Translational, Clinical Pharmacology Considerations and Learnings From Approved AAV Therapies

Tremendous advancements in genetic engineering and biotechnology have propelled the development of novel therapeutic modalities including the cell and gene therapies. While there has been a significant growth in the development of AAV gene therapy however, several gaps and challenges continue to exist. For instance, conventional PK/PD concepts are not applicable, conventional allometric dose scaling approaches might be less precise, and hence there is no consensus on the utility of preclinical studies to select human doses for gene therapies. Similarly, understanding dose-exposure/response relationships and drivers for safety and efficacy for AAV gene therapies in the clinic can be challenging. Within the AAPS GCTP Community, we have formed an ADME working group which consists of subject matter experts from different companies working in the area of cell and gene therapies. The AAPS GCTP ADME Working Group members have discussed the translational and clinical pharmacology aspects and challenges related to AAVs in detail and the learnings from those discussions will be shared through this symposium presentation. This presentation will discuss translational challenges and considerations in FIH human dose selection for AAV gene therapies. In addition, key challenges in PK/PD analysis and modeling of AAV gene therapies as compared to traditional molecules as well as evolving PK/PD modeling approaches including empirical (e.g. GEF), semi-mechanistic, and physiologically-based approaches will be covered. Finally, the presentation will discuss the key PK/PD learnings (including translational and clinical) from approved AAV gene therapies.