更新于：2024-05-01

P2X4 receptor

P2X嘌呤受体-4

更新于：2024-05-01

基本信息

别名

嘌呤能P2X4受体、ATP receptor、P2RX4

+ [5]

简介

ATP-gated nonselective transmembrane cation channel permeable to potassium, sodium and calcium (PubMed:9016352). Activated by extracellularly released ATP, it plays multiple role in immunity and central nervous system physiology (PubMed:35165166). Plays a key role in initial steps of T-cell activation and Ca(2+) microdomain formation (By similarity). Participates also in basal T-cell activity without TCR/CD3 stimulation (By similarity). Promotes the differentiation and activation of Th17 cells via expression of retinoic acid-related orphan receptor C/RORC (PubMed:35165166). Upon activation, drives microglia motility via the PI3K/Akt pathway (By similarity). Could also function as an ATP-gated cation channel of lysosomal membranes (By similarity).

关联

项与 P2X4 receptor 相关的药物

NC-2600

靶点

P2X4 receptor

作用机制

P2X4 receptor拮抗剂

在研机构

Kyushu University [+1]

原研机构

Nippon Chemiphar Co., Ltd.

在研适应症

神经痛

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

Purinergic P2X4 receptor antagonist(Bayer AG)

靶点

P2X4 receptor

作用机制

P2X4 receptor拮抗剂

在研机构

Bayer AG

原研机构

Bayer AG

在研适应症

子宫内膜异位症

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

BAY-2328065

靶点

P2X4 receptor

作用机制

P2X4 receptor拮抗剂

在研机构

Bayer AG

原研机构

Bayer AG

在研适应症

子宫内膜异位症

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

项与 P2X4 receptor 相关的临床试验

NCT04851483 / Completed临床1期

Characterization of Single Dose Bioavailability of Two Novel Formulations of BAY 2328065 in Healthy Male Participants Including Dose Proportionality of One Formulation and Investigation of Safety, Tolerability and Pharmacokinetics of Multiple Dose Administration in Healthy Female Participants

Researchers are looking for a different way to treat women with a condition in which tissue that normally lines the uterus grows outside the uterus. This condition is called endometriosis. Before a treatment is available to all patients, researchers study it in clinical trials to better understand its safety and what happens to it in the body.
BAY2328065 is being developed to help treat women who have endometriosis. Women with endometriosis often have very painful menstrual periods, as well as pain in the pelvic area which is not related to menstrual periods and pain during intercourse. Many women with endometriosis may also have problems becoming pregnant. The trial treatment, BAY2328065, works by blocking a certain protein that causes pain and swelling of the tissue and is thought to play a role in endometriosis.
In this trial, the researchers want to compare what happens to different medicinal forms of BAY2328065 in the body. They also want to learn if eating a meal affects what happens to BAY2328065 in the body.
This trial will include about 32 men and women who are aged 18 to 55. There will be 4 groups of participants in this trial. The participants in Groups 1, 2, and 3 will be men. The participants in Group 4 will be women. There will be 3 treatment courses to the trial for Groups 1, 2 and 3 and 1 treatment course for Group 4.
During the trial, the participants in Groups 1, 2, and 3 will stay at the trial site for 15 days (3 times 5 days with times in between during which they stay at home). The participants in Group 4 will stay at the trial site for 16 days continuously. But, the trial will last about 6 weeks for the participants in Groups 1, 2, and 3. The trial will last about 9 weeks for the participants in Group 4.
All of the participants in Groups 1 and 2 will take the different medicinal forms of BAY2328065, with and without food. All of the participants in Groups 1 and 2 will take dose 2 of BAY2328065 in all 3 treatment courses. In Group 1, they will take BAY2328065 one time each during the following treatment courses:
A medicinal form of BAY2328065 without food in treatment course 1, then
A medicinal form of BAY2328065 differing from the one used in treatment course 1 without food in treatment course 2, then
The medicinal form of BAY2328065 used in treatment course 1 with food in treatment course 3 The participants in Group 2 will do the same, but they will take each form of BAY2328065 in a different order. Information gathered from Group 1 and 2 will help the researchers learn which form of BAY2328065 will be most suited to give to the participants in Groups 3 and 4.
The participants in Group 3 will take 3 different doses of BAY2328065 with food in each treatment course. They will take one time each during the following treatment courses:
Single administration of dose 1 in treatment course 1, then
Single administration of dose 2 in treatment course 2, then
Single administration of dose 3 in treatment course 3 This will help the researchers learn the safest dose to give to the participants in treatment course 4.
The participants in Group 4 will either take dose 3 or 2 of BAY2328065 based on the results of treatment course 3, or a placebo. A placebo looks like a treatment but does not have any medicine in it. All of the participants will take either:
Multiple administrations of dose 3 of BAY2328065 or dose 2 of BAY2328065, OR
the placebo The participants will take BAY2328065 or placebo over 12 days without food.
The doctors/ healthcare staff will:
take blood and collect urine samples
check the participants' heart health
The participants will:
answer questions about how they are feeling
say if they have any medical problems
say if they have taken any medications

