Ibrutinib

SMMT昨天官宣要在25年底前递交BLA，但股价却跌了4.5%。看看这波股价攻防战-中国散户vs华尔街的经典战役。 再看看SMMT股价，不由得心疼散户一秒： 宣布递交BLA本是好事，但市场居然用盘前-10%来响应，明明Harmoni-6的三期很棒啊。很多散户不信邪，这才有了上面那边股价攻防战。 给大家一个建议：看好AK112，那就直接买入康方>>>买入SMMT。 理由一、性价比 虽然AK112的海外预期在康方估值占比过半，也就是说SMMT与康方的长期走势非常相关。 但是康方更有性价比：1100亿港币的康方与150亿美金的SMMT，前者是真正的原研，还有其他双抗和ADC管线，还附赠一年近30亿销售额。 康方风险更低：SMMT的下限是最后没找到买家，自己筹措资金去销售，到时候怎么撑得住150亿美金估值？ 在美股150亿美金的biotech要么研发平台强、有爆款潜力的晚期产品，要么已经有很好的销售额。没有并购预期的SMMT，潜在跌幅很大，这点很多SMMT粉并没有考虑到。 而康方的下限是虽然没有MNC出手，但有个SMMT去卖货，甭管咋地，总是能赚。downside小太多了。 理由二、300亿卖身的可能性，很低 很低 很多SMMT粉期待的是公司被收购，立刻赚个100%，其实你抱着这个心态，不如去买Revolution。 粉丝们的自信源于觉得华尔街看不懂康方的中国数据，而自己有China angel，其实华尔街前年、去年确实有错判，但别人学习能力强。在康方一路上涨后，他们现在看的比谁都明白。 粉丝们觉得SMMT可以复制PCYC 210亿美金的收购奇迹，作为PCYC当时交易的亲历者，小越只能给大家说：假设PCYC的M&A交易难度是10，那么SMMT的难度就是60-100。 原因很简单，10年前的制药届，竞争卷度和现在根本没法比。美国的biotech原来最大的卖点就是：自己做自己的药，没啥人跟，死了就死了，一旦做成就是独家，买方别无选择。 伊布替尼在2015年被收购，收购前不到2年时间，获批了四个适应症的NDA，竞争对手大概也就阿卡替尼（而且比它晚了4年整获批）。 这样的低竞争蓝海市场，才是210亿美金收购的最大推手。很多人在推SMMT时会说FIC>BIC的逻辑，但这个逻辑源头的销售数据已经过时，很大程度上失效了。 现在的创新药，FIC市场份额不一定大于BIC，就算大，也大不了多少，因为竞争过于激烈，FIC的市场独占期大大减少了。BCMA=CAR-T、ADC（trop2）等赛道，都证明了这点。 在FIC优势没那么显著的情况下，凭借一款大药，卖200-300亿美金的交易，难度非常大。 现在的PD-1/VEGF，你可以说MSD买了礼新不一定会快推，BMS和Pfizer呢？都是重金出手，都很想增强I/O领域。 除此外，国内还有4-5家非常愿意出售的同类分子，进度/价格都不错。在全球地缘政治风险大增的今天，让药企出200-300亿现金买一个领先2年-3年的分子，CEO不干了，董事会疯了? 别说SMMT了，就算PCYC面对这个格局，也很难卖。过往的成功，和现在的成功，根本不是一码事。 理由三、薛定谔的BLA 经过一次又一次的迷惑公告，SMMT的信誉现在大家都懂，前面说FDA要求OS统计性差异是必要条件（necessary），现在又说自己为了患者利益考虑，还是决定递交BLA。又当又立典型！ 哪里是为了患者考虑，是为了自己的money。有不少韭菜心甘情愿的认为：老杜这么有把握去递交BLA，那肯定是和FDA沟通过，FDA肯定默许拉？ Excuse me？照你这么说，Harmoni-3两次重大变更临床入组方案，也都是FDA点头啦。当然不是，请你了解下美国的监管体系。 如果人人都学SMMT这么搞三期，没事就扩组+单独做不同亚组的重点统计，把1个III期搞成2个。这么有样学样下去，全美III期实验数量可以减半。 与其辛辛苦苦找新的site、涉及新方案、重走一遍注册临床，不如学SMMT直接在已有III期里扩组、扩亚群、改统计方案嘛。 动动脑子想想，SMMT的这些临床策略是多么取巧，你确定FDA都同意了？ 可以肯定的是：现在这个BLA是否能批，市场上没有任何人可以预测，属实是薛定谔的BLA。老杜也不能预测，千万别对创始人造神，别崇拜减持-别对公司有感情 现在的创新药赛道全部是卷王，别迷信老登。老登他们唯一能赢的地方是够老。现在的中生代都是红海里杀出来，他们回到老登所在的10-20年前，能够轻松碾压老登。 虽然康方上次高位减持的操作也很骚（明显提前知道数据），比起SMMT老登的信誉，还是好上太多。 如果你真的喜欢SMMT，可以卖掉仓位补康方。。。别再去听SMMT电话会、看会议纪要了，老登的油嘴滑舌你要是都能看透，早就纵横资本市场了，还在这买创新药?属实是越研究越贫穷。 投资创新药，欢迎加入越学习越贫穷知识星球，从此不再被忽悠。定期分享上市公司点评、职场、投资避坑。欢迎优秀生物医药公司合作。 公众号右上角点击：设为星标。越学习越贫穷，一个只说真话的公众号，加群添加wx：yuexuexiyuepinqiong

编者按：随着研发技术的不断进步，新一代共价药物的开发已成为业界高度关注的方向。截至目前，已有超过50种共价药物成功获批上市，并在多个疾病领域展现出显著疗效。值得关注的是，新一代共价药物正不断突破局限，向可逆性共价结合及靶向半胱氨酸以外氨基酸残基的方向快速拓展，为攻克“不可成药”靶点带来全新契机。依托端到端的CRDMO赋能平台，药明康德致力为全球合作伙伴提供覆盖共价药物发现与开发的一体化解决方案。本文将重点介绍药明康德在共价药物发现领域的技术与能力。 共价药物作为现代药物研发的重要方向，正在不断拓展治疗的边界。早在上世纪，阿司匹林和青霉素的成功已充分证明了共价药物在临床中的重要价值。与传统非共价抑制剂不同，共价药物通过与靶点形成稳定的化学键，实现持久的抑制效果。凭借这一独特机制，共价药物不仅能够以更低的剂量给药，还可显著提升靶点占有率，展现出极具潜力的广阔临床应用前景。 根据结合特性的不同，共价药物可分为不可逆与可逆两类：前者如青霉素，能够形成长期抑制作用；后者如硼替佐米（bortezomib），在结合过程中仍具备一定的可逆性，从而兼具疗效的持续性与可调控性。在过去十年里，共价药物进入了快速发展阶段。截至2024年，已有超过50款共价药物获FDA批准上市。这些药物已广泛应用于癌症、病毒感染、遗传性疾病及心血管疾病等多个治疗领域。其中，BTK抑制剂伊布替尼（ibrutinib）与EGFR抑制剂阿法替尼（afatinib）是首批通过理性设计问世的共价抑制剂。它们的成功不仅再次证明了共价结合的临床潜力，也确立了一种重要的开发策略——在已有可逆性结合分子的骨架上，引入能够与靶点形成共价键的化学基团，从而显著增强药物活性与选择性。 