A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of GDC-8264 in Preventing Cardiac Surgery-Associated Acute Kidney Injury and Major Adverse Kidney Events

The aim of this study is to evaluate the efficacy and safety of GDC-8264 compared with placebo in participants undergoing cardiac surgery who are determined to be at moderate to high risk of developing AKI and subsequent MAKE at 90 days after surgery (MAKE90). The study will be performed in two parts- Part 1 and Part 2.

开始日期2024-11-04

申办/合作机构

Genentech, Inc.

CTR20233988 / Recruiting临床1期

评价AC-003胶囊联合糖皮质激素治疗糖皮质激素耐药的急性移植物抗宿主病（aGVHD）的安全性、耐受性、初步疗效及药代动力学特征的Ib期临床试验

主要目的：评价AC-003胶囊治疗aGVHD的安全性和耐受性；次要目的：观察AC-003胶囊治疗aGVHD的初步疗效；评价AC-003胶囊在aGVHD受试者中的药代动力学特征；其他目的：研究AC-003给药后的生物标志物/药效标志物。

开始日期2024-07-22

申办/合作机构

爱科诺生物医药（苏州）有限公司初创企业

NCT06477926 / Active, not recruiting临床1期

A Phase 1 Relative Bioavailability and Food Effect Study of ABBV-668 Extended-Release Formulations

The objectives of this study are to assess safety and tolerability of the new ABBV-668 ER tablets, to assess the oral bioavailability of the ABBV-668 ER tablets relative to the ABBV-668 IR capsules, and to assess the pharmacokinetics of the ER tablets under fasting and fed conditions in healthy adults.

开始日期2024-07-09

申办/合作机构

AbbVie, Inc.

100 项与 RIPK1 相关的临床结果

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100 项与 RIPK1 相关的转化医学

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0 项与 RIPK1 相关的专利（医药）

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2,167

项与 RIPK1 相关的文献（医药）

2025-01-01·JOURNAL OF ETHNOPHARMACOLOGY

Dachengqi decoction dispensing granule ameliorates LPS-induced acute lung injury by inhibiting PANoptosis in vivo and in vitro

Article

作者: Yang, Shenglan ; Lin, Qifeng ; Shang, Luorui ; Wang, Shuhan ; Li, Jinxiao ; Zhou, Fangyuan ; Cai, Yuju ; Zhang, Mengqi

ETHNOPHARMACOLOGICAL RELEVANCE:

Acute lung injury (ALI) is a serious health-threatening syndrome of intense inflammatory response in the lungs, with progression leading to acute respiratory distress syndrome (ARDS). Dachengqi decoction dispensing granule (DDG) has a pulmonary protective role, but its potential modulatory mechanism to alleviate ALI needs further excavation.

AIM OF THE STUDY:

This study aims to investigate the effect and potential mechanism of DDG on lipopolysaccharide (LPS)-induced ALI models in vivo and in vitro.

MATERIALS AND METHODS:

LPS-treated Balb/c mice and BEAS-2B cells were used to construct in vivo and in vitro ALI models, respectively. Hematoxylin-eosin (HE), Wet weight/Dry weight (W/D) calculation of lung tissue, and total protein and Lactic dehydrogenase (LDH) assays in BALF were performed to assess the extent of lung tissue injury and pulmonary edema. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-18 (IL-18) in BALF, serum, and cell supernatant. The qRT-PCR was used to detect inflammatory factors, Z-DNA binding protein 1 (ZBP1), and receptor-interacting protein kinase 1 (RIPK1) expression in lung tissues and BEAS-2B cells. Double immunofluorescence staining and co-immunoprecipitation were used to detect the relative expression and co-localization of ZBP1 and RIPK1. The effects of LPS and DDG on BEAS-2B cell activity were detected by Cell Counting Kit-8 (CCK-8). Western blot (WB) was performed to analyze the expression of PANoptosis-related proteins in lung tissues and BEAS-2B cells.

