AZD-5069

2024年6月26日，全球首个双重PDE3/4抑制剂Ensifentrine（恩塞芬汀）在FDA获批上市。这款号称“一药双效”的创新药物，成功打破COPD治疗僵局，开启了“抗炎+扩支”的整合治疗时代。 2024年9月27日，赛诺菲宣布，达必妥®（度普利尤单抗注射液）获得中国国家药品监督管理局（NMPA）批准，用于血嗜酸性粒细胞升高且控制不佳的慢性阻塞性肺疾病成人患者，借此开启了COPD生物治疗时代。 2024年12月20日，这款由健康元与拜耳合作开发的慢阻肺（COPD）治疗药物，是目前单靶点口服药市场仅有的新药产品，也可能成为中国首款创新机制的COPD口服药。 2025年2月21日，GSK宣布其IL-5单抗Nucala（美泊利珠单抗）的新药上市申请获国家药监局受理，用于作为嗜酸性粒细胞表型慢性阻塞性肺病（COPD）患者的附加维持治疗，再次将COPD领域的靶向生物药疗法推向了高潮。 不到一年，COPD领域的新药研究似乎就成为了香饽饽，不仅MNC接连布局，国内Biotech企业更是将其作为赶超全球的大好机会，这是为何？ 更关键的是，COPD领域背后究竟有何魅力？如今的在研领域又是怎样一个局面？ 庞大的患者群体 所谓慢阻肺，即一种常见的、可预防和治疗的慢性气道疾病，其特征是持续存在的气流受限和相应的呼吸系统症状，是一种较常见的慢性疾病，病死率较高，且严重影响患者的生命质量，并给其家庭与社会带来沉重的经济负担。 据悉，COPD已成为全球第三大死亡原因，全球约有3.9亿例COPD患者，中国约有1亿例COPD患者，占全球COPD病例的近25%，潜在用药市场庞大。 而随着慢阻肺规范化诊疗的推行，虽然慢阻肺死亡率逐年下降，但随着空气指数下降、吸烟等因素，其整体发病率却出现反向上涨的趋势。 更关键的是，由于目前慢阻肺的发病机制尚未完全明确，氧化应激、炎症反应、蛋白酶/抗蛋白酶失衡等多种因素均可导致组织重构，进而致病，相对复杂的致病原理也为COPD新药研究带来巨大困难。 局限严重的传统治疗 一直以来，临床上针对稳定期慢阻肺病治疗基本围绕两个目标进行，即减轻症状和降低风险，两个目标相互关联、相互促进，共同构成了慢阻肺病管理的重要内容。 尽管这些药物及干预措施虽能显著改善慢阻肺病患者的症状，但其局限性也相对比较大，比如治疗精准性不足、疾病异质性高、无法逆转病程、传统治疗副作用明显、耐药性严重等。 更关键的是现阶段临床药物治疗无法覆盖所有慢阻肺病疾病表型，并且鉴于慢阻肺病的发病机制相当复杂且尚未完全阐明，目前临床上仍缺乏针对病因的有效治疗药物。 这也使取得一定临床成就的创新疗法无法复制到 COPD 治疗领域，相关新药临床研究推进异常缓慢。 两极分化的在研方向 在历史上，COPD新药主要分为三个时代，即传统支气管扩张剂时代、抗炎治疗兴起时代、生物制剂革命时代。而围绕三个时代的发展，也演变出如今在研COPD新药的两大方向，即老药新发展与生物靶向药替代。 图片来源：博药（点击查看大图） 老药新发展 首先，有一点需要明确：老药并非“不行”。 事实上，在几十年临床使用上的经久不衰已是老药的最佳证明，而老药新发展，既是指临床目标不变（减轻症状+降低风险），针对不良反应、临床有效性等方向进行了诸多优化性设计。 新型吸入 β2 受体激动剂（LABA） 由于β2受体激动剂主要作用于气道平滑肌细胞、肥大细胞膜表面的β2受体，其在缓解COPD临床症状方面有着广泛认可的作用，也是目前COPD临床治疗主力药物之一。 从短效β2受体激动剂到长效β2受体激动剂，临床上用于COPD治疗的LABA在频繁用药、药物剂量、实用性、患者依从性、安全性方面做出系列产品更迭，也确定了新型LABA的主线方向。 药品名称 靶点 适应症最高临床阶段 原研单位 最新临床进展时间 （近三年有进展即“活跃管线”） 阿贝特罗 Abediterol ADRB2 临床Ⅱ期 Almirall Ltd;阿斯利康 2019-12-12 琥珀酸巴芬特罗 Batefenterol Succinate ADRB2;CHRM2;CHRM3 临床Ⅱ期 Innoviva Inc 2016-01-21 AZD-2115 ADRB2;mAChR 临床Ⅱ期 Pearl Therapeutics Inc;阿斯利康 2017-03-06 卡莫特罗 Carmoterol ADRB2 临床Ⅱ期 田边三菱制药株式会社 2011-10-19 维兰特罗 Vilanterol ADRB2 临床Ⅱ期 葛兰素史克 2007-08-21 数据来源：公开数据整理、药智数据 时至今日，研发端上仍有药企致力于新型β2受体激动剂方向，但受限于临床替代难度较大，其中大多数管线的临床推进已不再积极。其中，比较具有代表意义的有几种新型β2受体激动剂： 卡莫特罗（Carmoterol）活性及对β2受体的选择性高，起效快，作用时间达30h，治疗过程中耐受性和安全性与沙美特罗无显著差异。 维兰特罗（Vilanterol）较沙美特罗起效快、治疗指数高、内在活性好，作用时间超过24h。 但从目前该领域的研发活跃情况来看，可以预见的是未来新型LABA大概率将不再是COPD新药研发的主要方向，至少已很少有企业愿意在朝这方面努力了。 新型长效抗胆碱药（LAMA） 抗胆碱能药物主要通过阻断M1-M3胆碱受体，进而扩张气道平滑肌、改善气流受限和慢阻肺症状，20世纪70年代，短效抗胆碱药物（SAMA）开始被用于慢阻肺的治疗，但虽起效迅速，但作用时间仅6—8小时，对于COPD这样的慢病而言，局限性较大，因此21世纪初，长效抗胆碱能药物（LAMA）问世，作用时间大幅增长，部分产品甚至可超过24小时。 比如，2017年获批上市的格隆溴铵（Glycopyrrolate），对M3受体的选择性较噻托溴铵高，起效时间较噻托溴铵快4.8倍，安全性好；GSK的乌美溴铵改善FEV1的效果与噻托溴铵相似，效果与剂量无相关性，吸收迅速（Tmax=5～15min），在血液中代谢迅速，耐受性好。 药品名称 靶点 适应症最高临床阶段 原研单位 最新临床进展时间（近三年有进展即“活跃管线”） 乌美溴铵 Umeclidinium Bromide CHRM1;CHRM2;CHRM3;CHRM4;CHRM5 已上市 葛兰素史克 2023-11-08 阿地溴铵 Aclidinium Bromide CHRM3 已上市 Almirall SA；精鼎医药（许可） 2024-08-13 噻托溴铵 Tiotropium Bromide CHRM3 已上市 勃林格殷格翰 2025-02-06 TRN-157 CHRM3 临床Ⅱ期 Theron Pharmaceuticals Inc；山东鲁抗医药（许可）；长风药业（许可） 2024-08-09 数据来源：公开数据整理、药智数据 而目前，在新型长效抗胆碱能药（LAMA）研发层面，其整体情况与LABA的局面类似，绝大多数管线的临床进展并不积极，仅少数产品还在持续推进，其中山东鲁抗的TRN-157，目前其已在美国完成了I期和IIa期临床试验，在国内已完成了健康受试者单次给药的I期临床试验，安全性均良好，本品已获得国家药品监督管理局同意开展IIa期临床试验。 