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-fold improvement in potency in mice and up to a 30-fold potency improvement in humans, resulting in overall lower effective dose and exposure levels. 2′-Methoxyethyl–modified antisense oligonucleotide conjugated to GalNAc3 (ISIS 702843) is specific for human transmembrane protease serine 6 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 (NHPs), including pharmacokinetic and pharmacology assessments. Suprapharmacologic doses of ISIS 702843 were well tolerated in NHPs after chronic dosing, and the data indicate that the overall safety profile is very similar to that of the unconjugated 2′-(2-methoxyethyl)-D-ribose (2′-MOE) ASOs. Notably, the GalNAc3 moiety did not cause any new toxicities nor exacerbate the known nonspecific class effects of the 2′-MOE ASOs. This observation was confirmed with multiple GalNAc3-MOE conjugates by querying a data base of monkey studies containing both GalNAc3-conjugated and unconjugated 2′-MOE ASOs.
SIGNIFICANCE STATEMENT This report documents the potency, pharmacology, and overall tolerability profile of a triantenarry N-acetyl-galactosamine (GalNAc3)-conjugated 2′-(2-methoxyethyl)-D-ribose (2′-MOE) antisense oligonucleotide (ASO) specific to transmembrane protease serine 6 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 with the unconjugated 2′-MOE ASOs given the increased potency.
Footnotes
- Received July 16, 2020.
- Accepted January 5, 2021.
Financial support for this project was provided by Ionis Pharmaceuticals, Inc.
The authors report the following disclosures. T.A.Z., J.A.E., Y.W., S.B., B.P., M.A., S.G., and S.P.H. are full-time Ionis employees and have stock or stock options in Ionis Pharmaceuticals. B.K. and L.B. have no conflicts of interest.
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This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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