RESULTS:

In vivo, DDG pretreatment could dose-dependently improve the pathological changes of lung tissue in ALI mice, and reduce the W/D ratio of lung, total protein concentration, and LDH content in BALF. In vitro, DDG reversed the inhibitory effect of LPS on BEAS-2B cell viability. Meanwhile, DDG significantly reduced the levels of inflammatory factors in vitro and in vivo. In addition, DDG could inhibit the expression levels of PANoptosis-related proteins, especially the upstream key regulatory molecules ZBP1 and RIPK1.

CONCLUSION:

DDG could inhibit excessive inflammation and PANoptosis to alleviate LPS-induced ALI, thus possessing good anti-inflammatory and lung-protective effects. This study establishes a theoretical basis for the further development of DDG and provides a new prospect for ALI treatment by targeting PANoptosis.

2024-12-01·Molecular biology reports

RIPK3 and RIPK1 gene expression in pterygium: unveiling molecular insights into pathogenesis

Article

作者: Divandari, Mahnaz ; Javadifar, Amin ; Janatabadi, Ali Akbar ; Moghadam, Arezoo Baradaran

BACKGROUND:

Pterygium, characterized by the abnormal proliferation of epithelial cells, matrix remodeling, vascularization, and lesion migration, is a prevalent ocular surface disease involving the growth of fibrovascular tissue on the cornea. Despite the unclear underlying causes of pterygium, numerous investigations have indicated the involvement of cell death pathways in the regulation of cell cycle dynamics. Consequently, the objective of this study was to assess the expression levels of necroptosis markers in individuals diagnosed with pterygium, aiming to shed light on the potential role of necroptosis in the pathogenesis of this condition.

METHODS:

This study aimed to investigate the expression patterns of receptor-interacting serine/threonine kinase 3 (RIPK3) and receptor-interacting serine/threonine kinase 1 (RIPK1) genes in pterygium tissues. 41 patients undergoing pterygium excision surgery were recruited. Resected pterygium samples and normal conjunctival tissues were collected, and RIPK3 and RIPK1 mRNA levels were measured using quantitative real-time PCR.

RESULTS:

Our findings reveal that the expression of RIPK3 is significantly increased in samples obtained from individuals with pterygium. However, no significant alterations were observed in the expression of RIPK1 in these samples. Results showed significantly higher RIPK3 expression in pterygium tissues compared to controls. Moreover, increased RIPK3 levels correlated negatively with pterygium recurrence rates.

CONCLUSIONS:

These findings suggest RIPK3 may play a protective role against pterygium recurrence through necroptosis.

2024-12-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Design, synthesis, and preclinical evaluation of 11C/18F-labeled inhibitors for RIPK1 PET imaging

Article

作者: Wu, Rui ; Yin, Honghai ; Bai, Ping ; Luo, Tianwen ; Meng, Hui ; Wu, Xiaoai ; Wang, Yanli ; Kang, Leyi ; Wang, Yongle ; Xie, Weiyao ; Wang, Changning ; Zhou, Yanting ; Zhao, Chenyao

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a promising target for the diagnosis and treatment of various diseases, especially neurodegenerative disorders. Developing PET imaging probes targeting RIPK1 is beneficial for visualizing the connections between RIPK1 and diseases, as well as for related drug development. In this study, we report the design and synthesis of a series of novel RIPK1 inhibitors. Three potent inhibitors, 7i, 7k, and 8a, with good cell anti-necroptosis potency and physicochemical properties, were identified and selected for PET imaging probe development. Subsequently, three PET imaging radioligands ([¹¹C]7k, [¹⁸F]7i, and [¹⁸F]8a) were successfully synthesized. In mouse PET imaging studies, all three radioligands showed good brain uptake. Among them, probe [¹⁸F]8a exhibited good binding specificity in both in vitro autoradiography and in vivo PET imaging studies. Additionally, [¹⁸F]8a demonstrated good in vivo metabolic stability. This work highlights the potential of probe [¹⁸F]8a for imaging brain RIPK1 in live animals, laying the groundwork for the future development of RIPK1 PET radioligands.

