A Phase I, Single-site, Open-label, Partially Randomized Study to Evaluate the Relative Bioavailability and Pharmacokinetics of Evobrutinib Following Administration of Different Formulations in Healthy Participants

The purpose of this study is to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and safety and tolerability of evobrutinib after oral administration of immediate release (IR) and modified release (MR) formulations in healthy participants.

开始日期2022-02-02

申办/合作机构

Merck Healthcare KGaA

[+1]

NCT05248945

/ Completed临床1期

Phase I, Open-Label, Single-Sequence Study of the Effect of Multiple Doses of Carbamazepine on Single-Dose Evobrutinib Pharmacokinetics in Healthy Participants

The purpose of this study is to investigate the effect of multiple doses of carbamazepine on two single doses of evobrutinib pharmacokinetics (PK) in healthy participants. Study details include:
Study Duration: up to 54 days. Treatment Duration: 25 days. Visit Frequency: Participants will be resident in the Clinical Research Unit from Day 1 to Day 20 and return on Day 26 for a Safety Follow-Up visit.

开始日期2022-01-13

申办/合作机构

Merck Healthcare KGaA

NCT05064488

/ Completed临床1期

A Phase I, Open-Label, Two-Part Study of the Effect of Multiple-Dose Evobrutinib on Transporter Substrates Digoxin, Metformin, Rosuvastatin, and Sumatriptan Pharmacokinetics in Healthy Participants

This study consists of 2 parts: Part 1 and 2. The purpose of this study is to evaluate the pharmacokinetic, safety and tolerability of multiple doses of evobrutinib on single doses of digoxin, metformin and rosuvastatin in Part-1 and sumatriptan in Part-2 of the study.

开始日期2021-10-04

申办/合作机构

Merck Healthcare KGaA

100 项与 Evobrutinib 相关的临床结果

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100 项与 Evobrutinib 相关的转化医学

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100 项与 Evobrutinib 相关的专利（医药）

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项与 Evobrutinib 相关的文献（医药）

2025-09-01·EUROPEAN JOURNAL OF PHARMACOLOGY

Next generation Bruton's tyrosine kinase inhibitors – characterization of in vitro potency and selectivity

Article

作者: Angst, Daniela ; Cenni, Bruno ; Pulz, Robert

Bruton's tyrosine kinase (BTK) mediates B cell receptor and Fc receptor signaling and is a key regulator of autoimmunity and allergy. A series of novel BTK inhibitors (BTKi) are currently in development for non-oncologic indications with covalent-irreversible (remibrutinib, evobrutinib, tolebrutinib, orelabrutinib), covalent-reversible (rilzabrutinib), and non-covalent reversible (fenebrutinib) binding modes. This study characterizes their in vitro potency and selectivity profiles under the same conditions to minimize assay differences across the different binding modes. Covalent BTKi showed human in vitro blood BTK binding in a time- and concentration-dependent manner with remibrutinib being the most potent and fastest in onset of action. Cellular BTK pathway inhibition was determined in human blood B cells and basophils, and for covalent BTKi correlated well with BTK binding. In contrast to the covalent-irreversible remibrutinib, the non-covalent reversible fenebrutinib showed rapid loss of cellular BTK inhibition after washout. Kinase selectivity was assessed in a binding screen across the human kinome, followed by quantification of binding affinities for a selection of kinases. BTKi ranked in their selectivity as follows (most selective to least): remibrutinib, fenebrutinib, evobrutinib, orelabrutinib, rilzabrutinib and tolebrutinib. These data suggest that next generation BTKi show important differences in their in vitro target binding and selectivity when compared under the same conditions.

2025-04-11·ACS Pharmacology & Translational Science

Comprehensive Characterization of Bruton’s Tyrosine Kinase Inhibitor Specificity, Potency, and Biological Effects: Insights into Covalent and Noncovalent Mechanistic Signatures

Review

作者: Servant, Nicole B. ; King, Alastair J. ; Jahic, Mirza ; Darragh, Antonia C. ; Lipner, Justin H. ; Hanna, Andrew M.

Uncovering a drug's mechanism of action and possible adverse effects are critical components in drug discovery and development. Moreover, it provides evidence for why some drugs prove more effective than others and how to design better drugs altogether. Here, we demonstrate the utility of a high-throughput in vitro screening platform along with a comprehensive panel to aid in the characterization of 15 Bruton's tyrosine kinase (BTK) inhibitors that are either approved by the FDA or presently under clinical evaluation. To compare the potency of these drugs, we measured the binding affinity of each to wild-type BTK as well as a clinically relevant resistance mutant of BTK (BTK C481S). In doing so, we discovered a considerable difference in the selectivity and potency of these BTK inhibitors to the wild-type and mutant proteins. Some of this potentially contributes to the adverse effects experienced by patients undergoing therapy using these drugs. Overall, noncovalent BTK inhibitors showed stronger potency for both the wild-type and mutant BTK when compared with that of covalent inhibitors, with the majority demonstrating a higher specificity and less off-target modulation. Additionally, we compared biological outcomes for four of these inhibitors in human cell-based models. As expected, we found different phenotypic profiles for each inhibitor. However, the two noncovalent inhibitors had fewer off-target biological effects when compared with the two covalent inhibitors. This and similar in-depth preclinical characterization of drug candidates can provide critical insights into the efficacy and mechanism of action of a compound that may affect its safety in a clinical setting.

