編者按：今年以來，siRNA療法在治療凝血相關(guān)疾病的研究方面取得了重要里程碑進(jìn)展。RNA干擾（RNAi）機(jī)制通過在肝臟細(xì)胞中沉默編碼凝血因子或天然抗凝物的mRNA，為治療凝血相關(guān)疾病提供了一種全新的治療模式?；贕alNAc偶聯(lián)的遞送技術(shù)，是將治療性siRNA分子高效遞送到肝臟的關(guān)鍵之一。藥明康德旗下WuXi TIDES團(tuán)隊(duì)圍繞siRNA等分子，打造了涵蓋定制合成、共價(jià)連接、以及一體化CMC的一站式服務(wù)平臺，更好地滿足全球合作伙伴的研發(fā)需求，加速創(chuàng)新轉(zhuǎn)化，惠及全球病患。本文將探討siRNA在治療凝血相關(guān)疾病方面的應(yīng)用，并展示W(wǎng)uXi TIDES如何助力合作伙伴加速GalNAc偶聯(lián)siRNA療法的開發(fā)。

siRNA療法與凝血相關(guān)疾病

由于大多數(shù)調(diào)控凝血過程的蛋白都在肝細(xì)胞中合成，這使肝臟成為高度適配的治療靶點(diǎn)。GalNAc通過與肝細(xì)胞表面高度表達(dá)的去唾液酸糖蛋白受體（ASGPR）結(jié)合，促進(jìn)siRNA藥物被肝細(xì)胞選擇性攝取，使其在調(diào)控凝血系統(tǒng)時(shí)展現(xiàn)出高度精準(zhǔn)性。

進(jìn)入肝臟后，這些siRNA可長期沉默目標(biāo)基因，使蛋白水平在一次皮下注射后顯著下降并維持?jǐn)?shù)月之久。對于治療負(fù)擔(dān)高、用藥依從性弱的疾病而言，這一特點(diǎn)尤其重要。siRNA藥物不但可以提供高度可預(yù)測的療效，給藥間隔可延長至8周甚至更久。對患者而言，這意味著治療負(fù)擔(dān)更輕，用藥更容易融入日常生活。

此外，siRNA藥物的藥效動力學(xué)平穩(wěn)，能夠?qū)δ胶膺M(jìn)行持續(xù)而溫和的調(diào)節(jié)。今年獲得FDA批準(zhǔn)的Qfitlia（fitusiran）就是范例之一。

在血友病中重新平衡止血

血友病長期以來被視為一種缺失性疾?。阂蛉狈δ蜃覸III（FVIII）或IX（FIX），患者易發(fā)生自發(fā)出血、關(guān)節(jié)損傷和長期并發(fā)癥。過去幾十年，治療焦點(diǎn)始終圍繞如何替代缺失因子展開。siRNA療法為解決這個問題提供了新思路。它不試圖恢復(fù)FVIII或FIX，而是從凝血信號通路的另一方面入手，通過降低內(nèi)源性抗凝物來提升凝血酶生成，從而調(diào)控凝血通路的整體平衡。

這一理念在2025年3月得到監(jiān)管驗(yàn)證。美國FDA批準(zhǔn)了Qfitlia（fitusiran）用于血友病A或B青少年及成人的常規(guī)預(yù)防。作為一種靶向抗凝血酶的皮下注射siRNA，fitusiran在3期臨床試驗(yàn)中使年化出血率下降約90%。患者只需每兩個月接受一次治療。

對于許多患者而言，這種改變意義深遠(yuǎn)。長期頻繁的靜脈輸注一直是治療依從性的巨大障礙，尤其對靜脈條件差或存在治療疲勞的患者而言。Fitusiran每年僅需注射約6次，且為皮下給藥，為患者和家庭帶來了截然不同的治療節(jié)奏。

