Oligonucleotides: Evolution of Carcinogenicity and Risk Assessment Strategy

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.