更新于：2024-11-21

Genistein

更新于：2024-11-21

概要

研发状态

概要

基本信息

药物类型

小分子化药

别名

4',5,7-trihydroxyisoflavone、5,7,4'-trihydroxyisoflavone、5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one

+ [12]

靶点

Top II

作用机制

Top II抑制剂(拓扑异构酶II抑制剂)、Tyrosine kinase inhibitors、细胞凋亡刺激剂

治疗领域

肿瘤感染呼吸系统疾病+ [3]

在研适应症

肺损伤新冠肺炎后遗症肺纤维化+ [6]

非在研适应症

急性放射综合征腺癌前列腺腺癌+ [4]

原研机构

The Henry M. Jackson Foundation

在研机构

Lawson Health Research Institute

Humanetics Corp.

National Institutes of Health

+ [1]

非在研机构

National Cancer Institute西安恒泰本草科技有限公司

Uman Pharma, Inc.

+ [1]

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)无进展

特殊审评快速通道 (美国)

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结构

分子式C15H10O5

InChIKeyTZBJGXHYKVUXJN-UHFFFAOYSA-N

CAS号446-72-0

关联

项与 Genistein 相关的临床试验

NCT06634108 / Recruiting临床1/2期IIT

Cardiovascular Genistein Therapy for Heart Failure Inflammation

This Phase 1b/2a study aims to investigate the safety and efficacy of genistein in patients with Transthyretin (TTR) Amyloidosis. The focus is on its impact on inflammatory and cardiometabolic biomarkers, along with the effects on cardiac function and exercise capacity.
Blood samples will be collected at baseline, following each dose of genistein, and after a six-week placebo washout period. These samples will undergo extensive analyses, including profiling for inflammatory cytokines and novel molecular markers, and routine tests like CBC, Chem 7, LFT, HbA1c, NT-proBNP, CRP, troponin T, and serum TTR. RNA-seq analyses on peripheral blood mononuclear cells (PBMCs) and isolation of plasma exosomes for inflammatory biomarkers are also part of the protocol.
Following ESC/AHA guidelines, echocardiography will assess cardiac structure and function, focusing on the left and right ventricles and valvular function. Additionally, exercise capacity will be evaluated through a standardized 6-minute walk test, and NT-proBNP levels will be measured as a cardiac stress biomarker.
The trial will include an 18-week follow-up period post-enrolment, with the primary endpoint being the change in inflammatory markers from baseline to three months. Secondary endpoints are cardiac function and exercise capacity changes over the same timeframe. This study aims to provide significant insights into genistein's therapeutic potential for TTR Amyloidosis and its broader implications in managing heart failure.
Following ethical committee approval and written informed consent, the Investigators aim is to enroll 40 participants. This is an open-label study. Each patient will receive genistein by mouth: 250 mg twice a day for 4 weeks (500 mg total/day), 500 mg twice a day for 4 weeks (1000 mg total/day), and 750 mg twice a day (1500 mg total/day) for an additional 4 weeks. This will be followed by a 6-week washout period to conclude the study. An 18-month study is anticipated based on the average enrollment rates. Results from this study are expected to offer critical insights for future larger studies.

开始日期2024-09-27

申办/合作机构

Lawson Health Research Institute

[+1]

NCT06501768 / Recruiting临床1/2期IIT

A Pilot Clinical Trial of Cardiovascular Genistein Therapy for Heart Failure Inflammation

This Phase 1b/2a open-label study is designed to assess the safety and efficacy of genistein in patients with heart failure (HF). The investigation will focus on its impact on inflammatory and cardiometabolic biomarkers, as well as its effects on cardiac function and exercise capacity.
Blood samples will be collected at baseline, following each administration of genistein, and after a six-week placebo washout period. These samples will be subjected to comprehensive analyses to evaluate inflammatory cytokines and novel molecular markers. Routine tests, including Complete Blood Count (CBC), Basic Metabolic Panel (Chem 7), Liver Function Tests (LFT), Hemoglobin A1c (HbA1c), N-terminal pro b-type natriuretic peptide (NT-proBNP), C-Reactive Protein (CRP), and troponin T will be performed. Advanced assessments will include RNA sequencing (RNA-seq) on peripheral blood mononuclear cells (PBMCs) and the isolation of plasma exosomes to identify inflammatory biomarkers. In addition, a subset of the blood samples will be used to generate induced pluripotent stem cells (iPSCs) to further explore the treatment's impact on heart failure-related inflammatory markers.
Echocardiography, in accordance with the European Society of Cardiology (ESC) and the American Heart Association (AHA) guidelines, will be utilized to evaluate cardiac structure and function with a specific focus on the left and right ventricular functions and valvular integrity. Exercise capacity will be gauged through a standardized six-minute walk test. Levels of NT-proBNP will be measured as an indicator of cardiac stress and function.
Participants will be followed up for 18 weeks post-enrolment, with the primary endpoint being the change in inflammatory markers from baseline to the three-month mark. Secondary endpoints will include changes in cardiac function and exercise capacity over the same period. The trial aims to enrol 40 participants, following ethical committee approval and the acquisition of written informed consent. Each patient will receive genistein at a dosing regimen starting with 250 mg twice daily (BID) for 4 weeks, escalating to 500 mg BID for the subsequent 4 weeks, and 750 mg BID for another 4 weeks, culminating in a 6-week follow-up period.
The insights garnered from this study are expected to be pivotal in guiding future larger-scale studies and to elucidate the therapeutic potential of genistein in the management of heart failure.

