Double-blind, Randomised, Placebo-controlled, Dose-finding Phase IIb Trial to Evaluate the Efficacy, Safety, and Tolerability of a 12-week-treatment With Naronapride in Adult Participants With at Least Moderate Idiopathic or Diabetic Gastroparesis

This is a double-blind, randomized, multicenter, placebo-controlled, comparative phase II dose-finding trial. The trial will be conducted with four treatment groups in the form of a parallel group comparison and will serve to compare oral treatment with daily doses of 10, 20, or 40 mg Naronapride vs. placebo for the treatment of patients with Gastroparesis.

开始日期2023-01-03

申办/合作机构

Dr. Falk Pharma GmbH

EUCTR2007-005008-41-IT / Not yet recruitingN/A

A Phase II, Randomized, Adaptive Design, Multicenter, Parallel Group, Placebo-controlled, 58-day, Dose-ranging Study of ATI-7505 in Patients with Postprandial Distress Syndrome - ND

开始日期2008-04-23

申办/合作机构

Procter & Gamble Pharmaceuticals, Inc.

NCT00630370 / Terminated临床2期

A Phase II, Randomized, Adaptive Design, Multicenter, Parallel Group, Placebo-Controlled, 58 Day, Dose-Ranging Study of ATI 7505 in Patients With Postprandial Distress Syndrome

To assess the efficacy of 3 oral dosing regimens of ATI 7505 compared to placebo in patients with PDS by comparing at the end of Day 42 the percentage of patients in each treatment group who have had adequate relief of postprandial distress syndrome symptoms on at least 50% of the treatment days.

开始日期2008-02-01

申办/合作机构

Procter & Gamble, Inc.

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项与 Naronapride dihydrochloride 相关的文献（医药）

2022-12-12·Expert opinion on pharmacotherapy

Pharmacotherapeutic advances for chronic idiopathic constipation in adults

Article

作者: Bassotti, Gabrio ; Villanacci, Vincenzo ; Bellini, Massimo ; Lai, Mariantonia ; Usai Satta, Paolo ; Berti, Ginevra

INTRODUCTION:

Chronic idiopathic constipation is a common gastrointestinal disorder whose treatment is still far from being satisfactory for patients. Osmotic laxatives, in particular polyethylene glycol, are the first-line approach, but new emerging pharmacological agents may be useful in refractory patients.

AREAS COVERED:

Published articles regarding the development and clinical efficacy of new agents in treating chronic idiopathic constipation were reviewed. Among emerging agents, elobixibat, a drug blocking the reabsorption of bile acids, is a promising one, especially in slow transit constipation. Linaclotide, lubiprostone and plecanatide, by a secretagogue action, improve stool consistency and increase colonic transit. Apart from prucalopride, approved in Europe for refractory chronic idiopathic constipation patients, the selective 5-HT4 agonists velusetrag and naronapride are in advanced development. In addition, relamorelin, a ghrelin agonist, seems promising for accelerating colonic transit.

EXPERT OPINION:

Several new promising drugs have been released with the potential to be effective in the treatment of chronic idiopathic constipation. On the other hand, the experience with these new agents is still limited, especially for long-term treatment. Another important point is that these new treatments for chronic idiopathic constipation are not available worldwide and their use could be somewhat limited by their still relatively high cost.

2021-04-01·Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society3区 · 医学

Prokinetic actions of luminally acting 5‐HT₄ receptor agonists

3区 · 医学

Article

作者: Guseva, Daria ; Wykosky, Jill ; Bischoff, Stephan C. ; Joyce, Emily ; Haag, Melody M. ; Lavoie, Brigitte ; Mawe, Gary M. ; Gibson, Tony S. ; Hurd, Molly ; Hennig, Grant W. ; Konen, John R. ; Falk, Matthew D. ; Kerrigan, Colleen B. ; Swann, Steve ; Griffin, Luana ; Linton, Alisha A. ; Matsukawa, Jun

Abstract:

Background:

5‐HT4 receptor (5‐HT4R) agonists exert prokinetic actions in the GI tract, but non‐selective actions and potential for stimulation of non‐target 5‐HT4Rs have limited their use. Since 5‐HT4Rs are expressed in the colonic epithelium and their stimulation accelerates colonic propulsion in vitro, we tested whether luminally acting 5‐HT4R agonists promote intestinal motility.

Methods:

Non‐absorbed 5‐HT4R agonists, based on prucalopride and naronapride, were assessed for potency at the 5‐HT4R in vitro, and for tissue and serum distribution in vivo in mice. In vivo assessment of prokinetic potential included whole gut transit, colonic motility, fecal output, and fecal water content. Colonic motility was also studied ex vivo in mice treated in vivo. Immunofluorescence was used to evaluate receptor distribution in human intestinal mucosa.