171

项与 RIPK1 相关的新闻（医药）

2024-09-20

·BioSpace

Sanofi’s Tolebrutinib Delays MS Progression in Phase III Study Following Earlier Flops

iStock, JHVEPhoto The positive readout in patients with non-relapsing secondary progressive multiple sclerosis comes on the heels of back-to-back failures in which tolebrutinib was unable to improve relapse rates in patients with relapsing MS. Sanofi on Friday announced that its investigational BTK inhibitor tolebrutinib delayed the onset of disability progression by 31% in patients with non-relapsing secondary progressive multiple sclerosis. The results come from the Phase III HERCULES study, a double-blinded randomized trial that compared daily oral tolebrutinib against placebo in terms of confirmed disease progression at six months, defined using scores in the expanded disability status scale. Friday’s readout from HERCULES also showed that 10% of patients on tolebrutinib experienced confirmed disability improvement, versus around 5% in the placebo arm. This corresponded to an 88% increase in the likelihood of improvement, with a nominal p-value of 0.021, according to Sanofi. In terms of safety, preliminary data from HERCULES pointed to a “slight increase” in adverse events among patients treated with tolebrutinib. Of the patients treated with the BTK inhibitor, 4.1% saw liver enzyme elevations greater than thrice the upper limit of normal, as compared with only 1.6% among placebo comparators. “All but one” case of liver enzyme elevation resolved without medical intervention. One patient in the tolebrutinib arm underwent liver transplantation and died due to complications related to the surgery. This fatality occurred after Sanofi revised its protocol to have more stringent and frequent monitoring, which has since “mitigated such serious liver sequelae.” Tolebrutinib “has demonstrated its ability to delay disability by targeting underlying drivers” of non-relapsing secondary progressive multiple sclerosis (nrSPMS), Houman Ashrafian, Sanofi’s head of R&D, said in a statement. The company will bring these finding to global regulatory authorities, with submissions set to start in the second half of 2024. Jefferies analyst Peter Welford called HERCULES’ readout “promising” in a note to investors. “We view data as positive to enable global filings and approvals given current unmet need for nrSPMS with no effective drugs available.” Importantly, Friday’s findings from HERCULES now makes tolebrutinib a “de-risked $2-3bn opportunity,” Welford wrote. Designed to be administered orally, tolebrutinib is a small molecule inhibitor of the BTK protein, which under healthy circumstances is important for the development and activity of antibody-producing B cells. Tolebrutinib’s mechanism of action allows it to suppress B cells and the disease-driving microglia. Sanofi secured the rights to tolebrutinib in August 2020, when it acquired Principia Biopharma for almost $3.7 billion. The drug candidate has since become a pillar of Sanofi’s multiple sclerosis program , alongside the late-stage antibody frexalimab and the Phase II RIPK1 inhibitor oditrasertib. However, tolebrutinib’s clinical development has not been without its challenges. In June 2022, the FDA slapped a partial clinical hold on the drug and suspended enrollment in its Phase III trials due to drug-induced liver injuries. Earlier this month, Sanofi reported back-to-back Phase III failures for tolebrutinib, which was unable to significantly improve relapse rates in the patients with relapsing forms of MS.