开始日期2021-04-28

申办/合作机构

Bayer AG

NCT04027192 / Completed临床1期

Randomized, Placebo-controlled, Double-blind, Parallel Group Study to Investigate Safety, Tolerability and Pharmacokinetics of Increasing Multiple Oral Doses of BAY2328065 Including the CYP3A4 Induction Potential of BAY2328065 and Randomized Cross-over Investigation of the Relative Bioavailability Between Solution and Tablet Formulation in Healthy Male Participants

Study on the safety and tolerability of a new drug BAY2328065 when given increased doses as tablet or solution over 12 days to healthy male participants. Researcher want to study how the body absorbs, breaks down and excrete the new drug, also when given together with a test meal. In addition the study will investigate changes that take place in the body when BAY2328065 is given together with another drug.

开始日期2019-07-31

申办/合作机构

Bayer AG

NCT03427788 / Completed临床1期

Randomized, Placebo-controlled, Double-blind, Parallel Group Study to Investigate the Safety, Tolerability and Pharmacokinetics of Increasing Single Oral Doses of BAY2328065 Including the Relative Bioavailability Between Solution and Tablet Formulation and the Effect of Food on the Pharmacokinetics of BAY2328065 in Healthy Men

This single center, double-blind, randomized study with up to 11 treatment groups evaluates the safety and tolerability, pharmacokinetics, relative bioavailability and food effect of single ascending doses of BAY2328065

开始日期2018-03-21

申办/合作机构

Bayer AG

100 项与 P2X4 receptor 相关的临床结果

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100 项与 P2X4 receptor 相关的转化医学

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0 项与 P2X4 receptor 相关的专利（医药）

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799

项与 P2X4 receptor 相关的文献（医药）

2024-03-01·Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society

Whole-exome sequencing identifies cancer-associated variants of the endo-lysosomal ion transport channels in the Saudi population.

Article

作者: Lama Binobaid ; Homood M As Sobeai ; Khalid Alhazzani ; Lama AlAbdi ; Meshari M Alwazae ; Moureq Alotaibi ; John Parrington ; Ali Alhoshani

Background:

Although national efforts are underway to document the genomic variability of the Saudi population relative to other populations, such variability remains largely unexplored. Genetic variability is known to impact the fate of cells and increase or decrease the risk of a variety of complex diseases including cancer forms. Therefore, the identification of variants associated with cancer susceptibility in Saudi population may protect individuals from cancer or aid in patient-tailored therapies. The endo-lysosomal ion transport genes responsible for cationic ion homeostasis within the cell. We screened 703 single-nucleotide polymorphisms (SNPs) of the endo-lysosomal ion transporter genes in the Saudi population and identified cancer-associated variants that have been reported in other populations.