2025-04-01·JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY

Comparative effects of biologics and small molecule inhibitors on cutaneous disease activity in lupus erythematosus: A systematic review and network meta-analysis

Article

作者: Gou, David ; Sun, Wayne ; Rayner, Daniel G ; Xi, Cheng En ; Silang, Isabella ; Khosravi-Hafshejani, Touraj ; Dutz, Jan P

Meta-anal. of comparative effects of biologics and small mol. inhibitors on cutaneous disease activity in lupus erythematosus.Our review builds upon the limitations of previous network meta-analyses by including 29 more trials investigating 25 addnl. unique interventions in our analyses on CLASI-A scores.In addition to anifrolumab, deucravacitinib, and litifilimab, we identified superior efficacy of sifalimumab and daxdilimab compared to placebo-all of which target the type 1 interferon pathway. Litifilimab and daxdilimab inhibit BDCA2 and Ig-like transcript 7, resp., which reside on dendritic cells and stimulate the production of type 1 interferons.Meanwhile, sifalimumab directly inhibits interferon-, and anifrolumab and deucravacitinib target the interferon-receptor and tyrosine kinase 2, resp.-two proteins involved in the interferon signaling pathway.These findings support the continued investigation of the type 1 interferon pathway in the management of CLE.

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项与 Evobrutinib 相关的新闻（医药）

2025-06-03

·药时代

卖身疑云令股价上涨！为何一条自免管线能撑起30亿美元

正文共2000字预计阅读时间6分钟2025年6月2日，根据英国《金融时报》报道，德国默克曾在今年年初向MoonLake Therapeutics提出超过30亿美元的收购要约。尽管早在2023年就有传闻称MoonLake可能被收购，但其首席执行官Da Silva明确表示公司无意出售，并计划独立完成Sonelokimab的商业化。即便如此，受此消息影响，MoonLake股价在盘后交易中上涨了5.6%，市值超过了26亿美元。这一“卖身疑云”或许需要等到今年夏季MoonLake核心药物Sonelokimab的三期试验数据公布后才能揭晓。图片来源：雪球网我们先来解密一下，这家尚处于临床阶段的生物技术公司为何仅凭一条核心管线便撑起了30多亿美元的市值。Moonlake一条核心管线打天下Moonlake Therapeutics成立于2021年，专注于开发针对IL-17A和IL-17F的靶向疗法。同年，Moonlake就与默克签订许可协议，以2990万美元首付款以及未来高达3.071亿欧元的里程碑付款将其核心产品IL17A/F三抗Sonelokimab授予德国默克。Sonelokimab是一种分子量约40 kDa的人源化纳米抗体，由三个抗体重链可变区蛋白域共价连接而成。其中两个蛋白域可以高亲和力选择性结合IL-17A和IL-17F，从而抑制IL-17A/A、IL-17A/F和IL-17F/F二聚体介导的信号传导。第三个蛋白域结合人类白蛋白，促进sonelokimab在炎症水肿部位的富集。临床前研究表明，纳米抗体形式的Sonelokimab因为分子量小，对深层组织的炎症效果要比常规抗体效果更好，可显著减轻如银屑病、化脓性汗腺炎等自免疾病的炎症反应。图片来源：Moonlake官网2022年Moonlake合并SPAC成功上市，其主打药物Sonelokimab具有挑战Cosentyx的潜力，吸引了BVF、Cormorant、RTW等知名Biotech投资机构的投资，近一年涨幅达156.29%，成为2022年以来表现最好的De-SPAC医药公司之一。2023年6月25日，MoonLake宣布Sonelokimab用于治疗化脓性汗腺炎（HS)的II期临床试验结果达到了主要终点和所有关键次要终点，经过12周的治疗后，sonelokimab显著改善了患者的银屑病面积和严重程度指数。公布后，股价一度涨超100%。2024年3月，MoonLake再传喜讯，宣布Sonelokimab用于治疗银屑病关节炎（PsA）的2期临床试验达到主要终点，符合美国风湿病学会（ACR）50应答标准（疾病症状较基线改善50%以上）的患者比例从第12周开始持续改善，并在第24周超过60%。约有40%的患者在第24周达到更严格的ACR70标准。2024年5月13日，MoonLake Therapeutics在Clinicaltrials.gov网站上注册了Sonelokimab的两项三期临床试验，均用于治疗中至重度化脓性汗腺炎。临床试验结果预计将在今年夏季揭晓，若试结果积极，首席执行官Da Silva表示Sonelokimab有望于2027年正式上市销售，成为这一自免领域的重要竞争者。同时，MoonLake还计划探索该药物在其他适应症中的潜力，包括青少年患者的治疗。此次结果或将决定MoonLake是否会被收购的命运。据弗若斯特沙利文预测，到 2030 年全球自身免疫性疾病药物市场将达到 1767 亿美元，已然是继肿瘤药物后的下一个重要市场。TD Cowen的分析师预测称，MoonLake如果在化脓性汗腺炎（HS）和银屑病关节炎（PsA）等多个自免领域开发成功，Sonelokimab药物的峰值年销售额在2034年可能超过40亿美元。那么，默克的收购意愿如何呢？今年4月28日，默克以39亿美元的股权价值完成了对SpringWorks的收购，补充了默克在罕见肿瘤领域的布局。默克是否会在一年内频繁出手，还需打个疑问？而在自免领域，默克经历了一次滑铁卢。作为BTK抑制剂在自免领域的先锋，其Evobrutinib在三期试验中未能达到降低年复发率的主要重点，导致该药物的开发被终止。不过，今年5月德国默克的自免领域迎来了转机，默克宣布其潜在“first-in-class”口服小分子enpatoran在临床二期试验WILLOW中取得了积极成果。在接受enpatoran治疗的皮肤红斑狼疮（CLE）和伴有活动性狼疮皮疹的系统性红斑狼疮（SLE）患者中，超过90%的患者显示出了疾病活动度显著减少。此时，默克想在自免领域乘胜追击，补充一条具有潜在商业价值的自免管线也十分合理。毕竟千亿自免市场是下一个爆发点。MoonLake与默克早在2021年便展开合作，核心产品Sonelokimab的上市指日可待。若完成对MoonLake的收购，不仅能够增强默克在自免业务方面的药物开发能力，还能通过默克丰富的商业化经验加速Sonelokimab的成功落地。目前最大的变数都集中在即将公布的Sonelokimab三期试验数据上。药时代会为您持续关注。参考资料：1.MoonLake 官网2.默克官网3.《金融时报》4其他公开资料图片来源：pixabay95亿美元！111亿美元！20.1亿美元！这个星期一很疯狂！2025-06-02马斯克的Neuralink估值96亿美元！脑机接口“心灵感应”要来了！2025-06-01备受争议的脑肠轴有了新突破：大脑活动速变肠道菌群，瘦素是关键2025-05-31版权声明/免责声明本文为原创文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢!药时代官方网站:www.drugtimes.cn联系方式:电话:13651980212微信:27674131邮箱:contact@drugtimes.cn点击这里，查看更多精彩！