Key Results:

Pharmacological screening demonstrated selectivity and potency of test agonists for 5‐HT4R. Bioavailability studies showed negligible serum detection. Gavage of agonists caused faster whole gut transit and colonic motility, increased fecal output, and elevated fecal water content. Prokinetic actions were blocked by a 5‐HT4R antagonist and were not detected in 5‐HT4R knockout mice. Agonist administration promoted motility in models of constipation. Evaluation of motility patterns ex vivo revealed enhanced contractility in the middle and distal colon. Immunoreactivity for 5‐HT4R is present in the epithelial layer of the human small and large intestines.

Conclusions and Inferences:

These findings demonstrated that stimulation of epithelial 5‐HT4Rs can potentiate propulsive motility and support the concept that mucosal 5‐HT4Rs could represent a safe and effective therapeutic target for the treatment of constipation.

2019-11-01·The lancet. Gastroenterology & hepatology1区 · 医学

Efficacy of drugs in chronic idiopathic constipation: a systematic review and network meta-analysis

1区 · 医学

Review

作者: Pavit Luthra ; Christopher J. Black ; Eamonn Martin Quigley ; Michael Camilleri ; Nicholas E. Burr ; Alexander C. Ford

BACKGROUND:

There are several drugs available for the treatment of chronic idiopathic constipation, but their relative efficacy is unclear because there have been no head-to-head randomised controlled trials. We did a network meta-analysis to compare the efficacy of these therapies in patients with chronic idiopathic constipation.

METHODS:

We searched Medline, Embase, Embase Classic, and the Cochrane Central Register of Controlled Trials for randomised controlled trials published from inception to week 3 June, 2019, to identify randomised controlled trials assessing the efficacy of drugs (osmotic or stimulant laxatives, elobixibat, linaclotide, lubiprostone, mizagliflozin, naronapride, plecanatide, prucalopride, tegaserod, tenapanor, or velusetrag) in adults with chronic idiopathic constipation. Participants had to be treated for a minimum of 4 weeks, and we extracted data for all endpoints preferentially at 4 weeks, 12 weeks, or both. Trials included in the analysis reported a dichotomous assessment of overall response to therapy (response or no response to therapy). We pooled the data using a random effects model, and reported efficacy and safety of all treatments as a pooled relative risk (RR) with 95% CIs to summarise the effect of each comparison tested. To rank treatments, we used P-scores, which measure the extent of certainty that a treatment is better than another treatment, averaged over all competing treatments.

FINDINGS:

We identified 33 eligible randomised controlled trials of drugs, comprising 17 214 patients. Based on an endpoint of failure to achieve three or more complete spontaneous bowel movements (CSBMs) per week, the stimulant diphenyl methane laxatives bisacodyl and sodium picosulfate, at a dose of 10 mg once daily, were ranked first at 4 weeks (RR 0·55, 95% CI 0·48-0·63, P-score 0·99), and prucalopride 2 mg once daily ranked first at 12 weeks (0·82, 0·78-0·86, P-score 0·96). When response to therapy was defined as falilure to achieve an increase of one or more CSBM per week from baseline, diphenyl methane laxatives at a dose of 10 mg once daily ranked first at 4 weeks (0·44, 0·37-0·54, P-score 0·99), with prucalopride 4 mg once daily ranked first at 12 weeks (0·74, 0·66-0·83, P-score 0·79), although linaclotide 290 μg once daily and prucalopride 2 mg once daily had similar efficacy (P-scores of 0·76 and 0·71, respectively). Bisacodyl ranked last in terms of safety for total number of adverse events and abdominal pain (P-score 0·08).

INTERPRETATION:

Almost all drugs studied were superior to placebo, according to either failure to achieve three or more CSBMs per week or or failure to achieve an increase of one or more CSBM per week over baseline. Although diphenyl methane laxatives ranked first at 4 weeks, patients with milder symptoms might have been included in these trials. Prucalopride ranked first at 12 weeks, and many of the included trials recruited patients who previously did not respond to laxatives, suggesting that this drug is likely to be the most efficacious for patients with chronic idiopathic constipation. However, because treatment duration in most trials was 4-12 weeks, the long-term relative efficacy of these drugs is unknown.

FUNDING:

None.

