更新于：2024-05-01

LYN

酪氨酸蛋白激酶Lyn

更新于：2024-05-01

基本信息

别名

JTK8、Lck/Yes-related novel protein tyrosine kinase、LYN

+ [5]

简介

Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors and plays an important role in the regulation of innate and adaptive immune responses, hematopoiesis, responses to growth factors and cytokines, integrin signaling, but also responses to DNA damage and genotoxic agents. Functions primarily as negative regulator, but can also function as activator, depending on the context. Required for the initiation of the B-cell response, but also for its down-regulation and termination. Plays an important role in the regulation of B-cell differentiation, proliferation, survival and apoptosis, and is important for immune self-tolerance. Acts downstream of several immune receptors, including the B-cell receptor, CD79A, CD79B, CD5, CD19, CD22, FCER1, FCGR2, FCGR1A, TLR2 and TLR4. Plays a role in the inflammatory response to bacterial lipopolysaccharide. Mediates the responses to cytokines and growth factors in hematopoietic progenitors, platelets, erythrocytes, and in mature myeloid cells, such as dendritic cells, neutrophils and eosinophils. Acts downstream of EPOR, KIT, MPL, the chemokine receptor CXCR4, as well as the receptors for IL3, IL5 and CSF2. Plays an important role in integrin signaling. Regulates cell proliferation, survival, differentiation, migration, adhesion, degranulation, and cytokine release. Down-regulates signaling pathways by phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIM), that then serve as binding sites for phosphatases, such as PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1, that modulate signaling by dephosphorylation of kinases and their substrates. Phosphorylates LIME1 in response to CD22 activation. Phosphorylates BTK, CBL, CD5, CD19, CD72, CD79A, CD79B, CSF2RB, DOK1, HCLS1, LILRB3/PIR-B, MS4A2/FCER1B, SYK and TEC. Promotes phosphorylation of SIRPA, PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1. Mediates phosphorylation of the BCR-ABL fusion protein. Required for rapid phosphorylation of FER in response to FCER1 activation. Mediates KIT phosphorylation. Acts as an effector of EPOR (erythropoietin receptor) in controlling KIT expression and may play a role in erythroid differentiation during the switch between proliferation and maturation. Depending on the context, activates or inhibits several signaling cascades. Regulates phosphatidylinositol 3-kinase activity and AKT1 activation. Regulates activation of the MAP kinase signaling cascade, including activation of MAP2K1/MEK1, MAPK1/ERK2, MAPK3/ERK1, MAPK8/JNK1 and MAPK9/JNK2. Mediates activation of STAT5A and/or STAT5B. Phosphorylates LPXN on 'Tyr-72'. Kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. Phosphorylates SCIMP on 'Tyr-107'; this enhances binding of SCIMP to TLR4, promoting the phosphorylation of TLR4, and a selective cytokine response to lipopolysaccharide in macrophages (By similarity). Phosphorylates CLNK (By similarity). Phosphorylates BCAR1/CAS and NEDD9/HEF1 (PubMed:9020138).

关联

项与 LYN 相关的药物

Pirfenidone

吡非尼酮

靶点

CCL2 x IL-10 x IL-6 x IL1 x TNF-α

作用机制

CSF-1R拮抗剂 [+13]

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段批准上市

首次获批国家/地区

日本

首次获批日期2008-10-16

Masitinib mesylate

甲磺酸马赛替尼

靶点

LYN x PDGFRα x PDGFRβ x c-Kit

作用机制

LYN抑制剂 [+3]

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段申请上市

首次获批国家/地区-

首次获批日期1800-01-20

SKLB-1028

靶点

Abl family x EGFR x FLT3 x LYN

作用机制

Abl family inhibitors [+3]

在研机构

石药集团中奇制药技术（石家庄）有限公司 [+2]

原研机构

四川大学

在研适应症

急性髓性白血病 [+3]

非在研适应症

FLT3阳性急性髓性白血病 [+2]

最高研发阶段临床3期

首次获批国家/地区-

首次获批日期1800-01-20

313

项与 LYN 相关的临床试验

NCT06241560 / Not yet recruiting临床2期

An Open-label, Single-group Trial to Evaluate the Effect of Pirfenidone on the Pharmacokinetics of a Single Oral Dose of BI 1015550

This study is open to adults with idiopathic pulmonary fibrosis (IPF) who are 40 years and older. The purpose of this study is to find out whether a medicine called pirfenidone changes the amount of a medicine called BI 1015550 in the blood. Some people may take more than one medicine at a time. Therefore, it is important to understand how different medicines influence one another.
Participants take one dose of BI 1015550 as a tablet. Participants then take one tablet of pirfenidone 3 times a day for one week. The dose is then increased to 2 tablets 3 times a day for the second week. In the third week the dose is increased further to 3 tablets 3 times a day. Participants then take another dose of BI 1015550 as a tablet.
Participants are in the study for a little over 1 month. During this time, they visit the study site 15 times. Two of the visits include overnight stays at the study site. The study staff also contacts the participants by phone. During the visits, the doctors collect information about participants' health and take blood samples from the participants. They compare the amount of pirfenidone and BI 1015550 in the blood. Doctors also regularly check participants' health and take note of any unwanted effects.