双靶点支气管扩张剂（MABA） MABA是一类新型具有毒蕈碱拮抗剂和β2激动剂双重作用的双靶点药物，能够实现在一个分子上同时作用两大靶点的创新设计，具有M受体拮抗和β受体激动两种功能，可协同扩张气管和抗炎。 对比LABA与LAMA单靶点产品，从机制上其具备了核心的三大优势： 双靶点协同，疗效提升：双靶点机制不仅成功规避了LAMA、LABA单药治疗可能面临的疗效局限性和潜在副作用风险，更通过“双靶点”的协同作用，实现COPD疾病症状以及肺功能的双重改善，大幅提升治疗效果和患者的治疗依从性。 兼顾速效与长效，治疗优势凸显：数据显示，该药物兼具速效与长效的双重治疗优势，能够迅速响应急性期的需求实现快速缓解，同时亦适合作为长期维持治疗的选择，有望对现有治疗方案形成强有力的补充甚至替代。 安全设计、无忧治疗：该药物独特的季铵盐结构设计能够有效避免药物进入中枢神经系统，从而大幅降低对中枢神经系统产生副作用的可能性，提升了治疗的安全性，为慢阻肺患者带来更加高效、便捷且安全的治疗新选择。 药品名称 靶点 关键适应症与阶段 适应症最高临床阶段 原研单位 最新临床进展时间（近三年有进展即“活跃管线”） 琥珀酸巴芬特罗 Batefenterol Succinate ADRB2;CHRM2;CHRM3 临床Ⅱ期：慢性阻塞性肺病 临床Ⅱ期 Innoviva Inc 2016-01-21 CHF-6366 ADRB2;CHRM3 临床Ⅱ期：哮喘;慢性阻塞性肺病 临床Ⅱ期 意大利凯西制药公司 2017-12-14 DBM-1152A ADRB2;CHRM3 临床Ⅰ期：慢性支气管炎;慢性阻塞性肺病;支气管痉挛;肺气肿引起支气管痉挛 临床申请：哮喘 临床Ⅰ期 硕佰医药 2024-08-08 TQC-3927 ADRB2;CHRM3 临床Ⅰ期：慢性阻塞性肺病 临床申请：哮喘 临床Ⅰ期 正大天晴 2024-12-02 数据来源：公开数据整理、药智数据 目前，MABA类双靶点制剂相对前两类药物的研发热情明显更高，是COPD新药研究的重要方向之一，其中Innoviva的Batefenterol、阿斯利康的Navafenterol与凯西制药的CHF-6366临床进度较靠前，但进展相对不那么积极。而对比之下，部分国内管线明显更加活跃，比如硕佰医药与健康元的DBM-1152A、正大天晴的TQC-3927，目前均已进入临床I期，且临床推进迅速。 PDE双靶点抑制剂 PDE主要分布于体内各种炎症细胞内，家族的成员多达11位，每位成员各司其职，参与不同的生理过程，其中PDE-4抑制剂可以阻止PDE-4对cAMP/cGMP的水解作用，使cAMP/cGMP在炎症细胞内聚集。 因此，PDE4抑制剂对于治疗慢性阻塞性肺疾病（COPD）非常有吸引力。 但由于PDE4在全身多处组织中广泛表达，导致其具备潜力的同时，不良反应也极大地限制了其发展。因此，寻求一款兼具高有效性与低不良反应的PDE4抑制剂成为该领域的主线任务。 多项研究表明，相比于单独抑制PDE3或PDE4，同时抑制PDE3和PDE4产生的抗炎和松弛平滑肌作用更强，同时较低的副作用也使得PDE3/4双重抑制剂顺势成为COPD新药研发的趋势之一。 数据来源：公开数据整理、药智数据（点击查看大图） 其中，2024年全球首个获FDA获批上市的PDE3/4抑制剂Ensifentrine（恩塞芬汀）就是显著代表，“一药双效”的创新药物，成功打破COPD治疗僵局，开启了“抗炎+扩支”的整合治疗时代。 国内领域，目前也有多家企业有所布局，进入临床阶段的产品包括正大天晴的TQC-3721与恒瑞医药的HRS-9821，不出意外的话，首款国产PDE3/4抑制剂将在两者中产生。 PI3Kδ 抑制剂 虽然PI3K药物大多集中肿瘤领域（包括实体瘤和血液肿瘤），目前已获批上市的PI3K抑制剂适应症也均为肿瘤，但近年来的研究表明PI3K在慢性阻塞性肺疾病（COPD）、哮喘、特发性肺纤维化（IPF）以及神经系统疾病病理过程中也扮演重要角色，这也导致部分企业对上述适应症的临床试验兴趣大涨。 其中，在一些COPD患者中对诸如皮质类固醇的常规疗法的抗性已被归因于PI3Kδ/γ途径的上调。另外，PI3Kδ/γ的双重抑制强烈地涉及气道及其他自身免疫性疾病的过敏及非过敏性炎症作为干预策略。 因此，针对PI3Kδ/γ信号传导的抑制提供了一种旨在对抗免疫炎性反应的新手段。 药品名称 靶点 关键适应症与阶段 产品最高临床阶段 适应症最高临床阶段 原研单位 最新临床进展时间（近三年有进展即“活跃管线”） 奈米利司 Nemiralisib PI3Kdelta 临床Ⅱ期：PI3Kδ过度活化综合征;哮喘;慢性阻塞性肺病 临床Ⅱ期 临床Ⅱ期 葛兰素史克 2018-10-23 RV-6153 PI3K 临床Ⅰ期：慢性阻塞性肺病 临床Ⅰ期 临床Ⅰ期 RespiVert Ltd 2015-07-28 RV-1729 PI3K;PI3Kdelta;PIK3CG 临床Ⅰ期：慢性阻塞性肺病 临床Ⅰ期 临床Ⅰ期 RespiVert Ltd 2014-05-14 数据来源：公开数据整理、药智数据 目前，在该领域中涉及COPD的临床阶段管线数量不多，且绝大多数管线临床状态并不活跃，其中GSK的Nemiralisib是目前临床阶段最靠前的创新疗法，其次则是RespiVert的RV-6153与RV-1729。 CXCR拮抗剂 早些年，小分子趋化因子受体（CXCR）拮抗剂在呼吸系统疾病中的作用仍是一个活跃的研究领域，研究发现COPD患者体内CXCL8、CXCL1和CXCL5的水平升高，与CXCR2受体结合后，使中性粒细胞和单核细胞增多并激活。 口服CXCR拮抗剂具有抑制肺部慢性中性粒细胞性炎症的作用，临床研究还发现CXCR2拮抗剂同样具有抑制肺部慢性中性粒细胞性炎症的作用，提示对COPD具有潜在的治疗作用。 药品名称 靶点 关键适应症与阶段 产品最高临床阶段 适应症最高临床阶段 原研单位 最新临床进展时间（近三年有进展即“活跃管线”） 多西帕司他钠 Dociparstat Sodium CXCL12;CXCR4 临床Ⅲ期：SARS-CoV-2感染;急性肺损伤;急性髓系白血病 临床Ⅱ期：慢性阻塞性肺病 临床Ⅲ期 临床Ⅱ期 Cantex Pharmaceuticals Inc;Chimerix Inc 2021-02-26 AZD-5069 CXCR2 临床Ⅱ期：呼吸系统疾病;哮喘;慢性支气管炎;慢性阻塞性肺病;支气管扩张;肝癌;肺气肿;肺病 临床Ⅱ期 临床Ⅱ期 阿斯利康 2022-03-07 达尼利星 Danirixin CXCR2 临床Ⅱ期：慢性阻塞性肺病;流感病毒感染 临床Ⅰ期：呼吸道合胞病毒感染 临床Ⅱ期 临床Ⅱ期 葛兰素史克 2018-03-01 QBM-076 CXCR2 临床Ⅱ期：慢性阻塞性肺病 临床Ⅰ期：三阴性乳腺癌;结直肠癌;肾细胞癌;非小细胞肺癌 临床Ⅱ期 临床Ⅱ期 诺华制药 2016-05-09 数据来源：公开数据整理、药智数据 但随着研究深入，目前大多数针对趋化因子受体和介质的药物研究已经停止，仅有少数几个针对CXCR1与CXCR2拮抗剂的研究还在继续。 生物靶向药崛起 对COPD生物药的开发探索，一直都是当前创新药研发的重点方向，但由于创新疗法的局限性，对新开发项目来说，不确定因素往往更多，这也导致十数年里全球制药企业在COPD生物药研发过程中折戟无数。 