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更新于：2025-11-22

BIA-102474

更新于：2025-11-22

概要

概要

基本信息

药物类型

小分子化药

别名

BIA 10、BIA 10 2474、BIA 102474

+ [2]

靶点

FAAH

作用方式

抑制剂

作用机制

FAAH抑制剂(脂肪酸酰胺水解酶抑制剂)

治疗领域

神经系统疾病其他疾病

在研适应症-

非在研适应症

疼痛

原研机构

BIAL-Portela & Cia SA

在研机构-

非在研机构

BIAL-Portela & Cia SA

权益机构-

最高研发阶段终止临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

分子式C16H20N4O2

InChIKeyDOWVMJFBDGWVML-UHFFFAOYSA-N

CAS号1233855-46-3

关联

100 项与 BIA-102474 相关的临床结果

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100 项与 BIA-102474 相关的转化医学

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100 项与 BIA-102474 相关的专利（医药）

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项与 BIA-102474 相关的文献（医药）

2021-01-02·Critical reviews in toxicology2区 · 医学

Non-clinical toxicology evaluation of BIA 10-2474

2区 · 医学

Article

作者: Soares-da-Silva, Patrício ; Moser, Paul ; Weber, Klaus ; Hayes, A. Wallace

In 2016, one subject died and four were hospitalized with neurological symptoms during a clinical trial with the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474. The present paper reviews the regulatory toxicology studies that were carried out to support the clinical trial application for BIA 10-2474. Animal studies complied with national and international standards including European regulatory guidelines (e.g. EEC Council Directive 75/318/EEC and subsequent amendments). The CNS effects seen in the rat and mouse appear to be common in rodents in such studies and do not in principle seem to be of the type to generate a signal. In the same way in non-human primates, insignificant alterations in the mesencephalon, and especially of the autonomic nervous system (Meissner's plexus in the bowel) in rodents and monkeys were observed in some animals treated with a high dose. Overall, these data, as well as the extensive additional data generated since the accident, support the conclusion that the tragic fatality that occurred during the clinical trial with BIA 10-2474 was unpredictable and that the mechanism responsible remains unknown, from a non-clinical toxicological perspective.

2020-09-01·EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY

First-in-human dose: current status review for better future perspectives

Article

作者: Reeta, Kh ; Mishra, Archana ; Sarangi, Sudhir Chandra

AIM:

The aim of this article is to understand the pros and cons of various methods involved in first-in-human (FIH) dose calculation and act decisively in dose escalations when calculating the maximum tolerated dose.

SUBJECTS AND METHODS:

We reviewed early phase clinical trials for methods of FIH dose and dose-escalation steps and discuss them in line with existing guidelines. We also reviewed the clinical trial registry to recognize trends in trial registration in recent years and after a massive failure in a few trials.

RESULTS:

Phase 1 trials of TGN 1412 and BIA10-2474 would always be remembered as catastrophes for pharmaceutical development plans. Quite often than not, healthy human volunteers are the guinea pigs in this stage of drug development. And, the most important aspect of designing an early phase study is deciding upon the dose to be started with, apart from the selection of cohort and escalation steps. The common principles used for FIH dose calculation include no observed adverse effect level, minimum anticipated biological effect level, pharmacologically active dose, pharmacokinetic/pharmacodynamic approach, and similar drug comparison approach.

CONCLUSION:

Early phase clinical trials are basically foundation stones on which lies the entire onus of the later stages of development. Deciding FIH dose is a crucial step that necessitates the incorporation of detailed data from the preclinical stages and application of the most conservative approach for the safety/benefit of the volunteers in these studies.

2020-05-01·British Journal of Pharmacology

Preclinical pharmacological evaluation of the fatty acid amide hydrolase inhibitor BIA 10‐2474

Article

作者: Moser, Paul ; Sousa, Filipa ; Loureiro, Ana I. ; Bonifácio, Maria‐João ; Fernandes‐Lopes, Carlos ; Soares‐da‐Silva, Patrício ; Aires, Cátia ; Palma, Pedro Nuno ; Pires, Nuno M.

Background and Purpose:

In 2016, one person died and four others had mild‐to‐severe neurological symptoms during a phase I trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10‐2474.

