A Phase 2, Multi-Center, Randomized, Double-Blind, Placebo-Controlled Parallel-Group Study to Evaluate the Safety, Tolerability, and Efficacy of Olorinab in Subjects With Irritable Bowel Syndrome Experiencing Abdominal Pain

The purpose of this study is to determine whether olorinab is a safe and effective treatment for abdominal pain in participants with irritable bowel syndrome (IBS).

开始日期2019-07-24

申办/合作机构

Arena Pharmaceuticals, Inc.

NCT03155945 / Completed临床2期

A Randomized, Open-label, Parallel, Phase 2a Study to Determine the Tolerability, Pharmacokinetics, and Efficacy of APD371 in Participants With Crohn's Disease Experiencing Abdominal Pain

The purpose of this randomized, open-label, parallel, phase 2a study is to determine the tolerability, pharmacokinetics, and efficacy of olorinab in participants with Crohn's disease experiencing abdominal pain.

开始日期2017-07-19

申办/合作机构

Arena Pharmaceuticals, Inc.

100 项与 Olorinab 相关的临床结果

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100 项与 Olorinab 相关的转化医学

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100 项与 Olorinab 相关的专利（医药）

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项与 Olorinab 相关的文献（医药）

2023-12-01·Clinical Gastroenterology and Hepatology

Cannabinoids and the Gastrointestinal Tract

Review

作者: Zheng, Ting ; Camilleri, Michael

The synthesis and degradation of endocannabinoids, location of cannabinoid (CB) receptors, and cannabinoid mechanisms of action on immune/inflammatory, neuromuscular, and sensory functions in digestive organs are well documented. CB₂ mechanisms are particularly relevant in immune and sensory functions. Increasing use of cannabinoids in the United States is impacted by social determinants of health including racial discrimination, which is associated with tobacco and cannabis co-use, and combined use disorders. Several conditions associated with emesis are related to cannabinoid use, including cannabinoid hyperemesis or withdrawal, cyclic vomiting syndrome, and nausea and vomiting of pregnancy. Cannabinoids generally inhibit gastrointestinal motor function; yet they relieve symptoms in patients with gastroparesis and diverse nausea syndromes. Cannabinoid effects on inflammatory mechanisms have shown promise in relatively small placebo-controlled studies in reducing disease activity and abdominal pain in patients with inflammatory bowel disease. Cannabinoids have been studied in disorders of motility, pain, and disorders of gut-brain interaction. The CB₂-receptor agonist, cannabidiol, reduced the total Gastroparesis Cardinal Symptom Index and increases the ability to tolerate a meal in patients with gastroparesis appraised over 4 weeks of treatment. In contrast, predominant-pain end points in functional dyspepsia with normal gastric emptying were not improved significantly with cannabidiol. The CB₂ agonist, olorinab, reduced abdominal pain in inflammatory bowel disease in an open-label trial and in constipation-predominant irritable bowel syndrome in a placebo-controlled trial. Cannabinoid mechanisms alter inflammation in pancreatic and liver diseases. In conclusion, cannabinoids, particularly agents affecting CB₂ mechanisms, have potential for inflammatory, gastroparesis, and pain disorders; however, the trials require replication and further understanding of risk-benefit to enhance use of cannabinoids in gastrointestinal diseases.

2023-05-01·Neurogastroenterology & Motility

Efficacy and safety of olorinab, a full agonist of the cannabinoid receptor 2, for the treatment of abdominal pain in patients with irritable bowel syndrome: Results from a phase 2b randomized placebo‐controlled trial (CAPTIVATE)

Article

作者: Cash, Brooks D. ; Cataldi, Fabio ; English, Brett A. ; Lipkis, Donald ; Turner, Stewart ; Tack, Jan ; Lembo, Anthony ; Chang, Lin ; Lindstrom, Beatriz ; Skare, Sharon ; Kunkel, David C. ; Gu, Guibao ; Gilder, Kye

Abstract:

Background:

Olorinab is a highly selective, peripherally acting, full agonist of cannabinoid receptor 2. This study assessed the efficacy and safety of olorinab to treat abdominal pain in patients with irritable bowel syndrome with diarrhea (IBS‐D) and constipation (IBS‐C).

Methods:

CAPTIVATE was a phase 2b, randomized, double‐blind, placebo‐controlled, parallel‐group trial. Eligible participants aged 18–70 years with IBS‐C and IBS‐D diagnosed per Rome IV received olorinab 10 mg, 25 mg, or 50 mg three times daily (TID) or placebo TID for 12 weeks. The primary endpoint was the change in patient‐reported average abdominal pain score (AAPS) from baseline to Week 12.