Fitusiran的獲批不僅具有里程碑意義，也揭示了RNAi作為技術(shù)平臺的可拓展性。研究人員正在探索更多抗凝靶點(diǎn)，如肝素輔因子II和蛋白S，前期研究顯示，沉默這些蛋白同樣能夠在FVIII或FIX缺失背景下恢復(fù)凝血酶生成。

siRNA為血栓疾病開辟新方向

正如siRNA可用于增強(qiáng)出血性疾病患者的凝血功能，它同樣能夠在血栓風(fēng)險(xiǎn)高的患者中抑制凝血活動。在這一領(lǐng)域中，備受關(guān)注的靶點(diǎn)之一是凝血因子XI（FXI）。先天性FXI缺乏患者的血栓風(fēng)險(xiǎn)顯著降低，卻通常僅出現(xiàn)輕度出血。這些人類遺傳學(xué)研究結(jié)果為新一代抗凝策略提供了啟示：抑制FXI活性可能比傳統(tǒng)抗凝藥具有更寬廣的安全窗口。

目前，多款靶向FXI的藥物已經(jīng)進(jìn)入臨床開發(fā)并獲得顯著進(jìn)展。例如，拜耳（Bayer）公司的FXIa抑制劑asundexian在全球性3期臨床試驗(yàn)中獲得積極頂線結(jié)果，在顯著降低患者缺血性卒中風(fēng)險(xiǎn)的同時(shí)，并未增加主要出血風(fēng)險(xiǎn)。

多家生物技術(shù)公司也在探索通過siRNA藥物降低FXI蛋白表達(dá)的治療策略。例如，瑞博生物開發(fā)的在研GalNAc偶聯(lián)siRNA藥物RBD4059已經(jīng)完成在健康志愿者中進(jìn)行的1期臨床試驗(yàn)，試驗(yàn)結(jié)果顯示RBD4059呈現(xiàn)出劑量依賴性、可預(yù)測的藥代動力學(xué)特性、以及顯著（>90%）和持久的FXI活性和蛋白水平降低效果；同時(shí)，在安全性和耐受性方面達(dá)到主要終點(diǎn)，在研究的劑量范圍內(nèi)未發(fā)現(xiàn)不良安全信號，顯示出良好的安全性。目前這款藥物已經(jīng)進(jìn)入2期臨床試驗(yàn)。

此外，靖因藥業(yè)與CRISPR Therapeutics共同開發(fā)的FXI靶向siRNA藥物SRSD107也已完成2期臨床試驗(yàn)首例患者給藥。Sirnaomics公司的在研siRNA藥物STP122G目前正在1期臨床試驗(yàn)中接受檢驗(yàn)。City Therapeutics公司的新一代siRNA療法CITY-FXI已經(jīng)遞交臨床試驗(yàn)申請，預(yù)計(jì)在2026年初啟動1期臨床試驗(yàn)。

這些在研療法的未來愿景明確：通過每年數(shù)次皮下注射實(shí)現(xiàn)對靜脈血栓或卒中的長期防護(hù)，同時(shí)不顯著增加重大出血風(fēng)險(xiǎn)。如果成功，將代表著抗凝策略的重大革新。

一體化平臺助力GalNAc偶聯(lián)siRNA藥物開發(fā)

盡管GalNAc偶聯(lián)siRNA藥物在治療凝血相關(guān)疾病方面表現(xiàn)出顯著潛力，但藥物實(shí)現(xiàn)規(guī)?；瘧?yīng)用，還需要強(qiáng)有力的全方位技術(shù)整合能力作為支撐。一家生物技術(shù)公司在研發(fā)治療心血管疾病的GalNAc偶聯(lián)siRNA候選藥物時(shí)，就曾遇到難題：由于缺乏成熟的GalNAc分子來源，加之產(chǎn)率和粗純度低下，項(xiàng)目推進(jìn)受阻。他們找到了WuXi TIDES，尋求解決方案。