开始日期2024-08-06

申办/合作机构

Boehringer Ingelheim GmbH

CTR20240581 / Active, not recruiting临床1期

在中国健康受试者中随机、开放、两周期、双交叉餐后状态下吡非尼酮双释片（受试制剂）与吡非尼酮片（对照制剂）的药代动力学比较试验，并进行受试制剂与对照制剂的生物等效性考察

主要目的：以越洋医药开发（广州）有限公司研制的吡非尼酮双释片（规格：600 mg/片）为受试制剂，盐野义制药株式会社生产的吡非尼酮片（商品名：Pirespa®，规格：200 mg/片）为对照制剂，比较餐后状态下口服受试制剂与对照制剂在中国健康受试者体内的血药浓度及主要药代动力学参数，并进行受试制剂与对照制剂的生物等效性考察。次要目的：评价中国健康受试者餐后状态下口服受试制剂吡非尼酮双释片和对照制剂吡非尼酮片后的安全性。

开始日期2024-04-08

申办/合作机构

越洋医药开发（广州）有限公司

NCT06329401 / Recruiting临床2期

A Randomized, Double-Blind, Placebo-Controlled, Phase 2b Study Evaluating the Safety and Efficacy of Pirfenidone Solution for Inhalation (AP01) in Participants With PPF

A randomized, double-blind, placebo-controlled clinical study to evaluate the safety and efficacy of 2 doses of AP01 versus placebo on top of standard of care in participants with PPF over 52 weeks.

开始日期2024-04-03

申办/合作机构

Avalyn Pharma, Inc.

[+1]

100 项与 LYN 相关的临床结果

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100 项与 LYN 相关的转化医学

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0 项与 LYN 相关的专利（医药）

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2,568

项与 LYN 相关的文献（医药）

2024-02-06·International journal of molecular sciences

Unveiling Novel Urease Inhibitors for Helicobacter pylori: A Multi-Methodological Approach from Virtual Screening and ADME to Molecular Dynamics Simulations.

Article

作者: Paulina Valenzuela-Hormazabal ; Romina V Sepúlveda ; Melissa Alegría-Arcos ; Elizabeth Valdés-Muñoz ; Víctor Rojas-Pérez ; Ileana González-Bonet ; Reynier Suardíaz ; Christian Galarza ; Natalia Morales ; Verónica Leddermann ; Ricardo I Castro ; Bruna Benso ; Gabriela Urra ; Erix W Hernández-Rodríguez ; Daniel Bustos

Helicobacter pylori (Hp) infections pose a global health challenge demanding innovative therapeutic strategies by which to eradicate them. Urease, a key Hp virulence factor hydrolyzes urea, facilitating bacterial survival in the acidic gastric environment. In this study, a multi-methodological approach combining pharmacophore- and structure-based virtual screening, molecular dynamics simulations, and MM-GBSA calculations was employed to identify novel inhibitors for Hp urease (HpU). A refined dataset of 8,271,505 small molecules from the ZINC15 database underwent pharmacokinetic and physicochemical filtering, resulting in 16% of compounds for pharmacophore-based virtual screening. Molecular docking simulations were performed in successive stages, utilizing HTVS, SP, and XP algorithms. Subsequent energetic re-scoring with MM-GBSA identified promising candidates interacting with distinct urease variants. Lys219, a residue critical for urea catalysis at the urease binding site, can manifest in two forms, neutral (LYN) or carbamylated (KCX). Notably, the evaluated molecules demonstrated different interaction and energetic patterns in both protein variants. Further evaluation through ADMET predictions highlighted compounds with favorable pharmacological profiles, leading to the identification of 15 candidates. Molecular dynamics simulations revealed comparable structural stability to the control DJM, with candidates 5, 8 and 12 (CA5, CA8, and CA12, respectively) exhibiting the lowest binding free energies. These inhibitors suggest a chelating capacity that is crucial for urease inhibition. The analysis underscores the potential of CA5, CA8, and CA12 as novel HpU inhibitors. Finally, we compare our candidates with the chemical space of urease inhibitors finding physicochemical similarities with potent agents such as thiourea.

2024-02-01·PNAS nexus

Decoding the genetic symphony: Profiling protein-coding and long noncoding RNA expression in T-acute lymphoblastic leukemia for clinical insights.

