上海
編者按：高血脂是心血管疾病及相關死亡的重要風險因素。世界心臟聯盟（WHF）指出，全球約39%的成年人膽固醇水平升高，每年導致數百萬人死亡。盡管他汀類藥物是常用的降脂藥物，但由于服藥依從性等問題，許多患者仍難以達到目標低密度脂蛋白膽固醇（LDL-C）水平。近年來，基于寡核苷酸的療法通過在肝臟靶向干預膽固醇的合成或代謝，正逐步改變高脂血癥的治療方式，有望實現每3至6個月注射一次，即可長期穩定降脂。其背后的關鍵推動力之一，是基于N-乙酰半乳糖胺（GalNAc）的靶向遞送技術。目前，多款siRNA、反義寡核苷酸（ASO）以及堿基編輯療法均采用GalNAc偶聯技術進行肝臟遞送，在臨床試驗中展現出顯著且持久的降脂效果。為滿足全球合作伙伴的研發需求，藥明康德旗下獨特的CRDMO平臺WuXi TIDES，圍繞GalNAc分子及偶聯物建立了一體化服務平臺，覆蓋從藥物發現、CMC開發，到商業化生產的全生命周期，加速將合作伙伴的創新構想轉化為現實，造福全球病患。本文將從基于寡核苷酸的降脂療法出發，介紹GalNAc遞送技術以及WuXi TIDES團隊如何助力合作伙伴應對GalNAc偶聯藥物開發中的挑戰。
從3個月一針到一次性治療，新一代療法正在改變高血脂治療模式
目前，多款針對膽固醇代謝靶點的siRNA和ASO療法正處于后期臨床開發階段。它們通過在mRNA水平干預與膽固醇代謝相關蛋白的表達，僅需每3或6個月注射一次，便可顯著降低LDL-C水平。此類長效療法不僅有望解決傳統療法中的依從性難題，還可靶向他汀類藥物難以干預的信號通路，為患者提供更全面的血脂管理手段。在減少給藥頻次的基礎上，更進一步的堿基編輯療法正探索通過“一次性治療”實現長期甚至永久的降脂效果，開辟高脂血癥治療的新路徑。
▲部分處于臨床開發階段的寡核苷酸和堿基編輯降脂療法（數據來源：公開資料）
這些前沿療法的共同特征，是采用GalNAc偶聯技術以提升藥物在肝臟中的靶向遞送效率。有的將GalNAc直接偶聯至寡核苷酸片段本身，以提高穩定性和細胞攝取效率；也有部分堿基編輯療法將GalNAc修飾在脂質納米顆粒（LNP）表面，以增強遞送系統的組織特異性。
GalNAc偶聯技術：靶向肝臟的精準遞送系統
GalNAc是半乳糖的氨基糖衍生物，可與肝細胞表面高度表達的去唾液酸糖蛋白受體（ASGPR）高親和力結合，促進藥物的細胞內吞。目前FDA已批準7款siRNA療法，其中6款采用了GalNAc偶聯技術。這項技術同樣適用于ASO遞送，如2023年12月獲批的Wainua（eplontersen）即是成功應用的代表。
▲GalNAc偶聯技術遞送寡核苷酸藥物的機制（圖片來源：參考資料[7]）
自問世以來，GalNAc偶聯技術不斷迭代升級，無論是在化學修飾方式還是多價分子的設計合成方面，均取得顯著進展。由于ASGPR對GalNAc的親和力與其配體數目密切相關，研究人員廣泛探索并開發了多種三價、四價GalNAc簇（cluster）及其在寡核苷酸上的偶聯策略，以提高遞送效率。
▲多價GalNAc簇與寡核苷酸偶聯的不同方式（圖片來源：參考資料[3]）
隨著技術不斷成熟，GalNAc偶聯藥物的合成與工藝開發日益復雜。WuXi TIDES團隊在合成GalNAc分子方面擁有豐富經驗，已合成100多種GalNAc分子及其衍生物，包括單-GalNAc、三-GalNAc、四-GalNAc、GalNAc酰胺、GalNAc PFP酯、GalNAc N3和GalNAc-PEG偶聯物等。借助全面的平臺能力，WuXi TIDES能夠提供GalNAc定制合成、工藝開發和生產一體化服務，支持從藥物發現到臨床開發再到商業化生產。下面的案例將介紹WuXi TIDES如何幫助合作伙伴加速推進GalNAc偶聯siRNA藥物的開發。
14個月完成兩款GalNAc偶聯siRNA藥物IND申報準備
一家生物技術公司在開發用于治療心血管疾病的GalNAc偶聯siRNA候選藥物時，由于缺乏成熟的GalNAc分子來源，加上產率和粗純度低下等問題，項目推進受阻。他們找到了WuXi TIDES，尋求解決方案。
首先要解決的便是非常規GalNAc分子的供應問題。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技術，并優化了溶劑體系，使重結晶收率高達94.8%，4個月內成功交付4.5公斤高純度定制GalNAc分子，有效保障了項目的原料供應。
隨后，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，簡化合成和純化流程，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，同時利用先進的無菌灌裝生產線和優化的生產流程設計，在GMP批次的生產中達到99%的產率，顯著降低了API的損失。多團隊的全方位協作使兩款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。
以上案例只是WuXi TIDES一體化CRDMO平臺能力的一個縮影。除了GalNAc偶聯寡核苷酸，WuXi TIDES也可為GalNAc偶聯多肽藥物提供一站式開發支持。隨著越來越多GalNAc偶聯藥物進入臨床開發階段，像這樣的產業協同將成為加快研發步伐的重要推動力。
圖片來源： 123RF
今年發表在