临床2期并购临床3期临床成功临床失败

2025-05-28

·靶点圈

一文带你了解BTK抑制剂的十年变革：从血液肿瘤到自身免疫病的跨界征途

01BTK的分子结构与作用机制BTK的分子结构BTK是一种由659个氨基酸组成的非受体酪氨酸激酶，分子量约76kDa，属于Tec激酶家族。其结构包含5个主要功能域，从N端到C端依次为：● PH结构域：结合磷脂酰肌醇三磷酸(PIP3)，介导细胞膜定位；● SH3结构域：结合富含脯氨酸的蛋白(如BCAP)，参与信号复合物组装，是BCR信号激活的前提；● SH2结构域：识别磷酸化酪氨酸残基，与活化的CD79a/b等分子结合，传递BCR信号；● SH1/TK结构域：包含关键的催化位点(Cys481、Tyr551)和ATP结合口袋；● C端尾部：含核定位信号(NLS)和核输出信号(NES)，调控BTK在胞质与细胞核间的穿梭，影响其功能多样性。这些结构域通过协同作用，实现BTK的膜定位、信号传导和底物磷酸化功能。图1 BTK的化学结构BTK的信号通路调控BTK通过BCR、TLR、CXCR4等受体激活，从而磷酸化下游分子(如PLC-γ)激活NF-κB和MAPK通路，参与免疫应答和炎症反应。图2 BTK在BCR、TLR、趋化因子受体和FcR信号转导通路中的作用BTK与其他激酶的协同作用与Lyn、Syk、PI3K等激酶形成信号网络。Lyn磷酸化CD79A/B的ITAM招募Syk，Syk激活BTK，共同维持BCR通路活化。PI3K通过生成PIP3激活Akt/mTOR通路，与BTK协同促进细胞生存代谢。图3 刺激B细胞中BTK活化的细胞表面受体02BTK的表达调控与生物学功能BTK的广泛表达BTK不仅表达于B细胞，还存在于髓系细胞(如单核细胞/巨噬细胞、树突状细胞、肥大细胞、中性粒细胞)中，参与多种免疫细胞的信号传导。BTK的功能及作用机制● 调控B细胞活化与自身抗体产生：1)B细胞发育与激活：BTK是B细胞受体(BCR)信号通路的关键激酶，调控B细胞的发育、活化与分化，促进B细胞增殖与抗体分泌。其异常激活与B细胞恶性肿瘤(如慢性淋巴细胞白血病CLL、套细胞淋巴瘤MCL)、自身免疫病密切相关。2)B细胞代谢调控：BTK抑制B细胞线粒体呼吸，影响其活化状态。在多发性硬化(MS)中，BTK通过调节B细胞代谢，增强其刺激T细胞分泌促炎因子(如IFN-γ、TNF-α)的能力。3)B细胞与T细胞的协同作用：BTK抑制B细胞表面共刺激分子(如CD80/CD86)的表达，减少其对T细胞的激活，抑制Th1/Th17型免疫反应。反之，BTK过度激活会增强B-T细胞相互作用，加剧自身免疫炎症。图4 NLC、LAM和恶性B细胞之间的相互作用和信号转导● 调控固有免疫细胞的炎症放大作用：1)巨噬细胞与树突状细胞(DCs)：BTK通过Toll样受体(TLR)信号通路激活巨噬细胞和DCs，促进M1型促炎表型，增加促炎因子(如IL-23、TNF-α)和趋化因子(如CXCL13)的分泌，参与银屑病、RA等炎症性疾病的发病。2)肥大细胞与嗜碱性粒细胞：在慢性自发性荨麻疹(CSU)中，BTK介导IgE-FcεRI信号，促进肥大细胞释放组胺和炎症介质，引发过敏反应和气道高反应性。3)中性粒细胞与破骨细胞：BTK调控中性粒细胞的氧化应激反应(如超氧化物生成)，参与银屑病皮损炎症；同时促进破骨细胞分化，加剧类风湿关节炎(RA)患者的骨侵蚀。图5 BTK在骨髓细胞中的作用BTK的结构异常与疾病关联● XLA(X连锁无丙种球蛋白血症)：BTK基因缺失或突变(如C481突变)导致B细胞发育停滞，表现为抗体缺乏和反复感染。● 自身免疫病：BTK过度激活或构象改变(如C端尾部磷酸化异常)可增强B细胞和固有免疫细胞的活化，促进自身抗体产生和炎症反应(如SLE、RA)。03BTK抑制剂的分类与耐药机制BTK抑制剂(BTKIs)的分类图6 BTK抑制剂的作用机制● 共价不可逆抑制剂：不可逆结合BTK的C481位点(如伊布替尼、阿卡替尼、泽布替尼)，阻断BCR信号，用于B细胞恶性肿瘤，显著改善患者生存。但长期使用易诱导C481S突变，导致耐药。● 共价可逆抑制剂：可逆结合C481位点(如瑞扎布替尼)，减少脱靶效应。但仍可能因C481S或L528W突变耐药。● 非共价可逆抑制剂：不结合C481，通过阻断ATP结合或降低激活标记物(如芬布替尼)，适用于C481突变(如C481S)的耐药患者。