在这一策略之外，KRAS G12C抑制剂sotorasib和adagrasib的诞生，展现了共价药物研发理念转变的临床实践。面对长期被视为“不可成药”的KRAS靶点，研究人员突破性地采用直接筛选策略，寻找能够与KRAS突变体半胱氨酸快速形成共价键的小分子化合物。这一方法不同于以往依赖修饰现有非共价分子的模式，而是开创性地针对全新靶点的突变位点进行共价结合与优化，最终推动了首批KRAS靶向疗法的问世，标志着共价药物研发正从传统分子改造迈向更具前瞻性的靶点创新。 与此同时，新一代共价药物在提升选择性的同时，其研发也正逐步拓展至更广泛的靶点范围。传统聚焦于半胱氨酸的策略，正逐步拓展至赖氨酸、丝氨酸、苏氨酸及酪氨酸等非半胱氨酸残基，并通过引入新型共价弹头（warhead）结构，实现更高的特异性与更低的脱靶风险。这一创新路径不仅有望进一步提升药物的安全性和疗效，也为众多长期被视为“难以成药”的靶点开辟了全新解决方案，从而为更多疾病患者带来切实的临床获益。 为帮助全球合作伙伴加速下一代共价药物的研发——从早期发现到IND申报，药明康德建立了一体化发现平台。该平台融合了三大互补技术：共价DNA编码化合物库（cDEL）、共价片段药物发现（cFBDD）以及共价高通量筛选（cHTS），为共价药物发现提供了高效的解决方案。 ▲药明康德共价药物发现能力 cDEL是一项功能强大的筛选技术，能够高效探索庞大的化学空间，大幅提升发现多样化共价分子及其结合弹头的可能性。通过将DNA标签作为“分子条形码“，该平台可在仅需极少量蛋白和化合物的条件下，实现快速且具成本效益的苗头化合物发现，在化学多样性至关重要的早期研发阶段尤为突出。凭借灵活的筛选策略，药明康德的cDEL平台拥有可逆与不可逆的共价结合物库，筛选后通过测序解码、再合成以及严格的DNA连接与非DNA连接检测方法进行系统验证。为满足不同合作伙伴的研发需求，药明康德提供两种不可逆共价药物筛选模式：DELink Pro——涵盖16亿化合物和184种专门设计的共价弹头，并提供独特且可定制的一步式解决方案；以及DELinkLite——包含超过1400万化合物的精简平台，可为客户提供更便捷的数据获取与利用。 ▲药明康德共价DEL库介绍 药明康德的cFBDD平台基于一个经过严格筛选的化合物库，包含超过2600个结构多样化的片段，每个片段均按照“三规则”设计（即药物片段的分子量应不超过300 Da，cLogP不大于3，且氢键供体或受体的数量不超过3，以确保其分子保持小巧、具备良好溶解性），以确保理化性质与化学多样性的优化。该平台以小而低复杂度的分子片段为核心，高效探索结合位点，并通过引入带有亲电基团的片段，快速识别可作为优化起点的共价结合物。结合高通量质谱以及X射线晶体学、核磁共振（NMR）等结构生物学方法，cFBDD能够在原子水平提供片段–蛋白相互作用的深度洞察，从而支持理性设计与系统优化。该片段库无化学反应性与稳定性问题，且具备良好的可合成性。凭借结构精度、快速周期与高效的苗头至先导化合物转化，cFBDD已成为推动新型共价先导分子的重要工具，尤其适用于挑战性靶点或传统意义上“不可成药”的靶点。 ▲共价片段药物发现平台筛选流程 药明康德的cHTS平台是集合了药明康德cHTS共价库和多种筛选方法的高通量筛选平台。药明康德的cHTS共价库约有6万9千个分子，涵盖50多种不同类型的共价弹头，反应活性范围多样。这些化合物能够作用于九类不同的氨基酸残基，将共价药物发现的范围从半胱氨酸扩展至丝氨酸、赖氨酸以及其他残基专属的化合物库。由于这些替代性残基在蛋白中更为丰富，并具备环境特异性的反应活性，该化合物库不仅能够拓展潜在的治疗靶点空间，还有望提升药物选择性并减少脱靶作用。 cHTS平台可以提供多种筛选方法：作为共价药物发现中最成熟的方法之一，功能性实验支持的高通量筛选能够直接在酶学或细胞系统中测试大量含亲电基团的分子，快速生成功能性数据，以确认化合物的真实抑制活性。同时高通量质谱筛选可以快速直接检出靶点分子量位移，以确认化合物的实际结合。这确保了所识别的苗头化合物具备下游优化和临床开发的理想特性，为后续药物研发奠定坚实基础。同时药明康德的cHTS平台提供多种正交苗头化合物验证，可以为从苗头到先导保驾护航。整合了高通量化学的cHTS平台同时提供D2B解决方案。D2B解决方案包括了快速合成和快速检测，为苗头化合物扩展提供支持。药明康德的cHTS共价平台不只是一个单一的筛选平台，而是同时可以为苗头化合物发现和从苗头到先导提供全方位支持。 ▲药明康德共价HTS库介绍 除了作为抑制剂之外，共价药物也在新兴疗法中展现出日益广阔的应用前景，尤其是在诱导邻近（induced proximity）领域。例如，通过发现能够作用于E3泛素连接酶的共价招募分子，研究人员有望进一步拓展靶向蛋白降解（TPD）的作用范围。与此同时，针对OTUB1的共价招募分子的发现，推动了去泛素化酶靶向嵌合体（DUBTAC）平台的建立，该平台能够稳定囊性纤维化（CF）患者中的突变型CFTR蛋白，从而为这一严重遗传疾病提供了全新的治疗方向。可见，共价分子的应用价值已远不止于抑制作用，而是逐渐延伸至多维度的治疗策略，为创新药物研发开辟了更广阔的发展空间。 在共价药物筛选平台之外，药明康德还建立了一整套早期药物发现技术平台，涵盖生物物理学、生物化学及细胞学检测，为全球合作伙伴共价药物的开发提供坚实的支持。依托端到端的一体化CRDMO赋能平台，药明康德致力于加速突破性疗法的开发，帮助合作伙伴将创新成果高效转化为造福全球患者的解决方案，以践行“让天下没有难做的药，难治的病”的愿景。 Redefining the Undruggable: Covalent Therapies Driving a New Era for Small Molecules With advances in biopharmaceutical research and development, next-generation covalent drugs have emerged as a major focus across the industry. To date, more than 50 covalent drugs have been approved for clinical use, demonstrating substantial value across a broad range of therapeutic areas. Importantly, these next-generation therapies are advancing toward reversible