Methods:

Utilizing previously derived local data of Whole-Exome Sequencing (WES), we examined SNPs of TPCN1, TPCN2, P2RX4, TRPM7, TRPV4, TRPV4, and TRPV6 genes. The SNPs were identified for those genes by our in-house database. We predicted the pathogenicity of these variants using in silico tools CADD, Polyphen-2, SIFT, PrimateAI, and FATHMM-XF. Then, we validated our findings by exploring the genetics database (VarSome, dbSNP NCB, OMIM, ClinVar, Ensembl, and GWAS Catalog) to further link cancer risk.

Results:

The WES database yielded 703 SNPs found in TPCN2, P2RX4, TRPM7, TRPV4, and TRPV6 genes in 1,144 subjects. The number of variants that were found to be common in our population was 150 SNPs. We identified 13 coding-region non-synonymous variants of the endo-lysosomal genes that were most common with a minor allele frequency (MAF) of ≥ 1 %. Twelve of these variants are rs2376558, rs3750965, rs61746574, rs35264875, rs3829241, rs72928978, rs25644, rs8042919, rs17881456, rs4987682, rs4987667, and rs4987657 that were classified as cancer-associated genes.

Conclusion:

Our study highlighted cancer-associated SNPs in the endo-lysosomal genes among Saudi individuals. The allelic frequencies on polymorphic variants confer susceptibility to complex diseases that are comparable to other populations. There is currently insufficient clinical data supporting the link between these SNPs and cancer risk in the Saudi population. Our data argues for initiating future cohort studies in which individuals with the identified SNPs are monitored and assessed for their likelihood of developing malignancies and therapy outcomes.

2024-02-14·Nature

Bone marrow plasma cells require P2RX4 to sense extracellular ATP.

Article

作者: Masaki Ishikawa ; Zainul S Hasanali ; Yongge Zhao ; Arundhoti Das ; Marieke Lavaert ; Carly J Roman ; Jennifer Londregan ; David Allman ; Avinash Bhandoola

Plasma cells produce large quantities of antibodies and so play essential roles in immune protection¹. Plasma cells, including a long-lived subset, reside in the bone marrow where they depend on poorly defined microenvironment-linked survival signals¹. We show that bone marrow plasma cells use the ligand-gated purinergic ion channel P2RX4 to sense extracellular ATP released by bone marrow osteoblasts through the gap-junction protein pannexin 3 (PANX3). Mutation of Panx3 or P2rx4 each caused decreased serum antibodies and selective loss of bone marrow plasma cells. Compared to their wild-type counterparts, PANX3-null osteoblasts secreted less extracellular ATP and failed to support plasma cells in vitro. The P2RX4-specific inhibitor 5-BDBD abrogated the impact of extracellular ATP on bone marrow plasma cells in vitro, depleted bone marrow plasma cells in vivo and reduced pre-induced antigen-specific serum antibody titre with little posttreatment rebound. P2RX4 blockade also reduced autoantibody titre and kidney disease in two mouse models of humoral autoimmunity. P2RX4 promotes plasma cell survival by regulating endoplasmic reticulum homeostasis, as short-term P2RX4 blockade caused accumulation of endoplasmic reticulum stress-associated regulatory proteins including ATF4 and B-lineage mutation of the pro-apoptotic ATF4 target Chop prevented bone marrow plasma cell demise on P2RX4 inhibition. Thus, generating mature protective and pathogenic plasma cells requires P2RX4 signalling controlled by PANX3-regulated extracellular ATP release from bone marrow niche cells.

2024-02-13·Biochimie

Renal ischemia and reperfusion impact the purinergic signaling in a vascular bed distant from the injured site.

