同行致遠 | 里程碑！siRNA療法為這類疾病帶來新希望 | Bilingual

編者按：今年以來，siRNA療法在治療凝血相關疾病的研究方面取得了重要里程碑進展。RNA干擾（RNAi）機制通過在肝臟細胞中沉默編碼凝血因子或天然抗凝物的mRNA，為治療凝血相關疾病提供了一種全新的治療模式。基于GalNAc偶聯的遞送技術，是將治療性siRNA分子高效遞送到肝臟的關鍵之一。藥明康德旗下WuXi TIDES團隊圍繞siRNA等分子，打造了涵蓋定制合成、共價連接、以及一體化CMC的一站式服務平臺，更好地滿足全球合作伙伴的研發需求，加速創新轉化，惠及全球病患。本文將探討siRNA在治療凝血相關疾病方面的應用，并展示WuXi TIDES如何助力合作伙伴加速GalNAc偶聯siRNA療法的開發。

siRNA療法與凝血相關疾病

由于大多數調控凝血過程的蛋白都在肝細胞中合成，這使肝臟成為高度適配的治療靶點。GalNAc通過與肝細胞表面高度表達的去唾液酸糖蛋白受體（ASGPR）結合，促進siRNA藥物被肝細胞選擇性攝取，使其在調控凝血系統時展現出高度精準性。

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

此外，siRNA藥物的藥效動力學平穩，能夠對凝血平衡進行持續而溫和的調節。今年獲得FDA批準的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病：因缺乏凝血因子VIII（FVIII）或IX（FIX），患者易發生自發出血、關節損傷和長期并發癥。過去幾十年，治療焦點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FVIII或FIX，而是從凝血信號通路的另一方面入手，通過降低內源性抗凝物來提升凝血酶生成，從而調控凝血通路的整體平衡。

這一理念在2025年3月得到監管驗證。美國FDA批準了Qfitlia（fitusiran）用于血友病A或B青少年及成人的常規預防。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。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奏。

Fitusiran的獲批不僅具有里程碑意義，也揭示了RNAi作為技術平臺的可拓展性。研究人員正在探索更多抗凝靶點，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缺失背景下恢復凝血酶生成。

siRNA為血栓疾病開辟新方向

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

目前，多款靶向FXI的藥物已經進入臨床開發并獲得顯著進展。例如，拜耳（Bayer）公司的FXIa抑制劑asundexian在全球性3期臨床試驗中獲得積極頂線結果，在顯著降低患者缺血性卒中風險的同時，并未增加主要出血風險。

多家生物技術公司也在探索通過siRNA藥物降低FXI蛋白表達的治療策略。例如，瑞博生物開發的在研GalNAc偶聯siRNA藥物RBD4059已經完成在健康志愿者中進行的1期臨床試驗，試驗結果顯示RBD4059呈現出劑量依賴性、可預測的藥代動力學特性、以及顯著（>90%）和持久的FXI活性和蛋白水平降低效果；同時，在安全性和耐受性方面達到主要終點，在研究的劑量范圍內未發現不良安全信號，顯示出良好的安全性。目前這款藥物已經進入2期臨床試驗。

此外，靖因藥業與CRISPR Therapeutics共同開發的FXI靶向siRNA藥物SRSD107也已完成2期臨床試驗首例患者給藥。Sirnaomics公司的在研siRNA藥物STP122G目前正在1期臨床試驗中接受檢驗。City Therapeutics公司的新一代siRNA療法CITY-FXI已經遞交臨床試驗申請，預計在2026年初啟動1期臨床試驗。

這些在研療法的未來愿景明確：通過每年數次皮下注射實現對靜脈血栓或卒中的長期防護，同時不顯著增加重大出血風險。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siRNA藥物開發

盡管GalNAc偶聯siRNA藥物在治療凝血相關疾病方面表現出顯著潛力，但藥物實現規模化應用，還需要強有力的全方位技術整合能力作為支撐。一家生物技術公司在研發治療心血管疾病的GalNAc偶聯siRNA候選藥物時，就曾遇到難題：由于缺乏成熟的GalNAc分子來源，加之產率和粗純度低下，項目推進受阻。他們找到了WuXi TIDES，尋求解決方案。

首先要解決的便是GalNAc的供應問題。針對合作伙伴提出的特殊需求，團隊迅速建立合成路線，采用先進的流動化學及重結晶技術，獲得了純度超過98%的高質量產品，在短短4個月內，成功制備出4.5公斤高純度定制GalNAc分子，保障了穩定的供應鏈，大幅縮短了項目周期。

在關鍵的偶聯環節，憑借在多種偶聯類型、偶聯化學和修飾策略上的經驗積累，WuXi TIDES團隊選擇了具有高度選擇性的“點擊化學”策略，顯著降低副產物產生，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的高純度和穩定性。

同時，基于一體化CMC服務能力，WuXi TIDES團隊平行開展了分析方法、制劑開發等多項工作，同時利用無菌灌裝生產線和生產流程設計，在GMP批次生產中達到99%產率，顯著降低API損失。全方位協作使兩款siRNA候選藥物在14個月內順利完成了IND申報準備，加速推進至臨床階段。

展望未來，隨著更多siRNA藥物正進入臨床開發，類似的產業協同將持續發揮重要作用，進一步推動藥物研發的快速前進。

結語

siRNA正在重塑凝血障礙的治療模式。通過沉默肝臟中關鍵蛋白的生成，siRNA提供了持久且可精確調控的治療方式。FDA批準首款siRNA血友病療法，標志著凝血系統調控可從體內實現這一概念已被驗證。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展到患者人數眾多的常見病，有望變革高血壓、高血脂和肥胖癥等慢性病的治療模式。據統計，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入臨床開發階段。RNAi領域的“明星公司”Alnylam表示，預計在2030年前解決主要組織的遞送挑戰，最大限度地釋放RNAi技術的潛力。面向未來，WuXi TIDES將持續基于其一體化CRDMO平臺，賦能包括RNAi在內的寡核苷酸藥物開發，助力合作伙伴加快將科學創新轉化為新藥、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

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