Key Results:

A total of 273 participants were randomized to receive olorinab 10 mg (n = 67), olorinab 25 mg (n = 67), olorinab 50 mg (n = 69), or placebo (n = 70). Although a treatment response was observed across all groups, the weekly change in average AAPS from baseline to Week 12 was not significantly different between placebo and any olorinab dose. In a prespecified subgroup analysis of participants with a baseline AAPS ≥6.5, olorinab 50 mg (n = 35) significantly improved AAPS compared with placebo (n = 30) (p = 0.014). Adverse event rates were comparable between olorinab and placebo and there were no reported serious adverse events or deaths.

Conclusion and Inferences:

Although olorinab was well‐tolerated and improved weekly AAPS, the primary endpoint was not met. However, in participants with moderate‐to‐severe pain at baseline (AAPS ≥6.5), olorinab 50 mg significantly improved weekly AAPS compared with placebo. ClinicalTrials.gov: NCT04043455.

2023-03-15·Nature communications1区 · 综合性期刊

Structural basis of selective cannabinoid CB₂ receptor activation.

1区 · 综合性期刊

ArticleOA

作者: de Paus, Laura V ; Liu, Zhi-Jie ; Heitman, Laura H ; van den Berg, Richard J B H N ; Li, Xiaoting ; Lichtman, Aron ; Kumar, Sanjay Sunil ; Wu, Lijie ; Hua, Tian ; Yu, Yanan ; van der Stelt, Mario ; Mustafa, Mohammed ; Bouma, Jara ; van der Horst, Cas ; Pacher, Pal ; Chang, Hao ; Janssen, Antonius P A ; Paloczi, Janos ; Mukhopadhyay, Partha

Cannabinoid CB₂ receptor (CB₂R) agonists are investigated as therapeutic agents in the clinic. However, their molecular mode-of-action is not fully understood. Here, we report the discovery of LEI-102, a CB₂R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate the selective CB₂R activation by binding kinetics, site-directed mutagenesis, and cryo-EM studies. We identify key residues for CB₂R activation. Highly lipophilic HU308 and the endocannabinoids, but not the more polar LEI-102, APD371, and CP55,940, reach the binding pocket through a membrane channel in TM1-TM7. Favorable physico-chemical properties of LEI-102 enable oral efficacy in a chemotherapy-induced nephropathy model. This study delineates the molecular mechanism of CB₂R activation by selective agonists and highlights the role of lipophilicity in CB₂R engagement. This may have implications for GPCR drug design and sheds light on their activation by endogenous ligands.