Experimental Approach:

Pharmacodynamic and pharmacokinetic studies were performed with BIA 10‐2474, PF‐04457845 and JNJ‐42165279 using mice, rats and human FAAH expressed in COS cells. Selectivity was evaluated by activity‐based protein profiling (APBB) in rats. BIA 10‐2474 effect in stroke‐prone spontaneously hypertensive rats (SHRSP) was investigated.

Key Results:

BIA 10‐2474 was 10‐fold less potent than PF‐04457845 in inhibiting human FAAH in situ but inhibited mouse brain and liver FAAH with ED50 values of 13.5 and 6.2 μg·kg−1, respectively. Plasma and brain BIA 10‐2474 levels were consistent with in situ potency and neither BIA 10‐2474 nor its metabolites accumulated following repeat administration. FAAH and α/β‐hydrolase domain containing 6 were the primary targets of BIA 10‐2474 and, at higher exposure levels, ABHD11, PNPLA6, PLA2G15, PLA2G6 and androgen‐induced protein 1. At 100 mg·kg−1 for 28 days, the level of several lipid species containing arachidonic acid increased. Daily treatment of SHRSP with BIA 10‐2474 did not affect mortality rate or increased the incidence of haemorrhage or oedema in surviving animals.

Conclusions and Implications:

BIA 10‐2474 potently inhibits FAAH in vivo, similarly to PF‐04457845 and interacts with a number of lipid processing enzymes, some previously identified in human cells as off‐targets particularly at high levels of exposure. These interactions occurred at doses used in toxicology studies, but the implication of these off‐targets in the clinical trial accident remains unclear.

