Navigating Complexities in Oligonucleotides: DMPK Strategies and CNS-Targeting Solutions

Oligonucleotides have emerged as a rapidly growing class of therapeutics in recent years, with nearly 20 oligonucleotide-based drugs approved by the U.S. FDA to date. However, due to their novelty, chemical complexity, and evolving regulatory landscape, oligonucleotides have more technical challenges and uncertainties for drug developers compared to conventional small molecules and biologics. As such, oligonucleotides require pharmacokinetic (PK) evaluation systems that differ from traditional assays in significant ways. With advancements in delivery, including conjugation technologies and nanoparticles, the complexity and necessity of early PK evaluation also increases. In the preclinical development stage, study strategies must be customized according to the unique characteristics of the oligonucleotide to accelerate its development. For in vitro ADME study, it is necessary to select an appropriate in vitro metabolic model based on the structural characteristics of the drug and the in vitro-in vivo extrapolation (IVIVE); for in vivo PK study, different administration methods can be used to investigate the PK properties.

In this session, we will share our strategies to tackle these DMPK challenges and accelerate oligonucleotide drug development. We have accumulated rich experience in early-stage screening studies as well as IND filings of oligonucleotides.

Targeted CNS oligonucleotide drugs primarily enter the brain through administration via the nervous system. Methods of nervous system administration include cerebrospinal fluid injection (ventricular injection, cisterna magna injection, lumbar injection) and nasal administration, with lumbar injection being the most widely used due to its relative simplicity and the ability for repeated administration. After years of refining technical details, a standardized administration platform has been established. This webinar aims to comprehensively introduce the technical details of lumbar administration in monkeys.