Remibrutinib

CSU treatment evolves beyond anti-IgE biologics as novel drugs, biosimilars, and oral therapies reshape the competitive landscape Xolair leads but faces biosimilar pressure; Dupilumab, remibrutinib, and novel drugs like Barzolvolimab aim to reshape treatment with unique mechanisms.” — DataM Intelligence AUSTIN, TX, UNITED STATES, May 28, 2025 / EINPresswire.com / -- The chronic spontaneous urticaria (CSU) space is witnessing a pivotal transformation. Long recognized as a frustrating and poorly understood skin condition, CSU is now at the center of a therapeutic renaissance, fueled by cutting-edge biologics, advanced small molecules, and a sharpened industry focus on targeting non-responders and refractory cases. CSU is characterized by the sudden, recurrent appearance of hives, angioedema, or both, persisting for six weeks or more-often without any identifiable external trigger. Affecting nearly 1% of the global population, it tends to strike individuals in their prime years, most commonly between the ages of 20 and 40. While some experience symptoms for just a few years, others endure fluctuating episodes over a decade or more. Women are disproportionately affected, with incidence rates nearly double that of men. Book You CI Consultation Call for Free: https://www.datamintelligence.com/strategic-insights/ci/chronic-spontaneous-urticaria-csu This previously underserved market is now drawing heightened interest from global pharmaceutical leaders, driven by significant unmet needs and a growing patient base. Traditional antihistamines and the widely used anti-IgE biologic, omalizumab (Xolair), have been foundational treatments-but their limitations are increasingly apparent. A substantial subset of patients remain symptomatic despite these therapies, highlighting the urgent demand for more personalized, effective, and convenient options. A Therapeutic Landscape in Motion Approved therapies for CSU have evolved beyond antihistamines and Xolair, which remains the gold standard due to its robust real-world data and clinician trust. However, the competitive pressure is intensifying. A new wave of therapies is being designed to fill critical gaps, offering hope to patients who have historically had few alternatives. Sanofi and Regeneron’s Dupixent (dupilumab), already a blockbuster in other atopic diseases, is now being positioned for biologic-refractory CSU. With its mechanism targeting IL-4 and IL-13, it has demonstrated promise in addressing type 2 inflammation that plays a role in certain CSU patients. Meanwhile, Novartis is preparing to introduce Remibrutinib, a BTK inhibitor that represents a new class of oral small molecules in CSU. Designed specifically for antihistamine-refractory cases, this candidate could be a game-changer for patients seeking alternatives to injectables. And it doesn't stop there. Biotech innovators are developing therapies that target other key pathways in CSU pathogenesis, such as mast cell activation, JAK1/TYK2 inhibition, and the KIT receptor. Candidates like Barzolvolimab (Celldex), TLL-018 (Hangzhou Highlightll), and CMAB007 (Taizhou Mabtech) bring novel mechanisms of action that aim to redefine how CSU is managed across varying patient profiles. Biosimilars: Disruption with Access and Affordability The rise of biosimilars in the anti-IgE space is reshaping market dynamics. Players like Celltrion (OMLYCLO), Kashiv BioSciences (ADL-018), and Teva (TEV-45779) are introducing cost-effective versions of omalizumab, promising broader patient access without compromising efficacy. These products, many in advanced stages of regulatory approval, are likely to erode market share from branded biologics and increase pricing pressure across the board. This biosimilar wave is not merely a cost play. With proven interchangeability, favorable safety profiles, and growing physician confidence, they are expected to become integral components of treatment protocols, especially in cost-sensitive markets. Strategic Differentiation: The New Standard for Emerging Therapies Emerging CSU therapies must meet a higher bar than ever before. Speed of action, durability of response, convenience, and safety have become non-negotiable for success. According to analysts tracking the market, the most competitive agents will be those that can: • Deliver rapid relief (within 1–2 weeks) • Sustain remission over six months or more • Offer convenient oral or monthly dosing • Demonstrate efficacy in biologic non-responders • Maintain a clean safety profile with minimal immunosuppression • Target novel mechanisms beyond the conventional IgE and IL-4/13 pathways • Additionally, the rise of companion diagnostics and biomarker-driven personalization is expected to further optimize outcomes. By identifying likely responders in advance, developers can strengthen their value proposition to both clinicians and payers, accelerating adoption. Ask for Free Sample of Chronic Spontaneous Urticaria (CSU) Competitive Intelligence : https://www.datamintelligence.com/strategic-insights/sample/chronic-spontaneous-urticaria-csu The Competitive Pulse While Xolair continues to dominate with over a decade of physician loyalty and strong efficacy data, it now faces formidable competition. Dupixent and Remibrutinib are positioning themselves as high-efficacy alternatives, especially for patients not well controlled with current options. Meanwhile, first-in-class agents like Barzolvolimab are targeting mast cell pathways with the potential to establish entirely new treatment paradigms. Companies across North America, Europe, and Asia are racing to secure regulatory approvals, with several candidates in pre-registration phases in major markets like the U.S., EU, China, and the UK. This global expansion is expected to significantly widen the therapeutic footprint of CSU treatments over the next three years. Looking Ahead: Innovation Meets Opportunity The CSU market is entering a golden age of therapeutic innovation. As more targeted and differentiated agents reach commercialization, the outlook for patients is becoming increasingly hopeful. What was once a chronic, often invisible struggle is now drawing the attention of top-tier drug developers, regulatory bodies, and clinicians alike. The convergence of scientific discovery, commercial opportunity, and patient need is setting the stage for a transformative era in CSU management. Whether through best-in-class biologics, next-generation small molecules, or cost-effective biosimilars, the market is well-positioned for sustained growth and disruption. Final Word Chronic Spontaneous Urticaria is no longer an orphaned disease in the shadows. As the market evolves beyond anti-IgE monoclonals, new entrants with novel mechanisms and compelling value propositions are unlocking the next growth frontier. For stakeholders across the pharmaceutical value chain-developers, investors, clinicians, and patients-the CSU space has never been more dynamic or full of promise. About DataM Intelligence: DataM Intelligence 4Market Research LLP is a leading provider of Competitive Intelligence (CI) services, empowering life sciences and healthcare companies with real-time, actionable insights. We specialize in tracking competitor strategies, pipeline developments, clinical trials, regulatory updates (FDA/EMA), and market trends across key therapy areas and indications. Our offerings include CI insights, commercial analytics, opportunity analysis, KOL overviews, pricing and reimbursement strategies, social media listening, brand/LCM strategies, and market entry assessments. We also offer in-house tools, clinical trial databases, newsletters, and conference coverage to support your strategic decision-making. With deep industry expertise and a commitment to timely intelligence, we help you stay ahead in a fast-evolving global market. Read our Related CI Reports: 1. Frontotemporal Dementia | Competitive Intelligence 2. Obstructive Sleep Apnea | Competitive Intelligence Sai Kiran DataM Intelligence 4market Research LLP +1 877-441-4866 email us here Visit us on social media: LinkedIn X Legal Disclaimer: EIN Presswire provides this news content "as is" without warranty of any kind. We do not accept any responsibility or liability for the accuracy, content, images, videos, licenses, completeness, legality, or reliability of the information contained in this article. If you have any complaints or copyright issues related to this article, kindly contact the author above.

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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