但可能因T474I、L528W等新突变导致耐药。表1 BTK抑制剂分类由BTK基因突变引发的耐药● 激酶功能型突变：1)C481位点突变：如C481S/R/F/Y，占共价抑制剂耐药的60–90%。突变导致BTK与共价抑制剂(如伊布替尼)的共价结合失效，但保留激酶活性，维持BCR信号传导。2)T474I突变：位于激酶结构域，增强BTK自身磷酸化(Y223位点)，激活下游PLCγ2/NF-κB通路，常见于阿卡替尼治疗后。● 激酶失活型突变：1)L528W突变：导致BTK激酶活性丧失，但通过“支架功能”与HCK、ILK等激酶结合，维持下游信号传导，常见于泽布替尼治疗后的CLL。2)其他位点突变：如V416L、A428D、M437R等，通过改变BTK构象或与抑制剂结合口袋，导致非共价抑制剂(如吡托布鲁替尼)耐药。● 下游信号通路激活：1)PLCγ2突变：如S707F、R665W、E1139del，激活下游NF-κB通路，绕过BTK信号维持B细胞存活，常见于WM、CLL。图7 BTK和PLCγ2突变由其他因素引发的耐药● 肿瘤微环境(TME)：基质细胞通过CXCL12/CXCL13及整合素(如VLA-4)提供生存信号，激活PI3K/AKT通路增强肿瘤细胞黏附与存活，绕过BTK抑制的凋亡信号。● 表观遗传与转录因子：如TCF4过表达在ABC-DLBCL中替代BTK激活PLCγ2，导致伊布替尼耐药。如EP300、MLL2突变，通过表观遗传机制维持肿瘤细胞存活，与CLL耐药相关。04BTK抑制剂与降解剂BTK抑制剂的临床应用● 第一代BTKIs(如伊布替尼)：用于CLL、MCL、WM等，显著延长患者生存期。但存在脱靶效应(如抑制EGFR、TEC)导致出血、房颤等毒性，60%患者因C481S突变耐药。● 第二代BTKIs(如阿卡替尼、泽布替尼)：选择性更高，毒性更低，因安全性优势逐渐替代伊布替尼。阿卡替尼不抑制ITK和EGFR，房颤发生率低于伊布替尼，用于CLL/SLL和MCL。泽布替尼在CLL中ORR更高，但仍面临L528W等突变耐药。Tirabrutinib(日本获批用于PCNSL)、Orelabrutinib(中国获批用于R/RCLL/MCL)。● 第三代BTKIs(如吡托布鲁替尼)：可克服C481S突变耐药，对野生型和突变型BTK均有抑制作用。用于C481S突变的复发患者，但需警惕非C481突变(如L528W、T474I)导致交叉耐药。Fenebrutinib(用于RA、SLE)、Nemtabrutinib(针对C481S突变)处于II/III期试验。表2 已上市的BTKIs药物清单表3 目前正在进行临床试验的BTKIs药物清单BTK的靶向新策略：蛋白降解剂(PROTACs)● 作用机制及优势：通过双功能分子连接BTK配体与E3泛素连接酶，诱导BTK泛素化并经蛋白酶体降解，而非单纯酶抑制。可降解突变型BTK，且降解效率高，初步显示对耐药突变有效，但长期安全性尚需验证。图8 BTK降解剂作用机理● 代表药物与临床进展：1)NX-2127：降解BTK野生型及C481S、L528W突变体，同时降解IKZF1/3(增强T细胞功能)。I期试验显示，在复发CLL中缓解率33%，BTK降解率达86%。2)NX-5948：选择性降解BTK，血脑屏障穿透性强，用于中枢神经系统淋巴瘤，I期显示良好的耐受性和BTK降解效果。3)BGB-16673：I/II期数据显示在R/RCLL中可快速降低BTK水平，部分患者达部分缓解，但需警惕A428D突变导致的耐药。● 联合疗法：BTK降解剂与其他靶向药物(如BCL-2抑制剂)联用可能克服PLCγ2突变等非BTK依赖耐药机制。05BTK在不同疾病中的病理机制淋巴瘤● 原发性中枢神经系统淋巴瘤(PCNSL)PCNSL高频突变的MYD88和CD79B可异常激活BCR通路，使肿瘤细胞高度依赖BTK存活。BTKIs通过阻断PLCγ2，抑制肿瘤细胞增殖并诱导凋亡。此外，BTKIs还可调节肿瘤微环境，减少免疫逃逸，与免疫检查点抑制剂联用可增强抗肿瘤免疫应答。表4 用于PCNSL的BTKIs的临床试验● 慢性淋巴细胞白血病(CLL)BTK参与调节CLL细胞与肿瘤微环境的相互作用，影响疾病的进展。BTKIs可阻断BCR信号传导，诱导肿瘤细胞凋亡，同时调节免疫微环境，减少Treg细胞、增强CD8+T细胞功能并抑制巨噬细胞M2极化。