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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

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This summary is machine-generated.

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.

Keywords:

anti-drug antibodies immunogenicity regulatory submissions siRNA therapeutics

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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.