Article

作者: Deepak Verma ; Shruti Kapoor ; Sarita Kumari ; Disha Sharma ; Jay Singh ; Mercilena Benjamin ; Sameer Bakhshi ; Rachna Seth ; Baibaswata Nayak ; Atul Sharma ; Raja Pramanik ; Jayanth Kumar Palanichamy ; Sridhar Sivasubbu ; Vinod Scaria ; Mohit Arora ; Rajive Kumar ; Anita Chopra

T-acute lymphoblastic leukemia (T-ALL) is a heterogeneous malignancy characterized by the abnormal proliferation of immature T-cell precursors. Despite advances in immunophenotypic classification, understanding the molecular landscape and its impact on patient prognosis remains challenging. In this study, we conducted comprehensive RNA sequencing in a cohort of 35 patients with T-ALL to unravel the intricate transcriptomic profile. Subsequently, we validated the prognostic relevance of 23 targets, encompassing (i) protein-coding genes-BAALC, HHEX, MEF2C, FAT1, LYL1, LMO2, LYN, and TAL1; (ii) epigenetic modifiers-DOT1L, EP300, EML4, RAG1, EZH2, and KDM6A; and (iii) long noncoding RNAs (lncRNAs)-XIST, PCAT18, PCAT14, LINC00202, LINC00461, LINC00648, ST20, MEF2C-AS1, and MALAT1 in an independent cohort of 99 patients with T-ALL. Principal component analysis revealed distinct clusters aligning with immunophenotypic subtypes, providing insights into the molecular heterogeneity of T-ALL. The identified signature genes exhibited associations with clinicopathologic features. Survival analysis uncovered several independent predictors of patient outcomes. Higher expression of MEF2C, BAALC, HHEX, and LYL1 genes emerged as robust indicators of poor overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS). Higher LMO2 expression was correlated with adverse EFS and RFS outcomes. Intriguingly, increased expression of lncRNA ST20 coupled with RAG1 demonstrated a favorable prognostic impact on OS, EFS, and RFS. Conclusively, several hitherto unreported associations of gene expression patterns with clinicopathologic features and prognosis were identified, which may help understand T-ALL's molecular pathogenesis and provide prognostic markers.

2024-01-30·Proceedings of the National Academy of Sciences of the United States of America

Tracking the role of Aire in immune tolerance to the eye with a TCR transgenic mouse model.

Article

作者: Mianmian Yin ; Jennifer A Smith ; Marissa Chou ; Jackie Chan ; Yingyos Jittayasothorn ; Douglas B Gould ; Rachel R Caspi ; Mark S Anderson ; Anthony L DeFranco

Roughly one-half of mice with partial defects in two immune tolerance pathways (Aire^GW/+Lyn^-/- mice) spontaneously develop severe damage to their retinas due to T cell reactivity to Aire-regulated interphotoreceptor retinoid-binding protein (IRBP). Single-cell T cell receptor (TCR) sequencing of CD4⁺ T cells specific for a predominate epitope of IRBP showed a remarkable diversity of autoantigen-specific TCRs with greater clonal expansions in mice with disease. TCR transgenic mice made with an expanded IRBP-specific TCR (P2.U2) of intermediate affinity exhibited strong but incomplete negative selection of thymocytes. This negative selection was absent in IRBP^-/- mice and greatly defective in Aire^GW/+ mice. Most P2.U2^+/- mice and all P2.U.2^+/-Aire^GW/+ mice rapidly developed inflammation of the retina and adjacent uvea (uveitis). Aire-dependent IRBP expression in the thymus also promoted Treg differentiation, but the niche for this fate determination was small, suggesting differences in antigen presentation leading to negative selection vs. thymic Treg differentiation and a stronger role for negative selection in preventing autoimmune disease in the retina.

