同行致远 | 里程碑！siRNA疗法为这类疾病带来新希望 | Bilingual

编者按：今年以来，siRNA疗法在治疗凝血相关疾病的研究方面取得了重要里程碑进展。RNA干扰（RNAi）机制通过在肝脏细胞中沉默编码凝血因子或天然抗凝物的mRNA，为治疗凝血相关疾病提供了一种全新的治疗模式。基于GalNAc偶联的递送技术，是将治疗性siRNA分子高效递送到肝脏的关键之一。药明康德旗下WuXi TIDES团队围绕siRNA等分子，打造了涵盖定制合成、共价连接、以及一体化CMC的一站式服务平台，更好地满足全球合作伙伴的研发需求，加速创新转化，惠及全球病患。本文将探讨siRNA在治疗凝血相关疾病方面的应用，并展示WuXi TIDES如何助力合作伙伴加速GalNAc偶联siRNA疗法的开发。

siRNA疗法与凝血相关疾病

由于大多数调控凝血过程的蛋白都在肝细胞中合成，这使肝脏成为高度适配的治疗靶点。GalNAc通过与肝细胞表面高度表达的去唾液酸糖蛋白受体（ASGPR）结合，促进siRNA药物被肝细胞选择性摄取，使其在调控凝血系统时展现出高度精准性。

进入肝脏后，这些siRNA可长期沉默目标基因，使蛋白水平在一次皮下注射后显著下降并维持数月之久。对于治疗负担高、用药依从性弱的疾病而言，这一特点尤其重要。siRNA药物不但可以提供高度可预测的疗效，给药间隔可延长至8周甚至更久。对患者而言，这意味着治疗负担更轻，用药更容易融入日常生活。

此外，siRNA药物的药效动力学平稳，能够对凝血平衡进行持续而温和的调节。今年获得FDA批准的Qfitlia（fitusiran）就是范例之一。

在血友病中重新平衡止血

血友病长期以来被视为一种缺失性疾病：因缺乏凝血因子VIII（FVIII）或IX（FIX），患者易发生自发出血、关节损伤和长期并发症。过去几十年，治疗焦点始终围绕如何替代缺失因子展开。siRNA疗法为解决这个问题提供了新思路。它不试图恢复FVIII或FIX，而是从凝血信号通路的另一方面入手，通过降低内源性抗凝物来提升凝血酶生成，从而调控凝血通路的整体平衡。

这一理念在2025年3月得到监管验证。美国FDA批准了Qfitlia（fitusiran）用于血友病A或B青少年及成人的常规预防。作为一种靶向抗凝血酶的皮下注射siRNA，fitusiran在3期临床试验中使年化出血率下降约90%。患者只需每两个月接受一次治疗。

对于许多患者而言，这种改变意义深远。长期频繁的静脉输注一直是治疗依从性的巨大障碍，尤其对静脉条件差或存在治疗疲劳的患者而言。Fitusiran每年仅需注射约6次，且为皮下给药，为患者和家庭带来了截然不同的治疗节奏。

Fitusiran的获批不仅具有里程碑意义，也揭示了RNAi作为技术平台的可拓展性。研究人员正在探索更多抗凝靶点，如肝素辅因子II和蛋白S，前期研究显示，沉默这些蛋白同样能够在FVIII或FIX缺失背景下恢复凝血酶生成。

siRNA为血栓疾病开辟新方向

正如siRNA可用于增强出血性疾病患者的凝血功能，它同样能够在血栓风险高的患者中抑制凝血活动。在这一领域中，备受关注的靶点之一是凝血因子XI（FXI）。先天性FXI缺乏患者的血栓风险显著降低，却通常仅出现轻度出血。这些人类遗传学研究结果为新一代抗凝策略提供了启示：抑制FXI活性可能比传统抗凝药具有更宽广的安全窗口。