Nature Medicine上的文章表示，基于GalNAc偶聯遞送技術的寡核苷酸和堿基編輯的膽固醇和血脂控制手段的涌現，有望為醫生提供一系列靈活的治療選擇，從每日服用的藥片，到只需幾個月一針的注射療法，以及 潛在一次性 的堿基編輯療法。展望未來，WuXi TIDES將持續基于其一體化CRDMO平臺，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 Single Dose for Long-Lasting Cholesterol Reduction: How a Breakthrough Technology Is Reshaping Hyperlipidemia Management
Hyperlipidemia is a major contributor to cardiovascular disease and mortality. According to the World Heart Federation (WHF), about 39% of adults globally have elevated cholesterol levels, causing millions of deaths annually. While statins are commonly used to lower LDL-C, many patients fail to reach target levels due to poor adherence and other factors. Oligonucleotide-based therapies have recently emerged as a promising alternative, targeting cholesterol synthesis and metabolism directly in the liver.
These treatments offer long-lasting effects with dosing as infrequent as every three to six months—enabled largely by N-acetylgalactosamine (GalNAc)-based targeted delivery. Multiple approved and investigational siRNAs and antisense oligonucleotides (ASOs) now use GalNAc conjugation to enhance liver-specific delivery. Clinical trials have shown these therapies can achieve sustained lipid-lowering effects.
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 GalNAc molecules and conjugates, covering from drug discovery and CMC development to commercial-scale manufacturing. This article introduces GalNAc delivery technologies from the perspective of oligonucleotide-based lipid-lowering therapies and illustrates how the WuXi TIDES team supports partners in overcoming the challenges of GalNAc-conjugated drug development.
New Generation of Therapies Is Reshaping Hyperlipidemia Management
Multiple siRNA and ASO therapies targeting cholesterol metabolism pathways are currently in late-stage clinical development. These candidates work by modulating mRNA expression of proteins involved in lipid regulation, achieving substantial LDL-C reductions with dosingrequiredonly once every three or six months.
These long-acting therapies not only address the issue of poor patient compliance but also target biological pathways that are difficult to modulate with statins, offering patients more comprehensive lipid control. This signals a potential paradigm shift in how hyperlipidemia is treated.
