同行致远 | 有望明年递交上市申请！这类治疗模式正拓展代谢治疗新边界 | Bilingual

（来源：药明康德）

转自：药明康德

编者按：近年来，胰高血糖素样肽-1受体激动剂（GLP-1RAs）在糖尿病与肥胖等代谢性疾病的治疗中持续取得突破，正在重塑全球治疗范式。随着多肽类GLP-1RAs的广泛应用与小分子GLP-1RAs的快速崛起，GLP-1疗法正由单纯“控糖”迈向“综合代谢管理”。其中，小分子GLP-1RAs凭借口服便利与易于规模化生产等优势，有望进一步提升患者依从性，并推动个体化的代谢疾病管理。长期以来，药明康德依托一体化、端到端CRDMO平台，深度参与并赋能全球GLP-1药物的发现、开发与生产，助力新一代GLP-1疗法加速从创新走向临床应用，造福更多患者。

在过去几年里，胰高血糖素样肽-1受体激动剂（GLP-1RAs）深刻改变了2型糖尿病（T2DM）和肥胖的治疗格局。通过增强胰岛素分泌、抑制胰高血糖素释放，并帮助减少食欲以促进体重管理，这类疗法不仅实现了持续、稳定的血糖控制，也带来了显著且持久的临床改善。随着疗效的不断验证，GLP-1RAs在改善代谢与心血管预后方面发挥了重要作用，推动治疗理念从单纯“控糖”迈向更全面的代谢疾病综合管理。

在多肽类GLP-1RAs持续提升疗效的同时，可口服、易于规模化生产的小分子GLP-1RAs正成为新的突破方向。这类药物具有化学性质稳定、生产工艺成熟等优势，且无需额外的渗透增强剂即可口服使用，有望进一步提升全球患者的治疗可及性与用药便利性，为更多患者带来更优的治疗体验。

在作用机制上，小分子GLP-1RAs通过创新的受体结合策略，如变构调节、偏向性激动和选择性激活G蛋白通路等，精准模拟多肽类似物的疗效优势。借助高分辨率结构数据的支持，这类药物有望实现更精细的受体信号调控，同时保持良好的药代动力学特征和口服生物利用度。

值得一提的是，小分子GLP-1RAs的出现也为联合治疗开辟了新的空间。其口服、与进食无关的剂型特点，使其能够与SGLT2抑制剂或二甲双胍等已获批口服药物联合，开发为固定剂量的复方制剂。此类联合方案可在血糖管理、体重控制及心代谢保护方面形成协同效应，实现多靶点、多通路的疾病调控，从源头上降低心血管及肾脏疾病风险。同时，简化的给药方案有助于提升患者长期依从性。

目前，临床进展最快的小分子GLP-1RAs之一正处于治疗T2DM患者的3期临床试验阶段。已公布的临床数据显示，该疗法在降低糖化血红蛋白（A1C）水平和体重方面均表现出显著疗效，预计将于2026年向全球监管机构递交上市申请。

需要强调的是，小分子与多肽类GLP-1RAs并非相互替代，而是相辅相成。两类治疗模式的协同发展，不仅拓展了患者的治疗选择，也让临床医生能够根据患者特征、生活方式及照护需求制定更具针对性的个体化治疗方案，从而进一步提升疗效与生活质量。

药明康德化学业务平台以一体化、端到端的CRDMO模式，自上而下贯穿药物发现（R）、开发（D）到商业化生产（M）全链条，业务范围覆盖从早期研发到规模化制造的每个环节，致力于为全球合作伙伴提供快速、灵活、高效、可靠的小分子、寡核苷酸、多肽及各种复杂偶联物新药研发一站式解决方案。

在今年9月举办的药明康德投资者开放日活动上公布的数据显示，全球有近百款GLP-1RAs处于临床试验阶段或已上市，其中23款由药明康德化学业务平台支持。展望未来，药明康德将继续秉持“让天下没有难做的药，难治的病”的愿景，依托全球研发基地与生产网络，凭借独特的一体化、端到端CRDMO模式，持续推动新一代GLP-1药物的开发进程，造福全球患者。

Small-Molecule GLP-1 Receptor Agonists: Expanding the Horizon of Metabolic Disease Treatment