项与 Naronapride dihydrochloride 相关的新闻（医药）

2024-11-07

·生物制药小编

报团取暖只为新赛道

近日，瑞士罕见病制药公司Relief Therapeutics与美国私营公司Renexxion签订了初步反向并购意向书。拟合并后的公司将优先开发Renexxion的胃轻瘫药物naronapride。在司美格鲁肽和替尔泊肽风靡的当下，GLP-1类药物的副作用——胃轻瘫的治疗药物已经逐步成为众多药企试图抢占的市场。这次尝试的naronapride实际上是一款在其他适应症上失败了多年的老药，可即便如此，为了新市场，这两家企业仍然愿意通过报团取暖的方式押注这一新赛道。失败的naronapride naronapride本身是一种口服小分子药物，最初的研发代码是ATI-7505，是一种选择性血清素5-HT4受体激动剂和D2拮抗剂。在胃轻瘫患者中，由于患者胃排空能力受到损伤，食物会长期滞留在患者胃部。需要通过药物促进肠道蠕动，尽可能排空患者胃内食物。 5-HT4受体激动剂和D2受体拮抗剂都是常见的促胃动力药物，而且在临床实践中也常常联合使用。 5-HT4受体激动剂如莫沙必利、伊托必利等，通过激活5-HT4受体，刺激消化道平滑肌神经丛，从而促进胃肠道的运动和蠕动，加速胃排空和肠道蠕动。这类药物能够显著改善患者的恶心、呕吐、腹胀等症状。早先的5HT4激动剂Propulsid(西沙必利)实现了近10亿美元的全球销售额，但由于5-HT4受体也存在于心脏，激动心脏组织里的5-HT4受体就会导致心律失常……由于这一副作用丑闻，西沙必利在2000年退出市场。而ATI-7505采用高选择性设计，保留了相同的作用机制，同时消除了安全问题。 D2受体拮抗剂，如多潘立酮等，主要作用在胃肠道的多巴胺D2受体上，通过阻断D2受体的功能，协调食管和近端小肠的运动，促进胃排空。此外，D2受体拮抗剂还具有止吐作用，能够缓解患者因胃排空延迟而引起的恶心和呕吐症状。显然这两种机制并不新颖，对于胃轻瘫来说，算是“新瓶装旧酒”。最初的开发公司ARYx Therapeutics倒是打算将其用于便秘这一适应症的开发，授权合作伙伴是宝洁制药公司，然而，2008年时，II期临床进行到半途，就遭到宝洁退货，II期临床宣告失败。 ARYx公司后续试图递交特殊方案评估（SPA）将其强行推进到III期临床，但公司已经没有资金支撑到FDA给予回复的时候了，因此倒闭破产。倒闭前反而责备FDA没有及时提供指导意见。而到了司美格鲁肽等GLP-1类药物大行其道之时，才有人将尘封已久的naronapride重新拿出来用于胃轻瘫和PPI无效的胃食管反流。新公司Renexxion某种意义上是ARYx Therapeutics的“重生”。领导班子几乎就是原ARYx Therapeutics的原班人马。总结实际上此次合并的另外一家公司Relief Therapeutics近年来的状况也并不好，今年更是把产品版税权出售给了金融公司换取现金，公司管理层也出现多次变动。孤注一掷下，双方报团取暖是否能够重新把握住胃轻瘫的市场仍未可知。参考来源： https://www.rnexltd.ie/pascal-druzgala.html https://news.pg.com/news-releases/news-details/2006/Procter--Gamble-Pharmaceuticals-and-ARYx-Therapeutics-Form-Alliance-for-an-Investigational-Treatment-for-Gastrointestinal-Disorders/default.aspx https://www.centerwatch.com/articles/23243 https://relieftherapeutics.com/newsblog-detail/?newsID=2874171

并购临床2期临床3期

2024-08-13

·GlobeNewswire-Health Care

Renexxion Ireland Ltd. and Dr. Falk Pharma GmbH Announce Expansion of the Phase 2b MOVE-IT Study of Naronapride in Gastroparesis and Dosing of the First United States Patient