Article

作者: Jeferson Stabile ; Raquel Silva Neres-Santos ; Isabela Dorta Molina Hernandes ; Carolina Victória Cruz Junho ; Geovane Felippe Alves ; Isabella Cardoso Silva ; Marcela Sorelli Carneiro-Ramos ; Cristina Ribas Fürstenau

AIMS:

Acute kidney injury (AKI) is a public health problem and represents a risk factor for cardiovascular diseases (CVD) and vascular damage. This study aimed to investigate the impact of AKI on purinergic components in mice aorta.

MAIN METHODS:

The kidney ischemia was achieved by the occlusion of the left kidney pedicle for 60 min, followed by reperfusion for 8 (IR8) and 15 (IR15) days. Renal function was assessed through biochemical assays, while gene expression levels were evaluated by RT-qPCR.

KEY FINDINGS:

Analyses of renal parameters showed renal remodeling through mass loss in the left kidney and hypertrophy of the right kidney in the IR15 group. Furthermore, after 15 days, local inflammation was evidenced in the aorta. Moreover, the aorta purinergic components were significantly impacted by the renal ischemia and reperfusion model, with increases in gene expression of the pro-inflammatory purinoceptors P2Y1, P2Y2, P2Y6, and P2X4, potentially contributing to the vessel inflammation. The expression of NTPDase2 and ecto-5'-nucleotidase were also significantly increased in the aorta of the same group. In addition, both ATP and AMP hydrolysis were significantly increased in the aorta from IR15 animals, driving the entire purinergic cascade to the production of the anti-inflammatory adenosine.

SIGNIFICANCE:

In short, this is the first time that inflammation of the aorta due to AKI was shown to have an impact on purinergic signaling components, with emphasis on the adenosinergic pathway. This seems to be closely implicated in the establishment of vascular inflammation in this model of AKI and deserves to be further investigated.