图9 CLL细胞及其环境中的BTK抑制● 套细胞淋巴瘤(MCL)在MCL中，持续激活的BCR-BTK信号通路可促进MCL细胞的增殖和存活，影响肿瘤的发展。同时，BTK还与MCL细胞的黏附、迁移等过程相关，影响肿瘤细胞在体内的弥散。● 弥漫大B细胞淋巴瘤(DLBCL)在ABC型DLBCL中，BTK的持续激活可导致NF-κB通路的过度活化，驱动肿瘤细胞的生长和存活。然而在GCB型DLBCL中，BTK的依赖性相对较低。研究表明，部分DLBCL患者中存在BTK基因的扩增，与疾病的侵袭性和不良预后相关。伊布替尼单药治疗客观缓解率不高且无进展生存期短，目前多探索联合治疗方案。● 华氏巨球蛋白血症(WM)BTK的激活可促进WM细胞的存活、增殖以及免疫球蛋白的分泌。有研究显示，WM患者中常见的MYD88突变可增强BTK的活性，进一步促进肿瘤细胞的生长。伊布替尼、泽布替尼均获批用于WM治疗，客观缓解率较高。表5 已发表的针对CLL/SLL、MCL、WM、MZL的共价BTKIs表6 用于CLL/SLL、MCL、WM、MZL的非共价BTKIs和降解剂自身免疫性疾病● 自身免疫性水疱病BTK激活B细胞产生抗桥粒芯蛋白(如Desmoglein)的IgG抗体，破坏皮肤细胞间黏附，导致水疱形成；同时激活固有免疫细胞(如中性粒细胞、肥大细胞)，释放蛋白酶和炎症介质，加重表皮损伤。Rrilzabrutinib在II期试验中快速控制病情，减少糖皮质激素用量，尤其适用于抗桥粒芯蛋白抗体介导的自身免疫性水疱病。表7 自身免疫性水疱病临床前和临床试验中测试的BTKIs● 系统性红斑狼疮(SLE)BTK促进B细胞过度产生抗核抗体，形成免疫复合物沉积于肾脏、皮肤等组织，激活补体系统并诱发组织损伤；同时调控T细胞极化，促进Th1/Th17型免疫反应。在小鼠模型中，BTKIs可减少抗核小体抗体和组蛋白抗体，抑制DC和巨噬细胞过度活化，改善狼疮肾炎，但对抗dsDNA抗体影响有限，在人类II期试验中(如Fenebrutinib、Evobrutinib)疗效也有限。表8 系统性红斑狼疮临床前和临床试验中测试的BTKIs● 类风湿关节炎(RA)BTK在滑膜巨噬细胞和破骨细胞中激活，促进IL-6、MMPs等因子分泌，导致关节炎症、软骨破坏和骨侵蚀。B细胞通过BCR信号分泌类风湿因子(RF)和抗瓜氨酸化蛋白抗体(ACPA)，加剧自身免疫反应。BTKIs可抑制B细胞活化和抗体产生，减少滑膜炎症。临床前模型显示，CGI1746、GDC-0834等可减轻关节损伤，但部分II期临床试验(如BMS-986142)未达主要终点。表9 类风湿性关节炎临床前和临床试验中测试的BTKIs● 干燥综合征(SS)BTK驱动B细胞异常增殖和自身抗体(如抗SSA/Ro、抗SSB/La)分泌，导致唾液腺和泪腺的炎症及功能障碍。固有免疫细胞(如DCs)通过TLR-BTK通路分泌趋化因子，招募免疫细胞至外分泌腺体。Remibrutinib和Tirabrutinib在早期试验中尝试调节B细胞和唾液腺炎症，但疗效尚未突破。表10 干燥综合征临床前和临床试验中测试的BTKIs● 多发性硬化(MS)BTK通过调控B细胞和髓系细胞参与神经炎症和脱髓鞘过程，此外，BTK可能通过调节B细胞代谢(如线粒体呼吸)影响其与T细胞的交互作用。BTKIs穿透血脑屏障，抑制中枢神经系统内B细胞和髓系细胞的BTK信号，减少促炎因子释放和自身抗体产生，从而减轻炎症和神经损伤。Evobrutinib、Tolebrutinib在II期试验中减少MRI病灶，改善神经功能。表11 在多发性硬化症和重症肌无力的临床前和临床试验中测试的BTKIs炎症性疾病● 慢性自发性荨麻疹(CSU)BTK通过FcεRI信号激活肥大细胞和嗜碱性粒细胞，促进IgE介导的组胺释放和炎症细胞浸润，导致风团和瘙痒。● 银屑病BTK调控中性粒细胞的BTK通路，维持氧化应激和炎症状态；同时激活γδT细胞分泌IL-17A，促进角质形成细胞过度增殖。● 哮喘BTK参与IgE-FcεRI介导的气道炎症，促进Th2型细胞因子(如IL-4、IL-13)分泌和嗜酸性粒细胞浸润，导致气道重塑和高反应性。表12 在银屑病、慢性自发性荨麻疹、特应性皮炎和哮喘的的BTKIs06BTK抑制剂的不良反应与安全性常见副作用● 出血：与BTK/TEC抑制导致血小板功能障碍相关(如伊布替尼引起瘀斑、鼻衄)。