ROSCREA, Ireland and FREIBURG, Germany, Aug. 13, 2024 (GLOBE NEWSWIRE) -- Renexxion Ireland Limited (“Renexxion”), a private biopharmaceutical company committed to delivering innovative drugs to patients with high unmet need in gastrointestinal (“GI”) disorders, in collaboration with its partner Dr. Falk Pharma GmbH (“Dr. Falk Pharma”), announce dosing of the first patient in the United States (U.S.) in the ongoing global Phase 2b MOVE-IT study (ClinicalTrials.gov ID: NCT05621811) evaluating the safety and efficacy of naronapride for the treatment of gastroparesis. The MOVE-IT study started dosing patients in Europe in February 2023 and has now expanded to include U.S. patients after recent IND clearance from the FDA for investigating naronapride in gastroparesis patients. “As a part of our goal to harmonize clinical development and regulatory pathways in the U.S. and EU, we are delighted to announce the dosing of the first U.S. patient in our collaborative Phase 2b study with Dr. Falk Pharma, marking a key milestone in the development of naronapride for gastroparesis. This latest achievement is a testament to the strength of our joint-clinical development team, and our unwavering commitment to provide a safe and effective treatment for gastroparesis.” said Dr. Peter Milner M.D., FACC, Chairman, and CEO of Renexxion. “The rapid integration of multiple research sites across the U.S. signifies the widespread recognition of the potential benefits that naronapride may offer to patients with gastroparesis.” Dr. Kai Pinkernell, M.D., Managing Director, Science & Innovation at Dr. Falk Pharma, added, "As the partner in Europe and Australasia, we are pleased to announce that Renexxion has facilitated the expansion of our ongoing Phase 2b MOVE-IT study to clinical sites in the U.S. The extension of this study is a testament to our strong partnership and will expedite the clinical development of naronapride for gastroparesis in our respective territories, as well as for other indications related to impaired GI motility." Naronapride is a potential best-in-class oral, locally acting pan-GI prokinetic that works by modulating two validated targets on the luminal surface of the intestinal wall, 5-HT4 receptor agonism and D2 receptor antagonism, with a well-differentiated pharmaceutical, pharmacokinetics, safety, and efficacy profile from other 5-HT4 agonists. Gastroparesis is characterized by delayed gastric emptying in the absence of mechanical obstruction and is caused primarily by diabetic and idiopathic etiologies, with some recent increases in iatrogenic disease potentially associated with widespread use of anti-obesity medications such as glucagon-like peptide-1 (GLP-1) agonists. Gastroparesis is a prevalent condition globally, with approximately 1.7% of the population in the U.S. and 1% in Europe having gastroparesis-like symptoms. Gastroparesis affects 9.3% of patients with diabetes, while 15-30% of patients taking GLP-1 agonists experience nausea and 5-10% experience vomiting, both of which are common symptoms of gastroparesis. There is a large, unaddressed demand for a safe and efficacious long-term therapy for gastroparesis. GI prokinetics play a crucial role in managing this condition. However, the most prescribed options have limited efficacy and cause off-target side effects, including permanent damage to the central nervous system and life-threatening cardiac arrhythmias. Naronapride is a potential best-in-class solution for this large and underserved patient population due to its clinically validated dual-action therapeutic approach and its favorable safety profile to date, which has been demonstrated across four Phase 2 trials and eight Phase 1 trials. Moreover, naronapride has already shown dose-dependent acceleration of gastric emptying in a GI transit study involving healthy human volunteers. “The rising prevalence of gastroparesis means increasingly more patients are experiencing symptoms of abdominal discomfort, nausea and vomiting, without having access to a safe and efficacious long-term treatment,” said Jan Tack, MD, PhD, Professor and Head of Clinic in the Department of Gastroenterology at University Hospitals Leuven, Leuven, Belgium, and Principal Investigator for the MOVE-IT study. “A recently published meta-analysis demonstrated that pure 5-HT4 agonists are associated with significant improvement in gastroparesis cardinal symptom index (GCSI) scores and faster gastric emptying time. This evidence supports the development of a novel 5-HT4 receptor agonist with the added synergistic benefit of D2 receptor antagonism, as a viable treatment for gastroparesis”, he added. About Naronapride Renexxion Ireland’s lead program is naronapride, a late-stage potential best-in-class drug candidate for unmet GI indications in the upper and lower GI tract. In scientific studies, naronapride has been demonstrated to possess a unique combination of both serotonin 5-HT4 receptor agonistic and dopamine D2 receptor antagonistic properties, both clinically validated targets. Naronapride was designed to be minimally absorbable and locally active in the gut lumen following oral administration to potentially enhance efficacy and safety. Four positive Phase 2 studies of naronapride have been completed. A Phase 2b study of naronapride in PPI-non-responsive symptomatic GERD is expected to commence in the next 12 months following the recent receipt of a May Proceed Letter and IND clearance from the FDA. Naronapride is also Phase 3 ready in chronic idiopathic constipation (“CIC”). About MOVE-IT MOVE-IT is a Phase 2b, double-blind, randomized, multicenter, placebo-controlled study designed to evaluate the efficacy, safety, and tolerability of naronapride in treating patients with idiopathic or diabetic gastroparesis. This trial compares the effects of three daily doses of naronapride (10 mg, 20 mg, and 40 mg TID) versus placebo over 12 weeks in approximately 320 patients, aiming to alleviate gastroparesis symptoms and improve quality of life. About Renexxion Ireland Renexxion Ireland Limited, a wholly owned Irish subsidiary of California-based Renexxion, Inc, is a privately held biopharmaceutical company committed to developing new drugs for patients with GI disorders. In addition to developing its lead product candidate, naronapride, Renexxion Ireland is currently advancing an additional research program focused on developing innovative drug candidates for inflammatory bowel disease (“IBD”) through the utilization of novel protein-drug conjugates. Further information on Renexxion Ireland can be found online: http://www.rnexltd.ie. About Dr. Falk Pharma GmbH Dr. Falk Pharma GmbH has been developing and marketing innovative medicines to treat a wide range of gastrointestinal disorders like inflammatory bowel disease or eosinophilic esophagitis as well as hepato-biliary disorders such as primary biliary cholangitis for over 60 years. As the international experts in digestive and metabolic medicine, the company brings together physicians, scientists, and patients to devise new and powerful approaches to patient care. Dr. Falk Pharma engages in pre-clinical and clinical stage research that aims to meaningfully improve therapeutic practice as well as patient health and well-being. A family-owned business with a global presence, Dr. Falk Pharma has ten affiliates in Europe and Australia and is continuously growing. The company has its headquarters and R&D facilities in Freiburg, Germany, its pharmaceutical products are manufactured in Europe, mainly at sites in Germany, France, Italy, and Switzerland. The Falk Group has a global workforce of around 1,250 employees, with 294 of the employees based in Freiburg. Further information on Dr. Falk Pharma can be found online: https://drfalkpharma.com. Media Inquiries: Press@rnexltd.ie +353 61 539121

