Hot Topic: Industry Discussions on Companion Diagnostics for AAV-Mediated Gene Therapy

Adeno-associated virus (AAV) vectors are a leading platform for gene delivery for treating various human diseases. Pre-existing antibodies to AAVs may inhibit the effectiveness of AAV-based gene therapies, through immune clearance and neutralization of cell transduction functions, and may also trigger inflammatory responses which lead to adverse effects. For these reasons, it may be necessary to screen patients for the presence of pre-existing antibodies to AAVs before any treatment can be administered, which often takes the form of standard bioanalytical immunogenicity assays such as an anti-AAV total antibody assay (TAb) or a functional cell-based transduction inhibition assay for detecting neutralizing antibodies (NAb) to the AAV serotype. The use of these bioanalytical assays for means of inclusion/exclusion of patients from enrollment in clinical trials then implicates these assays as an IVD companion diagnostic that is contemporaneously developed with the therapeutic drug for marketing approval. This presentation describes the clinical cut-off selection dilemma caused by the current guideline request to extensively validate the patient selection assay at the clinical cut-off before having performed any clinical study. It introduces the concept of a 'Class IVD' per AAV serotype, decribes how such a 'Class IVD' could be established, be used during clinical development and could further be verified as CDx.