项与 P2X4 receptor 相关的新闻（医药）

2024-04-07

·药渡

科瑞斯生物——三大技术平台助力药企进军千亿级别离子通道药物市场

来源：药渡撰文：四月的雨编辑：哦呼离子通道在人体内具有重要作为，作为细胞膜上的“门户”，离子通道控制着离子们的进进出出。而离子通道药物则可以影响这些离子通道，从而调节细胞内外的离子流动，进而改变细胞的功能。例如此类药物可以调节心脏细胞上的钠离子通道，从而调整心脏的节律。离子通道药物由于具有广阔的适应症，如心血管疾病、疼痛以及肿瘤等，因此具有广泛的应用前景。最为重要的是，离子通道药物潜力巨大。离子通道被认为是继GPCR之后第二大类药物靶点，但目前400多个编码离子通道的基因仅仅几十个得到初步的研究。销售额方面，离子通道药物全球销售额大约200亿美元，超千亿人民币，未来还有较大上升空间。离子通道药物虽然潜力巨大，研发壁垒也是较高，纵观研发史，多家巨头药企折戟在此。离子通道药物研发的成与败在众多的在研离子通道药物中，一些药物由于选择性差、毒性大或疗效不佳等原因而导致了最终的失败。在过去的几年，小分子离子通道药物尤其是Nav1.7/Nav1.8抑制剂的遭遇最为悲惨。2018年10月，Biogen宣布其在研Nav1.7抑制剂Vixotrigine临床2期试验失败，临床试验结果表明Vixotrigine未能达到减少患者平均每日疼痛的预期目标。几乎同时，罗氏也宣布终止了从Xenon收购的同类药物RG6029，另一个卖到梯瓦的Xenon同类药物TV-45070遭相似命运。作为VX-548的“兄弟”，VX-150却也难逃失败的命运。VX-150由于药代动力学性质差、临床剂量过大、存在安全性隐患等原因终止了其临床二期。明雨过后见彩虹，离子通道药物终于传来大捷喜讯。2024年1月30日，Vertex公布Nav1.8抑制剂VX-548治疗中至重度急性疼痛的临床3期数据，数据显示，与安慰剂相比,使用VX-548治疗的受试者疼痛有统计学意义上的显著改善,并且在腹部成形术和子宫切除术的随机对照试验中,疼痛在临床意义的减轻。VX-548的单臂研究显示,在长达14天的大范围手术和非手术性疼痛情况下,使用VX-548进行治疗是有效的。在所有三项研究中,VX-548都是安全的。Vertex计划在2024年中期向FDA提交新药申请。作为近年来首款非阿片类急性疼痛药物，VX-548的获批具有里程碑意义。电压门控一直为离子通道药物研发热点，下表1为以Nav1.8靶点为代表的部分在研药物，除VX-548取得临床3期试验成功外，当前还有多款处于临床2期阶段，除此以外还有多款药物处于临床1期阶段，这里就不再一一列举。全球Nav1.8抑制剂研发管线数量并不多，其中还有相当一部分因各种原因被终止临床，目前全球对于离子通道药物的研发仍有巨大的进步空间。表1.在研离子通道药物（部分）除电压门控以外，配体门控、TRP通道等也是当今研发主流靶点，适应症涉及疼痛、咳嗽、癫痫、脑卒中以及退行性疾病、抑郁症以及癫痫等多项适应症。涉及靶点包括嘌呤受体（P2X2, P2X3, P2X2/3, P2X4, P2X7等）、GABA受体（α1β3γ2, α2β2γ2, α5β2γ2, α6β2γ2等）以及NMDA受体（NR1/2A, NR1/2B；NR1/2C, NR1/2D等）等多种，下表2为部分在研药物。表2.在研药物（部分）作为配体门控受体，P2X3以及GABA受体与多种疾病直接相关，并且逐渐成为“优质”靶点。以GABA受体为例，目前该靶点在研药物适应症主要包括抑郁症、癫痫以及麻醉等多种，皆为中枢神经领域的适应症，这也是当今离子通道药物研发的重要方向。进度方面，由奥鸿医药/华西医院所研发的麻醉药物ET-26以处于临床3期阶段，除此以外，还有多款药物处于临床2期阶段。离子通道靶点——高壁垒下蕴含巨大潜力与机遇众多药企在离子通道药物新药研发上折戟沉沙可以看出离子通道药物研发难度之高，究其根本原因则是离子通道药物特异性差、成药性差、研发过程复杂并且副作用难以控制，最后导致了研发成本的升高。对于离子通道药物的研发，其中涉及了药物化学、生物学、药理学等多个领域的知识和技术。高壁垒下蕴藏大机遇，目前离子通道靶向药物的全球销售大约在200亿美元左右。适应症方面，离子通道药物适用于心律失常、疼痛、癫痫、抑郁、慢性阻塞性肺病、自身免疫性疾病以及糖尿病等多个领域，由于适应症范围广阔，未来离子通道药物市场将进一步提高。对于离子通道药物，人体内参与编码离子通道的基因多达400多个，但目前仅有60余个得到初步研究，仍有大量离子通道的功能及与疾病的关系有待阐明，当某一基因或某几个基因的研究获得突破时，或许离子通道药物的研发将更上一层楼，所以未来离子通道药物潜力巨大。当某款离子通道药物取得突破时，迎接它的便是巨大的机遇，VX-548便是如此。VX-548临床3期试验的成功意义重大，意味着患者不再局限于阿片类药物的选择。