covalent binding and targeting amino acid residues beyond cysteine, thereby opening new possibilities for addressing previously “undruggable” targets. Leveraging its fully integrated, end-to-end CRDMO enabling platform, WuXi AppTec provides global partners with comprehensive solutions for covalent drug discovery and development. This article highlights WuXi AppTec’s capabilities and strengths in enabling innovation in covalent drug discovery. Covalent drugs have become a powerful force in modern drug discovery, continuously expanding the boundaries of therapeutic innovation. As early as the last century, aspirin, with its well-recognized anti-inflammatory and analgesic effects, and penicillin, the first antibiotic effective against a wide range of bacterial infections, demonstrated the immense clinical value of covalent interactions. Unlike traditional non-covalent inhibitors, covalent drugs form stable chemical bonds with their targets, enabling durable inhibition. This unique mechanism allows for lower dosing requirements and higher target occupancy, underscoring their broad potential in clinical applications. Based on their binding characteristics, covalent drugs can be classified into irreversible and reversible categories. Irreversible inhibitors, such as penicillin, provide long-lasting suppression, while reversible covalent drugs like bortezomib retain a degree of flexibility, balancing durability with tunability. Over the past decade, covalent drugs have entered a phase of rapid growth. By 2024, more than 50 covalent drugs had been approved for clinical use across a wide range of therapeutic areas, including oncology, infectious diseases, genetic disorders, and cardiovascular conditions. Among them, ibrutinib (a BTK inhibitor) and afatinib (an EGFR inhibitor) were the first rationally designed covalent inhibitors. Their success not only reaffirmed the clinical value of covalent bonding but also established a key development strategy: introducing covalent warheads into reversible scaffolds to significantly enhance potency and selectivity. Beyond this strategy, the approval of KRAS G12C inhibitors sotorasib and adagrasib represents a landmark in the clinical application of a new paradigm in covalent drug discovery. Confronting KRAS—a target long regarded as “undruggable”—researchers adopted a direct-screening strategy to identify small molecules capable of rapidly forming covalent bonds with the mutant cysteine residue. Unlike traditional approaches that relied on modifying existing non-covalent scaffolds, this method focused directly on the mutation site to achieve covalent binding and the optimization of molecules against a new target. This signaled a forward-looking shift in covalent drug discovery from conventional molecular modification to innovative, target-driven