项与 LYN 相关的新闻（医药）

2024-03-15

·动脉网

比尔·盖茨加入投资的公司，让精神病患者一周只吃一次药

一个臃肿羸弱的人躺在沙发上，沉默不语、眼神呆滞。表面上看，这可能只是一个疲劳过度的普通人。可实际上，眼神呆滞是因为视力退减，已经到了罹患糖尿病的边缘；沉默不语是因为同时承受着胸痛、精神错乱、恐慌和紧张；而身体上的肥胖，则极有可能是抗精神病药物恶性综合征的体现。这是北美当前最负盛名的独立调查记者之一——罗伯特·科尔克（Robert Kolker）于2020年出版的非虚构作品《隐谷路：一个精神分裂症家族的绝望与希望》（Hidden Valley Road：Inside the Mind of an American Family，下称《隐谷路》）中的精神分裂患者。这位曾记录了革命性基因编辑技术CRISPR发展史的非虚构文学作家以他特有的笔触、多线并进的叙事方式，回叙了一个精神分裂症家庭希腊悲剧般的一生，以及美国上世纪精神分裂症治疗的曲折发展史。根据科尔克的叙述，上世纪中叶，对精神分裂症不胜其弊的治疗手段也是书中家族悲剧的始作俑者之一，这或许在医疗领域中，也是让人感到吊诡的所在。好在，随着治疗技术革新、医疗界和社会的认知逐步提升，尽管病因未明、药物疗效有限，精神分裂症患者已无需在黑暗中摸索。只是，新的问题随之诞生。作为精神障碍疾病中的重性疾病，精神分裂症因患者治疗依从性低而导致的复发率高、病情反复成为疾病治疗中的一大难点：当前，口服抗精神病药物是主流疗法，但仍有高达70%的精神分裂症患者在出院两年内出现不依从情况，而中断治疗是疾病复发的首要风险。临床上也有一些解决患者依从性低的办法，如通过设计患者日志监控患者按时服药，或通过抽血检测患者血液中的相应指标来监测服药情况；近年来，数字健康的兴起也让用药管理App走进医生和患者群的视野。与此同时，也有一种观点认为，从药物的角度去解决依从性低的问题是更为行之有效的办法，例如，借助长效注射制剂、长效口服制剂等，让患者一周、乃至一个月只用吃一次药。这也是刚刚完成1.1亿美元E轮融资的Lyndra Therapeutics（下称Lyndra）所专攻的方向。两度换帅，南非的“工厂学徒”和美国中部“小镇女孩”浏览Lyndra的公司官网，会发现董事会一栏，传奇的罗伯特·兰格立于C位。事实上，Lyndra的LYNX™长效给药平台就是出自罗伯特·兰格和麻省理工学院教授Giovanni Traverso在实验室发明的技术，在设计、工程和材料科学方面有50多项专利创新，可大幅减少给药次数，Lyndra正是拥有该实验室的独家技术许可。Tyler Grant博士和Rosemary Kanasty博士在麻省理工学院兰格实验室与兰格合作，分别完成了博士后和博士研究，两人在完成LYNX™药物输送系统的研究后正式加入由Polaris Partners 管理合伙人、法学博士Amy Schulman（现任Lyndra董事会成员）牵头的初创企业Lyndra，成为创始团队成员。与其他创始人直接管理公司日常经营的创新药企业不同，Grant和Kanasty并未继续在Lyndra任职，至于Lyndra本身，作为一家走到E轮的药物递送技术研发公司，还在吸纳不同的人才加入。2023年，在卸任Lyndra的首席执行官之前，Patricia Hurter博士曾对外介绍使用激光焊接工艺和挤压塑料部件来组建的LYNX™药物输送平台，并指出，药物本身的“焊接点”是关键功能之一，且焊接质量必须优秀，这样才能保证Lyndra的给药技术能在一周、未来能在一个月内稳定释放药物。Hurter的措辞听起来似乎与制造业的亲缘关系更近，这并不奇怪。Hurter在南非长大，在她10岁时，她父亲开始了自己的替代燃料生意，并怂恿Hurter在假期期间来工厂实习。他甚至让Hurter参与到工厂正在解决的科学和工程问题中，因此Hurter接下来了各种奇怪的任务，例如开发一种从椰子中提取优质椰子油的工艺。这种解决实际工程问题的理念贯穿着Hurter的职业生涯。在她的领导下，Lyndra将LYNX™长效口服给药技术推进到关键试验阶段，并建立了GMP生产设施；同时，为了达到目标效果，Hurter结合多个高科技行业的制造工艺，以实现在设计、工程和材料科学方面的创新。接任Hurter首席执行官岗位的Jessica Ballinger也并非Lyndra创始团队成员，2016年加入Lyndra，于2018年晋升为首席运营官，于2021年担任总裁。在很长一段时间内，Ballinger一直是Hurter一天中的首个交谈对象。或许很难想象Ballinger成长自圣路易斯东部，一个仅有700人的蓝领小镇，来自一个退役军人家庭，并常常需要依靠福利维持生活。Ballinger也是家中第一个上大学的人，且仅用了三年时间就在伊利诺伊大学获得了生物化学理学学士学位。在25年的职业生涯中，Ballinger已经为超过 15 种前沿患者疗法的开发和商业化做出了贡献，并曾在百健和辉瑞担任领导职务，负责以患者为中心的技术开发组织。