Safety, Pharmacokinetic, and Pharmacodynamic Evaluation of a 2?-(2-Methoxyethyl)-D-ribose Antisense Oligonucleotide–Triantenarry <i>N</i>-Acetyl-galactosamine Conjugate that Targets the Human Transmembrane Protease Serine 6

Cellular uptake of antisense oligonucleotides (ASOs) is one the main determinants in vivo activity and potency. A significant advancement improving into cells has come through conjugation ASOs to triantenarry N-acetyl-galactosamine (GalNAc3), a ligand for asialoglycoprotein receptor on hepatocytes. The impact oligonucleotides, which are already taken up hepatocytes, 10-fold improvement potency mice 30-fold humans, resulting overall lower effective dose exposure levels. 2?-Methoxyethyl–modified oligonucleotide conjugated GalNAc3 (ISIS 702843) specific human transmembrane protease serine 6 currently clinical trials treatment ?-thalassemia. This report summarizes chronic toxicity study ISIS 702843 nonhuman primates (NHPs), including pharmacokinetic pharmacology assessments. Suprapharmacologic doses were well tolerated NHPs after dosing, data indicate that safety profile very similar unconjugated 2?-(2-methoxyethyl)-D-ribose (2?-MOE) ASOs. Notably, moiety did not cause any new toxicities nor exacerbate known nonspecific class effects 2?-MOE observation was confirmed with multiple GalNAc3-MOE conjugates by querying base monkey studies containing both GalNAc3-conjugated SIGNIFICANCE STATEMENT documents potency, pharmacology, tolerability (GalNAc3)-conjugated (ASO) cynomolgus monkey. Collective analysis 15 independent shows consistency response character hepatic platelet across sequences will result much larger margins when compared given increased