Eplontersen

The FDA approved Ionis’ rare disease medicine donidalorsen and the company hopes to convince a majority of patients who use differing prophylactic and on-demand treatments to use its drug. Ionis said Thursday that donidalorsen, which is branded as Dawnzera, is now the first RNA-targeted drug for hereditary angioedema, or HAE. The disease is a genetic disorder characterized by recurrent episodes of swelling in the capillary beds. The episodes can start in patients as young as 2 years old, and Ionis estimates there are about 20,000 patients in the US and EU. The label indicates that the drug can be self-administered with an autoinjector once every four weeks or eight weeks. The price per dose is $57,462, according to an Ionis spokesperson. About 70% of HAE patients are currently receiving treatment, CEO Brett Monia told Endpoints News , either with an approved prophylactic drug or on an as-needed basis whenever a swelling attack occurs. All of those treatments are either antibodies or small molecules. But Monia believes patients will opt for the RNA-targeting Dawnzera as a way to control their swelling. The label includes a warning for anaphylaxis. “Earlier this year, and after the data cuts included in our publications, a couple of patients in the OLE [open-label extension] had a hypersensitivity reaction, each of which resolved quickly,” the spokesperson said. “We don’t believe that this will have any meaningful impact on the Dawnzera launch.” The swelling attacks, which typically manifest in the abdomen, hands, face and throat, “can be extremely severe, and are always disfiguring, and some are very often debilitating,” Monia said. They’re also unpredictable, and patients want “reassurance and the peace of mind that they’re not going to get an attack.” Dawnzera isn’t expected to be a blockbuster. The drug is expected to be a “$500 million-plus opportunity” at most, Monia said. And getting to that number will require Ionis to succeed in switching most of the patients currently on other drugs. But for Monia, the approval is a sign of bigger things to come. Ionis, which is most known for developing the SMA drug Spinraza and licensing it to Biogen, has been on a path to becoming a “fully integrated biotech” that can launch and support drugs on its own, according to Monia. Dawnzera is now the second drug Ionis has taken from development to launch by itself after it won approval for Tryngolza late last year in another rare disease. The company also has a half-dozen Phase 3 readouts expected by the end of next year, including two studies for Tryngolza in September. The goal is to get Tryngolza’s label expanded into a more prevalent condition: severe hypertriglyceridemia. The other readouts include wholly-owned rare disease drugs and partnered programs with Novartis, GSK, Roche and Otsuka. But the “big-ticket item” is slated for the second half of 2026, Monia said. That’s when Ionis and AstraZeneca anticipate they will read out Phase 3 data for Wainua in a rare heart disease called transthyretin amyloid cardiomyopathy, or ATTR-CM. The drug was first approved in 2023 for patients with polyneuropathy of hereditary transthyretin-mediated amyloidosis, or ATTR-PN. There have been two new approvals for ATTR-CM in the last year, for drugs developed by BridgeBio and Alnylam, and the competition with an older Pfizer franchise is fierce. Wainua also won’t be the last entrant in ATTR-CM: Novo Nordisk plans to take a Prothena-partnered program into Phase 3 by the end of 2025. Editor’s note: This story was updated to include pricing and prescribing information.

