Study on the efficacy and safety of pancreatic enzyme replacement therapy for total enteral nutrition-related diarrhea in moderately to severely active Crohn's disease

开始日期2024-07-10

申办/合作机构-

ChiCTR2400079788 / Suspended早期临床1期IIT

A multicenter prospective clinical study of transanal loop resection for anorectal stenosis of refractory Crohn’s disease

开始日期2024-01-11

申办/合作机构

江苏省中医院

EUCTR2021-005019-30-DE / Not yet recruiting临床2/3期

A Phase 2/3, Multicenter, Randomized, Double-blind Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Oral Ozanimod (RPC1063) in Pediatric Participants with Moderately to Severely Active Crohn’s Disease with an Inadequate Response to Conventional Therapy

开始日期2023-09-27

申办/合作机构

Celgene International II SARL

100 项与活动性重度克罗恩病相关的临床结果

登录后查看更多信息

100 项与活动性重度克罗恩病相关的转化医学

登录后查看更多信息

0 项与活动性重度克罗恩病相关的专利（医药）

登录后查看更多信息

项与活动性重度克罗恩病相关的文献（医药）

2023-07-01·Crohn's & Colitis 360

Pretreatment Vitamin D Concentrations Do Not Predict Therapeutic Outcome to Anti-TNF Therapies in Biologic-Naïve Patients With Active Luminal Crohn’s Disease

Article

作者: Lin, Simeng ; Bewshea, Claire ; McDonald, Timothy J ; Bishara, Maria ; Nice, Rachel ; Goodhand, James R ; Kennedy, Nicholas A ; Chanchlani, Neil ; Ahmad, Tariq ; Hamilton, Benjamin ; Roberts, Christopher ; Smith, Rebecca

AbstractBackground and AimsVitamin D has a regulatory role in innate and adaptive immune processes. Previous studies have reported that low pretreatment vitamin D concentrations are associated with primary non-response (PNR) and non-remission to anti-TNF therapy. This study aimed to assess whether pretreatment 25-hydroxyvitamin D concentrations predicted PNR and non-remission to infliximab and adalimumab in patients with active luminal Crohn’s disease.Methods25-Hydroxyvitamin D concentrations were measured in stored baseline samples from 659 infliximab- and 448 adalimumab-treated patients in the Personalised Anti-TNF Therapy in Crohn’s disease (PANTS) study. Cut-offs for vitamin D were deficiency <25 nmol/L, insufficiency 25–50 nmol/L, and adequacy/sufficiency >50 nmol/L.ResultsAbout 17.1% (189/1107; 95% CI, 15.0–19.4) and 47.7% (528/1107; 95% CI, 44.8–50.6) of patients had vitamin D deficiency and insufficiency, respectively. 22.2% (246/1107) of patients were receiving vitamin D supplementation. Multivariable analysis confirmed that sampling during non-summer months, South Asian ethnicity, lower serum albumin concentrations, and non-treatment with vitamin D supplementation were independently associated with lower vitamin D concentrations. Pretreatment vitamin D status did not predict response or remission to anti-TNF therapy at week 14 (infliximab Ppnr = .89, adalimumab Ppnr = .18) or non-remission at week 54 (infliximab P = .13, adalimumab P = .58). Vitamin D deficiency was, however, associated with a longer time to immunogenicity in patients treated with infliximab, but not adalimumab.ConclusionsVitamin D deficiency is common in patients with active Crohn’s disease. Unlike previous studies, pretreatment vitamin D concentration did not predict PNR to anti-TNF treatment at week 14 or nonremission at week 54.

2020-09-01·The Ulster medical journal

Diverticular Disease: A Review on Pathophysiology and Recent Evidence.