项与 BIA-102474 相关的新闻（医药）

2025-11-13

·东药西毒

药物中的杂质需要做毒理学试验吗？

前言今年的DABT考试中有好几道题目涉及到药物杂质，比如说药物NDA时杂质需要做多久的毒理学试验？ICH Q3D中 2类杂质的评估方法？杂质的限量是多少？我翻看之前的文章没有涉及过药物杂质的安全性评价，正好这次补上。指导原则目前关于药物杂质评估的指导原则包括： ICH： Q3A新原料药中的杂质、 Q3B新药制剂中的杂质、 Q3C杂质：残留溶剂的指导原则、 Q3D元素杂质指导原则、 M7遗传毒性杂质 M3非临床研究 FDA： NDAs: Impurities in Drug Substances； Control of Nitrosamine Impurities in Human Drugs: Guidance for Industry； Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities； ANDAs: Impurities in Drug Products: Guidance for Industry； ANDAs: Impurities in Drug Substances: Guidance for Industry CDE：《化学药物杂质研究技术指导原则》《化学药物中亚硝胺类杂质研究技术指导原则（试行）》总论药物中杂质（Impurity）定义是新药制剂中除了原料药或赋形剂以外的任何其他成分。目前杂质可分为下列类型： *有机杂质（与工艺和药物结构有关的） *无机杂质 *残留溶剂（为在原料药或辅料的生产中以及制剂制备过程中使用或产生的有机挥发性化合物）需要指出的是，这里的杂质不包括：外源性污染物：不应该存在于新原料药中，可以用GMP来控制的；多晶型；对映异构体杂质。杂质的质量控制中需要定义三个限值：报告限度、鉴定限度和界定限度。报告限度（Reporting Threshold）：高于此限度的杂质需在分析证书（CoA）或监管提交中报告杂质的水平。它确保了杂质监测的透明度。鉴定限度（Identification Threshold）：高于此限度的杂质必须进行化学表征以确定其结构和来源的水平。这有助于了解杂质的潜在来源（例如，降解、合成副产物）。界定限度（Qualification）：高于此限度的杂质必须通过毒理学研究或风险评估确保其安全性。这确保了杂质不会对患者构成重大风险。各论新原料药杂质限值如下：新药制剂中的杂质限值如下：杂质鉴定和界定的决策树：界定要求：根据具体情况，单剂量药物可进行单剂量试验。一般最短14天，最长90天。结语这一篇先写这些，关于溶剂、元素和遗传毒物的杂质在下一篇梳理。参考文献： Determination of Impurities in Pharmaceuticals: Why and How? DOI: 10.5772/intechopen.83849 ICH指导原则 FDA指导原则正版书籍推荐药物非临床安全性评价系列文章药物临床试验和上市前分别需要做哪些非临床安全性评价项目毒理学在药物研发中的作用如何将新药快速推进到I期临床试验药物研发指导原则介绍-ICH 新药相关化学实体毒性资料检索美国FDA药品数据库使用攻略近30年FDA上市了哪些新药 FDA颁布的药物非临床研究技术指导原则 OECD颁布的毒理学技术指导原则动物剂量如何换算成人体等效剂量毒性剂量低于临床治疗暴露量怎么办？辨析: 临床前 vs. 非临床不常见的给药途径和动物模型介绍药物给药方式选择和注意事项单次给药毒性试验剂量探索试验重复给药毒性试验之一重复给药毒性试验之二我们需要知道的遗传毒理学试验知识药物免疫毒性试验怎么做-I 药物免疫毒性试验怎么做-II 非啮齿类动物使用注意事项药物非临床致癌性试验怎么做毒理学试验如何选择合适的动物种属毒理学试验高剂量选择指南不能忽视的安全药理学试验浅谈动物年龄实验动物需要检疫多久？食蟹猴，恒河猴，狨猴，毒理学试验怎么选择非人灵长类动物小型猪在药物安评中的应用毒代和药物安全性评价局部刺激性试验药物过敏性试验如何开展新药非临床生殖发育毒性试验DART是怎么回事非临床依赖性试验怎么做？毒理学中的卫星组与药物安全性有关的临床试验事件（上；TGN1412）与药物安全性有关的临床试验事件（下; BIA 10-2474) 疫苗非临床安全性评价要点以Skysona为例讲解如何开展基于细胞的基因治疗产品临床前安全性评价造影剂非临床安全性评价 ADC药物的非临床安全性评价吸入制剂非临床安全性评价儿科用药非临床安全性研究眼部给药的非临床安全性评价详解NOAEL part 1 详解NOAEL part 2 详解NOAEL part 3 详解NOAEL part 4 你知道这些药物毒理学概念的区别吗？监管部门推荐的先进治疗药品分类动物毒理学剂量如何换算新药人体首次剂量 FDA 指南：基于寡核苷酸的治疗的非临床安全性评估-翻译整理稿古代经典名方中药复方制剂安评怎么做？都叫免疫缺陷小鼠，有什么区别？药物毒理学中的肝脏损伤标志物药物毒理学中的肾脏损伤标志物药物毒理学中的心脏-骨骼肌损伤标志物药物毒理学中的血管和神经系统损伤标志物药物毒理学中的免疫系统标志物 I 药物毒理学中的免疫系统标志物 II 毒理学研究中的统计学 I 毒理学研究中的统计学 II 毒理学研究中的统计学 III 致癌性试验皮肤给药制剂剂量设计浅谈受试物纯度替代毒理学：器官芯片和类器官毒理学认证考试教程系列文章通过毒理学家认证有什么用 DABT美国毒理学家认证考试备考Tips（2025年版）欧洲毒理学家ERT认证攻略 RQAP-GLP (美国GLP注册QA资质考试) 备考Tips 中国毒理学家认证考试备考Tips（2025版）号外 | 毒理学家认证考试备考服务内容简介重磅推出 | 毒理学家认证考试培训班开班了号外 | 英文和中文毒理学家认证考试题库都上线了毒理学家认证考试微信群矩阵毒理学资格考试教程（1）毒理学资格考试教程（2）毒理学资格考试教程（3）毒作用及其影响因素毒理学资格考试教程（4）毒理学资格考试教程（5）靶器官毒理学毒理学资格考试教程（6）毒代动力学毒理学资格考试教程（7）吸收毒理学资格考试教程（8 吸收：各种暴露方式））毒理学资格考试教程（9）分布毒理学资格考试教程（10）生物转化毒理学资格考试教程（11）排泄毒理学资格考试教程（12）细胞毒性毒理学资格考试教程（13）风险评估 I 毒理学资格考试教程（14）风险评估 II 毒理学视角 Deepseek能帮毒理学工作者做什么？毒理学家使用Deepseek的注意事项 “毒枸杞”的毒理学毒理学视角看“油罐车煤油食用油混装”事件流感爆发，神药“安乃近”去哪了？ “毒”土地是什么毒？药物毒理学和2023年诺贝尔生理学或医学奖 2024年诺贝尔生理学或医学奖和药物毒理学被韩国拒收的月饼竟然是因为它-脱氢乙酸钠写给职场觉醒者的你 | 公众号两周年记 “铅中毒”知多少预制菜和毒理学 2025年印度止咳糖浆药害事件 --END-- 版权声明 | 免责声明仅供感兴趣的个人参考，非商用，非投资用。欢迎朋友们批评指正！衷心感谢！文中图片来自微信公共图片库，或取自网络。根据CC0协议使用，版权归拥有者。任何问题，请与我们联系。衷心感谢。