目前，多款靶向FXI的药物已经进入临床开发并获得显著进展。例如，拜耳（Bayer）公司的FXIa抑制剂asundexian在全球性3期临床试验中获得积极顶线结果，在显著降低患者缺血性卒中风险的同时，并未增加主要出血风险。

多家生物技术公司也在探索通过siRNA药物降低FXI蛋白表达的治疗策略。例如，瑞博生物开发的在研GalNAc偶联siRNA药物RBD4059已经完成在健康志愿者中进行的1期临床试验，试验结果显示RBD4059呈现出剂量依赖性、可预测的药代动力学特性、以及显著（>90%）和持久的FXI活性和蛋白水平降低效果；同时，在安全性和耐受性方面达到主要终点，在研究的剂量范围内未发现不良安全信号，显示出良好的安全性。目前这款药物已经进入2期临床试验。

此外，靖因药业与CRISPR Therapeutics共同开发的FXI靶向siRNA药物SRSD107也已完成2期临床试验首例患者给药。Sirnaomics公司的在研siRNA药物STP122G目前正在1期临床试验中接受检验。City Therapeutics公司的新一代siRNA疗法CITY-FXI已经递交临床试验申请，预计在2026年初启动1期临床试验。

这些在研疗法的未来愿景明确：通过每年数次皮下注射实现对静脉血栓或卒中的长期防护，同时不显著增加重大出血风险。如果成功，将代表着抗凝策略的重大革新。

一体化平台助力GalNAc偶联siRNA药物开发

尽管GalNAc偶联siRNA药物在治疗凝血相关疾病方面表现出显著潜力，但药物实现规模化应用，还需要强有力的全方位技术整合能力作为支撑。一家生物技术公司在研发治疗心血管疾病的GalNAc偶联siRNA候选药物时，就曾遇到难题：由于缺乏成熟的GalNAc分子来源，加之产率和粗纯度低下，项目推进受阻。他们找到了WuXi TIDES，寻求解决方案。

首先要解决的便是GalNAc的供应问题。针对合作伙伴提出的特殊需求，团队迅速建立合成路线，采用先进的流动化学及重结晶技术，获得了纯度超过98%的高质量产品，在短短4个月内，成功制备出4.5公斤高纯度定制GalNAc分子，保障了稳定的供应链，大幅缩短了项目周期。

在关键的偶联环节，凭借在多种偶联类型、偶联化学和修饰策略上的经验积累，WuXi TIDES团队选择了具有高度选择性的“点击化学”策略，显著降低副产物产生，简化合成和纯化过程，使最终收率从13%提升至62%，粗品纯度从18%提高到75%，确保了适合临床试验的高纯度和稳定性。

同时，基于一体化CMC服务能力，WuXi TIDES团队平行开展了分析方法、制剂开发等多项工作，同时利用无菌灌装生产线和生产流程设计，在GMP批次生产中达到99%产率，显著降低API损失。全方位协作使两款siRNA候选药物在14个月内顺利完成了IND申报准备，加速推进至临床阶段。

展望未来，随着更多siRNA药物正进入临床开发，类似的产业协同将持续发挥重要作用，进一步推动药物研发的快速前进。

结语

siRNA正在重塑凝血障碍的治疗模式。通过沉默肝脏中关键蛋白的生成，siRNA提供了持久且可精确调控的治疗方式。FDA批准首款siRNA血友病疗法，标志着凝血系统调控可从体内实现这一概念已被验证。目前，全球已有8款siRNA疗法获批上市，治疗的疾病类型也从罕见病扩展到患者人数众多的常见病，有望变革高血压、高血脂和肥胖症等慢性病的治疗模式。据统计，截至今年7月，全球在研RNAi疗法接近400款，其中约三分之一已进入临床开发阶段。RNAi领域的“明星公司”Alnylam表示，预计在2030年前解决主要组织的递送挑战，最大限度地释放RNAi技术的潜力。面向未来，WuXi TIDES将持续基于其一体化CRDMO平台，赋能包括RNAi在内的寡核苷酸药物开发，助力合作伙伴加快将科学创新转化为新药、好药，造福全球病患。

