PH-762

编者按：寡核苷酸药物是全球新药开发的重要热点，近年来在罕见病等多个领域得到快速应用。当前，全球共有超过300款寡核苷酸疗法管线已进入临床开发阶段，未来有望造福更多病患。为帮助合作伙伴更高效地推动寡核苷酸药物从实验室走向临床，药明康德化学业务旗下WuXi TIDES平台围绕寡核苷酸、多肽及其相关化学偶联药物建立了一体化解决方案，覆盖定制合成、共价偶联、工艺开发和CMC等关键环节，赋能创新项目加速进入临床阶段。本文将回顾2025年第三季度寡核苷酸领域的最新进展，并介绍药明康德的一体化CRDMO平台如何高效助力该领域药物的开发。 寡核苷酸疗法在罕见病领域获得持续进展 寡核苷酸疗法正成为突破罕见病治疗的重要力量。2025年第三季度，寡核苷酸疗法也持续迎来多项进展。美国FDA在8月批准反义寡核苷酸配体偶联（LICA）药物Dawnzera（donidalorsen），用于预防12岁及以上成人和儿童患者的遗传性血管性水肿（HAE）发作。根据新闻稿，Dawnzera是获批用于HAE的首个RNA靶向药物。欧盟（EU）则在9月批准反义寡核苷酸（ASO）疗法Tryngolza（olezarsen）作为饮食控制的辅助疗法，用于治疗经遗传学确认的家族性乳糜微粒血症（FCS）成人患者。值得一提的是，该疗法用于治疗重度高甘油三酯血症（sHTG）的3期试验也在同月迎来积极结果，每月一次的olezarsen使患者的空腹甘油三酯相较安慰剂平均降低72%，急性胰腺炎事件减少85%。由此可见，起初定位于罕见病的寡核苷酸疗法，具潜力拓展应用于非罕见疾病治疗。 此外，补体C5靶向siRNA疗法cemdisiran，在用以治疗成人全身性重症肌无力（gMG）的NIMBLE临床3期试验中达到试验终点。分析显示，每三个月皮下注射一次的cemdisiran单药显示出平均74%的补体活性抑制，而cemdisiran与C5抗体pozelimab的联合疗法则达成近99%的补体活性抑制。与此同时，ASO疗法zilganersen也在关键试验中显著改善罕见神经系统疾病亚历山大病（AxD）患者的步行能力。根据新闻稿，zilganersen是在AxD患者中显示出改变疾病进程影响的首款在研疗法。以上两款疗法皆预计于2026年第一季度提交相关监管申请。另一方面，用以治疗Dravet综合征的在研ASO疗法zorevunersen在为期3年的扩展研究中，显示可持续降低癫痫发作，并伴随认知与行为的持续改善。该疗法已在今年8月完成3期试验的首位患者给药。 同时，本季度FDA还向多款寡核苷酸疗法授予突破性疗法认定（BTD），适应症涵盖多种罕见疾病。其中，抗体/抗体片段-寡核苷酸偶联疗法del-zota与DYNE-251分别用于治疗适用外显子44与51跳跃的杜氏肌营养不良症（DMD）；同时，用于治疗天使综合征的ASO疗法apazunersen与ION582也获此认定。 寡核苷酸疗法在常见适应症的突破 寡核苷酸疗法的进展也逐渐从罕见病扩展至常见疾病。今年7月，美国FDA批准诺华（Novartis）每年两次给药的siRNA疗法Leqvio（inclisiran）的扩展适应症，允许其作为单药，与饮食控制和运动联合使用，以降低成人高胆固醇血症患者的低密度脂蛋白胆固醇（LDL-C）水平。值得一提的是，根据新闻稿，这次的标签更新是美国FDA根据该PCSK9靶向疗法降低LDL-C的积极数据，主动要求更新该药品的标签。而开发用以治疗代谢功能障碍相关脂肪性肝炎（MASH）的ASO疗法ION224也在本季度获得积极的2期临床试验结果。有近60%的最高剂量组患者达到主要终点，显示出在MASH疾病活动上的改善，而此数值在安慰剂组仅为19%。 在癌症领域，PD-1靶向siRNA疗法PH-762在治疗皮肤癌的1b期试验中也获得积极结果。入组的13名皮肤鳞状细胞癌（cSCC）患者中有6人在接受治疗后达到病理学完全缓解或接近完全缓解。另外，DNA癌症疫苗SCIB1与其改良版iSCIB1+在晚期不可切除黑色素瘤患者中展现亮眼疗效。临床2期试验结果显示，当两者与当前标准免疫检查点抑制剂联用时，患者的疾病控制率（DCR）高达88.0%。 与此同时，在9月，两款分别设计用以治疗肥胖与阿尔茨海默病的siRNA疗法RN3161与ARO-MAPT，也分别在澳洲与新西兰递交临床试验申请，标志着寡核苷酸疗法在更广泛适应症上的进一步拓展。 商业研发合作进展 今年9月，诺华接连达成两项大额siRNA疗法授权合作。其一，诺华与Arrowhead Pharmaceuticals就后者开发的α-突触核蛋白靶向siRNA疗法ARO-SNCA签署总额高达20亿美元的全球许可与合作协议。该疗法目前处于临床前阶段，拟用于治疗包括帕金森病在内的突触核蛋白病。其二，诺华与Argo Biopharma围绕多项心血管siRNA管线达成合作，交易总额最高可达52亿美元，进一步夯实其在心血管代谢领域的布局。 与此同时，Arrowhead Pharmaceuticals控股子公司维亚臻（Visirna Therapeutics）亦与赛诺菲（Sanofi）达成最高2.65亿美元的合作：赛诺菲将获得潜在“first-in-class”的siRNA疗法plozasiran（VSA001）在大中华区的开发与商业化独家权利。该疗法通过抑制载脂蛋白C-III（APOC3）的产生，用于治疗家族性乳糜微粒血症综合征及重度高甘油三酯血症。 ▲部分2025年第三季度寡核苷酸疗法相关合作交易与融资事件 此外，本季度Arnatar Therapeutics宣布结束隐匿模式并正式亮相。该公司已于2024年完成5200万美元A轮融资，其专有的DARGER平台将siRNA沉默技术与基于ASO的基因上调技术相结合，开发具双重作用机制的RNA疗法，面向心脏代谢、肝、肾及中枢神经系统等疾病领域。 综上，2025年第三季度，寡核苷酸疗法持续展现出从罕见病到常见疾病的进展。多款ASO和siRNA疗法迎来关键监管批准与积极临床数据，不仅推动了遗传性血管性水肿、家族性乳糜微粒血症、重症肌无力及亚历山大病等罕见病治疗的进展，也在高胆固醇血症、MASH及皮肤癌等常见适应症中展现突破。同时，部分药企通过多项高额合作进一步加码siRNA布局，显示产业对该领域的信心。 一体化平台高效赋能寡核苷酸药物研发 作为医药创新的赋能者，药明康德化学业务旗下WuXi TIDES平台围绕siRNA、ASO等寡核苷酸疗法，建立了化合物合成、工艺开发及生产的一站式服务平台，覆盖从药物发现、CMC开发，到商业化生产的全生命周期，加速将合作伙伴的创新构想转化为现实，更好地造福全球病患。以下案例将展示WuXi TIDES的一体化平台如何加速合作伙伴ASO药物的开发进程。 2023年，一家生物技术公司与WuXi TIDES合作进行ASO药物的早期筛选研究，WuXi TIDES的药物化学团队为其提供了超过400种携带骨架化学修饰的ASO化合物，以协助确定最具前景的分子。然而，早期研究发现，创新骨架修饰导致候选化合物中出现新的杂质。在最初的合成过程中，这些杂质占比高达25%，不仅降低了产率和纯化效率，还可能带来潜在毒性，给后续临床开发带来挑战。 面对这一难题，WuXi TIDES药物化学团队和工艺研发团队密切配合，从两个方向入手解决问题。