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Clinical Trial
. 2023 Jan;33(1):72-80.
doi: 10.1089/nat.2022.0044. Epub 2022 Nov 29.

Integrated Assessment of Phase 2 Data on GalNAc3-Conjugated 2'- O-Methoxyethyl-Modified Antisense Oligonucleotides

Brenda F Baker  1 , Shuting Xia  1 , Wesley Partridge  1 , T Jesse Kwoh  1 , Sotirios Tsimikas  1   2 , Sanjay Bhanot  1 , Richard S Geary  1
Affiliations
Clinical Trial

Integrated Assessment of Phase 2 Data on GalNAc3-Conjugated 2'- O-Methoxyethyl-Modified Antisense Oligonucleotides

Brenda F Baker et al. Nucleic Acid Ther. 2023 Jan.

Abstract

Receptor-mediated delivery of an antisense oligonucleotide (ASO) using the ligand-conjugated antisense technology is establishing a new benchmark for antisense therapeutics. The triantennary N-acetylgalactosamine (GalNAc3) cluster is the first conjugated ligand to yield a marked increase in ASO potency for RNA targets expressed by hepatocytes, compared to the unconjugated form. In this study, we present an integrated safety assessment of data available from randomized, placebo-controlled, phase 2 studies for six GalNAc3-conjugated 2'-O-methoxyethyl (2'MOE)-modified ASOs. The total study population included 642 participants (130 placebo; 512 ASO) with up to 1 year of exposure. The primary measures were the incidence of signals from standardized laboratory tests and the mean test results over time. The GalNAc3-conjugated ASOs were well tolerated with no class effect identified across all doses tested compared to placebo. These results extend prior observations from phase 1 studies, now with treatment up to 1 year.

Keywords: integrated safety analysis; ligand-conjugated antisense technology; phase 2; randomized placebo-controlled trials; triantennary N-acetylgalactosamine.

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Conflict of interest statement

All authors are employees of Ionis Pharmaceuticals, Inc.

Figures

FIG. 1.
FIG. 1.
Ligand-conjugated antisense technology. All ASOs are conjugated to the same GalNAc3 cluster and linker at the 5′ terminal 2′MOE-modified nucleotide by a phosphodiester group that hydrolyzes after receptor-mediated cellular uptake to release the unconjugated ASO [7,28]. 2′MOE, 2′-O-methoxyethyl; ASOs, antisense oligonucleotides; GalNAc3, triantennary N-acetylgalactosamine.
FIG. 2.
FIG. 2.
Mean sentinel laboratory tests over time by dose regime cohort, monthly (left column) and weekly (right column). Sentinel laboratory tests are for liver, alanine transaminase; kidney, serum creatinine; and hematology, platelets. The LLN and ULN displayed represent the median values. Screening was defined as average of all values measured before baseline. Each data point represents at least 6 subjects and 2 ASOs. LLN, lower limit of normal; SEM, standard error of the mean; ULN, upper limit of normal.
See this image and copyright information in PMC

References

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    1. Crooke ST, Liang XH, Crooke RM, Baker BF and Geary. RS (2021). Antisense drug discovery and development technology considered in a pharmacological context. Biochem Pharmacol 189:114196. - PubMed
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    1. Bennett CF, Baker BF, Pham N, Swayze E and Geary RS. (2017). Pharmacology of antisense drugs. Annu Rev Pharmacol Toxicol 57:81–105. - PubMed
    1. Kinberger GA, Prakash TP, Yu J, Vasquez G, Low A, Chappell A, Schmidt K, Murray HM, Gaus H, Swayze EE and Seth PP. (2016). Conjugation of mono and di-GalNAc sugars enhances the potency of antisense oligonucleotides via ASGR mediated delivery to hepatocytes. Bioorg Med Chem Lett 26:3690–3693. - PubMed

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