Industry Perspective on Translational and Clinical Pharmacology Aspects of Viral-based Gene Therapies and Vaccines-Key Considerations and Learnings From Approved Products.

Viral-based gene therapies and vaccines represent a rapidly evolving modality for treating a wide range of diseases. However, these novel modalities pose novel and complex challenges for translational PK/PD scientists and clinical pharmacologists during preclinical and clinical development. To support accelerated development of these transformative therapies, experts in the field formed a working group under the umbrella of AAPS and through this review provide a comprehensive overview of translational and clinical pharmacology considerations for viral vector-based gene therapies, including adeno-associated virus (AAV), oncolytic virus, adenovirus (AdV) and herpes simplex virus (HSV), and viral-vector based vaccines; with the help of robust discussion of the literature and learnings from the currently approved products. We discuss key developmental challenges, such as preclinical characterization, including dose-response evaluations and biodistribution assessments. The manuscript highlights how preclinical data, particularly the minimum effective dose (MED) and maximum tolerated dose (MTD) in relevant animal models, inform the selection of the First-in-Human (FIH) dose. We explore the challenges and strategies for clinical study design, including use of open-label, dose-escalation trials and the importance of monitoring for immunogenicity. The text also reviews clinical pharmacology considerations, such as vector shedding and tissue biodistribution, which are critical for determining product safety and efficacy. Finally, we discuss the emerging role of modeling and simulation approaches to improve preclinical-to-clinical dose translation and clinical dose optimization. By synthesizing lessons from approved products, this review aims to provide a valuable framework for navigating the complex translational and clinical pharmacology landscape of viral vector-based gene therapies and vaccines.