开始日期2024-07-01

申办/合作机构

UMC Ljubljana

[+1]

TCTR20220209010 / Completed临床2/3期IIT

Efficacy and safety of topical genistein nutraceutical products on skin in postmenopausal women

开始日期2022-05-17

申办/合作机构-

100 项与 Genistein 相关的临床结果

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100 项与 Genistein 相关的转化医学

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100 项与 Genistein 相关的专利（医药）

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12,092

项与 Genistein 相关的文献（医药）

2025-02-01·Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy

Probing the interactions of genistein with HMGB1 through multi-spectroscopic and in-silico approaches

Article

作者: Kuang, Yi ; Yu, Boyang ; Ge, Haixia ; Ye, Junyi ; Zhang, Jian ; Shen, Pingping ; Raj, Richa

Functional regulation of proteins by ligand-protein interactions plays a crucial role in understanding biological processes and identifying potential drugs. High mobility group box 1 (HMGB1) plays a pivotal role in sterile inflammation as a key immunomodulatory protein. Genistein, a well-known isoflavone compound, has been shown to have neuroprotective effects. In this study, we investigated the genistein-HMGB1 interactions using experimental and computational approaches. Our results revealed that genistein binds to HMGB1 with a KD value of 6.06 × 10^-5 M. The addition of genistein significantly quenched the fluorescence of HMGB1. Thermodynamic analyses demonstrated that hydrogen bonds and hydrophobic forces are the primary forces during the binding process. Furthermore, the interaction between genistein and HMGB1 led to changes in the microenvironment of protein chromogenic amino acids and subtle alterations in the protein secondary structure. Molecular modeling results indicate that Pro95, Pro98, and Lys154 are the major amino acid residues for genistein binding to HMGB1. Meanwhile, at the cellular level, an inhibitory effect of genistein on HMGB1-induced NO release from microglia was observed, demonstrating an inhibition rate of 42.1 %. Our studies demonstrated that genistein could be applied in treating neurological diseases through its interaction with HMGB1.

2025-01-01·Brain Research

Therapeutic efficacy of Genistein in activation of neuronal AC/cAMP/CREB/PKA and mitochondrial ETC-Complex pathways in experimental model of autism: Evidence from CSF, blood plasma and brain analysis

Article

作者: Tiwari, Aarti ; Narula, Acharan S ; Mehan, Sidharth ; Sharma, Tarun ; Kumar, Manjeet ; Kumar, Aakash ; Narula, Acharan S. ; Das Gupta, Ghanshyam ; Khan, Zuber ; kumar, Manjeet

Autism is a complex neurodevelopmental condition characterized by repetitive behaviors, impaired social communication, and various associated conditions such as depression and anxiety. Its multifactorial etiology includes genetic, environmental, dietary, and gastrointestinal contributions. Pathologically, Autism is linked to mitochondrial dysfunction, oxidative stress, neuroinflammation, and neurotransmitter imbalances involving GABA, glutamate, dopamine, and oxytocin. Propionic acid (PRPA) is a short-chain fatty acid produced by gut bacteria, influencing central nervous system functions. Elevated PRPA levels can exacerbate Autism-related symptoms by disrupting metabolic processes and crossing the blood-brain barrier. Our research investigates the neuroprotective potential of Genistein (GNT), an isoflavone compound with known benefits in neuropsychiatric and neurodegenerative disorders, through modulation of the AC/cAMP/CREB/PKA signaling pathway and mitochondrial ETC complex (I-IV) function. In silico analyses revealed GNT's high affinity for these targets. Subsequent in vitro and in vivo experiments using a PRPA-induced rat model of autism demonstrated that GNT (40 and 80 mg/kg., orally) significantly improves locomotion, neuromuscular coordination, and cognitive functions in PRPA-treated rodents. Behavioral assessments showed reduced immobility in the forced swim test, enhanced Morris water maze performance, and restored regular locomotor activity. On a molecular level, GNT restored levels of key signaling molecules (AC, cAMP, CREB, PKA) and mitochondrial complexes (I-V), disrupted by PRPA exposure. Additionally, GNT reduced neuroinflammation and apoptosis, normalized neurotransmitter levels, and improved the complete blood count profile. Histopathological analyses confirmed that GNT ameliorated PRPA-induced brain injuries, restored normal brain morphology, reduced demyelination, and promoted neurogenesis. The study supports GNT's potential in autism treatment by modulating neural pathways, reducing inflammation, and restoring neurotransmitter balance.