三期临床成功，对于全球第一大药物市场的美国来说意义重大。依据CDC数据，阿片类药物过量致死率正加速升高，截至2021年，死于药物过量的人数是1999年的六倍多，从2020年到2021年，药物过量死亡人数增加了16%以上，在2021年近10.7万例药物过量死亡中，涉及阿片类药物超75%。由此可见，VX-548获批后必然会成为众多患者的新选择，市场销售额有望款速扩增。图1.美国阿片过量致死率（图片来源：参考文献2）全球多家药企一直在致力于探索新型的镇痛药物，不仅能媲美阿片类药物的镇痛效果，还可以提高安全性并且避免成瘾，如今VX-548应运而生，必然会为Vertex带来巨大的收益。Vertex在VX-150上面折戟沉沙，但是VX-548的成功让其一扫阴霾，或许这就是离子通道药物高壁垒下蕴含巨大潜力与机遇的奇妙之处。科瑞斯生物——三大技术平台助力药企进军千亿级别离子通道药物市场药物研发当然要紧跟相关的指导原则与法规。2019年，FDA颁布了新的离子通道临床前心脏风险评估指导原则，这意味着对于离子通道药物的。临床前对药物心脏安评的结果，将直接关乎到项目的成败。而科瑞斯生物拥有全球顶级的离子通道新药研发服务及药物的临床前心脏风险评估平台，可为客户提供优质的服务，确保项目更快、更稳的推进。科瑞斯生物成立于2013年，是国内最早能提供离子通道靶点新药研发及专业化临床前药物心脏安全评估平台的企业。公司拥有多套先进的仪器和设备，能够提供从细胞到整体动物的不同水平的测试平台以及高通量化合物筛选平台。目前科瑞斯生物拥有三大服务平台，将助力您更好的进行离子通道药物研发。国内首家可提供临床前心脏安全评估平台科瑞斯生物临床前心脏安全评估平台涉及的技术主要包括手动膜片钳、细胞内动作电位记录、离体心脏灌流系统以及无创伤遥感系统等。由于离子通道药物临床上经常发生由于心电图QT延长而导致的室性扭转性心律失常(TdP)，这将导致药物的研发失败或药物退市。并且由于室性扭转性心律失常的产生几率非常低且在大多数临床实验中是检测不到的，所以药物前临床研发中进行心脏安评是非常有必要的。检测项目主要包括观察药物对hERG离子通道，心电图QTc及心脏上其他主要离子通道包括钠、钙、钾通道等8-10种离子通道的作用、药物对心肌细胞动作电位、离体心脏QTc的影响等，其中hERG及体外QTc是目前新药临床申请所必须提供的数据之一。而科瑞斯生物曾参与FDA及相关机构的CiPA 的工作，在心脏安评方面具有丰富的经验以及过硬的平台技术。图2.科瑞斯生物临床前心脏安全评估平台以离子通道为靶点的新药研发平台离子通道是细胞膜或细胞器膜表面的可以形成离子通透性通道的蛋白质，广泛参与机体细胞的众多生理过程，譬如：神经传导，肌肉收缩，感觉的形成，细胞的分泌，细胞增生和分化，学习与记忆，免疫反应等。离子通道的功能异常会导致诸多疾病，因此离子通道是非常具有吸引力的药物靶点，在新药研究中有着重要作用。科瑞斯生物离子通道为靶点的新药研发平台主要包括四大板块，分别为镇痛、房颤、离体心脏缺血模型以及脑片长时程增强记录。图3.科瑞斯生物离子通道新药研发平台临床前药物研发服务平台科瑞斯生物临床前药物研发服务平台业务包括靶点验证、活性化合物发现、活性化合物到先导化合物的筛选以及先导化合物的优化。目前科瑞斯生物已经开发出近100种离子通道相关的研发及化合物筛选平台，适应症方面则包括镇痛、癫痫、抑郁症、中风、慢性咳嗽以及心衰等多种。图4.科瑞斯生物临床前药物研发服务平台除此以外，科瑞斯生物与Reaction Biology Corporation (RBC)达成战略伙伴关系，RBC药物研发服务平台可提供细胞试验服务、生化试验服务、生物物理测定服务、重组蛋白以及动物实验等多项服务。科瑞斯生物建立的药物心脏安评平台及新药研发平台，是中国国内首个专业化的药物心脏风险评估公司，其技术在国内处于先进地位，并且与国际保持同步。小结离子通道药物有望为许多疾病的治疗带来新的可能性，但在开发和应用过程中，仍需深入的研究以确保药物安全有效的用于临床。关于科瑞斯科瑞斯·总部电话：0513-68015200邮箱：infor@pharmacorelab.com地址：江苏省海门市临江新区海门生物医药科技创业园科瑞斯·分公司地址：中国(上海)自由贸易试验区蔡伦路780号6D座参考文献[1]https://news.vrtx.com/news-releases/news-release-details/vertex-announces-positive-results-vx-548-phase-3-program[2]https://www.hanghangcha.com/pdf.html[3]科瑞斯生物官网及宣传手册本土Biotech与MNC合作进入2.0时代：汇总分析３起医药并购案例【药企裁员风波不断】三月汇总FDA九个月内批准的三种DMD治疗方法点击蓝字 | 关注我们