就在Ballinger就任Lyndra首席执行官几个月后，Lyndra完成1.01亿美元的E轮融资。据悉，该轮融资由Sarissa Capital领投，Sun Pharma和Polaris Partners参投，融资资金将用于支持Lyndra产品线的开发，包括即将完成关键性3期研究的长效口服利培酮（LYN-005）。此外，作为融资的一部分，Sun Pharma将获得在包括巴西和印度在内的六个国家生产和销售长效口服利培酮（LYN-005）、长效口服达帕格列净（LYN-045）和长效口服阿立哌唑（LYN-006）的独家许可，以待这些候选研究产品的进一步临床开发。LYNX™药物递送平台2024年1月4日，Lyndra宣布STARLYNG-1（LYN-005-C-301）试验的积极数据，试验比较了长效口服利培酮（LYN-005）与速释利培酮的药代动力（PK）特征，其中，速释利培酮会每日发放给患有精神分裂症和分裂情感障碍的成年患者，而长效口服利培酮则是每周服用。据悉，该研究计划共有90名参与者，并在46名参与者中进行中期分析。在中期分析中，试验达到了预先指定的主要终点；还达到了安全性和阳性和阴性症状量表（PANSS）评分（用于衡量精神分裂症症状严重程度的评分）的次要终点。有了这些积极结果，试验提前终止。● LYNX™药物递送平台介绍Lyndra的LYNX™药物输送平台是经过彻底改造的药物，旨在通过标准尺寸的胶囊、以口服形式提供长效治疗。LYNX™药物输送平台的工作原理如下：图片来自Lyndra官网首先，从外形上看，LYNX™药物输送平台和普通药物胶囊没有任何不同，不过包含在胶囊中的不是粉末或药物颗粒，而是一种有6个含药臂与柔性核心相连的、像海星一样的药物递送装置，可以折叠后装在标准口服胶囊内。其中，药臂由热熔挤出工艺制造，连接含药臂的核心是通过注射成型制造的，整个药物递送装置使用源自电子微芯片制造的拾放机器人制造技术进行组装。患者服用长效胶囊后，胶囊外壳溶解，同时胶囊内的药物递送装置展开折叠，形成海星状。这种形态有助于使剂型在人体胃中持续递送药物一周或更长时间，而不会直接进入幽门（胃和小肠之间的开口），过早被排泄掉。图片来自Lyndra官网给药结束后，这些连接到柔性核心的药臂会逐步软化，最后崩解。这些成分随后可以顺利穿过幽门，安全排出体外。对于患者和护理人员来说，LYNX™药物输送平台可能比目前的立即释放或缓释口服制剂持续更长时间，并且在药代动力学方面表现更好。此外，以利培酮为例，每周服用一次也并不会影响耐受性。● Lyndra现有管线Lyndra成立之初，主要专注于研发精神疾病、心脏代谢疾病和其他目前无法满足患者需求的疗法。目前，Lyndra率先推出了首个口服、超长效的缓释疗法，能够让患者每周、而不是每天服药。长效口服利培酮（LYN-005）是Lyndra目前的主要候选产品的其中之一。目前，利培酮是精神分裂症患者最常用的治疗药物之一。但对于中枢神经系统疾病患者及其护理人员来说，遵照处方服用药物很难，一旦擅自停药，就会增加复发和住院的风险，也会严重影响生活质量。而通过大幅降低给药频率，Lyndra的长效口服疗法有可能提高依从性、防止复发并改善疗效，也有助于患者早日摆脱日常服药的负担。Lyndra还计划在2024年启动一项关键安全性研究。这项双盲研究将比较每周口服长效利培酮与每日（立即释放）药丸的安全性。Lyndra同时还在研发心血管疾病、阿片类药物使用障碍、女性健康（避孕）和疟疾的长效口服疗法。其中，针对阿片类药物使用障碍的长效口服左旋美沙酮（LYN-014）已获得 FDA 针对该适应症的快速通道指定。Lyndra主要管线，图片来自Lyndra官网长效制剂抢滩登陆抗精神分裂药物的研发，已经经历了三代迭代：从典型抗精神病药，到以氯氮平、利培酮、奥氮平为代表的第二代药物，再到多巴胺受体激动剂；药物迭代更新，痛点却一直存在。市场份额方面，以国内为例，随着国家集采的深入推进，外企普通剂型的市场份额被慢慢挤占，转为聚焦难度更高的长效剂型药物，除了提高患者依从性、降低精神分裂症患者的住院率外，长效制剂也是延长专利过期药物生命周期的重要手段。跨国巨头依旧占据优势，强生棕桐酸帕利吸酮长效制剂销售额近十年一直保持强势增长，国内绿叶制药，丽珠医药等企业近年也实现了长效剂型上的突破。精神分裂症长效制剂也面临药物同质化严重的问题，Karuna等公司的新靶点产品已经进入临床后期阶段，国内的再鼎医药、索元生物等企业也以引进或自研的方式开发精神分裂症新药，Lyndra的药物递送创新只是其中的一种，但应用前景和适用病种范围可期。《隐谷路》中因种种因素停药的患者，除了精神分裂症的反复之外，在后期还被各种并发症所折磨，其惨状成为书中难以磨灭的形象。或许，有朝一日，得益于像Lyndra一类公司的创新技术，类似的悲剧不会再上演。文|宁晨微信|moiramido添加时请注明：姓名-公司-职位网站、公众号等转载请联系授权：Rekkiiie近期推荐声明：动脉网所刊载内容之知识产权为动脉网及相关权利人专属所有或持有。未经许可，禁止进行转载、摘编、复制及建立镜像等任何使用。动脉网，未来医疗服务平台