2025-01-01·Journal of Ethnopharmacology

Qian Yang Yu Yin Granule prevents hypertensive cardiac remodeling by inhibiting NLRP3 inflammasome activation via Nrf2

Article

作者: Sun, Zeqi ; Fang, Zhuyuan ; Xu, Junyao ; Huang, Hong ; Liu, Ming ; Yuan, Fang ; Li, Yin ; Li, Jie

ETHNOPHARMACOLOGICAL RELEVANCEQian Yang Yu Yin Granule (QYYYG), a traditional Chinese poly-herbal formulation, has been validated in clinical trials to mitigate cardiac remodeling (CR), and cardiac damage in patients with hypertension. However, the specific mechanism remains unclear.AIM OF THE STUDYThis study explored the potential effects and potential mechanisms of QYYYG on hypertensive CR by combining various experimental approaches.MATERIALS AND METHODSSpontaneously hypertensive rats (SHRs) were used as a model of hypertensive CR, followed by QYYYG interventions. Blood pressure, cardiac function and structure, histopathological changes, and myocardial inflammation and oxidative stress were tested to assess the efficacy of QYYYG in SHRs. For in vitro experiments, a cell model of myocardial hypertrophy and injury was constructed with isoprenaline. Cardiomyocyte hypertrophy, oxidative stress, and death were examined after treatment with different concentrations of QYYYG, and transcriptomics analyses were performed to explore the underlying mechanism. Nrf2 and the ROS/NF-κB/NLRP3 inflammasome pathway were detected. Thereafter, ML385 and siRNAs were used to inhibit Nrf2 in cardiomyocytes, so as to verify whether QYYYG negatively regulates the NLRP3 inflammasome by targeting Nrf2, thereby ameliorating the associated phenotypes. Finally, high performance liquid chromatography (HPLC) was conducted to analyze the active ingredients in QYYYG, and molecular docking was utilized to preliminarily screen the compounds with modulatory effects on Nrf2 activities.RESULTSQYYYG improved blood pressure, cardiac function, and structural remodeling and attenuated myocardial inflammation, oxidative stress, and cell death in SHRs. The transcriptomics results showed that the inflammatory response might be crucial in pathological CR and that Nrf2, which potentially negatively regulates the process, was upregulated by QYYYG treatment. Furthermore, QYYYG indeed facilitated Nrf2 activation and negatively regulated the ROS/NF-κB/NLRP3 inflammasome pathway, therefore ameliorating the associated phenotypes. In vitro inhibition or knockdown of Nrf2 weakened or even reversed the repressive effect of QYYYG on ISO-induced inflammation, oxidative stress, pyroptosis, and the NLRP3 inflammasome activation. Based on the results of HPLC and molecular docking, 30 compounds, including cafestol, genistein, hesperetin, and formononetin, have binding sites to Keap1-Nrf2 protein and might affect the activity or stability of Nrf2.CONCLUSIONIn conclusion, the alleviatory effect of QYYYG on hypertensive CR is related to its regulation of Nrf2 activation. Specifically, QYYYG blocks the activation of the NLRP3 inflammasome by boosting Nrf2 signaling and depressing myocardial inflammation, oxidative stress, and pyroptosis, thereby effectively ameliorating hypertensive CR.

项与 Genistein 相关的新闻（医药）

2024-10-03

·BioSpace

Humanetics Corporation Presents at the 2024 Department of Defense Scientific Meeting

Presentation to update the advanced development of BIO 300, an orally available medical countermeasure for Warfighters, to prevent toxicities due to radiation exposure. MINNEAPOLIS--(BUSINESS WIRE)--Updates on the development of Humanetics Corporation’s (Humanetics) new drug candidate, BIO 300, were presented at the 2024 Military Health System Research Symposium (MHSRS), held August 26-29 th in Kissimmee, Florida. MHSRS is the foremost scientific meeting of the U.S. Department of Defense (DOD), focusing on the unique medical needs of warfighters. BIO 300 was originally developed as a radioprotectant by researchers at the Armed Forces Radiobiology Research Institute (AFRRI) in Bethesda, Maryland. It was exclusively licensed to Humanetics for advanced development and commercialization. Collaborative studies continue with DOD scientists to develop BIO 300 as an oral drug that warfighters can take to provide protection against the effects of radiation from a radiological or nuclear event. Key Highlights of the Presentation: Novel Formulation: An overview of the BIO 300, an orally available drug designed for ease of use and rapid administration in various military and commercial settings. Efficacy and Safety: Insights into the nonclinical studies demonstrating the compound’s ability to protect against Acute Radiation Syndrome (ARS) and its safety in animal models. Clinical Development Pathway: An outline of clinical data supporting BIO 300’s safety and efficacy, including the proposed plan for human dose conversion under the FDA animal rule. Ongoing Development Activities: A detailed overview of ongoing and future development activities to support planned regulatory submissions. This work highlighted on BIO 300 research has positioned it as one of the most advanced prophylactic medical countermeasures currently under development for ARS. Developing countermeasures that protect individuals, especially military personnel, against ARS is paramount, considering the current geopolitical environment fueling the real and increasing threat of nuclear or radiological events. “We are thrilled to share our progress on the advanced development of BIO 300,” said Michael Kaytor, Ph.D., Vice President of Research and Development at Humanetics. “This drug could transform our ability to protect the men and women who serve our country, and anyone who may be at risk of intentional or accidental radiation exposure.” In addition to its military applications, BIO 300 is being evaluated in phase 2 clinical trials to prevent normal tissue injury resulting from cancer radiotherapy and to reduce inflammatory lung damage (e.g., COVID-19, Idiopathic Pulmonary Fibrosis, acute respiratory distress syndrome). The research presented was supported in part by grants from the US Department of Defense’s Congressionally Directed Medical Research Program and an Other Transaction Authority agreement with the Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense (JPEO-CBRND). The views expressed herein are those of Humanetics and may not reflect the official policy or position of the Department of Defense or the US Government. Reference herein to any specific commercial products, process, or service by trade name, trademark, manufacturer, or otherwise, does not constitute or imply its endorsement, recommendation, or favoring by the U.S. government and shall not be used for advertising or product endorsement purposes. About Humanetics Corporation Humanetics Corporation is a clinical-stage pharmaceutical company engaged in the accelerated discovery, development and commercialization of proprietary drugs in markets with urgent and unmet needs with a focus on radiation modulators for oncology and medical countermeasures. For more information, visit . Contacts Michael Kaytor VP – Research and Development mkaytor@humaneticscorp.com

