Implementing a Risk-Based Immunogenicity Strategy to Accelerate ASO Drug Development

Our understanding of immunogenicity risk of anti-sense oligonucleotide (ASO) therapeutics has evolved with over a decade of clinical experience, and we have adopted a risk-based approach to guide our ADA testing strategy. Despite this many in the industry are still deploying immunogenicity assessments typically devised for protein biologics using the 2019 FDA immunogenicity guidance as the basis for their approach. However, ASO therapeutics have been demonstrated to be far less immunogenic compared to protein-based modalities and are often delivered directly to relatively immune privileged sites, like the CNS. Often there is no clear scientific rational to support intensive monitoring of immunogenicity that has no expected clinical impact on safety or efficacy. We will present case studies of comprehensive immunogenicity risk assessments conducted for ASO therapeutics and determine the value of ADA monitoring in each case. In addition, we will present collective evidence of approved ASO therapeutics that demonstrate the lack of clinically relevant immunogenicity reported in this emerging and growing therapeutic modality. We will discuss how applying a science-first approach to immunogenicity evaluation can yield the critical information necessary to support product approval and avoid unnecessary and often confounding immunogenicity analyses that can derail development teams