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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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FIG. 1. GalNAc3-conjugated PS 2′MOE ASOs demonstrate an increased fraction of total liver distribution to hepatocytes compared with parent 2′MOE ASOs. (a) Targeted hepatocyte delivery by the asialoglycoprotein receptor, and (b) estimation of relative exposure at therapeutic doses. 2′MOE, 2′-O-methoxyethyl; ASO, antisense oligonucleotide; PS, phosphorothioate.
FIG. 1. GalNAc3-conjugated PS 2′MOE ASOs demonstrate an increased fraction of total liver distribution to hepatocytes compared with parent 2′MOE ASOs. (a) Targeted hepatocyte delivery by the asialoglycoprotein receptor, and (b) estimation of relative exposure at therapeutic doses. 2′MOE, 2′-O-methoxyethyl; ASO, antisense oligonucleotide; PS, phosphorothioate.CC BY-NC · PubMed Central
FIG. 2. Pharmacokinetic profile after multiple SC doses of GalNAc3 conjugate versus parent PS 2′MOE ASO. Comparison of 0- to 24-h plasma concentration–time profiles, (a) linear scale, and (b) semi-log scale. Data shown are the mean and error bars represent the standard deviation. SC, subcutaneous.
FIG. 2. Pharmacokinetic profile after multiple SC doses of GalNAc3 conjugate versus parent PS 2′MOE ASO. Comparison of 0- to 24-h plasma concentration–time profiles, (a) linear scale, and (b) semi-log scale. Data shown are the mean and error bars represent the standard deviation. SC, subcutaneous.CC BY-NC · PubMed Central
FIG. 3. Increased potency observed with GalNAc3-conjugated PS 2′MOE ASOs in phase 1 healthy volunteer studies. Data shown are the mean, error bars represent the standard error, and the lines are fit to the mean data.
FIG. 3. Increased potency observed with GalNAc3-conjugated PS 2′MOE ASOs in phase 1 healthy volunteer studies. Data shown are the mean, error bars represent the standard error, and the lines are fit to the mean data.CC BY-NC · PubMed Central
FIG. 4. Pharmacokinetic and pharmacodynamic profile of GalNAc3-conjugated PS 2′MOE ASO in humans after monthly SC doses on study days 1, 29, 57, and 85. (a) Mean plasma drug concentration–time profiles with intensive pharmacokinetic sampling on study days 1 and 85, predose, and ∼0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 48-h after the respective first and last SC injections. (b) Mean percent change from baseline over time in plasma prekallikrein levels in subjects who received monthly doses of PKK-L compared with pooled placebo-treated subjects. Blue arrowheads indicate dose days. PKK, prekallikrein.
FIG. 4. Pharmacokinetic and pharmacodynamic profile of GalNAc3-conjugated PS 2′MOE ASO in humans after monthly SC doses on study days 1, 29, 57, and 85. (a) Mean plasma drug concentration–time profiles with intensive pharmacokinetic sampling on study days 1 and 85, predose, and ∼0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 48-h after the respective first and last SC injections. (b) Mean percent change from baseline over time in plasma prekallikrein levels in subjects who received monthly doses of PKK-L compared with pooled placebo-treated subjects. Blue arrowheads indicate dose days. PKK, prekallikrein.CC BY-NC · PubMed Central
FIG. 5. Mean laboratory measurements over time for assessment of liver function in the weekly multidose regimen cohort, (a) alanine transaminase, (b) aspartate transaminase, (c) total bilirubin, (d) alkaline phosphatase, and (e) albumin. Each data point represents data from at least 10 subjects and 3 GalNAc3-conjugated 2′MOE ASOs during the treatment period. Gray dashed lines represent the median reference range values and yellow dashed lines indicate the event criteria. A tabulated summary of results is provided in Supplementary Table S3.
FIG. 5. Mean laboratory measurements over time for assessment of liver function in the weekly multidose regimen cohort, (a) alanine transaminase, (b) aspartate transaminase, (c) total bilirubin, (d) alkaline phosphatase, and (e) albumin. Each data point represents data from at least 10 subjects and 3 GalNAc3-conjugated 2′MOE ASOs during the treatment period. Gray dashed lines represent the median reference range values and yellow dashed lines indicate the event criteria. A tabulated summary of results is provided in Supplementary Table S3.CC BY-NC · PubMed Central
