AI Article Synopsis

  • * An analysis of data from eight clinical trials involving 195 participants found no significant safety issues for GalNAc-conjugated antisense oligonucleotides (ASOs), though some concerns arose with unconjugated ASOs, especially in liver enzyme levels.
  • * GalNAc-conjugated ASOs exhibited a considerably lower rate of skin reactions from injections (0.9% vs. 28.6%) and no flu-like symptoms, suggesting they are safer and better tolerated than their uncon

Article Abstract

The triantennary -acetylgalactosamine (GalNAc) cluster has demonstrated the utility of receptor-mediated uptake of ligand-conjugated antisense drugs targeting RNA expressed by hepatocytes. GalNAc-conjugated 2'--methoxyethyl (2'MOE) modified antisense oligonucleotides (ASOs) have demonstrated a higher potency than the unconjugated form to support lower doses for an equivalent pharmacological effect. We utilized the Ionis integrated safety database to compare four GalNAc-conjugated and four same-sequence unconjugated 2'MOE ASOs. This assessment evaluated data from eight randomized placebo-controlled dose-ranging phase 1 studies involving 195 healthy volunteers (79 GalNAc ASO, 24 placebo; 71 ASO, 21 placebo). No safety signals were identified by the incidence of abnormal threshold values in clinical laboratory tests for either ASO group. However, there was a significant increase in mean alanine transaminase levels compared with placebo in the upper dose range of the unconjugated 2'MOE ASO group. The mean percentage of subcutaneous injections leading to local cutaneous reaction was 30-fold lower in the GalNAc-conjugated ASO group compared with the unconjugated ASO group (0.9% vs. 28.6%), with no incidence of flu-like reactions (0.0% vs. 0.7%). Three subjects (4.2%) in the unconjugated ASO group discontinued dosing. An improvement in the overall safety and tolerability profile of GalNAc-conjugated 2'MOE ASOs is evident in this comparison of short-term clinical data in healthy volunteers.

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http://dx.doi.org/10.1089/nat.2023.0026DOI Listing

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