不过，随着医药基础研究水平的进步，靶向生物药市场验证机会也越来越多，近年来COPD生物靶向药逐渐有了新的希望，相关疗法也陆续取得不错的成绩，目前来看“IL/TSLP单抗”与“靶向双抗”是现阶段最被寄予厚望的技术方向。 单抗 多项研究表明，COPD患者的整个气道、肺实质和肺血管中都存在慢性炎症。这就表示包括1型细胞因子肿瘤坏死因子α(TNF-α)，2型细胞因子IL-4、IL-5、IL-13及其警报素IL-33、TSLP等都会参与COPD病理生理，而随着研究深入，TNF-α抑制剂单抗在COPD实际治疗中的临床疗效相对有限，逐渐被研究者放弃。 因此，COPD单抗的相关研究开始集中转向2型炎症，IL-4、IL-5、IL-33与TSLP逐渐成为COPD单抗研究的“四强”。 IL-5单抗方面，由于率先在嗜酸性粒细胞表型重症哮喘方面取得突破，如阿斯利康、GSK等MNC都希望能一鼓作气，将其药物用途拓展至COPD领域，彼时IL-4也被认为是最可能应用于COPD领域的IL单抗方向。但现实却是多个IL-5单抗在COPD适应症上接连失利。 数据来源：公开数据整理、药智数据（点击查看大图） 直至2024年9月，GSK的Mepolizumab治疗COPD的Ⅲ期MATINEE研究取得了积极结果，并于2025年2月11日在中国申报上市。 IL-4单抗方面，由于IL-5单抗在COPD领域的接连失利，其幸运地迎来了反超机会，2024年7月赛诺菲/再生元合作开发的IL-4Ra单抗Dupixent（Dupilumab/度普利尤单抗）在全球率先获得欧洲药品管理局（EMA）批准用于治疗血液嗜酸性粒细胞（BEC）升高且未得到控制的COPD成人患者，从而摘得首款COPD生物药桂冠。 数据来源：公开数据整理、药智数据（点击查看大图） 在其主要临床终点中，度普利尤单抗AECOPD平均年恶化率分别降低30%和34%，且肺功能（支气管扩张剂前FEV1）在12周时较基线改善160mL和139mL，而基线时分别为77mL和57mL。Dupixent的成功进一步通过试验验证了IL-4和IL-13信号传导在COPD中的作用。 IL-33单抗方面，作为驱动病毒感染和诱发AECOPD的关键细胞因子，在COPD患者的血浆和支气管上皮中可明显观察到IL-33的过度表达。目前已有多款靶向IL-33的单抗正处于COPD的Ⅲ期临床试验阶段 数据来源：公开数据整理、药智数据（点击查看大图） 赛诺菲的IL-33单抗Itepekimab，目前已处于临床Ⅲ期阶段，其临床数据显示其虽对急性加重率降低无统计学意义，但对曾吸烟者COPD急性加重率降低>40%，赛诺菲对其年销售峰值预期达50亿欧元。 而国内领域的布局管线虽临床进度较上述两者有所不及，但也极具潜力，其分别是正大天晴的TQC-2938、荃信生物的QX-007-N与三生国健的SSGJ-621。 TSLP单抗方面，相比于IL-4R等靶点，TSLP位于更上游，位于多个炎症级联反应顶端，是2型炎症重要驱动因素，在各种类型的炎症和免疫类疾病中充当促炎细胞因子。 图片来源：《TSLP: from allergy to cancer》 靶向TSLP抗体通常是通过阻断TSLP与其受体之间的相互作用来抑制TSLP介导的信号通路，从而抑制DC细胞、肥大细胞、自然杀伤细胞、TH2细胞介导炎症反应。目前TSLP靶点肿瘤适应症开发布局较为集中，其中哮喘适应症的临床进展最快，而由于COPD与哮喘的关联性，导致TSLP单抗用于COPD治疗的研究也同样火热。 数据来源：公开数据整理、药智数据（点击查看大图） 截止目前，全球领域尚无任何一款TSLP单抗获批用于治疗COPD，临床推进最快的是安进与阿斯利康的Tezepelumab、博奥信生物的BSI-045B、诺华制药的Ecleralimab、荃信生物的QX-008-N，均已进入临床Ⅱ期。但同时，值得注意的是，在TSLP单抗用于COPD治疗的在研药物领域中，国内Biotech企业得管线数目却占比较高，后续有望成为全球该领域的主要力量。 双抗 原则上来讲，双抗较单抗，确实具备诸多技术优势，比如双重靶向下的协同作用使得它在处理肿瘤的异质性和复杂生物学特性时，比单抗有更全面的覆盖、在增强治疗效果、克服耐药性等方面优势明显。 也正是因此，全球制药企业不出意外的均将其作为潜在创新疗法布局，而在COPD领域，目前已有少数企业开始积极推进，靶点主要主要集中于TSLP+IL、IL+IL两大方向。 分类 药品名称 靶点 关键适应症与阶段 产品最高阶段 适应症最高临床阶段 原研单位 最新临床进展时间（近三年有进展即“活跃管线”） 双抗 HB-0056 IL11;TSLP 临床Ⅰ期：哮喘;慢性阻塞性肺病;特发性肺纤维化;特应性皮炎 临床Ⅰ期 临床Ⅰ期 华奥泰生物 2025-01-24 RC-1416 IL4RA;IL5 临床Ⅰ期：哮喘 临床申请：慢性阻塞性肺病;特应性皮炎;肿瘤 临床Ⅰ期 临床申请 融捷康生物 2024-10-17 PM1017 IL4RA;IL5 临床前：哮喘;嗜酸粒细胞增多症;慢性阻塞性肺病 临床前 临床前 普米斯生物 2022-08-12 数据来源：公开数据整理、药智数据 据不完全统计，COPD双抗领域目前以华奥泰生物的HB-0056推进最快，前已处于临床I期，其次是融捷康生物的RC-1416与普米斯生物的PM1017，分别处于临床申请与临床前阶段。 华奥泰生物的HB-0056，是以抗TSLP人源化单克隆抗体为亲本抗体，在N端连接抗IL-11（白细胞介素-11）单链纳米抗体的双特异性抗体，能高特异性地靶向TSLP和IL-11这两个靶点。而TSLP和IL-11均以不同的机制参与诱导Th2（辅助型T细胞2）反应、气道炎症和COPD的发病机制，两者可以互补作用来影响该疾病。 融捷康生物的RC-1416，可以选择性结合IL-4R和IL-5，同时下调由IL-4、IL-5和IL-13诱导的信号，显著抑制炎症性Th2（2型炎症因子）细胞，以及下游的参与炎症反应的嗜酸性粒细胞、肥大细胞、嗜碱性粒细胞的活性，对多种Th2通路诱导的疾病都具备治疗效果。而IL-5目前被认为是Th2通路的关键驱动因子之一，IL-5与其受体结合后进一步激活下游JAK-STAT信号通路。 普米斯生物的PM1017，可以同时阻断慢性阻塞性肺病患者体内IL-4/IL-13/IL-4Rα/IL-13Rα1，以及IL-5/IL-5Rα两条非冗余的信号通路，从而更大限度地抑制疾病进展，同时避免临床上使用度普立尤单抗治疗，患者发生的嗜酸性粒细胞增多症等副作用。皮下注射剂型加上工程化改造的Fc片段缩短给药频率，PM1017可以为患者提供更加便捷，安全，有效的治疗方案。 难以看清的未来趋势 对于绝大多数自免、慢病而言，其患者群体庞大是其最大的优势，更何况其临床上还存在大量未满足的临床需求，因此近年来逐渐成为全球创新技术领域除肿瘤外的最大竞争地。 而对于COPD新药研发而言，虽然现阶段IL、TSLP等靶向制剂均以单抗技术为主，但就疗法未来而言，其患者顺应性的弊端或许也将成为限制其发展的关键之处（调查显示至少超过20%的患者不愿意使用注射剂型）。 