Abstract

Cellular uptake of antisense oligonucleotides (ASOs) is one of the main determinants of in vivo activity and potency. A significant advancement in improving uptake into cells has come through the conjugation of ASOs to triantenarry N-acetyl-galactosamine (GalNAc3), a ligand for the asialoglycoprotein receptor on hepatocytes. The impact for antisense oligonucleotides which are already taken up into hepatocytes, is a 10- to 30-fold improvement in potency, resulting in overall lower effective dose and exposure levels. ISIS 702843 is a GalNAc3-conjugated 2'-MOE ASO specific for human transmembrane protease, serine 6 (TMPRSS6), and is currently in clinical trials for the treatment of β-thalassemia. This report summarizes a chronic toxicity study of ISIS 702843 in nonhuman primates (NHP), including pharmacokinetic and pharmacology assessments. Suprapharmacologic doses of ISIS 702843 were well tolerated in NHP after chronic dosing, and the data indicate that the overall safety profile is very similar to that of the unconjugated 2'MOE ASOs. Notably, the GalNAc3 moiety did not cause any new toxicities, nor exacerbate the known non-specific class effects of the 2'-MOE ASOs. This observation was confirmed with multiple GalNAc3-MOE conjugates by querying a database of monkey studies containing both GalNAc3-conjugated and unconjugated 2'-MOE ASOs.

Significance Statement This report documents the potency, pharmacology and the overall tolerability profile of a GalNAc₃-conjugated 2'-MOE ASO specific to TMPRSS6 after chronic treatment in the cynomolgus monkey. Collective analysis of 15 independent GalNAc₃-conjugated and unconjugated 2'-MOE ASOs shows the consistency in the dose response and character of hepatic and platelet tolerability across sequences that will result in much larger safety margins for the GalNAc₃-conjugated 2'-MOE ASOs when compared to the unconjugated 2'MOE ASOs given the increased potency.