临床2期临床1期临床结果临床3期

2024-03-30

·今日头条

Akk菌或是免疫性肾病帮凶？Science子刊揭示机制

本期话题：免疫性肾病，癌症疫苗，大肠癌，具核梭杆菌，免疫治疗，纳米医学，代谢综合征，NAMPT，强生，BMS，NeurAxis，Naronapride，科前生物该篇日报由R·AI辅助创作生成，人工审核校对。 Science子刊：Akk菌通过翻译后修饰IgA1，促进免疫性肾病 Science Translational Medicine——[17.1] ① 获得性自身免疫疾病中，自身耐受性被破坏的机制仍不清楚，本研究发现免疫球蛋白A（IgA）肾病患者肠道菌群中的黏蛋白降解菌，尤其是Akk菌的相对丰度增加；② Akk菌能够在体外及小鼠肠道内去糖基化IgA1，产生被IgA肾病患者血清中的自身反应性IgG识别的新表位；③ 这种去糖基化IgA1可通过逆向转运穿过肠上皮进入血液循环，并在小鼠肾脏的肾小球中沉积；④ 在与IgA肾病风险位点相关的人群中，发现α-防御素能够抑制Akk菌的生长，而在IgA肾病患者中，发现α-防御素6的粪便浓度与Akk菌数量间的负相关性消失；⑤ 本研究表明肠道菌群失调促进了在IgA肾病患者和小鼠模型中产生自身抗原。【原文信息】 The gut microbiota posttranslationally modifies IgA1 in autoimmune glomerulonephritis 2024-03-27 , doi: 10.1126/scitranslmed.adl6149 国内团队：新mRNA癌症疫苗有望改善结直肠癌治疗 Advanced Science——[15.1] ① 中国科学院大学吕雪光、北京大学苗蕾作为共同通讯作者发表研究，开发出一款新型mRNA癌症疫苗，可通过使用脂质纳米粒子（LNP）共递送全反式视黄酸（ATRA）和mRNA来刺激肠道黏膜免疫反应；② ATRA纳入LNP不仅提高了其mRNA递送效率和脾脏的全身T细胞反应，而且还使激活的T细胞具有肠道趋向性，显著增加细胞毒性T细胞对原位结直肠肿瘤的浸润，从而增强治疗效果；③ 与不含ATRA的传统mRNA-LNP相比，ATAR-LNP能显著提高了肿瘤抑制和动物存活时间。【原文信息】 All-Trans-Retinoic Acid-Adjuvanted mRNA Vaccine Induces Mucosal Anti-Tumor Immune Responses for Treating Colorectal Cancer 2024-03-25 , doi: 10.1002/advs.202309770 苏州大学：调节线粒体，改善大肠癌放疗抵抗 Advanced Science——[15.1] ① 苏州大学的杨凯、郭凌川和刘腾团队合作发表文章，开发出调节线粒体功能的脂质体，能有效逆转结直肠癌的放射抗性，提高放疗效果；② 临床结直肠癌样本中，初次X射线照射导致翻译起始因子eIF2α的磷酸化和转录激活因子ATF4的表达增加，从而对后续放疗产生抵抗；③ 在放射抗性的CT26细胞中，X射线照射引起的不完全线粒体外膜通透性（iMOMP）是导致p-eIF2α和ATF4表达升高，从而产生放射抗性的关键；④ 二甲双胍和2-DG通过抑制p-eIF2α和ATF4协同逆转放射抗性；⑤ 制备了载有二甲双胍和2-DG的脂质体（M/D-Lipo）来增强分次放疗的效果，通过逆转放射抗性和防止T淋巴细胞耗竭，在治疗局部和转移性结直肠癌中显示出良好的疗效。【原文信息】 Mitochondria-Modulating Liposomes Reverse Radio-Resistance for Colorectal Cancer 2024-03-23 , doi: 10.1002/advs.202400845 房静远团队：具核梭杆菌诱导大肠癌化疗耐药的新机制 Gut Microbes——[12.2] ① 上海交通大学附属仁济医院房静远、Cheng-Bei Zhou与团队发现，肠道菌群失调中的具核梭杆菌通过调控Hippo信号通路，抑制化疗药物诱导的细胞焦亡，从而在结直肠癌（CRC）中诱导化疗耐药性；② 具核梭杆菌富集与化疗后CRC复发显著相关；③ 具核梭杆菌可显著抑制化疗药物引起的细胞焦亡，从而诱导CRC细胞的化疗耐药；④ 机制上，具核梭杆菌可调节Hippo通路并促进BCL2表达，从而抑制化疗药物诱导的Caspase-3/GSDME相关的细胞焦亡通路，介导CRC细胞化疗耐药；⑤ 本研究突出了具核梭杆菌在CRC化疗耐药中的重要作用，为CRC的临床诊断和治疗提供了新的理论基础。