多项上亿美元siRNA合作与监管突破，寡核苷酸疗法再迎新进展 | Bilingual

编者按：寡核苷酸药物已成为全球新药开发的重要热点，近年来在多个领域获得快速应用。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，药明康德围绕寡核苷酸及其相关化学偶联药物构建了一体化解决方案，覆盖定制合成、共价连接、工艺开发以及CMC等关键环节，为寡核苷酸及复杂偶联药物的发现与开发提供有力支持。本文将盘点2026年第一季度寡核苷酸领域的重要进展，带您了解这一快速发展领域的最新动态与趋势。

多款疗法递交上市申请，寡核苷酸进展横跨罕见病与常见疾病

2026年第一季度，多款寡核苷酸疗法在罕见疾病领域持续取得监管突破。例如，欧盟委员会（EC）在1月批准Dawnzera（donidalorsen）在欧盟上市，用于成人及12岁以上青少年遗传性血管性水肿（HAE）反复发作的常规预防。Dawnzera是一款反义寡核苷酸配体偶联（LICA）药物，旨在通过沉默前激肽释放酶（PKK）的表达，中断导致HAE发作的相关信号通路。在OASISplus开放标签延长期研究中，用药一年后患者的总体平均月发作率降低达94%。

与此同时，Ionis Pharmaceuticals用于治疗亚历山大病（AxD）的反义寡核苷酸（ASO）疗法zilganersen（ION373）也在本季度迎来监管进展。该疗法的新药申请（NDA）已获美国FDA受理，并被授予优先审评资格，PDUFA日期为2026年9月22日。AxD是一种罕见、进行性且最终致命的神经系统疾病。研究显示，在儿童及成人AxD患者中，50 mg zilganersen在第61周时相较对照组，在主要终点10米步行测试（10MWT）评估的步行速度方面实现了具有统计学意义且临床意义明确的稳定效果（最小二乘均值差异33.3%，P=0.0412），同时展现出良好的安全性和耐受性。

在临床研究方面，Wave Life Sciences旗下ASO疗法WVE-N531在FORWARD-53 2期临床研究中也取得积极进展。数据显示，接受治疗的杜氏肌营养不良症（DMD）患者在24至48周期间，经肌肉含量校正后的肌营养不良蛋白表达水平保持稳定，平均达到7.8%。肌肉组织学分析进一步显示，肌纤维从再生阶段向成熟阶段转变，同时肌肉纤维化显著减少（24至48周期间降低28.6%；p<0.01）。该公司计划于今年向美国FDA递交新药申请，寻求WVE-N531的加速批准。

除了罕见病领域，寡核苷酸疗法在常见疾病中的应用也在不断取得突破。FDA在本季度受理Ionis旗下ASO疗法olezarsen用于治疗严重高甘油三酯血症（sHTG）的补充新药申请（sNDA），并授予优先审评资格。该申请的PDUFA日期设定为2026年6月30日。研究数据显示，olezarsen可实现最高达72%的安慰剂校正甘油三酯水平降低，同时急性胰腺炎事件减少85%，并表现出良好的安全性和耐受性。此外，近90%接受olezarsen治疗的患者甘油三酯水平降至500 mg/dL以下，低于急性胰腺炎的风险阈值。这些结果表明，该疗法不仅能够显著降低甘油三酯水平，也有望降低与严重高甘油三酯血症相关的临床风险。

在疫苗领域，Moderna也在推进其mRNA技术平台的应用。该公司在2月与美国FDA就其季节性流感疫苗候选产品mRNA-1010的修订申报策略达成共识。根据更新后的计划，Moderna将为50至64岁成年人申请完全批准，并为65岁及以上成年人寻求加速批准。在提交修订申请后，FDA已正式受理该生物制品许可申请（BLA），并设定2026年8月5日为目标审评完成日期。mRNA-1010是一款基于mRNA技术的季节性流感疫苗，旨在针对流感A型和B型多种毒株提供更广泛且更高效的免疫保护。

