Clinical Pharmacology of RNA Interference–Based Therapeutics: A Summary Based on Food and Drug Administration–Approved Small Interfering RNAs

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 The FDArecently published a draft guidance for clinical pharmacology considerations for developing oligonucleotide therapeutics.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.