临床结果临床3期临床2期并购抗体药物偶联物

2024-09-13

·药明康德

首批！只需一年两针，罗氏重磅抗体疗法获FDA批准

▎药明康德内容团队编辑今日，罗氏（Roche）宣布美国FDA已批准Ocrevus Zunovo（ocrelizumab & hyaluronidase）皮下制剂用于治疗复发性多发性硬化（RMS）和原发性进展型多发性硬化（PPMS）。之前公布的临床结果显示，Ocrevus Zunovo几乎完全抑制了患者的临床复发和脑部病变。根据新闻稿，Ocrevus Zunovo是首个获批用于治疗RMS和PPMS的皮下制剂，该药物每年仅需注射两次，每次注射时间仅需10分钟。多发性硬化（MS）是一种慢性疾病，影响全球280多万人。当免疫系统异常攻击中枢神经系统中保护神经细胞的髓鞘时，会引起炎症和神经损伤。这种损伤会引起广泛的症状，包括肌肉无力、疲劳和视力困难，最终可能导致残疾。大多数MS患者在20至40岁之间出现首发症状，使该疾病成为年轻人非创伤性残疾的主要原因。复发缓解型多发性硬化症（RRMS）是最常见的MS形式，其特点是出现新的或加重的症状（复发期），然后进入恢复期。约85%的MS患者最初被诊断为RRMS。大多数RRMS患者最终会转变为继发进展型多发性硬化症（SPMS），即随着时间的推移，残疾逐渐加重。RMS包括RRMS患者和仍然经历复发的SPMS患者。PPMS是另一种MS形式，患者症状逐渐加重，通常没有明显的复发或缓解期，占总MS患者约15%。这次美国FDA的批准主要是基于OCARINA II临床3期试验的关键数据。分析显示，在RMS和PPMS患者中，Ocrevus Zunovo皮下制剂与Ocrevus静脉制剂相比，其安全性、有效性以及在血液中的浓度皆没有临床显著差异。在今年4月公布的长期随访结果显示，Ocrevus Zunovo（920毫克；n=236）在治疗阶段内几乎完全抑制了复发活动（97.2%的患者在治疗期间未发生复发）。在48周的核磁共振成像（MRI）检测中的年复发率为0.04，绝大多数患者无Gd+T1病变和无新的/扩大的T2病变。这些病变类型分别是活动性炎症和疾病负担的标志。图片来源：123RF 在OCARINA II试验中，除了患者的注射反应外，Ocrevus Zunovo与Ocrevus静脉制剂已知的安全性结果一致。Ocrevus Zunovo最常见的不良事件是注射反应。第一次注射时报告的注射反应较频繁，49%的受试者在第一次注射后出现注射反应。所有注射反应均为轻度或中度，没有患者因此停止治疗。此外，在探索性的患者报告结果中，患者（n=52）报告了高水平的满意度（92.3%的患者感到满意或非常满意）和便捷性（90.1%的患者认为它方便或非常方便）。 Ocrevus是一种人源化单克隆抗体，旨在靶向CD20阳性B细胞，这是一种被认为造成髓鞘和神经细胞轴突损伤的特定类型免疫细胞。这种神经细胞损伤可能导致MS患者的残疾。临床前研究显示，Ocrevus可与表达在某些B细胞表面上的CD20蛋白结合，但不与干细胞或浆细胞结合，因此患者仍可维持其免疫系统的重要功能。根据新闻稿，Ocrevus是获批可同时用于RMS与PPMS治疗的首款疗法。 Ocrevus Zunovo皮下制剂结合了Ocrevus与Halozyme Therapeutics专有的ENHANZE药物递送平台。该平台基于专有重组人透明质酸酶PH20（rHuPH20），这是一种在皮下空间局部和暂时降解透明质酸（一种体内的天然糖链）的酶。这增加了皮下组织的通透性，使Ocrevus能够进入并迅速扩散和吸收到血液中。这种半年一次、每次只需10分钟的皮下注射制剂使得医疗专业人员可在诊所或诊所外的环境中灵活使用，具潜力扩大Ocrevus在没有输液设施或输液能力有限治疗中心的使用。目前有多款MS在研疗法处于临床阶段。罗氏在这个月初公布临床2期试验FENopta的开放标签扩展（OLE）研究48周新数据。结果表明，接受其口服布鲁顿酪氨酸激酶（BTK）抑制剂fenebrutinib治疗长达一年的RMS患者中，高达96%患者没有发生疾病复发与进展。目前共有3项fenebrutinib相关的临床3期试验正在进行中，预计将于2025年底公布数据。今年4月，赛诺菲（Sanofi）公布其潜在“first-in-class”的CD40L靶向单抗frexalimab在2期试验中的积极结果，高达96%接受高剂量治疗的患者在48周治疗结束时没有发现新的脑部病灶。赛诺菲已启动相关3期临床试验对frexalimab作进一步检视。