Review

作者: Piscopo, Naomi ; Ellul, Pierre

Diverticular disease is common condition globally, especially in Western countries. Diverticulitis, Symptomatic uncomplicated Diverticular disease and Segmental Colitis associated with diverticula constitute diverticular disease. Although most patients with diverticula are asymptomatic, around 25% of patients will experience symptoms whilst 5% of patients have an episode of acute diverticulitis. The prevalence increases with age with more than one theory being put forward to explain its pathogenesis. Faecolith entrapment in diverticula results in colonic mucosal damage and oedema, bacterial proliferation and toxin accumulation leading to perforation. This mechanism may explain diverticulitis in elderly patients with multiple, larger diverticula. Ischaemic damage could be the cause of acute diverticulitis in younger patients with sparse diverticula where more frequent and forceful muscular contractions in response to colonic stimuli occlude the vasculature leading to ischaemia and microperforation. Chronic colonic active inflammation in the presence of diverticular disease is termed Segmental colitis associated with diverticulosis. Its pathophysiology is still indeterminate but together with its clinical picture, may mimic Inflammatory Bowel Disease. Treatment includes a high fibre diet together with antibiotics and/or salicylates with surgery in severe cases. Indications for elective surgery in diverticular disease have changed over the past decades as this may not suggest a reduction in morbidity and mortality. Prophylaxis with probiotics, laxatives, anti-spasmotics, anticholinergic drugs and salicylates are at the centre of recent studies. Studies are also challenging previously believed facts regarding dietary fibre, nuts and seeds whilst emphasizing the effect of healthy lifestyle and smoking on the increasing incidence of DD.

2020-03-01·Gut1区 · 医学

Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells

1区 · 医学

Review

作者: Lord, Graham M ; Pantazi, Eirini ; Yang, Feifei ; Parker, Aimee ; Afzali, Behdad ; Li, Katherine ; Stolarczyk, Emilie ; MacDonald, Thomas T ; Pin, Carmen ; Friedman, Joshua ; Mohamed, Rami ; Digby-Bell, Jonathan ; Bewick, Gavin A ; Tjir-Li, Tsui ; Minns, Danielle ; Cozzetto, Domenico ; Powell, Nick ; Kaser, Arthur ; Lavender, Paul ; Tsakmaki, Anastasia ; Pavlidis, Polychronis ; Saveljeva, Svetlana

ObjectiveThe functional role of interleukin-22 (IL22) in chronic inflammation is controversial, and mechanistic insights into how it regulates target tissue are lacking. In this study, we evaluated the functional role of IL22 in chronic colitis and probed mechanisms of IL22-mediated regulation of colonic epithelial cells.DesignTo investigate the functional role of IL22 in chronic colitis and how it regulates colonic epithelial cells, we employed a three-dimentional mini-gut epithelial organoid system, in vivo disease models and transcriptomic datasets in human IBD.ResultsAs well as inducing transcriptional modules implicated in antimicrobial responses, IL22 also coordinated an endoplasmic reticulum (ER) stress response transcriptional programme in colonic epithelial cells. In the colon of patients with active colonic Crohn’s disease (CD), there was enrichment of IL22-responsive transcriptional modules and ER stress response modules. Strikingly, in an IL22-dependent model of chronic colitis, targeting IL22 alleviated colonic epithelial ER stress and attenuated colitis. Pharmacological modulation of the ER stress response similarly impacted the severity of colitis. In patients with colonic CD, antibody blockade of IL12p40, which simultaneously blocks IL12 and IL23, the key upstream regulator of IL22 production, alleviated the colonic epithelial ER stress response.ConclusionsOur data challenge perceptions of IL22 as a predominantly beneficial cytokine in IBD and provide novel insights into the molecular mechanisms of IL22-mediated pathogenicity in chronic colitis. Targeting IL22-regulated pathways and alleviating colonic epithelial ER stress may represent promising therapeutic strategies in patients with colitis.Trial registration numberNCT02749630.