临床1期

2023-12-23

·生物制药小编

被两度转手的弃子管线，最终停止开发

近日（12月21日），爵士制药（Jazz Pharmaceuticals）宣布了该公司的PTSD（创伤后应激障碍）药物JZP150的II期临床数据，该实验未达所有主要终点和次要终点，这也宣告了这项曾被两度转手的产品最终停止了在PTSD这一唯一适应症的开发。从药品本身来看，JZP150（又名PF-04457845）是一款脂肪酸酰胺水解酶（FAAH）抑制剂，用于潜在治疗PTSD及相关症状。这款产品最初由辉瑞开发，后来又在2017年被辉瑞许可给了SpringWorks Therapeutics，而爵士制药最终又在2020年向SpringWorks购得该产品的独家全球权利。那么FAAH抑制剂本身靠谱吗？还确实有点不靠谱。爵士制药是一家大麻素科学相关的制药企业，许多产品和管线都与大麻素相关，而此次FAAH抑制剂的作用机理确实和大麻素相关。一例FAAH抑制剂致人脑死亡脂肪酸酰胺水解酶是一种完整的膜酶，它可以水解脂质递质的脂肪酰胺家族，包括研究最彻底的内源性大麻素，但也有很多其他受体也参与这一路径如PPARs，TRPV1，GPR55。从机制上来看，FAAH抑制剂/灭活剂能够增加内源性大麻素的浓度。而内源性大麻素是膜磷脂前体按需释放的脂质介质。内源性大麻素的增加相对于外源性激动剂来说会减少大麻素样的副作用。而从FAAH抑制剂的普遍性疗效来看，其实相对于那些外源性大麻素的效果还是相当不错的。在对于那些FAAH抑制剂，如JZP150（PF-04457845）、JNJ-42165279、SSR-411298、V-158866和URB597，来说，虽然长期结果尚且未知，但普遍观察结果是FAAH抑制剂并没有明显诱发通常与外源性大麻素相关的副作用，如认知障碍、运动协调和精神病。已完成的临床试验的可用数据还表明，FAAH抑制剂耐受性良好。JZP150（当时还是辉瑞在推动临床）的一项I期研究表明，与安慰剂相比，嗜睡的增加只是轻微的，对认知功能没有影响。相应的II期研究表明，该药物的安全性与安慰剂没有区别，其主要治疗相关副作用为头晕。但就在大家都以为副作用似乎不是很严重的时候，法国Biotrial Pharmacology Center开发的同类竞品BIA 10-2474在一项临床研究中出现了一例严重不良事件（SAE），一位志愿者之前服用较低剂量(20 mg)时未报告SAE。最严重的症状具有中枢神经系统特征的，可之后却出现迅速导致脑死亡的单一昏迷病例相关的症状。在其他5名住院参与者中，2名有严重的神经损伤(几天内临床症状明显改善)。由于这些事件，BIA 10-2474的临床立即终止。在Biotrial事故宣布后，作为预防措施，JNJ-42165279的两个试验也被暂停。辉瑞也在临床没什么成效（当时开发的是骨关节镇痛）后转手了给了SpringWorks。不明来源的发病机制法国国家药品和保健品安全局（ANSM）后续对于BIA 10-2474的报告还揭露了一些令人不安的事实：他们的简报提到了与大脑功能严格相关的症状，核磁共振成像观察显示存在“不同严重程度的微脑组织损伤和不同寻常的扫描断层”，而且这种损伤似乎还是因人而异的，有着“突然就出现”的特征。但是这种现象为什么会出现？这个问题并没有答案，也没人愿意或者再敢去回答，有些人认为可能是由与其他药理学靶点的相互作用引起的，或者是仅在超过特定浓度阈值时才变得重要，还有些人认为因为阻断了FAAH触发了人体内未知的替代补偿途径，但是也不知道人体内到底有什么触发的替代补偿途径。ANSM至少排除了制造相关问题，在临床前研究似乎也没什么问题，FAAH缺陷型小鼠(基因敲除)生长健壮，没有表现出异常行为症状，这支持了BIA 10-2474本身或其代谢产物而不是FAAH的抑制是不良反应原因的假设。总结很显然，因为人体机制可能存在的未接明机制使得HAAP复杂化，也没有太多人愿意冒着生命风险试探不可预知的风险，因此JZP150这一类的FAAH抑制剂的开发未来可能仍然存在许多问题，还需要很多基础研究。参考来源：Mallet C, Dubray C, Dualé C. FAAH inhibitors in the limelight, but regrettably. Int J Clin Pharmacol Ther. 2016 Jul;54(7):498-501. doi: 10.5414/CP202687. PMID: 27191771; PMCID: PMC4941643.https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-provides-update-phase-2-trial