赛诺菲同时和Denali Therapeutics合作开发RIPK1小分子抑制剂SAR443820/DNL788用以治疗MS患者，该疗法目前处于2期临床阶段，预计在2025年完成试验。而由Zenas BioPharma开发的CD19和FcγRIIb靶向双功能单抗obexelimab目前也在2期临床阶段受检视。图片来源：123RF 除了抗体与小分子类疗法，细胞与基因疗法也逐渐成为MS的研发方向之一。例如，Kyverna Therapeutics在今年4月宣布，其所开发的CD19靶向CAR-T疗法KYV-101在两名进展性多发性硬化患者的脑脊液中观察到CAR-T细胞的存在和扩增，并且在一名患者中观察到鞘内抗体水平的下降，这意味着CAR-T细胞可以靶向中枢神经系统中的CD19阳性B细胞。而NeuroGenesis Bio公司的主打细胞疗法NG-01在2期试验中使得MS患者血清中神经丝轻链（NfL）水平一致降低，这是神经退行性病变和预测MS疾病进展的可靠生物标志物。百时美施贵宝（Bristol Myers Squibb）的CD19靶向CAR-T疗法CD19 NEX-T目前则在1期试验当中受检视其治疗MS患者的潜力。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料： [1] FDA Approves Ocrevus Zunovo™ as the First and Only Twice-a-Year 10-Minute Subcutaneous Injection for People With Relapsing and Progressive Multiple Sclerosis. Retrieved September 13, 2024 from https://www.gene.com/media/news-features/fda-approves-first-and-only-twice-a-year-10-minute-subcutaneous-injection-for-people-with-relapsing-and-progressive-multiple-sclerosis [2] Roche’s OCREVUS subcutaneous administration approved by European Commission, as first and only twice-a-year injection for relapsing and primary progressive multiple sclerosis. Retrieved June 25, 2024 from https://www.globenewswire.com/news-release/2024/06/25/2903478/0/en/Roche-s-OCREVUS-subcutaneous-administration-approved-by-European-Commission-as-first-and-only-twice-a-year-injection-for-relapsing-and-primary-progressive-multiple-sclerosis.html [3] A Study to Evaluate the Effect of SAR443820 on Serum Neurofilament Levels in Male and Female Adult Participants With Multiple Sclerosis. Retrieved June 25, 2024 from https://clinicaltrials.gov/study/NCT05630547?intr=SAR443820&aggFilters=phase:2&rank=2 [4] Pipeline. Retrieved June 25, 2024 from https://zenasbio.com/pipeline/ [5] In the pipeline. Retrieved June 25, 2024 from https://www.bms.com/researchers-and-partners/in-the-pipeline.html 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