临床2期并购临床3期临床失败临床成功

2023-11-23

·赛柏蓝

近50条管线被终止！跨国药企业务精简

01近50条管线被终止研发近日，武田在第三季度财报中披露，因一系列不可控因素，武田净亏损增长，全年净利润预测下调了71%，且公布了4条需被精简的管线，覆盖肺癌、阿尔茨海默氏症等疾病治疗领域，其中还涉及一款已上市产品。就在上个月，武田经与FDA商议后宣布，将在美国启动琥珀酸莫博赛替尼（mobocertinib，商品名：安卫力/Exkivity）的主动退市。据悉，莫博赛替尼获得FDA、国家药监局批准上市是基于其I/II期二线单臂试验，之后，武田并未延续二线应用，转而将研究瞄准一线治疗，启动了EXCLAIM-2，由于在III期临床中的确证性研究未达到主要终点，EXCLAIM-2被终止。其主动撤回在美获批适应症的工作也随之展开，武田表示，莫博赛替尼在中国及其它已获批国家地区的后续计划也在与各地监管机构积极沟通中。除了莫博赛替尼，武田与Denali合作开发的阿尔茨海默氏症候选药物DNL-919/TAK-920因在最高剂量下出现“中度、可逆的血液学效应”而被停止开发；另外，候选药物酶替代疗法TAK-611、治疗恶心和呕吐的候选药物TAK-105，也因未达到主要终点和次要终点、数据不支持等原因而停止进一步开发。今年，十余家大型跨国药企公布了多起精简计划，近50条管线被削减（统计名单见文末）。日前，罗氏第三季度财报等信息显示，其有四条产品研发管线将被精简，其中一项已进入III期研究、两项已进入II期、一项处于I期，覆盖多发性骨髓瘤、糖尿病视网膜病变、精神分裂症等疾病治疗领域。具体包括因III期结果不及预期放弃Venclexta联合地塞米松治疗复发或难治性多发性骨髓瘤的研究；因无效性分析失败及未达到主要终点放弃TAAR1激动剂Ralmitaront治疗精神分裂症的II期项目；因未达到主要终点放弃Vicasinabin治疗糖尿病视网膜病变的II期项目；以及基于“全部疗效和安全性数据以及治疗领域不断变化的治疗格局”，放弃T细胞双特异性抗体Cibisatamab的实体瘤I期试验。半年前，罗氏也先后停止了多项药物研发，包括天使综合征ASO药物Rugonerse，处于III期阶段的替奈普酶治疗卒中适应症，II期阶段血友病A基因疗法RG6358等。 02半数被终止管线止步II期分临床阶段看，此次统计的48条被暂停管线中，II期项目最多（按更靠前进度统计，如IIb/III期计为III期，下同），占比约一半，达到24条。以辉瑞为例，其有至少8个临床项目止步于此阶段，包括用于治疗银屑病和特应性皮炎的局部PDE4抑制剂PF-07038124、用于治疗急性心力衰竭的β3-adrenergic受体拮抗剂APD418，以及Temanogrel用于治疗系统硬化继发性的微血管阻塞和雷诺氏综合征的临床等。 II期试验也称为疗效试验或临床效能试验，主要目的是初步评价药物对目标适应症患者的治疗作用和安全性。在这一阶段，受试者群体往往会在上一期试验的基础上扩大规模，随着受试者增加，药物的潜在安全性问题也更容易被发现；除了安全性，若药物在此阶段所表现的治疗效果与已有治疗方案相比没有显著优势，对应管线也很有可能被终止。在此次统计中，I期项目出现频次居于II期之后，约有16条管线在此阶段前后被终止；在III期被终止的项目约8项。分药物类型来看，小分子药物出现最为频繁。以拜耳为例，其公布终止的4条管线均为小分子药物，包括用于神经性疼痛的BDKRB1受体拮抗剂BAY 2395840、用于慢性肾病的口服可溶性鸟甘酸环化酶（sGC）激动剂Runcaciguat，以及用于子宫内膜异位症的BAY 2395840和一款P2X4拮抗剂。近年来，医药行业热门赛道常出现“扎堆”的现象，部分领域甚至出现几十、上百家药企布局研发，但最终真正能够顺利上市、实现商业化的企业不会是多数。随着市场环境变化，业务遍布全球的大型药企更需要对非核心产品管线进行终止、剥离，同时优化人员架构，以降本增效，实现新增长。END作者 | 陈芋来源 | 赛柏蓝赛柏蓝药械交流群扫描下方二维码加入医药代理商转型交流群扫描下方二维码加入