放射疗法临床2期

2024-10-01

·BioSpace

Humanetics to Participate in the Bio Investor Forum in San Francisco

MINNEAPOLIS--(BUSINESS WIRE)--Humanetics Corporation, an advanced clinical-stage specialty pharmaceutical company developing radioprotectant drugs for warfighters and cancer patients, will discuss BIO 300, its promising lead radioprotective drug candidate, at the BIO Investor Forum, Oct. 15-16, 2024. This event showcases drug development programs ready for partnering or venture funding, focusing on accelerating new therapeutic technologies into commercialization. It features panel discussions on policy, business, financing, and R&D, along with company presentations and BIO One-on-One Partnering™ meetings. The 2023 forum hosted over 1,600 partnering meetings. The conference takes place at the Fairmont Hotel in San Francisco. For more information: . About BIO 300 BIO 300 is a pioneering radioprotectant drug with dual military and medical applications. It’s designed as a prophylactic to protect normal tissues from radiation damage, distinguishing it from other drug candidates. The U.S. Department of Defense (DoD) has heavily funded and researched BIO 300 for its potential to mitigate radiation effects on warfighters and civilians in the event of a nuclear attack or radiological incident. The need for such a product has significantly increased due to current world events. Humanetics is working under a $25 million DoD contract to position BIO 300 for Emergency Use Authorization against Acute Radiation Syndrome (ARS). BIO 300 is also being studied to improve outcomes in cancer patients receiving radiotherapy with or without chemotherapy. These patients often suffer from unintended side effects that can reduce treatment efficacy or cause serious adverse events. Administered as an oral liquid nanosuspension, it may minimize normal tissue radiation damage without compromising tumor treatment efficacy. Positive Phase 1/2a results in non-small cell lung cancer patients undergoing chemoradiotherapy support its safety and potential clinical benefits. A Phase 2b trial of BIO 300 in patients with post-acute respiratory complications from severe COVID-19 has been completed. This randomized, double-blind, placebo-controlled study evaluated BIO 300’s safety and efficacy in improving lung function. Funded by the National Institute of Allergy and Infectious Disease (NIAID), results are expected by late 2024. About Humanetics Corporation Humanetics is an advanced clinical-stage specialty pharmaceutical company engaged in the development and commercialization of radioprotectant drugs to prevent harm caused by exposure to ionizing radiation; for protective use in cancer radiation therapy; and to guard against the long-term damaging effects of COVID-19. For more information, visit . Contacts Jason Brown Director, Investor Relations jbrown@humaneticscorp.com (612) 868-7009

放射疗法临床2期

2024-08-19

·蒲公英Ouryao

FDA审评：吡托布鲁替尼制剂溶出方法开发与标准制定(3)

