Divisions of Infectious Disease Pharmacology (X.J., V.A., K.S.R.) and Translational and Precision Medicine (H.R.), Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland
Divisions of Infectious Disease Pharmacology (X.J., V.A., K.S.R.) and Translational and Precision Medicine (H.R.), Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland.
Drug Metab Dispos. 2023 Feb;51(2):193-198. doi: 10.1124/dmd.122.001107. Epub 2022 Nov 4.
RNA-based oligonucleotide therapeutics are revolutionizing drug development for disease treatment. This class of therapeutics differs from small molecules and protein therapeutics in various ways, including both its mechanism of action and clinical pharmacology characteristics. These unique characteristics, along with evolving oligonucleotide-associated conjugates allowing specific tissue targeting, have fueled interest in the evaluation of RNA-based oligonucleotide therapeutics in a rapidly increasing number of therapeutic areas. With these unique attributes as well as growing therapeutic potential, oligonucleotide therapeutics have generated significant interest from a clinical pharmacology perspective. The Food and Drug Administration (FDA) previously published results of a survey that summarized clinical pharmacology studies supporting oligonucleotide therapies approved and in development between 2012 and 2018. Since the first approval of a small interfering RNA (siRNA) therapeutic in 2018, this class of modalities has gained momentum in various therapeutic areas. Hence, a comprehensive examination of the clinical pharmacology of FDA-approved siRNA therapeutics would benefit the path forward for many stakeholders. Thus, in this current review, we thoroughly examine and summarize clinical pharmacology data of the FDA-approved siRNA therapeutics approved from 2018 (year of first approval) to 2022, aimed at facilitating future drug development and regulatory decision making. SIGNIFICANCE STATEMENT: This review systematically summarizes the clinical pharmacology information of Food and Drug Administration (FDA)-approved small interfering RNAs (siRNA) therapeutics. SiRNAs are revolutionizing the drug development field. Unique clinical pharmacology characteristics represent a differentiating factor for this class of therapeutics. The FDArecently published a draft guidance for clinical pharmacology considerations for developing oligonucleotide therapeutics. As clinical development of this class of therapeutics is fast growing, this review will inform discovery and clinical-stage evaluation of upcoming siRNA-associated drug candidates.
基于 RNA 的寡核苷酸疗法正在彻底改变疾病治疗的药物开发。这类疗法在作用机制和临床药理学特征等方面与小分子和蛋白质疗法存在差异。这些独特的特性，以及不断发展的与寡核苷酸相关的缀合物允许特定的组织靶向，激发了人们对在越来越多的治疗领域评估基于 RNA 的寡核苷酸疗法的兴趣。由于这些独特的特性和不断增长的治疗潜力，寡核苷酸疗法引起了临床药理学领域的极大兴趣。美国食品和药物管理局（FDA）之前公布了一项调查结果，该调查总结了支持 2012 年至 2018 年期间批准和开发的寡核苷酸疗法的临床药理学研究。自 2018 年批准首个小干扰 RNA（siRNA）疗法以来，这类治疗方法在各种治疗领域取得了进展。因此，全面检查 FDA 批准的 siRNA 疗法的临床药理学将有益于许多利益相关者的前进道路。因此，在当前的综述中，我们彻底检查并总结了 2018 年（首次批准年）至 2022 年期间 FDA 批准的 siRNA 疗法的临床药理学数据，旨在促进未来的药物开发和监管决策。意义陈述：本综述系统总结了美国食品和药物管理局（FDA）批准的小干扰 RNA（siRNA）疗法的临床药理学信息。siRNA 正在彻底改变药物开发领域。独特的临床药理学特征是这类疗法的区别因素。FDA 最近发布了一份关于开发寡核苷酸疗法的临床药理学考虑因素的指南草案。随着这类治疗方法的临床开发迅速增长，本综述将为即将出现的与 siRNA 相关的候选药物的发现和临床评估提供信息。