【原文信息】 Fusobacterium nucleatum induces chemoresistance in colorectal cancer by inhibiting pyroptosis via the Hippo pathway 2024-03-27 , doi: 10.1080/19490976.2024.2333790 郑州大学：仿生纳米载体靶向消除瘤内具核梭杆菌，协同免疫治疗对抗乳腺癌 ACS Nano——[17.1] ① 郑州大学Yang Liying、刘军杰团队成功开发仿生纳米载体靶向清除瘤内具核梭杆菌（Fn），并与PD-L1阻断剂协同对抗乳腺癌；② Fn在乳腺癌中普遍存在，导致大量骨髓细胞涌入并产生免疫抑制肿瘤微环境，阻碍免疫检查点阻断（ICB）的疗效；③ 开发一种模仿Fn定位乳腺癌的仿生纳米载体，可实现抗生素甲硝唑的局部递送，有效消除瘤内Fn，而避免全身菌群失衡；④ 此纳米载体还共载铁蛋白纳米封装的阿霉素，与ICB疗法协同，显著提高PD-L1阻断剂的疗效，肿瘤抑制率超过90%，并延长4T1肿瘤小鼠的中位生存时间。【原文信息】 Biomimetic Nanovehicle-Enabled Targeted Depletion of Intratumoral Fusobacterium nucleatum Synergizes with PD-L1 Blockade against Breast Cancer 2024-03-18 , doi: 10.1021/acsnano.3c12687 国内团队：开发共生细菌衍生的纳米伪装，增强抗肿瘤免疫反应 ACS Nano——[17.1] ① 南京邮电大学汪联辉、丁显光团队成功开发了一种基于瘤内共生细菌外泌体（BEV）的纳米隐形斗篷（cBEV），可显著增强针对肿瘤和转移进程的免疫反应；② cBEV不仅克服严重的全身副作用，还通过细胞间应答性免疫原性增强免疫原性，并通过激活cGAS-STING途径促进树突细胞的成熟；③ 作为预防措施，使用纳米隐形斗篷包裹的cBEVs进行疫苗接种，能够强效防护细菌感染，同时大幅提高对抗肿瘤的预防效率；④ cBEV与免疫检查点抑制剂抗PD-L1抗体联合治疗，可激发强大的肿瘤特异性免疫反应，协同抑制肿瘤进展并减轻肺转移。【原文信息】 Programmed Nanocloak of Commensal Bacteria-Derived Nanovesicles Amplify Strong Immunoreactivity against Tumor Growth and Metastatic Progression 2024-03-19 , doi: 10.1021/acsnano.3c13194 国内团队：抗PD-1疗法在结直肠癌中的长期疗效——临床回顾研究 Journal of the National Comprehensive Cancer Network : JNCCN——[12.693] ① 中山大学肿瘤防治中心丁培荣、张晓实、潘志忠与云南省肿瘤医院的李云峰及团队对使用抗PD-1治疗达到完全临床缓解（cCR）的缺乏DNA错配修复（dMMR）/微卫星不稳定性高（MSI-H）局部晚期直肠癌患者的长期疗效进行一项临床回顾性分析；② 纳入中国4家医疗中心共24名患者进行分析，患者在接受抗PD-1基础治疗后达到cCR并采取非手术管理，中位随访时间为29.1个月，未观察到局部复发或远处转移；③ 患者三年内未复发率和总生存率均为100%；④ 对于dMMR/MSI-H局部晚期或低位直肠癌患者，抗PD-1基础治疗后达到cCR的长期结果是有希望的，但需要更大样本量的前瞻性临床试验来进一步验证。【原文信息】 Long-Term Outcomes of dMMR/MSI-H Rectal Cancer Treated With Anti-PD-1-Based Immunotherapy as Curative-Intent Treatment 2024-03-18 , doi: 10.6004/jnccn.2023.7096 江苏省中医院：代谢综合征与结直肠癌研究全球趋势 International Journal of Surgery——[15.3] ① 江苏省中医院的钱海华和张丹作为通讯作者在International Journal of Surgery发表最新研究，通过对616篇有关代谢综合征（MetS）与结直肠癌（CRC）的文献进行系统的计量学和可视化分析，揭示了两者间的紧密联系及研究热点；② 美国、中国和韩国在该研究领域的贡献最大，其中在公共科学图书馆发表的文献数量最多；③ 近年来，饮食、肥胖、胰岛素抵抗和肠道菌群等因素与MetS和CRC间的联系已成为研究的重点领域；④ 减重手术作为一种新兴的研究方向，显示出对MetS和CRC关系研究的潜在价值；⑤ 总之，本研究首次对CRC与MetS相关研究文献进行了计量学和可视化分析，为未来研究提供了方向和依据。