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Integrated Assessment of the Clinical Performance of GalNAc 3 -Conjugated 2′- O -Methoxyethyl Chimeric Antisense Oligonucleotides: I. Human Volunteer Experience

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Crooke, Stanley T., Baker, Brenda F., Xia, Shuting, Yu, Rosie Z., Viney, Nicholas J., Wang, Yanfeng, Tsimikas, Sotirios, Geary, Richard S.·2019·Nucleic Acid Therapeutics
DOI 10.1089/nat.2018.0753PMC PMC6386089
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Abstract

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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  1. Crooke ST, , Vickers T, , Lima W, and Wu H. (2008). Mechanisms of antisense drug action, an introduction. In: Antisense Drug Technology: Principles, Strategies, and Applications, 2nd edn. Crooke ST, ed. CRC Press, Boca Raton, FL, pp 3–46.
  2. Swayze EE, and Bhat B. (2008). The medicinal chemistry of oligonucleotides. In: Antisense Drug Technology: Principles, Strategies, and Applications, 2nd edn. Crooke ST, ed. CRC Press, Boca Raton, pp 143–182.
  3. Levin AA, , Yu RZ, and Geary RS. (2008). Basic principles of the pharmacokinetics of antisense oligonucleotide drugs. In: Antisense Drug Technology: Principles, Strategies, and Applications, 2nd edn. Crooke ST, ed. CRC Press, Boca Raton, FL, pp 183–215.
  4. Iversen PL. (2008). Morpholinos. In: Antisense Drug Technology: Principles, Strategies, and Applications. Crooke ST, ed. CRC Press, Boca Raton, pp 565–582.
  5. Manoharan M, and Rajeev KG. (2008). Utilizing chemistry to harness RNA interference pathways for therapeutics: Chemically modified siRNA and Anatgomirs. In: Antisense Drug Technology: Principles, Strategies, and Applications. Crooke ST, ed. CRC Press, Boca Raton, pp 437–464.
  6. Mercuri E, , Finkel R, , Kirschner J, , Chiriboga C, , Kuntz N, , Sun P, , Gheuens S, , Bennett C, , Schneider E, and Farwell W. (2017). Efficacy and safety of nusinersen in children with later-onset spinal muscular atrophy (SMA): end of study results from the phase 3 CHERISH study. Neuromuscul Disord, 27:S210. · DOI
  7. Lima W, , Wu H, and Crooke ST. (2008). The RNase H mechanism. In: Antisense Drug Technology: Principles, Strategies, and Applications, 2nd edn. Crooke ST, ed. CRC Press, Boca Raton, FL, pp 47–74.
  8. Geary RS, , Yu RZ, , Siwkowski A, and Levin AA. (2008). Pharmacokinetic/pharmacodynamic properties of phosphorothioate 2′-O-(2-methoxyethyl)-modified antisense oligonucleotides in animals and man. In: Antisense Drug Technology: Principles, Strategies, and Applications, 2nd edn. Crooke ST, ed. CRC Press, Boca Raton, FL, pp 305–326.
  9. Bennett CF. (2008). Pharmacological properties of 2′-methoxyethyl-modified oligonucleotides. In: Antisense Drug Technology: Principles, Strategies, and Applications, 2nd edn. Crooke ST, ed. CRC Press, Boca Raton, FL, pp 273–303.
  10. Ämmälä C, , Ahlstedt I, , Andersson E-M, , Andersson P, , Cavallin E, , Drury W, , Hung G, , Jansson-Löfmark R, , Johansson C, et al. (2017). The GLP1 receptor as a homing beacon for targeted delivery to pancreatic ß-cells: quantitating tissue selective productive uptake of antisense oligonucleotides. Diabetes, 66:A568.

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Metadata

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
DOI
10.1089/nat.2018.0753
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
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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