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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100 项与 Naronapride dihydrochloride 相关的临床结果

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100 项与 Naronapride dihydrochloride 相关的转化医学

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100 项与 Naronapride dihydrochloride 相关的专利（医药）

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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. ; Haag, Melody M. ; Joyce, Emily ; Lavoie, Brigitte ; Mawe, Gary M. ; Gibson, Tony S. ; Hurd, Molly ; Hennig, Grant W. ; Konen, John R. ; Kerrigan, Colleen B. ; Falk, Matthew D. ; 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 ; Michael Camilleri ; Eamonn Martin Quigley ; 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）

2024-11-26

·GlobeNewswire-Health Care

Renexxion Ireland Ltd. Announces Issuance of Fifth New U.S. Patent Covering Novel Crystal Isoform of Naronapride

ROSCREA, Ireland, Nov. 26, 2024 (GLOBE NEWSWIRE) -- Renexxion Ireland Limited (“Renexxion”), a private biopharmaceutical company dedicated to delivering innovative treatments for patients with significant unmet needs in gastrointestinal (“GI”) disorders, is pleased to announce a major milestone in its intellectual property portfolio. The United States Patent and Trademark Office (“USPTO”) has granted the fifth patent (Patent No. 12,098,149) in a comprehensive series, securing broad protection for a novel crystal isoform of naronapride, Renexxion’s lead compound, and its use in the treatment of GI disorders. “We are pleased to have secured this patent, which not only underscores the innovative nature of naronapride but also strengthens our ability to deliver transformative therapies to patients who urgently need new treatment options,” said Dr. Pascal Druzgala, PhD, Co-founder, Director and Chief Scientific Officer of Renexxion. “The patent is part of a comprehensive IP portfolio, solidifying our commitment to pioneering advancements in GI disorders as we continue to advance naronapride in mid-stage clinical trials.” This new pharmaceutical composition patent marks the fifth in a series covering naronapride, with its novel crystal isoform; a potential best-in-class, orally administered pan-GI prokinetic agent. Naronapride functions by modulating two clinically-validated targets: 5-HT4 receptor agonism and D2 receptor antagonism. It has demonstrated a well-differentiated profile in terms of pharmaceutical properties, pharmacokinetics, safety, and efficacy compared to other 5-HT4 agonists in clinical studies. Naronapride is Renexxion’s lead drug candidate, currently in mid-stage clinical development for gastroparesis and proton-pump inhibitor non-responsive symptomatic gastroesophageal reflux disease (“PPI-nrsGERD”), both of which represent high unmet needs with limited or no existing treatments. The new patent is also being prosecuted worldwide, including in Europe, Japan, and Greater China. “Securing this patent strengthens our intellectual property portfolio, continuing progress on naronapride’s global clinical development,” said Dr. Peter Milner, M.D., FACC, Chairman and CEO of Renexxion. “We are dedicated to sustaining this momentum and eagerly anticipate further achievements.” About Naronapride: Naronapride is Renexxion Ireland’s flagship program, addressing critical unmet needs in both upper and lower GI tract disorders. It uniquely combines serotonin 5-HT4 receptor agonistic and dopamine D2 receptor antagonistic properties, targeting clinically-validated receptors. Designed for minimal absorption and local activity in the gut lumen, naronapride aims to optimize both efficacy and safety. Following the completion of four successful Phase 2 studies, a global Phase 2b study in gastroparesis is currently underway (ClinicalTrials.gov ID: NCT05621811). An additional Phase 2b study targeting PPI-nrsGERD is anticipated to launch within the next year, following the FDA’s May Proceed Letter and IND clearance. Furthermore, Renexxion is preparing naronapride for Phase 3 trials in chronic idiopathic constipation (“CIC”). About Renexxion Ireland: Renexxion Ireland Limited, a wholly-owned subsidiary of California-based Renexxion, Inc., is a privately held biopharmaceutical company committed to pioneering innovative treatments for GI disorders. In addition to developing its lead product candidate, naronapride, Renexxion Ireland is advancing a research program targeting inflammatory bowel disease (“IBD”) through novel protein-drug conjugates. For further information on Renexxion Ireland, please visit: http://www.rnexltd.ie. Media Inquiries: Press@rnexltd.ie +353 61 539121

临床2期临床申请

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

100 项与 Naronapride dihydrochloride 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D09934	-	-	DB05542

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	ARYx Therapeutics, Inc.	2008-02-01
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	加拿大	ARYx Therapeutics, Inc.	2008-02-01