临床结果临床3期细胞疗法临床2期临床失败

2024-09-05

·医药笔记

两败一胜：赛诺菲BTK抑制剂公布多发性硬化三项三期临床进展

▎Armstrong 2024年9月2日，赛诺菲公布BTK抑制剂Tolebrutinib治疗多发性硬化症三项三期临床最新进展。治疗RMS的GEMINI 1，GEMINI 2没有达到ARR主要终点。治疗nrSPMS的HERCULES达到主要终点，成为首个也是唯一一个能延缓nrSPMS患者残疾累积（Disability accumulation）的药物。炎症免疫为赛诺菲最重要的业务板块，神经免疫则是其重点探索的赛道之一，布局了BTK抑制剂Tolebrutinib、CD40L抗体Frexalimab、RIPK1抑制剂SAR443820多款创新药。 Tolebrutinib围绕多发性硬化症开展了4项三期临床，包括最大亚型RMS的GEMINI 1和GEMINI2，nrSPMS的HERCULES，PPMS的PRESEUS。 RMS覆盖的患者人群为91万例，nrSPMS覆盖的患者人群为17万例，PPMS覆盖的患者人群为12万例。总结虽然措施RMS这一最广阔的患者人群，Tolebrutinib治疗nrSPMS的三期临床达到主要终点仍然是一个重要突破。去年，诺华BTK抑制剂那些CSU适应症，开启了BTK进军自免赛道的序幕。国内方面，百济神州泽布替尼在自免领域从膜性肾病切入，诺诚健华奥布替尼则从狼疮等适应症切入。翰森制药以7.29亿元引进麓鹏制药BTK抑制剂LP-168非肿瘤适应症的中国权益。 Armstrong技术全梳理系列 GPRC5D靶点全梳理； CD40靶点全梳理； CD47靶点全梳理；补体靶向药物技术全梳理；补体药物：眼科治疗的重要方向； Claudin 6靶点全梳理； Claudin 18.2靶点全梳理；靶点冷暖，行业自知；中国大分子新药研发格局；被炮轰的“me too”；佐剂百年史；胰岛素百年传奇； CUSBEA：风雨四十载；中国新药研发的焦虑；中国生物医药企业的研发竞争；中国双抗竞争格局；中国ADC竞争格局；中国双抗技术全梳理；中国ADC技术全梳理； Ambrx技术全梳理； Vir Biotech技术全梳理； Immune-Onc技术全梳理；亘喜生物技术全梳理；康哲药业技术全梳理；科济药业技术全梳理；恺佧生物技术全梳理；同宜医药技术全梳理；百奥赛图技术全梳理；腾盛博药技术全梳理；创胜集团技术全梳理；永泰生物技术全梳理；中国抗体技术全梳理；德琪医药技术全梳理；德琪医药技术全梳理2.0；和铂医药技术全梳理；荣昌生物技术全梳理；再鼎医药技术全梳理；药明生物技术全梳理；恒瑞医药技术全梳理；豪森药业技术全梳理；正大天晴技术全梳理；吉凯基因技术全梳理；基石药业技术全梳理；百济神州技术全梳理；百济神州技术全梳理第2版；信达生物技术全梳理；信达生物技术全梳理第2版；中山康方技术全梳理；复宏汉霖技术全梳理；先声药业技术全梳理；君实生物技术全梳理；嘉和生物技术全梳理；志道生物技术全梳理；道尔生物技术全梳理；尚健生物技术全梳理；康宁杰瑞技术全梳理；科望医药技术全梳理；科望医药技术全梳理2.0；岸迈生物技术全梳理；礼进生物技术全梳理；康桥资本技术全梳理；余国良的抗体药布局；荃信生物技术全梳理；安源医药技术全梳理；三生国健技术全梳理；仁会生物技术全梳理；乐普生物技术全梳理；同润生物技术全梳理；宜明昂科技术全梳理；派格生物技术全梳理；迈威生物技术全梳理； Momenta技术全梳理； NGM技术全梳理；普米斯生物技术全梳理；普米斯生物技术全梳理2.0；三叶草生物技术全梳理；贝达药业抗体药全梳理；泽璟制药抗体药全梳理；恒瑞医药抗体药全梳理；齐鲁制药抗体药全梳理；石药集团抗体药全梳理；豪森药业抗体药全梳理；华海药业抗体药全梳理；科伦药业抗体药全梳理；百奥泰技术全梳理；凡恩世技术全梳理。

临床3期抗体药物偶联物临床1期细胞疗法