财报临床3期基因疗法临床2期临床失败

2023-10-22

·生物谷

Nature Commun.｜复旦大学服部素之：合作揭示神经性疼痛相关的P2X4受体别构抑制的机制

P2X受体是非选择性的阳离子通道家族，受胞外ATP激活。该家族在脊椎动物中有七种亚型，以同源或异源三聚体的形式发挥生理功能。其中，P2X4主要在神经元、免疫细胞及心血管平滑肌与内皮细胞中表达，参与促炎症细胞因子的释放，与慢性神经性疼痛、神经性炎症有关，是个潜在的药物靶点。迄今已发现了一些P2X4亚型特异性的拮抗剂，然而，P2X4受拮抗剂抑制的详细机制仍不清楚。2023年10月13日，复旦大学生命科学学院服部素之团队与中国药科大学基础医学与临床药学学院汪津团队合作，于期刊Nature Communications发表题为“Structural insights into the allosteric inhibition of P2X4 receptors”的文章，利用单颗粒冷冻电子显微镜技术，解析了P2X4受体与其特异性拮抗剂BX430与BAY-1797的复合物结构，结合分子动力学模拟与电生理实验分析其作用机制，为P2X4亚型特异的药物设计提供结构信息。该研究发现两种拮抗剂结合在P2X4受体胞外结构域的同一别构位点。通过与之前报道的结构对比，发现了拮抗剂对结合口袋及配体的作用：一个Lys残基在结合配体后发生构象变化，其侧链由插入结合口袋转变为伸向受体外部，这一构象变化不仅为结合口袋容纳别构调节剂提供了足够的空间，而且在结合口袋外部与相邻亚基的Tyr的侧链形成稳定的相互作用，参与了对拮抗剂的稳定。除此之外，结合口袋也发生了配体依赖的扩张。图1. (a)P2X4与BX430复合物结构和(b)P2X4受体别构抑制的机制该研究提出了拮抗剂阻碍了亚基间相对运动的猜想，初步解释了P2X4别构抑制的分子机制。最后，通过突变设计与电生理实验，讨论了这种别构抑制在P2X家族不同亚型受体之间的差异。中国药科大学基础医学与临床药学学院的汪津副研究员与复旦大学生命科学学院的服部素之研究员为本文的共同通讯作者，复旦大学生命科学学院的博士生沈成与中国药科大学基础医学与临床药学学院的张雨晴、崔雯雯为本文共同第一作者。注：文中插图源于 Nature Communications原文链接：https://doi-org.libproxy1.nus.edu.sg/10.1038/s41467-023-42164-y本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！