編者按：隨著研發(fā)技術的不斷進步，新一代共價藥物的開發(fā)已成為業(yè)界高度關注的方向。截至目前，已有超過50種共價藥物成功獲批上市，并在多個疾病領域展現(xiàn)出顯著療效。值得關注的是，新一代共價藥物正不斷突破局限，向可逆性共價結(jié)合及靶向半胱氨酸以外氨基酸殘基的方向快速拓展，為攻克“不可成藥”靶點帶來全新契機。依托端到端的CRDMO賦能平臺，藥明康德致力為全球合作伙伴提供覆蓋共價藥物發(fā)現(xiàn)與開發(fā)的一體化解決方案。本文將回顧2025年共價小分子領域的最新進展，并介紹藥明康德在共價藥物發(fā)現(xiàn)領域的技術與能力。

臨床與監(jiān)管進展

2025年，美國FDA共批準四款共價藥物。7月，美國FDA加速批準迪哲醫(yī)藥（Dizal [Jiangsu] Pharmaceutical）研發(fā)的Zegfrovy（sunvozertinib），用于治療攜帶表皮生長因子受體（

EGFR

）第20號外顯子插入突變（exon20ins）的局部晚期或轉(zhuǎn)移性非小細胞肺癌（NSCLC）成人患者。Zegfrovy是一款口服、不可逆、針對多種EGFR突變亞型的高選擇性EGFR酪氨酸激酶抑制劑（TKI），此前已獲FDA授予突破性療法認定，用于全線治療

EGFR

exon20ins NSCLC患者。緊接著在8月，F(xiàn)DA又加速批準勃林格殷格翰（Boehringer Ingelheim）口服、不可逆HER2酪氨酸激酶抑制劑Hernexeos（zongertinib）上市，用于治療腫瘤攜帶HER2酪氨酸激酶結(jié)構(gòu)域（TKD）激活性突變、且已接受過系統(tǒng)治療的不可切除或轉(zhuǎn)移性非鱗狀NSCLC成人患者。同月，賽諾菲（Sanofi）的可逆布魯頓酪氨酸激酶（BTK）共價抑制劑Wayrilz（rilzabrutinib）也獲批用于治療既往治療應答不足的持續(xù)性或慢性免疫性血小板減少癥（ITP）成人患者。隨后在9月，諾華（Novartis）旗下BTK共價抑制劑Rhapsido（remibrutinib）獲FDA批準，用于治療H1抗組胺藥不能充分控制癥狀的慢性自發(fā)性蕁麻疹（CSU）成人患者。

除了新藥獲批之外，今年多款共價小分子藥物也迎來監(jiān)管進展。例如，阿斯利康（AstraZeneca）的BTK共價抑制劑Calquence（acalabrutinib）在1月獲得FDA擴展適應癥批準，可聯(lián)合苯達莫司汀和利妥昔單抗，用于治療不適合自體造血干細胞移植的初治成人套細胞淋巴瘤（MCL）患者。同時，大鵬藥品工業(yè)株式會社（Taiho Pharmaceutical）、Taiho Oncology與Cullinan Therapeutics也在11月底針對其聯(lián)合開發(fā)、靶向EGFR激活性突變體的共價小分子zipalertinib，向美國FDA滾動遞交新藥申請（NDA），用于治療既往接受過含鉑化療、攜帶

EGFR

exon20ins的局部晚期或轉(zhuǎn)移性NSCLC患者。該療法此前已獲FDA授予突破性療法認定。

值得關注的是，自KRAS G12C抑制劑sotorasib和adagrasib獲批以來，共價小分子在攻克癌癥領域“不可成藥”靶點方面的潛力愈發(fā)受到產(chǎn)業(yè)界廣泛重視。2025年，多款KRAS G12C共價抑制劑陸續(xù)獲得FDA授予的突破性療法認定，用于治療NSCLC，其中包括olomorasib、RAS（ON）G12C選擇性抑制劑elironrasib（RMC-6291），以及RAS（OFF）G12C選擇性抑制劑D3S-001。需要說明的是，RAS（ON）與RAS（OFF）分別指RAS分子處于活性與非活性狀態(tài)。

除KRAS G12C之外，其他KRAS靶向共價抑制劑的研發(fā)也在加速推進。例如，RAS（ON）G12D選擇性抑制劑zoldonrasib（RMC-9805）的臨床前研究成果已于今年7月發(fā)表在《科學》雜志上，目前這一療法也已進入臨床階段。公開數(shù)據(jù)顯示，在18例可評估療效、攜帶

KRAS

G12D突變的經(jīng)治NSCLC患者中，其客觀緩解率（ORR）達到61%，疾病控制率（DCR）為89%。此外，Vividion Therapeutics開發(fā)的一款共價抑制劑也在今年10月登上《科學》期刊，該分子可與PI3K p110α共價結(jié)合，從而阻斷RAS對PI3Kα活性的激活。在臨床前實驗中，該藥物可減緩攜帶RAS突變與HER2過表達腫瘤的生長。該療法目前已進入1期臨床試驗階段。