项与活动性重度克罗恩病相关的新闻（医药）

2024-10-25

·Pharmaceutical Technology

Sanofi-backed Agomab raises $89m to advance fibrotic disease treatments

Agomab’s lead candidate is being investigated as a treatment for patients with fibrostenosing Crohn’s disease (FSCD). Credit: Hananeko_Studio via Shutterstock. Agomab Therapeutics has secured $89m in Series D funding to support clinical trials of its fibrotic disease treatments, with some help from Sanofi . Belgium-based Agomab announced that Sanofi and Invus have joined as new investors in its latest funding round, following on from a $100m Series C round in October 2023, and a $114m Series B where Pfizer led an extension round. The funds will be used to advance the development of Agomab’s lead candidate AGMB-129, a treatment for patients with fibrostenosing Crohn’s disease (FSCD). The oral small molecule inhibitor of ALK5 (TGFβ1R) is currently being investigated in the Phase IIa STENOVA trial (NCT05843578). The company expects to share interim results from the 90-patient trial in early 2025. Positive data from the Phase I trial (NCT04933565) of AGMB-129 was reported in February 2023, where the candidate demonstrated high local exposure in the ileum, with no drug-related safety signals or dose-limiting toxicities. Patients with FSCD have strictures in the intestines caused by inflammation and scarring, for which there is no cure. The company also has an inhaled treatment for idiopathic pulmonary fibrosis (IPF), named AGMB-447, and a liver cirrhosis candidate AGMB-101. AGMB-447 is being investigated in a Phase I trial (NCT06181370) and Agomab plans to start clinical development of AGMB-101, which is “in the final stages of IND-enabling studies”. See Also: Dyno and Roche collaborate on neurological gene therapies Takeda and BMC partner to decarbonise US healthcare sector Sanofi continues to assert itself in the immunology space, signing deals with parties such as Recludix, Teva Pharmaceutical and IGM Biosciences . The company expanded its immunology pipeline further in June 2024, entering a $700m strategic partnership with Belharra Therapeutics to spur the development of small molecule therapies for immunological diseases. Sanofi and Regeneron’s immune-targeting biologic Dupixent (dupilumab) has been picking up label expansions since its 2017 US Food and Drug Administration (FDA) approval for atopic dermatitis. The drug earned $11.6bn last year, as per Regeneron’s financials, and is set to generate $23.6bn in 2030, according to GlobalData consensus forecasts. GlobalData is the parent company of Pharmaceutical Technology. In the announcement accompanying the funding, Agomab’s CEO Tim Knotnerus said: “We are thrilled to have Sanofi and Invus joining our investor syndicate. Their investment as well as the continued support from our existing shareholders is another validation of the trailblazing work our team is conducting in the fields of fibrostenosing Crohn’s disease and idiopathic pulmonary fibrosis.”

临床1期临床2期上市批准免疫疗法临床结果

2024-10-25

·EndPoints

Sanofi backs fibrosis biotech Agomab as it raises $89M Series D

Agomab Therapeutics is benefiting from Sanofi’s push to become an immunology powerhouse. The Antwerp-based biotech said Friday that the French drug giant and Invus are new investors in its $89 million Series D that arrived one year after its $100 million Series C . Pfizer and Boehringer Ingelheim have also backed Agomab. The company wasn’t seeking additional money. “The $100 million is still in the bank,” Agomab CEO Tim Knotnerus said in an interview. But after receiving inbound interest from Sanofi, the biotech’s execs discussed it with the board and then did a “very selective reach-out” to other investors. It took only a month to close the round, the CEO said. The new financing will fund an ongoing Phase 2a of Agomab’s lead therapy — an oral small molecule for a subset of Crohn’s disease patients — and another oral drug candidate already in Phase 1 for idiopathic pulmonary fibrosis. It also plans to take a MET agonistic antibody into human studies in the first half of next year for liver cirrhosis. Agomab anticipates interim data for the first 40 of 90 patients from the Phase 2a of AGMB-129 in early 2025. Investigators are testing the gut-restricted ALK5 inhibitor in patients with fibrostenosing Crohn’s disease, which impacts about half the people with the inflammatory bowel disease. It has the FDA fast track tag. “Can we indeed avoid the known cardio toxicity that is associated with ALK5?” Knotnerus said. “We believe we can because of the way our compound has been designed, so that we have high local exposure of our ALK5 asset in the gastrointestinal tract and very low systemic exposure.” In the first half of next year, the biotech also expects to have the first batch of healthy volunteer data from the Phase 1 trial in IPF for its ALK5 inhibitor that is lung-restricted, according to Knotnerus. IPF leads to difficulties with breathing and impairs multiple other functions, eventually leading to death for many patients within about five years. Boehringer and Roche each market medicines for IPF, and both were approved by the FDA 10 years ago. Many drug developers are following up with next-generation medicines. Amid a broader restructuring of its business, Sanofi has continued to bet on oncology and I&I. In recent months, it invested in several companies developing IPF medicines like Vicore Pharma and Graviton Bioscience . The company also earmarked up to $1.5 billion for the anti-TL1A race in a partnership with Teva . Agomab broke cover in 2019 with a $23 million Series A. It snagged a $74 million Series B in 2021 and bought Spanish startup Origo Biopharma later that year. The 60-employee startup also now has an office in Cambridge, MA. It added former Seagen leader David Epstein to its board this summer, and Pierre Kemula — who headed finance at CureVac when it went public — is set to start as CFO on Nov. 1.