● 心血管事件：房颤(与CSK或PI3K信号抑制有关)，第二代抑制剂(如泽布替尼)风险较低。● 感染：抑制中性粒细胞和巨噬细胞的抗菌功能，增加曲霉、肺孢子菌等机会性感染风险，尤其在CLL患者中。● 皮肤毒性：出现皮疹(EGFR脱靶效应)、指甲改变(如伊布替尼)。表13 BTKIs的不良事件当前挑战● 毒性管理：需监测血小板功能、心电图及肝功能，权衡疗效与感染风险，尤其是长期用药患者。● 耐药监测：实时检测BTK突变选择合适的抑制剂类型以便及时地调整治疗方案。未来方向● 新型抑制剂开发：高选择性非共价抑制剂(如Vecabrutinib)、双功能降解剂(如LP-168)，覆盖耐药突变，减少脱靶毒性。● 联合疗法：BTKIs+免疫检查点抑制剂、CAR-T细胞疗法、JAK抑制剂或补体抑制剂联用，增强抗肿瘤免疫。● 早期干预与预防：探索BTKIs在癌前病变或高风险人群中的应用。抗体发现服务 & 产品01羊驼免疫&骆驼免疫—自建现代化养殖农场02万亿级天然抗体库产品—轻松DIY科研抗体03配套产品—助您轻松搭建基因工程抗体平台关于仁域生物成都仁域生物成立于2019年1月，是一家专注基因工程抗体技术和天然抗体库开发的公司，拥有优化的噬菌体展示抗体库技术和现代化的骆驼/羊驼养殖免疫基地。可为客户提供14天、100%成功率的先导抗体分子发现服务，彻底解决传统抗体定制的周期长、失败率高、成本高三大难题。目前已经成功完成300+靶点抗体筛选项目！protocol 获取 / 产品咨询邮箱｜find@renyubio.com电话｜19136178673地址｜成都市经开区科技产业孵化园关注我们，小编将持续更新相关内容～参考文献Liu X, Lin Y, Zhuang Q, Deng H, Liu A, Sun J. 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Xing Y, Zhao K, Zhang Y, Wang Y. BTK inhibition in primary central nervous system lymphoma: mechanisms, clinical efficacy, and future perspectives. Front Oncol. 2024 Dec 24;14:1463505.Bravo-Gonzalez A, Alasfour M, Soong D, Noy J, Pongas G. Advances in Targeted Therapy: Addressing Resistance to BTK Inhibition in B-Cell Lymphoid Malignancies. Cancers (Basel). 2024 Oct 10;16(20):3434. Jiang Q, Peng Y, Herling CD, Herling M. The Immunomodulatory Mechanisms of BTK Inhibition in CLL and Beyond. Cancers (Basel). 2024 Oct 23;16(21):3574. Tavakoli GM, Yazdanpanah N, Rezaei N. Targeting Bruton's tyrosine kinase (BTK) as a signaling pathway in immune-mediated diseases: from molecular mechanisms to leading treatments. Adv Rheumatol. 2024 Aug 21;64(1):61. Cool A, Nong T, Montoya S, Taylor J. BTK inhibitors: past, present, and future. Trends Pharmacol Sci. 2024 Aug;45(8):691-707.Mehra S, Nicholls M, Taylor J. The Evolving Role of Bruton's Tyrosine Kinase Inhibitors in B Cell Lymphomas. 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临床1期细胞疗法引进/卖出