A Milestone Breakthrough: siRNA Therapy Brings New Hope to Coagulation Disorders

In March 2025, the U.S. FDA approved Qfitlia (fitusiran), an siRNA therapy, as a prophylactic treatment to reduce bleeding risk in patients with hemophilia. The approval represents an important milestone for the use of siRNA in coagulation-related diseases. RNA interference (RNAi) enables targeted silencing of mRNA encoding coagulation factors or natural anticoagulants within hepatocytes, opening a new therapeutic paradigm for disorders of hemostasis and thrombosis.

A key enabler of this modality is GalNAc-conjugated delivery, which facilitates efficient and selective transport of therapeutic siRNA molecules to the liver.To meet rising demand in this field, WuXi TIDES, a unique CRDMO platform that is part of WuXi AppTec, has established an integrated service platform around siRNA molecules and conjugates, covering from drug discovery and CMC development to commercial-scale manufacturing. This article reviews the emerging role of siRNA in coagulation disorders, and highlights how the WuXi TIDES team supports partners in overcoming the challenges of GalNAc-conjugated drug development.

siRNA Therapies: A Precise Modality for Coagulation Disorders

Because most proteins that regulate coagulation are synthesized in hepatocytes, the liver presents an important site for therapeutic intervention. GalNAc ligands bind to the asialoglycoprotein receptor (ASGPR), which is abundantly expressed on hepatocytes, enabling highly selective uptake of siRNA and precise modulation of the coagulation cascade.

Once internalized, siRNA can silence target genes for extended periods, producing sustained reductions in protein levels for months after a single subcutaneous dose. This long-acting profile is particularly meaningful for diseases associated with high treatment burden and poor adherence.siRNA therapies deliver predictable efficacy while extending dosing intervals to eight weeks or more, allowing treatment to integrate more easily into patients’ daily lives.

Their smooth pharmacodynamic profile also supports gradual, durable adjustments to the coagulation balance. Qfitlia (fitusiran), approved by the FDA this year, demonstrates these advantages in clinical practice.

Restoring Hemostatic Balance in Hemophilia

Hemophilia has long been defined by the absence of a single component, coagulation factor VIII (FVIII) or IX (FIX), leading to spontaneous bleeding, joint damage, and long-term complications. For decades, therapy focused on replacing the missing factor.

siRNA therapy introduces a fundamentally different concept. Instead of restoring FVIII or FIX, it targets the pathway from the opposite direction by reducing endogenous anticoagulants to enhance thrombin generation and rebalance coagulation globally.

This approach received regulatory validation in March 2025, when the FDA approved Qfitlia (fitusiran) for routine prophylaxis in adolescents and adults with hemophilia A or B. As an siRNA that silences antithrombin mRNA, fitusiran reduced annualized bleeding rates by approximately 90% in Phase 3 trials, with dosing required only once every two months.

For many patients, this represents a transformative shift. Frequent intravenous infusions, long a major barrier to adherence, can now be replaced by around six subcutaneous injections per year. For individuals with poor venous access or treatment fatigue, this new rhythm of care offers tremendous relief.

Beyond its clinical benefits, fitusiran underscores the scalability of RNAi as a platform. Researchers are actively investigating additional anticoagulant targets, including heparin cofactor II and protein S, and early findings suggest that silencing these proteins may similarly restore thrombin generation in the absence of FVIII or FIX.

siRNA Opens New Frontiers in Thrombotic Disease

Just as siRNA can augment coagulation in bleeding disorders, it can also attenuate coagulation for patients at high risk of thrombosis.Factor XI (FXI) has emerged as a particularly compelling target.

Individuals with congenital FXI deficiency experience substantially lower thrombosis risk yet typically only mild bleeding, an insight from human genetics that suggests FXI inhibition may offer a wider safety margin than conventional anticoagulants.