在肝炎领域，寡核苷酸疗法也迎来新的监管进展。日本厚生劳动省（MHLW）已受理Ionis与GSK联合开发的潜在“first-in-class”ASO疗法bepirovirsen的新药申请，用于治疗成人慢性乙型肝炎（CHB）。这是该疗法在全球范围内首次向监管机构递交上市申请。Bepirovirsen是一种具有三重作用机制的ASO疗法，可识别并靶向乙肝病毒的遗传成分（即RNA），从而帮助患者免疫系统重新获得对病毒感染的控制能力。研究显示，与单纯标准治疗相比，bepirovirsen联合标准治疗在所有预设层级终点中均实现更高的功能性治愈率，且差异具有统计学意义和临床意义。

与此同时，Wave Life Sciences还公布了其长效GalNAc修饰siRNA疗法WVE-007在INLIGHT首次人体试验（1期部分）的最新数据。随访6个月结果显示，单次240 mg给药即可持续改善超重或肥胖患者的身体成分结构，在减少脂肪的同时实现肌肉保留。此外，WVE-007还能够持续、剂量依赖性地抑制血清靶蛋白水平，这一效应至少可维持7个月，为每年一次或两次给药提供了依据。

另一家企业Tangram Therapeutics则在本季度完成其主打候选药物TGM-312的1/2期临床试验首例受试者给药。TGM-312是一种基于Tangram专有RNAi化学平台GalOmic开发的GalNAc-siRNA疗法，旨在特异性沉默肝细胞中的一个新靶点基因，用于治疗代谢功能障碍相关脂肪性肝炎（MASH）。该药物有望实现每季度一次的皮下给药，从而提升患者的用药便利性。

多家大药企达成上亿美元寡核苷酸疗法合作

在产业合作方面，多家大型制药企业在本季度达成多项规模可观的寡核苷酸合作交易。今年2月，罗氏（Roche）旗下基因泰克（Genentech）与圣因生物（SanegeneBio）达成全球研发合作与许可协议，双方将基于圣因生物专有的RNA干扰（RNAi）药物研发平台共同推进一款RNAi疗法的开发。根据协议条款，圣因生物将获得2亿美元首付款，并有权收取开发和销售里程碑付款，总金额最高可达15亿美元。该公司平台整合了新型药物化学修饰与递送技术，其中包括具有组织选择性的LEAD肝外递送技术，可支持多个疾病领域具有“best-in-class”或“first-in-class”潜力的RNAi药物开发。

同月，Madrigal Pharmaceuticals也与瑞博生物及其子公司Ribocure Pharmaceuticals达成最高达44亿美元的全球独家许可协议。双方将基于瑞博生物的肝靶向RiboGalSTAR平台，共同开发6款针对MASH的创新siRNA疗法。此外，GSK与前沿生物（Frontier Biotechnologies）也达成超过10亿美元的合作。根据协议，GSK将获得两款siRNA管线产品在全球范围内的独家开发、生产及商业化权利，其中一款候选药物已进入新药临床试验申请（IND）阶段，另一款仍处于临床前研究阶段。

与此同时，礼来（Eli Lilly and Company）也与Orna Therapeutics达成收购协议，交易金额最高可达24亿美元。Orna正在推进其细胞疗法平台，该平台基于工程化环状RNA，并结合新型脂质纳米颗粒技术，使患者自身能够在体内生成具有治疗作用的免疫细胞，从而靶向疾病的根本机制。Orna的主打项目为ORN-252，这是一款即将进入临床试验的体内CD19靶向嵌合抗原受体T细胞（CAR-T）疗法，拟用于治疗由B细胞驱动的自身免疫性疾病。

