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Research ArticleToxicology

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

Thomas A. Zanardi, Birgit Korbmacher, Laura Boone, Jeffrey A. Engelhardt, Yanfeng Wang, Sebastien Burel, Bobby Prill, Mariam Aghajan, Shuling Guo and Scott P. Henry
Journal of Pharmacology and Experimental Therapeutics April 2021, 377 (1) 51-63; DOI: https://doi.org/10.1124/jpet.120.000222
Thomas A. Zanardi
Ionis Pharmaceuticals, Carlsbad, California (T.A.Z., J.A.E., Y.W., S.B., B.P., M.A., S.G., S.P.H.), and Covance Preclinical Services GmbH, Munster, Germany (B.K., L.B.)
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Birgit Korbmacher
Ionis Pharmaceuticals, Carlsbad, California (T.A.Z., J.A.E., Y.W., S.B., B.P., M.A., S.G., S.P.H.), and Covance Preclinical Services GmbH, Munster, Germany (B.K., L.B.)
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Laura Boone
Ionis Pharmaceuticals, Carlsbad, California (T.A.Z., J.A.E., Y.W., S.B., B.P., M.A., S.G., S.P.H.), and Covance Preclinical Services GmbH, Munster, Germany (B.K., L.B.)
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Jeffrey A. Engelhardt
Ionis Pharmaceuticals, Carlsbad, California (T.A.Z., J.A.E., Y.W., S.B., B.P., M.A., S.G., S.P.H.), and Covance Preclinical Services GmbH, Munster, Germany (B.K., L.B.)
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Yanfeng Wang
Ionis Pharmaceuticals, Carlsbad, California (T.A.Z., J.A.E., Y.W., S.B., B.P., M.A., S.G., S.P.H.), and Covance Preclinical Services GmbH, Munster, Germany (B.K., L.B.)
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Sebastien Burel
Ionis Pharmaceuticals, Carlsbad, California (T.A.Z., J.A.E., Y.W., S.B., B.P., M.A., S.G., S.P.H.), and Covance Preclinical Services GmbH, Munster, Germany (B.K., L.B.)
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Bobby Prill
Ionis Pharmaceuticals, Carlsbad, California (T.A.Z., J.A.E., Y.W., S.B., B.P., M.A., S.G., S.P.H.), and Covance Preclinical Services GmbH, Munster, Germany (B.K., L.B.)
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Mariam Aghajan
Ionis Pharmaceuticals, Carlsbad, California (T.A.Z., J.A.E., Y.W., S.B., B.P., M.A., S.G., S.P.H.), and Covance Preclinical Services GmbH, Munster, Germany (B.K., L.B.)
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Shuling Guo
Ionis Pharmaceuticals, Carlsbad, California (T.A.Z., J.A.E., Y.W., S.B., B.P., M.A., S.G., S.P.H.), and Covance Preclinical Services GmbH, Munster, Germany (B.K., L.B.)
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Scott P. Henry
Ionis Pharmaceuticals, Carlsbad, California (T.A.Z., J.A.E., Y.W., S.B., B.P., M.A., S.G., S.P.H.), and Covance Preclinical Services GmbH, Munster, Germany (B.K., L.B.)
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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.

  • https://doi.org/10.1124/jpet.120.000222.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 377 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 377, Issue 1
1 Apr 2021
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Research ArticleToxicology

Tolerability Profile of a GalNAc3-Conjugated ASO in Monkeys

Thomas A. Zanardi, Birgit Korbmacher, Laura Boone, Jeffrey A. Engelhardt, Yanfeng Wang, Sebastien Burel, Bobby Prill, Mariam Aghajan, Shuling Guo and Scott P. Henry
Journal of Pharmacology and Experimental Therapeutics April 1, 2021, 377 (1) 51-63; DOI: https://doi.org/10.1124/jpet.120.000222

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Research ArticleToxicology

Tolerability Profile of a GalNAc3-Conjugated ASO in Monkeys

Thomas A. Zanardi, Birgit Korbmacher, Laura Boone, Jeffrey A. Engelhardt, Yanfeng Wang, Sebastien Burel, Bobby Prill, Mariam Aghajan, Shuling Guo and Scott P. Henry
Journal of Pharmacology and Experimental Therapeutics April 1, 2021, 377 (1) 51-63; DOI: https://doi.org/10.1124/jpet.120.000222
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