An Evaluation of First-in-Human Studies for RNA Oligonucleotides

Most oligonucleotide therapeutics use Watson-Crick-Franklin base-pairing hybridization to target RNA and mitigate disease-related protein production. Using targets that were previously inaccessible to small molecules and biologics, synthetic nucleotides have provided treatments for severely debilitating and life-threatening diseases. However, these therapeutics possess unique pharmacologies that require specific considerations for their distribution, clearance, and other clinical pharmacology characteristics. Namely, one hurdle in the drug development of these therapeutics remains the prediction of human dose that results in exposures comparable with or below those seen at no observed adverse effect level in animals. For first-in-human (FIH) clinical trials, this often involves allometric scaling based on body surface area (BSA) or body weight (BW). In this study, we reviewed the current literature and surveyed elements across 16 approved oligonucleotide therapeutic New Drug Applications approved by the U.S. Food and Drug Administration in the period from September 1998 to January 2024, and 89 Investigational New Drug (IND) programs with available FIH clinical trials conducted from January 2015 to January 2024, to understand dose selection in early-stage development of oligonucleotide therapeutics. The surveyed elements across these programs include study design, route of administration, dosing regimen, interspecies scaling approach, and the most sensitive species. Of 89 IND programs and 16 approved therapeutics, intravenous and subcutaneous were the most common route of administration, no observable adverse event levels were frequently derived from nonhuman primates, BSA and BW were adjusted for in similar frequencies, patients were predominantly enrolled in FIH trials, and the most common design was a single or multiple ascending dose trial.