一方面，药物化学团队与合作伙伴共同探索杂质产生的潜在原因，设计出定制化的amidite和分子砌块，规避杂质产生的关键合成机制，并快速生产这些新分子砌块，协助工艺研发团队加速验证工艺设计策略，以有效地控制杂质。此外，工艺研发团队通过优化工艺参数，系统性地降低了杂质的产生。最终，经过持续工艺优化，杂质占比成功从25%降低至5%，同时最终收率也从最初的0.5 g/mol提高到3.4 g/mol。 在该项目中，WuXi TIDES各团队高效协作，不仅在12个月内完成了先导化合物的优化、工艺开发及GMP生产，更帮助合作伙伴基于数据进行快速决策，选出综合效力、稳定性和开发潜力俱佳的ASO候选化合物，为后续临床研究奠定了坚实基础。随着越来越多的ASO以及其他寡核苷酸药物进入临床开发，这种产业协同模式将成为加快研发步伐的重要推动力。 CRDMO: Q3 2025 Review of Oligonucleotide Therapeutics Oligonucleotide-based therapeutics continue to stand out as a key area in global drug development, with rapid progress seen across rare diseases and beyond. Currently, over 300 oligonucleotide pipelines are in clinical development worldwide, offering hope to a growing number of patients. To support partners in efficiently advancing these innovative therapies from discovery to clinic, WuXi TIDES offers efficient, flexible, and high-quality solutions for the drug development of oligonucleotides, peptides and related synthetic conjugates. The platform greatly simplifies TIDES drug development by providing all discovery, CMC development and the entire manufacturing supply chain under one roof. Here, we summarize key developments in the oligonucleotide space during Q3 2025 and share a case study that illustrates how WuXi TIDES helps accelerate progress in this dynamic area. Oligonucleotide Therapies Continue to Advance Across Rare Diseases Oligonucleotide therapies have emerged as a powerful tool in transforming the treatment landscape for rare diseases. In the third quarter of 2025, the field marked several major milestones. In August, the U.S. FDA approved Dawnzera (donidalorsen), an antisense oligonucleotide ligand conjugate (LICA), for the prevention of hereditary angioedema (HAE) attacks in patients aged 12 and older. According to the press release, Dawnzera is the first RNA-targeted prophylactic treatment for HAE. In September, the European Union (EU) granted marketing authorization to the antisense oligonucleotide (ASO) therapy Tryngolza (olezarsen) as an adjunct to diet for adults with genetically confirmed familial chylomicronemia syndrome (FCS). Notably, olezarsen also achieved positive results in a Phase 3 trial in severe hypertriglyceridemia (sHTG), demonstrating a 72% average reduction in fasting triglycerides versus placebo and an 85% reduction in acute pancreatitis events. These findings underscore the potential of oligonucleotide therapies, originally developed for rare diseases, to expand into more common conditions. Further progress was seen with siRNA therapy cemdisiran, which achieved the primary endpoint in the Phase 3 NIMBLE trial for generalized myasthenia gravis (gMG). Results showed that subcutaneous cemdisiran given every three months as monotherapy suppressed complement activity by an average of 74%, while in combination with the C5 antibody pozelimab, suppression approached 99%. Meanwhile, the ASO therapy zilganersen demonstrated meaningful improvements in the 10-Meter Walk Test (10MWT) for patients with Alexander disease (AxD)—the first investigational therapy to show disease-modifying potential in this indication according to the company. Both