2025-04-28

·ETPharma

Germany's Merck KGaA in $3.9 billion deal to buy US biotech firm SpringWorks

Frankfurt: Merck KGaA has struck a deal to buy U.S. biotech company SpringWorks Therapeutics for an equity value of $3.9 billion, as the German company seeks to acquire treatments for rare tumours to boost its cancer drugs business. The family-controlled company said in a statement on Monday the purchase price of $47 per share in cash represents an equity value of about $3.9 billion, equivalent to an enterprise value of $3.4 billion (3.0 billion euros), when SpringWorks' cash holdings are deducted. The deal is one of the largest in years for Merck, but its price tag was 22 per cent lower than the about $60 per share analysts had expected after a Reuters report on February 10 that the companies were in advanced talks. Merck on April 24 lowered price expectations, saying the two companies were in late-stage discussions over a bid of around $47 per SpringWorks share. Merck's shares were down 0.4 per cent in early trade, underperforming the broader German stock market. The deal will be funded with available cash and new debt. It is expected to be accretive to Merck's earnings per share, adjusted for special items, in 2027, said a statement from the German group, based in Darmstadt, near Frankfurt. It added it would still be able to pursue larger transactions. Stamford, Connecticut-based SpringWorks, which listed its shares in New York in 2019, develops drugs to treat cancer and rare types of tumour. It has two products on the market: Ogsiveo with 2024 sales of $172 million to treat desmoid tumours, an aggressive disease affecting soft tissue, as well as Gomekli, which was approved in February to treat NF1-PN, characterised by nerve sheath tumours. "We have the unique opportunity with SpringWorks to establish a leadership position in rare tumours and build a strong foundation for further investments in this area," Peter Guenter, head of healthcare at Merck, said. The transaction will likely close during the second half of 2025, subject to approval of SpringWorks' shareholders and regulatory clearance, Merck added. TRUMP DISRUPTION JP Morgan analyst Anupam Rama previously said the lack of other serious bidders and the challenging macroeconomic environment had probably lowered the valuation. This year had been expected to be stellar for mergers and acqusitions in the sector until the disruption caused by U.S. President Donald Trump's policies, including massive layoffs at the U.S. Food and Drug Administration. That has brought uncertainty to the drug approval process, hampering projected drug sales and affecting valuations. Merck is particularly keen to strengthen its drug development pipeline after high-profile setbacks in late-stage drug trials, including a decision last year to halt development of head and neck cancer drug Xevinapant. A major trial testing multiple sclerosis drug Evobrutinib failed in December 2023. In 2015, the company agreed to buy U.S. lab equipment supplier Sigma-Aldrich for $17 billion, its biggest deal to date. In 2019, Merck acquired U.S. electronics materials manufacturer Versum for around $6.5 billion. (Reporting by Ludwig Burger, Emma-Victoria Farr in Frankfurt and Sabrina Valle in New York; Editing by Kirsten Donovan and Barbara Lewis)

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100 项与 Evobrutinib 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15170

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
横纹肌肉瘤	临床3期	美国	Merck KGaA	2019-09-10
横纹肌肉瘤	临床3期	德国	Merck KGaA	2019-09-10
复发性多发性硬化	临床3期	美国	Merck KGaA	2019-08-26
复发性多发性硬化	临床3期	德国	Merck KGaA	2019-08-26
复发-缓解型多发性硬化	临床3期	美国	Merck KGaA	2019-08-26
复发-缓解型多发性硬化	临床3期	德国	Merck KGaA	2019-08-26
系统性红斑狼疮	临床2期	美国	Merck KGaA	2017-01-04
系统性红斑狼疮	临床2期	日本	Merck KGaA	2017-01-04
系统性红斑狼疮	临床2期	阿根廷	Merck KGaA	2017-01-04
系统性红斑狼疮	临床2期	保加利亚	Merck KGaA	2017-01-04

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临床结果

适应症

分期

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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