由以上进展可以发现，本季度多项大型交易均围绕siRNA疗法展开。而在siRNA药物快速发展的背景下，如何通过体外研究准确预测其体内代谢行为，是核酸药物研发中的关键科学挑战之一。由于siRNA在体内主要经历核酸酶介导的逐步降解，其代谢过程高度依赖生物环境差异，传统体外模型往往难以真实反映体内代谢路径，进而影响候选分子的评价与开发效率。为满足客户的持续需求，药明康德DMPK团队通过系统性研究与方法论优化，建立了能够显著提升体外-体内相关性（IVIVC）的siRNA代谢评价体系，为体外模型预测能力提供了坚实的科学基础。

基于对代表性GalNAc偶联siRNA药物inclisiran的深入研究，团队系统比较了多种体外模型在模拟体内血液与肝脏代谢方面的表现，包括血清、不同抗凝条件下的血浆、肝匀浆、S9组分、tritosomes及贴壁肝细胞等模型，并结合体内数据验证其预测能力。研究结果表明，经肝素抗凝处理的血浆与血清能够较好模拟体内血液中的核酸酶代谢，而在肝脏代谢方面，特定pH条件下的肝匀浆、tritosomes以及优化培养条件下的肝细胞模型可有效重现体内代谢特征，从而显著提升体外研究对体内结果的预测准确性。此外，研究还发现实验条件如缓冲体系与pH值对代谢结果具有关键影响，强调了针对siRNA分子特性进行模型优化的重要性。

药明康德DMPK团队已经构建了涵盖血液、亚细胞组分及细胞模型的多层级体外代谢研究平台，可系统解析siRNA在循环系统与靶组织中的降解路径及代谢特征，并支持跨物种比较以提高临床转化可靠性。通过将机制研究与标准化实验流程相结合，该能力帮助研发团队更早识别代谢风险、优化分子设计策略，并降低从体外研究到体内验证过程中的不确定性，为siRNA药物高效迈向临床开发提供关键支撑。

Multiple Billion-Dollar siRNA Partnerships and Regulatory Breakthroughs Signal New Progress in Oligonucleotide Therapies

Editor’s Note:Oligonucleotide therapeutics have become a major focus of global drug development and have seen rapid adoption in recent years across multiple therapeutic areas. To help partners more efficiently advance oligonucleotide drugs from the laboratory to the clinic, WuXi AppTec has built an integrated solution centered on oligonucleotides and related chemically conjugated modalities. This solution covers key stages including custom synthesis, covalent conjugation, process development, and CMC, providing strong support for the discovery and development of oligonucleotides and complex conjugated drugs. This article reviews major developments in the oligonucleotide field in the first quarter of 2026 and highlights the latest trends in this rapidly evolving area.

Multiple Therapies File for Approval as Oligonucleotide Advances Span Rare and Common Diseases

In the first quarter of 2026, several oligonucleotide therapies continued to achieve regulatory breakthroughs in rare diseases. For example, in January theEuropean Commission approved Dawnzera (donidalorsen) in the European Union for routine prevention of recurrent attacks of hereditary angioedema (HAE) in adults and adolescents aged 12 years and older.Dawnzera is a ligand-conjugated antisense oligonucleotide (LICA) designed to interrupt signaling pathways that trigger HAE attacks by silencing the expression of prekallikrein (PKK). In the OASISplus open-label extension study, the overall average monthly attack rate decreased by 94% after one year of treatment.

Meanwhile, an antisense oligonucleotide (ASO) therapy developed by Ionis Pharmaceuticals for Alexander disease (AxD),zilganersen (ION373), also reached an important regulatory milestone this quarter.Its New Drug Application (NDA) has been accepted by the U.S. Food and Drug Administration and granted Priority Review, with a PDUFA date set for September 22, 2026. AxD is a rare, progressive, and ultimately fatal neurological disease. Studies showed that in both pediatric and adult AxD patients, 50 mg zilganersen demonstrated a statistically and clinically meaningful stabilization in walking speed at Week 61 as measured by the 10-meter walk test (10MWT) compared with the control group (least squares mean difference 33.3%, P=0.0412), while also showing good safety and tolerability.