A unifying feature among these therapies is their reliance on GalNAc conjugation to facilitate targeted liver delivery. By conjugating GalNAc to oligonucleotide payloads, the therapies gain enhanced molecular stability and improved cellular uptake, ultimately increasing their therapeutic efficacy.
GalNAc Conjugation: A Precision Delivery Platform for Liver-Targeted Therapies
GalNAc, an amino sugar derivative of galactose, binds with high affinity to asialoglycoprotein receptors (ASGPRs), which are highly expressed on hepatocytes. This binding promotes efficient endocytosis of the GalNAc-conjugated therapeutic. Of the seven siRNA drugs approved by the U.S. FDA, six utilize GalNAc conjugation. The technology is also effective for ASO delivery, as demonstrated by the approval of Wainua (eplontersen) in December 2023.
Since its introduction, GalNAc conjugation has evolved significantly through advances in chemical modification and the development of multivalent GalNAc clusters. Research shows that ASGPR binding affinity improves with the number of GalNAc ligands present, prompting the development of tri- and tetra-valent GalNAc constructs and optimized strategies for their conjugation to oligonucleotides.
As the technology matures, the synthesis and process development of GalNAc-conjugated drugs have grown increasingly complex. WuXi TIDES brings extensive experience in this area, having synthesized more than 100 types of GalNAc molecules and derivatives—including mono-GalNAc, tri-GalNAc, tetra-GalNAc, GalNAc amidites, GalNAc PFP esters, GalNAc N3, and GalNAc-PEG conjugates. Through the Company’s comprehensive capabilities and capacity, WuXi TIDES offers GalNAc custom synthesis, process development, and manufacturing support from the discovery phase to commercial launch. The following case study illustrates how WuXi TIDES helped a biotech partner rapidly advance a GalNAc-siRNA candidate.
Fast-Track to Phase I: Two siRNA IND CMC Packages Completed in 14 Months
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. Using advanced flow chemistry and an optimized solvent system, the team achieved a 94.8% recrystallization yield. 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, we 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.
A recent article published in
Nature Medicinenoted that the emergence of cholesterol- and lipid-lowering strategies based on GalNAc-conjugated oligonucleotides is expected to offer physicians a flexible toolbox. As these therapeutic modalities continue to evolve, WuXi TIDES will continue to leverage its integrated CRDMO platform to support partners in accelerating the transformation of scientific innovation into impactful medicines that improve lives worldwide.
參考資料：
[1] Fast-Track to Phase I: Two siRNA IND CMC Packages Completed in 14 Months. Retrieved July 9, 2025, from https://tides.wuxiapptec.com/wp-content/uploads/2024/07/Fast-Track-to-Phase-I-Two-siRNA-IND-CMC-Packages-Completed-in-14-Months-FINAL.pdf
[2] Zhang et al., (2025). Advancement of drugs conjugated with GalNAc in the targeted delivery to hepatocytes based on asialoglycoprotein receptor. Carbohydrate Research, https://doi.org/10.1016/j.carres.2025.109426
[3] Debacker et al., (2020). Delivery of Oligonucleotides to the Liver with GalNAc: From Research to Registered Therapeutic Drug. Molecular Therapy, https://doi.org/10.1016/j.ymthe.2020.06.015
[4] Kumar and Turnbull (2023). Targeted delivery of oligonucleotides using multivalent protein–carbohydrate interactions. Chem. Soc. Rev., DOI: 10.1039/D2CS00788F
[5] RNA gene therapies offer hope for millions with high cholesterol. Retrieved July 9, 2025, from https://www.nature.com/articles/d41591-025-00002-2
[6] Cholesterol. Retrieved July 10, 2025, from https://world-heart-federation.org/what-we-do/cholesterol/
[7] Cui et al., (2021). Liver-Targeted Delivery of Oligonucleotides with N-Acetylgalactosamine Conjugation. ACS Omega, DOI:10.1021/acsomega.1c01755.
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