therapies are expected to be submitted for regulatory review in Q1 2026. In parallel, investigational ASO zorevunersen for Dravet syndrome continued to show durable seizure reduction and cognitive and behavioral improvements in a three-year extension study, with dosing of the first patient in its Phase 3 program beginning in August. In addition, the FDA granted multiple Breakthrough Therapy Designations (BTD) to oligonucleotide candidates addressing rare diseases this quarter. These include the antibody/antibody fragment-oligonucleotide conjugates del-zota and DYNE-251 for Duchenne muscular dystrophy (DMD) exon 44 and 51 skipping, respectively, and the ASO therapies apazunersen and ION582 for Angelman syndrome. Breakthroughs in Common Diseases Encouragingly, oligonucleotide therapies are now extending their impact beyond rare diseases into more prevalent conditions. In July, the FDA approved an expanded indication for Novartis’s Leqvio (inclisiran), the twice-yearly siRNA therapy, allowing its use as monotherapy in combination with diet and exercise to lower LDL-C in adults with hypercholesterolemia. According to the company, this label expansion was proactively initiated by the FDA following compelling data on LDL-C reduction with this PCSK9-targeting therapy. Also in Q3, the ASO therapy ION224 for metabolic dysfunction-associated steatohepatitis (MASH) delivered positive Phase 2 data, with nearly 60% of patients in the highest-dose group achieving the primary endpoint, compared to just 19% in the placebo arm. In oncology, PD-1-targeting siRNA therapy PH-762 achieved positive results in a Phase 1b trial in cutaneous squamous cell carcinoma (cSCC), where 6 out of 13 treated patients achieved either complete or near-complete pathological responses. Meanwhile, the DNA cancer vaccines SCIB1 and its modified version iSCIB1+ demonstrated promising efficacy in advanced, unresectable melanoma. Phase 2 results showed that, when combined with standard immune checkpoint inhibitors, the disease control rate (DCR) reached 88.0%. In September, siRNA therapies also expanded into new frontiers, with clinical trial applications submitted in Australia for RN3161 (obesity) and in New Zealand for ARO-MAPT (Alzheimer’s disease)—signaling the growing scope of oligonucleotide-based innovation. Momentum in Strategic Partnerships September was also marked by high-profile collaborations in the siRNA space. Novartis announced two major licensing agreements: one with Arrowhead Pharmaceuticals for global rights to ARO-SNCA, an α-synuclein-targeting siRNA currently in preclinical development for synucleinopathies including Parkinson’s disease, in a deal worth up to USD 2 billion; and another with Argo Biopharma for multiple cardiovascular siRNA programs, valued at up to USD 5.2 billion, further strengthening its position in cardiovascular and metabolic diseases. In parallel, Arrowhead’s majority-owned subsidiary Visirna Therapeutics entered into a partnership with Sanofi, granting Sanofi exclusive rights in Greater China to develop and commercialize plozasiran (VSA001). This potential first-in-class siRNA therapy targets APOC3 to treat familial chylomicronemia syndrome and severe hypertriglyceridemia. Additionally, Arnatar Therapeutics emerged from stealth this quarter, following a USD 52 million Series A financing in 2024. Leveraging its proprietary DARGER platform, the company is developing RNA therapies that combine siRNA silencing with ASO-based gene upregulation, addressing cardiovascular, hepatic, renal, and central nervous system diseases. Overall, Q3 2025 underscored the accelerating momentum of oligonucleotide therapies, with significant advances spanning both rare and common diseases. Multiple ASO and siRNA candidates achieved key regulatory approvals and delivered positive clinical data, advancing treatment options for hereditary angioedema, familial chylomicronemia syndrome, myasthenia gravis, and Alexander disease, while also demonstrating potential in hypercholesterolemia, MASH, and oncology. Alongside these scientific breakthroughs, landmark licensing and collaboration deals highlighted the industry’s confidence and investment in the promise of oligonucleotide medicines. WuXi TIDES Accelerates Oligonucleotide Drug Development for Global Partners WuXi TIDES has built an end-to-end service platform for oligonucleotide therapeutics, including siRNA and ASO, encompassing compound synthesis, process development, and manufacturing. Covering the full lifecycle—from drug discovery and CMC development to commercial production—the platform enables partners to rapidly transform innovative ideas into reality and bring benefits to patients worldwide. The following case study highlights how WuXi TIDES’ fully integrated platform is accelerating the development of an ASO therapy for one of our partners. In 2023, a biotech company partnered with WuXi TIDES to conduct early-stage ASO screening. The discovery synthesis team undertook extensive SAR (Structure-Activity Relationship) exploration—screening more than 400 ASO variants with various types of backbone and ribose modifications to help identify the most promising candidates. However, early-stage studies revealed that novel backbone modifications introduced new impurities—up to 25% in some initial batches—significantly lowering yield and purification efficiency, while raising concerns about potential toxicity that could hinder clinical development. To address these challenges, WuXi TIDES’ Discovery Chemistry team and Process Development (PRD) team collaborated closely on two fronts. The Discovery Chemistry Team worked with the client to investigate the source of impurities and designed specialized amidites and building blocks to circumvent the pathway leading to key impurities. In parallel, the PRD team rapidly synthesized these components and supported swift validation of the optimized strategy. Additionally, the PRD team systematically optimized multiple process parameters to further reduce impurities. Ultimately, through a series of process refinements, the impurity level was reduced from 25% to just 5%, and the final yield increased from 0.5 g/mol