In clinical development, the ASO therapyWVE-N531from Wave Life Sciences also reported positive progress in the Phase 2 FORWARD-53 study. Data showed that in patients with Duchenne muscular dystrophy (DMD), dystrophin expression adjusted for muscle content remained stable at an average of 7.8% between Weeks 24 and 48.Histological analyses further demonstrated that muscle fibers transitioned from regeneration to maturation, while muscle fibrosis significantly decreased (28.6% reduction from Weeks 24 to 48; p<0.01). The company plans to submit an NDA to the U.S. FDA this year seeking accelerated approval for WVE-N531.

Beyond rare diseases, oligonucleotide therapies are also making progress in more common conditions.The FDA accepted a supplemental New Drug Application (sNDA) this quarter for the Ionis ASO therapy olezarsen for the treatment of severe hypertriglyceridemia (sHTG), granting Priority Review.The PDUFA date is set for June 30, 2026. Data show thatolezarsen achieved up to a 72% placebo-adjusted reduction in triglyceride levels, while reducing acute pancreatitis events by 85%and demonstrating favorable safety and tolerability. Additionally, nearly 90% of patients receiving olezarsen achieved triglyceride levels below 500 mg/dL, which is lower than the risk threshold for acute pancreatitis. These findings suggest that the therapy not only significantly lowers triglycerides but may also reduce clinical risks associated with sHTG.

In the vaccine field, Moderna is also advancing applications of its mRNA technology platform. In February, the company reached agreement with the U.S. FDA on a revised regulatory submission strategy for itsseasonal influenza vaccine candidate mRNA-1010.Under the updated plan, Moderna will seek full approval for adults aged 50 to 64 and accelerated approval for adults aged 65 and older. Following submission of the revised application,the FDA accepted the Biologics License Application (BLA) and set a target review completion date of August 5, 2026.mRNA-1010 is an mRNA-based seasonal influenza vaccine designed to provide broader and more effective immune protection against multiple influenza A and B strains.

In the hepatitis field, oligonucleotide therapies have also achieved regulatory progress.The Ministry of Health, Labour and Welfare in Japan has accepted the NDA for the potential first-in-class ASO therapy bepirovirsen, jointly developed by Ionis and GSK, for the treatment of adults with chronic hepatitis B (CHB).This marks the first global regulatory filing for the therapy. Bepirovirsen is an ASO therapy with a triple mechanism of action that recognizes and targets the genetic components (RNA) of the hepatitis B virus, potentially enabling patients’ immune systems to regain control over the infection. Studies showed that compared with standard of care alone, bepirovirsen combined with standard therapy achieved higher functional cure rates across all prespecified hierarchical endpoints, with statistically and clinically significant differences.

Wave Life Sciences also reported new data from the first-in-human trial (Phase 1 portion) of itslong-acting GalNAc-modified siRNA therapy WVE-007in the INLIGHT study. Six-month follow-up results showed thata single 240 mg dose produced sustained improvements in body composition in overweight or obese individuals, reducing fat while preserving muscle mass.In addition, WVE-007 produced sustained, dose-dependent suppression of serum target protein levels for at least seven months, supporting potential once- or twice-yearly dosing.

Another company, Tangram Therapeutics, completed first patient dosing in the Phase 1/2 clinical trial of its lead candidate TGM-312 this quarter.TGM-312 is a GalNAc-siRNA therapy developed using Tangram’s proprietary RNAi chemistry platform GalOmic, designed to specifically silence a novel target gene in hepatocytes for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). The drug may enable once-quarterly subcutaneous dosing, improving treatment convenience for patients.

