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Regulatory Strategy for Oligonucleotide Therapeutics
Aligning ASO and siRNA Science with Evolving Regulatory Expectations
Following strong engagement at both ACT 2025 and the 2026 Society of Toxicology (SOT) Annual Meeting, our experts, Simon Authier and Mike Templin, have advanced the conversation on regulatory strategy for antisense oligonucleotides (ASOs) and siRNAs. Through these sessions, participants explored how evolving regulatory expectations are shaping the development of oligonucleotide therapeutics and why early, scientifically grounded decisions are essential for downstream regulatory success.
Oligonucleotide therapeutics have now clearly established regulatory pathways across major health authorities. However, regulators consistently emphasize that these pathways should not be applied mechanically. ASOs and siRNAs share characteristics with both small molecules and biologics, yet they do not fully align with either category. As a result, regulators expect development programs to be tailored to the specific properties of each therapeutic rather than relying solely on historical precedent.
A central theme of the discussions was the importance of clearly defining and justifying the mechanism of action. Regulatory agencies place a high value on understanding how an ASO or siRNA achieves its intended effect and on the relevance of models used for safety assessment. Safety findings are interpreted in context, including whether observed effects align with the intended biological activity or suggest unintended or class-related toxicities. Developers are expected to articulate this rationale clearly and consistently.
Exposure interpretation also represents a critical consideration. Oligonucleotide therapeutics may demonstrate short systemic exposure while maintaining prolonged tissue activity. Regulators, therefore, focus on the duration of biological effect rather than plasma pharmacokinetics alone. Dose selection and safety justification must reflect this understanding to support a credible risk assessment.
Study designs are increasingly expected to be fit for purpose. Regulators favor thoughtful selection of endpoints, biomarkers, and assessment timing that directly inform human risk. Traditional study templates are no longer sufficient without scientific justification reflecting the specific therapeutic context. Likewise, alignment across assays and endpoints remains essential. Regulators emphasize whether the overall data package tells a consistent and biologically plausible story rather than relying on any single technology or dataset.
While regulatory guidance continues to evolve, core principles remain consistent. Risk-based decision making and relevance to patient safety are fundamental expectations worldwide. In practice, regulatory challenges often arise when early assumptions are not revisited as programs progress, leading to misalignment that becomes apparent late in development.
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Programs that integrate regulatory thinking early, maintain consistency across development stages, and clearly document the scientific rationale are better positioned for efficient, confident regulatory review.
Strong, clearly explained science drives regulatory confidence. Regulatory success in ASO and siRNA development depends on alignment between mechanism, exposure, and safety decisions from discovery through regulatory toxicology. Translating this alignment into practice can be complex, particularly as programs scale. Applying experienced regulatory safety assessment expertise helps derisk ASO and siRNA development by supporting sound scientific decisions early and throughout regulatory toxicology.
Supported by Charles River’s Safety Assessment specialists, including ASO regulatory expertise from scientific advisory services leaders such as Mike Templin, let’s discuss how we can move your program forward together.