Introduction: Triantennary N-acetyl galactosamine (GalNAc₃) – conjugated antisense oligonucleotides (ASOs) have demonstrated improved hepatocyte uptake and pharmacologic activity over their parent unconjugated ASOs in animals and humans.

Areas covered: In this review, the ADME (absorption, distribution, metabolism, and excretion) characteristics of GalNAc₃-conjugated ASOs in animals and in humans are summarized, and their clinical relevance is evaluated from the clinical pharmacology perspectives.

Expert opinion: ASOs distribute to tissues via receptor-mediated processes, and conjugation to a ligand specific to certain cell types can improve target tissue delivery. GalNAc₃-conjugation represents a good example on this regard and has demonstrated ideal characteristics of a prodrug to target delivery of ASOs to hepatocytes via the asialoglycoprotein receptor (ASGPR). The improved potency and safety margin permit more flexible dosing (e.g. monthly or less frequently if needed) taking full advantage of the long half-life of the parent ASO in humans. However, while still speculative, it should be noted that ASGPR-mediated uptake could become nonlinear with dose and factors that impact ASGPR expression or compete with ASGPR-mediated uptake could potentially affect the uptake of GalNAc₃-conjugated ASOs, further studies are warranted.