2025-04-25 シカゴ大学(UChicago)
<関連情報>
- https://news.uchicago.edu/story/studies-identify-promising-new-treatments-ulcerative-colitis
- https://www.nejm.org/doi/full/10.1056/NEJMoa2314076
- https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)01927-5/abstract
- https://www.nature.com/articles/s41591-024-03280-4
潰瘍性大腸炎に対する抗TL1Aモノクローナル抗体Tulisokibartのフェーズ2試験 Phase 2 Trial of Anti-TL1A Monoclonal Antibody Tulisokibart for Ulcerative Colitis
Bruce E. Sands, M.D. , Brian G. Feagan, M.D., Laurent Peyrin-Biroulet, M.D., Ph.D., Silvio Danese, M.D., David T. Rubin, M.D., Olivier Laurent, Ph.D., Allison Luo, M.D., +9 , for the ARTEMIS-UC Study Group
The New England Journal of Medicine Published: September 25, 2024
DOI: 10.1056/NEJMoa2314076
Abstract
Background
Tulisokibart is a tumor necrosis factor–like cytokine 1A (TL1A) monoclonal antibody in development for the treatment of moderately to severely active ulcerative colitis. A genetic-based diagnostic test was designed to identify patients with an increased likelihood of response.
Methods
We randomly assigned patients with glucocorticoid dependence or failure of conventional or advanced therapies for ulcerative colitis to receive intravenous tulisokibart (1000 mg on day 1 and 500 mg at weeks 2, 6, and 10) or placebo. Cohort 1 included patients regardless of status with respect to the test for likelihood of response. Cohort 2 included only patients with a positive test for likelihood of response. The primary analysis was performed in cohort 1; the primary end point was clinical remission at week 12. Patients with a positive test for likelihood of response from cohorts 1 and 2 were combined in prespecified analyses.
Results
In cohort 1, a total of 135 patients underwent randomization. A significantly higher percentage of patients who received tulisokibart had clinical remission than those who received placebo (26% vs. 1%; difference, 25 percentage points; 95% confidence interval [CI], 14 to 37; P<0.001). In cohort 2, a total of 43 patients underwent randomization. A total of 75 patients with a positive test for likelihood of response underwent randomization across both cohorts. Among patients with a positive test for likelihood of response (cohorts 1 and 2 combined), clinical remission occurred in a higher percentage of patients who received tulisokibart than in those who received placebo (32% vs. 11%; difference, 21 percentage points; 95% CI, 2 to 38; P=0.02). Among all the enrolled patients, the incidence of adverse events was similar in the tulisokibart and placebo groups; most adverse events were mild to moderate in severity.
Conclusions
In this short-term trial, tulisokibart was more effective than placebo in inducing clinical remission in patients with moderately to severely active ulcerative colitis. (Funded by Prometheus Biosciences, a subsidiary of Merck; ARTEMIS-UC ClinicalTrials.gov number, NCT04996797.)
中等症から重症の活動性潰瘍性大腸炎患者を対象としたGuselkumab(QUASAR):第3相二重盲検無作為化プラセボ対照導入・維持試験 Guselkumab in patients with moderately to severely active ulcerative colitis (QUASAR): phase 3 double-blind, randomised, placebo-controlled induction and maintenance studies
David T Rubin, MD ∙ Jessica R Allegretti, MD ∙ Julián Panés, MD ∙ Nicole Shipitofsky, PharmD ∙ Shadi S Yarandi, MD ∙ Kuan-Hsiang Gary Huang, MD ∙ et al.
The Lancet Published: December 17, 2024
DOI:https://doi.org/10.1016/S0140-6736(24)01927-5
Summary
Background
Interleukin-23 inhibition is effective in treating ulcerative colitis. Guselkumab is a dual-acting, human IgG1, interleukin-23p19 subunit inhibitor that potently neutralises interleukin-23 and can bind to CD64. We aimed to evaluate the efficacy and safety of guselkumab as induction and maintenance therapy in patients with ulcerative colitis.