本文作者：曾文亮博士，迪哲医药CMCRA副总监本文主要内容来自于FDA的审评报告：PRODUCT QUALITY REVIEW(S)，共30页。 NDA 序号 216059，批准时间：2023年申请人 Loxo 公司，礼来子公司药物名 JAYPIRCATM (pirtobrutinib) 片制型片剂规格 50mg和100mg 途径口服最大日用剂量 200mg 原研/非处方原研适应症既往接受过共价BTK抑制剂治疗的成年套细胞淋巴瘤(MCL)患者的治疗外观 Pirtobrutinib片50 mg或100 mg薄膜包衣、凹口片剂，用于口服给药。50mg片是一种蓝色的弧形三角形片剂，一边是“50”上的“Lilly ”,另一边是“6902”。100mg片是蓝色的圆形药片，一边是“Lilly ”,另一边是“7026”。储藏条件储存于20°C-25°C(68°F-77°F)；允许在15°C和30°C(59°F和86°F)之间偏移生物药剂学评估：拟议的QC溶解方法（USP方法/桨法，75rpm，900毫升pH 6.8（XX）缓冲液；37 C）和修订后的溶出度标准（Q =（30分钟XX%）适用于pirtobrutinib片剂在批量释放和稳定性测试/保质期期间的溶出测试。请注意，提交的PBBM的基于生理的药代动力学模型（PBPK）被认为不足以支持申请人最初提出的（更宽泛的）溶出度接受标准。有足够的体外和体内数据（i）支持将最终拟议上市的药物产品（50mg和100mg）与关键临床试验（100毫克）和注册/稳定性研究（50mg和100mg）中评估的片剂批次的桥接，以及根据21 CFR 320.22（d）批准申请人对拟议药物产品50毫克强度的生物豁免请求。在豁免50mg，申请人递交了如下14个文件，以支持将50mg规格的上市申请。基于pirtobrutinib药物在37C下各种pH介质和生物相关介质中的pH-溶解度数据，根据BCS分类标准，pirtobrutinib可以归为低溶解度化合物。后面更多内容被隐藏。原料药渗透性：高渗透申请人补充的报告研究LOXO-BTK-20007/第2部分，pirtobrutinib（两片100毫克“T2”pirtobrutinib片剂服用；关键临床试验批次19-0216-2）的绝对生物利用度（Fpo）为85.5%（相对于静脉注射（6）含有放射性标记药物物质的溶液，Fpo>85%表明pirtobrutinib可被认为是一种高渗透性药物物质。另外，企业没有提供使用Caco-2模型的体外渗透数据。根据相对溶解度和动物相对生物利用度数据，预计pirtobrutinib片在人中的口服生物利用度会更高。制剂溶出：在生理pH值范围内由缓慢到非常迅速。 Pirtobrutinib片为速释药物，其溶解度与pH值有关，在各种pH介质中显示溶解缓慢，除了在pH 6.8（b）*缓冲液中，有关详细信息，请参阅资料中表3.2中各种pH值和生物相关介质中“T2”片剂（100毫克开发批次BREC-2224-035）的溶解度数据。P.2.2.1.5.3.1.3-1，以及图3.2。P.2.2.3.1.1-1。另请参阅图3.2。P.2.2.3.2.2-1至图3.2。P.2.2.3.2.2-3，用于100mg注册稳定性批次D345037的pH溶解数据。50mg规格的T2片剂也观察到类似的pH溶解趋势。「解读」pirtobrutinib属pH依赖性化合物。FDA同意了企业拟定的溶出方法，但没有同意企业基于PBPK模型申请的宽泛溶出标准。溶出标准不仅涉及PK，还对于批次的放行起到区分作用，能将不满足质量要求的批次剔除出去。企业申请了两个上市规格50mg和100mg，其中关键临床使用过100mg规格，50mg没有用于关键临床，仅用在其他临床研究，这种情况下50mg可以申请上市吗？基于FDA给到的审评结果，企业申请了生物豁免，提交了50mg的其他临床数据，以及50mg规格与100mg规格之间的对比数据等，最后FDA同意了企业的豁免申请。 B.溶出方法和接收标准 pH值为6.8缓冲盐被选为最终的QC溶出介质，因为在pH值为6.8条下化合物可实现3倍漏槽条件和完全溶解，此外所选的介质足以实现溶出方法区分能力，改变药物的质量属性，该溶出方法足以区分。为降低溶出数据的波动，选择了浆法2，75转速度，900mL的溶出介质。漏槽条件：相关描述被隐藏了。区分力：只提到了原料药的粒度部分，其它内容被隐藏了。从以上数据来看，拟定的溶出方法具有一定的区分力。此外，拟定的溶出方法能够产生预期的水平等级关系，相关具体描述被隐藏了。溶出方法验证：溶出方法验证了HPLC与紫外检测。研究了分析方法的线性、准确性、精度、范围、耐用性（关于溶解法和HPLC方法参数）、标准和样品解决方案的稳定性、过滤器兼容性（全流速过滤器，采样类型（自动或手动））。「解读」本品是常规速释固体片剂，其溶出是制剂的一个关键质量属性，因此在相关的P2.3制剂开发部分，需要详细的溶出方法开发内容。审评报告只重点摘出了很少一部分论述，其中溶出的区分力被重点提及。提及了对原料药粒度进行了考察，溶出方法可一定程度区分不同粒度原料药得到的片剂。具体研究数据未在审评报告中展示。溶出接受标准，进行了修订。（最初）拟定的溶出接受标准是“Q =30分钟XX%。根据拟定的QC溶出度方法（方法G2535）生成的四个关键临床试验批次（即100mg T2片剂使用在支持稳定性研究中批次D322845和D322846，以及100mgT2片剂批次使用在初级稳定性研究D345038和D345039）的溶出度表征数据，FDA建议企业收紧溶出度接受标准，以“Q =30分钟XX%。收紧的溶出标准（Q =XX）在考虑其他三个额外关键临床试验100mg“T2”片剂的快速到非常快速的溶解特性时（由倒数第二个QC溶解方法生成），FDA认为，使用最终的QC溶解方法可以实现类似的（如果不是更快的）溶出。根据使用倒数第二种和最终QC溶出方法为一个研发批次（即100mgBREC-2224-035）生成的溶出曲线数据的比较，两种方法的溶出曲线相似，最终方法G2535预计将产生比倒数第二种方法BTP-548略高的溶出数据（即在30分钟时，（*%更高的溶出值））。