临床1期临床2期快速通道IPO上市批准

2024-09-12

·凯莱英药闻

全球首批！强生IL-23双重抑制剂古塞奇尤单抗获FDA批准用于溃疡性结肠炎

欢迎关注凯莱英药闻 2024年9月11日，强生（“Johnson & Johnson”）宣布美国食品药品监督管理局 (FDA) 已批准Tremfya（guselkumab，古塞奇尤单抗）用于治疗中度至重度活动性溃疡性结肠炎 (UC) 成人患者。公司声称，Tremfya是首个也是唯一一个获批用于治疗活动性溃疡性结肠炎的针对白细胞介素 23（IL-23）的双重作用抑制剂，此次获批巩固了强生在炎症性肠病领域的领导地位。关于古塞奇尤单抗古塞奇尤单抗是全球首个获批的白介素23（IL-23）抑制剂，可选择性结合IL-23的p19亚基，抑制其与IL-23受体的相互作用，对多种自身免疫性疾病具有良好疗效；它可阻断 IL-23，同时还可与产生 IL-23 的细胞上的受体 CD64 结合。目前已获批用于治疗斑块状银屑病、活动性银屑病关节炎和UC。此外，2024 年 6 月，强生向 FDA 提交了一份补充生物制品许可申请 (sBLA)，用于治疗中度至重度活动性克罗恩病（CD）成人患者。本次在UC的适应症获批主要基于2b/3 期 QUASAR 研究的数据，该研究评估了 Tremfya 对中度至重度活动性 UC 成人患者的疗效和安全性，这些患者对常规疗法、其他生物制剂和/或 JAK 抑制剂反应不足或不耐受。结果显示：其中，有 50%每四周 (q4w) 接受Tremfya 200 mg皮下 (SC) 维持治疗、以及有 45%每八周 (q8w) 接受Tremfya 100 mg SC维持治疗的患者，在第 44 周达到临床缓解的主要终点，而接受安慰剂治疗的患者这一比例为 19% (p<0.001)。接受 Tremfya SC 维持治疗一年后，34% (200 mg) 和 35% (100 mg) 的患者达到内镜缓解，而接受安慰剂治疗的患者这一比例为 15% (p<0.001)。在诱导治疗阶段，接受 Tremfya或安慰剂治疗的患者中，最常见的不良反应 (>2%) 是呼吸道感染。在维持治疗阶段，接受 TREMFYA 治疗或安慰剂治疗的患者中，最常见的不良反应 (>3%) 是注射部位反应、关节痛和上呼吸道感染。关于IL-23 p19药物 IL-23 p40是IL-12及IL-23的共同亚基，p40抗体可同时阻断IL12及23两条免疫通路，是一种经典免疫疗法。而近年来以古塞奇尤单抗为代表的IL-23 p19抗体展现了比p19抗体更好的疗效与更高的安全性。 p19除了与p40组成IL-23这一经典炎症因子，还会与EBI3组合成为IL-39激活IL-23R与gp130，这是由血管内皮细胞等介导的重要炎症通路。IL-23与IL39均可以激活胞内的JAK-STAT信号通路，刺激IL-17A/F的分泌。据不完全统计，目前在研的IL-23 p19药物约15种。 