首先要解決的便是GalNAc的供應(yīng)問題。針對合作伙伴提出的特殊需求，團(tuán)隊(duì)迅速建立合成路線，采用先進(jìn)的流動化學(xué)及重結(jié)晶技術(shù)，獲得了純度超過98%的高質(zhì)量產(chǎn)品，在短短4個月內(nèi)，成功制備出4.5公斤高純度定制GalNAc分子，保障了穩(wěn)定的供應(yīng)鏈，大幅縮短了項(xiàng)目周期。

在關(guān)鍵的偶聯(lián)環(huán)節(jié)，憑借在多種偶聯(lián)類型、偶聯(lián)化學(xué)和修飾策略上的經(jīng)驗(yàn)積累，WuXi TIDES團(tuán)隊(duì)選擇了具有高度選擇性的“點(diǎn)擊化學(xué)”策略，顯著降低副產(chǎn)物產(chǎn)生，簡化合成和純化過程，使最終收率從13%提升至62%，粗品純度從18%提高到75%，確保了適合臨床試驗(yàn)的高純度和穩(wěn)定性。

同時(shí)，基于一體化CMC服務(wù)能力，WuXi TIDES團(tuán)隊(duì)平行開展了分析方法、制劑開發(fā)等多項(xiàng)工作，同時(shí)利用無菌灌裝生產(chǎn)線和生產(chǎn)流程設(shè)計(jì)，在GMP批次生產(chǎn)中達(dá)到99%產(chǎn)率，顯著降低API損失。全方位協(xié)作使兩款siRNA候選藥物在14個月內(nèi)順利完成了IND申報(bào)準(zhǔn)備，加速推進(jìn)至臨床階段。

展望未來，隨著更多siRNA藥物正進(jìn)入臨床開發(fā)，類似的產(chǎn)業(yè)協(xié)同將持續(xù)發(fā)揮重要作用，進(jìn)一步推動藥物研發(fā)的快速前進(jìn)。

結(jié)語

siRNA正在重塑凝血障礙的治療模式。通過沉默肝臟中關(guān)鍵蛋白的生成，siRNA提供了持久且可精確調(diào)控的治療方式。FDA批準(zhǔn)首款siRNA血友病療法，標(biāo)志著凝血系統(tǒng)調(diào)控可從體內(nèi)實(shí)現(xiàn)這一概念已被驗(yàn)證。目前，全球已有8款siRNA療法獲批上市，治療的疾病類型也從罕見病擴(kuò)展到患者人數(shù)眾多的常見病，有望變革高血壓、高血脂和肥胖癥等慢性病的治療模式。據(jù)統(tǒng)計(jì)，截至今年7月，全球在研RNAi療法接近400款，其中約三分之一已進(jìn)入臨床開發(fā)階段。RNAi領(lǐng)域的“明星公司”Alnylam表示，預(yù)計(jì)在2030年前解決主要組織的遞送挑戰(zhàn)，最大限度地釋放RNAi技術(shù)的潛力。面向未來，WuXi TIDES將持續(xù)基于其一體化CRDMO平臺，賦能包括RNAi在內(nèi)的寡核苷酸藥物開發(fā)，助力合作伙伴加快將科學(xué)創(chuàng)新轉(zhuǎn)化為新藥、好藥，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.

參考資料：

[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

免責(zé)聲明：本文僅作信息交流之目的，文中觀點(diǎn)不代表藥明康德立場，亦不代表藥明康德支持或反對文中觀點(diǎn)。本文也不是治療方案推薦。如需獲得治療方案指導(dǎo)，請前往正規(guī)醫(yī)院就診。

版權(quán)說明：歡迎個人轉(zhuǎn)發(fā)至朋友圈，謝絕媒體或機(jī)構(gòu)未經(jīng)授權(quán)以任何形式轉(zhuǎn)載至其他平臺。轉(zhuǎn)載授權(quán)請?jiān)凇杆幟骺档隆刮⑿殴娞柣貜?fù)“轉(zhuǎn)載”，獲取轉(zhuǎn)載須知。