Several FXI-targeted therapies have already achieved meaningful clinical milestones. Bayer’s FXIa inhibitor asundexian demonstrated positive topline Phase 3 results recently, reducing ischemic stroke risk without elevating major bleeding events.

At the same time, multiple biotech companies are advancing siRNA strategies to lower FXI expression. Several GalNAc-siRNA candidates have demonstrated sustained reductions in FXI activity and protein levels in Phase 1 clinical trials and are in Phase 2 development. Collectively,these programs aim to deliver long-term protection against venous thrombosis or stroke through only a handful of subcutaneous injections per year—potentially redefining the future of anticoagulation.

Fast-Track to Phase 1: Two siRNA IND CMC Packages Completed in 14 Months

Despite their promise, GalNAc-siRNA therapies require robust technical infrastructure to achieve scalable, reliable development. One biotech company developing a GalNAc-siRNA therapy for cardiovascular disease faced multiple challenges—including limited supply of a unique GalNAc molecule, low yield, and poor purity—which stalled their program. To overcome these hurdles, they partnered with WuXi TIDES.

The priority was to ensure a stable supply of the GalNAc molecule. WuXi TIDES quickly designed a customized synthetic route tailored to the client’s specifications.By utilizing flow chemistry and recrystallization techniques, the team achieved a high-quality product with over 98% purity. Within just four months, they successfully delivered 4.5 kilograms of high-purity,custom GalNAc—effectively securing the supply of the starting material for the GalNAc-siRNA conjugate and shortening development timelines.

Next came the critical conjugation step. Drawing on extensive expertise in conjugation chemistries and modification strategies, the WuXi TIDES team adopted a highly selective “Click Chemistry” approach, minimizing byproduct formation and simplifying synthesis and purification. As a result,the overall yield increased from 13% to 62%, and crude purity improved from 18% to 75%, ensuring the production of clinical-grade material with superior purity and stability.

In parallel, WuXi TIDES leveraged its integrated CMC capabilities to advance analytical method development and formulation optimization. Together with an advanced sterile fill-finish line and optimal process design,the team achieved a batch yield of >99% in GMP production, significantly minimizing the overall loss of costly API.These coordinated efforts enabled two siRNA candidates to complete IND-enabling activities within just 14 months, accelerating progress toward the clinic.

The above case is just one example of the capabilities of WuXi TIDES’ integrated CRDMO platform. In addition to oligonucleotides, WuXi TIDES also provides comprehensive development solutions for GalNAc-conjugated peptide therapeutics. As more GalNAc-conjugated drugs advance into clinical development, integrated collaboration will be essential to accelerating innovation and bringing therapies to patients faster.

Looking Ahead

siRNA is redefining how coagulation disorders are treated. By silencing key liver-derived proteins, siRNA delivers precise, durable, and programmable modulation of hemostasis. The approval of the first siRNA therapy for hemophilia confirms that rebalancing the coagulation system from within the body is now a clinically validated strategy.

To date, eight siRNA therapies have been approved globally, with indications expanding beyond rare diseases to highly prevalent chronic conditions. They offer the potential to transform treatment strategies for hypertension, hyperlipidemia, and obesity. As of July this year, nearly 400 siRNA therapies are in development worldwide, with one-third already in clinical stages.

Looking ahead, WuXi TIDES will continue to leverage its integrated CRDMO platform to support the development of oligonucleotide therapeutics, including siRNA, and help partners transform scientific breakthroughs into new medicines that benefit patients across the globe.

参考资料：

[1] Ragni and Chan, (2023). Innovations in RNA therapy for hemophilia. Blood, https://doi.org/10.1182/blood.2022018661

[2] Presume et al., (2024). Factor XI Inhibitors: A New Horizon in Anticoagulation Therapy. Cardiol Ther., doi: 10.1007/s40119-024-00352-x

[3] Capodanno et al., (2025). Factor XI inhibitors for the prevention and treatment of venous and arterial thromboembolism. Nat Rev Cardiol, https://doi.org/10.1038/s41569-025-01144-z

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