放眼隔壁的IL-17领域，目前全球范围内已有多家创新药企在尝试推进IL-17口服制剂，且不乏辉瑞、礼来、赛诺菲等MNC药企的身影。比如礼来DC-806折戟后寄希望的小分子IL-17靶向药DC-853，赛诺菲以700万美金首付从C4X引进的IL-17A临床前小分子抑制剂；强生/Protagonist首个口服IL-23受体的靶向口服肽JNJ-2113。 当然，考虑到COPD用药特殊性，此处的IL单抗口服趋势不一定完全适用（毕竟长久以来吸入制剂制在呼吸系统的临床地位明显高于口服小分子），未来大概率会做出因地制宜的改变，比如IL单抗的吸入制剂、TSLP吸入单抗等。 但可以肯定的是，随着未来COPD靶向生物药的发展，COPD单抗制剂的竞争加剧，关于患者顺应性的考虑或许会在恰当的时候，进入研究者的视野中。 小结 综上所述，从数十年前LABA、LAMA被临床应用于COPD治疗，再到如今临床上LABA+LAMA+ICS的临床联用方案，很明显COPD的新药研发较肿瘤、自免疾病而言，明显慢了很多。 固然，这一方面是由于COPD相关基础临床研究不足，另一方面也是由于COPD短期研发收益低于肿瘤、肥胖、自免等风口疾病领域。但这并不表示COPD领域的市场不大，不存在临床需求。相反，长时间的无药可用的压抑之下，或许还会造就COPD领域更加迫切的临床需求。 而从目前COPD新药在研的情况来看，一部分企业选择继续沿用传统研发路线，对老药进行新的优化与升级，过程中诞生了一系列新型LABA、新型LAMA以及双靶点支气管扩张剂（MABA）等等，比如成功打破COPD治疗僵局的恩塞芬汀；而另一部分企业则倾向于将在肿瘤、自免新药开发上获得的经验复制于COPD领域，积极推进IL单抗、TSLP单抗与靶向双抗，比如赛诺菲与再生元的度普利尤单抗、GSK的美泊利珠单抗。 目前来看，就老药新发展与靶向生物药两方面发展而言，预计未来很长一段时间，靶向生物药或将成为COPD新药的主线剧情，直到双抗同质化那天，而过程中也必将有越来越多中国Biotech企业从中崛起。 当然，无论是老药新用，还是靶向生物药的大趋势，对于目前COPD的临床需求而言，仍不够完美，或未来，在逆转COPD病程、针对病因治疗、解决患者顺应性需求方面，小分子与生物药能协同一起，为更核心的需求服务。 来源 | 博药（药智网获取授权转载） 撰稿 | 博药内容中心 责任编辑 | 八角 声明：本文系药智网转载内容，图片、文字版权归原作者所有，转载目的在于传递更多信息，并不代表本平台观点。如涉及作品内容、版权和其它问题，请在本平台留言，我们将在第一时间删除。 合作、投稿 | 马老师 18323856316（同微信）  阅读原文，是受欢迎的文章哦

Repurposing existing cancer drugs to exploit a genetic weakness July 2023 Dr Rachael Natrajan, Leader of the Functional Genomics Group at the ICR, recently led investigative work on a gene called SF3B1, which plays a part in processing the genetic information used to build proteins. The gene has been linked to several types of cancer, including some ER+ breast cancers and certain types of leukaemia and melanoma. In the first stage of the study, the researchers, working in the Breast Cancer Now Toby Robins Research Centre at the ICR, showed that cells with an altered SF3B1 gene lack a protein called CINP. They found that they could exploit this using drugs called PARP inhibitors to hamper the cells’ ability to copy their DNA accurately, thereby preventing cancer growth. In the second stage, the team assessed the efficacy of 80 of these drugs against cancer cells with an altered SF3B1 gene, finding that the treatments reduced the cells’ ability to survive. The ICR has been involved in the development of PARP inhibitor drugs, which include olaparib, for many years, and these medications are already used to treat some breast, ovarian and prostate cancer patients who have inherited an altered BRCA1 or BRCA2 gene. This latest research suggests that PARP inhibitors could also be used to treat the thousands of patients with mutations in the SF3B1 gene, potentially transforming the treatment of multiple cancer types. Return to top Targeting blood cells that cancer uses to promote its growth October 2023 Researchers at the ICR co-led a recent study showing that it is possible to reverse drug resistance and slow tumour progression in prostate cancer by targeting myeloid white blood cells. Tumours can ‘hijack’ these cells to help fuel their growth, progression and resistance to treatment. Professor Johann De Bono, Regius Professor of Cancer Research at the ICR, led the study, which could lead to