【原文信息】 Global trends in colorectal cancer and metabolic syndrome research: a bibliometric and visualization analysis 2024-03-18 , doi: 10.1097/JS9.0000000000001342 与结直肠癌发生相关的炎症和代谢失调代谢物特征 Journal of the National Cancer Institute——[11.816] ① 本研究纳入684例结直肠癌（CRC）患者和684名健康对照，其中分为男性阵列（N=550）和女性阵列（N=818），通过其代谢组学以及疾病指标揭示炎症和代谢失调与结直肠癌风险相关的代谢特征；② 对代谢组中277种代谢物与炎症疾病指标（CRP、IL6、TNFRSF1B和GDF15）或代谢失调疾病指标（BMI、腰围、C肽和脂联素）进行相关性分析，发现100种代谢物可作为炎症特征，73种代谢物可作为代谢失调特征；③ 将所有277种代谢物与CRC进行多元逻辑回归分析，发现55种代谢物与男性或女性的 CRC 有显著相关性；④ 男性中两个疾病代谢物特征均与CRC风险相关，而在女性中未发现这种关联；⑤ 此外，11种代谢物特征被鉴定为CRC发展过程中炎症和代谢失调途径的潜在介质。【原文信息】 Metabolomic signatures of inflammation and metabolic dysregulation in relation to colorectal cancer risk 2024-03-01 , doi: 10.1093/jnci/djae047 NAMPT在结直肠癌中的免疫抑制作用 Advanced Science——[15.1] ① 本研究探索烟酰胺磷酸核糖转移酶（NAMPT）在结直肠癌（CRC）进展中的作用；② NAMPT在与免疫抑制活动相关的SPP1+ 肿瘤相关巨噬细胞（TAMs）中高表达，且与CRC患者的预后不良相关；③ NAMPT缺失导致巨噬细胞中HIF-1α不稳定，减少M2型TAM的极化，并显著降低巨噬细胞的吞噬活性，增强STING信号传导和I型干扰素反应基因的诱导；④ 以上基因的表达通过增强肿瘤微环境中细胞毒性T细胞的活性，有助于抗肿瘤免疫；⑤ 本研究揭示了针对NAMPT的策略或可为在CRC进展中建立免疫刺激性TME提供治疗方法。【原文信息】 NAMPT-Driven M2 Polarization of Tumor-Associated Macrophages Leads to an Immunosuppressive Microenvironment in Colorectal Cancer 2024-02-02 , doi: 10.1002/advs.202303177 强生「古塞奇尤单抗」新适应证上市申请获受理 ① 3月27日，强生公司的古塞奇尤单抗注射液新适应证上市申请获药监局受理；② 该药物推测用于治疗中重度活动性克罗恩病（CD）成年患者，已被纳入优先审批；③ 古塞奇尤单抗是首个获批的白介素23（IL-23）抑制剂，用于治疗多种自身免疫性疾病；④ 此前，该药物用于治疗中重度斑块状银屑病成人患者已在中国获批上市；⑤ 古塞奇尤单抗2023年全球销售额达到31.47亿美元（约合人民币227.47亿元）。【原文信息】强生「古塞奇尤单抗」新适应症申报上市，治疗中重度活动性克罗恩病 2024-03-27 , 医药魔方info BMS公布Ozanimod治疗克罗恩病新临床结果 ① 3月28日，百时美施贵宝（BMS）对外表示，Ozanimod在治疗中重度活动性克罗恩病YELLOWSTONE项目中第一个为期12周的诱导研究上，未达到主要终点；② Ozanimod是一款1-磷酸鞘氨醇（S1P）受体调节剂，该产品已在美国获批治疗多发性硬化症、溃疡性结肠炎；③ YELLOWSTONE研究项目包含两项为期12周的诱导研究、一项为期52周的维持研究和264周的开放标签扩展研究；④ 诱导研究主要终点为患者临床缓解情况，即克罗恩病活动指数（CDAI）评分低于150的患者比例，诱导研究（n=600）结果显示，第12周时未达到临床缓解主要终点。【原文信息】 BMS公布两项III期研究结果 2024-03-29 , 医药魔方 NeurAxis公布IB-Stim治疗儿童肠-脑互作障碍临床结果 ① 3月27日，NeurAxis宣布一项IB-Stim治疗儿童肠-脑互作障碍（DGBI）的临床研究结果；② IB-Stim是一种经皮神经电刺激疗法，研究显示，IB-Stim对治疗儿童DGBI相关的胃肠症状和功能有显著改善，持续效果达到12个月；③ 研究涉及7个美国大型三级护理中心，共有292名患者参与，其中92%的患者之前药物治疗无效；④ 患者在治疗前后使用腹痛指数（API）等多个验证性量表进行评估，结果显示，治疗4周后各时间点患者API均有显著改善。