因此，对于任何给定的药物批次，同一溶出采样时间点（例如30分钟）的溶出数据预计最终溶出方法产生的溶出数据略高于倒数第二个溶出方法产生的溶出数据。因此，基于使用倒数第二和最终的溶出方法，FDA认为，任何使用倒数第二个溶出方法在30分钟内都能达到用最终QC溶出方法在30分钟内达到的Q值。此外，对于Q=XX%30分钟时，将足以拒绝那些不符合质量接受标准的片剂批次，这些批次包括那些明显低于目标溶出的片剂。FDA认为，进一步评估单点溶出标准区分批次的能力很重要。此外，即使根据BCS分类标准，pirtobrutinib化合物是一种低溶解化合物，基于以下考虑，制定2点溶出标准被认为是没有必要（即防止超快速溶解，这可能导致更短的Tmax和更高的Cmax），基于以下考虑： 1. 基于企业递交的数据，一些关键临床试验批次表现出非常快速的溶出（即在15分钟内至少85%）。 2.注册批次和工艺验证批次在12个月的长期稳定性时间点中，在QC介质中都表现出快速的溶出释放（15人种内至少85%）。 3.一项彻底的QT研究显示，超治疗剂量（即900mg）的pirtobrutinib片没有导致健康受试者的临床相关QT延长。 4.根据对MCL患者疗效和安全性的暴露反应分析，pirtobrutinib片不是一种治疗窄窗药物。「解读」针对pirtobrutinib制剂的溶出接受标准，FDA从以下几个方面给到意见： 1. 建议收紧溶出接受标准，至30分钟XX%，理由是基于多个关键临床批次的溶出数据，展示了药物在QC介质条件下非常快速的溶出特征。 2. 基于递交的溶出数据，使用修订后的按受标准可以区分拒绝那些不满足质量标准的批次。 3. 即使属于BCS 2/4的低溶解化合物，也可以不设定2点溶出接受标准，FDA给到了非常具体的4点考量。即关键临床批次的快速溶出表现、注册批次/工艺验证批次在稳定性研究期间的快速溶出、超剂量时没有QT的延长，以及药物本身不属于治疗窄窗药。 4. 溶出方法的选定非常重要，最终会决定接受标准时间点和Q值的选择，以及是否设定2点的接受标准。 5.企业在溶出方法开发过程中，一些关键临床批次的测试有使用到另外一个溶出方法测试而不是最终的QC方法测试，两种方法差异不大，最终的QC方法是在后期拟定的，溶出可能更快，前期的部分批次可能没有被QC方法测试，这种情况下，FDA接受了企业的做法。稳定性批次的溶出数据 50mg和100mg规在HDPE瓶中的三批注册稳定性批次的12个月长期（30°C/65% RH）和6个月的加速（40°C/75% RH）稳定性数据，在拟定的包装中储存，片剂最初拟定的有效期为24个月。值得注意的是，最终拟定的QC溶出方法（方法G2535）用于分析注册批次和其它稳定性批次的稳定性样品所有溶出曲线数据。在12个月的长期稳定性研究期间，30分钟的溶出数据没有观察到有稳定性趋势。在加速稳定性条件下第6个月，两种规格片剂的溶出度似乎都略有下降；然而数据仍在拟定修改的限度耐受范围内（Q = XX%在30分钟），因此FDA建议企业收紧溶出接受标准在该Q值。注意到，100mg规格三个注册稳定性批次的两批次（即D345038 A/C和D345039 A/C）在稳定性进行到10个月至11个月时，用于关键临床试验。图5显示，这两批稳定性批次/关键临床批次没有出现各稳定性时间点的溶出数据变化。另外两个关键临床试验批次（D322845、D322846）在关键临床试验使用时，其稳定性时间点为7个月至11个月。在企业回复FDA中，企业（i）同意FDA的建议，基于关键临床试验批次、注册批次/稳定性批次和工艺验证批次的溶出数据，以及FDA对PBBM模型数据的评估，将溶出接受标准从“Q= XX%，30min”收紧到“Q = XX%，30 min”，（ii）修订成品QC溶出接受标准和其他相关的NDA文件，以及（iii）确认，根据迄今为止得到的稳定性溶出数据（以及药品稳定性证据），注册批次能够相应地符合（并预计能够）符合修订后的溶出接受收标准。「解读」FDA从另外一个维度，即关键临床批次和注册稳定性批次在稳定性时间点及用药时间点，其溶出数据仍然符合修订的接受标准。企业QC溶出接受标准不仅基于多批次的关键临床批次，注册批次的溶出曲线数据，同时基于3批注册批次在稳定性研究阶段各时间点的溶出数据情况。本制剂同时也收集了PPQ批次的溶出数据，进一步证实了商业化批次溶出数据仍可满足修订后的溶出标准。作者精彩原创集锦 1、创新药研发中原料药工艺与沟通交流常见难点 2、创新药研发中「制剂工艺」常见难点 3、创新药研发中「变更」相关难点 4、创新药研发中「质量分析控制」相关难点（1） 5、创新药研发中「质量分析控制」相关难点（2） 6、创新药研发难点分析与CMC研究策略探讨 7、《已上市化学药品药学变更研究技术指导原则（试行）原料药变更的问答》浅析 8、FDA：原料药中亚硝胺风险评估的最新观点 9、亚硝胺「传奇」：5年来监管和制药界的反思 10、【学习笔记】2023年度CDE审评报告曾文亮博士迪哲医药CMCRA副总监，公众号“文亮频道”主理人。山东大学本科与硕士，上海中医药大学博士。近20年药物研发经验，擅长新药研发与注册申报，近5年积累了近十个小分子新药中美IND申报成功和两个1类抗肿瘤新药上市申报成功经验。先后任职于某大型CRO医药研发公司、USP大中华区研发中心和港资原料药厂等，主导过MNC质量研究项目、USP各论更新和药厂QC实验室通过国家GMP检查和WHO审计。受中国医药保健品进出口商会邀请在二十二届世界制药原料药中国展（CPHI）主导策划了“小分子创新药质量研究和注册策略”沙龙并发表主题演讲；同时受专业药学论坛邀请发表了《创新药质量研究要点和案例分析》、《中美新药申报沟通交流常见问题和案例分析》、《亚硝胺杂质的FDA和EMA控制策略》、《分析方法开发，验证和转移的统计学评价》和《FDA483中清洁验证的典型案例分析》等十余次主题演讲。更多精彩内容可关注： ▲ 关注文亮频道，探索未知世界

