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Reduced Genotoxicity Testing Is Possible for Noncoding Oligonucleotide-Based Therapeutics Containing

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Summary

Regulatory guidance for oligonucleotide-based therapeutics (ONTs) genotoxicity testing is lacking. Regulators accept reduced testing for ONTs if sufficient class experience is demonstrated, particularly for established chemical modifications.

Keywords:
European Medicines Agencygenotoxicity assessmentnonclinicaloligonucleotidesregulatory

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Area of Science:

  • Pharmacology
  • Toxicology
  • Regulatory Science

Background:

  • Harmonized regulatory guidance for evaluating the genotoxic potential of oligonucleotide-based therapeutics (ONTs) is currently lacking.
  • Specific circumstances for deviating from the standard genotoxicity test battery are not well-established.

Purpose of the Study:

  • To analyze genotoxicity testing strategies and rationales for noncoding ONTs that received European Scientific Advice.
  • To identify critical considerations for genotoxicity evaluation by examining applicant positions and EU regulatory opinions.

Main Methods:

  • Retrospective analysis of genotoxicity testing data for 91 noncoding ONTs.
  • Review of European Scientific Advice documentation (2004-2024).
  • Examination of applicant submissions and European Union regulatory feedback.

Main Results:

  • The standard genotoxicity test battery was used for most ONTs, but reduced testing strategies were proposed for 10 products.
  • European Union regulators permit deviations from the standard battery when substantial evidence of class experience exists.
  • Well-characterized modifications (e.g., phosphorothioate, 2'-methoxyethyl, 2'-Omethyl) supported reduced testing, rendering the standard battery redundant in these instances.

Conclusions:

  • EU regulators accept reduced genotoxicity testing for ONTs based on demonstrated class experience.
  • Clear definition of 'sufficient evidence for class experience' in upcoming ICH S13 guidelines is crucial for harmonized reduced testing.
  • Increased industry data sharing will foster a harmonized approach to noncoding ONT genotoxicity assessment.