to 3.4 g/mol. Thanks to efficient cross-functional collaboration, WuXi TIDES completed hit-to-lead optimization, process development, and GMP manufacturing within 12 months. The partner was able to make data-driven decisions and select a lead ASO candidate with optimal potency, stability, and development potential—laying a strong foundation for clinical studies. As more ASO therapies enter development, this model of collaborative development will be critical for accelerating future breakthroughs. Advances in chemical modification and delivery technology have enabled oligonucleotide therapeutics to reach previously inaccessible tissue targets—offering new hope for rare and hard-to-treat diseases. Looking ahead, the continued evolution of this field is expected to deliver more innovative treatments to benefit patients worldwide. WuXi TIDES remains committed to leveraging its integrated CRDMO platform to empower the development of oligonucleotide therapeutics, helping partners translate scientific innovation into life-changing medicines. 参考资料： [1] Oligonucleotides Clinical Trial Pipeline Analysis Demonstrates 280+ Key Companies at the Horizon Expected to Transform the Treatment Paradigm, Assesses DelveInsight. Retrieved June 18, 2025 from https://www.globenewswire.com/news-release/2025/06/17/3100992/0/en/Oligonucleotides-Clinical-Trial-Pipeline-Analysis-Demonstrates-280-Key-Companies-at-the-Horizon-Expected-to-Transform-the-Treatment-Paradigm-Assesses-DelveInsight.html [2] Olezarsen significantly reduces triglycerides and acute pancreatitis events in landmark pivotal studies for people with severe hypertriglyceridemia (sHTG). Retrieved September 30, 2025 from https://ir.ionis.com/news-releases/news-release-details/olezarsen-significantly-reduces-triglycerides-and-acute [3] Arrowhead Pharmaceuticals and Novartis Enter into a Global License and Collaboration Agreement. Retrieved October 1, 2025 from https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-pharmaceuticals-and-novartis-enter-global-license-and [4] Argo Biopharma Announces Multi-Asset License and Option Agreements with Novartis for Novel Molecules for Cardiovascular Diseases. Retrieved October 1, 2025 from https://www.prnewswire.com/news-releases/argo-biopharma-announces-multi-asset-license-and-option-agreements-with-novartis-for-novel-molecules-for-cardiovascular-diseases-302544452.html [5] Gene, Cell, & RNA Therapy Landscape Report. Q2 2025 Quarterly Data Report. Retrieved September 5, 2025, from https://www.asgct.org/global/documents/cl-080125report-asgct-citeline-q2-2025-jn7765-fina.aspx [6] Oligonucleotides Clinical Trial Pipeline Analysis Demonstrates 280+ Key Companies at the Horizon Expected to Transform the Treatment Paradigm, Assesses DelveInsight. Retrieved October 10, 2025, from https://www.globenewswire.com/news-release/2025/06/17/3100992/0/en/Oligonucleotides-Clinical-Trial-Pipeline-Analysis-Demonstrates-280-Key-Companies-at-the-Horizon-Expected-to-Transform-the-Treatment-Paradigm-Assesses-DelveInsight.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，聚焦全球生物医药健康创新