临床结果申请上市ASH会议放射疗法

100 项与 Genistein 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11680	Genistein	-	DB01645

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
新冠肺炎后遗症	临床2期	美国	Humanetics Corp.	2020-11-11
肺纤维化	临床2期	美国	Humanetics Corp.	2020-11-11
非肌层浸润性膀胱肿瘤	临床2期	美国	National Institutes of Health	2017-05-19
新型冠状病毒感染	临床2期	-	Humanetics Corp.	-
骨质疏松症	临床前	中国	西安恒泰本草科技有限公司	2017-04-11
晚期恶性实体瘤	临床前	加拿大	Uman Pharma, Inc.	2012-11-01
非小细胞肺癌	临床前	加拿大	Uman Pharma, Inc.	2012-11-01
前列腺腺癌	临床前	美国	National Cancer Institute	2011-12-01
腺癌	临床前	瑞典	Axcentua Pharmaceuticals AB	2010-11-01
乳腺癌	临床前	美国	National Cancer Institute	2006-01-01

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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


NCT01489813 (CTgov)	临床2期	非肌层浸润性膀胱肿瘤	36	sugar pill (Sugar Pill)	齋餘蓋鹽網齋觸鑰夢獵(齋齋憲廠鹹遞鹽廠範繭) = 觸遞繭顧範鬱餘鹹獵襯繭願製衊窪壓鏇衊餘夢 (製淵願齋淵齋鹽範糧觸, 襯選願蓋簾蓋築鑰襯鹹 ~ 衊顧襯遞獵艱簾憲鬱願) 更多	-	2024-07-25
				Genistein (Genistein Supplement)	齋餘蓋鹽網齋觸鑰夢獵(齋齋憲廠鹹遞鹽廠範繭) = 觸選鹽築鹽壓簾廠遞鑰繭願製衊窪壓鏇衊餘夢 (製淵願齋淵齋鹽範糧觸, 蓋網構築製積積鹽構鏇 ~ 築築獵願鏇蓋壓簾夢艱) 更多
EULAR2024	N/A	大动脉炎	-	Genistein	選網鹽願選製製願壓膚(廠衊衊衊膚蓋築鑰顧夢) = 醖膚襯窪觸積衊繭廠艱繭鏇製鑰繭淵醖鑰遞醖 (繭簾鹹選窪鏇鏇憲夢願 )	积极	2024-06-05
NCT02624388 (UVA-Gen001, CTgov)	临床2期	霍奇金淋巴瘤 \| 急性淋巴细胞白血病 \| 肾母细胞瘤 \| 儿童恶性实体瘤 \| 横纹肌肉瘤 \| 尤文肉瘤 \| 软组织肉瘤 \| 神经母细胞瘤 \| 髓母细胞瘤 \| 小儿淋巴母细胞非霍奇金淋巴瘤	4	Placebo+Genistein (Arm A: Genistein Followed by Placebo)	憲襯願鏇築獵襯衊淵觸(繭齋顧憲鏇襯築築廠繭) = 憲鏇鹽鬱觸簾淵獵構願簾積築選鏇繭膚膚選鬱 (齋鹽衊範顧繭築衊憲觸, 簾鹽觸糧選繭積願製遞 ~ 醖鏇鹽廠顧網襯廠憲夢) 更多	-	2024-05-06