除KRAS外，其他靶點的共價抑制劑研發(fā)同樣持續(xù)推進。例如，評估潛在“best-in-class”口服共價Werner解旋酶抑制劑MOMA-341的1期臨床試驗近日完成首例患者給藥，該研究主要面向具有高微衛(wèi)星不穩(wěn)定性（MSI-H）和/或DNA錯配修復缺陷（dMMR）的晚期或轉(zhuǎn)移性實體瘤患者，包括結(jié)直腸癌、胃癌和子宮內(nèi)膜癌等。同時，由Biomea Fusion開發(fā)的menin共價抑制劑icovamenib也在2期試驗中展現(xiàn)出治療糖尿病的積極信號。在重度胰島素缺乏型糖尿病患者中，即使在停藥9個月（第52周）后，icovamenib仍維持治療獲益，其糖化血紅蛋白（HbA1c）較安慰劑校正后平均下降1.8個百分點。在皮膚病領域，ITK/JAK3雙靶點抑制劑ATI-2138在治療中重度特應性皮炎（AD）的2a期試驗中達到主要及關鍵次要終點，其療效與活性對照藥物相當，并展現(xiàn)出良好安全性，研發(fā)方計劃進一步評估其在斑禿及機制相關疾病中的潛在療效。

研發(fā)合作與融資進展

共價藥物領域的活躍也體現(xiàn)在研發(fā)合作與資本投入上。7月，諾華（Novartis）與Matchpoint Therapeutics達成金額最高約10億美元的獨家選擇權與許可協(xié)議，雙方將合作開發(fā)并商業(yè)化一款靶向炎癥相關轉(zhuǎn)錄因子的口服共價抑制劑。根據(jù)協(xié)議，Matchpoint將依托其Advanced Covalent Exploration（ACE）平臺推進早期研究，直至完成候選化合物篩選。此外，Odyssey Therapeutics也在9月完成2.13億美元融資，計劃通過人工智能及共價化學平臺加速自身免疫疾病新藥研發(fā)。

與此同時，Flagship Pioneering在10月宣布成立歷經(jīng)三年孵化的Expedition Medicines公司，并提供首輪5000萬美元資金支持。該公司專注于構(gòu)建生成式共價化學（generative covalent chemistry）平臺，旨在實現(xiàn)靶向多種疾病相關靶點的小分子藥物發(fā)現(xiàn)，并推進其在腫瘤學、免疫學等領域的項目布局。此外，在Flagship與輝瑞（Pfizer）的戰(zhàn)略合作框架下，Expedition已啟動多靶點探索合作，以識別具有潛力的前列腺癌創(chuàng)新療法。

總體來看，共價抑制劑已從腫瘤領域逐步擴展至免疫、炎癥等多類疾病，其獨特結(jié)合機制、持久活性以及高選擇性特點，正在為多種疾病治療帶來新的可能。隨著技術平臺持續(xù)成熟、產(chǎn)業(yè)協(xié)同不斷深化，這一領域有望在未來數(shù)年迎來更多臨床與商業(yè)化突破。

藥明康德助力加速共價藥物開發(fā)

為幫助全球合作伙伴加速下一代共價藥物的研發(fā)——從早期發(fā)現(xiàn)到IND申報，藥明康德建立了一體化發(fā)現(xiàn)平臺。該平臺融合了三大互補技術：共價DNA編碼化合物庫（cDEL）、共價片段藥物發(fā)現(xiàn)（cFBDD）以及共價高通量篩選（cHTS），為共價藥物發(fā)現(xiàn)提供了高效的解決方案。

cDEL是一項功能強大的篩選技術，能夠高效探索龐大的化學空間，大幅提升發(fā)現(xiàn)多樣化共價分子及其結(jié)合彈頭的可能性。通過將DNA標簽作為“分子條形碼”，該平臺可在僅需極少量蛋白和化合物的條件下，實現(xiàn)快速且具成本效益的苗頭化合物發(fā)現(xiàn)，在化學多樣性至關重要的早期研發(fā)階段尤為突出。

藥明康德的cFBDD平臺則基于一個經(jīng)過嚴格篩選的化合物庫，包含超過2600個結(jié)構(gòu)多樣化的片段。該平臺以小而低復雜度的分子片段為核心，高效探索結(jié)合位點，并通過引入帶有親電基團的片段，快速識別可作為優(yōu)化起點的共價結(jié)合物。結(jié)合高通量質(zhì)譜以及X射線晶體學、核磁共振（NMR）等結(jié)構(gòu)生物學方法，cFBDD能夠在原子水平提供片段–蛋白相互作用的深度洞察，從而支持理性設計與系統(tǒng)優(yōu)化。

藥明康德的cHTS平臺是集合了藥明康德cHTS共價庫和多種篩選方法的高通量篩選平臺。藥明康德的cHTS共價庫約有6萬9千個分子，涵蓋50多種不同類型的共價彈頭，反應活性范圍多樣。這些化合物能夠作用于九類不同的氨基酸殘基，將共價藥物發(fā)現(xiàn)的范圍從半胱氨酸擴展至絲氨酸、賴氨酸以及其他殘基專屬的化合物庫。

在共價藥物篩選平臺之外，藥明康德還建立了一整套早期藥物發(fā)現(xiàn)技術平臺，涵蓋生物物理學、生物化學及細胞學檢測，為全球合作伙伴共價藥物的開發(fā)提供堅實的支持。依托端到端的一體化CRDMO賦能平臺，藥明康德致力于加速突破性療法的開發(fā)，幫助合作伙伴將創(chuàng)新成果高效轉(zhuǎn)化為造福全球患者的解決方案，以踐行“讓天下沒有難做的藥，難治的病”的愿景。

FromScienceto 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 inSciencein 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 inSciencein 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.”

參考資料：

[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

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