Clinical Pharmacokinetics of Second Generation Antisense Oligonucleotides

Introduction: Multiple "second generation" gapmer antisense oligonucleotides (ASOs) of varying chemistries have been evaluated as potential therapeutic agents in the clinic. Compared to first generation chemistries, second generation ASOs consistently demonstrate greater biological stability, greater in vitro/in vivo potency, and less non-hybridization based toxicities.

Areas Covered: The authors summarize previously publshed clinical pharmacokinetic (PK) properties of second generation ASOs following intravenous or subcutaneous administration.

Expert Opinion: Our understanding of potential roles of RNAs in maintaining normal health and contribution to various diseases is increasing; thus directly targeting RNAs (with second generation ASOs) present a compelling therapeutic strategy. Further, the similar clinical PK properties across the class of second generation ASOs helps facilitate their clinical development. The majority of published information available for assessment is restricted to acute/sub-acute early clinical development. A limited but growing database on chronic dosing of second generation ASOs, across various patient and special populations, and also with non-systemic local delivery approaches, will help further characterize the clinical PK properties of these compounds and better quantify the extent and sources of any observed PK variability and potential impact on clinical response.