NCT04338061 (evolutionRMS 2, CTgov)	临床3期	复发性多发性硬化	1,166	Teriflunomide (Teriflunomide)	觸糧選築衊淵窪築廠糧(鏇願襯壓鏇鑰製艱艱積) = 齋獵淵構積淵糧簾壓選選製網餘鹹遞積觸簾築 (衊鬱衊簾餘餘築廠襯齋, 夢製夢壓醖醖選壓顧範 ~ 簾壓齋網範繭簾糧遞簾) 更多	-	2025-01-14
				Evobrutinib (Evobrutinib)	觸糧選築衊淵窪築廠糧(鏇願襯壓鏇鑰製艱艱積) = 餘膚醖築觸衊壓艱鹹願選製網餘鹹遞積觸簾築 (衊鬱衊簾餘餘築廠襯齋, 遞夢衊窪製廠構餘壓觸 ~ 膚衊遞繭鹽繭選壓願繭) 更多
NCT04338061 \| NCT04338022 (evolutionRMS 1, Biospace) 人工标引	临床3期	复发性多发性硬化	-	Evobrutinib (evolutionRMS 1)	顧淵夢製獵鏇範蓋餘衊(窪鏇範廠鬱構鑰選衊醖) = 窪餘醖餘築願壓蓋淵觸構範鹹蓋蓋餘壓襯遞獵 (壓壓顧膚築範顧醖廠壓 ) 未达到	不佳	2023-12-05
				teriflunomide (evolutionRMS 1)	顧淵夢製獵鏇範蓋餘衊(窪鏇範廠鬱構鑰選衊醖) = 餘夢憲選獵夢獵範簾餘構範鹹蓋蓋餘壓襯遞獵 (壓壓顧膚築範顧醖廠壓 ) 未达到
NCT02975349 (Phase 2 OLE, ECTRIMS2023)	临床2期	Bruton型无丙种球蛋白血症	267	Evobrutinib 25mg QD	蓋願淵膚積積餘醖鬱構(獵壓鏇憲壓餘遞簾膚製) = Treatment-emergent adverse events (TEAEs) were reported by 142/164 PwRMS (86.6%) 網壓範齋鹽廠鑰網醖鹹 (選艱齋膚願網窪醖鏇簾 ) 更多	积极	2023-09-30
				Evobrutinib 75mg BID
NCT02975349 (Phase II, EAN2023)	临床2期	横纹肌肉瘤	45	Evobrutinib 75mg twice-daily	窪鏇顧廠繭製製壓構醖(餘鏇繭醖衊鹽衊遞選廠) = 夢鬱艱簾鹽鹹簾蓋鹹構齋構築獵膚襯淵選餘憲 (餘鬱繭襯蓋網繭蓋鹹繭 )	积极	2023-06-28
ACTRIMS2023	N/A	神经炎症	-	Evobrutinib	鹽積鬱構餘淵構選膚壓(積糧鬱糧遞蓋鹹簾憲鬱) = 遞範願餘築膚積網齋選窪網顧衊餘憲憲遞遞製 (衊鏇醖構壓觸遞憲餘鏇 )	积极	2023-05-30
				Anti-CD20 (clone: SA271G2)	網鬱願遞獵鏇夢廠簾鹹(憲廠醖觸糧廠鬱鏇壓製) = 襯鬱醖壓蓋醖遞鬱簾醖鹹夢構鏇淵獵顧夢鑰夢 (遞蓋鑰醖鑰選餘鑰廠餘 ) 更多
ACTRIMS2023	N/A	复发性多发性硬化	-	Evobrutinib 75 mg twice-daily	鏇鏇簾夢壓衊憲簾醖艱(築鏇餘簾積膚蓋廠糧選) = 壓齋窪鑰願艱鑰糧顧顧窪餘鑰廠鹽鏇顧窪簾艱 (築廠範窪壓築夢選構壓, 4.5)	-	2023-05-30
				mRNA COVID-19 vaccine	鏇鏇簾夢壓衊憲簾醖艱(築鏇餘簾積膚蓋廠糧選) = 選襯鹹糧壓願網鹹襯繭窪餘鑰廠鹽鏇顧窪簾艱 (築廠範窪壓築夢選構壓, 4.3)
AAN2023	N/A	神经炎症	-	Evobrutinib	鏇鏇廠獵艱鬱製製鏇簾(衊鏇鏇鏇鬱製繭蓋繭衊) = 衊範遞獵廠膚醖淵構蓋襯膚獵艱淵鏇簾顧繭淵 (醖衊蓋選鹽齋憲積鬱壓 ) 更多	积极	2023-04-25
NCT02975349 (AAN2023)	临床2期	复发性多发性硬化	45	Evobrutinib 75mg twice-daily	淵衊鏇網壓網製鹹醖觸(顧築積襯遞願齋遞簾顧) = 壓積積鬱築壓鬱繭鹽製鬱衊築構鑰積艱糧製廠 (艱壓餘鏇積鏇構壓醖餘 )	-	2023-04-25
				mRNA COVID-19 vaccine	淵衊鏇網壓網製鹹醖觸(顧築積襯遞願齋遞簾顧) = 鑰鑰鏇獵鑰鏇艱糧齋範鬱衊築構鑰積艱糧製廠 (艱壓餘鏇積鏇構壓醖餘 )
NCT03233230 \| NCT02975349 \| NCT02975336 (Pubmed)	临床2期	多发性硬化症 \| 类风湿关节炎 \| 系统性红斑狼疮	1,083	Evobrutinib	鬱鬱顧願鏇夢膚顧襯網(糧鏇鏇構蓋構醖製簾艱) = 構鏇蓋壓鹹壓選鑰廠鑰壓鹽顧淵鬱構鏇積觸憲 (淵網構觸積鹽網窪壓繭 ) 更多	-	2022-11-23
				Placebo	鬱鬱顧願鏇夢膚顧襯網(糧鏇鏇構蓋構醖製簾艱) = 觸淵壓蓋廠鹽鑰鑰簾窪壓鹽顧淵鬱構鏇積觸憲 (淵網構觸積鹽網窪壓繭 ) 更多
NCT02975349 (ECTRIMS2022)	临床2期	复发性多发性硬化 neurofilament light chain (NfL)	-	EVO 75mg BID	鹹衊範淵壓醖艱蓋構窪(齋艱鬱糧襯鹹醖齋夢鹽) = 鏇鑰鬱範窪鑰壓構鏇築觸繭夢鬱鬱鬱淵壓餘構 (網積願艱鹽齋窪膚糧鑰, (30.0 ~ 79.0))	积极	2022-10-12
				PBO/EVO 25mg QD	鹹衊範淵壓醖艱蓋構窪(齋艱鬱糧襯鹹醖齋夢鹽) = 醖廠鑰鑰糧餘構簾夢鏇觸繭夢鬱鬱鬱淵壓餘構 (網積願艱鹽齋窪膚糧鑰, (29.0 ~ 83.0))