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Immunogenicity Assessment for siRNA Therapeutics: A Risk-Based Proposal for Event-Driven Testing
An Zhao1, Sarah Bond2, Valerie Clausen2
1Regeneron Pharmaceuticals Inc., Tarrytown, New York, USA. an.zhao@regeneron.com.
The AAPS Journal
|May 19, 2026
Summary
Small interfering RNA (siRNA) therapeutics show low immunogenicity risk. A risk-based assessment strategy, rather than routine testing, is recommended for these oligonucleotide therapeutics to ensure safety and streamline development.
Area of Science:
- Biotechnology
- Pharmacology
- Molecular Biology
Background:
- Oligonucleotide therapeutics (ONTs), particularly siRNA, are successful treatments for various diseases.
- siRNA therapeutics utilize the RNA interference (RNAi) mechanism to regulate protein expression.
- Eight siRNA therapeutics have received global approval, highlighting their therapeutic potential.
Purpose of the Study:
- To present a framework for assessing the immunogenicity risk of siRNA therapeutics.
- To discuss challenges in developing anti-drug antibody (ADA) assays for siRNA.
- To review immunogenicity data for approved and investigational GalNAc-siRNA therapeutics.
Main Methods:
- Review of clinical development programs for GalNAc-siRNA therapeutics.
- Analysis of immunogenicity risk assessment strategies.
- Evaluation of anti-drug antibody (ADA) response data and its impact on pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety.
Main Results:
- GalNAc-conjugated siRNA therapeutics exhibit a low immunogenicity risk profile.
- Treatment-emergent ADA responses are low (≤6%) with no significant impact on PK, PD, efficacy, or safety.
- Comprehensive risk assessment and clinical data support the favorable immunogenicity profile.
Conclusions:
- Routine prospective ADA assessments may not be necessary for all siRNA therapeutics.
- A risk-based immunogenicity assessment strategy is advocated for siRNA therapeutics.
- This strategy involves early risk assessment and retrospective ADA testing for low-risk molecules if needed, ensuring patient safety and efficient development.
