Challenges and Opportunities of RNA Therapeutics, A Roller Coaster from Discovery to Recovery II: Translational Science with an Emphasis on Special Populations

Session Description

Antisense oligonucleotide (ASO) therapeutics are versatile molecules that can specifically target and modify RNA transcripts, interfering with mRNA activity in the cells, and elicit a pharmacological effect at a level upstream of the protein. ASOs share similar pharmacokinetic properties within class and linear pharmacokinetic in preclinical species.

Little attention has been paid to oligonucleotide tissue distribution and subcellular distribution which determines their functional activity and is affected by inter-individual variation in special populations. The session will provide a comprehensive overview of development of an ASO targeting Huntington’s disease, from discovery to approval. The session will focus on ADME properties of a few approved ASOs and provide a deep understanding of critical considerations when it comes to ASO administration to different populations including pediatrics, geriatrics, pregnancy, renal and hepatic impairment.

To be more ambitions for patients an overview of mechanistic modelling will present current understanding of underlying mechanisms and inter-subject variability for successful translation of these therapeutics from bench to bedside. While the magnitude of this variability is variable in special populations, physiologically based pharmacokinetic models can be utilized in predicting exposure, concentrations at the site of action. For developing such models, information on PK, dynamics of binding to cell surface, endocytosis and tissue distribution and accumulation and physiological parameters in each populations is required.

This session will cover examples of ASO ADME is special populations, discovery and development in special populations and rare disease, and the application of quantitative approaches to predict dosing regimens by integrating (pre)clinical data.

By bringing together clinicians and researchers, the session aims to initiate a dialogue on how to make informed clinical decisions when dealing with these new modalities in drug development. Participants will gain an understanding of applying recent advancements in their research and clinical practices with potential impacts on global health policy.

Learning Objectives

1. Gain insights on ADME properties of ASOs in healthy and diseased populations
2. Gather an overview of the clinical pharmacology considerations of ASOs in special populations.
3. Understand latest developments on utilization of in-silico models to predict pharmacokinetics of ASOs, input data to models, data gaps and dose adjustment in special population.

Session Schedule

Introduction
Bianca van Groen, PharmD, PhD

Clinical Pharmacology and Quantitative Analysis to Support Tominersen Clinical Development in Huntington’s Disease
Patricia Sanwald-Ducray, PharmD, PhD

Predicting Pharmacokinetics of Bepirovirsen: A Physiologically Based Approach for Antisense Oligonucleotide Therapeutics in Patients
Farzaneh Salem, PharmD, PhD

Impact of Altered Physiology on the ADME Characteristics of ASOs in Special Populations
Nina Isoherranen, MS, PhD

Q&A and Closing Remarks