Adagrasib

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。本文将回顾2025年共价小分子领域的最新进展，并介绍药明康德在共价药物发现领域的技术与能力。 临床与监管进展 2025年，美国FDA共批准四款共价药物。7月，美国FDA加速批准迪哲医药（Dizal [Jiangsu] Pharmaceutical）研发的Zegfrovy（sunvozertinib），用于治疗携带表皮生长因子受体（EGFR）第20号外显子插入突变（exon20ins）的局部晚期或转移性非小细胞肺癌（NSCLC）成人患者。Zegfrovy是一款口服、不可逆、针对多种EGFR突变亚型的高选择性EGFR酪氨酸激酶抑制剂（TKI），此前已获FDA授予突破性疗法认定，用于全线治疗EGFR exon20ins NSCLC患者。紧接着在8月，FDA又加速批准勃林格殷格翰（Boehringer Ingelheim）口服、不可逆HER2酪氨酸激酶抑制剂Hernexeos（zongertinib）上市，用于治疗肿瘤携带HER2酪氨酸激酶结构域（TKD）激活性突变、且已接受过系统治疗的不可切除或转移性非鳞状NSCLC成人患者。同月，赛诺菲（Sanofi）的可逆布鲁顿酪氨酸激酶（BTK）共价抑制剂Wayrilz（rilzabrutinib）也获批用于治疗既往治疗应答不足的持续性或慢性免疫性血小板减少症（ITP）成人患者。随后在9月，诺华（Novartis）旗下BTK共价抑制剂Rhapsido（remibrutinib）获FDA批准，用于治疗H1抗组胺药不能充分控制症状的慢性自发性荨麻疹（CSU）成人患者。 除了新药获批之外，2025年多款共价小分子药物也迎来监管进展。例如，阿斯利康（AstraZeneca）的BTK共价抑制剂Calquence（acalabrutinib）在1月获得FDA扩展适应症批准，可联合苯达莫司汀和利妥昔单抗，用于治疗不适合自体造血干细胞移植的初治成人套细胞淋巴瘤（MCL）患者。同时，大鹏药品工业株式会社（Taiho Pharmaceutical）、Taiho Oncology与Cullinan Therapeutics也在11月底针对其联合开发、靶向EGFR激活性突变体的共价小分子zipalertinib，向美国FDA滚动递交新药申请（NDA），用于治疗既往接受过含铂化疗、携带EGFR exon20ins的局部晚期或转移性NSCLC患者。该疗法此前已获FDA授予突破性疗法认定。 值得关注的是，自KRAS G12C抑制剂sotorasib和adagrasib获批以来，共价小分子在攻克癌症领域“不可成药”靶点方面的潜力愈发受到产业界广泛重视。2025年，多款KRAS G12C共价抑制剂陆续获得FDA授予的突破性疗法认定，用于治疗NSCLC，其中包括olomorasib、RAS（ON）G12C选择性抑制剂elironrasib（RMC-6291），以及RAS（OFF）G12C选择性抑制剂D3S-001。需要说明的是，RAS（ON）与RAS（OFF）分别指RAS分子处于活性与非活性状态。 除KRAS G12C之外，其他KRAS靶向共价抑制剂的研发也在加速推进。例如，RAS（ON）G12D选择性抑制剂zoldonrasib（RMC-9805）的临床前研究成果已于2025年7月发表在《科学》杂志上，目前这一疗法也已进入临床阶段。公开数据显示，在18例可评估疗效、携带KRAS G12D突变的经治NSCLC患者中，其客观缓解率（ORR）达到61%，疾病控制率（DCR）为89%。此外，Vividion Therapeutics开发的一款共价抑制剂也在2025年10月登上《科学》期刊，该分子可与PI3K p110α共价结合，从而阻断RAS对PI3Kα活性的激活。在临床前实验中，该药物可减缓携带RAS突变与HER2过表达肿瘤的生长。该疗法目前已进入1期临床试验阶段。 除KRAS外，其他靶点的共价抑制剂研发同样持续推进。例如，评估潜在“best-in-class”口服共价Werner解旋酶抑制剂MOMA-341的1期临床试验近日完成首例患者给药，该研究主要面向具有高微卫星不稳定性（MSI-H）和/或DNA错配修复缺陷（dMMR）的晚期或转移性实体瘤患者，包括结直肠癌、胃癌和子宫内膜癌等。同时，由Biomea Fusion开发的menin共价抑制剂icovamenib也在2期试验中展现出治疗糖尿病的积极信号。在重度胰岛素缺乏型糖尿病患者中，即使在停药9个月（第52周）后，icovamenib仍维持治疗获益，其糖化血红蛋白（HbA1c）较安慰剂校正后平均下降1.8个百分点。在皮肤病领域，ITK/JAK3双靶点抑制剂ATI-2138在治疗中重度特应性皮炎（AD）的2a期试验中达到主要及关键次要终点，其疗效与活性对照药物相当，并展现出良好安全性，研发方计划进一步评估其在斑秃及机制相关疾病中的潜在疗效。 研发合作与融资进展 共价药物领域的活跃也体现在研发合作与资本投入上。7月，诺华（Novartis）与Matchpoint Therapeutics达成金额最高约10亿美元的独家选择权与许可协议，双方将合作开发并商业化一款靶向炎症相关转录因子的口服共价抑制剂。根据协议，Matchpoint将依托其Advanced Covalent Exploration（ACE）平台推进早期研究，直至完成候选化合物筛选。此外，Odyssey Therapeutics也在9月完成2.13亿美元融资，计划通过人工智能及共价化学平台加速自身免疫疾病新药研发。 与此同时，Flagship Pioneering在10月宣布成立历经三年孵化的Expedition Medicines公司，并提供首轮5000万美元资金支持。该公司专注于构建生成式共价化学（generative covalent chemistry）平台，旨在实现靶向多种疾病相关靶点的小分子药物发现，并推进其在肿瘤学、免疫学等领域的项目布局。此外，在Flagship与辉瑞（Pfizer）的战略合作框架下，Expedition已启动多靶点探索合作，以识别具有潜力的前列腺癌创新疗法。 总体来看，共价抑制剂已从肿瘤领域逐步扩展至免疫、炎症等多类疾病，其独特结合机制、持久活性以及高选择性特点，正在为多种疾病治疗带来新的可能。随着技术平台持续成熟、产业协同不断深化，这一领域有望在未来数年迎来更多临床与商业化突破。 药明康德助力加速共价药物开发 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。 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。 药明康德的cFBDD平台则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。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。 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。 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。 From Science to Breakthrough Therapy Designation: Covalent Small Molecules Broaden the Innovation Landscape in 2025 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. Here, we summarize key developments in the covalent small molecules space in 2025 and highlight WuXi AppTec’s capabilities and strengths in enabling innovation in covalent drug discovery. Clinical and Regulatory Progress In 2025, the U.S. FDA approved four covalent medicines. In July, the FDA granted accelerated approval to Zegfrovy (sunvozertinib), developed by Dizal (Jiangsu) Pharmaceutical, for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion (exon20ins) mutations. Zegfrovy is an oral, irreversible, and highly selective EGFR tyrosine kinase inhibitor (TKI) designed to target multiple EGFR mutation subtypes. The therapy had previously received Breakthrough Therapy Designation (BTD) from the FDA for the