【原文信息】 NeurAxis Announces IB-Stim Results from a Large, Pediatric, Multi-Center Registry 2024-03-27 , GlobeaNewswire Naronapride治疗胃轻瘫IND申报获批 ① 3月27日，Renexxion与Dr. Falk Pharma两家公司宣布，Naronapride用于治疗胃轻瘫的新药临床试验申请（IND）获得FDA批准；② Naronapride是一种口服胃肠道促动力药物，通过作用于肠壁表面的5-HT4受体激动和D2受体拮抗来发挥作用；③ 该药物已在四项2期临床试验中显示出良好的安全性和有效性；④ Renexxion和Dr. Falk Pharma计划扩大MOVE-IT研究的规模，顶线结果预计将在2025年中期公布。【原文信息】 Renexxion Ireland Ltd. and Dr. Falk Pharma GmbH Announce FDA Clearance of the Investigational New Drug Application for Naronapride to Treat Gastroparesis and Subsequent Expansion of the Ongoing Phase 2b MOVE-IT Study to the United States 2024-03-27 , GlobeNewswire 科前生物宣布猪丁型冠状病毒灭活疫苗获批成新兽药 ① 3月28日，武汉科前生物股份有限公司宣布其猪丁型冠状病毒灭活疫苗（CHN-HN-2014株）获新兽药注册证书；② 疫苗由科前生物联合华中农业大学等单位研制，监测期为5年，注册证书号为（2024）新兽药证字10号，注册分类为一类；③ 猪丁型冠状病毒可感染不同日龄和品种的猪，临床上以腹泻、呕吐、脱水为主要特征，对新生仔猪的危害最为严重，发病率可达100%。【原文信息】武汉科前生物股份有限公司关于获批新兽药注册证书的自愿性信息披露公告 2024-03-28 , 上海证券报感谢本期日报的审核者：九卿臣，章台柳，圆圈儿，RZN，Johnson，Alex Zhang，Richard 点击阅读过去10天的日报： 0329 | 33页综述纵论：超加工食品健康转型的新策略 0328 | Science子刊：锁定肠道中让病毒逃脱免疫的"避风港" 0327 | 10文聚焦菌群-肠-脑轴研究新进展 0326 | 100分综述详解：IBD细胞因子疗法最前沿 0325 | 大肠癌患病为何年轻化？遗传与生活方式的双重影响 0324 | 大型临床试验：补钙补D如何影响老年女性长期健康？ 0323 | Lancet+JAMA领衔，聚焦炎症性肠病诊断与治疗 0322 | 陈豪燕/洪洁等Cell子刊：免疫治疗对老年人更有效，肠道菌群或是隐藏功臣 0321 | 今日Nature双发：促肠癌菌和宿主-菌群互作研究均有新突破 0320 | 12页高分综述解析：抗生素扰乱菌群，对宿主代谢有何影响？

疫苗信使RNA临床1期免疫疗法临床结果

100 项与 Naronapride dihydrochloride 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
糖尿病性胃轻瘫	临床2期	美国	Dr. Falk Pharma GmbH	2023-01-03
糖尿病性胃轻瘫	临床2期	比利时	Dr. Falk Pharma GmbH	2023-01-03
胃轻瘫	临床2期	美国	Dr. Falk Pharma GmbH	2023-01-03
胃轻瘫	临床2期	比利时	Dr. Falk Pharma GmbH	2023-01-03
胃轻瘫	临床2期	比利时	Renexxion LLC	2023-01-03
便秘	临床2期	美国	Renexxion LLC	2016-11-16
消化不良	临床2期	美国	Renexxion LLC	2016-10-26
餐后窘迫综合征	临床2期	美国	Procter & Gamble, Inc.	2008-02-01
餐后窘迫综合征	临床2期	美国	ARYx Therapeutics, Inc.	2008-02-01
餐后窘迫综合征	临床2期	加拿大	Procter & Gamble, Inc.	2008-02-01