基因疗法放射疗法

2024-03-10

·药渡

舒沃哲上市四个月卖9128 万，迪哲医药做对了什么？

来源：药渡撰文：四月的雨编辑：维他命近日，迪哲医药披露了2023年度业绩快报，2023年度实现营收9128.86万元。此外据报告显示，其2022年营收为零元，2021年度营收为1028.54万元，收入来源为向阿斯利康收取的技术支持服务费。迪哲医药在2023年业绩快报中表示，报告期内，公司首次实现产品销售收入，营收全部由其核心产品舒沃哲在上市后四个月的销售额贡献。舒沃哲的上市，开启了迪哲医药收入结构根本性转变之路。PART.01上市即王炸舒沃哲放量迅速舒沃哲（舒沃替尼）是迪哲医药首款进入商业化的源头创新产品。作为首款针对EGFR 20号外显子插入（exon20ins）突变型晚期非小细胞肺癌（NSCLC）的国创新药，舒沃哲于2023年8月23日通过优先审评程序在中国通过获批上市。图1. 舒沃替尼知识图谱，来源：药渡数据近20年来，EGFR Exon20ins突变一直缺乏安全有效的靶向治疗手段，患者生存获益短，是亟需解决的临床痛点。针对经治EGFR exon20ins突变型晚期NSCLC的中国注册临床研究显示，舒沃哲具有高效低毒、同类潜在最佳等优势，其主要研究终点独立影像评估委员会（IRC）确认的客观缓解率（ORR）达61%，突破现有治疗瓶颈（既往药物ORR均未达50%）。舒沃哲是肺癌领域首个获中、美双“突破性疗法认定”的国创新药，也是目前全球唯一获批上市的靶向EGFR exon20ins突变型NSCLC的小分子药物。上市首个季度，舒沃哲就取得了耀眼的商业化成绩。据迪哲医药披露的2023年第三季度季报显示，截至2023年9月30日舒沃哲已经拿下4010万元的销售收入，此时距离上市仅40天。如此耀眼的商业化表现很难不让资本市场掀起波澜，在披露三季报后的第二个交易日（2023年10月30日），迪哲医药股价涨幅超过10%。如今上市四个月卖出9128万销售额，更是引发了行业的广泛关注。与此同时，不禁要问，迪哲医药对舒沃哲做了怎样的“包装”？0124小时无缝接力，强大供应链显“神威”在舒沃哲获批的那一刻，迪哲就全面开启了“24小时不间断”商业化上市推进。在短短4天内，从定稿说明书、包材印刷、生产、包装、检验、质量放行、全国配送、上架、开单，公司和外部合作伙伴日夜兼程无缝接力，将舒沃哲送达全国各地。2023年8月26日上午11点23分，首批舒沃哲到达南京医药第一药店，门店第一时间完成验收入库、上架。获批后第4天正式开始面向全国各医院和药房供药，刷新非自有工厂（由药明康德旗下的合全药业代工）发货最快行业纪录，迪哲医药在供应链上下足了功夫。02销售市场持续投入，商业化团队成熟供应链的优势还不足以带动舒沃哲销售额飙涨，还需商业化团队“给力”。据其业绩预告称，为产品市场覆盖做好充分准备，自舒沃哲上市以来迪哲医药商业化团队不断扩大，在产品上市后的销售渠道部署以及市场推广等方面不断增加投入。迪哲医药是由阿斯利康（持股41.50%）与国投创新（持股41.50%）在2017年合资建立，可谓一出生就含着“金汤匙”。而迪哲医药营销负责人吴清漪于2019年6月加入百济神州，并于2021年9月离职后加入迪哲医药。迪哲医药的董事、监事、高级管理人员及核心技术人员中，多人有阿斯利康任职经历，吴清漪也有多年阿斯利康任职经历。论营销能力，阿斯利康在业内是“顶流”般的存在。03疗效——最好的营销强大的商业化团队和卓越的团队领导者，对于舒沃哲的加速放量起到了加持作用。但打铁还需自身硬，疗效才是最好的营销模式。在疗效方面，舒沃哲展示了卓越的实力：主要终点由独立影像评估委员会（IRC）根据RECIST 1.1评估确认的肿瘤缓解率（cORR）为60.8%，针对基线伴有经治且稳定的脑转移患者cORR达48.4%。抗肿瘤疗效覆盖多种突变亚型，无论Exon20ins突变亚型和插入位点如何，对在近环端（ORR=62%）、远环端（ORR=54%）和C-螺旋发生的插入突变（ORR=100%），均显示良好的抗肿瘤活性。治疗期间绝大多数患者出现的不良事件（AE）为CTCAE 1级或2级，可通过安全性管理进行恢复。半衰期更长（~50h），药物峰值和谷底浓度差更小（~2倍），有利于对靶点的持续抑制，且降低由于药物峰值浓度过高带来的不良事件发生。舒沃哲从国内首例临床研究受试者入组到获批上市，用时不到4年，建立肺癌靶向药临床推进速度新标准；从获批到首方，仅用4天，迪哲速度再创行业纪录。凭借扎实的源头创新和高效的商业运营，迪哲医药拿到了一张战力值超强的王牌。但迪哲医药的王牌远不止舒沃哲。PART.02王牌不止舒沃哲潜力管线加速集结迪哲医药以治疗肿瘤和免疫性疾病为目标，保持在转化科学及药化和分子设计领域的竞争优势。其以自主研发为主，着眼全球市场为发展战略。基于行业领先的转化科学和新药分子设计与筛选技术平台，迪哲医药已建立了五款具备全球竞争力的产品管线，除已获批上市的舒沃哲外，还有处于全球关键性临床试验阶段的戈利昔替尼。图2. 