FIG. 6. Mean laboratory measurements over time for assessment of kidney function in the weekly multidose regimen cohort, (a) serum creatinine, (b) blood urea nitrogen, and (c) calculated glomerular filtration rate. Each data point represents data from at least 10 subjects and 3 GalNAc3-conjugated 2′MOE ASOs during the treatment period. Gray dashed lines represent the median reference range values and yellow dashed lines indicate the event criteria. A tabulated summary of results is provided in Supplementary Table S4.
FIG. 6. Mean laboratory measurements over time for assessment of kidney function in the weekly multidose regimen cohort, (a) serum creatinine, (b) blood urea nitrogen, and (c) calculated glomerular filtration rate. Each data point represents data from at least 10 subjects and 3 GalNAc3-conjugated 2′MOE ASOs during the treatment period. Gray dashed lines represent the median reference range values and yellow dashed lines indicate the event criteria. A tabulated summary of results is provided in Supplementary Table S4.CC BY-NC · PubMed Central
FIG. 7. Mean laboratory measurements over time for assessment of hematology in the weekly multidose regimen cohort, (a) platelets, (b) hemoglobin, (c) hematocrit, (d) lymphocyte count, and (e) absolute neutrophil count. Each data point represents data from at least 10 subjects and 3 GalNAc3-conjugated 2′MOE ASOs during the treatment period. Gray dashed lines represent the median reference range values and yellow dashed lines indicate the event criteria. A tabulated summary of results is provided in Supplementary Table S5.
FIG. 7. Mean laboratory measurements over time for assessment of hematology in the weekly multidose regimen cohort, (a) platelets, (b) hemoglobin, (c) hematocrit, (d) lymphocyte count, and (e) absolute neutrophil count. Each data point represents data from at least 10 subjects and 3 GalNAc3-conjugated 2′MOE ASOs during the treatment period. Gray dashed lines represent the median reference range values and yellow dashed lines indicate the event criteria. A tabulated summary of results is provided in Supplementary Table S5.CC BY-NC · PubMed Central
FIG. 8. Individual subject assessment of platelet counts over time in the weekly multidose regimen cohort by dose level, (a) Placebo, (b) > 0–10 mg, (c) > 10–20 mg, (d) > 20–40 mg, (e) > 40–60 mg, and (f) > 60 mg. Gray dashed lines represent the median reference range values and yellow dashed lines indicate the event criteria.
FIG. 8. Individual subject assessment of platelet counts over time in the weekly multidose regimen cohort by dose level, (a) Placebo, (b) > 0–10 mg, (c) > 10–20 mg, (d) > 20–40 mg, (e) > 40–60 mg, and (f) > 60 mg. Gray dashed lines represent the median reference range values and yellow dashed lines indicate the event criteria.CC BY-NC · PubMed Central
FIG. 9. Mean laboratory measurements of coagulation and complement activation over the 24-h period postdose 1 in single and weekly multidose regimen cohorts, (a) activated partial thromboplastin time, (b) prothrombin time, (c) complement split product Bb, and (d) complement split product C5a. Each data point represents data from at least 10 subjects and 3 GalNAc3-conjugated 2′MOE ASOs. Gray dashed lines represent the median reference range values and yellow dashed lines indicate the event criteria. A tabulated summary of results is provided in Supplementary Tables S6 and S7.
FIG. 9. Mean laboratory measurements of coagulation and complement activation over the 24-h period postdose 1 in single and weekly multidose regimen cohorts, (a) activated partial thromboplastin time, (b) prothrombin time, (c) complement split product Bb, and (d) complement split product C5a. Each data point represents data from at least 10 subjects and 3 GalNAc3-conjugated 2′MOE ASOs. Gray dashed lines represent the median reference range values and yellow dashed lines indicate the event criteria. A tabulated summary of results is provided in Supplementary Tables S6 and S7.CC BY-NC · PubMed Central

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Citations

Cites

Show all 39 references

Research works printed but not linked: 10

  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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