临床2期临床1期临床终止

2016-01-22

·BioSpace

Johnson & Johnson Halts Trial of Drug Similar to One Linked to Brain Dead Tragedy in France

January 22, 2016 By Alex Keown , BioSpace.com Breaking News Staff NEW BRUNSWICK, N.J. -- Johnson & Johnson has halted a trial of an experimental fatty acid amide hydrolase inhibitor, a drug similar to one being tested in France by a Portuguese pharmaceutical company that left one patient brain dead and five others hospitalized, Reuters reported this morning. A Johnson & Johnson spokesperson told Reuters the company voluntarily suspended two mid-stage trials and “had not received reports of serious adverse events in its studies of patients with social anxiety disorder and major depressive disorder with anxious distress.” During Phase I studies of its FAAH drug, Johnson & Johnson reported few side effects of the drug, although three patients did show increased liver enzymes after taking 100 milligram doses of the drug for 10 days. During the Phase II trials, which were halted, patients were only being given doses of 25 milligrams and reported “no observed effects on liver enzymes,” Reuters said. The company said it would reevaluate the trials when it has more information, Reuters added. Still, it seems the tragedy of the French trials, of the FAAH inhibitor being developed by Portugal-based Bial-Portela was enough to cause Johnson & Johnson to step back and reassess before moving forward. FAAH inhibitors are designed to break down endocannabinoids, including anandamide, in the brain and are being investigated for use in the treatment of chronic pain. These molecules activate cannabinoid receptors—the same ones that bind THC, the key component of cannabis, a report in Science magazine said. Bial ’s BIA 10-2474, the drug tested in the French facility, is designed to inhibit FAAH, and thus slow the breakdown of endogenous cannabinoids, which might help fight pain, the magazine said. Initial reports said the Bial drug was cannabis based, but it turned out to be a drug aimed at targeting the body’s cannabinoid system. Seth Yakatan , chief executive officer of California-based Kalytera Therapeutics , a company developing cannabinoid-based drugs for the treatment of obesity and osteoporosis, said he spent much of the weekend dispelling rumors about the Bial drug. Because of the inaccuracies being reported, Yakatan said it was important to quell any relationship between the Bial trial and cannabis-based therapeutics. There are two medications that contain cannabinoid chemicals in pill form that have been approved by the U.S. Food and Drug Administration . Researchers are investigating the use of cannabinoids for the treatment of several diseases and conditions including HIV/AIDS, multiple sclerosis, Alzheimer’s disease and pain. Other pharmaceutical companies are developing FAAH inhibitors, including Merck and Pfizer , which are developing FAAH inhibitors for treatment of osteoarthritis pain, insomnia, Tourette syndrome and cannabis withdrawal.

临床2期临床1期临床结果

100 项与 BIA-102474 相关的药物交易

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