迪哲医药管线，来源：迪哲医药官网01JAK1抑制剂：戈利昔替尼戈利昔替尼是迪哲医药自主研发的新一代、强效且高选择性JAK1抑制剂，其首个申报上市的适应症为复发/难治性（r/r）外周T细胞淋巴瘤（PTCL），于2023年9月获药品监督管理局（NMPA）受理并纳入优先审评，此外正在中国、美国、韩国和澳大利亚等国家开展关键性临床试验。2022年2月，戈利昔替尼获FDA“快速通道认定”（Fast Track Designation），成为首个且唯一获FDA“快速通道认定”的PTCL国创新药，也是全球首个且唯一针对PTCL的高选择性JAK1抑制剂。JAK抑制剂自上市以来因其独特的作用机制，安全性和耐受性一直备受质疑，美国FDA已多次作出审查延迟的决定，并就多家药企研发的多款相关药物给出了黑框警告，有着JAK抑制剂“开山鼻祖”之称的辉瑞便是其中一员。据辉瑞长达6年的研究表明，作为自免领域全球首款JAK抑制剂的Tofacitinib会显著增加心脏相关副作用和致癌风险。基于这项研究结果，FDA对Tofacitinib添加“黑框警告”警示心脏安全和致癌风险。同一时间，收到FDA“红牌警告”的还有礼来的Baricitinib和艾伯维的Upadacitinib。此次风波，对JAK抑制剂的声誉和使用都造成了不小的打击。而戈利昔替尼是一种新一代、口服、强效、高选择性JAK1抑制剂，相比其他JAK抑制剂，对JAK1具有更高的选择性，有效地降低了泛JAK抑制导致的药物安全性风险。以此同时，戈利昔替尼还具备较好的药代动力学特征，因此可实现对JAK/STAT通路的持续有效抑制，同时确保临床安全性。国际多中心关键临床研究（JACKPOT8的B部分）中，戈利昔替尼单药显示出强效持久的抗肿瘤活性，客观缓解率（ORR）达44.3%，且其中一半以上肿瘤缓解的受试者达到了完全缓解（CR），CR率达23.9%，经独立影像评估委员会（IRC）评估的中位缓解持续时间（DoR）长达20.7个月。此外，临床试验研究也已证实戈利昔替尼与已获批用于治疗r/r PTCL的普拉曲沙、罗米地辛、贝林司他和西达本胺等药物相比，在疗效性和安全性上均具有明显优势。其实JAK1抑制剂最扎堆的适应症并不是肿瘤领域，而是自免领域，在迪哲医药筹划IPO上市之时（截至2021年8月），全球已获批上市的7款JAK1抑制剂中，只有诺华的芦可替尼获批了骨髓纤维化/真性红细胞增多症肿瘤相关适应症，而在研的JAK1抑制剂中，自免适应症也多过于肿瘤。据统计，2019年全球JAK1抑制剂市场规模约为55亿美元，预计到2030年将达305亿美元，可以说自免领域对JAK1抑制剂市场规模的贡献要大于肿瘤领域，或许是出于抢占市场的考虑，迪哲医药在开发戈利昔替尼的策略上，选择了先肿瘤后自免的思路。02LYN/BTK双靶点抑制剂：DZD8586除了戈利昔替尼外，另一款抗肿瘤药，即LYN/BTK双靶点抑制剂DZD8586也来头不小。DZD8586是迪哲自主研发的一款针对B细胞非霍奇金淋巴瘤（B-NHL）的非共价LYN/BTK双靶点抑制剂，可完全穿透血脑屏障。在现有的B-NHL治疗药物中，BTK抑制剂的耐药问题仍是全球性挑战。临床前研究表明，DZD8586可同时阻断BTK依赖性和非依赖性BCR信号通路，有效抑制多种B-NHL亚型细胞的生长，有望克服BTK抑制剂的耐药问题。前有舒沃哲在NSCLC领域大展拳脚，后有戈利昔替尼和DZD8586接力，共同打造差异化竞争优势的肿瘤和免疫产品矩阵，能取得这样的“突飞猛进”，离不开迪哲的重金研发。而又正是因为在研发上的大手笔投入，使得迪哲医药被退市争议缠身。PART.03亏损并不等于退市兑现期正在路上2023年度迪哲医药归属于母公司所有者的扣除非经常性损益后的净亏损达117,300 万元左右，比上年同期增加亏损38,800万元左右，同比亏损增加49%左右。亏损增大主要是因为公司各在研产品在稳步推进研发过程中，整体研发投入仍维持在较高水平。2023年，迪哲医药研发费用为81000万元左右，比上年同期增加14500万元左右，同比增加22%左右。在2023年9月7日的投资者关系活动会议上，有投资者担心迪哲医药是否会因为长期亏损退市，吕洪斌则表示：根据科创板上市规则，公司目前没有退市风险。据悉，根据上交所的规定，科创版带U的股票上市第四年起才会存在退市的风险，但是上交所可以根据实际情况调整退市指标，甚至对财务也没有考核。距离迪哲医药2021年12月在科创板鸣锣上市仅有两年之余，留给迪哲医药自证的时间还有两年。而这两年，正是舒沃哲销售额增长爆发期，加之戈利昔替尼获批在即，商业化产品矩阵将迎来新成员，或许属于迪哲医药的收获期才刚开始。参考资料：1、迪哲医药官网2、迪哲医药的野心：IPO的钱还没用完，还要融资？；华博商业评论3、迪哲医药顺利摘U已不远？；药渡Daily*声明：本文仅是介绍医药疾病领域研究进展或简述研究概况或分享医药相关讯息，并非也不会进行治疗或诊断方案推荐，也不对相关投资构成任何建议。内容如有疏漏，欢迎沟通指出！商业化权益收回——开始独当一面的中国创新药企利润飙升408.11%！微芯生物“两驾马车”驱动，研发之路高歌猛进这十款药物，今年有望获FDA批准！