an entirely new way of treating prostate cancer. Based on their knowledge that myeloid cells are elevated in patients with more aggressive tumours, the scientists had theorised that the cells contributed to treatment resistance. For the study, they recruited patients with advanced prostate cancer and gave them an experimental drug called AZD5069 alongside the hormone therapy commonly used to treat the disease. The addition of AZD5069, which blocks tumour cells from recruiting myeloid cells, led to increased tumour shrinkage and decreased circulating levels of prostate specific antigen (PSA), a marker of the disease. Return to top Using AI to improve the accuracy of diagnosis November 2023 Collaborative work from the ICR and its hospital partner, The Royal Marsden, has shown that artificial intelligence (AI) has the potential to benefit thousands of cancer patients each year by improving the accuracy of diagnosis. Professor Christina Messiou, Consultant Radiologist at The Royal Marsden and Professor in Imaging for Personalised Oncology at the ICR, led the study, in which a new AI algorithm was revealed to be around twice as accurate as a biopsy in grading the aggressiveness of a rare soft tissue cancer called retroperitoneal sarcoma. The researchers created the algorithm using CT scans from 170 people with this disease, all of whom were treated at The Royal Marsden. When they tested it on nearly 90 patients based in Europe and the US, they found that the model accurately determined the likely aggressiveness of 82 per cent of the tumours analysed. This was much higher than the 44 per cent correctly graded using a biopsy. The model was also able to differentiate between the two most common forms of retroperitoneal sarcoma in 84 per cent of cases, while radiologists were only able to do this in 35 per cent of the sarcomas tested. By improving the accuracy of diagnosis, this technique could improve the management of the disease, leading to better outcomes for patients. Return to top Identifying a potential new drug target in acute myeloid leukaemia November 2024 A team of researchers led by Professor Kristian Helin, Chief Executive and Professor of Epigenetics and Cancer at the ICR, set out to identify new vulnerabilities in acute myeloid leukaemia (AML), an aggressive form of blood cancer with a low survival rate. The scientists decided to focus on MLL-rearranged AML – a type of the disease driven by a common mutation that affects blood cell production. They used a versatile tool called CRISPR interference (CRISPRi) to screen 1,046 genes associated with regulating the packaged DNA in these cancer cells. The aim was to identify genes involved in packaging DNA that was also required for sustaining the proliferation of AML cells. This led to the identification of an alternative form of the nucleosome remodelling factor (NURF) that plays an important part in regulating gene expression. The scientists showed that the alternative NURF complex comprises proteins called BPTF, SMARCA5 and BAP18, and