design. At the same time, next-generation covalent drugs are progressing rapidly toward improved selectivity. In parallel, they are being developed to address an increasingly broad spectrum of therapeutic targets. While earlier strategies largely focused on cysteine residues, new approaches are expanding to lysine, serine, threonine, and tyrosine. By incorporating novel covalent warhead chemistries, these strategies aim to achieve higher specificity with reduced off-target risk. This innovative path not only promises to improve the safety and efficacy of covalent therapies but also offers new solutions for protein targets once deemed intractable—ultimately delivering tangible clinical benefits to patients across a wide range of diseases. To help global partners accelerate the development of next-generation covalent drugs, from early discovery through IND-enabling studies, WuXi AppTec has established an integrated platform. By combining three complementary, state-of-the-art technologies—covalent DNA-Encoded Library (cDEL), covalent Fragment-Based Drug Discovery (cFBDD), and covalent High-Throughput Screening (cHTS)—the platform provides a highly efficient solution to advance covalent drug discovery. ▲WuXi AppTec’s capabilities in covalent drug discovery cDEL is a powerful screening technology that enables the efficient exploration of vast chemical libraries, greatly increasing the likelihood of identifying covalent binders with diverse warheads. Leveraging DNA tags as molecular barcodes, the platform allows rapid and cost-effective deconvolution of hits while requiring only minimal quantities of protein and compound. This makes it particularly valuable in the early discovery stage, where broad chemical diversity is essential. Through tailored selection strategies, WuXi AppTec’s cDEL platform uncovers both reversible and irreversible covalent hits, which are further validated through decoding, resynthesis, and rigorous on-DNA and off-DNA assays. To meet diverse partner needs, WuXi AppTec offers two models for irreversible covalent drug screening: DELink Pro, an exclusive, customizable solution featuring a comprehensive library of 1.6 billion compounds and 184 specialized warheads; and DELink Lite, a streamlined option with more than 14 million compounds that provides clients with enhanced access to screening data. ▲Introduction of WuXi AppTec's cDEL WuXi AppTec’s cFBDD platform builds on a rigorously curated library of more than 2,600 structurally diverse fragments, each designed under the “rule of three (Ro3)” to ensure optimal physical properties and chemical diversity. (Ro3 holds that drug fragments should be ≤300 Da, cLogP ≤3, and carry no more than 3 hydrogen bond donors or acceptors to remain small, soluble, and readily optimized.) By focusing on small, low-complexity molecules, the