Integrated Assessment of the Clinical Performance of GalNAc 3 -Conjugated 2′- O -Methoxyethyl Chimeric Antisense Oligonucleotides: I. Human Volunteer Experience
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Advances in medicinal chemistry have produced new chemical classes of antisense oligonucleotides (ASOs) with enhanced therapeutic properties. Conjugation of the triantennary N -acetylgalactosamine (GalNAc 3 ) moiety to the extensively characterized phosphorothioate (PS)-modified 2′- O -methoxyethyl (2′MOE) ASO exemplifies such an advance. This structure-activity optimized moiety effects receptor-mediated uptake of the ASO prodrug through the asialoglycoprotein receptor 1 to support selective targeting of RNAs expressed by hepatocytes. In this study we report the integrated assessment of data available from randomized placebo-controlled dose-ranging studies of this chemical class of ASOs administered systemically to healthy human volunteers. First, we compare the pharmacokinetic and pharmacodynamic profiles of a subset of the GalNAc 3 -conjugated PS-modified 2′MOE ASOs to the parent PS-modified 2′MOE ASOs for which plasma analytes are available. We then evaluate the safety profile of the full set of GalNAc 3 -conjugated PS-modified 2′MOE ASO conjugates by the incidence of signals in standardized laboratory tests and by the mean laboratory test results as a function of dose level over time. With hepatocyte targeted delivery, the ED 50 for the GalNAc 3 -conjugated PS-modified 2′MOE ASO subset ranges from 4 to 10 mg/week, up to 30-fold more potent than the parent PS-modified 2′MOE ASO. No GalNAc 3 -conjugated PS-modified 2′MOE ASO class effects were identified from the assessment of the integrated laboratory test data across all doses tested with either single or multidose regimens. The increase in potency supports an increase in the safety margin for this new chemical class of ASOs now under broad investigation in the clinic. Although the total exposure is limited in the initial phase 1 trials, ongoing and future investigations in patient populations will support evaluation of the effects of long-term exposure.
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Reduced renal function and platelet count have been observed with some first-generation antisense oligonucleotides.
“With regard to safety, there were no confirmed instances of reduced renal function or platelet count with vupanorsen, 2 issues that have been observed with some first-generation antisense oligonucleotides.16,17”
From Effect of Vupanorsen on Non–High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70 (2022) · cites this paper as [17]
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IONIS-PKK Rx a Novel Antisense Inhibitor of Prekallikrein and Bradykinin Production
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Self-citationMeeting the needs of patients with ultrarare diseases
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Transport Oligonucleotides—A Novel System for Intracellular Delivery of Antisense Therapeutics
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Self-citationAntisense oligonucleotide is a promising intervention for liver diseases
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Self-citation
- Authors
- Crooke, S. T., Baker, B. F., Xia, S., Yu, R. Z., Viney, N. J., Wang, Y., Tsimikas, S., & Geary, R. S.
- Affiliations
- Ionis Pharmaceuticals (United States) (US)
- Corresponding author
- Crooke, Stanley T.
- ORCID
- Venue
- Nucleic Acid Therapeutics
- Publisher
- SAGE Publications
- Published
- 2019-02-01
- Volume
- 29
- Issue
- 1
- Pages
- 16-32
- ISSN
- 2159-3337 (ISSN-L)
- 2159-3345
- PMC
- PMC6386089
- OpenAlex
- W2906651560
- Cited by
- 127
- References
- 39
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 12 · 2023: 17 · 2022: 17 · 2021: 20 · 2020: 21 · 2019: 8
- FWCI
- 4.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nucleic Acid Therapeutics (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
- Funders
- Ionis Pharmaceuticals
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- phosphorothioate modification, ASGR1, pharmacokinetics, pharmacodynamics, safety profile, dose-ranging, healthy volunteers, RNA-targeted therapeutics
- MeSH terms
- Acetylgalactosamine, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, RNA, Structure-Activity Relationship, Oligonucleotides, Antisense, Hepatocytes, Asialoglycoprotein Receptor, Biomarkers, Pharmacological, Phosphorothioate Oligonucleotides, Healthy Volunteers
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