCTAVE Induction 1&2 non‐responders and OCTAVE Sustain completers/treatment failures. Patients in remission at OCTAVE Open baseline received tofacitinib 5 mg b.d.; all others received 10 mg b.d. Incidence rates (unique patients with events/100 patient‐years) for adverse events of special interest were calculated; ≤7.0 years of observation. Efficacy endpoints derived from Mayo score were reported ≤36 months (last scheduled endoscopy visit).ResultsIn OCTAVE Open, 769 of 944 patients (81.5%) initially received tofacitinib 10 mg b.d. Among all patients (2440.8 patient‐years of exposure), incidence rates (IRs; 95% confidence intervals) for deaths and adverse events of special interest were: deaths, 0.25 (0.09‐0.54); serious infections, 1.61 (1.14‐2.20); herpes zoster (non‐serious and serious), 3.16 (2.47‐3.97); opportunistic infections, 0.87 (0.54‐1.33); major adverse cardiovascular events, 0.16 (0.04‐0.42); malignancies (excluding non‐melanoma skin cancer), 1.03 (0.67‐1.52); non‐melanoma skin cancer, 0.75 (0.45‐1.19); deep vein thrombosis, 0.04 (0.00‐0.23); pulmonary embolism, 0.21 (0.07‐0.48). At Month 36, 66.9% and 40.3% showed clinical response, 64.6% and 37.1% had endoscopic improvement, and 58.9% and 33.7% maintained or achieved remission, with tofacitinib 5 and 10 mg b.d. respectively.ConclusionTofacitinib demonstrated consistent safety up to 7.0 years. Data collected up to Month 36 support long‐term efficacy beyond the 52‐week maintenance study.

BACKGROUND: Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator selectively targeting S1P 1 and S1P 5 , demonstrated superior efficacy and safety vs placebo for up to 52 weeks in adults with moderately to severely active ulcerative colitis (UC) in a phase 3 study (True North). In this post-hoc analysis, we evaluated the impact of prior biologic exposure on response to ozanimod. METHODS: True North consisted of two cohorts. In cohort 1, patients with UC received double-blind treatment with once-daily ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or placebo. In cohort 2, patients received open-label once daily ozanimod 0.92 mg. Ozanimod responders after a 10-week induction were re-randomized to double-blind maintenance with ozanimod 0.92 mg or placebo through week 52. Outcomes based on prior biologic exposure (biologic-naïve, 1 biologic, and 2+ biologics) and prior biologic type (anti-tumor necrosis factor [TNF] agents, vedolizumab, or both) were analyzed for clinical remission, clinical response, endoscopic improvement, and mucosal healing. Patients exposed to only a JAK inhibitor were excluded from the analysis. RESULTS: A total of 992 patients (n = 213 placebo and n = 426 ozanimod in cohort 1, n = 353 ozanimod in cohort 2) were included in the analysis for induction; 616 were biologic-naïve, 162 had exposure to 1 biologic, and 214 were exposed to 2 or more biologics. At baseline, biologic-exposed patients had more prior corticosteroid use, longer disease duration, and more extensive disease than biologic-naïve patients. During induction, greater therapeutic effects of ozanimod were generally seen in biologic-naïve vs biologic-exposed patients, and ozanimod-treated patients had greater responses on nearly all reported endpoints at week 10 (cohort 1). Clinical remission was achieved in 23% vs 6.6% of patients on ozanimod vs placebo who were biologic naïve, 17.2% vs 8.3% on 1 prior biologic, and 3.7% vs 2.5% on 2 or more biologics. Clinical response was reached in 53% vs 28% of patients on ozanimod vs placebo who were biologic naïve, 50% vs 33% on 1 biologic, and 27% vs 15% on 2 or more biologics. During maintenance, ozanimod-treated patients had greater responses on all endpoints versus placebo, with similar proportions of patients achieving clinical response to ozanimod regardless of prior biologic exposure (61% for biologic naïve, 60% for 1 biologic, and 55% for 2 or more biologics). At week 52, the proportion of patients on ozanimod with clinical remission was similar in the 1-biologic and 2+-biologic exposure groups (28% and 26%, respectively), and proportions of patients on ozanimod with endoscopic improvement and mucosal healing were similar for the 1-biologic and biologic-naïve groups (47% and 50%, 30%, and 33%, respectively). Among patients with inadequate response to prior anti-TNF agents, vedolizumab, or both at baseline, treatment effects favored ozanimod vs placebo on these endpoints in all three groups during both induction and maintenance. CONCLUSION: Ozanimod improved clinical, endoscopic, and histologic outcomes in both biologic-exposed and -naïve patients. Patients with prior biologic use may require additional time to respond to treatment. Outcomes were improved with ozanimod regardless of prior use of anti-TNF agents and vedolizumab.