				Placebo+Genistein (Arm B: Placebo Followed by Genistein)	憲襯願鏇築獵襯衊淵觸(繭齋顧憲鏇襯築築廠繭) = 構夢夢膚壓膚鬱願壓範簾積築選鏇繭膚膚選鬱 (齋鹽衊範顧繭築衊憲觸, 鏇廠廠膚鑰繭鑰餘觸鬱 ~ 鹹襯積夢範鑰醖鏇構鹹) 更多
NCT02567799 (Biospace) 人工标引	临床1/2期	非小细胞肺癌	21	BIO 300	(遞鏇鏇齋構選廠糧構艱) = 製鹹醖範構醖構構範願夢襯窪簾範繭築選齋構 (窪糧壓夢製鹽顧襯蓋壓 ) 更多	积极	2023-09-19
NCT02766478 (GeniPro, CTgov)	临床2期	代谢综合征 \| 前列腺癌	10	Genistein (Genistein)	糧構膚憲糧淵襯遞鹹壓(壓鹹艱顧鹹簾艱醖獵鹽) = 醖窪鏇鬱齋鑰獵窪製壓齋築夢襯鏇衊蓋壓遞積 (選鑰糧艱糧壓襯觸製憲, 廠築顧廠艱廠衊範壓鑰 ~ 齋顧觸願遞窪餘壓願窪) 更多	-	2022-09-27
				Placebo (Placebo)	糧構膚憲糧淵襯遞鹹壓(壓鹹艱顧鹹簾艱醖獵鹽) = 淵廠選淵網鏇鹽顧憲鹹齋築夢襯鏇衊蓋壓遞積 (選鑰糧艱糧壓襯觸製憲, 製夢糧餘繭襯構壓夢鹽 ~ 鹽膚醖膚糧鹹願膚膚餘) 更多
NCT04650555 (BusinessWire) 人工标引	临床1期	-	34	BIO 300	鑰鹹願鑰壓衊廠網艱遞(餘衊構鏇衊餘觸齋觸餘) = increase survival in persons exposed to lethal levels of radiation 艱鏇鏇築壓窪製製積顧 (齋夢簾廠膚構壓窪廠廠 )	积极	2021-09-22
NCT01985763 (Pubmed \| Cancer Chemother Pharmacol) 人工标引	临床1/2期	转移性结直肠癌	13	FOLFOX+Bevacizumab+Genistein	(壓淵衊選餘淵構鏇鑰襯) = 1patirent (grade 3 hypertension) 製糧鏇壓鬱淵鹹顧簾夢 (齋窪齋廠築範簾製餘糧 ) 更多	积极	2019-09-01
NCT00287690 (CTgov)	临床2/3期	冠心病	71	Genistein (Genistein)	網膚範簾鬱淵衊獵夢夢(觸遞廠蓋築範遞齋網願) = 夢選構艱積壓憲鹽製憲壓遞構觸願鬱鹹淵醖廠 (築壓製鹹繭願簾鹹顧夢, 醖廠鹹醖齋夢鹹膚觸簾 ~ 選鏇構鬱繭醖製鑰夢範) 更多	-	2019-08-05
				Placebo (Placebo)	網膚範簾鬱淵衊獵夢夢(觸遞廠蓋築範遞齋網願) = 網積願齋鹽獵鏇構壓餘壓遞構觸願鬱鹹淵醖廠 (築壓製鹹繭願簾鹹顧夢, 醖壓蓋構艱糧鬱鏇窪襯 ~ 襯積壓構窪繭鹽範網顧) 更多
NCT01985763 (CTgov)	临床1/2期	直肠癌 \| 结肠癌 \| 转移性结直肠癌	13	Genistein	憲製憲廠鏇鬱繭獵網糧(遞構觸糧範鑰窪憲製廠) = 網齋鹽鹹願範衊醖齋構鏇壓範築獵餘窪壓鹽淵 (遞鹽醖淵蓋網醖夢醖蓋, 憲窪膚鬱壓構襯繭積襯 ~ 遞壓醖壓糧糧構壓壓襯) 更多	-	2019-05-10
UEGW	N/A	-	-	Genistein	鏇襯艱製淵製襯簾襯艱(簾鹹襯選醖醖襯醖鹽製) = 遞廠觸鏇構築窪觸醖壓艱壓鬱廠廠顧願淵蓋鏇 (範鏇壓鹹製積鑰顧膚鑰 )	-	2018-10-01
				genistein (Control group)	鏇壓顧構夢憲鑰鏇築糧(繭網簾壓鹽觸範艱壓簾) = 鹹獵築壓製壓糧淵鏇獵積築選觸襯餘鬱膚艱齋 (網構鹹鬱簾繭積鑰齋選 ) 更多