treatment of EGFR exon20ins NSCLC across all lines of therapy. This was followed in August by the FDA’s accelerated approval of Boehringer Ingelheim’s Hernexeos (zongertinib), an oral irreversible HER2 tyrosine kinase inhibitor, for the treatment of adult patients with unresectable or metastatic non-squamous NSCLC whose tumors harbor activating HER2 tyrosine kinase domain (TKD) mutations and who have received prior systemic therapy. Also in August, Sanofi’s reversible covalent Bruton’s tyrosine kinase (BTK) inhibitor Wayrilz (rilzabrutinib) was approved for the treatment of adult patients with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to prior therapy. In September, Novartis received FDA approval for Rhapsido (remibrutinib), a BTK covalent inhibitor indicated for adult patients with chronic spontaneous urticaria (CSU) who remain symptomatic despite H1-antihistamine treatment. Beyond new approvals, multiple covalent small-molecule therapies also advanced through regulatory milestones during the year. For example, AstraZeneca’s BTK covalent inhibitor Calquence (acalabrutinib) received an expanded FDA indication in January for use in combination with bendamustine and rituximab to treat adult patients with previously untreated mantle cell lymphoma (MCL) who are not candidates for autologous stem cell transplantation. In addition, Taiho Pharmaceutical, Taiho Oncology, and Cullinan Therapeutics initiated rolling submission of New Drug Application (NDA) to the FDA in late November for zipalertinib, a jointly developed covalent small molecule targeting activated EGFR mutations. The filing seeks approval for the treatment of locally advanced or metastatic NSCLC harboring EGFR exon20ins mutations in patients previously treated with platinum-based chemotherapy. The therapy had earlier been granted BTD by the FDA. Importantly, since the approvals of sotorasib and adagrasib targeting KRAS G12C mutations, covalent small molecules have gained increasing industry recognition for their potential to address historically “undruggable” cancer targets. In 2025, several KRAS G12C covalent inhibitors have received BTD for NSCLC, including olomorasib, the RAS (ON) G12C-selective inhibitor elironrasib (RMC-6291), and the RAS (OFF) G12C-selective inhibitor D3S-001. Notably, “RAS(ON)” and “RAS (OFF)” refer to active and inactive conformational states of the RAS protein. Beyond KRAS G12C, development of KRAS-targeted covalent inhibitors continues to accelerate. For example, preclinical findings for the RAS (ON) G12D-selective inhibitor zoldonrasib (RMC-9805) were published in Science in July, and the therapy has now advanced into clinical development. Data published to date show that among 18 evaluable, previously treated NSCLC patients harboring KRAS G12D mutations, the objective response rate (ORR) reached 61%, with a disease control rate (DCR) of 89%. In addition, a covalent inhibitor developed by Vividion Therapeutics was also featured in Science in October. The molecule covalently binds PI3K p110α, thereby blocking RAS-mediated activation of PI3Kα. In preclinical testing, the therapy demonstrated tumor growth inhibition in models harboring RAS mutations and HER2 overexpression, and it has now entered Phase 1 clinical development. Progress is also being seen across other covalent drug targets. A Phase 1 clinical study evaluating MOMA-341, an investigational oral covalent Werner helicase inhibitor with best-in-class potential, completed first-patient dosing. The trial is enrolling patients with advanced or metastatic solid tumors characterized by high microsatellite instability (MSI-H) and/or mismatch repair deficiency (dMMR), including colorectal, gastric, and endometrial cancers. Meanwhile, menin covalent inhibitor icovamenib, developed by Biomea Fusion, has demonstrated encouraging clinical activity in Type 2 diabetes during Phase 2 evaluation. Among patients with severe insulin-deficient diabetes, icovamenib continued