Multiple Large Pharmaceutical Companies Announce Billion-Dollar Oligonucleotide Partnerships

In terms of industry collaboration, several major pharmaceutical companies entered large oligonucleotide-focused deals this quarter. In February, Roche subsidiaryGenentech signed a global research collaboration and license agreement with SanegeneBio to jointly develop an RNAi therapy based on SanegeneBio’s proprietary RNAi drug discovery platform.Under the agreement, SanegeneBio will receive an upfront payment of $200 million and may earn development and commercial milestone payments totaling up to $1.5 billion. The company’s platform integrates novel chemical modification and delivery technologies, including the tissue-selective LEAD extrahepatic delivery technology, enabling the development of breakthrough RNAi drugs with potential best-in-class or first-in-class profiles across multiple disease areas.

In the same month,Madrigal Pharmaceuticals signed a global exclusive licensing agreement worth up to $4.4 billion with RiboLife Science and its subsidiary Ribocure Pharmaceuticals.The companies will jointly develop six innovative siRNA therapies targeting MASH using RiboLife’s liver-targeted RiboGalSTAR platform. In addition,GSK and Frontier Biotechnologies entered a collaboration exceeding $1 billion.Under the agreement, GSK will obtain global exclusive rights to develop, manufacture, and commercialize two siRNA pipeline candidates, one of which has entered the Investigational New Drug (IND) stage while the other remains in preclinical development.

Meanwhile,Eli Lilly and Company also reached an acquisition agreement with Orna Therapeutics valued at up to $2.4 billion.Orna is advancing a cell therapy platform based on engineered circular RNA combined with novel lipid nanoparticle technology, enabling patients to generate therapeutic immune cells in vivo to target the underlying mechanisms of disease. Orna’s lead program, ORN-252, is an in vivo CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy approaching clinical trials, intended for the treatment of B-cell-driven autoimmune diseases.

Advancing Predictive Metabolism Research to Support siRNA Drug Development

These developments show that many of the major transactions this quarter were centered around siRNA therapies. As siRNA therapeutics continue to advance rapidly, establishing reliable in vitro metabolic models has become essential for accurately predicting in vivo behavior and enabling efficient development decisions. Unlike traditional small molecules, oligonucleotides, particularly GalNAc-conjugated siRNAs, undergo complex nuclease-mediated metabolism that varies significantly across biological compartments, making conventional in vitro systems insufficient for translational prediction. To better meet clients’ need,WuXi AppTec DMPK team has developed a comprehensive framework for building and validating predictive in vitro metabolic models tailored specifically for oligonucleotide therapeutics, integrating mechanistic experimentation with translational pharmacokinetic insight.

As shown from a recent peer-reviewed study investigating the metabolism of a representative GalNAc-conjugated siRNA, WuXi AppTec scientists systematically evaluated multiple biological systems to determine which models most accurately replicate in vivo metabolism. The research demonstrated that carefully selected matrices, such as serum and heparin-anticoagulated plasma for blood metabolism, along with optimized liver homogenates, tritosomes, and plated hepatocytes for hepatic metabolism, can closely reproduce metabolite profiles observed in vivo, significantly improving in vitro–in vivo correlation (IVIVC) for oligonucleotide candidates . Importantly, the study also revealed how experimental conditions, including buffer composition and pH, influence nuclease activity and metabolic outcomes, underscoring the need for modality-specific model optimization rather than reliance on conventional assay formats.

Building upon these insights, WuXi AppTec DMPK platform incorporates a diverse panel of validated in vitro stability and metabolism systems, including plasma, tissue homogenates, subcellular fractions, and hepatocyte models, to characterize degradation pathways, metabolite formation, and compartment-specific disposition mechanisms. Cross-species evaluation strategies further support translational relevance by identifying metabolic differences between animal models and humans, helping reduce clinical uncertainty early in development.

Through the integration of mechanistic metabolism studies, advanced bioanalysis, and model validation workflows, WuXi AppTec DMPK enables developers to better predict oligonucleotide stability, optimize molecular design, and refine development strategies with greater confidence. These capabilities provide a robust scientific foundation for understanding oligonucleotide biotransformation and accelerate the progression of RNA-based therapeutics from discovery toward clinical application.

参考资料：

[1] 各公司官网

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