2023年10月，礼来的Omvoh（mirikizumab）获FDA批准上市，用于治疗中重度活动性UC成人患者，这是首个用于治疗这一患者群体的IL-23p19拮抗剂。此外，艾伯维的利生奇珠单抗是首个获得FDA批准用于治疗IBD的IL-23药物，2022年6月获批用于CD，2024年6月亦获批用于UC。关于炎症性肠病炎症性肠病（IBD）是一种非特异性的慢性复发性肠道炎症性疾病，通常表现为腹泻、直肠出血、腹痛、疲劳和体重减轻。目前IBD的病因和发病机制仍未被完全阐明，主流观点认为是自身免疫功能紊乱，触发异常的免疫反应，导致免疫系统攻击消化道内的正常细胞。 IBD包括溃疡性结肠炎（UC）和克罗恩病（CD）。UC和CD在肠道受累位置和病理特征上有所区分： UC会导致大肠（结肠）和直肠表层覆膜引起炎症和溃疡； CD会导致消化道内膜发炎，炎症通常会累及消化道的深层-小肠，少数情况下还可能累及大肠和上消化道。 2019年IBD的全球患病人数约为490万，其中中国的患者数量达到了91万。从1990年到2019年，中国男性IBD发病数从每十万人1.72例上升到了3.35例，女性发病数从每十万人1.20例上升到了2.45例。当前全球IBD市场规模已增加至180亿美元。研究表明，IBD肠道炎症发生和持续的关键是白细胞迁移到肠道组织中，这个过程依赖于内皮细胞表面的黏附分子（如VCAM-1， MAdCAM-1）与白细胞表面的整合素（由α和β亚单位构成）的特异性结合。因此，以内皮细胞表面的黏附分子和整合素为靶点，阻断二者特异性结合，可以有效治疗IBD肠道炎症。目前，肿瘤坏死因子α（TNF-α）、白介素12/23（IL-12/23）、白细胞黏附因子等表达升高常见于IBD疾病活动期，阻断以上细胞因子可有效阻止下游炎性反应以及白细胞趋化运动导致的肠黏膜损伤。此外，Janus激酶（JAK）/STAT通路和肠道菌群等作为靶点在IBD中的作用也逐渐被揭示。治疗指南支持的常规策略如下：由于IBD的病因和发病机制尚不明确，无法根治，药物治疗的主要目的是减轻炎症活动、维持缓解、降低复发率及手术率。常用的治疗药物包括抗炎药，免疫系统抑制剂，抗生素，小分子口服药剂和生物制剂。其中，相对于5-氨基水杨酸类、激素和免疫抑制剂等传统药物，生物制剂因其更为明确的疗效和良好的安全性而成为IBD的主流治疗方法。关于强生在IBD的布局在 IBD 领域，强生布局了TNF-α单抗英夫利西单抗以及戈利木单抗，两种药物在2023年的销量均超过20亿美元。除古塞奇尤单抗外，首个IL-12/23单抗 Stelara（乌司奴单抗）以及口服IL-23拮抗剂 JNJ-2113均在开发IBD适应症。此外，公司还在针对复发患者开发古塞奇尤单抗与戈利木单抗的复方制剂（JNJ-8408）。据不完全统计，目前强生在炎症性肠病领域布局的药物近20种。参考资料 1、公司官网 2、中信建投 3、XPharma 感谢关注、转发，转载授权、加行业交流群，请加管理员微信号“hxsjjf1618”。 “在看”点一下

免疫疗法上市批准