In recent years, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have achieved continuous breakthroughs in the treatment of diabetes and obesity, reshaping the global therapeutic paradigm. With the widespread adoption of peptide-based GLP-1RAs and the rapid emergence of small-molecule GLP-1RAs, GLP-1 therapies are evolving from a focus on “glycemic control” toward comprehensive metabolic management. Among them, small-molecule GLP-1RAs—offering the advantages of oral convenience and scalable manufacturing—hold great promise in enhancing patient adherence and advancing personalized management of metabolic diseases. Leveraging its fully integrated, end-to-end CRDMO platform, WuXi AppTec has long been deeply involved in and empowering the global discovery, development, and manufacturing of GLP-1 therapies. WuXi AppTec continues to help accelerate the innovation and clinical translation of next-generation GLP-1 therapeutics, bringing transformative treatments to patients around the world.

Over the past few years, GLP-1RAs have transformed care for type 2 diabetes mellitus (T2DM) and obesity. By enhancing glucose-stimulated insulin secretion, suppressing glucagon, and curbing appetite to support weight loss, these therapies deliver sustained glycemic control and meaningful clinical benefits. Their success has reset clinical expectations, improving metabolic and cardiovascular outcomes and ushering in a new era that addresses not only blood glucose but also the broader drivers of metabolic disease.

While peptide-based GLP-1RAs continue to elevate patient outcomes, the emergence of orally available, small-molecule GLP-1RAs opens a complementary frontier. These agents are chemically stable, readily manufactured at scale, and suitable for oral dosing without permeation enhancers, which expands accessibility and convenience for patients worldwide.

Mechanistically, small-molecule GLP-1RAs recapitulate the beneficial signaling of peptide analogs through novel receptor-engagement strategies, including allosteric modulation, biased agonism, and selective activation of G-protein–mediated pathways. Supported by high-resolution structural insights, these approaches enable precise control of receptor signaling while maintaining favorable pharmacokinetics and oral bioavailability.

The emergence of small-molecule GLP-1RAs is opening new possibilities for combination therapy. Their oral, food-independent formulation enables convenient co-administration with approved oral agents such as SGLT2 inhibitors or metformin to create fixed-dose combination regimens. These combinations may deliver synergistic benefits in glucose control, weight management, and cardiometabolic protection, while offering multi-target, multi-pathway modulation to help reduce cardiovascular and renal risks at their source. At the same time, a simplified dosing regimen can further improve long-term treatment adherence among patients.

Currently, one of the most advanced oral small-molecule GLP-1RAs is in Phase 3 clinical trials for patients with type 2 diabetes (T2DM). Published clinical data have demonstrated significant reductions in both A1C and body weight. The therapy is expected to be submitted for regulatory approval worldwide in 2026.

Importantly, small-molecule and peptide-based GLP-1RAs should not be viewed as competing alternatives but as complementary therapeutic options. Together, they expand the spectrum of treatment possibilities, enabling physicians to tailor personalized regimens based on patients’ characteristics, lifestyles, and care needs—ultimately improving clinical outcomes and enhancing quality of life.

WuXi AppTec’s Chemistry platform adopts an integrated, end-to-end CRDMO model that seamlessly connects drug discovery (R), development (D), and commercial manufacturing (M). Covering every stage from early discovery to large-scale production, the platform is committed to providing global partners with fast, flexible, efficient, and reliable one-stop small-molecule, oligonucleotides, peptides, and complicated conjugates drug development solutions.

According to data shared at WuXi AppTec’s Investor Day in September, nearly 100 GLP-1 receptor agonists are currently in clinical development or already on the market globally, with 23 supported by WuXi AppTec’s chemistry platform. Looking ahead, WuXi AppTec will continue to support the advancement of next-generation GLP-1 therapies through its unique integrated, end-to-end CRDMO platform, helping bring innovative therapeutic options to patients worldwide.

参考资料：

[1] Oral Small-Molecule GLP-1 Receptor Agonists: Mechanistic Insights and Emerging Therapeutic Strategies. Retrieved October 20, 2025 from https://www.mdpi.com/2218-0532/93/2/26

[2] Lilly's oral GLP-1, orforglipron, superior to oral semaglutide in head-to-head trial. Retrieved October 20, 2025 from https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-superior-oral-semaglutide-head

[3] WuXi Chemistry: A Global Leading CRDMO Platform. Retrieved November 3, 2025 from https://officialsite-static.wuxiapptec.com/upload/WXAT_2025_Investor_Day_Wu_Xi_Chemistry_CRDMO_bfb07e912d.pdf