platform efficiently probes binding sites and, through the incorporation of electrophilic fragments, identifies covalent hits that serve as highly effective starting points for optimization. Leveraging high-throughput mass spectrometry together with structural biology methods such as X-ray crystallography and NMR, cFBDD provides atomic-level insights into fragment–protein interactions, enabling rational design and systematic growth of covalent inhibitors. The fragment library is free from reactivity and stability issues, remains synthetically accessible, and delivers high-quality data with speed and precision. The combination of structural precision, rapid turnaround, and efficient hit-to-lead progression makes cFBDD a powerful approach for advancing novel covalent leads, particularly against the most challenging or traditionally “undruggable” targets. ▲Covalent FBDD workflow The cHTS platform from WuXi AppTec is a platform that incorporates various screening strategies. The covalent HTS library has approximately 69,000 covalent molecules featuring more than 50 distinct warhead chemotypes across a range of reactivities. Our library is purpose-built to engage with nine different amino acid residues, extending covalent drug discovery beyond cysteine to include serine-, lysine-, and other residue-focused libraries. Because these alternative residues are more abundant in proteins and exhibit environment-specific reactivity, the platform provides access to previously undruggable proteins while improving selectivity and reducing off-target interactions.  The cHTS platform provides different screening methods. The functional-assay-based high-throughput screening, as one of the most established approaches in covalent drug discovery, can test extensive collections of electrophile-containing molecules directly in enzymatic or cellular systems; Mass-Spectrometry-based high-throughput screening can test the molecular weight shifter upon covalent drug binding. These enable rapid generation of functional readouts or mass readouts that confirm actual inhibitory or binding activity, ensuring identification of hits that possess favorable properties for further optimization and clinical development. The cHTS platform can also provide a wide variety of assay for orthogonal hit confirmation, which can transfer the screening hits to confirmed hits. By integrating High-Throughput Chemistry (HTC), the cHTS platform offers a D2B solution that unites fast synthesis and quick-turnaround testing to speed hit expansion. More than a screening engine, cHTS supports the full workflow from Hit ID through Hit-to-Lead. ▲WuXi AppTec’s covalent compound library Beyond functioning as inhibitors, covalent drugs are demonstrating increasingly broad potential in emerging therapeutic approaches, particularly in the