to deliver clinical benefit even nine months (Week 52) after treatment cessation, achieving a placebo-adjusted mean HbA1c reduction of 1.8%. In dermatology, the dual ITK/JAK3 inhibitor ATI-2138 achieved its primary and key secondary endpoints in a Phase 2a study in moderate-to-severe atopic dermatitis (AD). The therapy demonstrated efficacy comparable to active control with a favorable safety profile, and the developer plans further evaluation in alopecia areata and other mechanistically related diseases. R&D Collaboration & Financing Progress Industry interest in covalent medicines is also reflected in partnership and investment activity. In July, Novartis and Matchpoint Therapeutics entered into an exclusive option and license agreement valued at up to approximately $1 billion to jointly develop and commercialize an oral covalent inhibitor targeting a transcription factor implicated in multiple inflammatory diseases. Under the agreement, Matchpoint will leverage its Advanced Covalent Exploration (ACE) platform to progress early-stage discovery through candidate selection. In September, Odyssey Therapeutics announced completion of a $213 million financing round to advance new medicines for autoimmune diseases powered by artificial intelligence and covalent chemistry platforms. Meanwhile, in October, Flagship Pioneering unveiled Expedition Medicines — a company incubated over three years — and provided an initial $50 million investment. Expedition is building a generative covalent chemistry platform designed to enable small-molecule discovery across a wide spectrum of disease-relevant targets, while advancing programs in oncology, immunology, and other defined diseases. In addition, under Flagship’s strategic collaboration framework with Pfizer, Expedition has initiated a multi-target discovery partnership aimed at identifying novel therapeutic candidates for prostate cancer. Overall, covalent inhibitors continue to expand beyond oncology into immune-mediated and inflammatory disease settings. Their unique binding mechanisms, durable activity, and high selectivity are opening new therapeutic possibilities across multiple indications. As enabling technologies mature and cross-industry collaboration deepens, the field is expected to see further clinical and commercial breakthroughs in the years ahead. WuXi AppTec Empowers the Development of Covalent Drugs 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. 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. WuXi AppTec’s cFBDD platform builds on a rigorously curated library of more than 2,600 structurally diverse fragments. 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 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. 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： [1] Vividion Announces Publication in Science of Preclinical Data on Covalent Inhibitors of RAS-PI3K that Block Tumor Growth. Retrieved December 24, 2025 from https://vividion.com/news/vividion-announces-publication-in-science-of-preclinical-data-on-covalent-inhibitors-of-ras-pi3k-that-block-tumor-growth/ [2] Biomea Fusion Announces Positive 52-Week Results from Phase II COVALENT-111 Study in Type 2 Diabetes Demonstrating Non-Chronic Treatment with Icovamenib Benefits Two Distinct Patient Populations. Retrieved December 24, 2025 from https://www.globenewswire.com/news-release/2025/10/06/3162080/0/en/Biomea-Fusion-Announces-Positive-52-Week-Results-from-Phase-II-COVALENT-111-Study-in-Type-2-Diabetes-Demonstrating-Non-Chronic-Treatment-with-Icovamenib-Benefits-Two-Distinct-Patie.html [3] Flagship Pioneering Unveils Expedition Medicines to Expand the Boundaries of Small Molecule Medicines with Generative Design. Retrieved December 24, 2025 from https://www.prnewswire.com/news-releases/flagship-pioneering-unveils-expedition-medicines-to-expand-the-boundaries-of-small-molecule-medicines-with-generative-design-302590755.html 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