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Antisense oligonucleotide (ASO) carcinogenicity testing is evolving. Shorter studies and data from related drugs can now support waiving long-term rodent bioassays, aligning with new regulatory guidance.

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Area of Science:

  • Pharmacology and Toxicology
  • Drug Development
  • Regulatory Science

Background:

  • Antisense oligonucleotides (ASOs) carcinogenicity has been assessed via 2-year rodent bioassays since 2006.
  • No human-relevant tumors have been found in nonclinical ASO studies to date.
  • Evolving strategies leverage prior data, platform risk assessments, and regulatory guidance for ASO carcinogenicity testing.

Purpose of the Study:

  • To review the changing landscape of ASO carcinogenicity testing.
  • To highlight opportunities for reducing or waiving long-term carcinogenicity studies.
  • To discuss the integration of new regulatory guidelines, such as ICH S1B(R1), into ASO testing strategies.

Main Methods:

  • Review of historical and current ASO carcinogenicity testing approaches.
  • Analysis of regulatory guidance, including ICH S1B(R1) addendum.
  • Case examples of modified carcinogenicity assessments for ASO therapeutics (e.g., eplontersen, olezarsen).

Main Results:

  • Traditional 2-year rodent bioassays are increasingly being replaced by shorter-term studies (e.g., 6-month Tg.rasH2 mouse study).
  • Waivers or single-species studies are supported by existing data from related ASOs (e.g., inotersen, volanesorsen).
  • The ICH S1B(R1) addendum provides a clear pathway for sponsors to reduce long-term studies based on comprehensive evidence.

Conclusions:

  • The field of ASO carcinogenicity testing is shifting towards more efficient and data-driven strategies.
  • Regulatory acceptance of reduced or waived long-term studies is increasing, supported by the totality of evidence.
  • These evolving approaches align with the maturation of ASO technology and drug development.