寡核苷酸药物（ONTs）的致癌性评价正经历从“强制双种属2年试验”向“机制驱动的分级策略”的重要转变。ICH S1B（R1）引入的证据权重（WoE）方法允许在特定情况下豁免2年大鼠试验，而2024年启动的ICH S13草案进一步引入了“充分表征的ONTs”和“类别经验”概念，为ONTs的致癌性评价提供了更加灵活的框架。系统梳理ICH S1系列指导原则的演变及WoE方法的应用边界，对24个已上市ONTs的致癌性试验数据进行全面汇总与分析。12个品种完成了大鼠2年致癌性试验（完成率50.0%），11个品种开展了转基因小鼠6个月致癌性试验（完成率45.8%）；其中Mipomersen和Volanesorsen双种属结果均呈阳性，Fitusiran、Inclisiran、Eteplirsen等双种属结果均呈阴性，而Inotersen呈现“转基因小鼠阴性、大鼠阳性”的差异性结果。基于上述分析及ICH S13草案决策树，提出了4级分级评价策略——数据有限的ONTs采用双种属策略、充分表征ONTs（靶点风险未知）采用单种属策略、充分表征ONTs（靶点风险已知可控）采用平台数据豁免策略、特殊给药途径采用个案策略，旨在为ONTs致癌性试验的设计与监管沟通提供参考。

The carcinogenicity assessment of oligonucleotide-based therapeutics (ONTs) is undergoing a paradigm shift from “mandatory two-species 2-year studies” to “mechanism-driven, tiered strategies”. The weight of evidence (WoE) approach introduced by ICH S1B(R1) allows for waiver of the 2-year rat study under specific circumstances, while the ICH S13 draft guideline initiated in 2024 further introduces the concepts of “well-characterised ONTs” and “class experience”, providing a more flexible framework for the carcinogenicity assessment of ONTs. This article systematically reviews the evolution of the ICH S1 guidance series and the application boundaries of the WoE approach, and comprehensively summarizes and analyzes carcinogenicity study data from 24 marketed ONTs. The results show that 12 products completed 2-year rat carcinogenicity studies (completion rate, 50.0%), and 11 products conducted 6-month transgenic mouse carcinogenicity studies (completion rate, 45.8%). Among them, mipomersen and volanesorsen showed positive results in both species; fitusiran, inclisiran, eteplirsen, etc. were negative in both species; while inotersen presented a discordant result (negative in transgenic mice and positive in rats). Based on the above analysis and the ICH S13 draft decision tree, this article proposes a four-tiered carcinogenicity evaluation strategy—two-species strategy for ONTs with limited data, single-species strategy for well-characterised ONTs with unknown target risk, platform data waiver strategy for well-characterised ONTs with known and manageable target risk, and case-by-case strategy for special routes of administration—to provide a reference for the design of carcinogenicity studies and regulatory communication for ONTs.

R979.1

中国药品检定研究院关键技术研究基金（GJJSYJ202401）；国家重点研发计划资助项目（2025YFF0730400）