编者按：高血脂是心血管疾病及相关死亡的重要风险因素。世界心脏联盟（WHF）指出，全球约39%的成年人胆固醇水平升高，每年导致数百万人死亡。尽管他汀类药物是常用的降脂药物，但由于服药依从性等问题，许多患者仍难以达到目标低密度脂蛋白胆固醇（LDL-C）水平。近年来，基于寡核苷酸的疗法通过在肝脏靶向干预胆固醇的合成或代谢，正逐步改变高脂血症的治疗方式，有望实现每3至6个月注射一次，即可长期稳定降脂。其背后的关键推动力之一，是基于N-乙酰半乳糖胺（GalNAc）的靶向递送技术。目前，多款siRNA、反义寡核苷酸（ASO）以及碱基编辑疗法均采用GalNAc偶联技术进行肝脏递送，在临床试验中展现出显著且持久的降脂效果。为满足全球合作伙伴的研发需求，药明康德旗下独特的CRDMO平台WuXi TIDES，围绕GalNAc分子及偶联物建立了一体化服务平台，覆盖从药物发现、CMC开发，到商业化生产的全生命周期，加速将合作伙伴的创新构想转化为现实，造福全球病患。本文将从基于寡核苷酸的降脂疗法出发，介绍GalNAc递送技术以及WuXi TIDES团队如何助力合作伙伴应对GalNAc偶联药物开发中的挑战。 从3个月一针到一次性治疗，新一代疗法正在改变高血脂治疗模式 目前，多款针对胆固醇代谢靶点的siRNA和ASO疗法正处于后期临床开发阶段。它们通过在mRNA水平干预与胆固醇代谢相关蛋白的表达，仅需每3或6个月注射一次，便可显著降低LDL-C水平。此类长效疗法不仅有望解决传统疗法中的依从性难题，还可靶向他汀类药物难以干预的信号通路，为患者提供更全面的血脂管理手段。在减少给药频次的基础上，更进一步的碱基编辑疗法正探索通过“一次性治疗”实现长期甚至永久的降脂效果，开辟高脂血症治疗的新路径。 ▲部分处于临床开发阶段的寡核苷酸和碱基编辑降脂疗法（数据来源：公开资料） 这些前沿疗法的共同特征，是采用GalNAc偶联技术以提升药物在肝脏中的靶向递送效率。有的将GalNAc直接偶联至寡核苷酸片段本身，以提高稳定性和细胞摄取效率；也有部分碱基编辑疗法将GalNAc修饰在脂质纳米颗粒（LNP）表面，以增强递送系统的组织特异性。 GalNAc偶联技术：靶向肝脏的精准递送系统 GalNAc是半乳糖的氨基糖衍生物，可与肝细胞表面高度表达的去唾液酸糖蛋白受体（ASGPR）高亲和力结合，促进药物的细胞内吞。目前FDA已批准7款siRNA疗法，其中6款采用了GalNAc偶联技术。这项技术同样适用于ASO递送，如2023年12月获批的Wainua（eplontersen）即是成功应用的代表。 ▲GalNAc偶联技术递送寡核苷酸药物的机制（图片来源：参考资料[7]） 自问世以来，GalNAc偶联技术不断迭代升级，无论是在化学修饰方式还是多价分子的设计合成方面，均取得显著进展。由于ASGPR对GalNAc的亲和力与其配体数目密切相关，研究人员广泛探索并开发了多种三价、四价GalNAc簇（cluster）及其在寡核苷酸上的偶联策略，以提高递送效率。 ▲多价GalNAc簇与寡核苷酸偶联的不同方式（图片来源：参考资料[3]） 随着技术不断成熟，GalNAc偶联药物的合成与工艺开发日益复杂。WuXi TIDES团队在合成GalNAc分子方面拥有丰富经验，已合成100多种GalNAc分子及其衍生物，包括单-GalNAc、三-GalNAc、四-GalNAc、GalNAc酰胺、GalNAc PFP酯、GalNAc N3和GalNAc-PEG偶联物等。借助全面的平台能力，WuXi TIDES能够提供GalNAc定制合成、工艺开发和生产一体化服务，支持从药物发现到临床开发再到商业化生产。下面的案例将介绍WuXi TIDES如何帮助合作伙伴加速推进GalNAc偶联siRNA药物的开发。 14个月完成两款GalNAc偶联siRNA药物IND申报准备 一家生物技术公司在开发用于治疗心血管疾病的GalNAc偶联siRNA候选药物时，由于缺乏成熟的GalNAc分子来源，加上产率和粗纯度低下等问题，项目推进受阻。他们找到了WuXi TIDES，寻求解决方案。  首先要解决的便是非常规GalNAc分子的供应问题。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技术，并优化了溶剂体系，使重结晶收率高达94.8%，4个月内成功交付4.5公斤高纯度定制GalNAc分子，有效保障了项目的原料供应。 随后，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，简化合成和纯化流程，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，同时利用先进的无菌灌装生产线和优化的生产流程设计，在GMP批次的生产中达到99%的产率，显著降低了API的损失。多团队的全方位协作使两款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。 以上案例只是WuXi TIDES一体化CRDMO平台能力的一个缩影。除了GalNAc偶联寡核苷酸，WuXi TIDES也可为GalNAc偶联多肽药物提供一站式开发支持。随着越来越多GalNAc偶联药物进入临床开发阶段，像这样的产业协同将成为加快研发步伐的重要推动力。 今年发表在Nature Medicine上的文章表示，基于GalNAc偶联递送技术的寡核苷酸和碱基编辑的胆固醇和血脂控制手段的涌现，有望为医生提供一系列灵活的治疗选择，从每日服用的药片，到只需几个月一针的注射疗法，以及潜在一次性的碱基编辑疗法。展望未来，WuXi TIDES将持续基于其一体化CRDMO平台，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 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 dosing required only 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 Medicine noted 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. 参考资料（可上下滑动查看） [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. 免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，传递医学新知