项与 Olorinab 相关的新闻（医药）

2023-02-11

·药渡Daily

新冠可能引起IBS？IBS的新药研发进展

中国疾病预防控制中心在1月25日发文称新冠感染已过高峰期，自2022年12初以来，各省份报告人群核酸检测阳性数及阳性率呈现先增加后降低趋势，2023年1月23日已降至1.5万。然而，感染新冠病毒之后可能会使感染者出现的长期新冠症状（Long Covid），一项对735,006名患者的荟萃分析显示，出现至少一种症状的COVID-19的合并长新冠患病率为 37.8%。全国在院新冠病毒感染者每日变化情况来源：全国新型冠状病毒感染疫情情况“长期新冠”的症状涉及呼吸系统、神经系统、心血管系统、胃肠系统等多个系统，会产生包括疲劳、焦虑、抑郁、呼吸急促、脑雾、心悸等不同症状。其中消化道症状主要包括腹泻（发病率4.00%）和腹痛（发病率3.82%）。近日，来自意大利研究人员在Gut（IF: 23.06）上发表了一项研究称COVID-19患者的肠易激综合征(irritable bowel disease, IBS)发生率明显高于对照组。GI-COVID-19是一项前瞻性、多中心、对照研究，该研究纳入了2183名住院患者，排除先前存在胃肠道症状和/或手术的情况，主要分析统计883名患者（614名COVID-19患者和269名对照患者）的情况。经1、6、12个月的随访发现，与对照组相比COVID-19患者的胃肠道症状发生率更高，根据罗马IV标准COVID-19 患者报告的IBS发生率也要更高(0.5% vs 3.2%)。12个月随访中肠道-大脑相互作用诊断(DGBI)障碍的患者比例来源：10.1136/gutjnl-2022-328483IBS是最常见的功能性胃肠道疾病之一，其症状包括腹部反复疼痛和排便习惯的改变（可能是腹泻、便秘或两者兼而有之）。根据排便习惯的改变，IBS在临床上可分为以下四种亚型，即腹泻型肠易激综合征（IBS-D)、便秘型肠易激综合征（IBS-C）、混合型肠易激综合征（IBS-M）、未分类型肠易激综合征（IBS-U）。IBS分类来源：Examine.com目前IBS发病机制远未明确，病因包括上皮细胞通透性增加、生态失调、炎症、内脏超敏反应、表观遗传学和遗传学，以及脑-肠相互作用改变等。因发病机制尚未能完全阐明且患者临床表现差别较大，目前已有的IBS治疗方案中的药物主要以对症治疗（便秘、腹泻、腹痛、腹泻等）为主。IBS常用药物IBS全球发病率为9.8%~12.8%，且近年来的患病率有提升趋势，而目前的治疗选择仍存在疗效不显著或者具有较大的副作用等局限性。许多公司正在开发和评估新型肠易激综合征候选药物，以改善治疗前景。临床阶段的IBS药物BEKINDA（Ondansetron）BEKINDA是由RedHill Biopharma开发的一种5-HT3受体拮抗剂Ondansetron的研究性双峰释放、每日给药一次的新制剂，其独特之处在于其能够将速释昂丹司琼与缓释基质相结合，以快速缓解症状，以维持长达24小时的治疗效果。BEKINDA（12mg）已在IBS-D的2期研究中表现出良好的疗效和安全性，RedHill目前正在完成两项关键3期研究的设计。OlorinabOlorinab（APD-371）是Arena发现的候选药物，它是大麻素2型受体（CB2）的完全激动剂。该化合物通过其对CB2与CB1的选择性，可以缓解疼痛而没有精神活性不良反应。一项在273名受试者中进行的随机、双盲、安慰剂对照2b期临床试验结果表明，尽管olorinab耐受性良好，但未达到从基线至第12周总AAPS实现统计学显著改善的主要有效性终点，主要终点是每周平均腹部疼痛评分（AAPS）相对基线的改善情况。使用olorinab治疗的第一周内疼痛有所减轻，并且在第4周和第8周观察到AAPS较基线水平有统计学显著改善。ORP101ORP101是由OrphoMed开发的外周阿片受体μ的部分激动剂以及阿片受体κ的拮抗剂。2018年，ORP-101被FDA授予治疗IBS-D的快速通道认证。ORP-101在治疗IBS-D的双盲、安慰剂对照、II期研究种展现出积极结果。总体而言， ORP-101 100 mg组在II期研究中达到了其主要终点，没有便秘的不良事件，也没有阿片类中枢神经系统效应（欣快感，运动或呼吸效应，醉酒等）。在12周治疗期间内，ORP-101 100 mg对没有胆囊的患者也是安全的。BlautixBlautix是4D pharma开发的一种单株人类肠道共生菌，具有独特的代谢行为，可能允许治疗肠易激综合征。在肠道内，Blautix消耗的气体会引起腹胀、腹痛和排便频率的变化。在II期试验中，Blautix在IBS-C和IBS-D中都表现出了临床活性信号，并且具有高度良好的安全性和耐受性。SK08活菌散SK08活菌散是知易生物基于脆弱拟杆菌（Bacteroides fragilis）开发的LBP药物。2022年12月，SK08活菌散完成了IBS-D上的一项随机、双盲、安慰剂平行对照、多中心、剂量探索的II期临床试验的所有入组和试验。该临床研究的初步结果显示SK08有着非常好的安全性，探索到了剂量关系，观察到了SK08对于IBS-D的有效性，为后续III期临床提供了非常必要的支持。TNP-2092TNP-2092是丹诺医药开发的一个多靶点偶联分子，通过抑制 RNA 聚合酶、DNA 旋转酶和拓扑异构酶IV的多靶点活性产生杀菌作用。TNP-2092口服剂与利福昔明具有类似的药代动力学特性，也是一个胃肠道专属性的药物，具有较低的耐药频率以及更强的抗菌活性。目前，TNP-2092口服剂已经进入II期临床试验。CrofelemerCrofelemer是Napo Pharmaceuticals开发的一种CFTR/CaCC双抑制剂，它是一种植物提取物。在腹泻时，Cl-分泌增多、伴有高容积水的丢失，Crofelemer通过阻断氯离子转运使胃肠道氯离子和水流动正常化。目前Crofelemer在IBS适应症上的开发处于临床II期阶段。RQ-00310941RQ-00310941是RaQualia开发的一种具有高活性和选择性的5-HT2B拮抗剂，该化合物已在动物模型中被证明可有效缓解内脏超敏性引起的疼痛和排便异常问题，而不影响正常排便。目前处于治疗IBS-D的临床I期试验阶段，还没有公布相关临床结果。SMP-100SMP-100是科岭源开发的5-HT3受体部分激动剂，有望在保持对症有效的情况下降低传统拮抗剂的副作用，成为潜在的Best-in-Class药物。在澳洲完成两项临床I期研究中，SMP-100显现出良好的耐受性和优异的安全性，国内I期临床研究仍在进行中。小结-IBS是临床上最常见的功能性胃肠病之一，全球发病率约为9.8%~12.8%，一项统计数据说明新冠感染者的IBS发生率可能更高。-IBS的症状已腹痛、腹胀、排便习惯改变为主，因症状长期存在、病程迁延反复，对患者的生活质量造成严重影响。-因发病机制不明、临床表现差异较大，IBS的用药策略以对症治疗为主。-目前针对IBS的新药研发仍在进行中，国内方面知易生物、丹诺医药和科岭源药业都有临床阶段的IBS管线。参考来源https://www.chinacdc.cn/jkzt/crb/zl/szkb_11803/jszl_13141/202301/t20230125_263519.htmlThe prevalence and long-term health effects of Long Covid among hospitalised and non-hospitalised populations: A systematic review and meta-analysis. EClinicalMedicine. 2022 Dec 1;55:101762.Marasco G, Cremon C, Barbaro MR the GI-COVID19 study group, et alPost COVID-19 irritable bowel syndromeGut Published Online First: 09 December 2022.中华医学会消化病学分会胃肠功能性疾病协作组, 中华医学会消化病学分会胃肠动力学组. 2020年中国肠易激综合征专家共识意见. 中华消化杂志,2020,40 (12): 803-818.END👇关注药渡数据媒体矩阵