that BPTF is essential for AML cells to grow and multiply. Overall, this protein complex promotes the survival of AML, meaning drugs that target it could potentially control or eliminate the disease. This important work has opened the door to a new therapeutic strategy that might lead to much-needed new treatments for AML. Return to top Overcoming a longstanding technical challenge in drug discovery April 2024 The structural biology community is likely to benefit from a groundbreaking methodological advance made by scientists at the ICR. The team developed a new cryogenic electron microscopy (cryo-EM) workflow that provided higher-resolution images in a shorter timeframe. The resulting images will help scientists determine the structure and interactions of protein complexes more accurately. Cryo-EM can reveal the detailed structure of biological molecules by rapidly freezing samples to below -150° before passing a beam of electrons through them to collect images from different angles. However, both the resolution of the images and the time it takes to produce them can limit the use of this technique. In the study, led by Dr Basil Greber, Structural Biology of DNA Repair Complexes Group Leader at the ICR, the researchers developed an improved cryo-EM workflow involving two stages. They began by performing rapid screening using a less costly and more readily available cryo-EM instrument to select the specimens with high potential. For these only, they then used a cold field emission gun to obtain higher resolution images. This approach allowed the team to achieve exceptional images at a resolution that had only ever been achieved for one protein complex of a similar size before. It also made it possible for the team to determine more than 12 structures per day – an impressively high number. In this case, the researchers used their new technique to determine 16 detailed structures of a protein complex known as CAK, which has shown promise as a target for cancer drugs. However, the team believes that scientists in other labs will be able to apply the new methodology to drug discovery, meaning it could support the design of multiple next-generation therapeutics. Return to top Finding a new treatment approach for a cancer of unmet need April 2024 Groundbreaking work co-led by researchers at the ICR has demonstrated the feasibility of a new treatment approach for acute myeloid leukaemia (AML), an aggressive type of blood cancer for which there are currently limited treatment options. The team, led by Professor Kamil Kranc, Professor of Haemato-Oncology at the ICR, investigated enzymes called prolyl hydroxylases (PHDs), which promote aggressive AML by targeting proteins called HIF proteins for destruction. PHDs become less active when oxygen levels are low, and the scientists had previously used this to show that these conditions result in increased levels of HIF. In this study, the team successfully used genetic modification to inactivate PHDs in mice and used existing anaemia drugs to do the