field of induced proximity. For example, the discovery of covalent recruiters for E3 ubiquitin ligases has the potential to expand the scope of targeted protein degradation (TPD). At the same time, the identification of covalent recruiters for OTUB1 has led to the development of the deubiquitinase-targeting chimera (DUBTAC) platform, which can stabilize mutant CFTR proteins in patients with cystic fibrosis (CF), offering a new therapeutic direction for this severe genetic disease. Therefore, the value of covalent molecules extends far beyond inhibition, gradually evolving into multidimensional therapeutic strategies that open broader possibilities for innovative drug discovery. Complementing its advanced screening capabilities, WuXi AppTec offers a comprehensive suite of early discovery technology platforms—including biophysical, biochemical, and cellular assays—to support global partners in advancing covalent drug development. Backed by an integrated, end-to-end CRDMO enabling platform, WuXi AppTec is committed to accelerating the development of transformative therapies that deliver meaningful benefits to patients worldwide—fulfilling its vision that “Every drug can be made and every disease can be treated.” 参考资料（可上下滑动查看） [1] Discovery of a Novel Covalent Inhibitor using DNA Encoded Library. Retrieved August 18, 2025, from https://discoverybiology.wuxiapptec.com/public-api/resource/preview?resourceId=54202208 [2] Progressive Covalent DEL in WuXi. Retrieved August 18, 2025, from https://discoverybiology.wuxiapptec.com/public-api/resource/preview?resourceId=54202205 [3] Covalent Drug Discovery. Retrieved August 18, 2025, from https://discoverybiology.wuxiapptec.com/public-api/resource/preview?resourceId=54202180 [4] 百年应用历史却被“有意回避”，这种药物开发策略如今能攻克不可成药靶点吗？Retrieved August 18, 2025, from https://mp.weixin.qq.com/s?__biz=MzAwMDA5NTIxNQ==&mid=2650031219&idx=1&sn=5bc46ed3b8cbcaeb66f8d9fea5753b4b&chksm=82eec2f3b5994be5fa330dd8dd877cd24597710394dfdc248a5f0a3466e08493b26b9c94bcab#rd [5] 小分子药物的复兴：站在新时代的前沿. Retrieved August 18, 2025, from https://mp.weixin.qq.com/s?__biz=MzAwMDA5NTIxNQ==&mid=2650077742&idx=1&sn=ce33194f2842a8abcf946c497713bbaf&chksm=82ee7caeb599f5b89b311f5ba5d271669253e62d7fb6804bf8b172f918cbda8e4f5565ce3da0#rd [6] Hameed et al., (2024). Advancements, challenges, and future frontiers in covalent inhibitors and covalent drugs: A review. European Journal of Medicinal Chemistry Reports, https://doi-org.libproxy1.nus.edu.sg/10.1016/j.ejmcr.2024.100217 [7] Strategies for Screening and Characterizing Targeted Covalent Inhibitors from Discovery to IND. Retrieved August 21, 2025 from https://www.genengnews.com/multimedia/webinars/strategies-for-screening-and-characterizing-targeted-covalent-inhibitors-from-discovery-to-ind/ 免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，传递医学新知