优先审批上市批准财报突破性疗法临床研究

2024-02-26

·GlobeNewswire-Health Care

Biodexa Announces Positive Top Line Phase I Clinical Trial Results for Diffuse Midline Glioma and Provides R&D Update

Biodexa Announces Positive Top Line Phase I Clinical Trial Results for Diffuse Midline Glioma and Provides R&D Update Median Overall Survival of 16.5 Months vs 10.0 months in Comparable Cohort February 23, 2024 – Biodexa Pharmaceuticals PLC, (Nasdaq: BDRX), a clinical stage biopharmaceutical company developing a pipeline of innovative products for the treatment of diseases with unmet medical needs including Type 1 diabetes and rare / orphan brain cancers, announces an R&D updat including positive top-line clinical trial results of a recently completed Phase 1 study of MTX110 in patients with diffuse midline glioma, or DMG, and results of a preclinical experiment designed to demonstrate tolimidone’s potential for beta cell proliferation in an in vitro model. In an investigator initiated study conducted by Columbia University Irving Medical Center, patients newly diagnosed with DMG were administered MTX110 via convection enhanced delivery (“CED”) using a subcutaneous pump connected to a catheter directly implanted into the pons in a 3+3 dose-escalating design (NCT 04264143). As this was the first ever study of repeated infusions to the pons via an implanted CED catheter, the primary objective of the study was safety and tolerability and, accordingly, the number of infusions was limited to two, each of 48 hours, 7 days apart. Nine patients were treated in the study (30 M group, n=3; 60 M group, n=4; 90 M group (optimal dose), n=2). One patient in the 60 M group suffered a severe adverse event assessed by the investigators as not related to the study drug but related to the infusion and tumor anatomy. Although the study was not powered to reliably demonstrate efficacy, median overall survival (OS) of patients in the study was 16.5 months. This compares favourably with median survival rate in a cohort of 316 cases of 10.0 months (Jansen et al, 2015. Neuro-Oncology 17(1):160-166). Study investigators are planning to present detailed results of the trial at the 21st International Symposium on Pediatric Neuro-Oncology (ISPNO 2024) being held on June 28-July 2, 2024 in Philadelphia, PA. On the Company’s behalf, a CRO conducted an in vitro experiment designed to demonstrate tolimidone’s potential for beta cell proliferation using reaggregated pancreatic islets. The results of the experiment were inconclusive in that they did not correlate with the results previously seen in in vitro and in vivo studies of tolimidone. The Company believes there are a few possible explanations to the outcome of this in vitro study and accordingly, plans to move ahead rapidly with an in vivo preclinical study with similar objectives while continuing preparations for its planned Phase IIa open-label study of tolimidone in patients with Type 1 diabetes due to start recruitment later this year. Biodexa Pharmaceuticals PLC (listed on NASDAQ: BDRX) is a clinical stage biopharmaceutical company developing a pipeline of innovative products for the treatment of diseases with unmet medical needs. The Company’s lead development programmes include tolimidone, under development as a novel agent for the treatment of type 1 diabetes and MTX110, which is being studied in aggressive rare/orphan brain cancer indications, and Tolimidone is an orally delivered, potent and selective inhibitor of lyn kinase. Lyn is a member of the Src family of protein tyrosine kinases, which is mainly expressed in hematopoietic cells, in neural tissues, liver, and adipose tissue. Tolimidone demonstrates glycemic control via insulin sensitization in animal models of diabetes and has the potential to become a first in class blood glucose modulating agent. MTX110 is a solubilised formulation of the histone deacetylase (HDAC) inhibitor, panobinostat. This proprietary formulation enables delivery of the product via convection-enhanced delivery (CED) at chemotherapeutic doses directly to the site of the tumour, by-passing the blood-brain barrier and potentially avoiding systemic toxicity. Biodexa is supported by three proprietary drug delivery technologies focused on improving the bio-delivery and bio-distribution of medicines. Biodexa’s headquarters and R&D facility is in Cardiff, UK. For more information visit www.biodexapharma.com. The content above comes from the network. if any infringement, please contact us to modify.