same in patient samples. In both cases, PHD inactivation led to higher HIF levels and stopped leukaemia from starting or progressing. The researchers then built on these findings to develop a new first-in-class PHD inhibitor called IOX5, which blocked AML progression by selectively inhibiting PHDs. They were then able to further increase the anti-cancer effect of IOX5 by combining it with an existing leukaemia drug called venetoclax. Return to top Gaining an important insight into the mechanisms promoting breast cancer recurrence March 2024 Early-stage research carried out by scientists in the Breast Cancer Research Division at the ICR has uncovered the role of epigenetic changes – which alter how genes work without changing the body’s DNA code – in breast cancer recurrence. The group, led by Professor Luca Magnani, Professor of Epigenetic Plasticity at the ICR, found that specific changes to proteins in chromatin, which is the condensed structure of DNA in cells, can cause oestrogen receptor positive (ER+) breast cancer cells to ‘hibernate’, allowing them to survive treatment. They can then ‘wake up’ years later, causing a relapse that is difficult to treat. The work, which was started at Imperial College London and completed in the Breast Cancer Now Toby Robins Research Centre at the ICR, showed that hormone therapy could trigger these epigenetic changes. By targeting an enzyme called G9a, the scientists were able to block the changes, destroying cells that had already become dormant and preventing other cells from entering this state. This work could support the development of new treatments that prevent breast cancer from recurring following initial treatment for the disease. Return to top Using the cell’s own machinery to destroy a key cancer protein May 2024 A new and innovative technology has successfully been used by ICR scientists to destroy RIPK1, a protein that is crucial for breast cancer cells to remain undetected and survive. Through a process known as targeted protein degradation, the technology – called proteolysis targeting chimera (PROTAC) – eliminates RIPK1, which triggers a particular form of cell death that switches on the immune system and makes it alert to the cancer. Once mobilised, the immune system can destroy any remaining cancer cells that have evaded treatment or become resistant to it. For the pre-clinical study, which was carried out using mouse models, scientists in the Breast Cancer Now Toby Robins Research Centre at the ICR, led by Professor Pascal Meier, collaborated with colleagues at the ICR’s Centre for Cancer Drug Discovery and Centre for Protein Degradation. Their new approach to killing breast cancer cells, which effectively trains the immune system to recognise them, could provide patients with longer lasting protection from the disease. This approach may be effective for a range of cancer types, including triple negative breast cancer, which is known for its high recurrence rate and for being particularly difficult to treat. Reducing the