临床结果

100 项与 Olorinab 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11429	-	-	DB14998

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
腹泻型肠易激综合征	临床2期	美国	Arena Pharmaceuticals, Inc.	2019-07-24
腹痛	临床2期	美国	Arena Pharmaceuticals, Inc.	2017-07-19
克罗恩病	临床2期	美国	Arena Pharmaceuticals, Inc.	2017-07-19

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04043455 (CTgov)	临床2期	腹泻型肠易激综合征 \| 腹痛	273	Olorinab (Main Study Period: Olorinab 10 mg)	範齋選衊蓋鏇夢積獵齋(選齋遞選窪觸齋窪鬱壓) = 襯壓糧壓壓衊糧積觸簾鑰顧艱齋鹹衊餘構願襯 (衊繭繭鬱蓋衊艱鹽廠廠, 窪衊糧廠糧獵壓鏇襯夢 ~ 鬱鹽鏇繭鬱遞築廠顧艱) 更多	-	2022-10-12
				Olorinab (Main Study Period: Olorinab 25 mg)	範齋選衊蓋鏇夢積獵齋(選齋遞選窪觸齋窪鬱壓) = 窪鬱遞選餘築鬱齋簾壓鑰顧艱齋鹹衊餘構願襯 (衊繭繭鬱蓋衊艱鹽廠廠, 鏇鏇繭醖願憲網觸餘鹽 ~ 網鏇糧蓋獵壓齋繭遞壓) 更多
NCT03155945 (CTgov)	临床2期	克罗恩病 \| 腹痛	14	Olorinab (Olorinab 25 mg TID)	蓋觸鹹壓餘憲廠鹹夢夢(積艱選顧鏇鹽壓獵遞艱) = 齋繭顧壓壓獵鹽鏇願膚願艱壓膚餘壓壓顧築蓋 (願積膚鏇淵衊鹽獵選鏇, 網構餘構廠觸鹽醖膚簾 ~ 獵鹹鏇衊積蓋膚醖壓範) 更多	-	2021-11-02
				Olorinab (Olorinab 100 mg TID)	蓋觸鹹壓餘憲廠鹹夢夢(積艱選顧鏇鹽壓獵遞艱) = 製築壓鹹壓廠簾願獵艱願艱壓膚餘壓壓顧築蓋 (願積膚鏇淵衊鹽獵選鏇, 醖網鹹壓艱製鏇觸醖選 ~ 積衊構繭鹽顧鑰願製糧) 更多
NCT04043455 (CAPTIVATE, BusinessWire) 人工标引	临床2期	腹痛	273	Olorinab	鹹鏇鹹艱網鬱襯鏇觸艱(簾選獵憲夢糧憲構觸夢) = Moderate to severe pain population at 50 mg showed statistically significant, clinically meaningful improvement vs placebo in Average Abdominal Pain Score (AAPS) 廠製鹹糧鏇衊構衊願餘 (壓夢鹹憲繭鏇簾膚醖鏇 ) 更多	积极	2021-03-02
				Placebo