Methods
The primary populations of these two phase 3, randomised, double-blind, placebo-controlled studies (QUASAR phase 3 induction and maintenance) included randomised and treated adults with moderately to severely active ulcerative colitis (induction baseline modified Mayo score from 5 to 9) with inadequate response or intolerance to conventional or advanced ulcerative colitis therapy. Patients were randomly assigned (3:2) to receive guselkumab 200 mg given intravenously or placebo at weeks 0, 4, and 8 (phase 3 induction study). All patients were randomly assigned using web-based interactive response technology. Patients in clinical response 12 weeks after guselkumab induction given intravenously (from QUASAR phase 2b and phase 3 induction studies) were randomly assigned (1:1:1) at maintenance week 0 to guselkumab 200 mg given subcutaneously every 4 weeks or 100 mg every 8 weeks or placebo for 44 weeks (maintenance). Primary endpoints were clinical remission at induction week 12 and maintenance week 44. This study is registered with ClinicalTrials.gov, NCT04033445.
Findings
The induction study primary population included 701 patients (guselkumab 200 mg given intravenously 60% [421 patients]; placebo 40% [280 patients]). The maintenance study primary population included 568 guselkumab induction responders randomly assigned to receive guselkumab 200 mg given subcutaneously every 4 weeks (190 [33%] patients) or 100 mg every 8 weeks (188 [33%] patients) or placebo (guselkumab withdrawal 190 [33%] patients). A significantly greater proportion of patients treated with guselkumab given intravenously had clinical remission at induction week 12 (23% [95 of 421 patients]) than did placebo-treated patients (8% [22 of 280 patients]; adjusted treatment difference 15%, 95% CI 10–20; p<0·0001). Clinical remission at maintenance week 44 was achieved by a significantly greater proportion of patients treated with guselkumab 200 mg given subcutaneously every 4 weeks (50% [95 of 190 patients]; adjusted treatment difference 30%, 95% CI 21–38; p<0·0001) and 100 mg every 8 weeks (45% [85 of 188 patients]; adjusted treatment difference 25%, 16–34; p<0·0001) than with placebo (19% [36 of 190 patients]). The overall safety profile was favourable and consistent with that of guselkumab in approved indications. In the induction study, adverse events were reported by 49% of patients in both groups (208 of 421 guselkumab-treated patients and 138 of 280 placebo-treated patients), serious adverse events were reported by 3% (12 of 421) of guselkumab-treated patients and 7% (20 of 280) of placebo-treated patients, and adverse events leading to treatment discontinuation were reported by 2% (seven of 421) of guselkumab-treated patients and 4% (11 of 280) of placebo-treated patients. In the maintenance study, adverse event rates were similar among groups, and the most frequently reported adverse events in all groups were ulcerative colitis, COVID-19, and arthralgia. No active tuberculosis, anaphylaxis, serum sickness, or clinically important hepatic disorders were reported in either study.
炎症性腸疾患の非侵襲的な微生物ベースの診断 Noninvasive, microbiome-based diagnosis of inflammatory bowel disease
Jiaying Zheng,Qianru Sun,Mengjing Zhang,Chengyu Liu,Qi Su,Lin Zhang,Zhilu Xu,Wenqi Lu,Jessica Ching,Whitney Tang,Chun Pan Cheung,Amy L. Hamilton,Amy L. Wilson O’Brien,Shu Chen Wei,Charles N. Bernstein,David T. Rubin,Eugene B. Chang,Mark Morrison,Michael A. Kamm,Francis K. L. Chan,Jingwan Zhang & Siew C. Ng
Nature Medicine Published:04 October 2024
DOI:https://doi.org/10.1038/s41591-024-03280-4
Abstract
Despite recent progress in our understanding of the association between the gut microbiome and inflammatory bowel disease (IBD), the role of microbiome biomarkers in IBD diagnosis remains underexplored. Here we developed a microbiome-based diagnostic test for IBD. By utilization of metagenomic data from 5,979 fecal samples with and without IBD from different geographies and ethnicities, we identified microbiota alterations in IBD and selected ten and nine bacterial species for construction of diagnostic models for ulcerative colitis and Crohn’s disease, respectively. These diagnostic models achieved areas under the curve >0.90 for distinguishing IBD from controls in the discovery cohort, and maintained satisfactory performance in transethnic validation cohorts from eight populations. We further developed a multiplex droplet digital polymerase chain reaction test targeting selected IBD-associated bacterial species, and models based on this test showed numerically higher performance than fecal calprotectin in discriminating ulcerative colitis and Crohn’s disease from controls. Here we discovered universal IBD-associated bacteria and show the potential applicability of a multibacteria biomarker panel as a noninvasive tool for IBD diagnosis.