likelihood of disease recurrence, and the associated anxiety, could significantly improve quality of life for people whose initial treatment proves successful. Return to top Making a ‘practice-changing’ discovery that may spare patients from unnecessary treatment May 2024 Professor Chris Parker, Professor of Prostate Oncology at the ICR and Consultant Clinical Oncologist at The Royal Marsden, was chief investigator on the phase III RADICALS-HD trial, which produced findings that might change the standard of care in a certain group of prostate cancer patients. In the trial, the scientists assessed the value of hormone therapy when given alongside radiotherapy following surgery to remove the prostate. A total of 1,480 people with low-risk prostate cancer were randomly assigned to two groups – the first received only postoperative radiotherapy and the second received hormone therapy in addition. After 10 years, the team found that 79 per cent of the people in the first group had survived without their cancer spreading, compared with 80 per cent of those in the second group. This small difference, which could be due merely to chance, demonstrates that hormone therapy provides no significant benefit for this patient group. This means that patients with a lower chance of their cancer returning could be spared from hormone therapy, which can cause a range of side effects, including erectile dysfunction and loss of muscle mass and bone density. Return to top Identifying previously unknown cancer drivers that could aid precision November 2024 A large-scale analysis of whole-genome sequencing data revealed 330 unique genes likely to have a role in driving cancer, 74 of which had not previously been identified. The study, led by Professor Richard Houlston, Head of the Division of Genetics and Epidemiology at the ICR, used data from 10,478 patients spanning 35 cancer types. All these individuals were participating in the 100,000 Genomes Project, a UK initiative to provide an information bank that could help researchers study the role of human genes in various diseases. The researchers looked for common associations between mutations and cancer types to help them identify possible culprit genes. They were able to detect up to 80 per cent of the known driver genes, confirming the validity of their approach. In addition, they identified new cancer driver genes in several cancer types, including uterine, bladder and colorectal. Importantly, the researchers believe that about 55 per cent of patients’ tumours are likely to harbour a mutation that could predict their response to certain treatments. In addition, they estimate that 15 per cent of patients may be eligible for a currently approved therapy targeting known oncogenes, which include HER2 in breast cancer and KRAS in multiple cancer types. Using the information from this study and similar work to inform diagnostic panels could, therefore, help clinicians determine the optimal treatments for patients based on the genetics of their cancer. Return to top