消减腹部脂肪的创新siRNA疗法

据世界卫生组织（WHO）的统计，自1990年以来，全球肥胖成人数目翻了一番，截至2022年已有超过10亿人患有肥胖症。肥胖显著提高心血管疾病、糖尿病、代谢障碍相关性脂肪性肝炎（MASH）等多种慢性病的风险，已成为全球性的重大公共健康挑战。

近年来，GLP-1类药物在肥胖和相关代谢疾病治疗中表现出显著疗效。产业界在持续挖掘GLP-1及其它肠促胰岛素通路潜力的同时，也开始关注其它体重调节相关的创新靶点，为肥胖治疗打开新的方向。例如，2022年发表在Nature Communications上的一项研究揭示了与腹部脂肪减少相关的关键基因突变。研究发现，INHBE基因的突变与较低的腰臀比相关。携带该突变的人群同时表现出甘油三酯水平降低、高密度脂蛋白胆固醇（HDL，俗称“好”胆固醇）水平升高，空腹血糖水平下降等有利于代谢健康的特征。

INHBE编码的激活素E（activin E）是一种由肝脏分泌的细胞因子，可与脂肪组织中的ACVR1C（又名ALK7）受体结合，抑制脂肪分解（lipolysis），从而促进腹部脂肪堆积，增加肥胖症、心血管疾病和2型糖尿病的风险。

针对该信号通路，多家生物技术公司正在开发靶向INHBE和/或ACVR1C的siRNA疗法，通过降低信号通路中配体或受体的表达水平，以激活脂肪分解，从而实现减重并降低心血管疾病和糖尿病的发病风险。目前，多款靶向INHBE的siRNA药物已进入临床开发阶段。在临床前研究中，它们与低剂量GLP-1受体激动剂联用，可在减少更多脂肪的同时保留肌肉质量，并有助于减轻GLP-1类药物停药后的体重反弹。

这些靶向INHBE的siRNA疗法普遍采用GalNAc偶联技术，以实现对肝脏的高特异性递送。自GalNAc递送技术问世以来，经过持续迭代，已在siRNA药物开发领域得到广泛应用。目前已上市的7款siRNA药物中，有6款采用了GalNAc偶联技术。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。

除GalNAc之外，WuXi TIDES全面的平台能力包括寡核苷酸、多肽和⼩分⼦，涵盖配体、毒素、连接子、脂质、PEG等，可以为复杂的寡核苷酸偶联药物提供一站式解决方案。

今年发表在《自然》的一篇文章表示，减重治疗正进入一个飞速发展的新阶段。随着创新疗法的不断涌现，肥胖治疗正迈向集药物干预、生活方式管理和个体化医学融合的综合模式，共同应对这一日益严峻的全球健康挑战。药明康德将持续聚焦独特的“一体化、端到端”CRDMO模式，助力合作伙伴将更多创新减重药物快速、高质量地推向全球市场，造福更多患者。

CRDMO: Accelerating the Next Generation of Weight-Loss Therapies

With the impressive clinical performance of GLP-1 drugs in obesity treatment, the development of weight-loss therapies has become a major focus in the global pharmaceutical industry. While GLP-1 based therapies currently dominate the field, researchers are increasingly exploring novel mechanisms beyond GLP-1. Thanks to advances in delivery technologies such as GalNAc conjugation, siRNA therapies targeting liver and fat metabolism pathways are emerging as promising long-acting treatments—requiring only one injection every few months while sustaining meaningful weight loss. Several of these candidates are now progressing through clinical development.

To support the growing R&D needs of global partners, WuXi TIDES, a unique CRDMO platform that is part of WuXi AppTec, has established an integrated service platform for siRNA and other oligonucleotide therapies. This platform covers all types of oligonucleotides, their monomers, linkers, ligands and conjugates. It supports all stages of development, from drug discovery and CMC development to commercial-scale manufacturing. This article explores the progress of siRNA therapies for obesity and showcases how WuXi TIDES empowers the development of oligonucleotide-based drugs, including siRNAs, through its integrated CRDMO platform.

Innovative siRNA Therapies Targeting Abdominal Fat

According to the World Health Organization (WHO), the global population of obese adults has doubled since 1990, with more than 1 billion people affected by obesity as of 2022. Obesity dramatically increases the risk of cardiovascular disease, diabetes, and metabolic dysfunction-associated steatohepatitis (MASH), posing a significant public health burden worldwide.

While GLP-1 therapies have delivered strong efficacy in treating obesity and associated metabolic conditions, the industry is actively investigating alternative therapeutic pathways. One promising direction is the exploration of new targets involved in fat distribution and metabolic health. For instance, a 2022 study published in Nature Communications identified a key mutation linked to reduced abdominal fat. Specifically, mutations in the INHBE gene were associated with a lower waist-to-hip ratio, along with favorable metabolic markers such as decreased triglyceride levels, elevated HDL cholesterol (commonly referred to as “good” cholesterol), and lower fasting glucose.

The INHBE gene encodes activin E, a liver-secreted cytokine that binds to the ACVR1C receptor (also known as ALK7) in adipose tissue, suppressing lipolysis and promoting abdominal fat accumulation. This mechanism contributes to heightened risks of obesity, cardiovascular disease, and type 2 diabetes.

To counteract this pathway, several biotech companies are developing siRNA therapies targeting INHBE and/or ACVR1C. By reducing the expression of either the ligand or receptor, these therapies enhance lipolysis and promote fat loss, potentially reducing cardiometabolic disease risk. Several siRNA candidates targeting INHBE are already in clinical development. In preclinical studies, combining these agents with low-dose GLP-1 receptor agonists enhanced fat loss while preserving muscle mass and reduced weight rebound after stopping GLP-1 therapy.

GalNAc Conjugation: Enabling Liver-Targeted siRNA Delivery

Most siRNA therapies rely on GalNAc conjugation for precise liver targeting. Since its introduction, GalNAc delivery technology has undergone continuous innovation and is now a cornerstone of siRNA drug development. Of the seven FDA-approved siRNA drugs to date, six utilize GalNAc conjugation.

As this technology matures, the synthesis and process development of GalNAc-conjugated therapeutics have become 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 capability 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 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, WuXi TIDES 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. 

Beyond GalNAc, WuXi TIDES’ strong capabilities extend to oligonucleotides, peptides, and small molecules, including ligands, toxins, linkers, lipids, PEG, and more. We are well positioned to provide a one-stop solution for complex oligonucleotide-based conjugated drugs, from discovery through development to commercial manufacturing. 

Toward a New Era in Obesity Treatment

A recent article in Nature highlighted that weight-loss therapies are entering a period of rapid evolution. With the emergence of innovative therapies, obesity treatment is shifting toward a more integrated model—combining pharmacological intervention, lifestyle management, and personalized medicine. This multifaceted approach is essential to tackling one of the most pressing global health challenges of our time.

WuXi AppTec remains committed to its unique integrated, end-to-end CRDMO model, helping partners rapidly and reliably bring innovative weight-loss therapies to market—delivering better outcomes for patients around the world.

参考资料：

[1] Arrowhead Pharmaceuticals Showcases Two Clinical-Stage RNAi-Based Candidates to Treat Obesity and Metabolic Diseases. Retrieved July 16, 2025, from https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-pharmaceuticals-showcases-two-clinical-stage-rnai

[2] Wave Life Sciences Announces Initiation of Phase 1 INLIGHT Clinical Trial of WVE-007 in Obesity. Retrieved July 16, 2025, from https://www.globenewswire.com/news-release/2025/02/06/3022032/0/en/Wave-Life-Sciences-Announces-Initiation-of-Phase-1-INLIGHT-Clinical-Trial-of-WVE-007-in-Obesity.html

[3] Alnylam R&D Day. Retrieved July 16, 2025, from https://capella.alnylam.com/wp-content/uploads/2025/02/Alnylam-RD-Day-2025.pdf

[4] Dozens of new obesity drugs are coming: these are the ones to watch. Retrieved February 27, 2025, from https://www.nature.com/articles/d41586-025-00404-9?linkId=12914818

[5] Obesity and overweight. Retrieved February 27, 2025, from https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight

[6] Wave Life Sciences Research Day. Retrieved July 17, 2025, from https://ir.wavelifesciences.com/static-files/a5c9e0ba-6662-41a9-a33b-400938d637c2